Background
In 1882, Gessard first discovered Pseudomonas, a strictly aerobic, gram-negative bacterium of relatively low virulence. The organism is ubiquitous, with a predilection to moist environments, primarily as waterborne and soilborne organisms. Pseudomonal species have been found in soil, water, plants, and animals; Pseudomonas aeruginosa colonization reportedly occurs in more than 50% of humans, and P aeruginosa is the most common pseudomonal species.
Pseudomonas is a clinically significant and opportunistic pathogen, often causing nosocomial infections. In addition to causing serious and often life-threatening diseases, these organisms exhibit innate resistance to many antibiotics and can develop new resistance after exposure to antimicrobial agents. Some pseudomonal species that previously were considered the causative agents of old diseases now are being reexamined for their potential use as biological warfare agents.
The current classification of the genus Pseudomonas is divided into 5 groups based on ribosomal RNA (rRNA)/DNA homology. Of the more than 20 pseudomonal species that have been found from human clinical specimens, the following 4 representative organisms are discussed in this article:
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P aeruginosa (homology group I)
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Burkholderia (Pseudomonas) cepacia (group II)
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Burkholderia (Pseudomonas) pseudomallei (group II)
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Burkholderia (Pseudomonas) mallei (group II)
Pathophysiology
Pseudomonas aeruginosa
Although P aeruginosa is a common human saprophyte, it rarely causes disease in healthy persons. Most infections with this organism occur in compromised hosts. Examples of compromising conditions include disrupted physical barriers to bacterial invasion (eg, burn injuries, intravenous [IV] lines, urinary catheters, dialysis catheters, endotracheal tubes) and dysfunctional immune mechanisms, such as those that occur in neonates and in individuals with cystic fibrosis (CF), [1] acquired immunodeficiency syndrome (AIDS), neutropenia, complement deficiency, hypogammaglobulinemia, and iatrogenic immunosuppression.
The complete sequence of the genome of P aeruginosa strain, PAO1, is noted for its large size and diverse metabolic capacity. The pathogenesis of this organism is multifactorial and involves various toxins and proteases (eg, exotoxin A, lecithinase) and the glycocalyx "slime." P aeruginosa is both invasive and toxigenic. The 3 stages of Pseudomonas infections are (1) bacterial attachment and colonization, (2) local infection, and (3) bloodstream dissemination and systemic disease.
Efflux systems are thought to contribute to antimicrobial resistance in P aeruginosa; thus, efflux pump inhibitors are thought to be useful in reducing the invasiveness and antimicrobial resistance of P aeruginosa and may be promising as new anti-infectious agents. The genome annotation is continually updated, and the database functionality is being expanded to facilitate accelerated discovery of P aeruginosa drug targets and vaccine candidates.
Pseudomonal infection, as described by Pollack, occurs in 3 stages: (1) bacterial attachment and colonization, followed by (2) local invasion and (3) dissemination and systemic disease. [2]
In healthy children, disease is primarily limited to the first 2 stages (as in diseases such as otitis externa, urinary tract infections (UTIs), dermatitis, cellulitis, and osteomyelitis), although recent case reports describe bacteremia, sepsis, and GI infections in previously healthy children.
In immunocompromised hosts, including neonates, infection can progress rapidly through the 3 stages and cause pneumonia, endocarditis, peritonitis, meningitis, ecthyma gangrenosum (EG), bacteremia, and overwhelming septicemia.
Pseudomonas cepacia
In 1949, Walter Burkholder of Cornell University first described P cepacia (now known as Burkholderia cepacia) as the phytopathogen responsible for the bacterial rot of onions. [3] In the 1950s, B cepacia was first reported as a human pathogen that causes endocarditis. Subsequently, the organism has been found in numerous catheter-associated UTIs, wound infections, and IV catheter–associated bacteremias.
In 1971, this species was reported as the causative organism of foot rot in US troops on swamp training exercises in northern Florida; it also was isolated from troops serving in Vietnam's Mekong Delta. In 1972, B cepacia was discovered as an opportunistic human pathogen in a patient with CF. Since then, B cepacia has emerged with increasing frequency as the cause of pneumonia and septicemia in children with CF.
Pseudomonas mallei
P mallei (now known as Burkholderia mallei) causes glanders, a serious infectious disease of animals (primarily horses, although it has also been isolated in donkeys, mules, goats, dogs, and cats). Transmission is believed to occur through direct contact. Glanders transmission to humans is rare and presumably occurs through inoculation of broken skin or the nasal mucosa with contaminated discharges. Manifestation of the disease in humans varies, ranging from an acute localized suppurative infection, acute pulmonary infection, or acute septicemic infection to chronic suppurative infection. Fulminant disease with multiple organ system involvement occurs with septicemic infection.
Pseudomonas pseudomallei
P pseudomallei (now known as Burkholderia pseudomallei) causes melioidosis (from the Greek, "resemblance to distemper of asses"). Melioidosis, also called Whitmore disease, clinically and pathologically resembles glanders but has an entirely different epidemiologic profile from B mallei. It occurs in many animals (eg, sheep, goats, horses, swine, cattle, dogs, cats). Transmission is believed to occur through direct contact, although inhalation reportedly is a possible route of acquisition. Since the first description of the disease from North Queensland, Australia, in 1962, melioidosis has spread to Southeast Asia.
B pseudomallei is found in contaminated water and soil. The pathogen spreads to humans and animals through direct contact with a contaminated source. In otherwise healthy hosts, disease manifestations range from acute to chronic local suppurative infections to septicemia with multiple abscesses in all organs of the body.
Epidemiology
Frequency
United States
According to data from the Centers for Disease Control and Prevention (CDC) National Nosocomial Infections Surveillance System, P aeruginosa can be rated as follows:
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Number 1 cause of intensive care unit (ICU)–related pneumonia
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Number 1 cause of osteochondritis
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Number 2-ranked gram-negative organism, responsible for 9% of all nosocomial bacterial and fungal isolates
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Number 2 cause of nosocomial pneumonia
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Number 3-ranked isolate in hospital-acquired UTIs
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Number 4 cause of surgical site infections and of hospital-acquired gram-negative rod bacteremia
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Number 5 hospital pathogen
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Number 8-ranked bloodstream isolate
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Causes 10% of nosocomial infections
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Most common bacteria isolated from mild-to-severe form of external otitis and chronic suppurative otitis media
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Most common gram-negative organism isolated from corneal ulcers and endocarditis
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Frequent cause of contact lens–associated keratitis
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Second most frequent cause of brain abscess and meningitis in patients with cancer
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Third most common cause of recurrent UTIs complicated by obstruction, catheters, or stones
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Fifth most common cause of recurrent UTIs in schoolchildren
B cepacia is associated with increased illness and death in patients with CF. In several small focal hospital outbreaks that involved patients who did not have CF, the typical cause was a contaminated common source (eg, IV solutions, disinfectant preparations). In the early 1980s, the organism emerged as a major threat, causing superinfection in as many as 40% of patients in some CF centers. Approximately 35% of patients infected with B cepacia develop accelerated pulmonary deterioration or fulminant necrotizing pneumonia with rapidly fatal bacteremia, a condition also referred to as cepacia syndrome.
A retrospective analysis of the U.S. National Hospital Discharge Surveys from 1996-2010 found that Pseudomonas aeruginosa septicemia incidence declined from 6.5 per 10,000 in 1996 to 3.1 per 10,000 in 2001 and then increased to 6.5 per 10,000 in 2010. [4]
International
Numerous B cepacia epidemics associated with CF have been reported. A particular highly transmissible strain, which spread epidemically within and between CF centers in Western Europe and the United States, carries the cblA gene. This cblA strain has spread across Canada and now has been isolated in 50% of CF centers in the United Kingdom. Another strain of B cepacia has been found in CF centers in 4 regions of France. The propensity for transmission evidently varies among strains; most strains are not involved in epidemics but appear to be acquired independently without evidence of epidemic transmission.
A study reviewed German NICU surveillance data on more than 44,000 infants below 1500 g birth weight with the aim to quantify the pathogen-specific risk of a blood stream infection in preterm infants after an index case of the same pathogen in the NICU department. The relative risk was markedly elevated for Serratia and Pseudomonas aeruginosa. With only 38 cases of Pseudomonas aeruginosa out of the 2004 culture-positive infections, the relative risk was still high at 64.5. [5]
Glanders caused by B mallei has not occurred in the United States since the 1940s, although it remains common in domestic animals in Africa, Asia, the Middle East, Central America, and South America.
Melioidosis caused by B pseudomallei is endemic in Southeast Asia. The highest concentrations of cases occur in Vietnam, Cambodia, Laos, Thailand, Malaysia, Myanmar (formerly Burma), and northern Australia. Melioidosis also occurs in the South Pacific, Africa, India, and the Middle East. The B pseudomallei organism is so prevalent that it is often found as a contaminant.
Mortality/Morbidity
Pseudomonal infections (eg, bacteremic pneumonia, sepsis, burn wound infections, meningitis) are associated with an extremely high mortality rate.
Monocular blindness is primarily due to bacterial keratitis, the causes of which include pseudomonal infection. Colonization with B cepacia has been associated with increased morbidity and mortality in patients who are immunocompromised, especially those with CF.
Untreated glanders and melioidosis bloodstream infections are usually fatal within 7-10 days. P aeruginosa bacteremia has an estimated mortality rate exceeding 50% and is associated with fatality rates higher than those associated with other gram-negative bacteremic infections. Pseudomonal pneumonia, especially the bacteremic type, is associated with mortality that typically occurs 3-4 days after the first signs or symptoms of pulmonary or extrapulmonary infection. Ventilator-associated pneumonia (VAP) caused by P aeruginosa is associated with higher mortality rates (estimated to be as high as 68%) than VAPs caused by other infectious organisms. The mortality rate is high for the septicemic form of EG and is approximately 15% for the nonsepticemic form of the disease.
Race
Black men reportedly have an increased incidence of pseudomonal endocarditis.
Sex
Sternoarticular pyarthrosis caused by pseudomonal infections occurs in young men, particularly those who engage in IV drug abuse. Some studies cite a 5.4:1 male-to-female ratio of P aeruginosa endocarditis.
Age
Infants younger than 1 year have direct vascular communication with the epiphysis across the growth plate, allowing direct spread of pseudomonal osteomyelitis from the metaphysis to the epiphysis and, eventually, the joint. In older children, the growth plate provides a barrier; thus, the epiphysis and the joints seldom are involved.
Children have a higher predilection than adults to pseudomonal osteochondritis infections following puncture wounds of the foot. Older patients are more susceptible to pseudomonal bone and joint infections. Children have a higher likelihood of developing pseudomonal folliculitis than adults. Endocarditis occurs most often in young (mean age 29 y) black men.
In patients with CF, prevalence of pseudomonal pneumonia ranges from 21% in those younger than 1 year to more than 80% in those older than 19 years. The increasing longevity of patients with CF has created a significant shift in the proportion of adult patients with CF; their proportion has increased 4-fold, from 8% in 1969 to 33% in 1990.
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Erythematous papulopustules of pseudomonas folliculitis. Courtesy of Mark Welch, MD.
