Immunocompromised patients have increased susceptibility to all the common hospital- and community-acquired bacterial infections affecting the general population. As a result, the bacterial species most frequently isolated in routine hospital inpatient blood cultures (staphylococci, streptococci, enterococci, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Enterobacter spp. etc.) are also the most commonly isolated in the immunocompromised.
For example, community-acquired pneumonia in both the immunocompetent and immunocompromised, is predominantly (~85%) due to Streptococcus pneumoniae, Haemophilus influenza, or Moraxella catarrhalis. Most of the remaining 15% is caused by Mycoplasma pneumoniae, Chlamydophila pneumoniae, or Legionella spp. In most circumstances, therefore, standard first-line antibiotic protocols are appropriate in the immunocompromised.
However, the immunocompromised are also more susceptible to bacterial infections that do not ordinarily cause severe disease in the immunocompetent host. Frequent hospitalization and recurrent use of antibiotics make the dangers posed by multi-resistant organisms particularly significant in this group. This chapter focuses on bacterial pathogens of particular relevance in the immunocompromised.
Mycobacteria, so named because of their fungus-like growth on culture, are aerobes with thick, waxy cell walls, rich in mycolic acid. This cell wall gives them their characteristic ‘acid-fast’ staining. Once stained, the mycolic acid resists de-staining by alcohol or acids. There are many species, but those causing human disease are usually divided into Mycobacterium tuberculosis complex (MTBC), M. leprae, and the free-living environmental non-tuberculous mycobacteria (NTM).
Mycobacterium tuberculosis complex
MTBC includes the genetically closely related causative pathogens of tuberculosis (TB): M. tuberculosis, M. bovis (including BCG), M. africanum, M. canetti, M. microti, M. caprae, and M. pinipedii. The majority of human disease is caused by the first three. They grow very slowly, with a generation time of ~20–24 hours.
Approximately one-third of the global population is latently infected with M. tuberculosis and there are an estimated 9 million new cases of active disease and 1.5 million deaths from TB per year. Transmission is human to human by inhalation and deposition in the lungs. This leads to one of three possible outcomes: immediate clearance of the organism, primary disease, or latent infection. Latent infection may or may not lead to subsequent reactivation of disease. The most important host risk factor determining TB susceptibility is impaired immunity due to HIV co-infection. Other immunosuppressive conditions including cancer, diabetes, and medications such as glucocorticoids and TNF inhibitors also increase susceptibility to TB.
TB must always be considered in the immunocompromised. Of the ~9 million new cases of active TB per year, over a million of these are in patients infected with HIV. HAART greatly reduces the risk of developing TB, though incidence rates remain higher than in the general population. Presentation depends on the degree of immunosuppression. The classic presentation with fever, cough, weight loss, night sweats, and malaise with apical pulmonary cavitation is common in those with early HIV disease (CD4 count >200 cells/μL). As immunosuppression increases, pulmonary cavitation becomes less common (leading to less haemoptysis) and rates of extrapulmonary dissemination increase. The pleura and lymph nodes are the commonest site of extrapulmonary spread but any site can be involved (e.g. pericardium, meninges) Prolonged fever without respiratory symptoms should prompt a search for TB in the immunocompromised.
Rates of TB in SOT recipients are in the order of 20–80× higher than in the general population and are most frequently due to reactivation of latent disease (though nosocomially acquired and donor transmission cases have been reported). Case series of TB post SOT suggest that it manifests as pulmonary disease in ~50% of cases, extrapulmonary in ~15%, and disseminated in ~35%. Fever, night sweats, and weight loss are common symptoms.
The initial laboratory workup in suspected pulmonary TB should include three sputum specimens for microscopy and culture as well as at least one specimen for NAAT. The gold standard for diagnosis remains culture and this is necessary for drug susceptibility testing. While awaiting culture results (which may take weeks), microscopy/NAAT results and clinical context will guide the decision on commencing therapy.
Sputum: three early morning sputum samples from different days should be collected. Nebulized hypertonic saline can be used to induce sputum if needed. Sputum smears are less sensitive then sputum cultures; >5000–10,000 bacilli/mL are needed for detection of bacteria in stained smears, whereas culture can detect as few as 10 bacilli/mL of sputum. Due to its relatively low sensitivity, sputum microscopy is considered a preliminary result that is followed up by culture. Fluorescence microscopy is more sensitive than traditional Ziehl–Neelsen or Kinyoun staining and allows much quicker detection of mycobacteria. Quantification of the bacilli seen on sputum smears, along with clinical and radiographic parameters, can be used to monitor response to treatment.
Aspiration of enlarged lymph nodes and smear microscopy can detect AFBs in ~75% cases of extrapulmonary TB and this increases to >95% if lymph node tissue is cultured. In pleural TB, smears of pleural biopsy or aspirate give higher diagnostic yield in HIV-infected patients than sputum smears (69% vs 29%).
Is generally required for speciation and drug-susceptibility testing. The sensitivity and specificity of sputum culture are about 80% and 98% respectively. Growth in liquid media is faster (1–3 weeks) than on solid media (3–8 weeks). Culture of urine (first morning samples collected on 3 consecutive days) gives a good yield for diagnosing disseminated TB.
Allow rapid and sensitive detection of MTBC in a variety of clinical specimens including sputum and CSF, particularly when levels of mycobacteria are too low to detect by microscopy. 1–10 organisms/mL may give a positive result with NAAT and in smear-positive patients the technique has >95% positive predictive value in distinguishing MTBC from NTM. In smear-negative patients, NAATs can quickly detect MTB in 50–80% of patients (who, weeks later, would go on to be culture positive). One such assay, the Xpert® MTB/RIF assay, can rapidly amplify and detect both MTBC and rifampicin resistance with specificities approaching 99% and sensitivities of 98% in smear positive-, and ~70% in smear-negative patients.
Standard treatment for drug-sensitive pulmonary TB is with an intensive phase of four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) for 2 months and a continuation phase usually with isoniazid and rifampin for at least another 4 months. The exceptions are with CNS disease (12 months of therapy) and bone and joint disease (6–9 months of therapy). In cases where it is not possible to establish an immediate laboratory diagnosis, a presumptive clinical diagnosis is usually sufficient for initiating therapy.
National Institute for Health and Care Excellence (NICE) guidelines on managing of latent and active TB: https://www.nice.org.uk/guidance/ng33.
British Infection Society (BIS) guidelines on the management of central nervous system TB: https://www.britishinfection.org.
British HIV Association (BHIVA) guidelines on HIV/TB co-infection:
World Health Organization (WHO) guidelines on management of TB: http://www.who.int/publications/guidelines/tuberculosis/en/.
NTM are the non-tuberculous, non-leprae mycobacteria. They are free-living environmental organisms and globally distributed. >160 species of mycobacteria have now been classified using molecular taxonomy, but traditionally the NTMs have been organized according to their growth rate on culture.
Slow growers (>7 days to appear on in vitro culture)
Include M. avium complex (MAC), M. kansasii, M. marinum, M. xenopi, M. simiae, M. malmoense, and M. ulcerans.
Rapid growers (<7 days to appear on in vitro culture)
Include M. abscessus, M. fortuitum, and M. chelonae.
NTM are free-living saprophytes found in water, soil, dust, and food worldwide. In contrast to the MTBC, NTM infection is from the environment with no known human-to human transmission. Infection usually occurs through inhalation or ingestion. They are most strongly associated with HIV infection, but are also significant pathogens in other immunocompromised groups. MAC is the most frequently found NTM in immunocompromised. Often found in drinking water and of low inherent pathogenicity, it colonizes the respiratory tract of immunocompetent. M. kansasii is the second commonest NTM isolate after MAC in the US. It is the only NTM not found in soil and is regularly found in tap water.
Patients with HIV infection
MAC disease refers to infections caused by one of two NTM species: M. avium or M. intracellulare. MAC infection is most commonly seen among patients with HIV and with CD4 counts <50 cells/μL. Latent infection does not exist with this organism, so unlike some other opportunistic infections in HIV, MAC disease always represents recent acquisition rather than reactivation. Infection is via the respiratory tract and GI tract with bacteraemia following dissemination via the lymphatics.
Presentation is with either disseminated or local disease. Disseminated MAC presents non-specifically with fever, night sweats, abdominal pain, diarrhoea, and weight loss (which often precedes the onset of fever). The diagnosis is confirmed by the isolation of MAC from the blood. Localized MAC presents as focal lymphadenitis with fever, leucocytosis, and inflammation in a lymph node (usually cervical, intra-abdominal, or mediastinal). The diagnosis is confirmed by culture of lymph node aspirate. Blood cultures are almost always been sterile. Prior to HAART, localized disease was rare in HIV.
Non-MAC disease: M. kansasii is the most frequently isolated NTM after MAC. Tap water is thought to be the most likely environmental source of exposure. Clinical manifestations are mostly similar to those of TB, although M. kansasii is a less virulent pathogen. Typical symptoms include fever, night sweats, weight loss, cough with sputum, dyspnoea, and weakness. M. xenopi presents with fever, wasting, and pulmonary infiltrates, similar to disseminated MAC. M. genavense infection has been associated with massive adenopathy and organomegaly. M. szulgai is associated with pulmonary disease, cutaneous lesions, osteomyelitis, and septic arthritis.
The rapidly growing mycobacteria M. fortuitum and M. chelonae can cause disseminated disease with pustular and nodular cutaneous lesions, localized pulmonary disease, multifocal osteomyelitis, and lymphadenitis.
NTM are more common aetiological agents of disease in SOT recipients than MTBC in countries where TB is non-endemic. Median onset of NTM infection is usually 1 year or more after transplantation. Pleuropulmonary disease is the most common manifestation of NTM infection after transplantation and lung transplant recipients are most commonly affected. MAC species are the most common NTM species isolated and typically involve the lungs. Cutaneous and disseminated infections are the next most common presentations. M. fortuitum and M. marinum tend to cause localized skin infections and may present as purplish papules or nodules. M. marinum infection, known as ‘fish tank granuloma’, usually occurs after exposure to aquariums or marine environments. M. abscessus tends to be particularly virulent and can cause pulmonary, cutaneous, and/or disseminated disease. Disseminated infection caused by NTM typically presents with constitutional symptoms (weight loss, fever, night sweats).
NTMs may colonize the respiratory or GI tract without causing disease, so a positive culture does not necessarily indicate infection. NTM found in sterile specimens, such as blood, are generally considered significant.
Microscopy and culture
Staining and microscopy for AFB followed by culture should be performed on all respiratory specimens. Diagnosis of NTM is made by isolation of the organism in culture usually of the blood or lymph node aspirates. When the BACTEC™ culture system is used, the cultures usually become positive in 7–10 days. Bone marrow culture often yields the organism before blood cultures turn positive. Mycobacterial blood cultures are collected in special media and the bottles must be specifically requested.
Biopsy of suitable lesions including skin biopsy should be performed in all patients with suspicious lesions where possible. This should be sent for microscopy and culture as well as histopathology.
Treatment of NTM is often difficult in immunocompromised hosts due to antimicrobial resistance and often adjuvant surgery is needed. At least two active drugs should be used due to the high risk of development of resistance, but the accuracy of in vitro testing is variable. At least three active agents, including one injectable, are recommended for patients with severe infection. Lung disease should be treated until sputum cultures taken over 12 consecutive months are negative; skin and soft tissue infections should be treated for at least 3–6 months. Close follow-up after completion of treatment is essential.
The following treatment recommendations are supported by the British Thoracic Society guidelines (due for publication in early 2018):
• MAC is treated with a combination of drugs in order to reduce the risk of drug resistance. First line is clarithromycin (or azithromycin) plus ethambutol plus rifampicin. In severe disease (smear-positive/severe symptoms/cavitation), additional amikacin (IV or nebulized for up to 3 months) should be considered. In clarithromycin-resistant disease, either isoniazid or moxifloxacin should be given as a substitute for a macrolide, and amikacin should also be considered.
• M. kansasii is usually treated with rifampicin, ethambutol, plus one of isoniazid/clarithromycin/azithromycin.
• M. malmoense is usually treated with rifampicin plus ethambutol plus clarithromycin/azithromycin. Amikacin (up to 3 months) should also be considered in severe disease.
• M. abscessus is usually treated in the initial phase (≥1 month) with clarithromycin/azithromycin (if sensitive) plus amikacin plus imipenem plus tigecycline. This is followed by a continuation phase of nebulized amikacin and oral clarithromycin/azithromycin plus one to three of the following drugs: clofazimine, linezolid (and pyridoxine), minocycline, moxifloxacin, TMP–SMX. This is usually for 12 months with surgical resection if possible.
• In macrolide-resistant disease, clarithromycin should be omitted from the initial phase. The continuation phase should consist of nebulized amikacin plus two to four of the above-listed drugs.
Non-pulmonary NTM disease
• M. fortuitum is usually treated with amikacin plus cefoxitin for 2–6 weeks followed by TMP–SMX or doxycycline.
• M. chelonae is treated with clarithromycin plus either tobramycin, imipenem, or linezolid followed by clarithromycin or moxifloxacin for at least 4 months (Box 14.1).
British Thoracic Society (BTS) guidelines on non-tuberculous mycobacteria: https://www.brit-thoracic.org.uk/standards-of-care/guidelines/.
American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) guidelines on non-tuberculous mycobacteria: http://www.idsociety.org/PracticeGuidelines/.
Unusual Gram-positive aerobic bacteria of the order Actinomycetales, so called because they form branching, fungal-like filaments which break up into either coccoid or bacillary units. Other aerobic actinomycetes causing human disease include Rhodococcus, Gordonia, and Tsukamurella. They are mostly saprophytes and infection arises from environmental exposure. >30 species of Nocardia are known to cause human disease, but the most common are N. asteroides, N. nova, and N. farcinia.
Inhalation of this globally dispersed environmental pathogen is the most common route of transmission and consequently the lung is most common site of disease. ~65% of cases are in patients with defective cell-mediated immunity and prolonged glucocorticoid use is a major risk factor.
Consider in any immunocompromised patient with recent or ongoing non-specific respiratory symptoms associated with CNS, skin, or soft tissue lesions. There are no pathognomonic signs and nocardiosis is commonly misdiagnosed as TB due to similar clinical and chest X-ray findings. ~50% of all lung infections disseminate, most commonly to the brain, so the brain should be imaged to look for abscess formation. Skin lesions are most commonly caused by direct inoculation and include mycetoma.
Microscopy and culture
An initial presumptive diagnosis may be made if filamentous, weakly acid-fast branching rods are seen on microscopy of sputum samples or skin biopsies. Inform laboratory staff if nocardiosis is suspected so they can optimize conditions for detection. Most routine cultures are discarded at 48–72 hours, whereas Nocardia spp. can take between 5 and 21 days to grow and special media may be used. Precise speciation and drug sensitivity testing are essential as there is significant variability in drug susceptibility. Isolates often need to be sent to a regional/national reference laboratory for this.
Depends on sensitivity but usually includes two out of TMP–SMX, amikacin, imipenem, and third-generation cephalosporins (ceftriaxone and cefotaxime) for severe infection. Therapy in immunocompromised patients is usually for at least 6 months with long-term suppression with oral TMP–SMX or doxycycline.
Like Nocardia spp., rhodococci are part of the diverse group of Gram-positive bacilli known as ‘aerobic actinomycetes’. Of the >30 species in the genus Rhodococcus, only one, R. equi, has been frequently associated with human disease. R. equi, initially identified as a cause of horse pneumonia, has become increasingly recognized as a cause of pulmonary and disseminated disease in immunocompromised humans. The pathogenic potential of R. equi results from its ability to persist in and destroy macrophages and most cases of disease are in association with HIV infection, lymphoproliferative malignancy, organ transplant, or immunosuppressive medication.
Rhodococcus spp. have a worldwide distribution and are frequently isolated from soil, particularly soil contaminated with herbivore faeces. Isolates of R. equi from sputum and indwelling lines point to inhalation and air contamination as primary sources of infection. Sequencing of some human isolates suggests a specific animal host and thus possible zoonotic transmission; contact with farm animals or manure has been reported in up to 50% of cases. Infection can also be acquired by traumatic inoculation or superinfection of wounds.
Pulmonary infections are the most common form of human disease caused by R. equi and most reported cases of pneumonia have occurred in immunocompromised hosts. Infection is usually subacute in onset but results in high fever, cough (± haemoptysis), fatigue, chest pain, and weight loss. Cavitation arises in >50% of cases and pleural effusion in ~20%. Malacoplakia, a chronic granulomatous condition, can result from R. equi infection of the lung parenchyma.
Extrapulmonary infections, which may present weeks to years after therapy for pulmonary disease, most commonly affect the skin (subcutaneous abscesses) and brain. Brain abscesses, with associated oedema and sometimes meningitis, may present as confusion, agitation, obtundation, coma, seizures, and motor weakness. Kidney, liver, and bone involvement or isolated bacteraemia also occur. In ~s25% of documented R. equi infections, there is no pulmonary disease; these cases include wound infections, peritoneal catheter-related peritonitis, and isolated fever with bacteraemia.
Suspect R. equi infection in immunocompromised patients with cavitating lung disease and epidemiological risk factors.
Diagnosis is made by culturing the organism from a clinical sample and R. equi is easily cultivated on ordinary non-selective media when incubated aerobically at 37ºC. Commercially available panels of biochemical tests (API® (RAPID) Coryne) can be employed to identify R. equi in cultures with the typical colony characteristics and Gram stain morphology.
The lung is the usual primary site, so send sputum ± bronchial washings, lung tissue, abscess contents, or pleural fluid.
Blood cultures are positive in >50% of immunocompromised patients with R. equi infection.
In suspected CNS disease, send CSF ± brain abscess aspirates.
Though easy to culture, R. equi may be dismissed as a contaminant, given its appearance as a diphtheroid, so the clinical team should liaise closely with the lab in suspected cases. Rhodococci may be reported as ‘aerobic actinomycetes’. If available, 16S rRNA sequencing and/or mass absorption laser depolarizing ionization time-of-flight may be used to diagnose rhodococci.
R. equi is generally susceptible in vitro to erythromycin and extended-spectrum macrolides, rifampin, fluoroquinolones, aminoglycosides, glycopeptides, linezolid, and imipenem.
Combination therapy, with at least two antimicrobial agents, is recommended in the immunocompromised to reduce the emergence of resistance. Initial therapy is often with a macrolide or fluoroquinolone in combination with rifampin. Survival within macrophages is a significant virulence factor in R. equi disease, so antibiotics with intracellular activity, such as rifampin, fluoroquinolones, and azithromycin are preferable. Once drug sensitivities are known, treatment should continue with two active agents; ideally including a macrolide or a quinolone.
In CNS involvement, the second agent must have good CNS penetration (e.g. imipenem, vancomycin, rifampin, or linezolid) since fluoroquinolones and macrolides do not penetrate CSF well.
Initial therapy in immunocompromised people should last at least 2 months and longer courses should be administered when there is persistent clinical or radiographic evidence of infection.
Secondary prophylaxis with a single oral agent with demonstrated in vitro activity should be administered to patients who remain immunosuppressed. Improving immune function and drainage/resection may be important adjuncts to antimicrobial therapy.
C. difficile is an anaerobic, Gram-positive, spore-forming, toxin-producing bacillus. It was so named due to the difficulties in isolating it and growing it on conventional media. First isolated from the intestinal flora of healthy newborns in the 1930s, it was not until the 1970s, when it was isolated from the stool of patients with antibiotic-associated pseudomembranous colitis, that its pathogenic role began to be appreciated. Outside the colon, it exists in a heat-, acid-, and antibiotic-resistant spore form. Inside the colon, the spores convert to their fully functional vegetative, toxin-producing forms and become susceptible to killing by antimicrobial agents. Though not invasive, certain strains release potent exotoxins (toxins A and B) which mediate diarrhoea and colitis. All known toxigenic strains contain toxin B, with or without the presence of toxin A. These toxins inactivate cellular regulatory pathways leading to cell retraction and apoptosis and disrupt intercellular tight junctions. In vivo, stool toxin levels correlate with disease severity. Up to 30% of C. difficile strains are non-toxigenic.
Antibiotic use disrupts the barrier function of normal colonic flora, allowing C. difficile to multiply and elaborate toxins.
Most cases of C. difficile-associated diarrhoea (CDAD) were initially attributed to the use of clindamycin. In the last two decades, however, the emergence of C. difficile infections (CDIs) that are more severe, refractory to standard therapy, and likely to relapse has been strongly correlated with increasing fluoroquinolone use. These cases are largely caused by the fluoroquinolone-resistant and hypervirulent NAP1/BI/027 strain, which produces substantially larger quantities of toxins A and B as well as an additional toxin known as ‘binary toxin’. In the last decade, a new C. difficile strain (ribotype 078) has emerged in Europe and causes infections of similar severity to type 027, though it appears to affect a younger population.
In 2011, an estimated 450,000 cases of C. difficile occurred in the US, of which approximately one-third were community acquired and two-thirds were healthcare associated. Transmission is via the faecal–oral route and the organism can be cultured from the hospital environment, including items in patients’ rooms and the hands and clothing of healthcare workers.
The C. difficile carrier rate among healthy adults is in the region of 3%, but among hospitalized adults and those in long-term care facilities it reaches 20–50%. Carriers of C. difficile act as a reservoir for environmental contamination regardless of clinical infection.
Antibiotic use is the principal risk factor for CDAD; the antibiotics most frequently implicated include fluoroquinolones, clindamycin, and broad-spectrum penicillins and cephalosporins. Any antibiotic, however, can predispose to C. difficile colonization, including metronidazole and vancomycin, the primary antibiotics used to treat it. In general, increased duration of therapy, the use of broad-spectrum agents, and the use of multiple antibiotic combinations all contribute to risk of CDAD
Advanced age, hospitalization, gastric acid suppression, GI surgery, enteral feeding, obesity, cancer chemotherapy, HSCT, and inflammatory bowel disease are other known risk factors. CDAD can also occur in the absence of any identifiable risk factors.
CDI can range from asymptomatic carriage to fulminant disease with toxic megacolon. Symptoms usually begin during antibiotic therapy or 5–10 days following antibiotic therapy. More rarely, onset may be as late as 10 weeks after cessation of antibiotic therapy.
Patients shed C. difficile in stool but do not have diarrhoea or other clinical symptoms.
Diarrhoea, lower abdominal pain/distention, fever, hypovolaemia, lactic acidosis, hypoalbuminemia, elevated creatinine, and marked leucocytosis. Complications include hypotension, sepsis, renal failure, toxic megacolon, and bowel perforation with peritonitis. Occasionally, CDI presents acutely as ileus, with little or no diarrhoea.
Defined by complete cessation of CDI symptoms while on appropriate therapy, followed by recurrence of symptoms post treatment. Up to 25% of patients experience recurrent C. difficile within 30 days of treatment, but recurrent CDI can occur as late as 3 months after completion of treatment. One recurrence significantly increases the risk of further recurrences and a recurrence most often represents a relapse rather than a reinfection, regardless of the interval between episodes.
Suspect CDI in all patients with clinically significant diarrhoea or ileus in the context of relevant risk factors.
Send liquid stool for C. difficile testing. This will not distinguish between CDAD and asymptomatic carriage (which does not need treatment), so only send stool for CDI testing in patients with clinically significant diarrhoea.
For patients with ileus, perirectal swabs may be sent for toxin assay or anaerobic culture; the sensitivity of rectal swab for C. difficile culture in the setting of ileus is high, though turnaround time is long.
Pseudomembranous colitis (seen on imaging or endoscopy) is highly suggestive and should prompt laboratory testing for CDI.
Laboratory diagnosis requires demonstration of C. difficile toxin(s) or detection of toxigenic C. difficile organisms.
Most labs now use PCR, often as part of an algorithm including initial enzyme immunoassay (EIA) screening for glutamate dehydrogenase (GDH) antigen and toxins A and B. Real-time PCR, which detects genes (usually tcdB) specific to toxigenic strains, is highly sensitive and specific and results can be available within hours. False negatives may occur if stool specimen collection is delayed or the patient has been treated empirically for suspected CDI.
GDH antigen cannot distinguish between toxigenic and non-toxigenic strains and is therefore most useful as an initial screening step in a multistep approach. GDH antigen testing has good sensitivity, and results are available quickly.
EIA for C. difficile toxins
Toxin B is the clinically important toxin, however, testing for both toxin A and B by EIA gives a higher sensitivity. The sensitivity of EIA for toxins A and B is ~75% and specificity is >95%.
Laboratory diagnostics for suspected recurrent CDI are the same as for initial infection. Repeat stool assays are not warranted during or following treatment in patients who are recovering or are symptom free. Up to 50% of patients have positive stool assays for as long as 6 weeks after completion of therapy. Imaging of the abdomen and pelvis is required for patients with clinical manifestations of severe illness or fulminant colitis to look for conditions needing surgical intervention, such as toxic megacolon or bowel perforation.
Stop the contributory antibiotic(s) as soon as possible and implement infection control measures. The use of soap and water is favoured over alcohol-based hand sanitization in a CDI outbreak. Empirical antibiotic treatment is usually started on clinical suspicion of CDI (after specimens are sent) and discontinued if the laboratory tests are negative.
Antibiotic treatment of confirmed cases must follow local guidelines; a summarized example of a current protocol is found in Box 14.2.
Public England (PHE) guidelines: https://www.gov.uk/government/publications/clostridium-difficile-infection-guidance-on-management-and-treatment.
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines: https://www.escmid.org/escmid_publications/medical_guidelines/escmid_guidelines/.
A Gram-positive rod whose natural habitat is soil and decaying vegetable matter. It may form short chains and characteristically exhibits tumbling motility on light microscopy at 25°C. It is a particularly virulent pathogen in immunocompromised groups, most notably in pregnancy, neonates, and those on corticosteroids.
Most infections result from oral ingestion followed by invasion of the intestinal mucosa and systemic infection. Up to 5% of healthy adults have Listeria detectable in the bowel. Food-borne outbreaks, usually present with fever and gastroenteritis after an incubation period of ~24 hours. Infection is most commonly associated with processed meats, soft cheeses, pâtés, and fruit. Systemic infections generally occur in those with at least one predisposing condition: pregnancy, glucocorticoid treatment, other immunocompromising condition (e.g. HIV or chemotherapy), or old age. Pregnant women (>20 weeks) are particularly vulnerable to Listeria. Infection can cross the placenta to cause fetal death, premature birth, or an infected neonate. L. monocytogenes is the most common cause of meningitis in patients with lymphoma, transplant recipients, and those on glucocorticoid therapy. Invasive listeriosis has a much longer incubation period (usually ~10 days).
Consider Listeria in cases of meningitis or sepsis in the immunosuppressed, elderly, or neonates. Listerial bacteraemia often leads to endocardial infection. Less common syndromes include pneumonia, arthritis, endophthalmitis, encephalitis, and CNS abscess. Most neonatal disease presents with septicaemia within 5 days of birth and has a mortality of 30–60%. In pregnancy, listerial infection is more common beyond 20 weeks and usually either asymptomatic or presents with relatively mild symptoms such as headache, sore throat, myalgia, and fever. (See Chapter 9.)
Microscopy and culture
Blood cultures are positive in 60–75% of patients with CNS infection and CSF cultures are positive in almost 100%. CSF microscopy with Gram staining, however, is positive in <50% of cases. Wet mounts of CSF may demonstrate the classical ‘tumbling motility’. Listeria may form chains and appear Gram variable on microscopy, so can be initially misidentified as cocci or diphtheroids.
IV ampicillin or TMX–SMT for at least 2 weeks for bacteraemia and 4 weeks for CNS infection. In severe disease, gentamicin may be added for up to 2 weeks.
British Infection Association (BIA) UK joint specialist societies guideline on meningitis: https://www.britishinfection.org/guidelines-resources/published-guidelines/for guidelines on CNS infection.
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines: https://www.escmid.org/escmid_publications/medical_guidelines/escmid_guidelines/for guidelines on CNS infection.
P. aeruginosa is a Gram-negative, aerobic rod, commonly present in the environment, especially in water. It may act as an opportunistic pathogen causing serious infections in the immunocompromised and often has multiple inherent and acquired antibiotic resistance mechanisms.
P. aeruginosa is a major pathogen worldwide and a significant cause of hospital-acquired infection; particularly ventilator-associated pneumonia, surgical site infection, catheter-related urinary infection, and nosocomial bacteraemia. It is the most common pathogen isolated from adults with cystic fibrosis and is well known as an opportunist pathogen in patients with neutropenia or burns. As well as multiple intrinsic mechanisms to avoid antibiotic killing (including AmpC beta-lactamase, efflux pumps, and biofilm formation), P. aeruginosa has acquired plasmids encoding both ESBLs and carbapenemases.
P. aeruginosa has two distinct forms of pathogenic behaviour: chronic colonization of the lungs (as in many patients with cystic fibrosis) and invasive disease (pneumonia, bacteraemia, and septic shock). Hospital-acquired P. aeruginosa bacteraemia can follow primary infection in the lungs, GI/biliary tract, urinary tract, skin/soft tissues, or from infected intravascular catheters. It is more common in neutropenia or other immunodeficiency states. It commonly presents, with endotoxin-induced shock, typically fever, tachycardia, tachypnoea, disorientation, and hypotension. Skin lesions, such as ecthyma gangrenosum, point towards P. aeruginosa as the causative organism. Mortality is higher in bacteraemia caused by P. aeruginosa than that caused by most other commonly isolated bacilli. Infective endocarditis due to P. aeruginosa is relatively rare, but strongly associated with prosthetic heart valves, pacemakers, and IV drug abuse.
Send blood and/or respiratory samples for culture and follow local empirical therapy guidelines for suspected pseudomonal infection while awaiting identification and sensitivity profile. Quantitative or semi-quantitative cultures may be performed on certain respiratory specimens as an aid to diagnosing ventilator-associated pneumonia.
Sensitivity patterns are crucial to treatment selection. Choices of treatment include antipseudomonal penicillins (e.g. piperacillin–tazobactam), antipseudomonal cephalosporins (e.g. ceftazidime), carbapenems (e.g. meropenem), or aminoglycosides (e.g. gentamicin). Fluoroquinolones are the only oral options, although isolates are frequently resistant. Nebulized colistin is also used in chronic respiratory infection.
British Thoracic Society (BTS) guidelines on bronchiectasis: https://www.brit-thoracic.org.uk/standards-of-care/guidelines/.
Cystic Fibrosis Trust UK https://www.cysticfibrosis.org.uk/the-work-we-do/clinical-care/consensus-documents for guidelines related to infections in cystic fibrosis.
Burkholderia cepacia complex
The B. cepacia complex includes >18 phenotypically similar species of Gram-negative, non-spore-forming bacilli. When first described in the 1950s by W.H. Burkholder, they were of note for the vinegar-like stench (‘sour skin’) they cause in onion bulbs. In recent decades, they have been recognized as opportunistic human respiratory pathogens in individuals with weakened immune systems or chronic lung disease, especially cystic fibrosis. Molecular taxonomy has grouped the many species into nine genomovars, of which two—B. cenocepacia (genomovar 3) and B. multivorans (genomovar 2)—are the most common causes of B. cepacia colonization and infection in cystic fibrosis patients. Various characteristics differentiate them from other cystic fibrosis pathogens and complicate management; they are highly transmissible, more virulent, and have inherent resistance to multiple antibiotics.
Endotoxin plays an important role in their pathogenesis; lipopolysaccharide from clinical isolates of B. cepacia have endotoxin activity almost ten times higher than endotoxin extracted from Pseudomonas aeruginosa. Other virulence factors include the ability of B. cepacia to form biofilms, adhere to epithelial cells and mucin, invade and survive inside airway epithelial cells and macrophages, and secrete catalases, proteases, and siderophores.
B. cepacia spp. are ubiquitous in nature and commonly found in soil and water. An estimated 3% of cystic fibrosis patients in the US and UK are infected with B. cepacia organisms and prevalence increases with age. Although transient infection occurs, the majority of infections cannot be eradicated.
Patient-to-patient spread of organisms can occur through social contact and this is particularly well described for the epidemic (ET-12) strain of B. cenocepacia. Recognition of this and the increased mortality rates associated with the epidemic strains, led to the policy of strict segregation in clinical units. Consequently, most new B. cepacia complex infections these days are with B. multivorans, acquired from as-yet unidentified environmental reservoirs.
B. cepacia infection is not limited to cystic fibrosis patients; other groups, such as those with chronic granulomatous disease, are vulnerable and it has occasionally caused disease in healthy individuals. It has been associated with cutaneous foot lesions in military personnel (‘swamp foot’) and been isolated from catheters, wounds, burns, sputum, and urine. Contamination of inhaled and IV solutions has resulted in airways infection or systemic sepsis.
Vary from asymptomatic carriage to accelerated decline in lung function to rapid, uncontrolled deterioration with septicaemia and necrotizing pneumonia (‘cepacia syndrome’). Prognosis depends in part on the species within the B. cepacia complex. With B. multivorans, the 5-year survival is similar to P. aeruginosa infection; however, B. cenocepacia is associated with a rapid deterioration and early death in up to a third of cases.
Cystic fibrosis patients are at a significantly higher risk of post-transplant pneumonia than other lung transplant recipients and are more likely to be colonized with multidrug-resistant B. cepacia and P. aeruginosa. Individuals with B. cenocepacia appear to have poorer post lung transplant outcomes and colonization with this strain is viewed as a relative contraindication to transplantation. Screening of all patients with cystic fibrosis for B. cenocepacia is advised.
The ‘recA’ PCR is currently the most sensitive and specific molecular identification method. More complex methods such as pulse field gel electrophoresis (PFGE) or restriction fragment length polymorphisms (RFLPs) are needed for epidemiological analysis and transmission mapping.
B. cepacia can be cultured from respiratory samples on specific media and commercial biochemical identification kits such as API™ 20NE are useful but have significant false positives. Stenotrophomonas maltophilia, Achromobacter xyloxidans, and occasionally P. aeruginosa can be erroneously diagnosed as B. cepacia organisms. False positives or negatives may lead to the patient being inappropriately cohorted and thereby facilitate transmission.
There is a lack of trial evidence to guide decision-making and antimicrobial therapy should be directed by in vitro sensitivities where available. Most isolates show high-level resistance to antipseudomonal antibiotics, including inherent resistance to colistin. Some centres have reported pan-resistance in >80% of patient isolates. Environmental strains are generally more susceptible than clinical strains.
The most consistently active agents in vitro appear to be ceftazidime, piperacillin–tazobactam, meropenem, imipenem, ciprofloxacin, trimethoprim, co-trimoxazole, and tetracyclines. Various combinations of two or three antibiotics (e.g. tobramycin plus meropenem plus ceftazidime) have shown synergy against B. cepacia complex. Temocillin has been trialled for treating exacerbations, with modest clinical improvement observed. Anecdotal evidence suggests that eradication can be enhanced by giving aerosolized amiloride and tobramycin in combination. There is little evidence on the best therapeutic approaches for ‘cepacia syndrome’ but combination therapy is usually tried. Aggressive eradication therapy for all new growths should be considered.
British Thoracic Society (BTS) guidelines on bronchiectasis: https://www.brit-thoracic.org.uk/standards-of-care/guidelines/.
Cystic Fibrosis Trust UK https://www.cysticfibrosis.org.uk/the-work-we-do/clinical-care/consensus-documents for guidelines related to infections in cystic fibrosis.
B. pseudomallei is a facultative, intracellular, Gram-negative bacterium and a widely distributed environmental saprophyte in soil and fresh surface water in endemic regions. Infection with B. pseudomallei can lead to the disease melioidosis, which is associated with high case-fatality rates. Functional neutrophil defects are important in the pathogenesis of melioidosis and the disease mostly occurs in adults with an underlying predisposing condition.
Melioidosis is a disease of public health importance in Southeast Asia and northern Australia, with seasonal peaks in the wet seasons. Cases may be acquired by visitors to endemic areas, with symptoms arising later.
The important risk factors for melioidosis are diabetes mellitus, alcohol abuse, and chronic renal or lung disease. B. pseudomallei can cause colonization and pulmonary infections in patients with cystic fibrosis. Children may develop infection without associated risk factors.
The major mode of transmission is thought to be percutaneous inoculation during exposure to wet season soils or contaminated water, though transmission can also occur via inhalation, aspiration, and occasionally ingestion. During severe weather events such as storms, inhalation may become the primary mode of B. pseudomallei transmission. Laboratory-acquired infections and iatrogenic infections from contaminated hospital or surgical equipment occasionally occur.
Following percutaneous inoculation the organism can disseminate via haematogenous spread. Incubation periods from inoculation range from 1 day to 3 weeks.
Most B. pseudomallei infections are subclinical and severe disease occurs mainly in those with risk factors.
The most common clinical manifestations are pneumonia (acute or subacute/chronic) and localized skin infection (ulcers/abscesses). >50% of all patients are bacteraemic and up to 25% present with septic shock.
Haematogenous spread of B. pseudomallei may lead to clinical manifestations in virtually any site:
• Genitourinary melioidosis (fever, suprapubic pain, dysuria, or acute retention).
• Septic arthritis or osteomyelitis.
• Encephalomyelitis—unilateral upper motor neuron limb weakness, cerebellar signs, cranial nerve palsies, or flaccid paraparesis.
• Abscesses in internal organs (spleen, kidney, prostate, and liver).
• Suppurative parotitis (particularly common in children in SE Asia).
Imaging of the chest, abdomen, pelvis, brain, and other clinically suspicious site is thus an essential part of the workup.
Culture, usually on Ashdown’s medium, is the mainstay of diagnosis.
Send blood, sputum, urine, ulcer swabs, abscess fluid, throat swabs, and rectal swabs. Gram stain of sputum or pus may reveal Gram-negative bacilli with a characteristic bipolar staining giving a ‘safety pin’ appearance.
Isolation of B. pseudomallei from any clinical specimen generally warrants treatment as residual colonization is usually associated with low-grade infection and there is a risk of subsequent invasive disease.
All cases of melioidosis should be treated with aggressive initial antimicrobial therapy. B. pseudomallei is resistant to penicillin, ampicillin, first- and second-generation cephalosporins, gentamicin, tobramycin, and streptomycin. Initial therapy usually consists of at least 2 weeks of IV ceftazidime, meropenem, or imipenem.
This should be followed immediately by longer-term oral eradication therapy to prevent recrudescence or relapse. TMP–SMX for at least 3 months (longer in bone or neurological disease) is a standard regimen.
Adjunctive therapies include abscess drainage and, in septic shock, the use of recombinant human G-CSF.
US Centers for Disease Control and Prevention (CDC) https://www.cdc.gov/melioidosis/index.html for further information.
A MDR, aerobic, Gram-negative bacillus that is ubiquitous in aquatic environments. Though an organism of low virulence, it is increasingly detected as a nosocomial pathogen in the immunocompromised.
Risk factors include underlying malignancy, immunosuppressant therapy, cystic fibrosis, exposure to broad-spectrum antibiotics, ICU admission, mechanical ventilation, recent surgery, HIV infection, and neutropenia. Invasive medical devices are usually the vehicle by which the organism bypasses normal host defences.
Consider in patients with indwelling catheters, those receiving immunosuppressant therapy or broad-spectrum antibiotics, or in patients with cystic fibrosis. S. maltophilia commonly colonizes the urine but is pathogenic only in those with impaired host defences. Cases of S. maltophilia causing a rapidly progressive haemorrhagic pneumonia have been reported in mechanically ventilated patients.
Usually by culture of the organism from body fluids. However, the presence of S. maltophilia may represent colonization alone and not disease. Growth of S. maltophilia from normally sterile sites (such as blood or peritoneal fluid) should be interpreted as representing true infection.
Empirical treatment is with TMP–SMX with the addition of ceftazidime or levofloxacin for severe infection.
British Thoracic Society (BTS) guidelines on bronchiectasis: https://www.brit-thoracic.org.uk/standards-of-care/guidelines/.
Cystic Fibrosis Trust UK https://www.cysticfibrosis.org.uk/the-work-we-do/clinical-care/consensus-documents for guidelines related to infections in cystic fibrosis.
Originally thought to be Rickettsiae, the bacterial genus Bartonella now has >20 species described. Of these, two species—B. henselae and B. quintana—are major causes of disease in patients with HIV. Transmission occurs by traumatic contact with infected animals or by insect vectors.
Both B. henselae and B. quintana are globally distributed. B. henselae infection is associated with cat exposure, most often a scratch, whereas B. quintana is transmitted via lice and is most often found among the homeless. Though much less common these days, due to the wide availability of HAART, Bartonella infection is still seen in HIV infection with CD4 counts <100 cells/μL.
Suspect in patients with HIV infection presenting with violaceous skin lesions. Though the vascular lesions of bartonellosis most often affect the skin (and may resemble Kaposi’s sarcoma), they also occur in lung, gut, bone, and brain. Peliosis hepatis (multiple blood-filled cavities in the liver), splenitis, and endocarditis (‘culture negative’) are also described in Bartonella co-infection with HIV. Constitutional symptoms (fever, malaise, headache, anorexia, etc.) are common.
Culture from blood or tissue is difficult due to the fastidious nature of Bartonella spp. If informed, the laboratory can use special conditions and prolonged culture periods to maximize yield.
Biopsy of an accessible lesion will show vascular proliferation and silver staining often demonstrates numerous bacilli.
Can be used to support a diagnosis, but is not definitive. A significant proportion of patients with HIV will not develop detectable antibody responses to Bartonella.
British HIV Association (BHIVA) and British Infection Association (BIA) http://www.bhiva.org/Guidelines.aspx for guidelines related to Bartonella spp. infections in HIV.
C. canimorsus are long, thin, slow-growing, Gram-negative rods which form part of the normal flora of the oral cavity of dogs and cats. They are a cause of fulminant sepsis in asplenic/hyposplenic individuals.
About half of patients diagnosed with C. canimorsus infection report a history of dog bite and most of the rest will have had some contact with dogs or cats. As well as impaired or absent splenic function, other risk factors include prolonged corticosteroid use, alcoholism, and cirrhosis.
Consider C. canimorsus in septicaemic shock in patients with a history of dog bite/exposure, particularly in the context of impaired immunity. May also present with pneumonia, cellulitis, meningitis, or pyrexia of unknown origin.
Send relevant clinical samples for culture; C. canimorsus is a slow-growing, fastidious bacteria, so if suspected, inform the laboratory in order that they can use appropriate media and leave the culture for a prolonged period.
Non-typhoidal Salmonella (NTS) spp.
NTS are motile, facultatively anaerobic, Gram-negative Enterobacteriaceae. The genus Salmonella consists of two species, S. enterica and S. bongori; most clinically important salmonellae are serotypes of S. enterica, subspecies enterica. NTS refers to all the serotypes except the human-restricted S. typhi and S. paratyphi which cause enteric fever. S. enteritidis and S. typhimurium are the pathogenic NTS serotypes most commonly isolated from blood
NTS species are associated with animal reservoirs worldwide and are a major cause of food-borne (mostly poultry, eggs, and milk) diarrhoeal outbreaks. In the context of impaired cellular immunity due to advanced HIV infection, corticosteroid use, or malignancy, NTS may cause more severe disease such as bacteraemia with metastatic foci.
The greatest burden of invasive NTS disease is in Africa where NTS species are a leading cause of bacteraemia in both children and adults and can occur in epidemics with high mortality. In addition to HIV, corticosteroid use, and malignancy, other risk factors for invasive disease include extremes of age, rheumatological disease, immunomodulatory drugs, transplantation, congenital immune deficiencies, liver disease, diabetes, sickle cell disease, schistosomiasis, and chronic granulomatous disease. Prior to the widespread availability of HAART, recurrent invasive Salmonella infection was a relatively frequent AIDS-defining infection.
NTS bacteraemia can lead to suppurative foci of infection throughout the body, including long bones, joints, muscles, lung, heart, and CNS. Foci tend to occur at sites of structural abnormality, e.g. endovascular atheroma, prosthetic grafts, or bones and joints damaged by avascular necrosis from sickle crises. In immunosuppression due to malignancy or steroid use, soft tissue and lung foci are more common. Meningitis is rare and most often occurs in children <1 year old. NTS bacteraemia in HIV (usually occurring when CD4 count <200 cells/μL) most often has a non-specific febrile presentation without diarrhoea or abdominal symptoms. Hepatomegaly and/or splenomegaly occur in up to half of cases.
NTS species grow vigorously in both aerobic and anaerobic culture. A ‘primary bacteraemia’ without preceding GI illness may be the first presentation of an underlying immune deficiency.
Laboratory isolation of salmonellae from stool usually requires a minimum of 48 hours and samples collected over several days are preferred. After stool and blood, urinary isolates are encountered next most frequently. ESBL genes are emerging in salmonellae in all areas
Depends on sensitivity patterns but fluoroquinolones are usually first line with azithromycin where quinolone resistance has emerged.
British HIV Association (BHIVA) and British Infection Association (BIA) http://www.bhiva.org/Guidelines.aspx for guidelines related to infections in HIV.
The immunocompromised represent a unique group for the acquisition of antimicrobial resistant infections due to their frequent encounters with the healthcare system, need for empiric and prophylactic antimicrobials, and immune dysfunction.
Enterococci (including vancomycin-resistant enterococci)
Enterococci are normal flora in the human and animal gut. Previously known as group D streptococci, they are Gram-positive facultative anaerobes which can survive high temperatures and grow in salty conditions. The genus Enterococcus has >18 species described, but only a handful are known to cause disease in humans. E. faecalis and E. faecium are the predominant species implicated in human disease (>90% clinical isolates) and it is E. faecium that is the cause of most vancomycin-resistant infections. Enterococci have both intrinsic and acquired antibiotic resistance mechanisms. High-level resistance to vancomycin (defined as a minimum inhibitory concentration (MIC) >32 micrograms/mL) is encoded by different clusters of genes referred to as the vancomycin-resistance gene clusters (e.g. vanA, vanB, and vanD gene clusters). VRE, particularly E. faecium strains, are frequently resistant to all antibiotics effective against vancomycin-susceptible enterococci.
Enterococci are among the most common causes of nosocomial infections. First reported in the 1980s, vancomycin-resistant strains are now widespread. Infecting strains of VRE most often originate from the patient’s gut flora. Individuals at risk for colonization include critically ill patients on long courses of antibiotics, SOT recipients, patients with haematological malignancies, and healthcare workers. Risk factors for VRE bacteraemia include intestinal colonization, prior long-term antibiotic use, increased severity of illness, haematological malignancy, bone marrow transplant, mucositis, neutropenia, indwelling urinary catheters, corticosteroid treatment, chemotherapy, and parenteral nutrition.
The virulence of enterococci is generally lower than that of organisms such as Staphylococcus aureus, but this is counterbalanced by the fact that enterococcal infections most often occur in debilitated patients and as part of polymicrobial infections. Nosocomial infections are often in very ill patients who have been exposed to broad-spectrum antibiotics. Urinary tract infections are the most common site of VRE, followed by bacteraemia. Enterococci, predominantly E. faecium, cause 5–15% of all cases of endocarditis; this tends to be left-sided and subacute (often without peripheral stigmata). Other sites of enterococcal infection include the abdomen, pelvis, and rarely the meninges (often associated with neurosurgical procedures).
Obtain cultures from blood, urine, and any other sites suspected to be infected (e.g. peritoneal fluid, joint fluid, CSF, pyogenic fluid collections in soft tissue). If endocarditis is suspected, obtain three sets of blood cultures over 1 hour or longer.
Send stool or perirectal cultures to screen for VRE colonization.
Therapy depends on antibiotic sensitivities. Treatment of bacteraemia due to susceptible enterococci (in the absence of suspected endocarditis) consists of ampicillin monotherapy. Bacteraemia due to ampicillin-resistant organisms is with vancomycin. Vancomycin-resistant E. faecium bacteraemia may be treated with daptomycin. Endocarditis is usually treated with a combination of ampicillin and low-dose gentamicin.
Public Health England (PHE) https://www.gov.uk/guidance/enterococcus-species-and-glycopeptide-resistant-enterococci-gre for guidelines on glycopeptide-resistant enterococci.
British Society for Antimicrobial Chemotherapy (BSAC) https://www.britishinfection.org/guidelines-resources/published-guidelines/ for guidelines relating to enterococcal endocarditis.
Staphylococcus aureus (MRSA/VRSA)
In the early 1960s, just a couple of years after the introduction of methicillin, resistant S. aureus isolates were first described. Resistance is defined as an oxacillin MIC >4 micrograms/mL and results from the PBP-2a encoding mecA gene. Studies suggest that the mec gene was acquired from closely related coagulase-negative staphylococci (CoNS) species. MRSA is now globally distributed and a common pathogen, both in hospitals and the community. The ability of S. aureus to form biofilms on invasive devices (such as endovascular catheters) partly accounts for its ubiquity as a nosocomial pathogen. Immunosuppression is associated with an increased risk of S. aureus colonization and therefore an increased risk of infection and morbidity. Mortality appears to be higher with bacteraemia due to MRSA than with methicillin-sensitive S. aureus (MSSA) organisms.
Vancomycin-intermediate and vancomycin-resistant (VISA/VRSA MIC 4–8 micrograms/mL and MIC ≥16 micrograms/mL respectively) S. aureus, were first described in 1997 and 2002 respectively. These have arisen via different mechanisms. VISA are thought to have resulted from mutations of MRSA strains exposed to vancomycin, whereas VRSA arose from transfer of genetic material from VRE.
Based on differences in clinical and molecular epidemiology, MRSA has traditionally been divided into healthcare-associated (HA-MRSA) and community-associated (CA-MRSA).
HA-MRSA is defined as infection occurring >48 hours after hospital admission or within 1 year of healthcare exposure. It is classically associated with severe disease such as pneumonia and bloodstream infection. Antibiotic use, long hospital stays, ICU admission, haemodialysis, MRSA colonization, and proximity to others with MRSA are all risk factors for HA-MRSA infection. By contrast, CA-MRSA has been most associated with skin and soft tissue infections in otherwise healthy individuals. Over recent years, however, the boundaries between CA- and HA-MRSA have blurred. HIV infection is a risk factor for MRSA colonization and infection, with skin and soft tissue infections being the predominant manifestation. Antibiotic use (particularly cephalosporin and fluoroquinolone use) strongly correlates with the risk of MRSA colonization and infection. MRSA transmission occurs via contact with a colonized individual or a contaminated fomite.
There have been globally scattered case reports of VRSA, with over a dozen cases reported in the US since 2002.
While skin and soft tissue infections are the most common presentations, S. aureus also is responsible for a wide spectrum of invasive infections including musculoskeletal infections, complicated pneumonia, and endocarditis. S. aureus is a leading cause of community- and hospital-acquired bacteraemia. Vascular catheters are a common source of infection and cardiac devices such as pacemakers often become colonized. The incidence of infective endocarditis in the setting of S. aureus bacteraemia is 10–15% and can be more aggressive than endocarditis due to other organisms. Osteomyelitis (most frequently vertebral) commonly occurs due to either haematogenous or direct spread from a contiguous focus of infection. Back or joint pain in a patient with S. aureus bacteraemia should prompt imaging to look for an osteomyelitic lesion. Among hospital inpatients, S. aureus pneumonia is associated with intubation or other respiratory tract instrumentation.
HIV-positive adults are known to have more frequent invasive S. aureus infections, notably bacteraemia, than HIV-negative controls and these infections are more often with drug-resistant strains.
S. aureus accounted for 10% of total cases of bacteraemia in a series of adults with malignancy with mortality rates ranging from 15% to 25%. The mortality rate for S. aureus pneumonia in adult cancer patients is particularly high (almost 50%).
Blood cultures and other sterile site sampling are the mainstay of diagnosis. Failure to clear bacteraemia on repeat culture (taken ~48 hours after initiation of therapy) should prompt evaluation of susceptibility data to ensure appropriate antibiotic selection and dosing, as well as clinical evaluation for occult focus of infection that may require drainage or surgery.
Repeated isolation of S. aureus despite seemingly appropriate therapy should prompt consideration of MRSA, VISA, or VRSA. VISA may emerge during treatment even if the MIC of the original isolate was within the susceptible range. Alternatively, persistent bacteraemia may reflect abscess or metastatic infection rather than reduced antibiotic susceptibility.
Disc diffusion or automated methods are insufficient for detection of S. aureus with reduced susceptibility to vancomycin; a MIC susceptibility testing method (such as broth microdilution or agar-gradient diffusion) should be used.
Eliminate potential sources of ongoing infection (e.g. implanted medical material, vascular catheter, abscess, etc.) Vancomycin or daptomycin are the agents of choice for treatment of invasive MRSA infections. Alternatives, if available, include teicoplanin, ceftaroline, linezolid, and telavancin. If the vancomycin MIC nears the limit of the susceptible range (2 micrograms/mL) and initial clinical response is poor, vancomycin should be discontinued and replaced with daptomycin.
Optimal regimens for infection due to VISA or VRSA are uncertain.
In the context of bacteraemia but with proven absence of deep-seated infection, monotherapy may be considered and options include ceftaroline, linezolid, and telavancin. In cases of bacteraemia and concomitant deep-seated infection, combination therapy is warranted to minimize the risk of resistance emerging during therapy. Possible combinations include daptomycin plus ceftaroline (or other beta-lactams); vancomycin plus ceftaroline (or other beta-lactams); daptomycin plus TMP–SMX; or ceftaroline plus TMP–SMX.
Enterobacteriaceae: extended-spectrum beta-lactamases and carbapenemases
Extended-spectrum beta-lactamases (ESBL) are enzymes which open the beta-lactam ring and inactivate most beta-lactam antibiotics. ESBL have so far been found exclusively in Gram-negative organisms, primarily Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca, but also in Acinetobacter, Burkholderia, Citrobacter, Enterobacter, Morganella, Proteus, Pseudomonas, Salmonella, Serratia, and Shigella spp. First reported in Gram-negative bacteria in the 1960s, plasmids encoding ESBL are now prevalent in Enterobacteriaceae worldwide. The most common ESBL currently described are CTX-M, TEM, and SHV beta-lactamases. The proportion of Enterobacter isolates producing ESBL is increasing and recent estimates from some centres are in the region of 15% of K. pneumoniae, 12% of E. coli, 10% of K. oxytoca, and 5% of P. mirabilis.
Carbapenemases are carbapenem-hydrolysing beta-lactamases which confer resistance to carbapenems as well as penicillins, cephalosporins, and other antibiotics. The widespread use of carbapenems to treat suspected cases of ESBL-producing bacteria has now led to the development and increasing prevalence of carbapenem resistance in these same bacterial species. They have been organized into four classes (A–D) based on their amino acid sequences; class A contains the best known and most prevalent carbapenemase, K. pneumonia carbapenemase (KPC).
GI colonization with ESBL/carbapenemase producing Enterobacteriaceae is a strong risk factor for subsequent infection and colonization is often driven by the use of broad-spectrum antibiotics. Prolonged hospitalization, mechanical ventilation, haemodialysis, malignancy, organ transplantation, and intravascular catheters are all associated with an increased risk of infection with resistant Gram-negative bacilli. Travelling to, and particularly receiving medical treatment in, regions with high rates of ESBL/carbapenemases, such as parts of Asia and Latin America, is also a well-described risk factor. Environmental, animal, and food contamination with ESBL-producing Gram-negative organisms have been extensively documented.
Gram-negative bacilli were once the predominant organisms associated with hospital-onset bloodstream infections, but over the last few decades, Gram-positive aerobes (e.g. coagulase-negative staphylococci, S. aureus, and enterococci), and Candida spp. have increased in relative importance. Gram negatives still account for a higher proportion of community-onset bacteraemias as these are more likely related to primary infections of the urinary tract, abdomen, and respiratory tract as opposed to device-related infections.
Fever and rigors are the most common presentation of Gram-negative bacteraemia, with hypotension, mental state changes, and respiratory failure suggestive of developing shock. Most hospitalized patients with Gram-negative bacteraemia will have at least one immunocompromising comorbidity and Gram-negative bacillary sepsis with shock has a high mortality rate (~10–40%).
Drug-resistant Enterobacteriaceae may cause infection at diverse sites but are most commonly encountered in bloodstream infections, ventilator-associated pneumonia, urinary tract infections, and catheter-related infections. Clusters and outbreaks have occurred due to hospital-based clonal spread.
Cultures of blood, urine, CSF, respiratory secretions, or any other clinically relevant and accessible sample should be taken prior to initiation of antimicrobial therapy. At least two sets of blood cultures taken from separate venepuncture sites should be obtained. Most clinically significant bacteraemias are detected within 48 hours with the use of instrument-based, continuous monitoring blood culture systems.
Recent technologies for organism identification, such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and next-generation gene sequencing may increase the speed of diagnosis and detection of known resistant strains.
The isolation of a drug-resistant strain should be discussed with the local microbiology team to consider antimicrobial options, infection control, and contact tracing/screening. Follow-up blood cultures are normally recommended when MDR strains are detected.
Optimal treatment should be guided by location and severity of infection as well as the sensitivity profile of the isolate. The only current proven therapeutic options for serious infections caused by ESBL producers are the carbapenems (meropenem, ertapenem, imipenem, and doripenem).
Carbapenem-resistant Enterobacteriaceae (CRE) causing an uncomplicated urinary tract infection can often be effectively treated with fosfomycin or an aminoglycoside (assuming they remain susceptible). Combination therapy with at least two drugs is used for more serious infections (including bacteraemia). The optimal combination is uncertain, but a polymyxin-based (colistin or polymyxin B) regimen should be used unless there is documented resistance. Meropenem, especially if the isolate has a MIC to meropenem ≤8 micrograms/mL, can be added as a second agent. For infections involving the GI tract and lungs, consider tigecycline as the second agent as it penetrates well into these tissues. Ceftazidime–avibactam is an alternative agent to use as part of a combination regimen if the isolate is susceptible. Aztreonam may be a useful additional agent for patients whose isolates carry a metallo-beta-lactamase and demonstrate in vitro susceptibility to this drug.
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) https://www.escmid.org/escmid_publications/medical_guidelines/escmid_guidelines/for guidelines on treatment of hospital-associated MDR Gram-negative bacteria.
Public Health England (PHE) https://www.gov.uk/government/publications/carbapenemase-producing-enterobacteriaceae-early-detection-management-and-control-toolkit-for-acute-trusts for guidelines on carbapenemase-producing Enterobacteriaceae.
Aerobic, Gram-negative, motile coccobacilli which naturally inhabit soil and water. >30 species have been described in the Acinetobacter genus, but A. baumannii is the most frequently isolated and clinically important species. It colonizes skin, wounds, the GI and respiratory tracts, and is associated with hospital outbreaks, particularly among ICU patients. A. baumannii has acquired many different antibiotic resistance mechanisms and MDR strains are an increasing threat.
A. baumannii is a significant cause of hospital-acquired infection worldwide and tends to occur in debilitated ICU patients—accounting for up to 10% of Gram-negative isolates in ventilator-associated pneumonia. Outbreaks have been linked to contaminated ventilator equipment as well as cross-infection from the contaminated hands of healthcare workers. Some Acinetobacter strains can survive desiccation for weeks.
Consider in all ventilator-associated pneumonia and hospital-acquired sepsis. Bloodstream infection usually results from pneumonia and vascular catheters, though wounds and the urinary tract are other possible primary sites. Risk factors for A. baumanni bacteraemia include immunosuppression, prior use of broad-spectrum antibiotics, mechanical ventilation, trauma, burns, malignancy, and prolonged hospitalization. Acinetobacter are also rare causes of infective endocarditis and nosocomial meningitis. Traumatic wound infections (notably war-related blast injuries) with MDR Acinetobacter are increasingly reported.
Culture: send clinically relevant samples (blood, respiratory samples, CSF) for culture and sensitivity. Distinction between colonization and infection can often be difficult and depends crucially on the clinical context and site of sampling. As with Pseudomonas spp., quantitative or semi-quantitative culture of respiratory samples may be helpful.
Treatment of severe disease depends on sensitivity but empirical treatment should be with a carbapenem ± a quinolone.
Public Health England (PHE) guidelines on multi-resistant Acinetobacter infections: https://www.gov.uk/government/publications/acinetobacter-working-party-guidance-on-the-control-of-multi-resistant-acinetobacter-outbreaks/working-party-guidance-on-the-control-of-multi-resistant-acinetobacter-outbreaks.