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Infectious Syndromes in Adults 

Infectious Syndromes in Adults
Chapter:
Infectious Syndromes in Adults
Author(s):

John W. Wilson

and Lynn L. Estes

DOI:
10.1093/med/9780190696924.003.0005
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date: 19 April 2019

Clinical Approach to Patients with Infection

Four-Step Approach to Successful Management of Infectious Diseases

  • Define the host: Identify factors that influence the type of infection, disease progression, and prognosis. These include:

    • Host factors such as patient age, immune status (eg, immunosuppression or absence of a spleen), presence of foreign bodies (eg, central venous catheter, permanent pacemaker, intracardiac defibrillator, prosthetic heart valves, prosthetic joints), or other comorbid conditions, AND

    • Environmental setting (infection acquired from the community vs hospital or nursing home) or recent antibiotic use (increased risk for MDR infections and Clostridium difficile colitis)

  • Define the infection syndrome: Determine the anatomic location of infection and extent of inflammation (eg, the “-itis”: meningitis, pyelonephritis, peritonitis, pneumonitis, endocarditis), rate of progression, and severity of infection (eg, localized vs multiorgan involvement or hemodynamic instability).

  • Define the pathogen: Determine the suspected pathogen(s) on the basis of the host and syndrome information or confirm the pathogen(s) from available laboratory test results (eg, cultures, stains, serologies, antigens). Appropriate cultures should be obtained before initiating antimicrobial therapy—consider 2 separate blood cultures and, as clinically indicated, the culture of other sites (eg, urine, cerebrospinal fluid (CSF), deep wounds, respiratory secretions, other body fluids).

  • Determine the optimal antimicrobial therapy: Decisions about antimicrobial therapy should be made after integrating information about the host, syndrome, and suspected or confirmed microorganism. When appropriate, target antimicrobial therapy against confirmed or suspected pathogens. Ensure that the selected antimicrobial therapy is dosed correctly and can adequately penetrate the anatomic site of infection.

Additional Considerations

Source Control

  • Determine whether the infection is amenable to specific source-control measures, including drainage of an abscess or local focus of infection, débridement of infected necrotic tissue, or removal of a potentially infected device.

    • Drainage: Intra-abdominal abscess, thoracic empyema, and cholangitis

    • Débridement: Necrotizing fasciitis, intestinal infarction, osteomyelitis, septic arthritis, and mediastinitis

    • Device removal: Infected permanent pacemaker or intracardiac defibrillator, vascular catheter, urinary catheter, and intrauterine device

    • Definitive control: Sigmoid resection for recurrent diverticulitis and cholecystectomy for gangrenous cholecystitis

  • Recognize sepsis, severe sepsis, and septic shock (see definitions listed below).

Emergent Antimicrobial Intervention

  • Identify syndromes requiring urgent antimicrobial intervention (eg, neutropenia with gram-negative bacteremia, bacterial meningitis, thoracic or subdural empyema, severe sepsis, septic shock, infective endocarditis with heart failure).

  • Pay particular attention to Gram stain results (which are rapidly available), cultures, molecular diagnostic results, and drug susceptibility information to further direct therapy.

  • Review each patient’s drug allergies and organ function (eg, renal, hepatic function) for optimal selection and dosing of antimicrobial therapy.

  • Ensure selected antibiotic adequately penetrates site of infection (eg, CSF).

Sepsis and Septic Shock

  • Perform aggressive resuscitation with fluids, vasopressors, and/or blood products, as indicated, within the first 6 hours of resuscitation. Targets are as follows: central venous pressure, 8-12 mm Hg; mean arterial pressure, ≥65 mm Hg; urine output, ≥0.5 mL/kg per hour; and central venous or mixed venous oxygen saturation, ≥70%.

  • Initiate empiric antibiotic therapy within the first hour after recognition of severe sepsis or septic shock and later modify and refine through appropriate culture results.

  • Consult with an infectious diseases specialist for all serious and complex infections.

  • Correctly define the clinical syndrome1:

    • Sepsis: Defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (ie, the body’s response to an infection injures its own tissues and organs)

    • Organ dysfunction can be identified as an acute change in total (sepsis-related) SOFA score ≥2 points consequent to infection2

      • Quick SOFA score criteria:

        1. 1. Respiratory rate <22 breaths/minute

        2. 2. Altered mentation

        3. 3. Systolic blood pressure >100 mm Hg

      • A SOFA score ≥2 suggests a mortality risk of approximately 10% in a general hospital patient population with suspected infection

    • Septic shock (a subset of sepsis): Defined as sepsis with persistent hypotension requiring vasopressors to maintain mean arterial pressure ≥65 mm Hg and having a serum lactate level >2 mmol/L (18 mg/dL), despite adequate volume resuscitation

      • Hospital mortality rate usually >40%

Other Markers of Organ Dysfunction Affected by Sepsis

  • Renal dysfunction: Urine output <0.5 mL/kg per hour for at least 2 hours or serum creatinine >2.0 mg/dL.

  • Coagulation abnormality: International normalized ratio >1.5 or an activated partial thromboplastin time >60 seconds.

  • Thrombocytopenia: Platelet count <100,000/μ‎L.

  • Tissue or organ hypoperfusion: Serum lactate level exceeding the laboratory’s established normal value.

  • Hyperbilirubinemia: Total plasma bilirubin level >2.0 mg/dL.

Respiratory Tract Infections

Clinical Syndromes and Common Pathogens

Acute Bronchitis

Diagnostic criteria include cough, symptoms of upper RTI, and negative findings on chest radiographs. Viral infection is the most common cause; therefore, antibiotics usually are not indicated. Sputum production does not differentiate viral from bacterial causes. Fever is uncommon.

  • Common viruses: Influenza, parainfluenza, rhinovirus, human metapneumovirus, adenovirus, coronavirus, and various other respiratory viruses

  • Less-common infectious agents (potentially antibiotic responsive): Mycoplasma pneumoniae, Chlamydophila pneumoniae, Bordetella pertussis

Community-Acquired Pneumonia

Diagnostic criteria for CAP include acute or subacute onset of 2 or more of the following symptoms: fever, cough, dyspnea, pleuritic chest pain, or delirium.

  • Common bacteria: Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, Haemophilus influenzae, and occasionally Staphylococcus aureus, including community-acquired MRSA

  • Viruses

    • Seasonal: Influenza and respiratory syncytial virus (the latter is most significant in infants and immunocompromised patients)

    • Nonseasonal: Parainfluenza, varicella, human metapneumovirus, adenovirus, coronaviruses (including SARS CoV and MERS CoV); preceding viral infection may increase subsequent risk of bacterial pneumonia

  • More chronic symptoms in specific epidemiologic conditions: Tuberculosis and other mycobacteria (eg, MAC, Mycobacterium kansasii), endemic fungi (Histoplasma, Blastomyces, Coccidioides), and zoonoses (Coxiella burnetii [Q fever], Francisella tularensis)

Aspiration Pneumonia

Diagnostic criteria include fever, cough, or pulmonary infiltrate in a lower lung field after a single or recurrent aspiration event. Acute aspiration may cause chemical lung injury, which does not require antibiotic therapy. Not all aspiration results in bacterial pneumonia.

  • Common bacteria: Mixed oral or upper gastrointestinal tract bacterial flora; often includes anaerobes

Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia

Patients hospitalized for >2 days are at risk of HAP; the diagnosis excludes patients in whom the organism was incubating at admission. VAP is most frequent in patients who are intubated for longer than 48 hours. Diagnostic criteria include fever, new pulmonary infiltrate, and increased ventilatory support. Other noninfectious conditions can mimic pneumonia in intubated patients.

  • Common bacteria: Organisms can vary considerably, and guidelines suggest determining local distribution of pathogens and susceptibility patterns. Some potential pathogens include S pneumoniae, S aureus, H influenzae, K pneumoniae, E coli, Proteus spp, P aeruginosa, Serratia marcescens, and A baumannii. See Table 38 for risk factors for MDR organisms.

Table 38. Risk Factors for MDR Organisms Causing HAP or VAP

Type of Pneumonia

Risk Factor

MDR VAP

Prior antibiotic use within 90 days

Septic shock at time of VAP

ARDS preceding VAP

5 or more days of hospitalization before VAP

Acute renal replacement therapy before VAP onset

MDR HAP and MDR Pseudomonas HAP or VAP

Prior antibiotic use within 90 days

Adapted from Kalil AC, et al. Clin Infect Dis. 2016 Sep 1;63(5):e61-111. Epub 2016 Jul 14. Used with permission.

Pneumonia in Immunocompromised Hosts

Diagnostic criteria include fever, cough, dyspnea, pleuritic chest pain, and abnormal lung imaging. Dyspnea may be more pronounced than radiographic findings might suggest. Management often requires invasive procedures (bronchoscopy or open-lung biopsy) for diagnosis of opportunistic infections.

  • Cell-mediated (T-cell) immune dysfunction (patients with HIV; organ transplant recipients; patients receiving long-term corticosteroid therapy)

    • Usual CAP pathogens

    • PCP, Legionella, Nocardia, Cryptococcus neoformans, Histoplasma capsulatum, cytomegalovirus, Toxoplasma gondii

  • Neutropenia

    • Usual CAP pathogens

    • P aeruginosa, Aspergillus spp (eg, A fumigatus), agents of mucormycosis (eg, Mucor, Rhizopus)

Novel Characteristics of Respiratory Pathogens

  • S pneumoniae: Acute onset fever with rigors, productive cough, shortness of breath, pleuritic chest pain; rapid progression of illness; air-space consolidation commonly seen on chest radiographs; bacteremia and pleural space infections also common

  • M pneumoniae: Sore throat, dry cough, headache; occasional pleural effusion; chest radiograph may show more significant infiltrate than that suggested by chest examination; uncommon extrapulmonary findings may include erythema multiforme and Stevens-Johnson syndrome, hemolytic anemia, changes in cardiac conduction, myocarditis or pericarditis, aseptic meningitis or encephalitis, Guillain-Barré syndrome, Raynaud phenomenon, glomerulonephritis, bullous myringitis

  • C pneumoniae: Sore throat and prolonged dry cough; biphasic symptoms; variable findings on chest radiographs; less-common extrapulmonary findings include endocarditis, meningoradiculitis, encephalitis

  • L pneumophila and other species: Typically high fever; nonproductive or minimally productive cough; hypoxia; variable presentation with sometimes severe symptoms; rapidly progressive illness (often fatal); findings on chest radiographs include segmental to lobar infiltrate; hyponatremia, hypophosphatemia, and diarrhea

  • H influenzae

    • Type B in unvaccinated children 4 months to 4 years old; also associated with pediatric meningitis, epiglottitis, otitis, and cellulitis

    • Non–type B H influenzae pneumonia, common in elderly patients and patients with chronic obstructive pulmonary disease; also associated with sinusitis and otitis

  • Community-acquired S aureus: Infrequent cause of CAP but can be rapidly progressive or necrotizing; may develop as a complication of influenza pneumonia; oxacillin-resistant strains (MRSA) are increasingly common.

  • Respiratory zoonoses

    • Chlamydophila psittaci (psittacosis): Exposure to birds

    • Coxiella burnetii (Q fever): Exposure to cattle, goats, sheep

    • Brucella: Risk for abattoir workers, animal contact, consumption of contaminated dairy products; rare in the United States

    • Bacillus anthracis (respiratory anthrax): Rare in the United States; “woolsorter’s disease”; raises concern for possible bioterrorism event

    • Francisella tularensis (tularemia): Exposure to rabbits, tick bite

    • Rhodococcus equi: Exposure to horses, cattle, pigs, sheep; mostly affects immunocompromised persons

    • Yersinia pestis (pneumonic plague): Exposure to rodents or fleas in the southwestern United States (desert area) or exposure to another human with pneumonic plague

Other Considerations

  • Persistent fever despite apparently appropriate therapy for pneumonia: consider empyema, drug-resistant organism, or alternative diagnosis

  • With CAP, early transition to oral therapy (decreases costs and adverse drug effects, may lead to shorter length of hospital stay, and is not associated with adverse outcomes)

  • With CAP, administer first antibiotic dose as soon as feasible for hospitalized patients; draw blood cultures (if any) before administration of antibiotics

  • Vaccination for S pneumoniae and influenza virus decreases incidence and severity of CAP

Table 39. Empiric Therapy for Respiratory Tract Infectionsa

Condition

Treatment Options

Acute bronchitis

Supportive measures only; antibiotic therapy is not indicated in most cases

Community-acquired pneumonia

Outpatient, no comorbidities, and no recent antibiotic therapy

One of the following:

azithromycin or clarithromycin PLUS amoxicillin if >25% of local S pneumoniae are resistant to macrolides; OR doxycycline PLUS amoxicillin if >25% of local S pneumoniae are resistant to tetracyclines; OR a respiratory fluoroquinolone (levofloxacin, moxifloxacin, or gemifloxacin)

Outpatient, recent antibiotic therapy, presence of comorbid conditionsb or other risk factors for drug-resistant S pneumoniae

After recent antibiotic therapy, use an alternative antimicrobial class:

A newer fluoroquinolone (levofloxacin, moxifloxacin, or gemifloxacin); OR

A combination of either azithromycin or clarithromycin plus 1 of the following: higher dose amoxicillin, amoxicillin-clavulanate, or an alternative β‎-lactam (ceftriaxone, cefuroxime, or cefpodoxime)

Hospitalized patient (non-ICU)

A combination of a parenteral β‎-lactam (ceftriaxone, cefotaxime, or higher-dose ampicillin) plus a select macrolide (azithromycin or clarithromycin); OR a fluoroquinolone (levofloxacin or moxifloxacin)

ICU admission

Combination therapy with a parenteral β‎-lactam (ceftriaxone, cefotaxime, ampicillin/sulbactam, or piperacillin/tazobactam) plus either a fluoroquinolone (levofloxacin or moxifloxacin) or azithromycin

If P aeruginosa is a concern:

An antipseudomonal β‎-lactamc plus either ciprofloxacin or levofloxacin; OR

An antipseudomonal β‎-lactamc plus an aminoglycoside and azithromycin

Possible community-acquired MRSA

Add vancomycin or linezolid to a CAP treatment regimen; daptomycin is not effective for pneumonia because it is inactivated by pulmonary surfactant

Aspiration pneumonia

Outpatient management

amoxicillin-clavulanate; OR

clindamycin

Hospitalized patient

One of the following:

A combination β‎-lactam/β‎-lactamase inhibitor (ampicillin/sulbactam, piperacillin/tazobactam); OR

A third- or fourth-generation cephalosporin combined with either metronidazole or clindamycin; OR

A fluoroquinolone combined with either metronidazole or clindamycin; OR

meropenem, ertapenem, doripenem, or imipenem

Hospital-acquired pneumoniad

Not at high risk of death, no IV antibiotics in the past 90 days, and absence of structural lung disease

One of the followinge:

piperacillin-tazobactam, cefepime, meropenem, imipenem, or levofloxacin

Use 2 antipseudomonal agents only if:

Use 2 antipseudomonal agents; choose 1 from each column

  • High risk of death (ventilatory support because of pneumonia or septic shock)

  • Receipt of IV antibiotics in the past 90 days

  • Structural lung disease (bronchiectasis or cystic fibrosis)

piperacillin-tazobactam

cefepime

meropenem

imipenem

aztreonam

levofloxacin

ciprofloxacin

tobramycin

gentamicin

amikacin

Add MRSA coverage only if these risk factors are present:

  • Receipt of IV antibiotics in the past 90 days

  • Prior detection of MRSA

  • Incidence of methicillin resistance among S aureus is >20% in the unit

Add to either of the 2 rows above:

vancomycin or linezolid

Ventilator-associated pneumoniad

Without risk factors for multidrug resistance (Table 38) and in an ICU where gram-negative resistance to the agent being considered is <10%

One of the followinge:

piperacillin-tozabactam, cefepime, levofloxacin, imipenem, or meropenem

Use 2 antipseudomonal agents only if:

Use 2 antipseudomonal agents; choose 1 from each column

  • Prior antibiotic use within 90 days

  • Septic shock at time of VAP

  • ARDS preceding VAP

  • ≥5 days of hospitalization or acute renal replacement therapy before VAP

  • In an ICU where gram-negative resistance to the first drug is >10%; OR local susceptibility rates are unknown

piperacillin-tazobactam

cefepime

meropenem

imipenem

ceftazidime

aztreonam

levofloxacin

ciprofloxacin

tobramycin

gentamicin

amikacin

polymyxin B or colistin IVf

Add MRSA coverage only if these risk factors are present:

Add to either of the 2 rows above:

vancomycin or linezolid

  • Receipt of IV antibiotics in the past 90 days

  • Prior detection of MRSA

  • Incidence of methicillin resistance among S aureus is unknown or >20% in the unit

a Initiate therapy after cultures are obtained. For pathogen-directed therapy, see Section IV on “Treatment of Specific Organisms.”

b Comorbid conditions include chronic heart, lung, liver, and renal disease; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions or use of immunosuppressing drugs; use of antimicrobials within the past 3 months (in which case, a drug from a different class should be selected); and other risks for drug-resistant S pneumoniae infection.

c Antipseudomonal β‎-lactams include piperacillin-tazobactam, cefepime, ceftazidime, imipenem, doripenem, and meropenem.

d De-escalate antimicrobials on the basis of culture results. For HAP and VAP, the standard duration of therapy should be 7 days.

e Can use aztreonam or ciprofloxacin if MRSA risk factors are present and vancomycin or linezolid is also being used.

f Reserve for settings with known resistance or empiric use when the incidence of multidrug resistance is high. Adapted from Mandell LA, et al. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27- 72. Used with permission.

Infective Endocarditis:

Diagnosis and Treatment

Common Infective Endocarditis Pathogens

Native Valves

  • Staphylococcus aureus

  • Viridans streptococci

  • Enterococci

  • HACEK organisms

Prosthetic Valves

  • Same as native valves, plus

    • Coagulase-negative staphylococci

    • Fungi

    • Gram-negative rods (early postoperative period)

Elements of Diagnosis

The diagnosis of IE relies on clear evidence of cardiac involvement and persistent bacteremia due to microorganisms that typically cause endocarditis. Establishing a microbiologic diagnosis is critical for therapeutic decisions. Every effort should be made to identify the causative organism.

Table 40. Definition of Terms Used in the Modified Duke Criteria for the Diagnosis of Infective Endocarditis

Major criteria

  • Blood culture positive for IE

    • Typical microorganisms consistent with IE from 2 separate blood cultures:

      • Viridans streptococci, Streptococcus gallolyticus (bovis), HACEK group, S aureus; or

      • Community-acquired enterococci, in the absence of a primary focus

    • Microorganisms consistent with IE from persistently positive blood cultures, defined as follows:

      • At least 2 positive cultures of blood samples drawn >12 hours apart; or

      • All of 3 or a majority of ≥4 separate cultures of blood (with first and last samples drawn at least 1 hour apart)

    • Single positive blood culture for Coxiella burnetii or anti−phase 1 IgG antibody titer >1:800

  • Evidence of endocardial involvement

  • Echocardiogram positive for IE, defined as follows:

    • Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; or

    • Abscess; or

    • New partial dehiscence of prosthetic valve

  • New valvular regurgitation (worsening or changing of pre-existing murmur not sufficient)

Minor criteria

  • Predisposition: Predisposing heart condition or injection drug use

  • Fever: Temperature >38°C

  • Vascular phenomena: Major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, and Janeway lesions

  • Immunologic phenomena: Glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factor

  • Microbiologic evidence: Positive blood culture but does not meet a major criterion as noted abovea or serologic evidence of active infection with an organism consistent with IE

a Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis.

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86 as updated from Li JS, et al. Clin Infect Dis. 2000 Apr;30(4):633-8. Used with permission.

Table 41. Definition of Infective Endocarditis by the Modified Duke Criteria

Definite IE

  • Pathologic criteria

    • Microorganisms: Demonstrated by culture or histologic examination of a vegetation, a vegetation that has embolized, or an intracardiac abscess specimen; or

    • Pathologic lesions: Vegetation or intracardiac abscess confirmed by histologic findings that show active endocarditis

  • Clinical criteria

    • 2 major criteria; or

    • 1 major criterion and 3 minor criteria; or

    • 5 minor criteria

Possible IE

  • 1 major criterion and 1 minor criterion; or

  • 3 minor criteria

Reject IE

  • Firm alternative diagnosis explaining evidence of IE; or

  • Resolution of IE syndrome with antibiotic therapy for ≤4 days; or

  • No pathologic evidence of IE at surgery or autopsy, with antibiotic therapy for ≤4 days; or

  • Does not meet the criteria for possible IE

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86 as updated from Li JS, et al. Clin Infect Dis. 2000 Apr;30(4):633-8. Used with permission.

Table 42. Use of Echocardiography During Diagnosis and Treatment

Initial echocardiography

  • Perform as soon as possible (<12 hours after initial evaluation)

  • Use TEE primarily; obtain TTE views of any abnormal findings for later comparison

  • Perform TTE if TEE is not immediately available

  • Use TTE in small children because it may be sufficient

Repeat echocardiography

  • Perform TEE as soon as possible after positive TTE for patients with high risk of complications for potential impact on prognosis and management

  • Repeat TEE 3-5 days after initial TEE if suspicion exists without diagnosis of IE or with worrisome clinical course during early treatment of IE

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86. Used with permission.

Table 43. Echocardiographic Features That Suggest Potential Need for Surgical Intervention

Vegetation

  • Persistent vegetation after systemic embolization

  • Anterior mitral leaflet vegetation, particularly if >10 mma

  • >1 embolic event during first 2 weeks of antimicrobial therapya

  • Increased vegetation size, despite appropriate antimicrobial therapya,b

Valvular dysfunction

  • Acute aortic or mitral insufficiency with signs of ventricular failureb

  • Heart failure unresponsive to medical therapyb

  • Valve perforation or ruptureb

Perivalvular extension

  • Valvular dehiscence, rupture, or fistulac

  • New heart blockb,c

  • Large abscess or extension of abscess, despite appropriate antimicrobial therapy

a Surgery may be required because of risk of embolization.

b Surgery may be required because of heart failure or failure of medical therapy.

c Echocardiography should not be the primary modality used to detect or monitor heart block.

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86. Used with permission.

Treatment of Endocarditis: Pathogen-Directed Therapy

Table 44. Therapy of Native Valve Endocarditis Caused by Highly Penicillin-Susceptible Viridans Group Streptococci and S gallolyticus (bovis) (MIC ≤0.12 mcg/mL)

Medication

Dosagea and Route

Duration

Comments

EITHER

   penicillin G

12-18 million units per day IV, either continuously or in 4-6 equally divided doses

4 wk

Preferred options in most patients >65 y or with impaired eighth cranial nerve function or impaired renal function

OR

   ceftriaxone

2 g per day IV or IM

4 wk

EITHER

   penicillin G

12-18 million units per day IV, either continuously or in 6 equally divided doses

2 wk

The 2-week regimen is not intended for patients with a known cardiac abscess or extracardiac infection or for those with ClCr <20 mL/min, impaired eighth cranial nerve function, or infection with Abiotrophia, Granulicatella, or Gemella

   PLUS

   gentamicinb

3 mg/kg per day IV or IM

2 wk

OR

   ceftriaxone

2 g per day IV or IM

2 wk

   PLUS

   gentamicinb

3 mg/kg per day IV or IM

2 wk

vancomycinc

30 mg/kg per day IV in 2 equally divided doses

4 wk

Use vancomycin only for patients unable to tolerate penicillin or ceftriaxone

Adjust dosage to obtain a trough level of 10-15 mcg/mL

a Recommended dosages are for adult patients with normal renal function.

b Other potentially nephrotoxic drugs (eg, NSAIDs) should be used with caution in patients receiving gentamicin therapy.

c Infuse vancomycin over at least 1 hour to reduce the risk of histamine release (red man syndrome).

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86. Used with permission.

Table 45. Therapy of Native Valve Endocarditis Caused by Relatively Penicillin-Resistant Strains of Viridans Group Streptococci and S gallolyticus (bovis) (MIC range, >0.12-0.5 mcg/mL)

Medication

Dosagea and Route

Duration

Comments

EITHER

   penicillin G

24 million units per day IV, either continuously or in 4-6 equally divided doses

4 wk

Use an enterococcal endocarditis regimen for patients with endocarditis caused by penicillin-resistant strains (MIC >0.5 mcg/mL)

   PLUS

   gentamicin

3 mg/kg per day IV or IM

2 wk

OR

   ceftriaxone

2 g per day IV or IM

4 wk

If the isolate is ceftriaxone susceptible, then ceftriaxone alone may be considered

   PLUS

   gentamicin

3 mg/kg per day IV or IM

2 wk

vancomycinb

30 mg/kg per day IV in 2 equally divided doses

4 wk

Use vancomycin only for patients unable to tolerate penicillin or ceftriaxone

a Recommended dosages are for adult patients with normal renal function.

b Adjust vancomycin dosage to obtain a trough level of 10-15 mcg/mL.

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86. Used with permission.

Table 46. Therapy for Prosthetic Valvea Endocarditis Caused by Viridans Group Streptococci and S gallolyticus (bovis)

Medication

Dosageb and Route

Duration

Comments

PENICILLIN-SUSCEPTIBLE STRAINS (MIC ≤0.12 mcg/mL)

EITHER

penicillin G

24 million units per day IV, either continuously or in 4-6 equally divided doses

6 wk

The addition of gentamicin has NOT demonstrated superior cure rates compared with penicillin or ceftriaxone monotherapy for patients with a highly susceptible strain

with or without (optional)

gentamicin

3 mg/kg per day IV or IM

2 wk

Do NOT use gentamicin in patients with ClCr <30 mL/min

OR

ceftriaxone

2 g per day IV or IM

6 wk

The addition of gentamicin has NOT shown superior cure rates compared with penicillin or ceftriaxone monotherapy for patients with a highly susceptible strain

with or without

(optional)

gentamicin

3 mg/kg per day IV or IM

2 wk

Do NOT use gentamicin in patients with ClCr <30 mL/min

vancomycinc

30 mg/kg per day IV in 2 equally divided doses

6 wk

Use vancomycin only for patients unable to tolerate penicillin or ceftriaxone

RELATIVELY OR FULLY PENICILLIN-RESISTANT STRAINS (MIC >0.12 mcg/mL)

EITHER

penicillin G

24 million units per day IV, either continuously or in 4-6 equally divided doses

6 wk

. . .

PLUS

gentamicin

3 mg/kg per day IV or IM

6 wk

OR

ceftriaxone

2 g per day IV or IM

6 wk

PLUS

gentamicin

3 mg/kg per day IV or IM

6 wk

vancomycinc

30 mg/kg per day IV in 2 equally divided doses

6 wk

Use vancomycin only for patients unable to tolerate penicillin or ceftriaxone

a Or other prosthetic material.

b Recommended dosages are for adult patients with normal renal function.

c Adjust vancomycin dosage to obtain a trough level of 10-15 mcg/mL.

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86. Used with permission.

Table 47. Therapy for Endocarditis Caused by Staphylococci, in the Absence of Prosthetic Materials

Medication

Dosagea and Route

Duration

Comments

OXACILLIN-SUSCEPTIBLE STRAINS

EITHER

nafcillin

12 g per day IV in 4-6 equally divided doses (same dosage for both drugs)

6 wk

Administer for 6 weeks for left-sided IE and for complicated right-sided IE; or use 2 weeks for uncomplicated right-sided IE

OR

oxacillin

For patients with non–anaphylactoid-type penicillin allergies:

cefazolin

6 g per day IV in 3 equally divided doses

6 wk

Consider skin testing; avoid cephalosporins in patients with anaphylactoid-type hypersensitivity to β‎-lactams—use vancomycin instead

OXACILLIN-RESISTANT STRAINS

EITHER

vancomycin

30 mg/kg per day IV in 2 equally divided doses

6 wk

Adjust to achieve a trough level of 10-20 mcg/mL

OR

daptomycin

≥8 mg/kg/dose daily

6 wk

Optimal dosing not well defined; await additional study data

a Recommended dosages are for adult patients with normal renal function.

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86. Used with permission.

Table 48. Therapy for Prosthetic Valve Endocarditis Caused by Staphylococci

Medication

Dosagea and Route

Duration

Comments

OXACILLIN-SUSCEPTIBLE STRAINS

nafcillin OR oxacillin

12 g per day IV in 6 equally divided doses (same dosage for both drugs)

≥6 wk

Substitute cefazolin for nafcillin or oxacillin in patients with non−anaphylactoid-type hypersensitivity reactions to penicillin; use vancomycin in patients with anaphylactoid-type hypersensitivity reactions to β‎-lactam antibiotics

PLUS

rifampin

900 mg per day IV or oral in 3 equally divided doses

≥6 wk

AND PLUS

gentamicin

3 mg/kg per day IV or IM in 2-3 equally divided doses

2 wk

OXACILLIN-RESISTANT STRAINS

vancomycin

30 mg/kg per day IV in 2 equally divided doses

≥6 wk

Adjust vancomycin to achieve a trough level of 10-20 mcg/mL

PLUS

900 mg per day IV or oral in 3 equally divided doses

≥6 wk

rifampin

AND PLUS

3 mg/kg per day IV or IM in 2-3 equally divided doses

2 wk

Adjust gentamicin to achieve peak level of 3-4 mcg/mL and trough level <1 mcg/mL

gentamicinb

a Recommended dosages are for adult patients with normal renal function.

b Gentamicin should be administered in close temporal proximity to vancomycin, nafcillin, or oxacillin dosing.

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86. Used with permission.

Table 49. Therapy for Native or Prosthetic Valve Enterococcal Endocarditis Caused by Strains Susceptible to Penicillin and Gentamicina

Medication

Dosageband Route

Duration

Comments

EITHER

ampicillin

12 g per day IV in 6 equally divided doses

4-6 wk

Native valve: Use 4-week therapy for symptoms lasting ≤3 months and 6-week therapy for symptoms lasting >3 months

PLUS

gentamicinc

3 mg/kg per day IV or IM in 2-3 equally divided doses

4-6 wk

Prosthetic valve or other prosthetic cardiac material: Use 6-week minimum therapy

OR

penicillin G

18-30 million units per day IV either continuously or in 6 equally divided doses

4-6 wk

PLUS

gentamicinc

3 mg/kg per day IV or IM in 2-3 equally divided doses

4-6 wk

Double β‎-lactam therapy

ampicillin

12 g per day IV in 6 equally divided doses

6 wk

Recommended for patients with initial ClCr <50 mL/min or who develop ClCr <50 mL/min during gentamicin therapy, and for IE due to gentamicin resistant, β‎-lactam−susceptible strains

PLUS

ceftriaxone

2 g IV every 12h

6 wk

a For strains resistant to gentamicin and susceptible to streptomycin, substitute streptomycin 15 mg/kg per day IV or IM in 2 divided doses. See full-text article of Baddour et al for management of enterococcal IE strains that are penicillin resistant and for management of strains resistant to penicillin, aminoglycosides, or vancomycin.

b Recommended dosages are for adult patients with normal renal function.

c Adjust gentamicin dosage to achieve a peak serum level of about 3 mcg/mL and a trough level of <1 mcg/mL. Patients with ClCr <50 mL/min should be treated in consultation with an infectious diseases specialist.

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86. Used with permission.

Table 50. Vancomycin-Containing Regimens for Vancomycin- and Aminoglycoside-Susceptible, Penicillin-Resistant Enterococcus Species for Native or Prosthetic Valve Endocarditis and in Patients Unable to Tolerate β‎-Lactam Therapy

Medication

Dosagea and Route

Duration

Comments

vancomycin

30 mg/kg per 24h IV in 2 equally divided dosesb

6 wk

For β‎-lactamase−producing strains; if a β‎-lactam antibiotic is tolerated, ampicillin-sulbactamc plus aminoglycoside therapy may be used

PLUS

gentamicin

3 mg/kg per 24h IV or IM in 3 equally divided dosesd

6 wk

a Dosages recommended are for adults with normal renal function.

b Dosage of vancomycin should be adjusted to obtain a serum trough concentration of 10-20 mcg/mL.

c Ampicillin-sulbactam dosing, 3 g IV q6h.

d Dosage of gentamicin should be adjusted to obtain serum peak and trough concentrations of 3-4 mcg/mL and <1 mcg/mL, respectively.

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86. Used with permission.

Table 51. Therapy for Native and Prosthetic Valve Endocarditis Caused by HACEK Microorganisms

Medication

Dosagea and Route

Duration

Comments

ceftriaxone

2 g per day IV or IM

Native valve: 4 wk

Prosthetic valve: 6 wk

Can substitute cefotaxime or another third- or fourth-generation cephalosporin for ceftriaxone

OR

ampicillin-sulbactam

12 g per day IV in 4 equally divided doses

Native valve: 4 wk

Prosthetic valve: 6 wk

OR

ciprofloxacinb

1,000 mg per day oral or 800 mg per day IV, in 2 equally divided doses

Native valve: 4 wk

Prosthetic valve: 6 wk

Fluoroquinolones may be considered in patients unable to tolerate a cephalosporin or ampicillin; levofloxacin or moxifloxacin may be substituted; fluoroquinolones are not generally recommended for patients younger than 18 years

a Recommended dosages are for adult patients with normal renal function.

b The fluoroquinolones are highly active in vitro against HACEK microorganisms. Few published data exist on the use of fluoroquinolone therapy for endocarditis caused by HACEK microorganisms.

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86. Used with permission.

Other Treatment Considerations:

Role of Surgery

Obtain prompt surgical evaluation of patients with congestive heart failure, fungal IE, MDR organisms, gram-negative IE, or endocarditis of prosthetic valves, and of patients with echocardiographic features suggesting the need for surgical intervention (see preceding section, “Elements of Diagnosis”).

Care During and After Completion of Antimicrobial Treatment

  • Initiate before or at completion of antimicrobial therapy:

    • TTE to establish new baseline

    • Drug rehabilitation referral for patients who use illicit injection drugs

    • Patient education about the signs of endocarditis and the need for antibiotic prophylaxis before certain dental, surgical, or invasive procedures

    • Thorough dental evaluation and treatment, if not performed earlier in the evaluation of IE

    • Prompt removal of intravenous catheter after administration of antimicrobial therapy

  • Short-term follow-up:

    • Obtain at least 3 sets of blood cultures from separate sites for any febrile illness and before initiation of antibiotic therapy

    • Conduct a physical examination for evidence of congestive heart failure

    • Evaluate for toxicity due to current or prior antimicrobial therapy

  • Long-term follow-up:

    • Obtain at least 3 sets of blood cultures from separate sites for any febrile illness and before initiation of antibiotic therapy

    • Evaluate valvular and ventricular function (eg, echocardiography)

    • Encourage scrupulous oral hygiene and frequent professional dental office visits

Adapted from Baddour LM, et al. Circulation. 2015 Oct 13;132(15):1435-86. Used with permission.

Infective Endocarditis Prophylaxis

Prevention of Endocarditis

The American Heart Association extensively revised guidelines for IE prevention in 2007. Key observations include the following:

  • Dental procedures are associated with a small number of cases of IE. Prophylaxis, even if 100% effective, would thus prevent only an extremely small number of IE cases.

  • The emphasis has shifted from use of antibiotic prophylaxis to good oral health and increased access to dental care.

  • Prophylactic antibiotics based on a patient’s lifetime risk of acquiring IE are no longer recommended. Instead, prophylaxis focuses on patients with the highest risk of adverse outcomes from IE.

Candidates for Prophylaxis

Only those patients with conditions that expose them to the highest risk of adverse outcomes from IE should receive prophylaxis. These high-risk conditions include:

  • Prosthetic heart valve

  • History of IE

  • Congenital heart disease ONLY for the following specific conditions:

    1. 1) Unrepaired cyanotic congenital heart defect, including palliative shunts and conduits

    2. 2) Completely repaired congenital heart defect with prosthetic material or a prosthetic device placed, either during surgery or by catheter intervention, within the first 6 months after the procedure

    3. 3) Congenital heart defect repair with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device

  • Development of cardiac valvulopathy after cardiac transplantation

(Adapted from Wilson W, et al. Circulation. 2007 Oct 9;116(15):1736-54. Epub 2007 Apr 19. Erratum in: Circulation. 2007 Oct 9;116(15):e376-7. Used with permission.)

IE Prophylaxis for Specific Procedures

Prophylactic antibiotics should be administered ONLY to patients with the high-risk conditions listed above.

Dental Procedures

Prophylaxis is directed against viridans group streptococci.

  • Prophylaxis is appropriate for high-risk candidates undergoing any dental procedures that involve manipulation of gingival tissue or the periapical region of the teeth or perforation of the oral mucosa.

  • Procedures that do NOT require prophylaxis include routine anesthetic injections through noninfected tissue, dental radiographs, placement of removable prosthodontic or orthodontic appliances, adjustment of orthodontic appliances, and placement of orthodontic brackets. Prophylaxis is also not recommended after the shedding of deciduous teeth or for bleeding from trauma to the lips or oral mucosa.

Respiratory Procedures

For candidates for prophylaxis as listed above:

  • It may be reasonable to give one of the above prophylactic regimens recommended for dental procedures (See Table 52, “Prophylactic Regimens for Infective Endocarditis Before Dental Procedures”) before an invasive procedure involving the respiratory tract that necessitates incision or biopsy of the respiratory mucosa (eg, tonsillectomy, adenoidectomy).

  • Prophylaxis is NOT recommended for bronchoscopy unless the procedure involves incision of the respiratory tract mucosa.

Table 52. Prophylactic Regimens for Infective Endocarditis Before Dental Proceduresa,b

Clinical Situation

Adult Prophylaxis (Use Only 1 Drug per Clinical Situation)

Pediatric Prophylaxis (Use Only 1 Drug per Clinical Situation)

Oral regimen

amoxicillin 2 g

amoxicillin 50 mg/kg

Unable to take oral medication

ampicillin 2 g IM or IV

OR

cefazolin 1 g IM or IV

OR

ceftriaxone 1 g IM or IV

ampicillin 50 mg/kg IM or IV

OR

cefazolin 50 mg/kg IM or IV

OR

ceftriaxone 50 mg/kg IM or IV

Allergy to penicillin or ampicillin

Oral regimen

cephalexinc,d 2 g

OR

clindamycin 600 mg

OR

azithromycin 500 mg

OR

clarithromycin 500 mg

cephalexinc,d 50 mg/kg

OR

clindamycin 20 mg/kg

OR

azithromycin 15 mg/kg

OR

clarithromycin 15 mg/kg

Unable to take oral medication

cefazolind 1 g IM or IV

OR

ceftriaxoned 1 g IM or IV

OR

clindamycin 600 mg IM or IV

cefazolind 50 mg/kg IM or IV

OR

ceftriaxoned 50 mg/kg IM or IV

OR

clindamycin 20 mg/kg IM or IV

a Give a single dose 30-60 minutes before the procedure.

b If the antibiotic is inadvertently not administered before the procedure, it may be administered up to 2 hours after the procedure.

c Or substitute another first- or second-generation cephalosporin in an equivalent dose.

d Do not use a cephalosporin in patients with a history of anaphylaxis, angioedema, or urticaria after treatment with penicillin or ampicillin.

Adapted from Wilson W, et al. Circulation. 2007 Oct 9;116(15):1736-54. Epub 2007 Apr 19. Erratum in: Circulation. 2007 Oct 9:116(15):e376-7. Used with permission.

Gastrointestinal or Genitourinary Tract Procedures

For candidates for prophylaxis as listed above:

  • Prophylaxis solely to prevent IE is NO longer recommended.

  • For patients undergoing an elective urinary tract manipulation who also have an enterococcal UTI or colonization, it may be reasonable to administer antibiotic therapy to eradicate enterococci from the urine before the procedure.

  • If the urinary tract procedure is not elective, it may be reasonable to administer an antimicrobial regimen that contains an agent active against enterococci.

  • Amoxicillin or ampicillin is the preferred agent for enterococcal coverage; vancomycin may be administered to patients unable to tolerate ampicillin.

Procedures Involving Infected Skin, Skin Structure, or Musculoskeletal Tissue

For candidates for prophylaxis as listed above:

  • Regimen administered for treatment of the skin and soft-tissue infection should contain an agent active against staphylococci and β‎-hemolytic streptococci.

  • An antistaphylococcal penicillin or cephalosporin is preferable; vancomycin or clindamycin may be administered to patients unable to tolerate a β‎-lactam or who are known or suspected to have an infection caused by MRSA.

Other Prophylactic Considerations

  • The presence of fever or other manifestations of systemic infection indicate the possibility of IE. In these cases, blood cultures and other relevant tests should be obtained before administering a prophylactic antibiotic. Failure to do so may delay the diagnosis or treatment of a case of IE.

  • If a patient is already receiving long-term antibiotic therapy with an agent that is also recommended for IE prophylaxis for a dental procedure, an antibiotic from a different class should be used.

  • If a patient requires a dental procedure while receiving parenteral antibiotic therapy for treatment of IE, the antibiotic therapy should be continued and the timing adjusted so that a dose is administered 30-60 minutes before the dental procedure.

  • Patients who undergo surgery for placement of prosthetic heart valves or prosthetic intravascular or intracardiac material should be given surgical prophylaxis directed primarily against Staphylococcus sp.

  • Antibiotic prophylaxis for dental procedures is NOT recommended for patients with coronary artery bypass grafting or coronary artery stents.

Adapted from Wilson W, et al. Circulation. 2007 Oct 9;116(15):1736-54. Epub 2007 Apr 19. Erratum in: Circulation. 2007 Oct 9;116(15):e376-7. Used with permission.

Intravascular Catheter-Related Infections

Elements of Diagnosis

  • Blood cultures through the catheter lumen should be obtained only if a catheter-related bloodstream infection (CRBSI) is suspected. Do NOT obtain routine or surveillance blood cultures through catheters.

  • Always obtain paired blood samples, drawn from a peripheral vein and through the catheter lumen, before starting empiric antimicrobial therapy.

A definite diagnosis of CRBSI requires one of the following:

  • A positive semiquantitative result (>15 cfu per catheter segment) by roll-plate culture, in which the same microorganism (species) is isolated from the catheter segment and peripheral blood culture.

  • Simultaneous quantitative cultures of blood, with a catheter:peripheral blood culture ratio of >3:1 cfu/mL.

  • Differential time to positivity (growth in a culture of blood obtained through a catheter hub is detected by an automated blood culture system at least 2 hours earlier than a culture of simultaneously drawn peripheral blood of equal volume).

Table 53. Commonly Encountered Pathogens in CRBSI

Clinical Situation

Common Organisms

All CRBSIs

Staphylococcus spp, including coagulase-negative staphylococci (most common) and S aureus

Other gram-positive bacteria (eg, Corynebacterium, Bacillus)

Prolonged hospitalization, critically ill patients, femoral catheters, and immunosuppressed patients (including those with neutropenia)

Staphylococcus spp and gram-negative bacteria, including Pseudomonas aeruginosa

Any of the above risk factors and total parenteral nutrition, prolonged use of antibacterial agents, and known Candida colonization

Staphylococcus spp, gram-negative bacteria, and Candida

  • After culture results are known, therapy should be de-escalated on the basis of the susceptibility profile of the responsible pathogen.

  • For pathogen-specific therapy, see Section IV, Table 34 (“Bacteria: Preferred and Alternative Treatment Options”) and Table 36 (“Fungi: Preferred and Alternative Treatment Options”).

Table 54. Complicated and Uncomplicated CVC-related Infections

CVC-related infection is considered uncomplicated if:

  • Fever and blood cultures resolve within 72 hours

  • Patient has no intravascular hardware

  • There is no evidence of endocarditis, suppurative thrombophlebitis, or osteomyelitis

  • There is no active malignancy or immunosuppression (in cases of S aureus infection)

CVC-related infection is considered complicated if:

  • The patient has local complications—tunnel infection or port abscess

  • The patient has systemic complications—septic thrombosis, endocarditis, osteomyelitis, etc

  • Blood cultures remain positive for >72 hours despite appropriate antimicrobial therapy

Catheter Removal vs Retention and Duration of Treatment

  • Figures 3 and 4 show management algorithms that include decisions about catheter removal vs retention and duration of antimicrobial treatment.

  • CVCs should be removed in cases of complicated infection (see definitions above), regardless of causative pathogen.

  • Infected short-term CVCs should generally be removed.

  • Infected long-term CVCs and ports with fungi, mycobacteria, P aeruginosa, drug-resistant bacteria (including VRE, ESBL-producing, and other MDR gram-negative bacteria) should be removed; with S aureus, consider removal of the infected catheter and administer prolonged antimicrobial therapy, except in select situations.

  • Patients with CRBSI due to S aureus may be treated with a shorter course (≤14 days) of systemic antibiotics if they are not diabetic, have no active malignancy, are not receiving immunosuppressive therapy, are not neutropenic, have no prosthetic intravascular device (eg, pacemaker, prosthetic heart valve, vascular graft), have negative TEE, or have bacteremia and fever that resolve within 72 hours of catheter removal and initiation of appropriate antimicrobial therapy.

  • When denoting duration of antimicrobial therapy, day 1 is the first day of negative blood cultures.

Figure 3. Management of Short-term CVC-Related Bloodstream Infections.
 AC indicates arterial catheter; CRBSI, catheter-related bloodstream infection; CVC, central venous catheter.

Figure 3. Management of Short-term CVC-Related Bloodstream Infections.

AC indicates arterial catheter; CRBSI, catheter-related bloodstream infection; CVC, central venous catheter.

(Adapted from Mermel LA, et al. Clin Infect Dis. 2009 Jul 1;49[1]:1-45. Used with permission.)

Figure 4. Management of Long-term CVC-Related Bloodstream Infections.
CRBSI indicates catheter-related bloodstream infection; CVC, central venous catheter.

Figure 4. Management of Long-term CVC-Related Bloodstream Infections.

CRBSI indicates catheter-related bloodstream infection; CVC, central venous catheter.

(Adapted from Mermel LA, et al. Clin Infect Dis. 2009 Jul 1;49[1]:1-45. Used with permission.)

Antibiotic or Ethanol Lock Therapy

  • Antibiotic or ethanol lock therapy is indicated for patients with CVC and ports with long-term uncomplicated infection by select susceptible bacteria when catheter retention is the goal; the highest success rates have been observed with coagulase-negative staphylococcus. For additional information on antibiotic lock solution options, see Mermel LA, et al. Clin Infect Dis. 2009 Jul 1;49(1):1-45 and Bookstaver PB, et al. Am J Health Syst Pharm. 2013 Dec 15;70(24):2185-98.

  • For CRBSI, antibiotic lock therapy should be used in conjunction with systemic antibiotic therapy.

  • If antimicrobial lock therapy cannot be used and CVC retention is the goal, systemic antibiotics should be administered through the colonized catheter lumen.

Other Considerations

  • Repeat blood cultures should be obtained if CVC retention is attempted; if blood cultures remain positive after 72 hours of appropriate antibiotics, remove CVC.

  • Routine blood cultures are unnecessary after completing antimicrobial therapy for CRBSI.

  • Linezolid should not be used for empiric therapy.

Central Nervous System Infections

Empiric Therapy for Acute Bacterial Meningitis

Elements of Diagnosis and Treatment

  • Clinical: The diagnosis of meningitis is suggested by the constellation of headache, fever, and neck stiffness. Some patients may have changes in mental status.

  • Radiology: CT or MRI of the brain may be indicated for immunocompromised patients and patients with papilledema or focal neurologic deficits. However, neuroimaging should not delay initiation of antimicrobial therapy.

  • Laboratory: CSF typically shows neutrophilic pleocytosis, high protein, and low glucose. Gram stain may provide rapid initial clues to the causative agent while awaiting results of CSF and blood cultures.

  • Treatment

    • Acute bacterial meningitis is a medical emergency. Avoid delays in antibiotic therapy, and institute empiric antimicrobial therapy promptly. Host factors and knowledge of the local susceptibility pattern are important when selecting empiric regimens. Adjust antibiotic therapy after defining the causative agent and its susceptibility profile. The duration of pathogen-directed therapy depends on the causative organism (see Table 56 on “Pathogen-Directed Therapy for Bacterial Meningitis”)

    • Use adjunctive dexamethasone (0.15 mg/kg q6h) for 2-4 days for neonates or children with Haemophilus influenzae meningitis and for adults with proven or suspected Streptococcus pneumoniae meningitis. Administer the first dose of dexamethasone before or concurrent with the first dose of antibiotic therapy.

    • Consider adding rifampin for suspected S pneumoniae, pending susceptibilities, if dexamethasone is used. If S pneumoniae is β‎-lactam susceptible, rifampin can be discontinued.

Table 56. Pathogen-Directed Therapy for Bacterial Meningitis

Pathogen

First-Line Treatment

Alternative Treatment

Duration

Enterococcus

   ampicillin susceptible

ampicillin plus gentamicin

linezolid, daptomycin

Individualizea

   ampicillin resistant

vancomycin plus gentamicin

   ampicillin and vancomycin resistant

linezolid

E coli and other Enterobacteriaceae

A 3rd- or 4th-generation cephalosporin (eg, ceftriaxone, cefotaxime, ceftazidime, cefepime)

carbapenem, aztreonam, TMP-SMX, or a fluoroquinoloneb

21 daysa

H influenzae

   β‎-Lactamase negative

ampicillin, cefotaxime, or ceftriaxone

cefepime or a fluoroquinoloneb

7 daysa

   β‎-Lactamase positive

ceftriaxone or cefotaxime

cefepime or a fluoroquinoloneb

L monocytogenes

ampicillin with or without an aminoglycoside OR

penicillin G with or without an aminoglycoside

TMP-SMX or meropenem

21 daysa

N meningitidis—penicillin MIC

   <0.1 mcg/mL

penicillin, ampicillin, ceftriaxone, or cefotaxime

meropenem or a fluoroquinoloneb

7 daysa

   0.1-1.0 mcg/mL

ceftriaxone or cefotaxime

meropenem or a fluoroquinoloneb

P aeruginosa

cefepime or ceftazidime

meropenem, ciprofloxacin, levofloxacin, or aztreonam

Individualizea

S aureus

   MRSA

vancomycin

TMP-SMX, linezolid, daptomycin

   MSSA

nafcillin or oxacillin

vancomycin, meropenem, linezolid, daptomycin

Individualizea

S epidermidis (MRSE)

vancomycin

linezolid, daptomycin

Individualizea

S agalactiae

penicillin or ampicillin

ceftriaxone or cefotaxime

14-21 daysa

S pneumoniae

   penicillin susceptible

penicillin G, ampicillin, ceftriaxone, or cefotaxime

cefepime

10-14 daysa

   penicillin intermediate

ceftriaxone or cefotaxime

cefepime or meropenem

   penicillin resistant

vancomycin plus either cefotaxime or ceftriaxone

fluoroquinolone

   cefotaxime or ceftriaxone MIC ≥0.5 mcg/mL

vancomycin plus either cefotaxime or ceftriaxone

fluoroquinolone

a Duration of therapy may be individualized on the basis of the patient’s clinical response.

b CSF levels vary by agent.

Adapted from Tunkel AR, et al. Clin Infect Dis. 2004 Nov 1;39(9):1267-84. Epub 2004 Oct 6. Used with permission.

Pathogen-Directed Therapy for Acute Bacterial Meningitis

Elements of Diagnosis and Treatment

  • Clinical: Adjust antimicrobial therapy on the basis of the results of Gram stain, bacterial cultures, and antimicrobial susceptibility pattern.

  • Laboratory: Use results of antimicrobial susceptibilities to guide the choice of pathogen-directed therapy.

  • Treatment: Continue adjunctive dexamethasone (0.15 mg/kg q6h) for 2-4 days in neonates or children with H influenzae meningitis and in adults with proven or suspected S pneumoniae meningitis.

Table 55. Empiric Therapy of Suspected Acute Bacterial Meningitis

Patient Variable

Suspected Pathogen

First-Line Treatment

Age

   <1 mo

S agalactiae

Escherichia coli

Listeria monocytogenes

Klebsiella spp

ampicillin plus either cefotaxime or an aminoglycoside

   1-23 mo

S pneumoniae

Neisseria meningitidis

E coli

S agalactiae

H influenzae

vancomycina plus either ceftriaxone or cefotaxime

   2-50 y

N meningitidis

S pneumoniae

vancomycina plus either ceftriaxone or cefotaxime

   >50 y

S pneumoniae

N meningitidis

L monocytogenes

Aerobic gram-negative bacilli

vancomycina plus ampicillin and 1 of the following: ceftriaxone, cefotaxime, or cefepime

Head trauma

   Basilar skull fracture

S pneumoniae

H influenzae

Group A (β‎-hemolytic) streptococci

vancomycina plus either ceftriaxone or cefotaxime

   Penetrating trauma

S aureus

Coagulase-negative staphylococci

Aerobic gram-negative bacilli, including Pseudomonas aeruginosa

vancomycina plus 1 of the following: cefepime, ceftazidime, or meropenem

After neurosurgery

S aureus

Coagulase-negative staphylococci

Aerobic gram-negative bacilli, including P aeruginosa, E coli, and K pneumoniae

vancomycina plus 1 of the following: cefepime, ceftazidime, or meropenem

CSF shunt-related

Coagulase-negative staphylococci

S aureus

Aerobic gram-negative bacilli, including P aeruginosa

Propionibacterium acnes

vancomycina plus 1 of the following: cefepime, ceftazidime, or meropenem

   Impaired cellular immunity

S pneumoniae

N meningitidis

L monocytogenes

Aerobic gram-negative bacilli, including P aeruginosa

vancomycina plus ampicillin and cefepime or meropenem

a Monitor serum levels. Maintain vancomycin trough concentration at 15-20 mcg/mL.

Adapted from Tunkel AR, et al. Clin Infect Dis. 2004 Nov 1;39(9):1267-84. Epub 2004 Oct 6. Used with permission.

Table 57. Recommended Doses of Select Antimicrobial Agents for Treatment of Bacterial Meningitis in Children and Adults with Normal Renal and Hepatic Function

Children (After Neonatal Period)

Adults

Antimicrobial Agent

Dose

Total Maximum Daily Dose

Dose

Total Daily Dose

ampicillin

300 mg/kg q24h divided q6h

12 g

2 g q4h

12 g

cefepime

150 mg/kg q24h divided q8h

6 g

2 g q8h

6 g

cefotaxime

225-300 mg/kg q24h divided q6h

12 g

2 g q4h (or 3 g q6h)

12 g

ceftazidime

150 mg/kg q24h divided q8h

6 g

2 g q8h

6 g

ceftriaxone

80-100 mg/kg q24h divided q12h

4 g

2 g q12h

4 g

ciprofloxacin

NA

NA

400 mg q8h (or 600 mg q12h)

800-1,200 mg

daptomycin

Limited data

Limited data

6 mg/kg q24h

Individualize

gentamicina

1.7-2.5 mg/kg q8h

Individualize

1.7-2.5 mg/kg q8-12h

Individualize

linezolid

30 mg/kg q24h divided q8h

30 mg/kg

600 mg q12h

1,200 mg

meropenem

120 mg/kg q24h divided q8h

6 g

2 g q8h

6 g

moxifloxacin

NA

NA

400 mg q24h

400 mg

nafcillin

200 mg/kg q24h divided q6h

12 g

2 g q4h

12 g

oxacillin

200 mg/kg q24h divided q6h

12 g

2 g q4h

12 g

penicillin G

300,000 units/kg q24h divided q4-6h

24 million units

20-24 million units per day as continuous IV infusion (load with 4-5 million units) or 4 million units q4h

20-24 million units

rifampin

10-20 mg/kg q24h divided q12-24h

600 mg

600 mg q24h

600 mg

tobramycina

1.7-2.5 mg/kg q8h

Individualize

1.7-2.5 mg/kg q8-12h

Individualize

TMP-SMX

10-20 mg/kg q24h divided q6-12h

20 mg/kg

15-20 mg/kg q24h divided q6-12h

15-20 mg/kg

vancomycinb

60 mg/kg q24h divided q6h

60 mg/kg

40-45 mg/kg q24h divided q8-12h

Individualize

a Monitor and adjust levels accordingly. Desired peak is 7-10 mcg/mL; trough, 0.6-1.2 mcg/mL.

b In children and adults, monitor serum levels and maintain trough concentration of 15-20 mcg/mL.

Adapted from Tunkel AR, et al. Clin Infect Dis. 2004 Nov 1;39(9):1267-84. Epub 2004 Oct 6. Used with permission.

Tubercular Meningitis

Elements of Diagnosis and Treatment

  • Clinical: The constellation of headache, fever, changes in mental status, and neck stiffness can be associated with tubercular meningitis. Concurrent pulmonary disease or other forms of extrapulmonary disease may or may not be present. An exposure history to persons with known TB should be obtained.

  • Radiology: Neuroimaging may be indicated for immunocompromised patients and for patients with papilledema or focal neurologic deficits.

  • Laboratory: Conduct CSF examination with AFB stain and mycobacterial culture, in addition to blood and respiratory cultures. Molecular tests to detect Mycobacterium tuberculosis nucleic acid may aid in diagnosis.

  • Adjunctive treatment: Corticosteroid therapy is recommended for at least 6 weeks (although longer durations are commonly required).

Table 58. Treatment of Tubercular Meningitis

Empiric Therapy

First-Line Treatment

Alternative Treatment

Mycobacterium tuberculosis

isoniazid 300 mg q24h plus all 3 of the following for 2 mo: rifampin 600 mg q24h, pyrazinamide 15-30 mg/kg q24h, and ethambutol 15-20 mg/kg q24h; then isoniazid 300 mg q24h and rifampin 600 mg q24h for 7-10 mo if M tuberculosis strain is drug susceptible

Adjunctive corticosteroid therapy generally is recommended

Management of drug-resistant TB should be guided by susceptibility testing, and patients should be referred to a TB management expert

Urinary Tract Infections

Elements of Diagnosis

Table 59. Elements of Diagnosis of Urinary Tract Infections

Clinical Syndrome

Diagnostic Considerations

Asymptomatic bacteriuria

Clinical diagnosis: Urine culture >105 CFU/mL in absence of symptoms; common in elderly patients and in patients with chronic catheterization, spinal cord injuries, and neurogenic bladder; typically requires no treatment EXCEPT during pregnancy and in young children

Cystitis in women (uncomplicated)

Clinical diagnosis: Cultures typically are not needed; urine dipstick esterase−positive culture should show >102 CFU/mL; symptoms include dysuria and frequency

Common pathogens: 75-95% Escherichia coli and other gram-negative bacteria; 5-20% Staphylococcus saprophyticus and Enterococcus

Pyelonephritis (community acquired)

Clinical diagnosis: Symptoms same as for cystitis (see above) plus low back or flank pain and fever; urinalysis for pyuria and bacteriuria; urine culture recommended

Common pathogens: E coli and other gram-negative bacteria (eg, Klebsiella, Enterobacter, Proteus mirabilis); most common gram-positive pathogens are S saprophyticus and Enterococcus

UTI in men (community acquired)

Clinical diagnosis: Dysuria, urinary frequency; evaluate for anatomic obstructive anomaly (ie, by postvoiding urinary tract ultrasound) in noncatheterized men

Common pathogens: 80% E coli; in elderly patients, Enterococcus

Bacterial prostatitis

   Acute

Clinical diagnosis: Fever, dysuria, urinary frequency, pelvic pain, rectal examination reveals tender prostate, possibly elevated PSA; urinalysis (pyuria and bacteriuria); culture expressed prostate secretions for pathogen

Common pathogens: E coli; less-frequent pathogens include Klebsiella, Enterobacter, P mirabilis, and Staphylococcus aureus

   Chronic

Clinical diagnosis: Low-grade fever, recurrent bacteriuria, pyuria; possibly elevated PSA; rectal examination reveals nontender prostate; culture expressed prostate secretions for pathogen

Common pathogens: E coli (80%), Klebsiella, Enterobacter, P mirabilis, Enterococcus, and S aureus

Catheter-associated UTI

Clinical diagnosis: Dysuria, frequency, urgency, suprapubic pain, fever, costovertebral tenderness, plus the presence of an indwelling urinary catheter for at least 48 hours; urine culture >102 CFU/mL; pyuria

Common pathogens: E coli and Proteus, Enterobacter, Pseudomonas, and Serratia; usually no treatment is needed unless symptomatic

Candiduria

Clinical diagnosis: Urinalysis with yeast (ie, Candida); urine culture >103 CFU/mL, with or without pyuria; urine dipstick not contributory

Frequently represents colonization, common with urinary catheters and poor collection procedures; depending on presentation, may not require treatment

Ileal conduit or urinary diversion

Clinical diagnosis: Nonsterile source for urine collection; urine cultures are often polymicrobial and not interpretable

Empiric Antimicrobial Selection

Table 60. Empiric Therapy for Acute Uncomplicated Cystitis

Host Considerations

Empiric Antimicrobial Selection

Asymptomatic bacteria and asymptomatic catheter-associated urinary infection

Treatment is generally contraindicated in the absence of symptoms; screening of urine culture is not recommended, except in pregnancy

Exceptions for which treatment may be beneficial: pregnancy, before urologic procedures with mucosal bleeding (eg, transurethral resection of the prostate), and possibly within 3 months of renal transplant

Acute uncomplicated cystitis in women

First-line treatment

  • nitrofurantoin monohydrate macrocrystals 100 mg bid for 5 days (if ClCr>30 mL/min)a

Other options:

  • TMP-SMX 160/800 mg bid for 3 days

    • Do not use if local E coli resistance rates exceed 20% (they exceed this rate in many areas)

  • cefdinir 300 mg bid for 5 daysb

  • cefpodoxime proxetil 100 mg bid for 5 daysb

  • fosfomycin tromethamine 3 g once (considerably more costly and may require preauthorization)

Note: Avoid fluoroquinolones (eg, ciprofloxacin, levofloxacin) in uncomplicated cystitis because of increasing resistance (>20% resistance for E coli in many areas) and to preserve fluoroquinolones for more serious (susceptible) infections

Men; or patients with symptoms for >1 week, with recent antimicrobial use, who are diabetic, or who are older than 65 y

Use a 7-day treatment course

Antimicrobial options are same as those outlined for acute uncomplicated cystitis in women

Pregnancy

5-Day treatment course is preferred:

  • nitrofurantoin monohydrate macrocrystals 100 mg bid

  • cefdinir 300 mg bidb

  • cefpodoxime 100 mg bidb

Note: Avoid use of TMP-SMX (pregnancy category C) in the first and third trimesters of pregnancy; avoid use of fluoroquinolones in pregnancy

a Avoid nitrofurantoin in patients with ClCr<30 mL/min.

b Susceptibility testing with cefazolin: MIC ≤16 mcg/mL infers oral cephalosporin susceptibility for uncomplicated UTIs due to E coli, K pneumoniae, and P mirabilis. Cefpodoxime, cefdinir, or cefuroxime may be tested individually, as some cefazolin-resistant isolates may be susceptible to those medications. CLSI document M100-S25. Wayne (PA): Clinical and Laboratory Standards Institute; c2015.

Data from Gupta K, et al. Clin Infect Dis. 2011 Mar 1;52(5):e103-20 and Grigoryan L, et al. JAMA. 2014 Oct 22-29;312(16):1677-84. Note that some recommendations were modified because resistance rates exceed 20% for TMP-SMX and fluoroquinolones in most areas.

Table 61. Empiric Therapy for Acute Pyelonephritis

Host Considerations

Empiric Antimicrobial Selectiona

Outpatient (uncomplicated) pyelonephritis

Note: Obtain urine cultures and determine antimicrobial susceptibilities on all patients because treatment may need to be revised on the basis of susceptibilities

Initial therapy:

  • ceftriaxone 1 g IV every 24 hours pending susceptibilitiesb

Oral step-down therapy if susceptible (may need to use alternatives based on susceptibility testing):

  • ciprofloxacin 500 mg bid for 7 daysb or ciprofloxacin XR 1 g daily for 7 daysb

  • levofloxacin 750 mg daily for 5 daysb

  • TMP-SMX 160/800 mg bid for 14 daysb

If Enterococcus is suspected by Gram stain:

  • amoxicillin 500 mg tid or 875 mg bid for 14 days

Inpatient uncomplicated pyelonephritis: 5-14 days total therapy (IV and oral)

Note: Obtain urine cultures and determine antimicrobial susceptibilities on all patients because treatment may need to be revised on the basis of susceptibilitiesb

Initial therapy with 1 of the following:

  • ceftriaxone 1g IV q24h

  • cefotaxime 1-2 g IV q8h

  • cefepime 1-2 g IV q12h

  • aztreonam 1 g IV q8h (only if the patient has type 1 β‎-lactam hypersensitivity)

Because of increasing resistance to fluoroquinolones and TMP-SMX (>20% nonsusceptible E coli in many areas), parenteral therapy should be continued until susceptibilities are known. If the organism is susceptible, oral step-down therapy can be used:

  • ciprofloxacin 500 mg PO bid or ciprofloxacin XR 1 g PO daily

  • levofloxacin 750 mg PO daily

  • TMP-SMX 160/800 mg PO bid

If Enterococcus is suspected by Gram stain, options include:

  • ampicillin 1-2 g IV q6h

  • ampicillin/sulbactam 1.5-3.0 g IV q6h

  • vancomycin (if recent penicillin use) 15 mg/kg IV q12h

Inpatient pyelonephritis: complicatedc and/or bacteremic

Note: Obtain urine and blood cultures and determine antimicrobial susceptibilities on all patients because treatment may need to be revised on the basis of susceptibilitiesb

Initial therapy:

  • Empiric coverage against more common organisms, including Enterobacteriaceae, Enterococcus, and S saprophyticus

Community-acquired:

  • ceftriaxone 1 g IV q24h (if patient is stable); add vancomycin if the urine Gram stain or blood cultures show gram-positive cocci

  • cefepime 2 g IV q12h; add vancomycin if the urine Gram stain or blood cultures show gram-positive cocci

  • piperacillin/tazobactam 3.375 g IV q6h

  • In areas with high rates of ESBL-producing organisms or if the patient is from one of these areas, consider an empiric carbapenem, pending susceptibilities

For any of the options above, consider adding an aminoglycoside for dual gram-negative coverage, pending cultures, if the patient has sepsis

For patients with type 1 penicillin hypersensitivity allergy:

  • vancomycin 15 mg/kg IV q12h (with normal renal function) plus aztreonam 1 g IV q8h

If the organism is known to be susceptible, the following fluoroquinolones are options, but high levels of resistance preclude its use as empiric monotherapy in most areas:

  • ciprofloxacin 400 mg IV q8-12h

  • levofloxacin 500-750 mg IV q24h

    (Oral step-down therapy can be used for stable patients who tolerate these)

Health care facility–acquired or catheter-associated infection (also includes activity against Pseudomonas aeruginosa):

  • piperacillin/tazobactam 3.375-4. 5 g IV q6h

  • cefepime 2 g IV q8-12h

  • meropenem 1 g IV q8h or 500 mg IV q6h

Consider adding vancomycin for suspected Enterococcus (or daptomycin if VRE colonized); add ciprofloxacin, levofloxacin, or aminoglycoside for dual gram-negative coverage, pending cultures, in a patient with sepsis

In areas with higher rates of ESBL-producing organisms, consider empiric carbapenem, pending susceptibilities

a Urine culture is recommended for directing targeted effective therapy; urine Gram stain can assist in the initial selection of an antimicrobial agent.

b Susceptibility is <90% for E coli in most locations; thus, give ceftriaxone pending susceptibility data. If local susceptibilities are >90% or organism is known to be susceptible to TMP-SMX or fluoroquinolone, then ceftriaxone can be omitted.

c Complicated UTI (nosocomial, immunocompromised, or concomitant with structural or functional abnormalities or nursing home exposure).

Table 62. Empiric Therapy for Special Conditions

Syndrome

Empiric Antimicrobial Selectiona

Acute bacterial prostatitis

Treat with 1 of the following:

  • ciprofloxacin 500 mg oral bid for 4 weeks

  • levofloxacin 500 mg oral daily for 4 weeks

  • TMP-SMX DS oral bid for 4 weeksb

Chronic bacterial prostatitis

Treat with 1 of the following:

  • ciprofloxacin 500 mg oral bid for 6-12 weeks

  • levofloxacin 500 mg oral daily for 6-12 weeks

  • TMP-SMX DS oral bid for 6-12 weeksb

Relapse: Treat for 12 weeks

Failure: Consider suppression with TMP-SMX SS daily or nitrofurantoin 50 mg daily

Candiduria

Treat with the following:

  • Remove Foley catheter (resolves infection in 40% of patients)

  • Treat with fluconazole 200-400 mg daily for 7-14 days only if patient is symptomatic, is neutropenic, or has renal allograft or urologic instrumentation

For patients with fluconazole-resistant Candida:

  • Consider amphotericinc IV with or without oral flucytosine

Candida pyelonephritis

For patients with fluconazole-susceptible organisms:

  • fluconazole 400 mg (6 mg/kg) daily for 14 days

For patients with fluconazole-resistant Candida:

  • Consider amphotericin IV with or without oral flucytosine

a Urine or prostate fluid cultures are recommended for directing targeted effective therapy; urine Gram stain can assist in the initial selection of an antimicrobial agent.

b Empiric use of TMP-SMX or TMP alone is acceptable only if TMP-SMX resistance in the community is <20%.

c Use amphotericin B deoxycholate, as lipid amphotericin formulations do not penetrate urine well.

Soft Tissue Infections:

Nontoxigenic

Elements of Diagnosis

Clinical Diagnosis

  • Diagnosis is largely based on history and physical examination findings.

  • Approximately 70% of cellulitis cases involve the lower extremity.

  • Risk of recurrent cellulitis is common (at least 20% of patients).

  • Leukocytosis may or may not be present.

  • Blood cultures have low yields (about 2-4%).

  • Radiologic procedures generally are not needed, except to evaluate patients for osteomyelitis (eg, chronic infection, postsurgical infection, diabetic foot, plantar puncture wound with prolonged symptoms), deep-tissue abscess, or necrotizing process.

  • Epidemiologic findings may influence causative pathogens and thus the choice of antibiotic therapy.

  • For cellulitis, elevate involved area, if feasible, to reduce induration.

  • Skin abscess is largely due to Staphylococcus aureus, and many of these strains are CA-MRSA.

Marine or Water Exposure

β‎-Hemolytic streptococci and staphylococci are possible pathogens or copathogens of nontoxigenic soft tissue infections associated with marine or water exposure. Determine treatment on the basis of exposure history and culture data.

  • Saltwater or brackish water: Vibrio vulnificus

  • Freshwater: Aeromonas, Pseudomonas (also common with hot tubs), Plesiomonas, Edwardsiella, and Erysipelothrix

  • Fish tank or saltwater fish–related injury: Mycobacterium marinum (lymphadenitis)

Other Considerations

  • Use of macrolides: Not currently as useful an empiric therapy in penicillin-allergic patients because some strains of β‎-hemolytic streptococci are resistant.

  • CA-MRSA: Should be considered if the patient does not respond to oral β‎-lactam therapy, if other close contacts have been infected with this organism, or if the patient presents with purulence.

  • Skin abscess: Incision and drainage are very important for purulent infections.

  • Referral for management: Lymphedema, refractory tinea pedis, chronic dermopathies, or venous insufficiency.

  • Additional measures: May be required in cases of frequent recurrence, including possible chronic daily suppressive therapy with antibiotics; elimination or prevention of interdigital tinea pedis is important.

  • Osteomyelitis: Consider evaluation for osteomyelitis in cases of chronic infections, postsurgical infections, pressure ulcers, and plantar puncture wounds that are highly contaminated.

  • Plantar puncture wounds: Clean thoroughly, remove foreign bodies, and administer a tetanus vaccination (if not up to date); surgical drainage or débridement may also be needed.

Table 63. Treatment of Nontoxigenic Soft Tissue Infections

Syndrome and Common Pathogens

First-Line Treatment

Alternative Treatment

CELLULITIS OR ERYSIPELAS

Uncomplicated cellulitis; no known exposures (eg, to β‎-hemolytic streptococci or Staphylococcus aureus)

cefazolin, nafcillin, oxacillin, dicloxacillin, cephalexin, or cefadroxil

clindamycin, vancomycin, or doxycycline

CA-MRSA likely (eg, spider bite–like lesions, abscesses, exposure to persons with CA-MRSA, or nonresponding or recurrent furuncles or impetigo)

minocycline, doxycycline, TMP-SMX, or (with negative inducible-resistance test) clindamycin

Moderate to severe infection: vancomycin

Incision and drainage are important for purulent lesions

Moderate to severe infection: linezolid, daptomycin, tigecycline, ceftaroline, telavancin, dalbavancin, oritavancin, or tedizolid

Erysipelas (β‎-hemolytic streptococci, usually group A)

penicillin

cefazolin, cephalexin, cefadroxil, nafcillin, oxacillin, dicloxacillin, clindamycin, or vancomycin

Immunocompromised (β‎-hemolytic streptococci, S aureus, Pseudomonas aeruginosa and other gram-negative bacteria, fungi, viruses)

Empiric therapy depends on clinical presentation; modify on the basis of established etiology, cultures, and sensitivities

SKIN ABSCESS

S aureus (most common)

Incision and drainage are important for purulent lesions

minocycline, doxycycline, TMP-SMX, or (with negative inducible-resistance test) clindamycin

Moderate to severe infection: vancomycin

Moderate to severe infection: linezolid, daptomycin, tedizolid, ceftaroline, dalbavancin, oritavancin, telavancin

IMPETIGO

S aureus, group A streptococci

cefazolin, nafcillin, oxacillin, dicloxacillin, cephalexin, cefadroxil, minocycline, or topical mupirocin

β‎-lactam allergic or MRSA: vancomycin, linezolid, clindamycin (with negative inducible-resistance test), daptomycin, telavancin, dalbavancin, oritavancin, or tedizolid

WOUND INFECTION

Bite wounds (often polymicrobial: Pasteurella, Capnocytophaga, anaerobes, viridans group streptococci, Eikenella, Haemophilus)

ampicillin/sulbactam or amoxicillin/clavulanate

Wound cleaning is important

Tetanus vaccination (if not up to date)

One of the following: piperacillin/tazobactam, a carbapenem,a or moxifloxacin;

OR combination therapy with one of the following: levofloxacin, ciprofloxacin, TMP-SMX, a third- or fourth-generation cephalosporin, or doxycycline

PLUS one of the following: metronidazole or clindamycin

Surgical site

   Clean procedures: Staphylococcus and Streptococcus

Débridement plus antimicrobials based on surgical site and culture results (see Stevens DL, et alb)

   GI tract procedures: Intestinal flora

Débridement plus antimicrobials based on surgical site and culture results (see Stevens DL, et alb)

   Rapidly progressive infection in first 48 hours after surgery: Clostridium and Streptococcus pyogenes

Plantar puncture (S aureus, group A streptococci, gram-negative bacteria such as P aeruginosa)

Antibiotics should optimally be based on culture results

Empiric therapy: cefepime or levofloxacin

Tetanus vaccination (if not up to date)

moxifloxacin (if Pseudomonas is not found or suspected)

DIABETIC FOOT OR PRESSURE ULCER

Diabetic foot (often mixed aerobic and anaerobic infection)

β‎-lactam/β‎-lactamase inhibitorc plus glucose control

A carbapenema or tigecycline; OR a combination of metronidazole plus one of the following: moxifloxacin, levofloxacin, or cefepime

Pressure ulcers (often mixed aerobic and anaerobic infection; may include MRSA or VRE)

β‎-lactam/β‎-lactamase inhibitorc or a carbapenem

A fluoroquinolone plus metronidazole; OR cefepime plus metronidazole; OR tigecycline

MRSA: vancomycin, linezolid, daptomycin, ceftaroline, or telavancin

VRE: linezolid, daptomycin, or tigecycline

a The carbapenems include meropenem, imipenem, doripenem, and ertapenem.

b Stevens DL, et al. Clin Infect Dis. 2005 Nov 15;41(10):1373-406. Epub 2005 Oct 14. Erratum in: Clin Infect Dis. 2006 Apr 15;42(8):1219. Dosage error in article text. Clin Infect Dis. 2005 Dec 15;41(12):1830.

c The β‎-lactam/β‎-lactamase inhibitors include piperacillin/tazobactam, ampicillin/sulbactam, and amoxicillin/clavulanate.

Table 64. Treatment of Nontoxigenic Soft Tissue Infections Due to Marine or Water Exposure

Type of Therapy

First-Line Treatment

Alternative Treatment

Empiric therapy

A newer fluoroquinolone (moxifloxacin or gemifloxacin) or a third- or fourth-generation cephalosporin

A carbapenem,a β‎-lactam/β‎-lactamase inhibitor,b or (for Aeromonas, Plesiomonas, or Edwardsiella) TMP-SMX

Saltwater exposure: Add a tetracycline

. . .

Fish tank exposure: As above. If Mycobacterium marinum is suspected, consider rifampin plus ethambutol, with or without a fluoroquinolone

Fish tank exposure: doxycycline, minocycline, TMP-SMX, or clarithromycin (with or without rifampin)

Sewage exposure: Add metronidazole

. . .

Pathogen-directed therapy

See Table 34 on Specific Treatment of Bacterial Organisms and section on Nontuberculosis Mycobacterial Infections

a The carbapenems include meropenem, imipenem, doripenem, and ertapenem.

b The β‎-lactam/β‎-lactamase inhibitors include piperacillin/tazobactam, ampicillin/sulbactam, and amoxicillin/clavulanate.

Soft Tissue Infections:

Necrotizing or Toxigenic

Elements of Diagnosis

  • A high index of suspicion is critical for the diagnosis of necrotizing or toxigenic soft tissue infections.

  • Minor or major trauma can predispose patients to necrotizing soft tissue infections, which are more common in patients with obesity or diabetes mellitus and in immunocompromised patients.a

  • Necrotizing or toxigenic soft tissue infections should be considered in the differential diagnosis of patients with presumed cellulitis and extreme pain disproportionate to localized skin and soft tissue findings.

  • Symptoms include swelling, erythema, and pain. These may progress to tense edema, blisters, necrosis, crepitus, or subcutaneous gas.a

  • Systemic symptoms include tachycardia, fever, and hypotension progressing to shock.a Ultrasonography, computed tomography, and magnetic resonance imaging can be helpful in making a diagnosis, but immediate surgical consultation should be obtained when necrotizing fasciitis is suspected.

  • Laboratory abnormalities sometimes include increased creatine phosphokinase, creatinine, peripheral white blood cell count, C-reactive protein, erythrocyte sedimentation rate, and decreased albumin.

  • Blood cultures can be helpful in establishing an etiologic diagnosis, particularly when a β‎-hemolytic streptococcus is the cause.

Other Considerations

  • Necrotizing fasciitis and clostridial myonecrosis often require immediate and serial surgical débridement.

  • Complications include multiple organ failure or metastatic foci of infection.

  • Streptococcal toxic shock syndrome is a well-recognized complication of necrotizing soft tissue infection caused by β‎-hemolytic streptococci.

  • Intraoperative findings of necrotizing fasciitis include gray necrotic tissue, lack of bleeding, thrombosed vessels, dishwater pus, and lack of resistance to blunt finger dissection.a

  • Initial histopathologic findings of surgically resected tissues may be of prognostic importance. A poor neutrophilic response with numerous organisms seen on routine stains suggests a poor prognosis.

  • Despite aggressive treatment, 15-30% (or more) of patients affected by necrotizing fasciitis and clostridial myonecrosis may die.

  • Hyperbaric oxygen as a treatment has not been fully defined and is not routinely recommended.

  • Case cohort studies and case reports have suggested some benefit to treatment with intravenous immunoglobulin in specific circumstances (eg, streptococcal toxic shock). However, because of the lack of randomized controlled trials, intravenous immunoglobulin should probably be reserved for select patients.

  • Viridans group streptococci can cause toxic shock syndrome in severely immunocompromised patients (eg, bone marrow transplant patients with prolonged neutropenia).

  • Surgical exploration of the incision is needed when toxic shock syndrome occurs.

Table 65. Treatment of Soft Tissue Infections

Syndrome and Common Pathogens

First-Line Treatment

Alternative Treatment

TOXIC SHOCK SYNDROME

Staphylococcus aureus, β‎-hemolytic streptococci, viridans group streptococci

EITHER

cefazolin plus clindamycin

OR

nafcillin plus clindamycin

Combination therapy with one of the following (especially for suspected MRSA): vancomycin, linezolid, daptomycin, telavancin, or tigecycline

PLUS

clindamycin

NECROTIZING FASCIITIS

EMPIRIC THERAPY

Mixed flora (various anaerobic and aerobic bacteria), β‎-hemolytic streptococci (groups A, B, C, F, G), and CA-MRSA

Until the pathogen is identified, broad-spectrum empiric coverage should include clindamycin plus one of the following: ampicillin/sulbactam, piperacillin/tazobactam, or a carbapenema

For patients allergic to penicillin:

EITHER

   tigecycline plus a fluoroquinolone or clindamycin plus a fluoroquinolone

OR

   cefepime plus metronidazoleb plus clindamycin

If CA-MRSA is prevalent in local community: add vancomycin

If CA-MRSA: linezolid, daptomycin, telavancin, ceftaroline, or tigecycline

PATHOGEN-DIRECTED THERAPY

Type 1

Mixed aerobic and anaerobic infection; often seen in patients with severe trauma or diabetes mellitus (eg, Fournier gangrene)

Until the pathogen is identified, broad-spectrum empiric coverage should include clindamycin plus one of the following: ampicillin/sulbactam, piperacillin/tazobactam, or a carbapenema

tigecycline

For patients allergic to penicillin:

EITHER

   tigecycline plus a fluoroquinolone or clindamycin plus a fluoroquinolone

OR

   cefepime plus metronidazoleb plus clindamycin

Add clindamycin for its toxin-inhibiting properties

Type 2

β‎-Hemolytic streptococci (usually Streptococcus pyogenes)

penicillin G plus clindamycin

For patients allergic to penicillin: vancomycin plus clindamycin

cefazolin can be used when penicillin allergy does not produce an immediate reaction (eg, anaphylaxis, hives) plus clindamycin

Type 3

Myonecrosis due to Clostridium, especially C perfringens

penicillin plus clindamycin

Broader option for cases in which polymicrobial infection is of concern: ampicillin/sulbactam, piperacillin/tazobactam, or a carbapenema

penicillin plus tetracycline

Type 4

CA-MRSA

vancomycin

EITHER

linezolid, daptomycin, ceftaroline, telavancin, tigecycline

OR

clindamycin (if tested negative for inducible resistance)

a The carbapenems include meropenem, imipenem, doripenem, and ertapenem.

b Only for patients without life-threatening (immunoglobulin E–mediated) allergic reaction to penicillin.

Osteomyelitis

Elements of Diagnosis

  • Clinical: Localized pain and tenderness of involved bone; systemic signs and symptoms of acute hematogenous osteomyelitis.

  • Radiology: Bone destruction or sequestrum in chronic cases; use of nuclear scanning, MRI, or CT may aid diagnosis and staging.

  • Laboratory: White blood cell count is often normal; erythrocyte sedimentation rate and C-reactive protein are usually elevated.

Table 66. Treatment of Osteomyelitis in Adults with Normal Organ Function

Clinical Feature

First-Line Treatment

Alternative Treatment

EMPIRIC THERAPY (TYPICALLY COVERING STAPHYLOCOCCI AND STREPTOCOCCI)

Acute pain, swelling with fever, leukocytosis

cefazolin 1-2 g IV q8ha,b

  • vancomycin 15 mg/kg IV q12hb

  • daptomycin 6 mg/kg IV q24h

Wound drainage, painful surgical site, prior surgery

vancomycin 15 mg/kg IV q12hb

daptomycin 6 mg/kg IV q24hb; OR

linezolid 600 mg IV or oral q12hb

Chronic pain, ulceration, or swelling without systemic symptoms (eg, foot ulceration in patients with diabetes mellitus)

Establish diagnosis; define pathogen before determining treatment option

PATHOGEN-DIRECTED THERAPY

Staphylococcus

oxacillin sensitive

nafcillin or oxacillin 1.5-2.0 g IV q4-6h for 4-6 weeks; OR

cefazolin 1-2 g IV q8h for 4-6 weeks

vancomycin 15 mg/kg IV q12h for 4-6 weeks

oxacillin resistant

vancomycin 15 mg/kg IV q12h for 4-6 weeks

linezolid 600 mg oral or IV q12h for 4-6 weeks; OR

daptomycin 6 mg/kg IV q24h for 4-6 weeks

β‎-Hemolytic Streptococcus or penicillin-sensitive S pneumoniae

ceftriaxone 2 g IV or IM q24h for 4-6 weeks; OR

penicillin G 20×106 units IV per day either continuously or in 6 equally divided doses for 4-6 weeks; OR

cefazolin 1-2 g IV q8h for 4-6 weeks

vancomycin 15 mg/kg IV q12h for 4-6 weeks

Enterobacteriaceae

ceftriaxonec 2 g IV q24h for 4-6 weeks; OR

ciprofloxacin 500-750 mg oral q12h for 4-6 weeks

imipenem 500 mg IV q6h for 4-6 weeks; OR

meropenem 1 g IV q8h (or 500 mg IV q6h) for 4-6 weeks; OR

ertapenem 1 g IV q24h for 4-6 weeks; OR

aztreonam 1 g IV q8h for 4-6 weeks

Pseudomonas, Enterobacter

meropenem 1 g IV q8h or 500 mg IV q6h for 4-6 weeks; OR

imipenem 500 IV q6h for 4-6 weeks; OR

cefepime 2 g IV q8-12h for 4-6 weeks

ertapenem 1 g IV q24h for Enterobacter (not Pseudomonas)

ciprofloxacin 750 mg oral q12h for 4-6 weeks; OR

ceftazidimec 2 g IV q8h for 4-6 weeks; OR

aztreonam 1-2 g IV q8h for 4-6 weeks

Polymicrobial infection (eg, diabetic foot)

Treatment depends on type and severity; refer to published guidelines in Lipsky et ald

a Consider using vancomycin in clinical situations with a high risk of methicillin-resistant S aureus or if the patient is hemodynamically unstable.

b Consider addition of gram-negative coverage in ill-appearing, hemodynamically unstable, or immunocompromised patients.

c Avoid use for organisms that produce ESBLs or for organisms that may have inducible β‎-lactamases (eg, Enterobacter).

d Lipsky BA, et al. Clin Infect Dis. 2012 Jun;54(12):e132-73.

Other Considerations

Surgery

Chronic osteomyelitis typically requires surgical débridement. To medically manage acute and chronic osteomyelitis when triaging, consult with a surgeon who manages bone and joint infections.

Therapy for Specific Scenarios

  • Hardware retained: Consider chronic suppression until fusion.

  • Vertebral osteomyelitis: Medical management alone may be sufficient.

  • Sternal osteomyelitis (eg, poststernotomy): Surgical débridement is often required.

Management of Complications

  • No clinical or laboratory improvement: Reassess diagnosis and adequacy of surgical débridement.

  • Recurrence of infectious syndrome: Consider the possibility that the patient has received suboptimal medical treatment; reassess adequacy of surgical débridement; and consider removal of any hardware.

Native Joint Infection

Elements of Diagnosis and Management

  • Clinical: Acute monoarticular swelling, typically of a large joint, with fever and pain.

  • Radiology: Normal osseous structures (early) with soft-tissue swelling.

  • Laboratory: Elevated leukocytes, erythrocyte sedimentation rate, and C-reactive protein.

  • Arthrocentesis: >50,000-100,000 leukocytes/mL (predominantly neutrophils), absence of crystals, Gram stain often negative; total cell count may be lower in partially treated patients or in selected immunocompromised states; infection and crystal-induced disease may coexist.

  • Consultation: Consider consultation with an orthopedic and infectious diseases specialist.

Table 67. Treatment of Acute Joint Infection in Adults with Normal Organ Function

Clinical Feature or Pathogen

First-Line Treatment

Alternative Treatment

INITIAL EMPIRIC THERAPYa

Acute joint swelling with fever, leukocytosis, and joint pain; no prior surgery

vancomycin 15 mg/kg IV q12hb

daptomycin 6 mg/kg IV q24hb or linezolid 600 mg IV or oral q12hb

Wound drainage, painful joint, prior surgery

vancomycin 15 mg/kg IV q12hb

daptomycin 6 mg/kg IV q24hb or linezolid 600 mg IV or oral q12hb

Polyarticular synovitis with rash in a young, sexually active patient (suspect disseminated Neisseria gonorrhoeae)

ceftriaxone 2 g IV q24h

ciprofloxacin (note increasing quinolone resistance to N gonorrhoeae) 500 mg oral q12h or 400 mg IV q12hc; or cefotaxime 1-2 g IV q8h

Chronic monoarticular swelling without systemic symptoms

Establish diagnosis before determining treatment

Gram stain positive

Treat as for Staphylococcus if gram-positive cocci are identified

Treat as for Pseudomonas if gram-negative bacilli are identified

PATHOGEN-DIRECTED THERAPYa

Staphylococcus aureus

    oxacillin sensitive

EITHER

nafcillin or oxacillin 2 g IV q4-6h for 3-4 weeks

OR

cefazolin 1-2 g IV q8h for 3-4 weeks

vancomycin 15 mg/kg IV q12h for 3-4 weeks

    oxacillin resistant

vancomycin 15 mg/kg IV q12h for 3-4 weeks

EITHER

linezolid 600 mg oral or IV q12h for 3-4 weeks

OR

daptomycin 6 mg/kg IV q24h for 3-4 weeks

β‎-Hemolytic streptococci or penicillin-sensitive pneumococci

ceftriaxone 2 g IV q24h for 2-3 weeks

OR

vancomycin 15 mg/kg IV q12h for 2-3 weeks

penicillin G 20,000 units per day IV either continuously or in 6 equally divided doses for 2-3 weeks

OR

cefazolin 1-2 g IV q8h for 2-3 weeks

Enterobacteriaceae

EITHER

ceftriaxoned 2 g IV q24h for 3-4 weeks

OR

ciprofloxacin 500-750 mg oral q12h for 3-4 weeks

EITHER

ertapenem 1 g IV q24h for 3-4 weeks

OR

aztreonam 1-2 g IV q8h for 3-4 weeks

Pseudomonas

EITHER

cefepime 2 g IV q8-12h for 3-4 weekse

OR

meropenem 1 g IV q8h for 3-4 weeks

EITHER

ciprofloxacin 750 mg oral q12h for 3-4 weeks

OR

ceftazidimed 2 g IV q8h for 3-4 weeks

a Adult doses for normal organ function and antimicrobial selection should be based on drug susceptibility testing.

b Consider the addition of gram-negative coverage in ill-appearing, hemodynamically unstable, or immunocompromised patients.

c Resistance in N gonorrhoeae is increasing in several regions and among men who have sex with other men; antimicrobial drug susceptibility testing should be performed. This suggestion pertains to oral and IV administration.

d Avoid use for organisms that produce extended-spectrum β‎-lactamases or for organisms that may have inducible β‎-lactamase (eg, Enterobacter, Citrobacter, Serratia).

e Neutropenia may be a concern for a prolonged treatment course.

Table 68. Management of Complications

Complicating Factors

Management

No clinical or laboratory improvement

Reassess diagnosis, consider noninfectious causes, exclude concomitant crystal arthritis, consider atypical or other organisms, consider surgical consultations for initial or repeat débridement

Periarticular osteomyelitis

Consider surgical débridement

Recurrence of infectious syndrome

Consider reassessing medical treatment, reassess adequacy of surgical débridement, exclude periarticular osteomyelitis

Long-term postseptic degenerative arthritis

Consider total joint arthroplasty

Table 69. Therapy for Specific Scenarios

Scenario

Management

Presence of prosthetic joint

See Prosthetic Joint Infection section

Septic arthritis after an animal bitea

Consider 1 of the following: piperacillin/tazobactam 3.375 g IV q6h, ampicillin/sulbactam 3 g IV q6h, or a carbapenemb

Immunocompromised host or standard bacterial cultures that are negative

Consider evaluating for fungal or mycobacterial organisms and treating as necessary

a Need to cover common animal mouth flora, including Pasteurella, Capnocytophaga, Fusobacterium, streptococci, etc.

b The carbapenems include meropenem, imipenem, ertapenem, or doripenem.

Prosthetic Joint Infection

Elements of Diagnosis and Management

  • Clinical: Acute, chronic, or subacute pain; fever and swelling are present in acute infection; postoperative persistent wound drainage or sinus tract formation can occur in early postoperative or chronic infection.

  • Radiology: Periprosthetic lucency may occur with chronic presentation.

  • Laboratory: Often normal leukocytes, elevated erythrocyte sedimentation rate, and elevated C-reactive protein.

  • Arthrocentesis: Elevated synovial leukocyte count (>1,700-10,000 leukocytes/μ‎L; >65% neutrophils); total cell count may be lower with total shoulder arthroplasty and in partially treated patients or in select immunocompromised states; Gram stain often negative.

  • Intraoperative findings: Purulence and acute inflammation upon histopathologic tissue examination.

  • Microbiology: A pathogen is isolated from culture from at least 2 separate tissue or fluid samples obtained from the affected joint (3-6 samples typically are obtained); ultrasonicate fluid from an explanted prosthesis may also be cultured.

  • Consultation: Consultation with an orthopedic and infectious disease specialist is highly recommended; antimicrobial therapy should be temporarily withheld, pending consultation, unless systemic illness or severe soft-tissue infection is present.

Table 70. Treatment of Prosthetic Joint Infections in Adults with Normal Organ Function

Clinical Feature or Pathogen

Surgical Therapy

First-Line Treatment

Alternative Treatment

INITIAL EMPIRIC MEDICAL THERAPYa,b

Acute septic arthritis syndrome

Débridement and retention of prosthesis

vancomycin 15 mg/kg IV q12h

daptomycin 6 mg/kg IV q24h or linezolid 600 mg IV or oral bid

Early postoperative infection

Débridement and retention of prosthesis

vancomycin 15 mg/kg IV q12h

daptomycin 6 mg/kg IV q24h or linezolid 600 mg IV or oral bid

Chronic pain or prosthesis loosening

Resection arthroplasty, with or without delayed reimplantation

vancomycin 15 mg/kg IV q12h

daptomycin 6 mg/kg IV q24h or linezolid 600 mg IV or oral bid

RESECTION, WITH OR WITHOUT DELAYED REIMPLANTATION: PATHOGEN-DIRECTED THERAPYa

Staphylococcus aureus

oxacillin sensitive

Resection with or without delayed reimplantation

nafcillin or oxacillin 2 g IV q4-6h for 4-6 weeks

vancomycin 15 mg/kg IV q12h for 4-6 weeks

OR

cefazolin 1-2 g IV q8h for 4-6 weeks

OR

ceftriaxonec 2 g IV q24h for 4-6 weeks

oxacillin resistant

Resection with or without delayed reimplantation

vancomycin 15 mg/kg IV q12h for 4-6 weeks

EITHER

linezolid 600 mg oral or IV q12h for 4-6 weeks

OR

daptomycin 6 mg/kg IV q24h for 4-6 weeks

β‎-Hemolytic streptococci

Resection with or without delayed reimplantation

ceftriaxone 2 g IV q24h for 4-6 weeks

vancomycin 15 mg/kg IV q12h for 4-6 weeks

OR

penicillin G 20,000 units/day IV either continuously or in 6 equally divided doses for 4-6 weeks

OR

cefazolin 1-2 g IV q8h for 4-6 weeks

Enterobacteriaceae

Resection with or without delayed reimplantation

EITHER

ceftriaxoned 2 g IV q24h for 4-6 weeks

OR

ciprofloxacin 500-750 mg oral bid for 4-6 weeks

EITHER

ertapenem 1 g IV q24h for 4-6 weeks

OR

aztreonam 1-2 g IV q8h for 4-6 weeks

Pseudomonas

Resection with or without delayed reimplantation

EITHER

cefepime 2 g IV q8-12h for 4-6 weeks

OR

meropeneme 1 g IV q8h for 4-6 weeks

EITHER

ciprofloxacin 750 mg oral bid for 4-6 weeks

OR

ceftazidimed 2 g IV q8h for 4-6 weeks

a Adult doses for normal organ function and antimicrobial selection should be based on drug susceptibility testing.

b Consider the addition of gram-negative coverage in ill-appearing, hemodynamically unstable, or immunocompromised patients.

c There is no consensus on the use of ceftriaxone for methicillin-susceptible S aureus prosthetic joint infection.

d Avoid use for organisms that produce extended-spectrum β‎-lactamases or for organisms that may have inducible β‎-lactamase (eg, Enterobacter, Citrobacter, Serratia).

e Other antipseudomonal carbapenems are acceptable.

Data from Osmon DR, et al. Clin Infect Dis. 2013 Jan;56(1):1-10.

Table 71. Débridement, Antibiotics, and Implant Retention; One-Stage Exchange; or Positive Intraoperative Cultures

Organism

First-line Treatment

Alternative Treatment

PATHOGEN-DIRECTED THERAPYa

Staphylococcus aureus

    oxacillin sensitive

nafcillin or oxacillin 2 g IV q4-6h for 4-6 weeks

OR

cefazolin 1-2 g IV q8h for 4-6 weeks

OR

ceftriaxoneb 2 g IV q24h for 4-6 weeks

AND each of the above with

rifampin 300-450 mg oral bid for 4-6 weeks

vancomycin 15 mg/kg IV q12h for 4-6 weeks

AND

rifampin 300-450 mg oral bid for 4-6 weeks

FOLLOWED BY

Companionc drug with rifampin for 1.5 months (hip) or 4.5 months (knee)

FOLLOWED BY

Companionc drug with rifampin for 1.5 months (hip) or 4.5 months (knee)

FOLLOWED BY

Chronic oral suppressiond (see Table 72)

FOLLOWED BY

Chronic oral suppressiond (see Table 72)

    oxacillin resistant

vancomycin 15 mg/kg IV q12h for 4-6 weeks

EITHER

linezolid 600 mg oral or IV q12h for 4-6 weeks

OR

daptomycin 6 mg/kg IV q24h for 4-6 weeks

AND

AND each with

rifampin 300-450 mg oral bid for 4-6 weeks

rifampin 300-450 mg oral bid for 4-6 weeks

FOLLOWED BY

FOLLOWED BY

Companionc drug with rifampin for 1.5 months (hip) or 4.5 months (knee)

Companionc drug with rifampin for 1.5 months (hip) or 4.5 months (knee)

FOLLOWED BY

FOLLOWED BY

Chronic oral suppressiond (see Table 72)

Chronic oral suppressiond (see Table 72)

β‎-Hemolytic streptococci

ceftriaxone 2 g IV q24h for 4-6 weeks

OR

penicillin G 20,000 units per day IV either continuously or in 6 equally divided doses for 4-6 weeks

OR

cefazolin 1-2 g IV q8h for 4-6 weeks

FOLLOWED BY

Chronic oral suppressiond (see Table 72)

vancomycin 15 mg/kg IV q12h for 4-6 weeks

Enterobacteriaceae

EITHER

EITHER

ceftriaxonee 2 g IV q24h for 4-6 weeks

ertapenem 1 g IV q24h for 4-6 weeks

OR

OR

ciprofloxacin 500-750 mg oral bid for 4-6 weeks

aztreonam 1-2 g IV q8h for 4-6 weeks

FOLLOWED BY

FOLLOWED BY

Chronic oral suppressiond (see Table 72)

Chronic oral suppressiond (see Table 72)

Pseudomonas

EITHER

EITHER

cefepime 2 g IV q8-12h for 4-6 weeks

ciprofloxacin 750 mg oral bid for 4-6 weeks

OR

OR

meropenemf 1 g IV q8h for 4-6 weeks

ceftazidimee 2 g IV q8h for 4-6 weeks

FOLLOWED BY

FOLLOWED BY

Chronic oral suppressiond (see Table 72)

Chronic oral suppressiond (see Table 72)

a Adult doses for normal organ function and antimicrobial selection should be based on drug susceptibility testing.

b There is not consensus on the use of ceftriaxone for methicillin-susceptible S aureus prosthetic joint infection.

c Companion drugs for methicillin-susceptible S aureus include levofloxacin; others are based on susceptibility testing, allergies, and intolerances.

d There is not consensus on the use of chronic suppression.

e Avoid use for organisms that produce extended-spectrum β‎-lactamases or for organisms that may have inducible β‎-lactamase (eg, Enterobacter, Citrobacter, Serratia).

f Other antipseudomonal carbapenems are acceptable.

Data from Osmon DR, et al. Clin Infect Dis. 2013 Jan;56(1):1-10.

Table 72. Drugs Used in Chronic Oral Suppression

Organism

First-line Treatment

Alternative Treatment

Staphylococci

oxacillin sensitive

cephalexin, cefadroxil

dicloxacillin, amoxicillin/clavulanate, clindamycin, TMP-SMX, doxycycline, minocycline

oxacillin resistant

TMP-SMX, doxycycline, or minocycline

. . .

β‎-Hemolytic staphylococci

penicillin V or amoxicillin

cephalexin or cefadroxil

Enterococci

penicillin V or amoxicillin

. . .

Pseudomonas

ciprofloxacin

. . .

Enterobacteriaceae

TMP-SMX

Oral second- or third-generation cephalosporin

Propionibacterium spp

penicillin V or amoxicillin

Oral first-generation cephalosporin, doxycycline, or minocycline

Adapted from Osmon DR, et al. Clin Infect Dis. 2013 Jan;56(1):1-10. Used with permission.

Suggested Reading

Osmon DR, et al. Clin Infect Dis. 2013 Jan;56(1):1–10.Find this resource:

Parvizi J, et al. Bone Joint J. 2013 Nov;95-B(11):1450–2.Find this resource:

Workgroup Convened by the Musculoskeletal Infection Society. J Arthroplasty. 2011 Dec;26(8):1136–8.Find this resource:

Gastrointestinal Infections

Orofacial Infections, Esophagitis, and Gastritis

Elements of Diagnosis

Orofacial Infections

  • Ludwig angina: Acute soft-tissue infection, usually of dental origin; spreads rapidly and is bilateral; involves submandibular and sublingual spaces and can spread to the neck; may include respiratory obstruction from edema.

  • Acute necrotizing ulcerative gingivitis (eg, Vincent angina, trench mouth): Mixed bacterial infection with gingival ulcerations and gingival breakdown, usually due to poor dental hygiene.

  • Lemierre syndrome: Suppurative jugulovenous thrombophlebitis, pharyngitis, and bacteremia, with potential for abscess formation and extension to mediastinum or septic pulmonary emboli; Fusobacterium necrophorum is the most common pathogen isolated.

  • Peritonsillar abscess (quinsy): Usually due to group A streptococci, often with anaerobic bacteria; often results in enlarged displaced tonsils, severe pharyngeal pain, dysphagia.

Esophagitis

  • More common in immunocompromised patients: HIV infection, hematologic malignancy, postchemotherapy, organ transplantation.

  • Most common pathogens: Candida (especially C albicans), HSV, CMV.

  • Less common pathogens: Histoplasma capsulatum, Blastomyces dermatitidis, Mycobacterium tuberculosis (and other Mycobacterium), Actinomyces.

  • Noninfectious causes: Gastroesophageal reflux disease, radiotherapy, antineoplastic chemotherapy, aphthous ulcers (in 5% of patients with AIDS and also in some patients with acute HIV infection).

  • Symptoms: Odynophagia, dysphagia, and substernal chest pain; oral thrush common with HIV-associated candidal esophagitis; pain common with HSV and CMV esophagitis.

Helicobacter pylori Gastric and Peptic Ulcer Disease

  • H pylori colonization and infection are more common with increasing age and in developing countries.

  • H pylori gastric colonization is associated with a 3- to 4-fold increase in the risk of gastric or duodenal ulceration; more than 90% of duodenal ulcerations are associated with H pylori infection (in the absence of drug-associated causes).

  • H pylori–associated chronic gastritis is considered a risk factor for development of gastric carcinoma and gastric mucosa−associated lymphoid tissue.

  • Diagnosis of H pylori infection can be made by endoscopy and biopsy or by noninvasive techniques such as serologic analysis, breath test, or fecal antigen analysis.

Table 73. Treatment of Gastrointestinal Infections: Oropharyngeal Infections, Esophagitis, and Gastritis

Syndrome or Common Pathogen

First-Line Treatment

Alternative Treatment

TREATMENT OF OROPHARYNGEAL INFECTIONS

Ludwig angina

   Viridans group streptococci or other streptococci, Fusobacterium, Bacteroides, Actinomyces

ampicillin/sulbactam, amoxicillin/clavulanate, piperacillin/tazobactam, or a carbapenem

EITHER

penicillin G plus metronidazole

OR

clindamycin

Acute ulcerative or necrotizing gingivitis

   Bacteroides, Fusobacterium, spirochetes, viridans group streptococci or other streptococci

See above

See above

Lemierre syndrome

   F necrophorum, Bacteroides

See above

See above

Peritonsillar abscess

   Group A streptococci, anaerobes

See above

See above

TREATMENT OF ESOPHAGITIS*

Candidaa

fluconazole

itraconazole, an echinocandin,b voriconazole, an amphotericin B product

HSVa

acyclovir, valacyclovir, famciclovir

foscarnet (for acyclovir-resistant strains)

CMV

IV ganciclovir, valganciclovir

foscarnet

Aphthous ulcers

prednisone

thalidomide

TREATMENT OF GASTRITIS

H pylori

A PPI plus amoxicillin and clarithromycin

For patients with penicillin allergy: A PPI plus metronidazole and clarithromycin

For patients with macrolide allergy: A PPI plus amoxicillin and metronidazole

One of the following combinations:

bismuth, metronidazole, tetracycline, and a PPI; OR

A PPI plus levofloxacin and amoxicillin; OR

A PPI plus rifabutin and amoxicillin

a Suppressive therapy may be needed after treatment for patients with AIDS and patients with marked immunosuppression.

b Echinocandins include caspofungin, micafungin, and anidulafungin.

* Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. Vol 1. 7th ed. Elsevier Churchill Livingstone; c2010. pp. 1335-7.

Diarrhea

Elements of Diagnosis

Noninflammatory Diarrhea

  • Site: Predominantly in the small intestine

  • Stool volume: Large, watery diarrhea

  • Fecal leukocytes: No

  • Common organisms

    • Bacteria: Vibrio cholerae, ETEC, Bacillus cereus, Staphylococcus aureus, Clostridium perfringens (type A enterotoxin)

    • Viruses: Rotavirus, Calicivirus, Norwalk-like viruses, adenovirus, Astrovirus

    • Parasites: Giardia lamblia, Cryptosporidium

Inflammatory Diarrhea

  • Site: Predominantly in the colon

  • Stool volume: Small

  • Fecal leukocytes: Yes

  • Common organisms

    • Bacteria: Shigella, Salmonella, Campylobacter jejuni, Vibrio parahaemolyticus, EIEC, E coli O157:H7 (enterohemorrhagic), Clostridium difficile (cytotoxin), M tuberculosis

    • Viruses: CMV

    • Parasites: Entamoeba histolytica, Schistosoma japonicum, S mansoni

Invasive Enteric Infections with Secondary Dissemination

  • Sites: Ileum, colon

  • Stool volume: Small

  • Fecal leukocytes: Yes

  • Common organisms

    • Bacteria: Salmonella enterica serotype Typhi (formerly S typhi), Yersinia enterocolitica, Vibrio vulnificus, Listeria monocytogenes, Brucella, Tropheryma whippelii (small-bowel predominance with T whippelii)

    • Parasites: E histolytica, Strongyloides stercoralis, Trichinella spiralis

Evaluation of Food-Borne Diarrhea1

  • Vomiting: Primary symptom, possibly with diarrhea

    • Viral gastroenteritis: Rotavirus, Norovirus, other caliciviruses

    • Preformed bacterial toxins (short incubation period [<6 hours]): S aureus toxin, Bacillus toxin

  • Noninflammatory diarrhea: Acute watery diarrhea without fever or dysentery; sometimes accompanied by fever

    • Viral gastroenteritis: Astrovirus, Norovirus, other caliciviruses, enteric adenovirus, Rotavirus

    • Bacteria: ETEC, V cholerae

    • Parasites: G lamblia, Cryptosporidium, Cyclospora cayetanensis

  • Inflammatory diarrhea: Invasive disease; possibly fever and (on gross examination) bloody stools

    • Bacteria: Campylobacter, Shigella, Salmonella, EIEC, V parahaemolyticus, E coli O157:H7, Y enterocolitica

    • Parasites: E histolytica

  • Seafood ingestion: Vibrio, Anisakis, and other genera

    • Persistent (≥14 days) diarrhea: Especially common in travelers to mountainous regions or areas with untreated water

    • Parasites: C cayetanensis, E histolytica, Cryptosporidium, G lamblia

  • Neurologic manifestations: Paresthesia, respiratory depression, bronchospasm, cranial nerve palsy

    • Bacteria: Clostridium botulinum toxin, Campylobacter-associated Guillain-Barré syndrome

    • Other: Organophosphate pesticides, thallium poisoning

  • Fish and shellfish poisoning:

    • Scombroid (histamine) poisoning: In inadequately refrigerated fish, large amounts of histamine are produced by bacterial decarboxylation of histidine; commonly involved fish include tuna, mackerel, bonito, mahi-mahi, bluefish, marlin, swordfish, and others; symptoms typically include facial and neck flushing, urticaria over neck and upper torso, headache, dizziness, diarrhea, and nausea

    • Ciguatera: Caused by ingestion of select reef fish (including grouper, amberjack, snapper, moray eel, and barracuda) containing toxins produced by the dinoflagellate Gambierdiscus toxicus; symptoms generally include a combination of diarrhea, nausea, and vomiting, along with perioral and extremity paresthesias, temperature-related dysesthesias, and often a sensation of loose teeth

    • Paralytic shellfish poisoning and neurotoxic shellfish poisoning: Caused by neurotoxins produced by dinoflagellates (Gonyaulax catanella and G tamarensis for PSP and Gymnodinium breve for NSP); microorganisms may bloom into “red tides” and become concentrated in shellfish; PSP can produce nausea, vomiting, paresthesias, weakness, paralysis, and respiratory failure; NSP can produce nausea, temperature-related dysesthesias, dizziness, and ataxia

  • Systemic illness: Fever, weakness, arthritis, jaundice

    • Bacteria: L monocytogenes, S enterica serotype Typhi (formerly S typhi) and S paratyphi, Brucella, V vulnificus

    • Viral: Hepatitis A and hepatitis E

    • Parasites: T spiralis, Toxoplasma gondii, E histolytica with extraluminal abscess

Traveler’s Diarrhea

  • Bacterial causes: E coli (most commonly ETEC), Shigella, C jejuni, Salmonella, Aeromonas, Plesiomonas shigelloides, noncholera Vibrio

  • Nonbacterial causes: Rotavirus (Mexico), Norovirus (Mexico), Giardia (North America, Russia), Cryptosporidium, Cyclospora, and (rarely) Entamoeba

  • High-risk areas: Developing countries of Latin America, Asia, Africa, and the Middle East

  • Intermediate-risk areas: Southern Europe and some Caribbean islands

  • Low-risk areas: United States, Canada, northern Europe, Australia, New Zealand

Noninfectious Considerations

  • Secretory diarrhea: Carcinoid syndrome, Zollinger-Ellison syndrome, medullary carcinoma of the thyroid, villous adenoma of the rectum, vasoactive intestinal peptide-secreting pancreatic adenoma

  • Inflammatory diarrhea: Inflammatory bowel disease, ischemic colitis, radiation enteritis, eosinophilic gastroenteritis

Management and Empiric Therapy of Diarrhea

Community-Acquired Diarrhea

  • Rehydration for initial management.

  • Stool culture (with fever, bloody stools, or abdominal pain) for Salmonella, Shigella, Campylobacter, and E coli O157:H7; consider testing for community-acquired C difficile.

  • Empiric therapy (pending cultures) with a fluoroquinolone or (for suspected fluoroquinolone-resistant Campylobacter) a macrolide.

  • Avoid antimicrobial therapy if E coli O157:H7 is suspected (eg, bloody diarrhea with hemolytic uremic syndrome).

Traveler’s Diarrhea

  • Rehydration is the goal of initial management.

  • No fever or bloody stool.

    • Mild diarrhea of 1-2 loose stools per day: No treatment, or treatment with only bismuth or loperamide

    • Moderate to severe diarrhea of >2 loose stools per day: Hydration plus bismuth or loperamide; add a fluoroquinolone for high stool output in select cases (to shorten duration of diarrhea); rifaximin is also an option

  • Fever, bloody stool, abdominal pain: A fluoroquinolone for 3 days; stool culture, if possible.

Diarrhea >7 Days

  • Stool examination for Giardia, Cryptosporidium, Cyclospora, Isospora, and other parasites.

  • Consider noninfectious causes for culture-negative prolonged inflammatory diarrhea (eg, inflammatory bowel disease).

Clostridium difficile Infection–Associated Diarrhea

  • C difficile is the most common cause of infectious diarrhea in the health care setting; it is associated with 20-30% of cases of antibiotic-associated diarrhea and is the cause of antibiotic-associated pseudomembranous colitis.

  • C difficile is an opportunistic pathogen that colonizes the intestinal tract after an alteration in the normal enteric flora, typically after antimicrobial therapy.

  • Clindamycin, fluoroquinolones, and cephalosporins are commonly associated with the development of C difficile colitis; however, nearly any antimicrobial agent can lead to C difficile infection.

  • C difficile NAP1 strains are fluoroquinolone resistant, produce more toxin A and B, may lead to more severe disease or be more refractory to standard therapies, and are associated with disease outbreaks.

  • An important component of C difficile therapy is minimizing unnecessary antimicrobial usage, including stopping the suspected offending drug.

Table 74. Treatment Guidelines for Clostridium difficile Infection

Disease Classification

Treatmenta

Initial episode

Mild to moderate:

   Leukocytes <15×109/L or unchanged creatinine

metronidazole 500 mg oral tid for 10-14 days

Severe uncomplicated:

   Leukocytes ≥15×109/L or creatinine increased by 50%

vancomycin 125 mg oral qid for 10-14 days

Severe complicated, no ileus:

   Plus hypotension, shock, megacolon, or perforation; severe colitis on CT scan

vancomycin 500 mg oral qid plus metronidazole 500-750 mg IV q8h

Consider colectomy for severe disease, as appropriate

Severe complicated, with ileus:

   Plus hypotension, shock, megacolon, or perforation; severe colitis on CT scan

vancomycin 500 mg oral or by nasogastric tube qid plus metronidazole 500-750 mg IV q8h and vancomycin (intracolonic) rectal enema 500 mg in saline qid

Retention enema: An 18-inch Foley catheter with a 30-mL balloon is inserted into the rectum; the balloon is inflated and vancomycin is instilled; the catheter is clamped for 60 minutes, then deflated and removed

Consider colectomy for severe disease, as appropriate

First recurrence

Re-treat with the initial regimen that was effective; if severe, use the appropriate treatment regimen outlined above

Alternative: fidaxomicin 200 mg orally twice daily for 10 days

Second recurrence

vancomycin 125 mg oral every 6 hours for 10-14 days, then 125 mg every 12 hours for 7 days, then 125 mg once daily for 7 days, then 125 mg every 48 hours for 4 weeks

For more severe complicated disease: Combine oral vancomycin 500 mg every 6 hours with IV metronidazole 500 mg IV every 8 hours for 14 days; then oral vancomycin 125 mg every 12 hours for 7 days, then 125 mg once daily for 7 days, then 125 mg every 48 hours for 4 weeks

Alternative: fidaxomicin 200 mg orally twice daily for 10 days

Multiple relapses

Consider fecal replacement therapy

Fidaxomicin 200 mg orally twice daily for 10 days (if not used previously)

Longer taper of oral vancomycin followed by rifaximin 400 mg tid for 14 days

IV immunoglobulin 400 mg/kg once (unclear benefit)

Note: Limited evidence supports the routine use of adjunct probiotics to decrease recurrences in patients with C difficile infection

a Fidaxomicin is a newer FDA-approved drug that may result in fewer recurrences of non-NAP1 strains. Because of its high cost, its role in disease management is not yet clearly defined.

Adapted from Ask Mayo Expert. Clostridium difficile infection [Mayo Clinic Intranet]. Mayo Foundation; c2016 [cited 2016 Mar 4]. Available from: https://askmayoexpert.mayoclinic.org. Used with permission of Mayo Foundation for Medical Education and Research.

Suggested Reading

Cohen SH, et al. Infect Control Hosp Epidemiol. 2010 May;31(5):431–55.Find this resource:

Surawicz CM, et al. Am J Gastroenterol. 2013 Apr;108(4):478–98. Epub 2013 Feb 26.Find this resource:

Gerding DN, et al. Clin Infect Dis. 2008 Jan 15;46(Suppl 1):S32–42.Find this resource:

Intra-abdominal Infections

Peritonitis and Polymicrobial Intra-abdominal Infections

Elements of Diagnosis

Primary Peritonitis (Spontaneous Bacterial Peritonitis)

  • Peritoneal infection without an obvious source.

  • Adult patients with cirrhosis and ascites (higher risk associated with GI bleeding, previous spontaneous bacterial peritonitis, or low protein concentration in ascitic fluid); occasionally affects patients with congestive heart failure, malignancy, or connective tissue disease.

  • Pediatric patients with postnecrotic cirrhosis, nephrotic syndrome, or UTIs.

  • Ascitic fluid with >250/mm3 polymorphonuclear neutrophils; fever; diffuse abdominal pain; clinical presentation may be more insidious with progressive ascites.

Secondary Peritonitis

  • Peritoneal infection, commonly by communication with GI or genitourinary tract (eg, due to perforation, trauma, PID); suppurative or obstructive biliary tract infection; abdominal abscess.

  • Fever, marked abdominal pain, tenderness to palpation (focal or diffuse, often with rebound tenderness and muscle rigidity), peripheral and peritoneal fluid leukocytosis.

  • Prompt abdominal and pelvic CT scan (optimal for identification of source and definition of treatment); possible surgical options.

Peritonitis in Patients Receiving Peritoneal Dialysisa

  • Peritoneal infection usually is attributable to catheter contamination by common skin organisms; other causes include catheter exit-site infections, subcutaneous-tunnel infections, transient bacteremia, contamination of the dialysate delivery system, and transmural migration through an intact intestinal wall or vaginal leak.

  • Fever, abdominal pain, tenderness to palpation (focal or diffuse), nausea or vomiting, diarrhea, cloudy effluent with leukocyte count >100 cells/mm3, peripheral leukocytosis, effluent Gram stain (9-50%), positive culture (90-95%).

Peritoneal, Retroperitoneal, or Pelvic Abscess

  • Numerous potential sources such as primary or secondary peritonitis (especially due to enteric perforation), appendicitis, diverticulitis, inflammatory bowel disease, PID, abdominal or pelvic surgery (eg, repair of enteric or biliary anastomotic leak; splenectomy).

  • Commonly due to polymicrobial infections (especially from enteric or genitourinary source); monomicrobial infections (in the setting of hematogenous seeding of devitalized tissue; retroperitoneal extension of discitis or vertebral osteomyelitis).

  • Clinical presentation typically is based on location and source of infection.

  • Abdominal CT (ideal) or ultrasound can define location and potential source, can aid percutaneous drainage.

Appendicitis

  • Most common in older children and young adults in their teens and 20s.

  • Early symptoms are nonspecific and may include periumbilical or epigastric pain. Later, when the parietal peritoneum becomes inflamed, more focused right lower quadrant pain develops.

  • Any stage of infection may be accompanied by mild fever, anorexia, and nausea or vomiting. Guarding or rebound tenderness may occur on examination.

  • Pain in the right flank, right back, or right upper quadrant may occur when the inflamed appendix is retrocecal or when appendicitis occurs during pregnancy (second and third trimesters).

  • Diagnosis is by clinical examination, observation, diagnostic laparoscopy (8-25% negative appendectomy rate), CT imaging of the abdomen, ultrasonography (in young women, children, or pregnant women), or MRI.

  • Treatment of acute appendicitis is surgical appendectomy; nonoperative management of acute appendicitis is controversial.

  • More prolonged, broadened antimicrobial therapy is indicated in acute appendicitis with perforation, abscess formation, and chronic or recurrent appendicitis; surgery or drainage may be needed.

Diverticulitis

  • Increased dietary fiber and exercise inversely correlate with incidence of diverticulosis; diverticulitis indicates inflammation from microscopic or macroscopic perforation of a diverticulum into pericolic fat.

  • Left lower quadrant pain is common, whereas right-sided diverticulitis occurs in only 1-2% (more common in Asians); bleeding may occur.

  • CT of the abdomen is the diagnostic procedure of choice. Findings consistent with diverticulitis include pericolic fat stranding (98%), diverticula (84%), bowel wall thickening (70%), and phlegmon or abscess formation. Ultrasound can exclude gynecologic abnormalities in women of childbearing age. Colonoscopy can rule out cancer, inflammatory bowel disease, irritable bowel disease, or other conditions that mimic diverticulitis.

  • Uncomplicated diverticulitis can usually be managed with antibiotics alone, although as many as one-third of patients will have another episode. Lack of response with antimicrobial therapy within 48-72 hours should prompt additional investigation.

  • Complicated diverticulitis includes perforation, uncontrolled sepsis, lack of response to antibacterial therapy, obstruction, abscess, or fistula (to bladder or vagina); typical management is with both surgery and antimicrobial therapy.

  • Surgery is generally advised after a first attack of complicated diverticulitis or after 2 or more episodes of uncomplicated diverticulitis.

Hepatobiliary Infections

Elements of Diagnosis

Cholecystitis and Cholangitis

  • Cholecystitis (inflammation of the gallbladder): 20-50% complicated by infection. Gallstone disease is the most common cause of cholecystitis in the US. Complications include gangrenous cholecystitis, emphysematous cholecystitis, gallbladder empyema, pyogenic liver abscess, and bacteremia. Murphy sign (ie, inhibition of inspiration by pain during palpation over gallbladder) is often present and may be induced by the ultrasound transducer probing the gallbladder.

  • Cholangitis (inflammation or infection of the common bile duct): Commonly associated with obstruction or strictures of the biliary tract. Symptoms include fever and continuous right upper quadrant abdominal pain.

    • Acute or ascending cholangitis: Charcot triad (right upper quadrant or epigastric abdominal pain, fever or chills, and jaundice [50-70%]); with hypotension and confusion (Reynold pentad: <14%).

  • Abdominal ultrasound frequently establishes the diagnosis. Abnormal findings include thickened (>4 mm) gallbladder wall, pericholecystic fluid, and intramural gas or ductal dilatation suggestive of cholecystitis. Common bile duct dilatation or visible obstruction may suggest cholangitis. A hepatobiliary iminodiacetic acid scan can be helpful if the ultrasound is nondiagnostic—failure of the gallbladder to accumulate the marker is highly suggestive of acute cholecystitis caused by obstruction of the cystic duct. Abdominal CT may also identify gallstones within the cystic duct, gallbladder distention and mural thickening, and enhancement of the liver adjacent to the gallbladder (“rim sign”) or ductal obstruction.

Viral Hepatitis

Note: Refer to tables on hepatitis B and hepatitis C for more detail.

  • Hepatitis A virus: Fecal-oral spread (by contaminated food or water); usually self-limiting; acute viral hepatitis in 40-60% of infections (more common in adults); fulminant disease in 8% of patients; no chronic infection. For prevention, administer the HAV vaccine. For postexposure prophylaxis, HAV immunoglobulins are recommended for patients younger than 12 months or older than 40 years and for those with immunosuppressive conditions, chronic liver disease, or HAV vaccine allergy; HAV vaccine is recommended for immunocompetent patients 12 months to 40 years old.

  • Hepatitis B virus: Transmission is typically through an IV route or contaminated needlestick, through birth from an infected mother, or by sexual contact; acute hepatitis develops in 30-40% of infections; chronic disease in 10-25%; increased risk of cirrhosis and hepatocellular carcinoma occurs with chronic HBV disease. For prevention, administer the HBV vaccine series. For postexposure prophylaxis, administer HBV immunoglobulins and the HBV vaccine series, depending on HBV infection status of source and recipient’s HBV vaccination status (see section on Occupational Postexposure Prophylaxis and Management).

  • Hepatitis C virus: Transmission is typically by IV or contaminated needlestick; sexual transmission is less common but possible; HCV disease becomes chronic in 85%, with cirrhosis developing in 20% of those patients within 20 years; hepatocellular carcinoma risk is increased with HCV-mediated cirrhosis. No HCV vaccine or immunoglobulins currently are available.

  • Hepatitis D virus: Consists of a defective RNA virus that uses hepatitis B surface antigen as its structural shell (requires HBV coinfection or is a superinfection in patients with chronic HBV infection). More aggressive liver disease occurs when hepatitis D superinfects patients with chronic HBV infection, with development of chronic hepatitis in ≥75% and cirrhosis in 70-80%.

  • Hepatitis E virus: Not a chronic disease. Transmission is by fecal-oral route (usually by contaminated water). Pregnant women have a 15-25% mortality rate, especially in the third trimester.

Hepatosplenic Candidiasis

  • Manifestation of chronic disseminated candidiasis; more common in patients with hematologic malignancies after prolonged chemotherapy-associated neutropenia.

  • Common presentation includes persistent fever despite antibacterial agents, especially with recovering neutrophils; occasional right upper quadrant abdominal pain, anorexia, and nausea or vomiting.

  • Diagnosis is by abdominal CT or MRI (most sensitive); characteristic features are multiple small nodular hypolucent lesions throughout the liver and spleen during neutrophil recovery; lesions are commonly absent with neutropenia.

Hepatic Abscess

  • Sources include intestinal infections with portal circulation (40-50%; eg, pylephlebitis from diverticulitis, pancreatitis, omphalitis, irritable bowel disease, postoperative infection), biliary duct system infections (cholangitis caused by intraductal stones, tumor, occluded stent), bacteremia (infective endocarditis, line sepsis; 5-10%), contiguous infections (5-10%), trauma (0-5%), or idiopathic (20-40%).

  • Bacterial or pyogenic hepatic abscesses generally occur with acute fever and right upper quadrant abdominal pain. Amebic abscesses are similar to pyogenic abscesses, resulting in fever, dull right upper quadrant pain, and GI symptoms (15-35% have nausea or vomiting, abdominal cramping, or diarrhea).

  • Diagnosis is by abdominal CT or ultrasound (preferred with suspected biliary disease) for diagnostic aspiration (Gram stain, aerobic or anaerobic culture) and to define treatment options. Blood cultures are positive in 50%.

  • Amebic abscesses: E histolytica serology; aspirate is not usually required but may be useful when the infection does not respond to treatment, if a secondary bacterial infection must be excluded, or if there is imminent risk of rupture.

Splenic Abscess

  • Sources include hematogenous seeding (eg, infective endocarditis and other endovascular infections, often in the presence of emboli or hemoglobinopathy), trauma, or contiguous extension from adjacent infected tissue.

  • Clinical presentation can be quite variable—fever, abdominal pain, and splenomegaly may all be present. Persistent fever or bacteremia is suspicious for infective endocarditis.

  • Abdominal CT or ultrasound for diagnosis and to define treatment options.

Table 75. Treatment of Peritonitis and Polymicrobial Intra-abdominal Infectionsa

Syndrome and Common Pathogens

First-Line Empiric Treatment

Alternative Empiric Treatment

Primary peritonitis

Escherichia coli, Klebsiella, Streptococcus pneumoniae, other streptococci, and Enterococcus

ceftriaxone, cefotaxime, or cefepime, for 5 days unless pain persists, then re-tap and treat for 10-14 days)

If health care−acquired or MRSA and pseudomonas organisms are concerns, consider vancomycin plus either cefepime, ceftazidime, or piperacillin-tazobactam

Consider IE if bacteremic with typical IE organism

A carbapenem, piperacillin-tazobactam, levofloxacinb, moxifloxacinb (use with caution in patients with end-stage liver disease; caution with empiric fluoroquinolone use because most medical centers report <80% susceptible E coli)

Secondary peritonitis

Enteric flora, commonly polymicrobial (eg, Enterobacteriaceae,c other aerobic gram-negative bacilli, Bacteroides, other anaerobic bacteria; occasionally aerobic gram-positive bacteria and Candida)

Mild-moderate severityd: ceftriaxone or cefotaxime plus metronidazole; piperacillin-tazobactam

High risk or high severitye: piperacillin-tazobactam, cefepime plus metronidazole, or ceftazidime plus metronidazole

If an ESBL-producing Enterobacteriaceae or Acinetobacter is suspected, an antipseudomonal carbapenem is preferred: meropenem, doripenem, or imipenem-cilastatin

If MDR Pseudomonas is a highly prevalent organism in health care−associated infection, consider adding an aminoglycoside (gentamicin, tobramycin, or amikacin) until susceptibilities are available

cefoxitin, ertapenem,f tigecycline,f fluoroquinoloneb plus metronidazole (caution with empiric fluoroquinolone use because most medical centers report <80% susceptible E coli)

Include anti-MRSA therapy (vancomycin) if MRSA infection is recovered or suspected from known colonization, prior treatment failure, or significant antimicrobial exposure

Include anti−Enterococcus faecalis therapy (anti-Enterococcus β‎-lactam agent; or vancomycin for severe penicillin allergy) for patients with health care–associated intra-abdominal infection, including postoperative infection, patients who recently received cephalosporins, and patients who are clinically unstable

Surgical débridement or drainage may be required for source control

Duration of treatment is variable and based on source and surgical intervention, if any

For immunocompromised or unstable patients, or for patients with recent antibacterial therapy, consider adding an anti-Candida therapy (fluconazole for C albicans; or an echinocandin if a non-albicans species of Candida is recovered or suspected, or if the patient is unstable) until microbiology is defined

Peritoneal dialysis peritonitis

Gram-positive bacteria (60-80%): Staphylococcus epidermidis, S aureus, Streptococcus, diphtheroids

Gram-negative bacteria (15-30%): E coli, Klebsiella, Enterobacter, Proteus, Pseudomonas

Intraperitoneal antibiotic therapy is superior to IV therapy and is dosed either intermittently (once daily per exchange; allow to dwell at least 6 hours) or continuously (all exchanges) (see Table 76 “Antibiotic Intraperitoneal Dosage for Peritonitis During Peritoneal Dialysis in Anuric Patients”)

See peritoneal dialysis−associated infection treatment guidelinesg

Treatment duration is 10-21 days; clinical improvement can be expected within 48-96 hours

Empiric coverage should cover gram-positive bacteria (cefazolin or vancomycin [if seriously ill or if MRSA is a concern]) and gram-negative bacteria (ceftazidime, cefepime, or an aminoglycoside)

Less-common pathogens: Candida, Acinetobacter, anaerobes, atypical mycobacteria (M chelonae or M fortuitum), M tuberculosis, Aspergillus fumigatus, Nocardia asteroides, Fusarium

Indications for catheter removal: Relapsing or refractory peritonitis, intraperitoneal abscess, refractory exit-site or tunnel infection; or fungal peritonitis

Consider catheter removal if the patient is unresponsive to therapy for multiple enteric organisms or if the patient has mycobacterial peritonitis

. . .

Abdominal abscess

Depends on location and suspected source (usually polymicrobial, if source is the intestinal tract)

Percutaneous catheter drainage or surgical débridement to evacuate devitalized or avascular infected material; define microbiology and determine duration of antimicrobial therapy

Initial therapy same as for secondary peritonitis

Targeted antimicrobial therapy on the basis of culture data and suspected source

. . .

Appendicitis

Acute, uncomplicated, nonperforated (with luminal obstruction)

Immediate surgery and perioperative antimicrobial prophylaxis: Single preoperative dose of cefoxitin; piperacillin-tazobactam; cefazolin plus metronidazole; OR clindamycin plus 1 of the following: levofloxacin,b ciprofloxacin,b aztreonam, or an aminoglycoside

Other standard surgical wound prophylaxis regimens

With perforation or abscess formation

Same as for secondary peritonitis

. . .

Diverticulitis

Consider surgery for repeated episodes, perforation, or fistula

Otherwise, treat same as for secondary peritonitis

. . .

a Treatment modifications may be needed based on culture and susceptibility results.

bE coli,Solomkin JS, et al. Clin Infect Dis. 2010 Jan 15;50[2]:133-64

c Enterobacteriaceae group includes E coli, Klebsiella, Enterobacter, Citrobacter, Serratia, Yersinia, Salmonella, and Shigella.

d Defined as intestinal perforation or abscessed appendicitis, diverticulitis (community-acquired).

eSolomkin JS, et al. Clin Infect Dis. 2010 Jan 15;50[2]:133-64

f Usage of tigecycline and carbapenems should be reserved for either isolation of drug-resistant pathogens or in patients unable to tolerate other agents. Ertapenem lacks Pseudomonas and Enterococcus activity and is not appropriate for severe or nosocomial infections.

gLi PK-T, et al. Perit Dial Int. 2016 Jun 9;36(5):481-508. Epub 2016 Jun 9

Table 76. Antibiotic Intraperitoneal Dosage for Peritonitis During Peritoneal Dialysis in Anuric Patientsa

Intraperitoneal Dose Recommendations

Medication

Intermittent

(per Exchange, Once Daily)

Continuous

(All Exchanges)

Loading

Dose, mg/Lb

Maintenance

dose, mg/Lb

Aminoglycosidec

   gentamicin

0.6 mg/kg

8

4

   tobramycin

0.6 mg/kg

3

0.3

   amikacin

2 mg/kg

25

12

Cephalosporin

   cefazolin

15-20 mg/kg

500

125

   cefepime

1 g

250-500

100-125

   ceftazidime

1.0-1.5 g

500

125

   cefotaxime

0.5-1 g

500

125

Penicillin

   ampicillin

No data

. . .

125

   oxacillin

No data

. . .

125

   penicillin G

No data

50,000 units/L

25,000 units/L

   piperacillin-tazobactam

No data

4 g/0.5 g

1 g/0.125 g

Antifungal

   fluconazole

200 mg/L IP q24-48h

No data

No data

   voriconazole

2.5 mg/kg daily

No data

No data

Other

   ciprofloxacin

No data

. . .

50

   vancomycind

15-30 mg/kg every 5-7 dayse

30 mg/kg per bag

1.5 mg/kg per bag

   aztreonam

2 g daily

1,000

250

   ampicillin-sulbactam

2 g/1 g q12h

1,000

100

   meropenem

1 g daily

No data

No data

   imipenem

500 mg in alternate exchanges

250

50

   clindamycin

No data

. . .

600 mg/bag

   daptomycin

No data

100

20

   polymyxin B

No data

. . .

300,000 units (30 mg)/bag

a Anuric is defined as <100 mL/day urine output; for patients with >100 mL/day urine output, increase dose by 25%.

b Doses are in mg/L unless otherwise specified.

c For aminoglycosides, intermittent therapy is preferred. Repeated or prolonged aminoglycosides should be avoided if an alternative antibiotic is available.

d For vancomycin, intermittent therapy is preferred over continuous therapy.

e Supplemental doses may be needed in patients receiving automated peritoneal dialysis.

Li PK-T, et al. Perit Dial Int. 2016 Jun 9;36(5):481-508

Table 77. Treatment of Hepatobiliary Infections

Infection and Common Pathogen

First-Line Treatment

Alternative Treatment

Cholecystitis and cholangitis

Enterobacteriaceaea and other aerobic gram-negative bacilli; enterococci and other gram-positive bacteria; occasionally Bacteroides and other anaerobes

Same as for secondary peritonitis (Table 75)

Monotherapy with a 2nd-, 3rd-, or 4th-generation cephalosporin; tigecycline,b ertapenemb

Less common (biliary tract): Clonorchis sinensis, Opisthorchis felineus, O viverrini, Fasciola hepatica

Acute cholecystitis, when gangrene or perforation is suspected: Immediate cholecystectomy with intraoperative cholangiogram

Unstable patients: Delay definitive surgery (cholecystotomy preferred)

Acute cholangitis: Drainage of biliary tract endoscopically (endoscopic retrograde cholangiopancreatography has a 90% success rate), surgically, or transcutaneously; treatment of parasites affecting the biliary tree

. . .

Viral hepatitis

Refer to Hepatitis B and Hepatitis C tables for details (Tables 116-118)

Hepatosplenic candidiasis

Candida albicans most common

Initial therapy: Lipid formulation of amphotericin B OR an echinocandin (anidulafungin, caspofungin, micafungin) for several weeks

Step-down therapy: Oral fluconazole daily

For fluconazole-resistant isolates: voriconazole or posaconazole if susceptible or an echinocandin if azole resistant

Continue therapy until lesions have resolved or calcified on imagingc

amphotericin B deoxycholate may be used in resource-limited settings

Hepatic abscess (often polymicrobial)

Common: E coli, Klebsiella, Streptococcus anginosus group, Enterococcus, other viridans streptococci, Bacteroides

Uncommon: Other Enterobacteriaceae, Pseudomonas, S aureus, β‎-hemolytic streptococci, other anaerobes

Pyogenic liver abscesses require surgical or percutaneous drainage; antimicrobial therapy should cover suspected pathogens while awaiting microbiology results (see section above on “Cholecystitis and Cholangitis”)

Entamoeba histolytica

Amebic liver abscess (E histolytica): Typically does not require drainage; metronidazole or tinidazole and an agent (eg, paromomycin) to eliminate enteric carrier state

Splenic abscess

S aureus, S anginosus group, other streptococci, E coli, Salmonella, anaerobes

Other: Fungi (Candida, Aspergillus) in immunocompromised patients; Mycobacterium tuberculosis

Empiric antibiotic selection depends on the suspected source and should cover common pathogens

Consider splenectomy for complex multifocal, Candida, or multiloculated bacterial abscess and percutaneous drainage for localized abscess, although antifungal therapy may be sufficient for Candida abscesses

a Enterobacteriaceae group includes E coli, Klebsiella, Enterobacter, Citrobacter, Serratia, Yersinia, Salmonella, and Shigella.

b Usage of tigecycline and carbapenems should be reserved for either isolation of drug-resistant pathogens or in patients unable to tolerate other agents.

cPappas PG, et al. Clin Infect Dis. 2016 Feb 15;62(4):e1-50. Epub 2015 Dec 16

Management of the Febrile Neutropenic Patient

Elements of Diagnosis

  • Fever: Single oral temperature ≥38.3°C (101°F) or a temperature ≥38.0°C (100.4°F) for ≥1 hour.

  • Neutropenia: An ANC of <500 cells/mm3 or ANC expected to decrease to <500/mm3 in the next 48 hours.

    • Severe neutropenia: ANC of <100 cells/mm3

Managerial Approach

  • Prompt clinical assessment and timely initiation of appropriate antimicrobial therapy are required.

  • Selection of appropriate antimicrobial therapy should be based on a number of factors.

    • Infection risk (high vs low); other medical comorbidities

    • The syndrome suspected of causing the fever, which further defines the potential infectious organisms

    • Colonization or prior infection with resistant bacteria (eg, MRSA, VRE, carbapenem-resistant Enterobacteriaceae, etc)

    • Concurrent antimicrobial prophylaxis and other recent antimicrobial therapies

    • Local hospital or clinic antibiograms (to identify patterns of drug resistance for select organisms)

    • Empiric antimicrobial therapy that generally includes anti-Pseudomonas activity

    • Preferable usage of bactericidal therapy when possible

Commonly Encountered Pathogens

Note: Type of pathogen causing the infection depends upon the timing of symptom onset, suspected source of infection, associated syndrome, or a combination of these elements.

  • Bacteria

    • Enterobacteriaceae (eg, Escherichia coli, Klebsiella, Enterobacter)

    • Nonfermenting gram-negative bacilli (eg, Pseudomonas aeruginosa, Acinetobacter, Stenotrophomonas maltophilia)

    • Gram-positive cocci (eg, Staphylococcus aureus, coagulase-negative staphylococci,a streptococci, enterococci)

    • Gram-positive bacilli (eg, Bacillus, Corynebacterium)a

  • Fungi

    • Candida spp

    • Aspergillus

    • Agents causing mucormycosis (eg, Rhizopus, Mucor)

    • Less-common organisms (eg, Fusarium, Scedosporium)

Initial Diagnostic Evaluation

  • Review exposure history, recent anti-infective therapy, and medications.

  • Conduct a physical examination, with particular attention to the pharynx, skin, IV access sites, lungs, sinuses, mouth, esophagus, and perianal area.

  • Perform laboratory tests, including complete blood cell count, liver function tests, and creatinine.

  • Obtain blood and urine cultures.

  • Order other cultures, depending on clinical circumstances.

  • Obtain a chest radiograph.

  • Conduct further site-specific imaging studies, as clinically indicated.

  • Consider Aspergillus galactomannan antigen and/or (1,3)-β‎-d-glucan testing in high-risk patients, as clinically indicated.

Defining the Relative Risk for Severe Infection, Complications of Infection, and Death for Patients with Fever and Neutropenia

High Risk

  • Sustained, severe neutropenia (ANC of <100 cells/mm3), anticipated to last >1 week.

  • Clinical instability, including hypotension, uncontrolled pain, etc.

  • Associated or contributing clinical conditions.

    • Oral, enteric, or colonic mucositis that interferes with eating, drinking, swallowing, or enteric absorption; or mucositis that causes severe diarrhea

    • New pulmonary infiltrates or respiratory insufficiency

    • New alterations in mental status

    • Complex, central intravascular catheter infections, especially tunnel infections

    • Hepatic insufficiency (eg, hepatic transaminases >5-fold higher than normal values)

    • Renal insufficiency (eg, ClCr <30 mL/min)

  • Presence of medical comorbidities, including uncontrolled or progressive cancer, chronic obstructive pulmonary disease, advanced age, poor functional status, etc.

  • Select hematologic cancers and associated treatments.

    • Acute leukemia, including patients receiving induction or consolidation chemotherapy

    • Allogeneic stem cell transplants, including haplo-identical and cord-blood transplants

Low Risk

  • Neutropenia expected to resolve within 1 week (usually includes patients receiving standard chemotherapy for most solid-tissue cancers).

  • Clinically or hemodynamically stable.

Multinational Association for Supportive Care in Cancer Risk Index Score

  • An alternative approach of identifying patients with high or low risk of infection-related complications and death.

  • Validated scoring system for assessing patient risk.

Table 78 shows an alternative approach, using a validated scoring system, to identify patients with high or low risk of infection-related complications and death.

Table 78. Multinational Association for Supportive Care in Cancer Risk-Index Score (MASCC) Patient Risk Assessment Systema

Characteristic

Weight

Burden of febrile neutropenia with no or mild symptomsb

5

No hypotension (systolic blood pressure >90 mm Hg)

5

No chronic obstructive pulmonary disease

4

Solid tumor or hematologic malignancy with no current or previous confirmed or suspected fungal infection

4

No dehydration requiring parenteral fluids

3

Burden of febrile neutropenia with moderate symptomsb

3

Outpatient status

3

Age <60 years

2

a The maximum theoretical score is 26. Scores ≥21 are considered low risk, and scores <21 are considered high risk (positive predictive value, 91%; specificity, 68%; sensitivity, 71%).

b “Burden of febrile neutropenia” refers to the general and subjective clinical status of the patient, as influenced by the febrile neutropenic episode. It should be evaluated by using the following scale: no or mild symptoms (score, 5); moderate symptoms (score, 3); and severe symptoms or moribund (score, 0). Scores of 3 and 5 are not cumulative. This subjective criterion has been identified as a potential limitation of the scoring system.

Adapted from Freifeld AG, et al. Clin Infect Dis. 2011 Feb 15;52(4):e56-93 and Klastersky J, et al. J Clin Oncol. 2000 Aug;18(16):3038-51. Used with permission.

Initial Empiric Therapy (Undefined Source of Infection)

High-Risk Patients

  • Initial therapy: Direct at aerobic and facultative gram-negative bacilli.

    • Monotherapy is recommended—use an antipseudomonal β‎-lactam agent (eg, cefepime, a carbapenem,a piperacillin-tazobactam); ceftazidime may be less reliable as monotherapyb

    • Modification of the initial empiric regimen (eg, addition of an aminoglycoside or a fluoroquinolone) should be considered for severely ill patients or those likely to be infected with antibiotic-resistant organisms. For bloodstream infections with a gram-negative bacillus, consider dual antipseudomonal antimicrobial coverage until organism speciation and antimicrobial susceptibility data are defined

    • Prior fluoroquinolone prophylaxis precludes the use of fluoroquinolones for initial empiric therapy

  • Add vancomycin,c if there is

    • Clinically suspected catheter-associated infection

    • Known colonization with MRSA or with penicillin- or cephalosporin-resistant pneumococci

    • Blood culture shows gram-positive organisms

    • Hypotension or other signs of severe sepsis

    • Soft tissue infection

    • Health care–associated pneumonia (documented radiographically)

  • Include coverage for anaerobic bacteria (eg, metronidazole, meropenem, imipenem, piperacillin-tazobactam), if there is

    • Evidence of perianal or perirectal infection

    • Presence of necrotizing gingivitis

    • Recovery of anaerobic bacteria in culture

    • Potential intra-abdominal infection (eg, neutropenic colitis)

Low-Risk Patients

  • Consider cautious outpatient management with oral or IV antibiotics after an observation period ≥4 hours.

  • Recommended oral regimen is ciprofloxacin plus amoxicillin-clavulanated; alternative options for patients not receiving fluoroquinolone prophylaxis include levofloxacin or moxifloxacin (if Pseudomonas aeruginosa infection is not a concern).

  • IV antibiotic regimens are the same as those used for high-risk patients.

Syndrome-Based Considerations Affecting Diagnostic Testing and Antimicrobial Therapy Selection

Oral Stomatitis, Esophagitis, or Oropharyngeal Pain

  • May be caused by chemotherapy-associated mucositis or esophagitis and/or secondary bacterial or viral infection.

  • HSV stomatitis (usually early after chemotherapy); HSV and CMV esophagitis.

  • For paraesophageal pain or stiffness, consider CT imaging to evaluate for abscess or phlegmon.

  • Persistent pharyngitis or esophageal pain may require esophagogastroduodenoscopy if the condition does not improve with therapy.

  • Empiric antimicrobial therapy might also include

    • Anaerobic antibacterial coverage

    • Anti-HSV therapy, especially if vesicular lesions are present

    • Antifungal therapy if thrush is present

Sinusitis, Sinus Pain, Periorbital Cellulitis

  • Consider prompt sinus and head CT (orbital CT, if indicated) to evaluate for possible invasive fungal disease.

  • Prompt otorhinolaryngology consultation (and ophthalmology, if indicated) for endoscopic evaluation and surgical débridement (if indicated).

  • Empiric antimicrobial therapy should include

    • Antifungal or antimold activity that includes coverage of Aspergillus spp and agents of mucormycosis

    • Broad antibacterial therapy

    • Include vancomycin if periorbital cellulitis is present

Abdominal or Perirectal Pain, Diarrhea

  • Abdominal pain

    • Inflammation of the GI tract may be attributable to select chemotherapies or to neutropenic colitis (typhlitis)

    • Bacterial and fungal bowel-wall translocation can occur

    • Consider abdominal or pelvic CT imaging

    • Pelvic MRI is more sensitive for perirectal or anal fissures and small perianal abscesses

    • Hepatosplenic candidiasis or chronic disseminated candidiasis

      • Suggested by elevated alkaline phosphatase

      • Characteristic radiologic small multifocal lesions on liver and spleen

      • Symptoms and findings may be more pronounced during or after neutrophil recovery

  • If diarrhea is present, consider testing for

    • C difficile toxin

    • Bacterial enteric pathogens (if indicated)

    • Rotavirus and norovirus, if episodes are concurrent with community or family cases of diarrhea

  • Empiric therapy

    • Oral vancomycin, if C difficile infection suspected

    • Broaden antimicrobial therapy to include anaerobic antibacterial and antiyeast coverage

Respiratory Symptoms and Radiologic Pulmonary Infiltrates

  • Differential diagnoses depend on many factors

    • Duration of symptoms (eg, acute, subacute, chronic)

    • Amount of sputum production, hemoptysis

    • Radiologic findings by chest radiography or CT (eg, pattern of infiltrates)

    • Selective exposures

      • Zoonotic (farm animals, especially chickens)

      • Sick children or daycare exposure, ill family members

      • History of exposure to persons with known pulmonary tuberculosis

    • Time of year (eg, winter or early spring; RSV, influenza, coronavirus, etc)

  • Diagnostic approaches (directed by clinical findings above and differential diagnoses)

    • Sputum sample (if available or producible)

    • Nasopharyngeal swab (respiratory virus and select bacterial testing via PCR)

    • Urine antigen studies (eg, Legionella pneumophila, Streptococcus pneumoniae; endemic fungi)

    • Blood studies (including bacterial, fungal, and mycobacterial cultures), serum galactomannan or β‎-d-glucan assay, select serologies

    • CT of the chest (to clarify location and pattern of radiologic infiltrates)

    • Consider bronchoscopy with bronchioalveolar lavage if the infection is unresponsive to initial antibacterial therapy, if diffuse infiltrates are present, or if fungal disease or hemorrhage are concerns; examine lavaged fluid with appropriate microbial stains, cultures, antigen studies (including galactomannan), and select PCR studies

      • Transbronchial biopsy can be considered when appropriate and platelet counts are acceptable; however, concurrent significant thrombocytopenia during the neutropenic period can be problematic for such procedures

  • Empiric therapy

    • Selection of appropriate initial antimicrobial therapy depends on the clinical differential diagnoses and underlying possibility of health care−associated pneumonitis, community-acquired illness, aspiration, etc.

    • Consider adding or including

      • Atypical bacterial coverage (eg, azithromycin or newer fluoroquinolone) for patients with community-acquired infection who are not receiving fluoroquinolone prophylaxis

      • Vancomycin: Include initially for health care−associated or severe pneumonia, unless an alternative pathogen or cause is identified

      • Antifungal therapy active against invasive molds for at-risk patients with supportive clinical and radiologic findings; especially for patients not responding to antibacterial therapy

      • Antiviral therapy during peak influenza season or during localized outbreaks

Skin Lesions, Cellulitis

  • Cellulitis—common associations include

    • IV catheter site (eg, exit site or tunnel infection)

    • Bone marrow biopsy site (eg, iliac crest region)

    • Lymphedema in the extremities (eg, resulting from prior radiotherapy, lymphatic [or other] surgical procedures, etc)

  • Vesicular lesions—consider localized or disseminated VZV or HSV

  • Other considerations (depending upon skin lesion appearance, duration and severity of neutropenia)

    • Fusarium spp infections—lesions commonly on extremities; appear as widespread, violaceous, or erythematous indurated elements; blood cultures often positive for Fusarium spp

    • Other cutaneous invasive molds (eg, Aspergillus spp, agents of mucormycosis)

    • Nocardia braziliensis

    • Non-TB mycobacteria (mycobacterial blood cultures are often positive)

  • Aseptic considerations may include

    • Drug rash (common)

    • Leukemia cutis and other cutaneous manifestations of malignancy

    • Engraftment syndrome (after hematopoietic stem cell transplantation); may occur before or during neutrophil recovery

  • Empiric therapy

    • Include agent active against gram-positive bacteria (eg, vancomycin)

    • Consider antimold therapy if Fusarium spp or other invasive mold is suspected

    • Consider skin biopsy when appropriate

Pathogen-Directed Therapy

  • Modify antibiotic selection after identifying the pathogen and obtaining corresponding in vitro susceptibility data.

  • Consider combination therapy (eg, a β‎-lactam plus an aminoglycoside) for severe infection due to P aeruginosa or other resistant gram-negative organisms (pending susceptibility data).

  • Use linezolid or daptomycin for patients colonized with vancomycin-resistant organisms until susceptibility data become available.

  • Discontinue vancomycin after 48-72 hours if cultures are negative for gram-positive organisms.

Persistent Fever Despite Empiric Antibiotic Therapy

  • If the patient is stable, the same antibacterial program can be continued while investigating additional potential causes.

  • If a new infection is identified, adjust antibiotic therapy accordingly.

  • If the patient is unstable or clinically worsening, broaden the antibacterial regimen to cover possible resistant gram-negative, gram-positive, anaerobic, or fungal infections (or combination of infections).

  • Consider adding an antifungal agent (eg, voriconazole, posaconazole, isavuconazole, an amphotericin B product,a an echinocandin) in high-risk patients who remain febrile for 4 days after initiating empiric antibacterial therapy (for patients who have been receiving antifungal prophylaxis with an azole, use either an amphotericin B productb or caspofungin).

  • The subsequent identification of a defined pathogen and corresponding antimicrobial susceptibilities should guide changes to the initial empiric antibiotic regimen.

  • Repeat diagnostic clinical examination (including CT of the chest or abdomen [or both] to assess for a possible occult fungal infection or an intra-abdominal process such as neutropenic enterocolitis).

Duration of Antibiotic Therapy

  • Stop empiric anti-infective therapy when the neutrophil count is500 cells/mm3 and rising daily, with

    • No evidence of focal infection

    • Negative findings on cultures

  • For documented infections, the duration of therapy is dictated by the causative organism and the location or syndrome of the infection. Appropriate antibiotics should ideally continue until ANC is >500 cells/mm3; but therapy may be modified on the basis of the expected neutrophil recovery, the particular infection syndrome, and the patient’s overall response to antimicrobial therapy.

Other Considerations

  • In patients with a history of a type 1 allergic reaction to penicillin, consider use of aztreonam or ciprofloxacinc for coverage of gram-negative organisms, in combination with vancomycin or clindamycin.

  • Aminoglycoside-based combination therapy can be considered in patients with a recent history of drug-resistant gram-negative bacterial infection or patients who are clinically unstable, pending culture results.

  • For patients with a history of vancomycin allergy, consider administering linezolid or daptomycin.

  • Guide choice of empiric anti-infectives by local or institutional antibiotic resistance profiles.

  • Remove long-term tunneled intravascular catheters from patients with suppurative thrombophlebitis, tunnel infection, septic thrombosis or emboli, endocarditis, hemodynamic instability, or persistent bloodstream infection after 48-72 hours of active antimicrobial therapy; also remove from patients with infections due to S aureus, P aeruginosa, multidrug-resistant bacteria, fungi, or mycobacteria.

  • Fluoroquinolone prophylaxis should be considered for high-risk patients expected to have prolonged and profound chemotherapy-associated neutropenia.

  • Primary antifungal prophylaxis

    • Should be given against Candida to allogeneic patients undergoing hematopoietic stem cell transplantation or receiving myeloablative chemotherapy

    • Can be considered against Aspergillus for select patients (age >13 years)

      • Undergoing intensive chemotherapy for acute myeloid leukemia, myelodysplastic syndrome, and other select hematologic malignancies, with expected prolonged durations of neutropenia

      • Postallogenic hematopoietic stem cell transplantation with delayed engraftment or chronic graft-vs-host disease

      • Other risk factors for invasive aspergillosis

  • Secondary antifungal prophylaxis with a mold-active agent is recommended in patients with prior confirmed or suspected invasive mold disease with anticipated neutropenia, concurrent graft-vs-host disease, or other clinically significant immunosuppressive conditions.

Suggested Reading

Baden LR, et al. J Natl Compr Canc Netw. 2016 Jul;14(7):882–913.Find this resource:

Freifeld AG, et al; Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52(4):e56–93.Find this resource:

Transplant Infections

Timeline of Infections After Transplantation

Elements of Diagnosis

  • Clinical: Infectious etiology may be predicted based on the time since transplantation (Table 79). Two major factors influence the risk of infection after transplantation: 1) the epidemiologic exposures of the recipient and of the organ or tissue donor; and 2) the net state of immunosuppression. The net state of immunosuppression is determined by host factors (eg, age, underlying illness, neutrophil and lymphocyte counts) and transplant-related factors (eg, mucosal break, ischemia, antigen mismatch, and immunosuppressive medications).

  • Laboratory: The clinical suspicion for infection may be confirmed by culture, antigen detection, nucleic acid testing, histopathology, and serology. Serologic test results must be interpreted with caution because immunosuppressed patients may have delays in antibody production.

Table 79. Timeline of Infectious Diseases and Syndromes After Transplantation

Time After Transplantation

Solid-Organ Transplantation

Hematopoietic Stem Cell Transplantation

Period 1

Immediate period: First month after transplantation

Pre-engraftment period: First month after transplantation

Major risks: Surgery and hospitalization; reactivation of latent infections; donor transmission

Major risks: Neutropenia; disruption of mucocutaneous barriers

Specific syndromes and pathogens

  • Complications associated with surgery and hospitalization (bacteremia and candidemia, surgical site infections, urinary infection, ventilator-associated pneumonia, Clostridium difficile)

  • Recurrent infections (Mycobacterium tuberculosis, Strongyloides stercoralis, viral hepatitides)

  • Donor-derived infections (bacteria [including drug-resistant pathogens], fungi, viruses)

  • HSV reactivation

Specific syndromes and pathogens

  • Fever and shock (neutropenic fever, bacteremia, candidemia, viridans group streptococci)

  • Vascular catheter-related infections (localized infection or bloodstream infections due to bacteria and fungi)

  • Diarrhea (neutropenic colitis, C difficile, enteroviruses)

  • Mucositis (Candida albicans, HSV)

  • Pneumonia (bacteria, fungi, viral, parasites)

  • Hepatitis (HSV, adenovirus, Candida spp, HHV-6)

  • Hemorrhagic cystitis (adenovirus, BK virus)

Period 2

Intermediate period: 1-6 months after transplantation

Major risks: Impaired cellular and humoral immunity

Specific pathogens

  • CMV, Epstein-Barr virus, HHV-6

  • HBV, HCV

  • Adenovirus

  • BK virus

  • Parvovirus B19

  • Respiratory viruses

  • Pneumocystis jiroveci

  • Aspergillus spp

  • Histoplasma capsulatum

  • Coccidioides immitis

  • Cryptococcus spp

  • Toxoplasma gondii

  • Leishmania spp

  • Trypanosoma cruzi

  • Cryptosporidium

  • Mycobacterium tuberculosis

Early postengraftment period: From engraftment through posttransplant day 100

Major risks: Impaired cellular and humoral immunity; restricted T-cell repertoire

Specific syndromes and pathogens

  • Pneumonia (P jiroveci, Aspergillus sp, other molds, influenza and other respiratory viruses, CMV, Strongyloides stercoralis, bacterial pathogens)

  • Diarrhea (CMV, adenovirus, C difficile, enteric pathogens)

  • Hepatitis (CMV, HHV-6, adenovirus, HBV)

  • Hemorrhagic cystitis (BK virus, adenovirus, CMV)

  • Encephalitis (HHV-6, HSV, CMV, JC virus, adenovirus, West Nile virus, toxoplasmosis)

Period 3

Late period: At least 6 months after transplantation

Late postengraftment period: At least 100 days after transplantation

Major risks: Augmented T-cell suppression for recurrent rejection and allograft dysfunction

Specific syndrome and pathogens

  • Community-acquired respiratory infections (Streptococcus pneumonia, Legionella pneumophila, RSV, influenza, others)

  • VZV

  • Nocardia spp

  • P jiroveci

  • Epstein-Barr virus− posttransplant lymphoproliferative disorder

  • CMV (late onset)

  • Nontuberculous mycobacteria

  • Atypical molds

Note: Patients receiving augmented immune suppression still have a high risk of opportunistic infections (similar to period 2)

Major risks: Impaired cellular and humoral immunity

Specific syndromes and pathogens

  • Infections due to encapsulated bacteria (eg, S pneumoniae): sinopulmonary infections, bacteremia

  • VZV

  • Infections among high-risk patients (graft-vs-host disease, CMV D/R+, myeloablative and radiation-based conditioning regimens)

    • Pneumonia (P jiroveci, Aspergillus spp, Mucor and other molds, Nocardia spp, influenza and other respiratory viruses, late-onset CMV, other bacterial pathogens)

    • Diarrhea (late-onset CMV disease, C difficile, adenovirus, enteric pathogens, Epstein-Barr virus−posttransplant lymphoproliferative disorders)

    • Hepatitis (CMV, HHV-6, adenovirus, HBV, HEV)

    • Hemorrhagic cystitis (BK virus)

    • Encephalitis (HHV-6, HSV, CMV, JC virus, adenovirus, West Nile virus, toxoplasmosis, Cryptococcus neoformans, Listeria monocytogenes)

Prevention of Infection After Transplantation

Elements of Diagnosis and Prevention

  • Clinical: Detailed clinical, physical, and laboratory assessments of the donor and recipient are important for preventing infection after transplantation.

  • Laboratory: Before transplantation, candidate donors and recipients are screened for HIV, HBV, HCV, CMV, HSV, Epstein-Barr virus, VZV, Mycobacterium tuberculosis, and Treponema pallidum. In some situations, serologic screening may be performed for Toxoplasma gondii, Trypanosoma cruzi, Strongyloides stercoralis, human T-cell lymphotrophic virus types 1 and 2, and Coccidioides immitis.

  • Prevention

    • Vaccination should be offered to all susceptible transplant candidates and recipients. Vaccines against HBV, pneumococcus, influenza, and others may be offered. Live-attenuated vaccines should be avoided 2-4 weeks before transplantation and avoided indefinitely after transplantation.

    • Antimicrobial prophylaxis is a common strategy of infection prevention after transplantation. Antibiotics generally are administered for a defined period after transplantation to prevent common or certain predictable infections, including serious bacterial infections (eg, viridans streptococci, Pseudomonas aeruginosa), invasive fungal infections (eg, Candida spp, Aspergillus spp, Pneumocystis jiroveci), and viral infections (HSV, CMV) (Table 80).

    • Preemptive therapy is another strategy of infection prevention by identifying the pathogen early, before the onset of clinical disease. Laboratory tests that are used for this purpose are antigen testing (eg, CMV p65, galactomannan for fungal infections) and nucleic acid testing (PCR for CMV). Specific treatment is initiated as soon as a pathogen is detected. One example is preemptive valganciclovir therapy when asymptomatic CMV infection is detected by weekly PCR testing.

Table 80. Prevention of Common Infections After Transplantation

Type of Infection

Solid-Organ Transplantation

Hematopoietic Stem Cell Transplantation

Bacteria (general prophylaxis)

cefazolin, cefotaxime, or cefepime, with or without vancomycin

  • Perioperative antibacterial prophylaxis may be modified or individualized, depending on 1) organ transplanted, 2) bacterial colonization, and 3) local resistance patterns

Fluoroquinolones (eg, levofloxacin) until neutrophil engraftment

  • Prophylaxis (variable, depends on resistance patterns; eg, penicillin, TMP-SMX, fluoroquinolones) may be continued after neutrophil engraftment for patients at risk of infection with encapsulated bacteria

HSV

acyclovir or valacyclovir

  • Deferred for patients receiving valganciclovir for CMV prophylaxis

acyclovir or valacyclovir

  • Deferred for patients receiving valganciclovir for CMV prophylaxis

CMV

valganciclovir

  • Alternative: IV ganciclovir

  • Prophylaxis or preemptive therapy

valganciclovir or IV ganciclovir

  • Preemptive therapy (or less commonly prophylaxis)

  • letermovir prophylaxis for allo-HSCT

Fungus (general prophylaxis)a

fluconazole, voriconazole, itraconazole

Echinocandins

Liposomal amphotericin B

  • Antifungal prophylaxis use is variable; target depends on 1) organ transplanted and 2) risk factors

fluconazole, voriconazole, posaconazole

  • Choice of antifungal prophylaxis depends on the predicted risk for invasive mold infections (eg, Candida spp, Aspergillus spp, Mucor spp)

Pneumocystis jirovecib

TMP-SMX

Alternatives: dapsone, pentamidine, atovaquone

TMP-SMX

Alternatives: dapsone, pentamidine, atovaquone

Toxoplasma gondiic

TMP-SMX

Alternatives: sulfadiazine or clindamycin in combination with pyrimethamine or primaquine

. . .

a Monitor for drug-drug interactions with the use of azoles.

b May also prevent infection by Toxoplasma gondii, Nocardia spp, Listeria monocytogenes, and respiratory and urinary tract infections from common bacterial pathogens.

c Therapy is indicated after heart transplantation because the risk of toxoplasmosis is higher.

Pathogen-Directed Therapy for Select Infections After Transplantation

Elements of Diagnosis and Treatment

  • Clinical: Early diagnosis is essential for a better clinical outcome. The clinical symptoms of infections in transplant recipients are often typical, but atypical manifestations may be observed because of immunosuppression. Infections after transplantation are generally considered complicated because of impaired host immune responses.

  • Radiology: Plain radiographs, MRI, ultrasound, CT scans, and tagged white blood cell scans may be used, as dictated by the clinical situation.

  • Laboratory: The cause of the infectious disease may be confirmed by various diagnostic tests, including culture, antigen detection, nucleic acid testing, histopathologic examination, and serology. Serologic test results must be interpreted with caution because transplant recipients with immunosuppression may have delays in antibody production.

  • Treatment: Early and aggressive treatment is important to ensure good outcome (Tables 81 and 82). In addition to prescribing specific antimicrobial therapies, consider a cautious reduction in the dose of immunosuppressive drugs. Some opportunistic infectious diseases do not have specific antimicrobial therapy; management relies mainly on minimizing immunosuppression to allow the host immune system to respond and eradicate the infection.

Table 81. Pathogen-Directed Therapy for Selected Opportunistic Viral and Fungal Infections After Transplantation

Pathogen

Therapy

Comments

CMV

valganciclovir, IV ganciclovir

Alternatives: foscarnet, cidofovir

Treatment duration guided by clinical response and viral load clearance

HHV-6

IV ganciclovir, foscarnet

Alternative: cidofovir

Treatment duration guided by clinical response and viral load clearance

HSV

acyclovir, valacyclovir

Treatment guided by clinical response and syndrome type

VZV

acyclovir, valacyclovir

Treatment guided by clinical response and syndrome type

BK virus

Reduction in immunosuppression

Could also consider cidofovir systemically or intravesically

Influenza virus

oseltamivir, zanamivir, peramivir

Treatment duration for 5 days

Cryptococcus neoformans

Liposomal amphotericin B (with flucytosine), fluconazole

Treatment is guided by clinical syndrome and response

Severe infections such as meningitis generally are treated initially with amphotericin B and later de-escalated to fluconazole

Duration of treatment is generally prolonged, but total duration is variable and depends on the clinical response

Aspergillus spp

voriconazole

isavuconazonium

amphotericin B products (liposomal amphotericin B preferred)

Echinocandins

posaconazole

voriconazole is first-line therapy; combination antifungal regimens may be used in severe cases

Mucor spp

posaconazole

isavuconazonium

amphotericin B products

. . .

P jiroveci

TMP-SMX

Alternatives: pentamidine (IV), atovaquone, clindamycin plus pyrimethamine, dapsone plus TMP

Corticosteroids may be considered for patients with severe hypoxemia

Table 82. Dose of Select Medications for Prevention and Treatment of Infections After Transplantation (Adult Patients with Normal Renal Function)

Medication

Treatment Dose

Prevention Dose

Antiviral

valganciclovir

900 mg orally twice daily

900 mg orally once daily

ganciclovir

5 mg/kg IV every 12 hours

5 mg/kg IV every 24 hours

acyclovir

5-10 mg/kg IV every 8 hours

400 mg orally twice daily

valacyclovir

1 g orally 2-3 times daily

0.5-1 g orally once daily

foscarnet

60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours

Not indicated as first-line therapy

cidofovir

5 mg/kg IV per week for 2 doses, then 5 mg/kg IV every 2 weeks

Not indicated as first-line therapy

oseltamivir

75 mg orally twice daily

75 mg orally once daily

zanamivir

10 mg (2 inhalations) twice daily

Not used as first-line therapy

Antifungal

fluconazole

200-800 mg orally or IV once daily

100-200 mg orally once daily

voriconazole

Oral dosing

  • Weight >40 kg: 200 mg every 12 hours (increase to 300 mg every 12 hours if inadequate response or subtherapeutic levels)

  • Weight <40 kg: 100 mg every 12 hours (increase to 150 mg every 12 hours if inadequate response or subtherapeutic levels)

IV dosing

  • 6 mg/kg every 12 hours for 2 doses, then 3-4 mg/kg every 12 hours (dose adjusted based on therapeutic drug monitoring)

Oral dosing

  • Weight >40 kg: 200 mg every 12 hours (increase to 300 mg every 12 hours if inadequate response or subtherapeutic levels)

  • Weight <40 kg: 100 mg every 12 hours (increase to 150 mg every 12 hours if inadequate response or subtherapeutic levels)

IV dosing

  • 6 mg/kg every 12 hours for 2 doses, then 3-4 mg/kg every 12 hours (dose adjusted based on therapeutic drug monitoring)

posaconazole

Oral suspension

  • Systemic infections: 200 mg qid or 400 mg bid (adjust based on levels)

  • Oropharyngeal candidiasis: 100 mg bid on day 1, then 100 mg once daily

  • Mucorales and other filamentous fungi: 200 mg qid or 400 mg bid (adjust dose based on serum levels)

Oral suspension: 200 mg orally 3 times daily

Delayed-release tablets: 300 mg twice daily for 1 day, then 300 mg once daily

Delayed-release tablets: 300 mg twice daily for 1 day, then 300 mg once daily

itraconazole

200 mg orally twice daily (adjust dose based on serum levels)

For severe infections, a loading dose of 200 mg orally 3 times daily is recommended

200 mg orally twice daily

caspofungin

70 mg IV loading dose, then 50 mg IV every 24 hours

70 mg IV loading dose, then 50 mg IV every 24 hours

anidulafungin

Candidemia and other invasive fungal infections: 200 mg IV loading dose, then 100 mg IV every 24 hours

Esophageal candidiasis: 100 mg IV loading dose, then 50 mg IV every 24 hours

200 mg IV loading dose, then 100 mg IV every 24 hours

micafungin

100-150 mg IV every 24 hours

50 mg IV every 24 hours

liposomal amphotericin B

3-7.5 mg/kg IV every 24 hours (dose based on indication)

Not indicated as first-line therapy

amphotericin B deoxycholate

0.5-1.5 mg/kg IV every 24 hours (dose based on indication)

Not indicated as first-line therapy

Antibacterial

levofloxacin

250-750 mg orally or IV every 24 hours

500 mg orally once daily

ciprofloxacin

250-750 mg orally every 12 hours

200-400 mg IV every 12 hours

400 mg IV every 8 hours for severe infection (eg, nosocomial pneumonia)

250-500 mg orally every 12 hours

penicillin

5-24 million units per day (divided) IV every 4 hours or as a continuous infusion

250-500 mg orally 3-4 times a day

TMP-SMX

15-20 mg/kg every 24 hours of TMP component in 3-4 divided doses

1 SS or DS tablet once daily or 3 times per week

cefazolin

1-2 g IV every 8 hours

1-2 g IV every 8 hours

cefotaxime

1-2 g IV every 8 hours

1-2 g IV every 8 hours

cefepime

1-2 g IV every 8-12 hours

1-2 g IV every 12 hours

vancomycin

15-20 mg/kg IV every 12 hours (adjust dose based on renal function and monitor serum trough levels)

15-20 mg/kg IV every 12 hours (adjust dose based on renal function and monitor serum trough levels)

Sexually Transmitted Diseasesa

Elements of Diagnosis

Urethritis

  • Abrupt-onset, purulent urethral discharge and dysuria are more common with Neisseria gonorrhoeae than with Chlamydia trachomatis and other NGU pathogens.

  • Mucopurulent or purulent urethral discharge and dysuria, which can occur with any pathogen, often impede clinical distinction.

  • Gram stain of urethral discharge shows >5 leukocytes per HPF.

  • Positive leukocyte esterase test on first-void urine.

  • Presence of gram-negative diplococci on stain or culture does not exclude coinfection with other pathogens.

  • Coinfection with N gonorrhoeae and C trachomatis or Ureaplasma urealyticum occurs in 15-20% of heterosexual men with urethritis.

  • Nucleic acid amplification tests for N gonorrhoeae and C trachomatis can be performed on urine specimens, obviating the need for urethral swab specimens.

Cervicitis

  • Mucopurulent or purulent endocervical discharge.

  • Gram stain of cervical discharge shows >10 leukocytes per HPF.

  • Most common in adolescent females.

  • Patients commonly present without symptoms.

  • Coinfection with N gonorrhoeae and C trachomatis or U urealyticum is common.

  • Abdominal pain and adnexal tenderness may signify pelvic inflammatory disease.

Vaginitis

  • Clinical clues include vaginal discharge, vulvar pruritus, and dyspareunia.

  • Microscopic examination with coverslip can reveal motile trichomonads and clue cells.

  • Potassium hydroxide (KOH) preparation enables identification of Candida as yeast or pseudohyphae.

  • Positive whiff test (strong fishy odor) with KOH is characteristic of trichomoniasis and BV.

  • Vaginal fluid pH is >4.5 with either trichomoniasis or BV.

Genital Ulcerative Diseases

  • Syphilis: Average incubation period of 21 days; painless ulcer (chancre); nontender, nonfluctuant adenopathy in primary syphilis.

  • Chancroid: Incubation period of 2-7 days; painful ulcers; fluctuant adenopathy.

  • Genital herpes: Incubation period of 2-7 days; multiple vesicles; painful ulcers; can recur.

  • Lymphogranuloma venereum: Variable incubation period; characteristic groove sign (lymphadenopathy above and below inguinal ligament); fluctuant buboes that can rupture.

  • Donovanosis (granuloma inguinale): Variable incubation period; painless ulcers; scar formation.

Common Pathogens and Clinical Characteristics

Urethritis: Urethral Discharge and Dysuria (Common)

  • N gonorrhoeae urethritis: Purulent discharge.

  • NGU: Symptoms are less abrupt; more mucoid discharge; more common than gonorrhea in the US and other developed countries.

    • C trachomatis: Most common NGU pathogen (15-40% of cases)

    • Mycoplasma genitalium: 15-25% NGU cases in the US

    • Less common pathogens (1-5%)

      • Herpes simplex virus

      • U urealyticum

      • Trichomonas vaginalis

Cervicitis: Possible Cervical Discharge or Asymptomatic

  • Same pathogens as urethritis

  • HPV

Vaginitis: Vaginal Discharge, Vaginal Irritation

  • BV: 30-45% of cases; replacement of normal vaginal lactobacilli, which produce hydrogen peroxide, with anaerobic bacteria (eg, Bacteroides, Mobiluncus, Peptostreptococcus, Gardnerella vaginalis, and Mycoplasma hominis).

    • Vaginal discharge: Moderate amount; gray or white; homogeneous and adherent; pH >4.5

    • Addition of KOH (whiff test): Positive (fishy odor)

    • Microscopy examination (KOH wet mount): Clue cells present; few leukocytes

  • Candida: 20-25% of cases; controversial vaginal sexually transmitted disease pathogen.

    • Vaginal discharge: Scant or moderate; white, clumped, adherent; pH 4.0-4.5

    • Whiff test: Negative (no fishy odor)

    • Microscopy examination (KOH wet mount): Pseudohyphae often present; few leukocytes

  • T vaginalis: 15-20% of cases.

    • Vaginal discharge: Profuse; green-yellow; homogeneous; frothy; pH 5.0-6.0

    • Whiff test: Positive (fishy odor)

    • Microscopy examination (KOH wet mount): Motile trichomonas; many leukocytes

Genital Ulcerative Disease: Cutaneous Ulcerations, Commonly with Adenopathy

  • Treponema pallidum: Syphilis

    • Lesions: Usually painless and solitary; occasionally multiple; sharply demarcated border; indurated, with red or smooth base

    • Lymphadenopathy: Unilateral or bilateral; nontender; firm

  • Haemophilus ducreyi: Chancroid

    • Lesions: Multiple, painful, nonindurated or mildly indurated; erythematous border with rough yellow-gray base

    • Lymphadenopathy: Usually unilateral; tender; may suppurate

  • Herpes simplex virus

    • Lesions: Multiple painful lesions; may coalesce; nonindurated, smooth, erythematous lesions

    • Lymphadenopathy: Usually bilateral; firm and tender

  • C trachomatis serovars L1, L2, and L3: Lymphogranuloma venereum

    • Lesions: Usually single; variable pain; nonindurated

    • Lymphadenopathy: Unilateral or bilateral; firm, tender; frequently suppurative; groove sign is common

  • Klebsiella granulomatis: Donovanosis; granuloma inguinale

    • Lesions: Solitary or multiple rolled or elevated rough lesions; usually nontender

    • Lymphadenopathy: Pseudoadenopathy; inguinal swelling

Other Conditions

Human Papillomavirus

  • Types 6 and 11: Condyloma acuminatum (anogenital warts); most common viral sexually transmitted disease in the US.

  • Types 16, 18, 31, 33, and 35: Cervical infection; oncogenic association with cervical cancer.

  • Most HPV infections are clinically asymptomatic; gynecologic examination with Papanicolaou test recommended.

  • HPV vaccine is now available for adolescents and young adults.

Therapy for External Genital and Perianal Warts

  • Patient applied

    • Podofilox 0.5% solution or gel; apply to visible warts twice daily for 3 days, then rest for 4 days; maximum 4 cycles

    • Imiquimod 3.75% or 5% cream; apply at bedtime and wash off after 6-10 hours, 3×/week every other day; maximum, 16 weeks

    • Sinecatechins 15% ointment

  • Provider administered

    • Cryotherapy

    • Trichloroacetic acid or bichloroacetic acid 80-90%; apply a small amount, dry; apply weekly, if necessary

    • Surgical removal

Molluscum Contagiosum: Benign Disease Caused by Poxviridae Virus

  • Classically 2- to 10-mm dome-shaped papules, often with central umbilication.

  • Treatment is local curettage or cryotherapy.

Pelvic Inflammatory Disease: Endometriosis, Salpingitis, Tubo-ovarian Abscess, Pelvic Peritonitis

  • Clinical diagnosis with findings of cervical motion tenderness; uterine and/or adnexal tenderness.

  • When associated with cervicitis, N gonorrhoeae and C trachomatis are the primary pathogens.

  • Anaerobic bacteria and Streptococcus may contribute.

  • IV treatment regimen

    • First-line treatment

      • cefotetan 2 g IV every 12 hours or cefoxitin 2 g IV every 6 hours plus doxycycline 100 mg IV or oral every 12 hours

      • clindamycin 900 mg IV every 8 hours plus gentamicin 2 mg/kg IV load, then gentamicin 1.5 mg/kg IV every 8 hours (or substitute with a single daily dose of gentamicin 3-5 mg/kg)

    • Alternative treatment

    • ampicillin/sulbactam 3 g IV every 8 hours plus doxycycline 100 mg IV every 12 hours

  • Non-IV treatment regimen

    • ceftriaxone 250 mg IM once, or cefoxitin 2 g IM with probenecid 1 g oral once; combined with doxycycline 100 mg oral twice daily for 14 days, with or without metronidazole 500 mg oral twice daily for 14 days

    • Another select third-generation cephalosporin (eg, ceftizoxime or cefotaxime) plus doxycycline 100 mg oral twice daily for 14 days, with or without metronidazole 500 mg oral twice daily for 14 days

    • An alternative oral option includes levofloxacin 500-750 mg (if infection with N gonorrhoeae is excluded), with metronidazole 500 mg 3 times daily for 14 days

Pediculosis Pubis

  • Pthirus pubis infestation (also termed pubic lice)

  • First-line treatment

    • permethrin 1% cream or pyrethrins with piperonyl butoxide; apply to affected area for 10 minutes and then wash off

  • Alternative treatment

    • ivermectin 250 mcg/kg oral; repeat in 2 weeks

    • malathion 0.5% lotion; apply to affected area for 8-12 hours and then wash off

Scabies

  • Causative organism (arthropod) is Sarcoptes scabiei.

  • First-line treatment

    • permethrin 5% cream; apply for 8-14 hours to all areas of the body from neck down and then wash off

    • ivermectin 200 mcg/kg oral; repeat in 2 weeks

  • Alternative treatment

    • lindane 1% (1 oz of lotion or 30 g of cream); apply thinly to all areas of body from neck down and then wash off after 8 hours

Note

  • Avoid fluoroquinolones and doxycycline during pregnancy.

  • Avoid metronidazole during the first trimester of pregnancy; metronidazole may cause a disulfiram-like reaction when taken with alcohol.

Table 83. Pathogen-Directed Therapy for Sexually Transmitted Diseases

Clinical Situation

First-Line Treatment

Alternative Treatment

Urethritis and cervicitisa

   N gonorrhoeaeb

ceftriaxone 250 mg IM once

PLUS

azithromycin 1 g oral once

If ceftriaxone is not available:

cefixime 400 mg oral once

PLUS

azithromycin 1 g oral once

If the patient has a cephalosporin allergy:

gemifloxacin 320 mg orally in a single dose PLUS azithromycin 2 g orally in a single dose

OR

gentamicin 240 mg IM in a single dose PLUS azithromycin 2 g orally in a single dose

   C trachomatis and other NGU pathogens

EITHER

azithromycin 1 g oral once

OR

doxycycline 100 mg oral bid for 7 days

One of the following:

erythromycin base 500 mg oral qid for 7 days; OR

erythromycin ethylsuccinate 800 mg oral qid for 7 days; OR

ofloxacin 300 mg oral bid for 7 days; OR

levofloxacin 500 mg oral q24h for 7 days

Recurrent or persistent urethritis or cervicitis (ensure that N gonorrhoeae and NGU pathogens are treated appropriately)

   M genitaliumc and U urealyticum

azithromycin or erythromycin regimen (dosing as above for C trachomatis and other NGU pathogens)

. . .

   T vaginalis

metronidazole 2 g oral once; OR

tinidazole 2 g oral once

metronidazole 500 mg twice daily for 7 days

Vaginitis

   Bacterial (BV)

One of the following:

metronidazole 500 mg oral bid for 7 days; OR

metronidazole gel 0.75% 5 g intravaginal daily for 5 days; OR

One of the following:

tinidazole 2 g oral daily for 2 days; OR

tinidazole 1 g oral daily for 5 days; OR

clindamycin cream 2% 5 g intravaginal at bedtime for 7 days

clindamycin 300 mg oral bid for 7 days; OR

clindamycin ovules 100 mg intravaginal daily for 3 days

   Candida

Intravaginal agents: butoconazole, clotrimazole, miconazole, nystatin, tioconazole, or terconazole

Oral systemic agents: fluconazole 150 mg once; itraconazole 200 mg once

. . .

   T vaginalis

One of the following:

metronidazole 2 g oral once; OR

tinidazole 2 g oral once

metronidazole 500 mg oral bid for 7 days

Genital ulcerative disease

   Primary syphilis

benzathine penicillin G 2.4 million units IM once

EITHER

doxycycline 100 mg oral bid for 14 daysOR

tetracycline 500 mg oral qid for 14 days

   Chancroid (H ducreyi)

One of the following:

azithromycin 1 g oral once; OR

ceftriaxone 250 mg IM once; OR

ciprofloxacin 500 mg oral bid for 3 days; OR

erythromycin base 500 mg oral qid for 7 days

. . .

HSV

   First episode

One of the following:

acyclovir 400 mg oral tid or 200 mg 5 times daily for 7-10 days; OR

valacyclovir 1 g oral bid for 7-10 days; OR

famciclovir 250 mg oral tid for 7-10 days

. . .

   Recurrent disease

One of the following:

acyclovir 400 mg tid or 800 mg bid for 5 days or 800 mg tid for 2 days; OR

. . .

valacyclovir 500 mg bid for 3 days or 1 g oral daily for 5 days; OR

famciclovir 125 mg orally bid for 5 days or 500 mg once followed by 250 mg oral bid for 2 days or 1 g oral bid for 1 day only

   Suppressive therapy

One of the following:

acyclovir 400 mg oral bid; OR

valacyclovir 500 mg to 1 g oral daily; OR

famciclovir 250 mg oral bid

. . .

Lymphogranuloma venereum

doxycycline 100 mg oral bid for 21 days

erythromycin base 500 mg oral qid for 21 days

azithromycin 1 g orally once weekly for 3 weeks is also likely effective

Donovanosis

doxycycline 100 mg oral bid for ≥3 weeks (until complete resolution)

One of the following:

ciprofloxacin 750 mg oral bid for ≥3 weeks (until complete resolution); OR

erythromycin base 500 mg oral qid for ≥3 weeks (until complete resolution); OR

azithromycin 1 g oral once weekly for >3 weeks; OR

TMP-SMX 1 DS tab bid for ≥3 weeks

a Unless excluded by laboratory testing, treat for N gonorrhoeae and C trachomatis and for other NGU pathogens.

b Nondisseminated.

c M genitalium has better response rate to azithromycin than to doxycycline.

Tuberculosis

Mycobacterium tuberculosis Complex

General Information

  • Group of mycobacteria that causes TB in humans or other organisms.

  • Pathogens are Mycobacterium tuberculosis, M bovis, M africanum, M microti, M canetti, and M mungi.

    • M tuberculosis causes TB in humans; other species predominantly cause disease in animals

  • M bovis

    • M bovis occasionally causes disease in humans

    • Attenuated BCG M bovis can cause progressive infection in immunosuppressed patients through either BCG vaccination or bladder irrigation

    • Resistant to pyrazinamide

M tuberculosis Diagnostic Tests

Latent TB Infection

LTBI occurs when M tuberculosis infection is present but the patient has no corresponding clinical or radiologic evidence of active disease. These patients are asymptomatic and without risk of transmitting M tuberculosis to others. Currently, no assay can directly diagnose LTBI in a patient; rather, the diagnosis relies on measuring a patient’s specific immune response to a current or prior infection with M tuberculosis (ie, it is an indirect or surrogate marker for the presence of M tuberculosis), along with a clinical evaluation and chest radiograph to exclude active disease.

  1. A. Assays for M tuberculosis infection via specific immunologic response

    1. 1. Tuberculin skin test:

      • Also called purified protein derivative or Mantoux test; consists of intradermal injection of 5 tuberculin units of purified protein derivative solution, which stimulates a delayed-type hypersensitivity response

      • Results are read by measuring the transverse diameter of the induration within 48 to 72 hours

      • False-positive results may be due to nontuberculous mycobacteria infection and BCG vaccination

      • False-negative results may be due to active infection, immunosuppression, natural waning of immunity, and technical limitations

        • TST interpretation

          • Depending on the clinical situation, induration sizes of ≥5, ≥10, and ≥15 mm are considered positivea,b

          • >5 mm induration is considered positive in the following persons:

            • Persons with HIV

            • Close contact with or exposure to persons with active TB

            • Persons with abnormal chest radiographs consistent with prior TB (eg, fibrotic changes, especially in the upper lobes)

            • Significant immunosuppression, including organ transplant recipients, persons taking the equivalent of >15 mg/day of prednisone for 1 month or longer, persons taking TNF-α‎ antagonists, and persons with hematologic malignancies (many types)

          • >10 mm induration is considered positive in the following persons:

            • Foreign-born persons with recent arrival (within 5 years) from TB-endemic countries

            • Patients with select immunomodulatory conditions that increase the risk of TB disease development (including diabetes mellitus, silicosis, end-stage renal disease, malnutrition, head and neck cancers, select hematologic malignancies with low T-lymphocyte functional impact, antineoplastic chemotherapy, gastrectomy, jejunoileal bypass, more than 10% loss of ideal body weight

            • Health care workers

            • Injection drug users

            • Residents and employees of high-risk congregate living settings

            • Children younger than 4 years

            • Mycobacterial laboratory personnel

            • Persons with TST conversion (>10 mm within a 2-year period)

            • >15 mm induration is considered positive in any person, including those with no known risk factors for TB infection or progression to disease

  2. 2. Interferon-γ‎ release assay:

    • Detects M tuberculosis antigen−specific interferon-γ‎ release from specific, previously sensitized memory T cells

    • Identifies patients with M tuberculosis complex infection (latent infection and active disease)

    • Differentiates M tuberculosis infection from previous M bovis BCG vaccination and most nontuberculous mycobacteria infections

    • False-positive results possible with M marinum, M kansasii, and M szulgai infection

    • IGRA may generally be used in the same clinical setting as the tuberculin skin test

      • Two types of IGRAs are available: 1) QuantiFERON-TB Gold In-Tube (QFT-GIT; Cellestis Ltd, Carnegie, Australia) and 2) T-SPOT.TB (Oxford Immunotec Ltd, Abingdon, United Kingdom)

  3. B. When to use IGRA vs TST for LTBI testing

    1. 1. An IGRA is preferred over a TST in patients >5 years old who have a high risk of M tuberculosis infection AND both of the following:

      • Low to intermediate risk of disease progression; AND

      • A history of BCG vaccination or the patient is unlikely to return for TST reading

      Notes:

      • Recommendation for IGRA testing is stronger in patients who have lived in TB-endemic countries AND have received prior BCG vaccination, but IGRA still is favored in patients who do not recall a prior BCG vaccination

      • IGRA testing has increased specificity for M tuberculosis infection compared with TST for patients who have received or may have received a prior BCG vaccination

      • TST is acceptable if IGRA is not available or feasible

    2. 2. Either IGRA or TST is acceptable for patients >5 years old who have a high risk of M tuberculosis infection and a high risk of progression to active TB disease

      Notes:

      • Data are insufficient to recommend one testing platform over the other in this setting

      • A positive TST or IGRA warrants LTBI therapy (emphasis on assay sensitivity over specificity)

    3. 3. No testing is recommended for persons with a low risk of M tuberculosis infection AND a low risk for progression to active TB disease (if infected), unless testing is obligatory for employment, school, or institutional communal living arrangement (jail, skilled care facility, etc)

      • In this setting, IGRA is preferred (for increased specificity of infection)

      • TST is an acceptable alternative if IGRA is not available or too expensive

      • If a screening IGRA or TST is positive, consider performing a second diagnostic test (IGRA or TST) and consider the person infected only if the subsequent test is also positive

    4. 4. A TST is preferred in children <5 years old who are being tested for M tuberculosis infection

      • IGRA can be an acceptable alternative if TST is not feasible

      • Data about IGRA use are limited for children <5 years old, and phlebotomy can be more difficult in this patient group

  4. C. Neither TST nor IGRA can distinguish between LTBI and active disease. A diagnosis of LTBI requires a chest radiograph and thorough clinical evaluation to exclude active disease

Table 84. Risk of M tuberculosis Infection and Progression to Active Disease

Risk Group

Example

Patients with higher risk of infection

Persons with close (household) contact with or exposure to persons with active TB

Mycobacterial laboratory personnel

Immigrants from TB-endemic countries

Residents and employees of high-risk congregate living settings

Health care workers

Patients with intermediate risk of progression to active TB disease

Patients with diabetes mellitus

Patients with chronic renal failure

IV drug abusers

Patients with high risk of progression to active TB disease

Patients with significant immunosuppressive conditions, including HIV infection; immunosuppression after organ transplantation; persons taking the equivalent of >15 mg/day of prednisone for at least 1 month; those taking TNF-α‎ antagonists, antineoplastic, or other significant immunosuppressive therapy; hematologic malignancies (many types)

Patients with an abnormal chest radiograph consistent with prior TB

History of silicosis

Table 85. When to Use IGRA vs TST for M tuberculosis Infection Testinga

Risk Group

Testing Strategy

Higher risk of infection

High risk of progression to disease

(TST >5 mm induration)

Adults

  • Acceptable: IGRA or TST

  • Consider dual testing, in which a positive from either test would be considered a positive result

Children aged < 5 years

  • Preferred: TST

  • Acceptable: IGRA or TST

  • Consider dual testing, in which a positive from either test would be considered a positive result

Higher risk of infection

Low to intermediate risk of progression to disease

(TST >10 mm induration)

Preferred: IGRA, where available

Acceptable: IGRA or TST

Unlikely to be infected

(TST >15 mm induration)

Testing for LTBI is not recommended

If testing is necessary (eg, for employment, residential home, school):

  • Preferred: IGRA, where available

  • Acceptable: IGRA or TST

  • For serial testing: IGRA or TST

  • Consider dual testing, in which a negative from either test would be considered a negative result

a Considerations when selecting the test method include prevalence of BCG vaccination, expertise of staff or laboratory, test availability, patient and staff perceptions, and programmatic concerns.

Lewinsohn DM, et al. Clin Infect Dis. 2017 Jan 15;64(2):111-5

Active TB disease

  • Acid-fast smear for Mycobacterium:

    • Detection in sputum allows rapid identification and isolation of individuals who are likely to be infected, pending definitive diagnosis

    • Auramine-rhodamine stain detects AFB directly in clinical specimens, including sputum, bronchial lavage or washing, gastric washing, urine, CSF, body fluid, and tissue

    • Artifacts may be confused with organisms

    • Ziehl-Nielsen stain additionally detects AFB in formalin-fixed, paraffin-embedded tissue blocks

  • Nucleic acid amplification assay:

    • Detects M tuberculosis complex DNA, including M tuberculosis, M bovis, M africanum, M microti, and M canetti directly in clinical specimens, including sputum, bronchial lavage or washing, gastric washing, urine, stool, CSF, body fluid, and tissue (fresh or paraffin embedded)

    • Preferred method for rapid detection of M tuberculosis complex

    • Does not distinguish among species in the M tuberculosis complex

    • Positive result does not distinguish between active disease and nucleic acid persisting from a prior infection

    • Negative result does not exclude the presence of M tuberculosis complex or active disease

    • Available tests include Enhanced Amplified Mycobacterium Tuberculosis Direct Test (E-MTD; Gen-Probe, San Diego, California) on AFB smear−positive and smear-negative respiratory specimens; and Amplicor Mycobacterium tuberculosis Test (Roche Diagnostics) on AFB smear−positive respiratory specimens

    • Also available, Xpert MTB/RIF assay (Cepheid, Sunnyvale, California) detects M tuberculosis complex DNA and rpoB gene mutations associated with rifampin resistance in unprocessed sputum and concentrated sputum

  • Mycobacterial culture and identification:

    • Various solid and liquid culture systems are available for culturing M tuberculosis complex

    • Liquid culture system with automated detection of positive cultures (eg, BACTEC MGIT 960 System) allows for rapid detection of mycobacteria

    • Available methods for the identification of M tuberculosis complex from culture include nucleic acid probes (eg, Gen-Probe AccuProbe system), which detects mycobacterial ribosomal RNA that attaches to a labeled complementary DNA probe; MALDI-TOF mass spectrometry; and DNA sequence analysis of mycobacterial 16S rRNA

Treatment of Latent TB Infection in Adults

Preferred Treatment

  • isoniazid 5 mg/kg daily (300 mg maximum) oral for 9 months (270 doses minimum)

  • isoniazid 15 mg/kg (900 mg maximum) oral and rifapentine 900 mg oral once weekly by DOT for 12 weeks (12 doses); note that once-weekly isoniazid and rifapentine is NOT recommended for treatment of LTBI in certain settings: 1) in HIV-infected patients receiving antiretroviral treatment, 2) in patients younger than 2 years, 3) in women who are pregnant or planning to become pregnant within the 12-week treatment period, and 4) when INH or rifampin resistance is suspected

  • rifampin 10 mg/kg daily (600 mg maximum) oral for 4 months (60 doses minimum)

Alternative Treatment

  • isoniazid 5 mg/kg daily (300 mg maximum) oral for 6 months (180 doses minimum; for patients not able to complete 9 months of therapy)

  • isoniazid 900 mg twice weekly (by DOT) for 9 months (76 doses minimum)

  • isoniazid 900 mg twice weekly (by DOT) for 6 months (52 doses minimum; for patients not able to complete 9 months of therapy)

Treatment of Pulmonary TB (Active Disease)

General Rules for Treatment of Drug-Susceptible M tuberculosis

  • All 6-month regimens should contain isoniazid, rifampin, and (initially, for 2 months) pyrazinamide.

  • All 9-month regimens should contain isoniazid and rifampin.

  • DOT strongly recommended for all patients and all treatment regimens.

Standard Therapy for Drug-Susceptible Pulmonary TB

Option 1: Preferred treatment regimen

Induction or intensive phase

  • isoniazid, rifampin, pyrazinamide, and ethambutola daily for 8 weeks (56 doses); OR

  • isoniazid, rifampin, pyrazinamide, and ethambutola 5 days per week for 8 weeks (40 doses)

Continuation phase

  • isoniazid and rifampin daily for 18 weeks (126 doses); OR 5 days per week for 18 weeks (90 doses)

Option 2: Preferred alternative regimen in situations when more frequent DOT during the continuation phase of therapy is difficult to achieve

Induction or intensive phase

  • isoniazid, rifampin, pyrazinamide, and ethambutola daily for 8 weeks (56 doses); OR

  • isoniazid, rifampin, pyrazinamide, and ethambutola 5 days per week for 8 weeks (40 doses)

Continuation phase

  • isoniazid and rifampin twice weekly for 18 weeks (36 doses)b

Option 3: Use with great caution in patients with HIV or cavitary disease (generally not preferred)

Induction or intensive phase

  • isoniazid, rifampin, pyrazinamide, and ethambutola 3 times weekly for 8 weeks (24 doses)b

Continuation phase

  • isoniazid and rifampin 3 times weekly for 18 weeks (54 doses)b

Option 4: Do not use twice-weekly regimens in patients with HIV, patients with AFB smear−positive infection, or patients with cavitary disease

Induction or intensive phase

  • isoniazid, rifampin, pyrazinamide, and ethambutola daily for 2 weeks (14 doses), then isoniazid, rifampin, pyrazinamide, and ethambutola twice weekly for 6 weeks (12 doses)b

Continuation phase

  • isoniazid and rifampin twice weekly for 18 weeks (36 doses)b

Option 5: For pregnant patients or those intolerant of pyrazinamidec,d

Induction or intensive phase

  • isoniazid, rifampin, and ethambutola daily for 8 weeks (56 doses); OR

  • isoniazid, rifampin, and ethambutola 5 days per week for 8 weeks (40 doses)

Continuation phase

  • isoniazid and rifampin daily for 31 weeks (217 doses); OR

  • isoniazid and rifampin 5 days per week for 31 weeks (155 doses); OR

  • isoniazid and rifampin twice weekly for 31 weeks (62 doses)b

Notes:

  • Daily DOT is preferred during the induction AND continuation phases of therapy.

  • Treatment 5 days per week is an acceptable alternative to 7 days per week if weekend DOT is problematic; this regimen still may be considered “daily” therapy.

  • Once-weekly high-dose isoniazidb and rifapentine are not recommended in the induction or continuation phases of therapy.

Treatment Duration for Drug-Susceptible Pulmonary TB

  • 2-Month induction phase

  • 4-Month continuation phase for most patients (6 months of total treatment)

  • 7-Month continuation phase (9 months of total treatment) is recommended for select patients, including:

    • Patients with cavitary disease on initial chest radiographs who have a positive sputum culture after 2 months of initial-phase treatment

    • Patients whose initial phase of treatment did not contain pyrazinamide

Special Circumstances

  • HIV co-infection: Consult an infectious diseases or HIV specialist.

    • Patients with newly diagnosed HIV and those not yet receiving antiretroviral therapy should initiate combination antiretroviral therapy during the TB treatment course

      • Patients with CD4 cell counts <50 cells/mcL should start combination antiretroviral therapy within the first 2 weeks of starting TB therapy

      • Patients with CD4 cell counts >50 cells/mcL should start combination antiretroviral therapy within 8-12 weeks of starting TB therapy

      • Patients with HIV and TB meningitis: Initiation of combination antiretroviral therapy should be delayed for 8 weeks after starting TB therapy (to minimize possible secondary symptoms from CNS immune reconstitution inflammatory syndrome)

    • For most patients with drug-susceptible pulmonary disease, appropriate treatment is the standard 6-month regimen with an induction or intensive phase of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by 4 months of isoniazid and rifampin

    • In the unusual situation of an HIV-infected patient not taking antiretroviral therapy (during TB treatment), the continuation phase of therapy should be extended from 4 to 7 months (9 months total therapy)

    • Every effort should be made to include a rifamycin (rifampin or rifabutin) in the TB treatment program. Selection of an alternative drug may be necessary in the antiretroviral treatment program to accommodate a rifamycin-containing TB treatment regimen

    • Rifampin is generally not recommended with most protease inhibitors or nonnucleotide reverse transcriptase inhibitorse

    • Rifabutin causes less hepatic cytochrome P450 enzyme induction than rifampin and may be used in place of rifampin (with dosing adjustmentsf) to reduce adverse drug-to-drug interactions

    • Do not use twice-weekly regimens in HIV-infected patients

  • Drug-resistant TB: Consult an infectious diseases or TB specialist. An effective treatment regimen depends on the type and number of drugs associated with resistance in that M tuberculosis isolate. Adverse effects are more common with second-line TB drugs, which require close monitoring.

  • Culture-negative TB (2 treatment options):

    • Option 1: isoniazid, rifampin, pyrazinamide, and ethambutol daily for 4-6 months (preferred)

      • Use of all 4 drugs for the duration of therapy is justified because of possible drug resistance

      • If source patient (index case) is known to have a drug-susceptible isolate, then pyrazinamide and ethambutol may be stopped after 2 months

    • Option 2: isoniazid, rifampin, pyrazinamide, and ethambutol for the first 2 months, followed by isoniazid and rifampin for 2 more months (4 months of total treatment)

  • Indications for use of vitamin B6 (pyridoxine) with isoniazid:

    • Alcoholism

    • Diabetes mellitus

    • Malnutrition

    • HIV infection

    • Preexisting peripheral neuropathy

    • Pregnancy (until 2 months postpartum)

    • Seizure disorder

    • Uremia

Table 86. Treatment of Drug-Susceptible Extrapulmonary TB

Duration of TB Treatment, Stratified by Location

Use of Corticosteroids

6 Months

   Disseminated disease in adults

No

   Genitourinary disease

No

   Lymph nodes

No

   Pericardial disease

No

   Peritoneal disease

No

   Pleural disease

No

6-9 Months

   Bones and joints (nonvertebral)

No

9 Months

   Disseminated disease in children

No

9-12 Months

   CNS disease or meningitis

Yesa

   Vertebral disease

No

a Adjunctive dexamethasone is recommended for all patients with CNS TB, particularly those with a decreased level of consciousness or TB meningitis.

Nahid P, et al. Clin Infect Dis. 2016 Oct 1;63(7):e147-95

Nontuberculosis Mycobacteria Management Pearls

NTM Diagnostic Considerations

Laboratory Testing

  • Microbial stains

    • AFB (Ziehl-Neelsen or Kinyoun) stain: Red (carbol-fuchsin) staining mycobacteria on a blue-green background

      • Beaded (“barber pole”) appearance with Mycobacterium kansasii

      • Nocardia spp and Rhodococcus spp will stain weakly AFB positive

    • Auramine-rhodamine stain (fluorescence microscopy): More sensitive but less specific than AFB stain

  • Culture

    • Blood culture: BACTEC MycoF/Lytic broth (Becton, Dickinson and Company) or lysis centrifugation followed by plating on solid media

    • Other specimens: BACTEC broth and Middlebrook agar plates

  • Rapid mycobacteria identification tests

    • Directly from respiratory sample or tissue: M tuberculosis−specific PCR assay

      • For detection of M tuberculosis with smear-positive and smear-negative specimens

    • From organisms grown in culture:

      • DNA probes from culture growth: Available for identifying MAC, M gordonae, M kansasii, and M tuberculosis complex

      • For other mycobacterial species: MALDI-TOF mass spectrometry or partial 16S rDNA sequencing

  • Susceptibility testing: Broth microdilution panel

  • Serum IGRA may be useful, pending above diagnostic microbial testing, to help differentiate (exclude) M tuberculosis infection from most NTM infections.

    • Note: IGRA tests can have positive results with select NTM: M marinum, M kansasii, M szulgai (contain ESAT-6 and CFP-10 proteins)

Specialized Diagnostic Criteria for NTM Pulmonary Disease

All 4 criteria must be met to establish the clinical diagnosis and to warrant therapy.

  • Clinical, more chronic pulmonary symptoms

  • Radiographic findings consistent with NTM disease, which can be variable, including fibronodular or cavitary infiltrates on chest radiograph or CT; often with multifocal bronchiectasis and with multiple small nodules; right middle lobe and lingular region are commonly involved.

  • NTM growth in 2 or more sputa samples, 1 bronchial wash or lavage, or biopsy

  • Exclusion of other diagnoses

NTM Clinical Syndromes and Treatment Considerations

Mycobacterium avium Complex

  • M avium—most common disseminated infection for patients with immunologically advanced HIV or AIDS.

  • M intracellulare—causes most cases of fibronodular pulmonary disease in women older than 50 years (Lady Windermere syndrome) and in men with a history of smoking or pulmonary cancer.

  • M chimera—outbreaks have been associated with heater-cooler devices used in cardiac surgery.

Syndromes

  • Pulmonary

    • Types of MAC lung disease

      • Fibrocavitary type: May appear similar to TB, with predominance of upper-lobe cavitary disease (about 50% of cases)

        • Typically affects men; common characteristics are heavy smoking, alcoholism, age <60 years

        • Higher MAC organism burden; AFB stain is commonly positive

        • Monomicrobial MAC infection is more common

      • Nodular bronchiectasis type: Presence of bronchiectasis with nodular disease (40% of cases)

        • Typically affects women (nonsmokers, nonalcoholics); mean age, 70 years

        • Lower MAC organism burden; AFB stain is commonly negative

        • Polymicrobial infections are common (eg, coexisting MAC, Pseudomonas aeruginosa, RGM, Aspergillus, Nocardia, and other MAC substrains)

    • Risk factors or associations with pulmonary MAC disease

      • α‎1-Antitrypsin deficiency

      • Ciliary dyskinesia

      • Cystic fibrosis

      • Gastroesophageal reflux disease

      • Prior pulmonary histoplasmosis

      • Slender body habitus with pectus excavatum

    • Disease course: High variability in pulmonary disease and rates of disease progression; patients with minimal pulmonary disease may not require treatment

    • Diagnosis: Pulmonary MAC and most other NTMs are diagnosed by a triad of findings: 1) active symptoms, 2) findings on chest radiograph (or CT scan), and 3) positive MAC cultures

    • Posttreatment recurrent MAC disease: Not uncommon, especially with chronic lung disorders (eg, bronchiectasis)

  • Hypersensitivity pneumonitis

    • Commonly associated with hot tubs, especially with indoor hot tubs (“hot tub lung”)

    • Patients: Often relatively young and healthy; chest CT may show diffuse infiltrate with ground-glass opacities

    • HP can also be seen with other NTMs, including RGM, M immunogenum, etc

  • Head or neck lymphadenitis (ie, cervical); infection predominantly affects children aged 1-5 years.

  • Disseminated disease, including patients with advanced HIV or AIDS.

    • Fever, night sweats, weight loss; hepatosplenomegaly is common; positive blood cultures in >90% of patients; CD4 counts usually <50/mcL

    • Enteric disease: Enteritis, colitis, malabsorption

    • Pulmonary disease: Less common

Treatment

  • Pulmonary

    • Susceptibility testing is recommended for clarithromycin and amikacin; no other susceptibility testing correlates well with clinical outcome

    • Perform monthly mycobacterium sputum cultures

    • A 2-drug regimen with clarithromycin (or azithromycin) plus ethambutol may be acceptable in select mild cases (eg, third agent not tolerated), but this approach generally is not recommended

    • For more severe cases (eg, extensive lung infection, cavitary disease, etc), daily therapy is recommended; consideration should be given to adding IV amikacin initially

  • Hypersensitivity MAC lung disease

    • Remove source of exposure (eg, avoid contaminated hot tubs)

    • Moderate to severe cases: Consider combination antimicrobial therapy for a short period (3-6 months), with or without corticosteroids (taper for 4-8 weeks)

  • Children with NTM cervical lymphadenitis (MAC, M scrofulaceum)

    • Excisional surgery without medication

    • Combination drug therapy if surgical excision is incomplete

  • Disseminated MAC disease (advanced HIV or AIDS)

    • Consider adding amikacin in more severe cases (initially, usually 2-3 months)

    • Treatment duration depends upon immunologic recovery; consider discontinuing after at least 12 months in asymptomatic patients with sustained increase in CD4 counts (>100/mcL) for >6 months after starting or modifying HAART

    • Avoid adverse drug interactions (eg, rifabutin or rifampin and select antiretroviral drugs) in patients with HIV

Table 87. Treatment for MAC

Preferred regimen

clarithromycin (or azithromycin) plus ethambutol plus rifampin (or rifabutin)

Alternative drugs

IV or aerosolized amikacin, clofazimine; possibly moxifloxacin, bedaquiline, linezolid, tedizolid, tigecycline, ethionamide

M kansasii

Syndromes

  • Pulmonary disease—thin-walled cavities are common on chest radiographs, although noncavitary and nodular bronchiectasis disease can occur.

  • Lymphadenitis (especially cervical lymph node involvement)

  • Granulomatous skin lesions, erythema nodosum

  • Bone, joint, and soft tissue infections

Treatment

  • Susceptibility testing

    • Drug susceptibility to rifampin and clarithromycin should be routinely tested in all M kansasii isolates

    • If the isolate is rifampin resistant or if the patient is treatment experienced, then test susceptibilities for amikacin, ciprofloxacin, clarithromycin, ethambutol, rifabutin, streptomycin, sulfonamides, isoniazid, and moxifloxacin

      • Standard concentrations of isoniazid used for TB drug susceptibility testing should NOT be used because MIC values for M kansasii are higher

  • M kansasii is among the more virulent NTM species, but it also is more successfully treated.

Table 88. Treatment for M kansasii

Preferred regimen

rifampin (or rifabutin) plus ethambutol plus isoniazid; OR

rifampin (or rifabutin) plus ethambutol plus either macrolide or fluoroquinolone

Alternative drugs

amikacin, sulfamethoxazole

M marinum

  • Known as “swimming pool granuloma” or “fish tank granuloma”; associated with exposure to salt water, freshwater, fish tanks, and swimming pools.

  • Infection acquired by skin inoculation.

Syndromes

  • Cutaneous disease

    • Granulomatous skin lesions; nodules commonly in line of lymphatic drainage (“ascending” appearance similar to that of cutaneous sporotrichosis or occasionally cutaneous nocardiosis)

  • Typically appears on extremities.

  • May be solitary, grouped, or widespread.

Treatment

  • May consider single-drug therapy for minimal disease in select cases (not generally recommended).

  • May require débridement with combination therapy for tenosynovitis and joint disease.

Table 89. Treatment for M marinum

Preferred regimen (2-3 drugs)

clarithromycin (or azithromycin) plus ethambutol; with or without rifampin (for deep tissue infections)

Alternative drugs

sulfamethoxazole, minocycline or doxycycline, moxifloxacin or levofloxacin or ciprofloxacin, linezolid

M leprae

  • Leprosy (Hansen disease) is found mainly in the tropics and subtropics; humans are the only host; infection is spread by direct contact (ie, close household contact; nasal discharge from infected patients is the most common mode of transmission).

  • Organism is NOT cultured with laboratory media; diagnosis is made clinically, with supporting tissue histology and microbial stains.

    • Localized skin lesions that are raised or flat, light or pigmented, with sensory loss in the lesion

    • Thickened peripheral nerves

    • Tissue histology with AFB present

  • The vast majority of exposures do NOT result in clinical leprosy disease; development of clinical disease is affected by genetic factors and underlying immunologic status.

Syndromes

  • Lepromatous leprosy

    • Symmetric nodules (widely distributed), thickened dermis, cooler areas of the body (extremities) are mostly affected

    • Skin biopsy shows many bacilli

  • Tuberculoid leprosy

    • Few hypopigmented anesthetic macules with distinct borders; distal hypesthesia with selective loss of pain and temperature is most common; peripheral nerves may become enlarged and palpable; prominent neurologic involvement

    • Skin biopsy shows only a few bacilli

  • Additional clinical findings of leprosy

    • Peripheral neuritis (ulnar nerve tropism leads to clawing of the fourth and fifth fingers, with decreased motor skill and decreased sensory and fine touch)

    • Nasal collapse

    • Renal amyloidosis

    • Uveitis or glaucoma

    • Gynecomastia (due to decreased testosterone)

    • Reversal reactions (clinical disease produced by change in the host immune response to M leprae)

    • Type 1 reactions: Induced by cell-mediated immunity

      • Upgrading reactions: Typically seen in patients with borderline lepromatous disease who undergo a shift to more tuberculoid (paucibacillary) forms; may develop after induction of therapy

      • Downgrading reactions: Occur with transformation from tuberculoid to more lepromatous (multibacillary) form; often develop in absence of therapy

      • Note: Both reaction types may appear similar clinically and may contain erythema and edema of existing skin lesions, with painful neuropathy and ulceration; treat severe reactions with a corticosteroid taper

    • Type 2 reactions: Immune complex–mediated; including erythema nodosum leprosum

      • Immune complex–mediated vasculitis; often ulceration with damage to nerves

      • Treatment options include NSAIDs, corticosteroids, clofazimine, thalidomide

Treatment

  • US National Hansen’s Disease program recommends 12 months for paucibacillary and 24 months for multibacillary disease (preferred).

  • World Health Organization (non-US) recommends 6 months for paucibacillary and 12 months for multibacillary disease (preferred).

Table 90. Treatment for M leprae

Paucibacillary disease

dapsone plus rifampin for 6-12 months

Multibacillary disease

dapsone plus rifampin plus clofazimine for 12-24 months

Alternatives

minocycline, moxifloxacin or levofloxacin, clarithromycin

M fortuitum Complex

  • M fortuitum complex includes M fortuitum, M neworleansense, M peregrinum, M boenickei, M alvei, M septicum, and M porcinum group (includes M porcinum, M bonickei, M houstonense, M neworleansense, M conceptionense, M farcinogenes, M senegalense, M mageritense).

  • Often more indolent compared with the M abscessus group.

Syndromes

  • Skin and soft tissue infections

    • Commonly in immunocompetent patients

    • Can be associated with whirlpools, footbaths, and pedicure procedures

  • Occasional bone and joint disease

  • Pulmonary disease (occasionally; note that not all patients with M fortuitum complex isolated from sputum require therapy)

Treatment

  • M fortuitum complex generally is more drug susceptible and readily treatable compared with other RGM species.

  • The rRNA methylase gene (erm) is present in the M fortuitum complex and methylates the ribosomal macrolide-binding site, conferring macrolide resistance.

  • Combination therapy is recommended. Active drugs vary and should generally be based on in vitro susceptibility testing.

Table 91. Treatment for M fortuitum Complex

Preferred drugs

fluoroquinolones, sulfonamides, amikacin (or tobramycin), imipenem, doxycycline-minocycline

Alternatives

cefoxitin, linezolid, tigecycline

M chelonae

Syndromes

  • Skin, soft tissue, and bone infections are most common.

  • Pulmonary disease occurs but is less common.

  • Keratitis (associated with contact lens wear, ocular surgery, and laser-assisted in-situ keratomileusis procedures).

Treatment

  • Combination therapy is recommended. Active drugs vary and should generally be based on in vitro susceptibility testing.

  • The rRNA methylase gene (erm) is not present in M chelonae. Macrolide agents are generally active (although resistance can develop by other mechanisms).

  • Tobramycin generally is more active than amikacin.

  • For corneal infections, combination topical and systemic therapy is recommended, along with close ophthalmology management.

    • Corneal transplantation may be required for more complex or severe cases

Table 92. Treatment for M chelonae

Preferred drugs

clarithromycin or azithromycin, tobramycin, imipenem, linezolid

Alternatives

fluoroquinolones, doxycycline-minocycline, sulfonamides, clofazimine, tigecycline

M abscessus Complex

  • M abscessus subspecies abscessus is much more drug resistant than other organisms in this complex. The erm gene is commonly expressed.

  • M abscessus subspecies massiliense (M massiliense) is more treatable; it usually has no functional erm gene (macrolides are generally active) and has better treatment outcomes.

  • M abscessus subspecies bolletti (M bolletti) genetically is very similar to M massiliense but generally is macrolide resistant.

Syndromes

  • Pulmonary disease (very difficult to cure because of limited drug treatment options)

  • Skin and soft tissue infections (through direct contact or secondary to disseminated disease)

  • CNS infections (rare; may cause meningitis or cerebral abscesses)

  • Disseminated disease (most commonly affects immunocompromised host)

  • Ocular or corneal infections

Treatment

  • Combination therapy is recommended. Active drugs vary and should generally be based on in vitro susceptibility testing (caution with delayed erm gene expression).

  • Cefoxitin or imipenem can be included in therapy, despite relatively elevated MIC values.

Table 93. Treatment for M abscessus Complex

Preferred drugs

macrolides, IV amikacin, cefoxitin (a common or preferred 3-drug regimen)

Alternatives

fluoroquinolones, imipenem, linezolid, tedizolid, clofazimine, tigecycline, bedaquiline, aerosolized amikacin

M smegmatis Group

  • M smegmatis group consists of M smegmatis sensu stricto, M goodii, and M wolinskyi.

Syndromes

  • Clinical disease is uncommon; associated with lymphadenitis, osteomyelitis, postsurgical wound infections, intravenous catheter infections.

Treatment

  • Combination therapy is recommended. Active drugs vary and should generally be based on in vitro susceptibility testing (erm gene expression may be present).

  • M wolinskyi is resistant to tobramycin but typically is sensitive to amikacin.

Table 94. Treatment for M smegmatis Group

Preferred drugs

amikacin IV, sulfamethoxazole, doxycycline, moxifloxacin, ciprofloxacin

Alternatives

cefoxitin, imipenem, macrolides (variable resistance reported), ethambutol

M immunogenum

Syndromes

  • Typically from contaminated water sources, including those used in metal working or cutting.

  • Can produce hypersensitivity pneumonitis.

Treatment

  • Combination therapy is recommended; optimal treatment program is unknown. Commonly drug resistant, but it is erm gene negative.

  • For hypersensitivity pneumonitis, the main therapy is corticosteroids plus removal of the source of infection. Antimicrobial therapy is given in more severe or refractory cases.

Table 95. Treatment for M immunogenum

Preferred drugs

macrolides, amikacin, tigecycline

Alternatives

linezolid, imipenem

M mucogenicum

Syndromes

  • Most commonly will cause central venous catheter infections with secondary bloodstream infections.

  • Less commonly will cause peritoneal dialysis catheter infections.

  • Occasional skin or soft tissue infections in immunosuppressed patients or after trauma.

  • Common contaminant in isolates from respiratory secretions.

Treatment

  • Combination therapy is recommended. Active drugs vary and should generally be based on in vitro susceptibility testing.

  • For endovascular line infections, intravenous catheter removal is required.

  • More drug susceptible compared with other rapidly growing mycobacterium species.

Table 96. Treatment for M mucogenicum

Preferred drugs

amikacin, macrolide, cefoxitin, fluoroquinolones, sulfamethoxazole, imipenem

Alternatives

amoxicillin, amoxicillin-clavulanate, linezolid, doxycycline or minocycline

M scrofulaceum

Syndromes

  • Cervical lymphadenitis in young children

  • Chronic cutaneous disease; bone and joint disease

  • Pulmonary disease (less common), isolation after recovery from disease may be due to contamination

Treatment

  • Optimal treatment regimen is unknown.

  • Combination therapy is recommended; M scrofulaceum can be multidrug resistant. Active drugs vary and should generally be based on in vitro susceptibility testing.

  • Surgical excision for localized lymphadenitis and cutaneous disease.

Table 97. Treatment for M scrofulaceum

Consider combination therapy

macrolide, fluoroquinolone

Alternatives

Not well defined; possible activity with isoniazid, rifamycin, ethambutol, minocycline

M haemophilum

  • Wide geographic distribution (Europe, United Kingdom, Israel, Africa, Fiji, Australia, Canada, and US).

  • More common and pronounced disease in immunocompromised patients (eg, transplant recipients, patients receiving long-term corticosteroids, HIV-positive or AIDS patients).

  • Fastidious in vitro growth; special in vitro growth requirements for hemin- or iron-containing compounds; growth at cooler (32°C) temperatures.

    • Commonly AFB-stain positive from tissue, but cultures may be negative

Syndromes

  • Cutaneous lesions are most common. Typically affect the extremities and can be chronic.

  • Lymphadenitis can occur in otherwise healthy children.

  • Septic arthritis

  • Disseminated disease may occur in immunosuppressed patients.

Treatment

  • Combination therapy is recommended. Active drugs vary and should generally be based on in vitro susceptibility testing.

  • In children and immunocompetent patients, isolated lymphadenitis may be treated with surgical excision alone.

Table 98. Treatment for M haemophilum

Preferred drugs

macrolide plus ciprofloxacin plus rifampin (or rifabutin)—a commonly preferred 3-drug regimen

Alternatives

doxycycline, sulfamethoxazole, amikacin, clofazimine

M terrae Complex

  • M terrae complex consists of M terrae, M triviale, M nonchromogenicum, M hiberniae, M arupense, M senuense, and M paraterrae.

Syndromes

  • Most commonly produces localized tenosynovitis. It often affects upper extremities, including wrists, hands, and fingers. Often associated with trauma.

  • Less commonly may lead to pulmonary disease (including cavitary disease), genitourinary, and gastrointestinal infections.

Treatment

  • Surgery may be required.

Table 99. Treatment for M terrae Complex

Preferred drugs

macrolide, ethambutol, rifampin

Alternatives

fluoroquinolone, linezolid, sulfamethoxazole, amikacin, ethionamide

M xenopi

  • Obligate thermophile; enhanced growth at 42ºC (commonly isolated from hot water taps and showerheads).

  • Common in Canada, United Kingdom, and other parts of Europe.

Syndromes

  • Commonly produces chronic pulmonary disease. Patients typically have underlying chronic lung disease, and multiple comorbidities are common.

  • May cause upper-lobe cavitary disease, and cavities may be large.

Treatment

  • Poor correlation between in vitro susceptibility testing and clinical response.

Table 100. Treatment for M xenopi

Preferred drugs

macrolide, ethambutol, rifampin (or rifabutin)

Alternatives

moxifloxacin, levofloxacin, streptomycin, amikacin; role of isoniazid remains unclear

M ulcerans

  • Geographic distribution in the tropical rain forests of Africa, Australia, southwestern Asia, South America, Central America, Papua New Guinea, and Malaysia.

  • Optimal growth at cooler (28-33ºC) temperatures; more commonly affects extremities; has a prolonged incubation period (>3 months) and slow growth.

  • Associated with minor penetrating trauma and concurrent or subsequent contact with contaminated soil or water.

Syndromes

  • African Buruli ulcer or Australian Bairnsdale ulcer: Cutaneous, necrotic, painless, progressive, granulomatous lesions. May involve large areas of skin and can become disfiguring.

Treatment

  • Wound débridement and skin grafting may be required.

  • Most agents are ineffective in the more advanced stages.

Table 101. Treatment for M ulcerans

Preferred drugs

macrolide, rifampin (or rifabutin), ethambutol, amikacin

Alternatives

sulfamethoxazole, tetracycline, moxifloxacin

M malmoense

  • Rare in the US but sometimes seen in Florida, Texas, and Georgia. More common in Northern Europe, Finland, Zaire, and Japan.

Syndromes

  • Pulmonary disease

  • Lymphadenitis

  • Less commonly may cause tenosynovitis, cutaneous disease, or disseminated disease.

Treatment

  • Poor correlation between in vitro susceptibility testing and clinical response.

  • Use of isoniazid is controversial (may or may not help).

Table 102. Treatment for M malmoense

Preferred drugs

rifampin (or rifabutin), ethambutol, macrolide, fluoroquinolone

Alternatives

isoniazid

M celatum

  • May cross-react with acridinium ester–labeled DNA probe used to identify M tuberculosis (AccuProbe; Gen-Probe, Inc; San Diego, CA).

Syndromes

  • Uncommon isolate; may cause respiratory disease in immunosuppressed patients.

Table 103. Treatment for M celatum

Preferred drugs

macrolide, fluoroquinolone, rifabutin (not rifampin), ethambutol

Alternatives

amikacin, isoniazid, pyrazinamide

M genavense

  • Difficult to grow in culture; requires supplemented media.

Syndromes

  • Disseminated disease in immunosuppressed patients (closely resembles disseminated MAC).

  • May involve blood, bone marrow, liver, enteric tissue, and spleen (splenomegaly is common).

Table 104. Treatment for M genavense

Preferred drugs

macrolide, rifampin or rifabutin

Alternatives

fluoroquinolone, amikacin, ethambutol, clofazimine

M simiae Complex

  • M simiae complex consists of M simiae spp, M sherrisii, M lentiflavum, M triplex, M heidelbergense, and M palustre.

  • Geographic distribution includes Israel, Cuba, and southwestern US (Texas, Arizona, New Mexico).

Syndromes

  • Pulmonary disease (uncommon; typically in immunocompromised patients or those with chronic lung disease)

  • Intra-abdominal infection (less common)

Treatment

  • M simiae spp has the highest level of drug resistance and generally correlates with poorer outcomes.

  • M sherrisii, M lentiflavum, M triplex, M heidelbergense, and M palustre are usually more drug susceptible.

  • Susceptibility data may not correlate with clinical outcome.

  • Rifampin plus ethambutol synergy is seen for M simiae complex members; however, this combination typically is not effective for M simiae subspecies.

Table 105. Treatment for M simiae Complex

Preferred drugs

clarithromycin, rifampin or rifabutin, ethambutol (for M simiae spp, consider clarithromycin plus moxifloxacin plus sulfamethoxazole)

Alternatives

sulfamethoxazole, linezolid, clofazimine, amikacin

M szulgai

  • Infections are rare; M szulgai is usually not a contaminant and typically affects immunosuppressed host.

  • AFB stain may show some banding (similar to that for M kansasii).

Syndromes

  • Pulmonary disease has a similar presentation to that of TB.

  • May also cause extrapulmonary disease such as osteomyelitis, joint infection, and skin and soft tissue infection (rare).

Treatment

  • More drug susceptible compared with many other NTMs and typically favorable treatment outcomes.

Table 106. Treatment for M szulgai

Preferred drugs

macrolide, rifampin, ethambutol

Alternatives

moxifloxacin, levofloxacin, isoniazid, amikacin, pyrazinamide

Medication Dosing for NTM Infections

Treatment Principles

  • Obtain CBC, creatinine, liver function tests at baseline, 2 weeks after starting combination therapy, and then monthly thereafter (more frequently if there are abnormalities or adverse symptoms).

  • May consider a staggered start or titration of medications and doses in patients with MAC who are elderly or petite. May consider in other NTM infections if the clinical scenario is appropriate.

  • For patients with cavitary or severe pulmonary disease, consider daily dosing rather than thrice-weekly dosing.

  • Several of these agents may prolong the QTc (macrolides, quinolones, clofazimine, bedaquiline). Consider ECG monitoring if patients are receiving these or other medications that may prolong the QTc or if patients have cardiac dysrhythmia.

Table 107. Medication Dosing for NTM Therapies

Medication

Dosing (Assuming Normal Renal Function)

Special or Additional Monitoring

amikacin IV

15 mg/kg Monday-Friday or 3 times per week

Consider starting with 8-10 mg/kg per day for elderly patients and those with mild renal impairment; titrate upward to goal Cmax

Obtain peak levels 2 and 6 hours after dose until therapeutic (goal back-extrapolated Cmax should be 35-45 mcg/mL); trough should be undetectable

If 2- and 6-hour postdose levels are not available, consider checking a 1-hour postinfusion “peak” with a target range of 25-35 mcg/mL

After reaching therapeutic levels, continue monitoring with weekly troughs and weekly SCr

Obtain audiograms at baseline and monthly

amikacin inhalation

250 mg/mL solution diluted with 3 mL 0.9% NaCl daily initially

If needed, can titrate up to 500 mg bid if no dysphonia

Administer via nebulizer

Obtain amikacin trough and SCr values after 1-2 weeks of therapy, then repeat in 1 month

Obtain audiograms at baseline and then monthly

amoxicillin or amoxicillin-clavulanate

500 mg tid

875 mg bid

None

azithromycin

250 mg oral daily or 500 mg 3 times per week

May consider 500 mg daily

Consider ECG monitoring if additional risk factors are present

Obtain audiograms at baseline, 1 month, and then every 3 months

bedaquiline

400 mg daily for 2 weeks, then 200 mg 3 times per week

Add Ca+, Mg+, and K+ to scheduled laboratory tests

Obtain ECG at baseline, 2 weeks, 12 weeks, and 24 weeks after initiation

clarithromycin

500 mg oral bid or 500 mg bid 3 times per week

Consider ECG monitoring if additional risk factors are present

Obtain audiograms at baseline, 1 month, and then every 3 months

cefoxitin

Inpatient: 1-2 g IV q6-8h

Outpatient: 3 g IV q12h

Obtain weekly CBC with differential, SCr, and ALT

ciprofloxacin

500-750 mg oral bid

Consider ECG monitoring if additional risk factors are present

clofazimine

100 mg daily

Consider ECG monitoring if additional risk factors are present

doxycycline

100 mg oral bid

None

ethambutol

15-25 mg/kg per day oral or 25-30 mg/kg 3 times per week

Perform eye examination at baseline and monthly visual acuity tests or color discrimination tests (Ishihara)

Perform funduscopic check at baseline and every 3 months

ethionamide

250 mg oral once per day initially; titrate up to a maximum of 1 g/day (in 3-4 divided doses) every 1-2 days; recommend checking serum drug levels to titrate dosing

Obtain baseline and monthly ALT and AST, blood glucose checks (more frequently for patients with diabetes mellitus)

Obtain TSH at baseline and every 3 months while receiving therapy

Perform eye examination at baseline and monthly visual acuity tests or color discrimination tests (Ishihara)

imipenem-cilastatin

1 g IV q12h (preferred); may consider 500 mg IV q12h for small, frail, or elderly patients

This is the preferred carbapenem for NTM infections

Obtain SCr, CBC with differential, and ALT weekly

isoniazid

5 mg/kg per day oral (maximum of 300 mg)

None

levofloxacin

500 mg daily

Consider ECG monitoring if additional risk factors are present

linezolid

600 mg oral or IV daily (may reduce to 300 mg/day in select cases or for drug intolerance)

Check CBC with differential weekly for 2 weeks, then every other week after that if blood counts are stable

minocycline

100 mg oral bid

None

moxifloxacin

400 mg oral daily

Consider ECG monitoring if additional risk factors are present

rifampin

10 mg/kg per day (maximum of 600 mg); may dose 3 times per week

Ensure liver function tests include ALT, AST, and bilirubin

rifabutin

300 mg/day oral daily; may dose 3 times per week

None

tigecycline

50 mg IV q24h (may consider lower dose of 25 mg for select patients who cannot tolerate higher dosing)

Obtain SCr, CBC with differential, ALT weekly

TMP-SMX

1 DS tab oral bid

Add K+ checks to scheduled laboratory tests (baseline, every 2 weeks for 1 month, then monthly)

tobramycin IV

5-7 mg/kg q24h IV daily

Obtain peak level 2 and 6 hours after dose until therapeutic (goal back-extrapolated Cmax should be 20-30 mcg/mL); trough should be undetectable

Obtain weekly CBC with differential, SCr, tobramycin troughs weekly (should remain <1.2 mcg/mL)

Obtain audiograms and clinical vestibular function tests at baseline and monthly

Therapeutic Drug Monitoring

  • When therapeutic drug monitoring may be helpful

    • HIV infection

    • Gastrointestinal abnormalities

    • Malnutrition

    • Renal dysfunction

    • Hepatic dysfunction

    • Not responding to therapy

  • Timing and goal Cmax levels

    • After a minimum of 1-2 weeks of therapy (for steady state achievement)

    • To measure Cmax, typically obtain peak level 2 hours after taking the oral dose

      • May obtain additional levels post-dose (eg, 6 hours) to determine peak plasma concentrations more accurately and to differentiate between delayed absorption and malabsorption

Table 108. Therapeutic Drug Monitoring

Medication

Timing for Peak, h

After Dose

Target Cmax, mg/L

azithromycin

2-3

0.2-0.7

ciprofloxacin

2-3

4-6

clarithromycin

2-3

2-7

clofazimine

2-3

0.5-4

ethambutola

2-3

2-3

2-6

4-12

isoniazida

1-2

1-2

3-5

9-15

levofloxacin

2

8-12

linezolid

2

Keep level >MIC

moxifloxacin

2

3-5

rifabutin

3

0.3-0.9

rifampin

2

8-24

tigecycline

1

1

a Assuming daily dosing. If dosing ethambutol twice a week, aim for a Cmax of 4-12 mg/L; if dosing isoniazid twice a week, aim for a Cmax of 9-15 mg/L.

Table 109. NTM Syndrome Duration of Therapy

Site of NTM Infection

Duration of Treatment or Adjunct Therapies

Pulmonary

Minimum 12 months after sputum culture conversion to negative

Disseminated disease

Minimum of 12 months (after sputum culture conversion to negative, if applicable)

May need secondary suppression beyond 12 months for advanced HIV infection until appropriate immunologic reconstitution

Lymphadenitis

Surgery alone may be curative in pediatric cases with select NTM cervical lymphadenitis (eg, MAC)

Combination drug therapy recommended when complete débridement is not possible

Skin and soft tissue

Typically 4-6 months of combination therapy

Vertebral disease

12 months of combination therapy is preferred

Other bone disease

6-9 months of combination therapy

Catheter-associated bloodstream infection

Remove IV catheter if possible

Treatment lasts typically 4-12 weeks, depending on immunologic status of the host and the NTM species

Pulmonary Hygiene and CPT

Pulmonary hygiene and CPT are especially important in patients with bronchiectasis, even if the disease is mild. Healthy habits and adequate hydration are also recommended. Consider a nurse education session with demonstration to initiate the use of nebulizers, appropriate bronchodilator inhaler technique, and the use of a flutter-valve device (eg, Acapella [Smiths Medical] or Aerobika [Monaghan Medical Corporation] oscillating positive expiratory pressure devices). Consider pulmonary consultation for moderate to severe cases.

  • Airway clearance or CPT techniques.

  • Use of an Acapella or Aerobika device or flutter valve.

  • Aerobika is a cleanable device; daily cleaning is recommended for patients with chronic airway bacterial colonization.

  • More advanced cases should have CPT such as postural drainage, percussion devices, and high-frequency chest wall oscillation (vest therapy).

  • No data are available to compare various CPT techniques.

  • Mucolytic agents

  • Hypertonic NaCl nebulizer solutions are safe and restore airway surface liquid in patients with CF and bronchiectasis.

  • 7% NaCl nebulizer solution in CF decreases exacerbations, increases short-term pulmonary function, and decreases symptoms.

  • Inhaled mannitol does not decrease the number of exacerbations but increases time to exacerbations and improves quality of life.

  • Data are limited and inconclusive regarding the effect of hypertonic NaCl nebulizer solution in patients with non-CF bronchiectasis, probably due to differences in methodology, patient groups, and findings.

  • Nebulized hypertonic saline (3-7%) can cause bronchoconstriction in patients with reactive airway disease. Consider use of bronchodilators or nurse monitoring to initiate hypertonic NaCl nebulization therapy in patients with coexisting asthma and significant chronic obstructive pulmonary disease.

  • DNase is used in patients with CF; acetylcysteine can be used in patients with or without CF.

Bronchodilators (inhaled) are used for patients with bronchodilator reversibility on pulmonary function tests (eg, short-acting β‎-agonist) but can also be used to optimize bronchial mucociliary clearance. Individualize pulmonary hygiene and CPT, depending on severity of bronchiectasis and clinical context.

  • Mild bronchiectasis, asymptomatic (<1 exacerbation/year).

    • Emphasize healthy habits and consider daily use of bronchodilators and flutter-valve device

    • Consider adding 3% NaCl nebulizer solution daily if bacterial colonization is present with occasional symptoms or as needed for occasional exacerbations; CPT can be more intensive, depending on the clinical setting and during acute exacerbation

  • Moderate bronchiectasis with exacerbations, signs of mucous plugs, recurrent infections, or ongoing infection (eg, MAC pulmonary disease).

    • Twice-daily use of bronchodilators, 3% NaCl nebulizer solution, flutter-valve device for treatment maintenance (thrice daily during active disease)

  • Severe bronchiectasis with frequent exacerbations.

    • Aggressive CPT: Use bronchodilators, 7% NaCl nebulizer solution, and flutter-valve device or postural drainage or percussion device or vest (all tid or qid, can use as needed for pulmonary congestion or wheezing)

    • Inhaled DNase for patients with CF

Suggested Reading

Griffith DE, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. Am J Respir Crit Care Med. 2007 Feb 15;175(4):367–416. Erratum in: Am J Respir Crit Care Med. 2007 Apr 1;175(7):744–5. Dosage error in article text.Find this resource:

Kasperbauer SH, De Groote MA. Clin Chest Med. 2015 Mar;36(1):67-78. Epub 2014 Nov 5.Find this resource:

Philley JV, Griffith DE. Clin Chest Med. 2015 Mar;36(1):79–90. Epub 2014 Nov 6.Find this resource:

Stout JE, et al. Int J Infect Dis. 2016 Apr;45:123–34. Epub 2016 Mar 11.Find this resource:

Fungal Infections

Select Taxonomy

Yeast

  • Candida

  • Cryptococcus neoformans and C gattii

  • Saccharomyces, Trichosporon, etc

Dimorphic Fungi

Two different growth forms: 1) outside the body (25°C), they grow as a mold, produce hyphae, and undergo asexual reproduction via spores; 2) inside the body (37°C), they grow in a yeast form.

  • Histoplasma capsulatum

  • Blastomyces dermatitidis

  • Coccidioides immitis and C posadasii

  • Paracoccidioides brasiliensis

  • Sporothrix schenckii

  • Penicillium marneffei

Filamentous Fungi (Molds)

  • Aspergillus spp

  • Agents of mucormycosis

    • Absidia spp

    • Apophysomyces spp

    • Basidiobolus spp

    • Conidiobolus spp

    • Cokeromyces spp

    • Cunninghamella spp

    • Mortierella spp

    • Mucor spp

    • Rhizomucor spp

    • Rhizopus spp

    • Saksenaea vasiformis

    • Syncephalastrum spp

  • Agents of entomophthoromycosis

    • Conidiobolus spp

    • Basidiobolus spp

  • Dematiaceous fungi

    • Alternaria spp

    • Aureobasidium spp

    • Bipolaris spp

    • Chaetomium spp

    • Cladophialophora bantiana

    • Curvularia spp

    • Drechslera spp

    • Epicoccum spp

    • Exophiala spp

    • Fonsecaea pedrosoi

    • Lecythophora spp

    • Madurella spp

    • Ochroconis spp

    • Phialophora spp

    • Scedosporium prolificans

    • Scytalidium dimidiatum

    • Ulocladium spp

    • Wangiella dermatitidis

  • Other pathogenic molds

    • Fusarium spp

    • Scopulariopsis spp

Select Fungi

Candida

Risk Factors for Localized, Mucocutaneous Candidiasis and Invasive or Disseminated Disease

  • Prolonged ICU stay with Candida colonization of multiple nonsterile sites

  • Prolonged use of systemic antibacterial agents (especially those with broad-spectrum activity)

  • Central venous catheters

  • Parenteral nutrition

  • Bowel perforation and surgery involving the intestinal wall (especially in patients receiving broad-spectrum antibacterial therapy)

  • Immunosuppressive conditions, including hematologic and solid malignancies, neutropenia, organ transplantation, diabetes mellitus, and corticosteroid use

  • Burn wounds

  • Estrogen therapy, oral contraceptive use, pregnancy (vaginal candidiasis)

  • Severe acute pancreatitis

  • Hemodialysis

  • In neonates, risk is increased by premature birth, low birth weight, low Apgar scores, select congenital malformations, etc.

Clinical Diseases

  • Oral thrush: More typical in immunosuppressed patients (eg, HIV, corticosteroids).

    • Pseudomembranous: White, creamy plaques on an inflamed base (eg, palate, tongue, buccal mucosa)

    • Hyperplastic: Candidal leukoplakia; white lesions that do not wipe off but respond to therapy

    • Erythematous (atrophic): Spotty or confluent red patches (often underdiagnosed)

    • Angular cheilitis (perlèche): Erythema and fissures at the corners of the mouth

  • Esophagitis: More common in immunosuppressed patients, although it occasionally occurs in immunocompetent patients; odynophagia and dysphagia are common; usually (but not always) presents with oral thrush.

  • Vaginitis (vaginal candidiasis): Associated with pregnancy, high-estrogen oral contraceptives, uncontrolled diabetes mellitus, tight-fitting clothing, antibiotics, and dietary factors.

    • Affects 75% of women of childbearing age

    • 40% of affected women have a second episode; 5% have recurrent disease (>4 episodes per year)

  • Cutaneous syndromes

    • Intertriginous infection: Affects warm, moist areas of the body; more common among patients with diabetes mellitus or obesity

    • Folliculitis: Infection of the hair follicles; more common in IV drug abusers and immunocompromised patients

    • Balanitis: Infection of the glans penis; may also involve the scrotum

    • Paronychial infection: Swelling, tenderness, erythema around nail

    • Disseminated: Macronodular lesions; lesions resemble ecthyma gangrenosum

  • Urinary candidiasis: Colony count from urine culture is not directly predictive of UTI; isolation of Candida from urine cultures often reflects colonization, not infection—clinical judgment is required.

  • Disseminated disease (acute or subacute)

    • Candidemia: Fourth most-common cause of nosocomial bloodstream infections in the US; only 25% of patients with extensive organ disease have positive blood cultures; ocular fundus should be evaluated for possible secondary involvement

    • Ocular candidiasis: All patients with candidemia should have a dilated retinal examination to evaluate for secondary hematogenous-driven fungal endophthalmitis and chorioretinitis

    • Meningitis: Especially affects patients with IV drug abuse; may occur with neurosurgery and CNS shunt infections

    • Osteomyelitis: Usually from hematogenous dissemination

    • Peritonitis: From peritoneal dialysis, bowel surgery, or perforated bowel

    • Endocarditis: Most common form of fungal infective endocarditis; large vegetations are typical

  • Hepatosplenic candidiasis (chronic disseminated candidiasis)

    • Typically seen in patients with hematologic malignancies; occurs after chemotherapy with prolonged neutropenia

    • May present as persistent fever with neutropenia, without focal signs or symptoms; unresponsive to antibacterial therapy; ultrasound and CT results may be normal initially during the period of neutropenia

    • With recovery from neutropenia, fever continues, with elevation of liver enzymes (especially ALP); abdominal ultrasound, CT, or MRI commonly shows multiple small, round, hypoechoic, or low-attenuated lesions scattered throughout the liver and spleen; lesions can later calcify

    • Predominantly a clinical and radiographic diagnosis; liver biopsy is commonly false-negative; blood cultures are usually negative

Treatment

Note: Preferred therapy is determined by the syndrome and type of Candida.

  • Oral thrush: Oral nystatin, clotrimazole troches, oral fluconazole

  • Esophagitis: Oral fluconazole, other azoles,a or an echinocandinb; for refractory disease, use an amphotericin B product

  • Vaginitis: Topical or oral azolea therapy

  • Ocular infections, including endophthalmitis and retinitis: Combination amphotericin B product plus flucytosine for serious or sight-threatening disease; fluconazole for less-severe disease (or step-down maintenance therapy); oral voriconazole for fluconazole-resistant Candida infection

  • Candidemia

    • Nonneutropenic host: Use fluconazolec or an echinocandinb; administer an amphotericin B product for refractory disease; for uncomplicated candidemia, treat for 2 weeks after last positive blood culture and improved symptoms

    • Neutropenic host: An echinocandin, an amphotericin B product, fluconazolec (not recommended for initial therapy in patients with recent azole exposure), voriconazole

    • Central catheters infected with Candida should be removed

  • Chronic disseminated candidiasis: Use fluconazolec or an amphotericin B product; alternative treatments include other azolesa and echinocandinsb; treatment duration is typically months for clinical response and radiographic maturation (multiple scattered, low-attenuation foci can persist, despite successful therapy, because of focal scarring and chronic inactive granulomatous changes).

  • Additional treatment information: See guidelines for treatment of candidiasis. (Pappas PG, et al; Infectious Diseases Society of America. Clin Infect Dis. 2009 Mar 1;48[5]:503-35.)

Cryptococcus

General Information and Endemic Areas

  • Encapsulated, round yeast (4-6 micrometers); neurotropic fungal infection.

  • Common sources include pigeon and other select bird droppings (C neoformans); contaminated soil; eucalyptus trees (C gattii).

  • C neoformans is distributed worldwide; commonly found in soil contaminated by pigeon and other bird droppings; accounts for most Cryptococcus infections.

  • C gattii (formerly known as C neoformans var gattii) cases are concentrated in Vancouver Island and the surrounding areas of Canada and the northwest US; cases also have been identified in other global regions; high propensity to cause infection in immunocompetent patients; high likelihood of producing CNS or pulmonary cryptococcomas (or both); some strains have an elevated MIC to azoles.

Clinical Disease

Note: Disease typically affects immunosuppressed patients.

  • Pulmonary cryptococcosis: Lungs are the portal of entry and the most common site of infection; can readily disseminate to other organs (especially CNS).

  • CNS disease: Includes meningitis, meningoencephalitis, and cerebral cryptococcomas; clinical symptoms may be acute (eg, headache, fever, nuchal rigidity), subacute, or chronic (eg, altered mental status, headache).

    • Hydrocephalus or high opening CSF pressure: >20 cm H2O is common; serial lumbar punctures or ventriculoperitoneal shunts often help reduce spinal and ventricular fluid pressure

    • Negative prognostic factors: Abnormal or reduced mental status; CSF cryptococcal antigen titer >1:1,024; CSF leukocytes <20 cells/mcL

  • Cutaneous: Wide variation in presentation (eg, papules, plaques, cellulitis, tumors); cutaneous cryptococcal lesions signal dissemination; cryptococcal skin papules can resemble molluscum contagiosum.

  • Other: Bone and joint disease; renal disease.

Diagnosis

Note: Any patient with a positive serum cryptococcal antigen or a positive blood or urine culture should have a CSF analysis via lumbar puncture to evaluate for CNS cryptococcal disease.

  • Cryptococcal antigen (serum and CSF): About 95% sensitive for disseminated or meningeal cryptococcal disease; false-positive results can occur with Trichosporon beigelii and with Stomatococcus and Capnocytophaga infections.

  • India ink: Visualization of polysaccharide capsule; 75% sensitivity in CSF cryptococcal disease.

  • Cultures: Blood, CSF, urine

Treatment

  • Selection and duration of antifungal therapy depend on location of disease and immune status of host.

  • See Tables 110-113.

Table 110. Cryptococcal Meningoencephalitis in HIV-Infected Patients

Regimen

Duration

Induction therapya

Liposomal amphotericin B (3-4 mg/kg per day) OR amphotericin B lipid complex (5 mg/kg per day) OR amphotericin B deoxycholate (0.7-1.0 mg/kg per day); PLUS flucytosine (25 mg/kg qid)

2 weeks

amphotericin B deoxycholate (0.7-1.0 mg/kg per day) OR liposomal amphotericin B (3-4 mg/kg per day) OR amphotericin B lipid complex (5 mg/kg per day)

4-6 weeks

Alternatives for induction therapyb

amphotericin B product (see above) PLUS fluconazole (800 mg per day)

2 weeks

fluconazole PLUS flucytosine

8 weeks

fluconazole (>800 mg per day; some experts favor 1,200 mg per day if used alone)

10-12 weeks

itraconazolec (200 mg bid)

10-12 weeks

Consolidation therapy

Fluconazole (400 mg per day)

≥8 weeks

Maintenance (suppressive) therapy

Fluconazole (200 mg per day)

≥1 year

Alternatives for maintenance therapy

itraconazolec (400 mg per day)

≥1 year

amphotericin B deoxycholatec (1 mg/kg per week); less effective than azoles

≥1 year

Notes

  • Monitor CSF opening pressure; repeat lumbar punctures may be needed

  • Can stop maintenance therapy (during effective HAART) in HIV-infected patients with a CD4 count >100 cells/mcL and undetectable (or very low) HIV viral load for ≥3 months after completing a minimum 12-month course of antifungal therapy

  • Restart antifungal maintenance therapy if the CD4 count decreases to <100 cells/mcL

a Begin HAART 2-10 weeks after initiating antifungal treatment.

b In unique clinical situations when primary recommendations are not available, alternative regimens may be considered but are not encouraged.

c Inferior to primary recommendation; monitor serum levels if itraconazole is used.

Perfect JR, et al. Clin Inf Dis. 2010 Feb 1;50(3):291-322

Table 111. Cryptococcal Meningoencephalitis in Organ Transplant Recipients

Regimen

Duration

Induction therapya

liposomal amphotericin B (3-4 mg/kg per day) OR amphotericin B lipid complex (5 mg/kg per day); PLUS flucytosine (25 mg/kg qid)

2 weeks

Alternatives for induction therapy

liposomal amphotericin B (6 mg/kg per day) OR amphotericin B lipid complex (5 mg/kg per day) OR amphotericin B deoxycholateb (0.7 mg/kg per day)

4-6 weeks

Consolidation therapy

fluconazole (400-800 mg per day)

8 weeks

Maintenance (suppressive) therapy

fluconazole (200-400 mg per day)

6 months to 1 year

Note

  • Monitor CSF opening pressure; repeat lumbar punctures may be needed

a Immunosuppressive management may require sequential or stepwise reductions.

b Many transplant recipients have been successfully treated with amphotericin B deoxycholate; however, treatment has considerable risk of added renal dysfunction with calcineurin inhibitor use, and the effective dose is imprecise.

Perfect JR, et al. Clin Inf Dis. 2010 Feb 1;50(3):291-322

Table 112. Cryptococcal Meningoencephalitis in HIV-Negative, Nontransplant Patients (Based on Limited Data)

Regimen

Duration

Induction therapy

liposomal amphotericin B (3-4 mg/kg per day) OR amphotericin B lipid complex (5 mg/kg per day) OR amphotericin B deoxycholate (0.7-1.0 mg/kg per day); PLUS flucytosine (25 mg/kg qid)

≥4 weeksa,b

amphotericin B deoxycholatec (0.7-1.0 mg/kg per day)

≥6 weeksa,b

amphotericin B product PLUS flucytosine (25 mg/kg qid)

2 weeksb,d

Consolidation therapy

fluconazolee (400-800 mg per day)

8 weeks

Maintenance therapy

fluconazole (200 mg per day)

6-12 months

a Four weeks of induction therapy is appropriate for patients with meningitis who have 1) no neurologic complications, 2) no significant underlying diseases or immunosuppression, and 3) no viable yeast from CSF culture after 2 weeks of treatment.

b For prevention of early relapse after induction therapy, fluconazole consolidation and maintenance therapy are recommended.

c For flucytosine-intolerant patients.

d For patients who have 1) a low risk of therapeutic failure, as determined by diagnosis of early cryptococcal infection, 2) no severe immunosuppression, and 3) an excellent clinical response to the initial 2-week antifungal combination therapy.

e The higher dose of fluconazole (800 mg per day) is recommended for patients with normal renal function who undergo the 2-week induction regimen.

Perfect JR, et al. Clin Inf Dis. 2010 Feb 1;50(3):291-322

Table 113. Nonmeningeal Cryptococcosis

Regimen

Duration, months

Pulmonary disease in immunosuppressed and immunocompetent patients

Mild-to-moderate pulmonary cryptococcosis—fluconazole (400 mg per day)

6-12

Severe pulmonary cryptococcosis—same treatment as for CNS disease

12

Patients with nonmeningeal, nonpulmonary cryptococcosis

Cryptococcemia—same treatment as for CNS disease

12

Nonpulmonary, non-CNS disease; single-site disease without fungemia in an immunocompetent patient—fluconazole (400 mg per day)

6-12

Note: Follow-up monitoring of serum cryptococcal antigens during therapy is not consistently helpful in predicting outcome

  • In immunosuppressed patients with pulmonary cryptococcosis, CNS involvement should be excluded by a spinal fluid evaluation

  • In immunocompetent patients with pulmonary cryptococcosis, a spinal fluid evaluation should be considered to exclude asymptomatic CNS involvement; however, spinal fluid evaluation is not required for patients with asymptomatic pulmonary nodule or infiltrate, no symptoms of CNS infection, and a negative or very low serum cryptococcal antigen level

  • For patients who are fluconazole intolerant, use itraconazole, voriconazole, or posaconazole for pulmonary cryptococcosis

Perfect JR, et al. Clin Inf Dis. 2010 Feb 1;50(3):291-322

Histoplasma capsulatum (H capsulatum var capsulatum)

General Information

  • Intracellular yeast (1-2×3 micrometers); calcium deposits are common in tissue (eg, lungs, liver, spleen).

  • H capsulatum is associated with soil contaminated by bird and bat droppings; common locations are chicken (and other bird) roosts, caves.

Endemic Areas

  • Found worldwide but is more common in the Mississippi and Ohio River valleys, in the south-central US, and in parts of Central and South America, Africa, and southeast Asia.

Clinical Disease

  • Acute pulmonary histoplasmosis: Often self-limiting, patchy pneumonitis; hilar and mediastinal adenopathy is common; lung infiltrate can be diffuse with heavier exposure or immunosuppression; erythema nodosum may be present.

  • Histoplasmoma: Small, calcified lung nodules (inactive), often with hilar calcification; may persist after resolution of the primary infection.

  • Chronic pulmonary histoplasmosis: Usually present in the upper lobes, often in cavities; can mimic tuberculosis radiologically; cavitary findings are often called “marching cavity” because the cavities gradually enlarge in >50% of cases.

  • Mediastinal lymphadenitis and mediastinal granuloma: Granulomatous inflammation and enlarged mediastinal lymph nodes can occasionally result in secondary airway compression or superior vena cava syndrome.

  • Fibrosing mediastinitis: Exaggerated inflammatory response leads to extensive fibrotic tissue deposition in the mediastinum; can result in hypoxemia, dysphagia, and superior vena cava syndrome; limited treatment options include surgery.

  • Disseminated histoplasmosis (ie, extrapulmonary spread, progressive): Can involve multiple sites.

    • Adrenal gland disease: May lead to adrenal insufficiency

    • Hepatosplenomegaly: Lesions may later calcify

    • Cutaneous lesions: Erythematous maculopapular lesions

    • Ocular disease: 2 general forms

      • Choroiditis in association with progressive, disseminated histoplasmosis

      • Presumed ocular histoplasmosis—postinfectious inflammatory syndrome with choroidal retinal scars

    • Bone marrow disease: Leukopenia, anemia, thrombocytopenia

    • Infective endocarditis, pericarditis

    • CNS disease: Can present as basilar meningitis or cerebral mass lesions

    • Oropharyngeal ulcers: Usually occur with disseminated disease

    • African histoplasmosis

      • Caused by H capsulatum var duboisii; the yeast forms are large (7-15 micrometer), thick-walled, and typically lemon-shaped, with a narrow budding pattern

      • Predominately found in central and western Africa (in addition to infections by H capsulatum var capsulatum found elsewhere in Africa)

      • Disease may present as a subacute skin or bone granuloma; it also may disseminate and involve lymph nodes and other tissues

Diagnosis

  • Culture

  • Serology: Serologic testing is insensitive and commonly negative with active disease; low serology titers are less specific for disease but may be helpful if >1:32 or positive for the presence of H or M bands.

  • Tissue staining

  • Histoplasma antigen: From urine, blood, CSF

Table 114. Treatment of Histoplasmosis

Type of Histoplasmosis

Severe Disease

Mild to Moderate Disease

Pulmonary

   Acute

Liposomal amphotericin B (3 mg/kg per day) OR amphotericin B lipid complex (5 mg/kg per day) OR amphotericin B deoxycholate (0.7-1.0 mg/kg per day) for 1-2 weeks, followed by itraconazolea (200 mg bid) for 12 weeks

For symptoms lasting ≤4 weeks: None

Corticosteroid supplementation (optional)b

For symptoms lasting >4 weeks: itraconazolea (200 mg 1-2 times per day) for 6-12 weeks

   Chronic cavitary

itraconazolea (200 mg 1-2 times per day) for 12-24 months

Same as for severe disease

Disseminated

Liposomal amphotericin B (3 mg/kg per day) OR amphotericin B lipid complex (5 mg/kg per day) OR amphotericin B deoxycholate (0.7-1.0 mg/kg per day) for 1-2 weeks; followed by itraconazolea (200 mg bid) for at least 12 monthsc,d

itraconazolea (200 mg bid) for at least 12 monthsc

Meningitis

Liposomal amphotericin B (5 mg/kg per day) for 4-6 weeks, followed by itraconazolea (200 mg 2-3 times per day) for at least 12 months

Same as for severe disease

Mediastinal lymphadenitis

itraconazolea,e (200 mg 1-2 times per day) for 6-12 weeks in patients with symptoms that warrant treatment with corticosteroids or with symptoms lasting >4 weeks

Mild symptoms lasting <4 weeks: None

Mediastinal granuloma

Symptomatic patients: itraconazolea (200 mg 1-2 times per day) for 6-12 weeks

Asymptomatic patients: None

Fibrosing mediastinitis

Antifungal treatment is not usually indicated; stenting of obstructed vessels may be useful

Select casesf: itraconazolea (200 mg 1-2 times per day) for 3 months

Same as for severe disease

Pericarditis

Corticosteroids PLUS itraconazolea,e (200 mg 1-2 times per day) for 6-12 weeks

Hemodynamic compromise: Pericardial drainage

NSAIDs for 2-12 weeks

Rheumatologic

Corticosteroids PLUS itraconazolea,e (200 mg 1-2 times per day) for 6-12 weeks

NSAIDs for 2-12 weeks

a Give itraconazole as a loading dose (200 mg tid) for 3 days, followed by 200 mg bid thereafter (or once daily with mild disease). Serum itraconazole levels should be monitored after 2 weeks to ensure adequate enteric drug absorption. Alternative azoles with either less activity or less published clinical data include fluconazole, voriconazole, and posaconazole.

b Effectiveness of corticosteroids is controversial.

c Therapy should be continued until Histoplasma antigen concentration is <2 units/mL in urine or serum. Antigen levels should be monitored for 12 months after therapy has ended to watch for early relapse of infection.

d Lifelong suppressive therapy may be required in patients with AIDS and inadequate immune reconstitution (eg, response to HAART) and in other patients with significant and irreversible immunosuppression.

e If corticosteroids are used to treat pericarditis or rheumatologic syndrome, concurrent use of itraconazole is recommended to reduce the risk of progressive infection.

f Therapy is controversial and probably ineffective, except in cases of mediastinal lymphadenitis or mediastinal granuloma misdiagnosed as fibrosing mediastinitis.

Wheat LJ, et al. Clin Infect Dis. 2007 Oct 1;45(7):807-25

Blastomyces dermatitidis

General Information

  • Thick-walled, broad-based budding yeast (5-15 micrometer); commonly associated with riverbanks, soil, decaying matter, wood.

Endemic Areas

  • South-central, southeastern, and midwestern US; St Lawrence River basin.

Clinical Disease

  • Pulmonary disease: Acute or chronic pneumonia; chronic infection (common) can last 2-6 months with weight loss, night sweats, and occasional cavitation.

  • Skin disease: Most common extrapulmonary finding; can present as verrucous or ulcerative lesions; subcutaneous nodules or “cold abscesses,” black pepper–like lesions, or eschar formation.

  • Osteomyelitis: Occurs in up to 25% of extrapulmonary cases; noncaseating granulomas with suppuration and necrosis.

  • Genitourinary infection: Prostatitis, epididymo-orchitis.

  • CNS infection: Rare; more common in immunosuppressed patients.

Diagnosis

  • Culture

  • Tissue staining: Characteristic broad-based budding yeast

  • Serology: Serologic testing is insensitive and can be negative with active disease.

  • Blastomyces antigen: Urine, blood

Table 115. Treatment of Blastomycosis

Type of Blastomycosis

Severe Disease

Mild to Moderate Disease

Pulmonary

Liposomal amphotericin B or amphotericin B lipid complex (3-5 mg/kg per day) or amphotericin B deoxycholateb (0.7-1.0 mg/kg per day) for 1-2 weeks, followed by itraconazolea (200 mg bid) for 6-12 months

itraconazolea (200 mg 1-2 times per day) for 6-12 monthsc

Disseminated

Liposomal amphotericin B or amphotericin B lipid complex (3-5 mg/kg per day) or amphotericin B deoxycholateb (0.7-1.0 mg/kg per day) for 1-2 weeks, followed by itraconazolea (200 mg bid) for 12 months

itraconazolea (200 mg 1-2 times per day) for 6-12 months

Osteoarticular disease: treat for 12 months

CNS infection

Liposomal amphotericin B or amphotericin B lipid complex (5 mg/kg per day) for 4-6 weeks (preferred), followed by an oral azoled for at least 1 year

Same as for severe disease

Blastomycosis in the setting of immunosuppressione

Liposomal amphotericin B or amphotericin B lipid complex (3-5 mg/kg per day) or amphotericin B deoxycholateb (0.7-1.0 mg/kg per day) for 1-2 weeks, followed by itraconazolea (200 mg bid) for 12 monthsf

Same as for severe disease

a Give itraconazole as a loading dose (200 mg tid) for 3 days, followed by 200 mg bid thereafter (or once daily for mild disease). Serum itraconazole levels should be monitored after 2 weeks to ensure adequate enteric drug absorption.

b The entire course of therapy with amphotericin B deoxycholate can be given to a total of 2 g; however, most clinicians prefer to use step-down itraconazole therapy after the patient’s condition improves. Liposomal amphotericin B and amphotericin B lipid complex have fewer adverse effects.

c Spontaneous cure without treatment can occur in some immunocompetent patients with mild disease; however, consider treating all infected patients to prevent extrapulmonary dissemination.

d Step-down therapy can be done with fluconazole (800 mg per day), itraconazole (200 mg 2-3 times per day), or voriconazole (200-400 mg bid). Longer treatment may be required for immunosuppressed patients.

e Includes transplant recipients or patients with HIV infection, hematologic malignancies, or other forms of immunosuppression.

f Lifelong suppressive treatment may be required in patients with advanced HIV infection (AIDS) without adequate immune reconstitution (eg, response to HAART) and in other patients with irreversible immunosuppression.

Chapman SW, et al. Clin Infect Dis. 2008 Jun 15;46(12):1801-12

Coccidioides immitis and C posadasii

General Information

  • Large, round spherules (20-80 micrometers) containing many small endospores.

  • Coccidioides flourish just below the surface of desert soil; outbreaks have been associated with dust storms and construction projects.

  • Persons of African or Filipino ancestry and immunosuppressed patients have increased risk of disseminated disease.

Endemic Areas

  • Desert southwestern US, Mexico, Central America, and Argentina.

Clinical Disease

  • Acute coccidioidomycosis or primary disease: Often self-limiting.

    • Pulmonary disease: A type of community-acquired pneumonia (described below); pulmonary disease may present alone or in combination with rheumatologic, skin, and systemic symptoms

    • Immune-mediated syndromes

      • Migratory polyarthralgia (nondeforming), “desert rheumatism”

      • Erythema nodosum (more frequent in women), erythema multiforme (“the bumps”)

    • Valley fever: Symptoms same as above, plus fever, myalgia, malaise, peripheral blood eosinophilia

  • Pulmonary disease: Cough, pleurisy, fever, and weight loss 1-3 weeks after exposure; hilar adenopathy, pleural effusion, or cavitation.

    • Residual pulmonary nodules: Affects about 4% of patients after primary pneumonia

    • Coccidioidal pulmonary cavities: Typically thin-walled cavities (affects 2-8% of adults)

    • Ruptured cavities: Bronchopleural fistula can form; dyspnea and chest pain are common; can occur in young, healthy patients; not associated with immunosuppression

    • Chronic fibrocavitary pneumonia: Can occur in patients whose primary pneumonia fails to resolve

    • Diffuse, reticulonodular pneumonia: Affects immunosuppressed patients

  • Extrapulmonary disease

    • Cutaneous disease: Most common site of dissemination; granulomas; subcutaneous abscesses; plaques with wart-like appearance

    • Osteomyelitis and joint infections: Typically in weight-bearing joints

    • Meningitis and CNS disease: Common extrapulmonary site; basilar disease; CSF eosinophilia is commonly present; hydrocephalus is a frequent sequelae

    • Other (less common) sites: Endocrine glands, eyes, liver, kidneys, genitalia, prostate, peritoneal cavity

Diagnosis

Note: Peripheral blood and CSF eosinophilia may be present.

  • Culture

  • Tissue staining: Identify characteristic spherules containing endospores.

  • Serology: Can be false-negative early in the disease course.

    • Complement fixation: Height of the complement fixation titer can correlate with disease extent and response to therapy; the same laboratory should conduct serial or longitudinal complement fixation testing

    • Immunodiffusion

    • Enzyme immunoassay

  • Head imaging and CSF evaluation: Should be performed in patients with recently diagnosed coccidioidomycosis who have unusual, persistent, or progressive headache; altered mental status; unexplained nausea or vomiting; or new focal neurologic deficit.

Treatment

  • Antifungal treatment options include:

    • fluconazole (400 mg/day); higher dosing can be used initially for CNS disease (400-1,200 mg/day)

    • itraconazole (200 mg tid) for 3 days, followed by 200 mg bid thereafter; serum itraconazole monitoring is recommended after 2 weeks to ensure adequate enteric drug absorption

    • liposomal amphotericin B or amphotericin B lipid complex (3-5 mg/kg per day); or amphotericin B deoxycholate (0.7-1.0 mg/kg per day)

    • voriconazole and posaconazole are alternative azoles with anti-Coccidioides activity, but few publications describe clinical experience

  • Relapse is common, especially for meningitis.

  • Pulmonary disease

    • Acute, uncomplicated disease: May be observed without treatment; however, treatment with either fluconazole or itraconazole is recommended for 3-6 months for the following:

      • Immunosuppressive conditions, including diabetes mellitus

      • Significant or persistent pulmonary or extrapulmonary symptoms; loss of >10% body weight; chest radiograph with infiltrates in over half of 1 lung or in both lungs

      • Consider treatment in patients with serum complement fixation titer >1:16 or if patients are of Filipino or African descent (higher risk of dissemination)

    • Diffuse or progressive pulmonary disease: Administer amphotericin B product initially, followed by fluconazole or itraconazole for at least 1 year

    • Pulmonary nodule (asymptomatic): Monitor without treatment; follow radiologically for 2 years to ensure no progression

    • Pulmonary cavity

      • Asymptomatic (in an immunocompetent host): Typically not treated, but patients should be followed clinically and radiologically

      • Symptomatic: Antifungal therapy warranted (variable duration); check for bacterial superinfection; surgical resection considered when cavities are present for >2 years and if symptoms return after stopping antifungal therapy

      • Ruptured coccidioidal cavity in pleural space: Well-recognized complication; surgical decortication (resection) of the cavity is recommended; antifungal therapy with an oral azole (or amphotericin product if ≥2 surgical débridements are required)

    • Chronic fibrocavitary pneumonia: Antifungal therapy for at least 1 year and surgery for refractory lesions or hemoptysis

  • Osteoarticular disease: Antifungal therapy with surgical débridement; variable treatment duration (eg, 6-12 months), depending on disease location, extent, and response to therapy (eg, monitor erythrocyte sedimentation rate, C-reactive protein, and anti-Coccidioides complement fixation serologic titers).

  • Meningitis and other CNS infections

    • Therapy with fluconazole (400-1,200 mg daily) is preferable—consider beginning with high-dose fluconazole (800-1,000 mg daily); alternative treatments include IV or intrathecal amphotericin B product, voriconazole, and itraconazole

    • For patients who respond to azole therapy, consider continuing azole indefinitely to prevent relapse

    • For patients who do not respond initially to systemic treatment, options include using a higher dose of fluconazole, changing to another azole agent,