Further emphasis on the recommendation that combination therapy be used for serious infections.
Brief section on endocarditis added.
Pseudomonas aeruginosa is a highly versatile environmental Gram-negative bacterium that can be isolated from a wide range of habitats, including soil, marshes, and the ocean, as well as from plants and animal tissues. It is resistant to many disinfectants and antibiotics, giving it a selective advantage in hospitals. It rarely causes infection in the healthy host but is a major opportunistic pathogen.
Clinical features—(1) In hospitals—causes a range of infections, including bacteraemia (often in association with neutropenia), ventilator-associated pneumonia, urinary tract infection, skin and soft-tissue infections, and bacteraemia associated with burns. (2) In the community—the largest group of people affected by P. aeruginosa are those with cystic fibrosis, who develop long-term colonization of the airways punctuated by episodes of clinical infection.
Diagnosis—this is usually straightforward when the organism is cultured from samples collected from normally sterile sites, but is often challenging when infection is suspected in sites such as a catheterized urinary tract, burns, or ulcers. Serology is of no value.
Treatment—P. aeruginosa is intrinsically resistant to a broad range of antimicrobial drugs. Appropriate and effective prescribing for high-risk patients requires (1) clinical awareness of risk factors for P. aeruginosa, combined with knowledge of the spectrum of diseases caused by this organism; (2) carefully considered empirical regimens based on local antimicrobial susceptibility data—these will typically include a β-lactam (e.g., ceftazidime, meropenem, or piperacillin) plus a second agent (e.g. a fluoroquinolone or aminoglycoside) for serious infections, although single agents may be used for uncomplicated infections; and (3) attention to susceptibility profiles once the causative strain has been isolated and tested.
Genetics and pathogenesis
The Pseudomonas aeruginosa genome is composed of a single chromosome of 6.3 Mbp containing around 5700 predicted open reading frames. This is markedly larger than most other sequenced bacterial genomes, and approaches the size of the simple eukaryote Saccharomyces cerevisiae, the genome of which encodes around 6200 proteins. The P. aeruginosa genome contains a high proportion of regulatory genes and a large number of genes involved in catabolism, transport, and efflux of organic chemicals. The size and complexity of the genome underpins its ability to thrive in diverse environments. P. aeruginosa produces a single polar flagellum and numerous fimbriae or pili which allow it to adhere to the respiratory epithelium. More than one-half of all clinical isolates produce pyocyanin (a blue pigment) and pyoverdin (a green pigment), which are responsible for the characteristic blue-green colour of P. aeruginosa colonies growing on solid media. Pyocyanin is an exotoxin that has immunomodulatory effects on respiratory epithelial cells, is toxic to neutrophils, and is involved in iron acquisition. Alginate mediates adherence to epithelial surfaces and protects the organism from phagocytosis. The production of alginate exopolysaccharide by mucoid strains of P. aeruginosa has been shown to be involved in the colonization of the lungs of patients with cystic fibrosis and is an adverse prognostic factor.
P. aeruginosa in the environment
P. aeruginosa is ubiquitous in the environment. In homes, it is often found in the aerators and traps of sinks, shower heads, water coolers, contact lens solutions, and cosmetics, as well as in swimming pools, whirlpool baths, and jacuzzis. It may also be cultured from a wide variety of raw fruit and vegetables. It is difficult to eradicate from the hospital environment, where it has been found in soap dishes, dialysis fluid, irrigation fluids, eye drops, disinfectants, ointments, and mechanical ventilators. P. aeruginosa is resistant to several commonly used disinfectants: ammonium acetate-buffered benzalkonium chloride solution will support the growth and division of P. aeruginosa, and the organism readily develops resistance to chlorhexidine. P. aeruginosa is killed by povidone-iodine, glutaraldehyde, bleach, and alcohol, but may be relatively resistant to these when present in a biofilm or embedded within proteinaceous material.
Human colonization and disease
P. aeruginosa is probably consumed regularly and is capable of colonizing the human gastrointestinal tract. It is rarely present on the intact skin or mucous membranes of healthy individuals but often colonizes severely ill patients, particularly those on broad-spectrum antibiotics. P. aeruginosa often colonizes areas of broken skin, such as ulcers, and medical devices in contact with the environment, such as long-term urinary catheters. The organism may cause a broad range of infections, most commonly in patients with one or more risk factors.
Bacteraemia occurs primarily in immunocompromised patients, particularly those with haematological malignancies, neutropenia, or severe burns. P. aeruginosa accounts for approximately one-quarter of all hospital-acquired bacteraemias, and has a mortality of 18%. In 2007, there were 3823 reported cases of pseudomonas bacteraemia in the United Kingdom (6.9 per 10 000 population), a 20% increase compared to 2003. Clinical features of sepsis associated with P. aeruginosa infection do not differ from those associated with other bacterial infections, and empirical antimicrobial prescribing for high-risk patients should include cover for P. aeruginosa. A primary source of infection (e.g. a chronic ulcer in a diabetic patient, a urinary catheter, etc.) should be sought and removed wherever possible. In rare cases of P. aeruginosa infection, patients may develop a skin lesion called ecthyma gangrenosum (Fig. 18.104.22.168.1) which, although not pathognomonic for P. aeruginosa, is rarely a feature of infection by any other organism. This presents as a painful, well-circumscribed, erythematous lesion anywhere on the body that progresses to necrosis within hours or days. Ecthyma rarely appears in a non-neutropenic host, and its appearance marks the failure of the host immune response to control the infection. In these patients, P. aeruginosa may often be cultured both from blood and from the lesion, but not every patient with ecthyma is detectably bacteraemic.
P. aeruginosa consistently ranks either first or second in frequency as a cause of ventilator-associated pneumonia in United States of America surveys (National Healthcare Safety Network). Diagnosis is complicated by the fact that severely ill patients commonly become colonized by P. aeruginosa, and appropriate sampling of patients with suspected ventilator-associated pneumonia requires the use of bronchoalveolar lavage or protected-specimen brush sampling of the distal airways. Tracheal aspirates are easier to obtain but less helpful (positive cultures are suggestive but not diagnostic). The diagnosis and treatment of ventilator-associated pneumonia is described in Section 18 and Chapter 18.4.3. P. aeruginosa commonly colonizes the respiratory tract of people with cystic fibrosis and is the leading cause of respiratory infection in this group. Asymptomatic P. aeruginosa colonization is associated with a more rapid decline in lung function and increased mortality from respiratory failure. It is difficult to obtain adequate sputum samples from children, and so in the context of cystic fibrosis, bronchoscopy is sometimes the only available diagnostic technique. Some clinicians have attempted to avoid invasive sampling by using serological tests, but the results are unreliable. Current evidence is that early treatment with nebuliszed tobramycin is capable of eradicating of P. aeruginosa from cystic fibrosis patients. Cystic fibrosis is discussed in Chapter 18.10. P. aeruginosa may cause a fulminant necrotizing pneumonia in neutropenic patients as part of a syndrome of disseminated infection.
Skin and soft tissue infection
P. aeruginosa rarely invades healthy skin and a breach of the integument (e.g. skin maceration from chronic immersion in water, a burn, a cut or nick from a razor blade or rose thorn, a surgical wound, or an ulcer) is usually required for infection to become established. ‘Hot tub’ dermatitis is a self-limiting skin infection in healthy people caused by exposure to water contaminated with P. aeruginosa and manifests as folliculitis or vesicular lesions. Outbreaks have been associated with jacuzzis, spas, and swimming pools. P. aeruginosa is a cause of surgical wound infections (4.6–11% according to annual National Nosocomial Infections Surveillance System surveys), but is far less common than Staphylococcus aureus. P. aeruginosa colonization of chronic leg ulcers is common, but it is rarely the only organism found from superficial swabs taken from this type of lesion and is usually a colonizer rather than an invader. Superficial swabs of ulcers are best avoided in the absence of clinical signs of active infection. When infection is present (e.g. cellulitis, associated osteomyelitis, bacteraemia), cultures from deep tissue that does not communicate with the ulcer or wound surface should be obtained. Ecthyma gangrenosum is described under the section on bacteraemia (see above). P. aeruginosa is an important cause of infection in patients with burns, the other important pathogen being S. aureus.
The initiating event in P. aeruginosa urinary tract infection is usually urinary catheterization or instrumentation of the urinary tract, although infection may occasionally occur by haematogenous spread to the kidneys. Patients with long-term indwelling urinary catheters are at particular risk, a combined effect of the presence of prosthetic material that provides a nidus for infection and because frequent antimicrobial therapy for recurrent urinary infection selects for resistant organisms such as P. aeruginosa. No specific clinical features distinguish P. aeruginosa urinary infections from infection caused by other pathogens. The diagnosis is made on urine culture in the presence of appropriate clinical features, predominant of which is fever. P. aeruginosa infection in this patient group is rarely cured without removal/replacement of the urinary catheter on which organisms persist within a biofilm. Catheter change should be performed towards the end of therapy once the burden of planktonic bacteria (bacteria free in urine) is much reduced. Routine urine culture of patients with long-term urinary catheters provides no useful information in the absence of clinical features of active infection. Renal imaging may be useful to exclude renal abscesses or calculi if the reason for the infection is not obvious.
P. aeruginosa is a leading cause of otitis externa, an infection of the external auditory canal that causes inflammation, pain (which is exacerbated by traction on the pinna), and, if severe, a purulent discharge. It is common to find lymphadenopathy just anterior to the tragus. The disease is usually seen in children and the source of infection includes underchlorinated swimming pools or fresh water (lakes or rivers). The diagnosis is based on signs and symptoms, and empiric treatment with eardrops is usually effective. Malignant otitis externa is rare but much more serious. It not a neoplastic process, but is so called because of the risk of localized destructive spread to the central nervous system. It most commonly occurs in elderly patients with diabetes and people with HIV infection, and is essentially an osteomyelitis of the mastoid and petrous temporal bone. Affected patients present with an erythematous oedematous inflamed external auditory canal, and the tympanic membrane is often hidden by oedema. Otoscopy is necessary to make the diagnosis, but is often poorly tolerated because of pain. Lymphadenopathy of the ipsilateral cervical lymph nodes may be present; facial nerve involvement produces an ipsilateral lower motor neuron seventh nerve palsy. Spread to the temporomandibular joint causes pain on mastication, and spread to the apex of the petrous temporal nerve produces Gradenigo’s syndrome (trigeminal and trochlear nerve palsies). Features of malignant otitis externa should prompt immediate referral to an ear, nose, and throat surgeon for assessment and debridement of the ear canal and adjacent bone. The diagnosis is made by demonstrating osteomyelitis of the skull base on a technetium-99 bone scintigram or on MRI, along with P. aeruginosa cultured from the discharge or from a bone biopsy.
The most common manifestation of P. aeruginosa eye infection is keratitis, which occurs following direct inoculation from trauma (e.g. contact sports, industrial accidents) or minor abrasions (e.g. contact lens use). Contact lens keratitis has been associated with contaminated contact lens disinfectant solutions. P. aeruginosa keratitis requires prompt ophthalmological referral and treatment since infection may be rapidly progressive and can result in corneal opacification and even perforation within 48 h. Pseudomonal endophthalmitis most commonly occurs as a consequence of penetrating injury or surgery, but there is also a rare syndrome of neonatal endophthalmitis that may be bilateral, the main risk factor for which is prematurity. Clinical features include severe pain, chemosis, loss of the red reflex, hypopyon, and corneal clouding. Neonatal pseudomonal endophthalmitis most commonly arises from haematogenous spread, frequently in association with a syndrome of disseminated disease that includes meningitis and pneumonia, and is commonly fatal. Endophthalmitis is diagnosed by culture of a vitreous humour biopsy.
P. aeruginosa endocarditis is a disease confined almost exclusively to injecting drug users, in whom it is usually right-sided. Extended intravenous combination therapy with a β-lactam and an aminoglycoside is required, and valve replacement is often necessary. In the case of left-sided endocarditis, antibiotic therapy alone is rarely sufficient and valve replacement is mandatory.
Bone and joint infection
Patients with diabetes may develop osteomyelitis of the foot following penetrating injury or local extension of an untreated chronic ulcer. Results from superficial swabs are of minimal clinical relevance, and diagnosis should be based on the results of bone biopsy which should be processed for culture and histopathology. Parenteral antimicrobials are not always successful and radical debridement or amputation may be necessary to clear the infection. Intravenous drug users are susceptible to P. aeruginosa septic arthritis and osteomyelitis of the axial skeleton.
Patients with HIV infection are more susceptible to P. aeruginosa infection, usually when the CD4 count is below 100 cells/µl. The incidence has fallen since the advent of highly active antiretroviral therapy (HAART). The presentation of P. aeruginosa infection in HIV patients is more indolent than that in neutropenic patients, but mortality is 22 to 34%. The fever is frequently low grade and ecthyma gangrenosum is rare. It is most commonly intravenous device related. Pneumonia is the most common community-acquired presentation, followed by sinusitis, and infections of the urinary tract, all of which may be associated with bacteraemia.
P. aeruginosa elaborates a range of β-lactamases (penicillinases and cephalosporinases) and has a relatively impermeable outer membrane, which makes it intrinsically resistant to a wide variety of antimicrobials, including all first-generation and second-generation cephalosporins, most penicillins, and all macrolides. The antipseudomonal cephalosporins ceftazidime and cefepime are effective; of the carbapenems imipenem and meropenem are effective. The antipseudomonal penicillins are piperacillin and ticarcillin (commonly available in combined preparations with tazobactam or clavulanate). The β-lactams are bactericidal and there is good clinical evidence for their efficacy and safety, except that cefepime monotherapy is associated with a higher all-cause mortality and cannot therefore be recommended. There is evidence from animal studies that continuous infusions of β-lactam are superior to intermittent dosing. The monobactam, aztreonam, has not found widespread use because isolates that are resistant to ceftazidime or piperacillin are generally also resistant to aztreonam. However, there are rare metallo-β-lactamase-producing strains of P. aeruginosa that may be resistant to carbapenems but sensitive to aztreonam. The aminoglycosides (gentamicin, amikacin, kanamycin, tobramycin, etc.) are effective in vitro and may be used in combination with β-lactams in empiric regimens for febrile neutropenic patients and for P. aeruginosa ventilator-associated pneumonia. Concerns that aminoglycosides are not effacious in neutropenia has led to the use of other empirical combinations (e.g. β-lactam plus fluoroquinolone). The aminoglycosides also have poor tissue penetration and are renal/ototoxic. Depending on the site of infection, inhaled or topical aminoglycosides may be preferable, e.g. inhaled tobramycin for cystic fibrosis patients, or topical gentamicin for otitis externa and superficial eye infections. The fluoroquinolone ciprofloxacin is active when administered orally, an attribute that makes it almost unique among the therapeutic options available for P. aeruginosa treatment.
Acquired drug resistance is a problem in patients who are antibiotic experienced (an important example being patients with cystic fibrosis), but resistance to commonly used antibiotics is a problem even outside this patient group. The United Kingdom Health Protection Agency reported that of the P. aeruginosa strains isolated from blood in 2009, 11% were not susceptible to ciprofloxacin, 8% to ceftazidime, 8% to piperacillin/tazobactam, 14% to imipenem, and 11% to meropenem, with a rise in the proportion of isolates resistant to carbapenems. It is not uncommon for resistance to develop during the course of treatment, an event that is associated with excess mortality. Gentamicin-resistant strains may remain susceptible to kanamycin or neomycin, but cross-resistance to tobramycin is common. Strains that colonize patients with cystic fibrosis frequently become multiply resistant: older antimicrobial agents such as colistin and polymyxin B may then be used.
The antimicrobial treatment and management of P. aeruginosa infection is complex because the infections are often system or patient-group specific and so a single guideline is not appropriate. For patients with serious suspected P. aeruginosa infection, increasing reistance rates mean first line therapy should include a β-lactam (e.g. piperacillin–tazobactam or meropenem) in combination with a second agent in order to achieve adequate coverage. Therapy should be reviewed when culture and susceptibility results are known. There is good in vitro evidence that monotherapy is associated with a slower rate of bacterial killing and the emergence of resistance; however, for uncomplicated infections, therapy with a single agent is probably adequate. Decisions on empirical antimicrobial therapy should be taken in the light of local information on patterns of resistance. The reader is encouraged to study this section in conjunction with other relevant chapters on the management of conditions including neutropenic sepsis, ventilator-associated pneumonia, cystic fibrosis, and urinary tract, ear, and eye infections.
Groups of patients (e.g. neutropenic patients, or patients with severe burns) who are particularly susceptible to invasive pseudomonal infection may be housed in clean units. Such units are equipped with filtered air supplies, and incoming water is chlorinated and continuously heated to 60° C. Attention is paid to the regular maintenance of air conditioning, hydrotherapy units, and water coolers. Visitors and staff are required to wear protective gowns and gloves, and to remove their shoes to avoid contaminating the hospital environment with bacteria brought in from outside the hospital. Fresh flowers and fruit are prohibited for the same reasons, and a rigorous regimen of hand washing is instituted for all visitors and staff. The emergence over the last decade of highly transmissible strains of multidrug-resistant P. aeruginosa in people with cystic fibrosis has necessitated the institution of measures to segregate affected patients. A number of vaccine candidates have entered phase II and III trials (e.g. IC43), but none are currently licensed for clinical use.
Flume et al. (2009). Cystic fibrosis pulmonary guidelines: treatment of
pulmonary exacerbations. Am J Respir Crit Care Med, 180, 802–8.
Find This Resource
Fujitani S, Sun HY, Yu VL, Weingarten JA (2011). Pneumonia due to Pseudomonas
aeruginosa: part I: epidemiology, clinical diagnosis, and source. Chest,
Find This Resource
Kaushik V, Malik
T, Saeed SR (2010). Interventions for acute otitis externa. Cochrane Database Syst
Rev, 1, CD004740.
Find This Resource
Langton Hewer SC, Smyth AR (2009). Antibiotic strategies for eradicating
Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst
Rev, 4, CD004197.
Find This Resource
Louie A, et al. (2010). The combination of meropenem and levofloxacin is
synergistic with respect to both Pseudomonas aeruginosa kill rate and resistance
suppression. Antimicrob Agents Chemother, 54, 2646–54.
Find This Resource
Paul M, Yahav D, Bivas A, Fraser A, Leibovici L (2010). Anti-pseudomonal
beta-lactams for the initial, empirical, treatment of febrile neutropenia: comparison of
beta-lactams. Cochrane Database Syst Rev, 11, CD005197.
Find This Resource
Shuman EK, Chenoweth CE (2010). Recognition and prevention of
healthcare-associated urinary tract infections in the intensive care unit. Crit Care
Med, 38, S373–9.
Find This Resource
Wu DC, et al. (2011). Pseudomonas skin infection: clinical features, epidemiology, and management. Am J Clin Dermatol, 12, 157–69.
Find This Resource