Version May 2024
INTRODUCTION — Pseudomonas aeruginosa, a gram-negative nonfermenting bacillus, is a much-feared pathogen. The organism is common in the environment, especially in water, even contaminating distilled water [1,2]; it is also an important cause of infections associated with hot tubs and contaminated contact lens solutions [3,4]. Considerable attention is paid to P. aeruginosa as a potential pathogen in hospitals because:
●It is often found in water in sinks and can contaminate respiratory equipment, which can serve as an environmental reservoir, especially in intensive care units (ICUs).
●The organism displays a predilection for infecting immunocompromised hosts, including burn patients.
●P. aeruginosa is the most serious pathogen causing ventilator-associated pneumonia (VAP).
●P. aeruginosa strains with resistance to multiple antibiotics have become common in some hospitals and regions.
The epidemiology and pathogenesis of infections due to P. aeruginosa will be reviewed here. The clinical manifestations, diagnosis, and treatment of infections due to this organism are discussed separately. (See "Pseudomonas aeruginosa pneumonia" and "Pseudomonas aeruginosa bacteremia and endocarditis" and "Pseudomonas aeruginosa skin and soft tissue infections" and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".)
MICROBIOLOGY — P. aeruginosa was first isolated from green pus by Gessard in 1882. It is a nonfermentative gram-negative aerobic rod that is ubiquitous in the environment and can be grown on a variety of media. The following features are helpful in confirming its identification on culture plates:
●Characteristic sweet, grape-like odor
●Elaboration of green pigment (picture 1)
●Oxidase-positive
Occasionally, identification by laboratory personnel may be delayed because some isolates lack pigments or produce unusual characteristics such as a "rotten potato" odor [5].
EPIDEMIOLOGY — P. aeruginosa is often an opportunistic pathogen, causing infections in patients with physical, phagocytic, or immunologic defects in host defense mechanisms. Historically, P. aeruginosa has been a major burn wound pathogen, a serious cause of bacteremia in neutropenic patients, and the most important pathogen in cystic fibrosis (CF) patients. However, these associations have undergone considerable change, with a shift in the spectrum of the hosts who are now commonly infected by P. aeruginosa.
P. aeruginosa is a common cause of health care-associated infections among the general population [6-9]. According to data reported to the National Healthcare Safety Network (NHSN) in the United States from 2018 to 2022, P. aeruginosa was the fifth most common cause of hospital-acquired infections. It was consistently found among the top pathogens from multiple anatomic sites; it was the second most common cause of ventilator-associated pneumonia (VAP), the third most common cause of catheter-associated urinary tract infection (CAUTI), and the tenth most common cause of catheter-related bloodstream infection (CLABSI) in adults admitted to acute care hospitals [6,7]. It is also a common pathogen globally; it was the third most common cause of bloodstream infections according to a SENTRY antimicrobial surveillance program that collected data from sites in 45 countries worldwide [8].
Patterns of antimicrobial resistance have geographical variation. (See 'Prevalence of resistance' below.)
Apart from causing human infections, P. aeruginosa is also an important plant pathogen, affecting tobacco, tomatoes, and lettuce; it can be found in most fresh water environments, including moist areas in hospitals.
Neutropenia and burns
●Patients with neutropenia – Since the early 1980s, the role of P. aeruginosa in infections in febrile neutropenic patients has diminished in Western Europe and North America. This organism previously accounted for one-third to one-half of gram-negative bacteremia in these patients but has become a much less frequent pathogen in this setting. As an example, in a single-centered retrospective study from China, P. aeruginosa accounted for only 3.5 percent of all gram-negative bacterial isolates from neutropenic patients with bacteremia [10]. However, P. aeruginosa remains one of the most common causes of gram-negative bacteremia among neutropenic patients with malignancy in certain locations, such as Japan and Spain [11,12], and an increasing proportion of isolates from such patients are carbapenem-resistant strains [13,14]. (See 'Prevalence of resistance' below.)
●Patients with burn injury – Similarly, P. aeruginosa was previously the single most important cause of burn wound sepsis and infectious deaths following burns, but there has been a reduction in infections due to this organism since the 1980s. However, P. aeruginosa continues to be an important cause of both bacteremia and recurrent bacteremia in combat-related burn casualties [15].
The reasons for the above trends are not entirely clear, although the use of empiric antibiotic regimens with antipseudomonal activity may play a role. Furthermore, it is likely that incidence of Pseudomonas infection in subpopulations of patients, such as patients with neutropenia and burn injury, is highly complex and related to acquisition and host factors that are poorly understood. (See "Overview of neutropenia in children and adolescents" and "Drug-induced neutropenia and agranulocytosis" and "Approach to the adult with unexplained neutropenia", section on 'Mechanisms'.)
Cystic fibrosis — P. aeruginosa is the most common pathogen isolated from adults with CF [16]. It is also the most common cause of respiratory failure in CF and is responsible for the deaths of the majority of these patients [17]. With time, however, its relative prevalence seems to have declined. Retrospective analyses of the data reported to the CF Foundation Patient Registry (CFFPR) found a significant decrease in overall incidence and prevalence of P. aeruginosa from 2003 to 2012 [18,19]. In a more recent CFFPR report the percentage of respiratory cultures positive for P. aeruginosa had declined from 55.1 percent in 2006 to 28.4 percent in 2021 [20]. This decreasing trend might be explained by improved infection control and strategies focusing on early eradication of the pathogen. One other explanation is the introduction of disease-modifying therapy such as ivacaftor, as some studies have compared respiratory cultures in patients taking ivacaftor versus those who are not, revealing a reduction in both P. aeruginosa infection and acquisition [21,22]. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Pseudomonas aeruginosa'.)
Acquisition of P. aeruginosa in patients with CF begins early in childhood (median one year) [17]. It is believed that the organism is initially acquired from environmental sources, but patient-to-patient spread may also occur in clinics and households [23,24]. (See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)
Over time, a number of mutations occur in P. aeruginosa in the CF lung environment that promote persistence of the organism. In one study, for example, 11 of 30 CF patients were colonized with a hypermutable strain of P. aeruginosa that persisted for years in most cases; such hypermutable strains were not isolated from patients with acute P. aeruginosa infection who did not have CF [25]. These hypermutable strains tend to be multidrug-resistant [25,26] and accumulate over time, often with the loss of virulence traits [26]. Interestingly, these adaptations are associated with reduced organism survival in a typical environmental habitat, such as tap water [26]. Nonmutated strains with maintained virulence represent a minority of organisms.
The initial acquisition of P. aeruginosa in the CF lung is with nonmucoid strains and occurs early in life (median one year) [17]. Over time (median 11 years), there is a transition to a mucoid phenotype that is associated with deterioration in cough scores, chest radiograph scores, and pulmonary function.
Clinical and in vitro data suggest synergism between respiratory syncytial virus (RSV) infections and P. aeruginosa in CF lung disease [27].
Health care-associated infections — P. aeruginosa is among the most common causes of VAP and carries the highest mortality among hospital-acquired infections [28]. As an example, in a multicenter study from intensive care units (ICUs) in hospitals from 56 countries, P. aeruginosa was the most commonly isolated gram-negative respiratory pathogen (25 percent of 7171 isolates) [29]. The frequency and morbidity of P. aeruginosa health care-associated pneumonia are unchanged despite infection control policies that aimed to control this serious complication of medical therapy. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults".)
Pseudomonas is also a frequent cause of health care-associated bacteremia [30-32], wound, and urinary tract infections, with occasional involvement of other sites following surgery (eg, gram-negative meningitis, sternal osteomyelitis) [33].
Studies of the molecular epidemiology of P. aeruginosa isolated from ICU patients have shown that most infections are endemic with high clonal diversity involving both antibiotic-resistant and relatively susceptible isolates [34]. However, "epidemic high-risk clones" can also spread among hospitalized patients.
Outbreaks of P. aeruginosa have occurred as a result of faulty or unclean medical equipment or products, environmental reservoirs (eg, colonized sink faucets), and cross-contamination within the hospital [35-38]. One of the largest outbreaks involved 231 patients in 24 hospitals in Norway; the major clinical manifestations were pneumonia and sepsis [35]. The cause of the outbreak was contamination of moist mouth swabs. The in-hospital mortality rate was 31 percent, occurring only in patients with severe underlying disease. Contamination of medical equipment may also cause pseudo-outbreaks, as illustrated by a report of isolation of extremely drug-resistant P. aeruginosa from the urine of both hospitalized and ambulatory patients due to contamination of an automated urine analyzer [39]. These reports highlight the importance of the environmental cleaning component of infection control in preventing such infections. (See "Infection prevention: General principles", section on 'Health care environment: Cleaning and disinfection'.)
Secondary infections in patients with COVID-19 — P. aeruginosa is a common cause of secondary bacterial infections in individuals hospitalized with COVID-19 [40-44]. In a systematic review of 30 studies including 3834 patients, 7 percent of hospitalized COVID-19 patients had a bacterial infection, and P. aeruginosa was the second most common, identified in 12 percent of secondary infections [40].
Among critically ill patients with COVID-19, P. aeruginosa is an important cause of VAP, as it is in the general ICU population. In a study of 50 patients with COVID-19 who required extracorporeal membrane oxygenation (ECMO), 86 percent developed VAP, 37 percent of which were caused by P. aeruginosa; P. aeruginosa was the predominant cause of recurrent VAP in this series [43]. Bloodstream infections with P. aeruginosa have also been reported in critically ill patients with COVID-19 [44].
In a more recent systematic review evaluating 49 studies including 21,2605 participants from 2020 to 2022, the pooled prevalence of bacterial coinfections (defined as coinfection, secondary infection, and super infection) was 26.84 percent showing an increase in the trend of coinfection, 11 percent of which were secondary to P. aeruginosa [45].
Studies evaluating the incidence of P. aeruginosa bloodstream infection have yielded conflicting results, with some reporting an increase while others reporting a decrease. Two recent systematic reviews evaluating the literature on this topic found a slight increase in P. aeruginosa infections during the pandemic; however, no concrete numbers were provided [46,47].
Community-acquired infections — There has been increasing recognition of P. aeruginosa as a cause of community-acquired infections, including folliculitis (due to hot tubs, whirlpools, or contaminated sponges) [3,48,49], pneumonia [50], puncture wound osteomyelitis [51], endocarditis in injection drug users [52,53], otitis externa after swimming in fresh water lakes [54], peritonitis or exit site infection in patients undergoing continuous ambulatory peritoneal dialysis [55-57], and community-acquired bacteremia and pneumonia in patients with AIDS [58,59].
P. aeruginosa is also an important pathogen in patients with bronchiectasis, many of whom eventually harbor multidrug-resistant P. aeruginosa as their final pathogen. (See "Bronchiectasis in adults: Maintaining lung health", section on 'Antibiotics for prevention of exacerbations'.)
ANTIMICROBIAL RESISTANCE — The fact that P. aeruginosa is both intrinsically resistant to a number of antibiotics and can acquire resistance during therapy contributes to its bacterial virulence.
The NHSN evaluates the antibiotic resistance rates of P. aeruginosa isolates according to the type of infection [60]. In a report spanning from 2018 to 2021 [7], the overall rate of multi-drug resistant (MDR) isolates in hospital-acquired infections was found to be 11.9 percent. According to the infection site in acute care hospitals, the rates were:
●2.9 percent for superficial surgical site infections, 3.9 percent for deep incisional surgical site infections
●15.4 percent in VAP
●8.7 percent in hospital wards compared to 10.6 percent in ICUs in CAUTIs
●11.9 percent in hospital wards compared to 14.2 percent in ICUs in CLABSI
After years of declining resistance, the COVID-19 pandemic seems to have exacerbated antibiotic resistance in P .aeruginosa. The CDC special report on antimicrobial resistance in COVID-19 reported an increase in MDR P. aeruginosa by 32 percent compared to 2019 [61].
Mechanisms of resistance — A variety of mechanisms of antibiotic resistance in P. aeruginosa have been described. These include:
●AmpC beta-lactamase [62,63]
●Extended-spectrum beta-lactamase (ESBLs) [64,65]
●Downregulation of the outer membrane protein OprD, a carbapenem-specific porin [66,67]
●Multidrug efflux pumps [68-72]
●Ability of the organism to form a biofilm [73,74]
●Possible transfer of a 16S rRNA methylase gene from Actinomycetes [75]
Acquired resistance, specifically, can result from mutation or acquisition of exogenous resistance determinants and can be mediated by a number of mechanisms, including degrading enzymes, reduced permeability, and active efflux [64,76].
With respect to degrading enzymes, plasmid-mediated ESBLs have been described at a limited number of geographic sites. TEM, SHV, and CTX-M ESBLs have been reported in P. aeruginosa, but are uncommon; VEB ESBLs are prevalent in the species in East Asia and are now scattered elsewhere, and PER types are widespread in Turkey. These enzymes confer high-level resistance to antipseudomonal cephalosporins, and some, such as PER-1, also degrade cephems and monobactams [65]. (See "Extended-spectrum beta-lactamases".)
The potential impact of PER-1 was illustrated in a series of 26 P. aeruginosa bloodstream infections (BSIs) from Siena, Italy [64]. Nine expressed PER-1 and the other 17 did not express any ESBL. Seven of the nine PER-1 BSIs failed to respond to antibiotic therapy, including carbapenems. In comparison, only 4 of 14 non-ESBL BSIs failed to respond, including only one of eight treated with a carbapenem.
Resistance to carbapenems, particularly imipenem, can arise by simple mutation resulting in the loss of a carbapenem-specific porin, OprD [65]. Less often, metallo-beta-lactamases (MBLs) are responsible: VIM and IMP MBLs have been reported internationally, whereas clones with SPM-1 enzymes have disseminated in Brazil. Some have caused major outbreaks, with dozens to hundreds of patients affected over prolonged periods. (See "Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)".)
Multidrug resistance in P. aeruginosa is believed to be secondary to efflux pumps on the bacterial surface. One study demonstrated that the addition of an efflux inhibitor in vitro decreased the minimum inhibitory concentrations (MICs) of P. aeruginosa isolates to various antibiotics by twofold or more [77].
In view of the variability in defining multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) in the medical literature, the European Center for Disease Prevention and Control (ECDC) as well as the United States Centers for Disease Control and Prevention (CDC) joined efforts in 2012 in order to establish a standardized international definition for these terminologies in multiple organisms, including P. aeruginosa [78]. They were defined as follows:
MDR: non-susceptibility to at least one agent in three or more antimicrobial categories.
XDR: non-susceptibility to at least one agent in all but two or fewer antimicrobial
categories (ie, bacterial isolates remain susceptible to only one or two categories).
PDR: non-susceptibility to all agents in all antimicrobial categories.
In 2018, Kadri et al proposed a new terminology, "difficult-to-treat" organisms, in other terms, organisms that are non-susceptible to first-line antibiotics (ie, intermediate or resistant to all reported agents in the carbapenems, beta-lactams, and fluoroquinolones categories) [79].
Prevalence of resistance — Patterns of antibiotic resistance in P. aeruginosa evolve over time and vary geographically and by type of infection. This geographical variation highlights the importance of local epidemiological data when choosing empiric therapy.
As an example, in North America from 2005 to 2010, resistance to fluoroquinolones among intra-abdominal and urinary tract infection isolates increased (from 22 to 33 percent); resistance to imipenem (20 percent) and other beta-lactams (piperacillin-tazobactam, cefepime, and ceftazidime; 23 to 26 percent) remained essentially unchanged; and resistance to amikacin declined (from 11 to 3 percent) [80]. Resistance patterns were different in other locations: in South Africa, resistance to piperacillin-tazobactam was 8 percent and to cefepime, ceftazidime, and imipenem was 25 to 26 percent; in China, resistance rates to amikacin and piperacillin-tazobactam were 12 and 8 percent, respectively. Among the countries of the Arab league, the highest prevalence of carbapenem-resistant P. aeruginosa occurred in Jordan (93 percent), followed by Algeria and Egypt (56 and 50 percent, respectively) [81]. In one study of 38 isolates from a burn-care hospital in Azerbaijan, there were high levels of resistance to all classes of antibiotics except colistin and polymyxin B, and 63 percent of the isolates were carbapenem resistant [82]. A study of over 6000 isolates from the Asia-Pacific region found that approximately 40 percent of isolates were either carbapenem-resistant or MDR; India had the highest rates of carbapenem resistance (29 percent) [83].
In the United States, surveillance suggests a trend toward declining rates of resistance, although rates still remain high [60]. Among catheter-related BSI, catheter-associated urinary tract infection (CAUTI), and VAP isolates, resistance ranged from 22 to 26 percent for extended-spectrum cephalosporins, 16 to 19 for piperacillin-tazobactam, 30 to 33 percent for fluoroquinolones, 24 to 28 percent for carbapenems, and 17 to 23 percent for aminoglycosides. Approximately 18 to 19 percent were MDR. Rates of resistance were generally lower (4 to 11 percent) among surgical site infection isolates.
Resistance to newer beta-lactam/beta-lactamase inhibitors (BL-BLIs), such as ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam, appears to be uncommon in the United States. In a study of over 3100 isolates from 71 hospitals from 2020 to 2021, susceptibilities were as follows: ceftazidime-avibactam 97.0 percent, ceftolozane-tazobactam 98.0 percent, and imipenem-relebactam 97.3 percent [84].
In Europe, antibiotic resistance is highly variable across countries, with studies demonstrating a high incidence of MDR and extensively drug-resistant (XDR) P. aeruginosa among patients with VAP in Greece, Italy, and Spain [85]. Resistance rates are especially high in Greece, where up to 89 percent of isolates were MDR, XDR, or pan-drug resistant. A European study of over 580 respiratory isolates revealed susceptibility rates of 95.5 percent to ceftazidime-avibactam, 94.3 percent to imipenem-cilastatin-relebactam, and 93.3 percent to ceftolozane-tazobactam; susceptibility rates were significantly lower in Eastern Europe than Western Europe [86].
In a recent systematic review based on 78 studies assessing the global rate of resistance of multiple pathogens to cefiderocol, the prevalence of nonsusceptibility in P. aeruginosa was found to be low (1.4 percent), even in carbapenem-resistant isolates (3.5 percent) [87].
Resistance to first-line beta-lactam antibiotics has been associated with higher rates of resistance to the newer BL-BLIs. In a multicenter study of gram-negative respiratory isolates from ICU patients from over 200 hospitals in 56 countries, 38 percent of P. aeruginosa isolates were not susceptible to piperacillin-tazobactam or meropenem, and 34 percent were not susceptible to ceftazidime [29]. Among isolates nonsusceptible to all three agents, 62 to 68 percent remained susceptible to ceftolozane-tazobactam.
The use of locally-derived antibiograms to predict susceptibility of individual antibiotics to P. aeruginosa may not be as reliable for patients who become infected during long hospital stays. In one study involving 3393 isolates of P. aeruginosa from a single tertiary care hospital, the utility of the hospital’s antibiogram dropped as the length of time from admission to recovery of P. aeruginosa increased [88]. In another study, the most important predictors of MDR P. aeruginosa infections among hospitalized patients were the number of prior antibiotics received, history of infection within the preceding three months, hospital prevalence of MDR strains, and complicated urinary tract infection [89].
Different strategies for administering antibiotics have been considered to overcome the increasing resistance patterns, including high-dose prolonged infusions of beta-lactams. This is discussed in detail elsewhere. (See "Prolonged infusions of beta-lactam antibiotics".)
PATHOGENESIS — Individual strains often contain numerous virulence factors, more than those encountered in other pathogens, such as group A streptococcus and Staphylococcus aureus. P. aeruginosa is capable of expressing a large number of toxins and surface components associated with virulence [90-92]. While each of these toxins and surface components show a deleterious effect in cell lines or even in an animal model, the role of many of these putative virulence factors remains unproven in humans.
In contrast to most other bacteria, P. aeruginosa has two modes of virulence expression, resulting in at least two forms of distinct pathogenetic behavior:
●Some strains remain confined to the lungs as a chronic, indolent colonizer (as occurs in many patients with CF).
●Other strains can invade tissues, causing pneumonia or bacteremia along with their potential complications of septic shock and death.
Chronic infection in cystic fibrosis — Studies that have serially examined both the bacterial diversity and load of the microbial flora in the lower respiratory tract of patients with CF demonstrated that bacterial diversity typically decreases as the severity of illness increases even though the total bacterial load remains relatively stable [93]. P. aeruginosa are present as part of the resident microbial flora in the lower respiratory tract of most patients with CF, and in some patients, P. aeruginosa becomes the dominant organism as the severity of CF illness progresses.
Most patients with CF eventually die from respiratory failure because of a gradual loss of lung function. This loss of function is a consequence of decades of continuous colonization with P. aeruginosa and inflammation triggered by the host response to the organism [94]. It may be argued that there is no expression of virulence in this setting and that the inflammation is simply a bystander reaction by the host to the presence of an organism in the airways. However, the fact that P. aeruginosa persists in the airways to the exclusion of most other bacteria suggests that there is active expression of specific genes to maintain this tropism. (See "Cystic fibrosis: Clinical manifestations of pulmonary disease", section on 'Infection'.)
A detailed, whole-genome analysis of P. aeruginosa isolates from a CF patient during eight years of infection found that virulence factors that are required for the initiation of acute infections are selected against during subsequent chronic infection [95].
Early airway colonization — Initial infection is generally acquired from the environment, although person-to-person transmission is also a plausible source [95]. There are at least three possible mechanisms allowing early airway colonization with P. aeruginosa in patients with CF:
●Following initial acquisition, P. aeruginosa has a propensity to attach to cells via pili and flagella, resulting in an initial infection [96]. This hypothesis suggests that there are more pilus receptors on CF cells or that there is a greater response to pilin binding than on normal airway cells [97]. Piliated organisms or purified pili lead to the production of interleukin-8 on airway epithelial cells; in one study, this response was four times higher in a CF cell line [96]. This attachment is thought to induce goblet cell hyperplasia and consequently mucus hyper-secretion, contributing to CF pathology [98].
●A CF transmembrane conductance regulator (CFTR) may function as a cellular receptor for P. aeruginosa that facilitates phagocytosis and clearance of the organism from the airways. Patients with CF may lack CFTR or express a mutant CFTR that prevents phagocytosis and clearance from the airway. In an in vitro study, murine cells expressing recombinant human wild-type CFTR ingested 30 to 100 times as many P. aeruginosa organisms as cells lacking CFTR or those expressing the mutant delta F508 CFTR protein seen in many patients with CF [99].
●The airways of patients with CF commonly manifest mucous hypersecretion and a defect in mucociliary clearance that progressively worsens with age; P. aeruginosa is able to bind to mucous in airways and thus is protected from phagocytosis [100,101].
Despite having most of its virulence factors downregulated once the infection becomes chronic, P. aeruginosa uses some virulence factors to establish a niche allowing for chronic infection as well as contributing to CF pathology [22]. In fact, elastase was found to decrease residual CFTR activity and expression and also to inhibit airway healing through degradation of interleukin-6 [102]. Furthermore, pyocyanin was found to inhibit ciliary beating as well as modulate mucin glycosylation, allowing for higher affinity to P. aeruginosa [103].
Of note, some studies have observed that isolates in CF patients with newly identified P. aeruginosa infection frequently have mucoid- and biofilm-forming phenotypes, which are more classically associated with adaptation towards chronic persistence in the CF lung [104,105]. (See 'Persistence of the organism in the airways' below.)
Persistence of the organism in the airways — An examination of P. aeruginosa organisms isolated from this chronic state of colonization in patients with CF frequently shows the following abnormalities:
●Downregulation of the production of toxins [106]
●Loss of lipopolysaccharides "O" side chains [107]
●Expression of an alginate coat that probably protects against phagocytosis [108,109] (see 'Mucoid phenotype' below)
●Frequent loss of the flagellum and pili [110,111]
Conventional wisdom about pathogenesis states that pathogens produce diseases by expressing their virulence factors. There are two possible explanations for downregulation of virulence factors:
●The immunologic response to virulence factors within colonizing strains of P. aeruginosa selects for survival of strains that have mutated to phenotypes that evade the host immune mechanisms in the lungs. The observation that P. aeruginosa flagellin synthesis is downregulated in the CF lung could represent an adaptive response by the organism to avoid detection by host defense mechanisms, as flagellin is highly immunogenic and subject to detection by host pattern recognition receptors [112]. Exposure of P. aeruginosa to reactive oxygen species by neutrophils is thought to be the principal mechanism that causes DNA damage allowing for mutations involved in the chronicity of the infection [108].
●Virulence factors may no longer be needed for chronic colonization, and they disappear from strains colonizing the airways because of random mutations in the genes responsible for their expression.
Although mutations such as those discussed above could explain why host defenses do not eradicate the organisms, it is probable that organisms with a normal phenotype are able to persist in the face of intact host defense mechanisms early in the life of many patients with CF. Thus, the best explanation for persistence may be defects in mucociliary clearance and in host killing of bacteria in CF.
Decreased bacterial killing — A number of studies have suggested that the lungs of patients with CF have defective mechanisms for bacterial killing. This may be related in part to the high chloride concentrations in pulmonary secretions [113]. Defects in bacterial killing induced by a high chloride environment include inactivation of beta-defensins, which are antimicrobial peptides secreted by respiratory epithelia [114,115], increased release of inflammatory mediators by neutrophils, and diminished neutrophil killing [116].
However, such defects in patients with CF do not explain the preferential selection of P. aeruginosa as a pathogen over other bacteria. The predisposition to Pseudomonas infection in patients with CF may be due in part to impaired clearance directly related to defects in CFTR discussed above [99,117]. For example, treatment with ivacaftor, which restores functioning of the CFTR protein, is associated with reduced P. aeruginosa culture positivity [118]. Similarly, CFTR-knockout mice have an impaired ability to control Pseudomonas lung infections characterized by increased binding of P. aeruginosa to respiratory epithelial cells, an effect that can be reversed by CFTR gene transfer [119,120].
Biofilm formation — Biofilm or microcolony formation in P. aeruginosa facilitates persistence of the organism in the airways of patients with CF. Organisms contained in biofilms are resistant to antibiotic treatment, which in turn facilitates persistence in airways [121]. As an example, in a study of CF patients with newly identified P. aeruginosa airway infection, wrinkly colony surface and irregular colony edges (phenotypes previously implicated in increased biofilm formation and aberrant quorum sensing) were associated with persistence following antibiotic treatment [104].
An in vitro study of P. aeruginosa showed that subinhibitory concentrations of aminoglycoside antibiotics induce biofilm formation [122]. A P. aeruginosa gene (aminoglycoside response regulator [arr]) was essential for this induction and contributed to biofilm-specific aminoglycoside resistance. Biofilm formation can be a specific defensive reaction to the presence of antibiotics: a mechanism that may be responsible for the differences in therapeutic outcome in CF patients treated with tobramycin aerosols. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)
Epigallocatechin-3-gallate, a bioactive ingredient of traditional green tea, appears to have an inhibitory effect in vitro on the development of biofilm, protease and elastase activity, and swimming and swarming motility of P. aeruginosa [123].
Mucoid phenotype — During prolonged colonization, P. aeruginosa isolates often convert to a mucoid phenotype through production of the polysaccharide alginate (picture 2). Alginate production contributes to biofilm growth, decreased clearance by host immune responses, and tissue damage [124]. One study demonstrated that alginate production was increased when the organisms were present in the relatively anaerobic environment of CF mucous [125]. This mucoid phenotype is seen infrequently in non-CF populations, but occurs in over 75 percent of P. aeruginosa isolated from patients with CF. Opsonic antibodies produced by the host in CF are unable to kill these mucoid organisms [126]. (See "Cystic fibrosis: Genetics and pathogenesis".)
Females with CF are colonized with mucoid P. aeruginosa more frequently and earlier in chronic infection than males. Estrogen production appears to be directly related to this finding, as illustrated by a study in which exposure to estrogens induced alginate production in a nonmucoid strain of P. aeruginosa in vitro [127]. In vivo, mucoid strains of P. aeruginosa were isolated more frequently during times of high estradiol production in six women with CF who were sampled throughout their menstrual cycles. Furthermore, among 23 women, mucoid P. aeruginosa accounted for 63 percent of strains isolated from pulmonary CF exacerbations that occurred during the follicular (high estradiol) phase of the menstrual cycle. In contrast, no strains isolated from exacerbations during the luteal phase (low estradiol) had the mucoid phenotype. Pulmonary exacerbations were also observed more frequently during the follicular phase.
Interactions with other pathogens
●S. aureus – P. aeruginosa may also promote S. aureus colonization in the lungs of patients with CF. An exoproduct of P. aeruginosa (HQNO) protects S. aureus from killing by aminoglycosides and selects for small-colony variants of S. aureus that have stable aminoglycoside resistance and persist in chronic infection [128]. HQNO can be detected in the sputum of CF patients infected with P. aeruginosa but not in uninfected patients. (See "Cystic fibrosis: Clinical manifestations of pulmonary disease", section on 'Progression of pulmonary disease'.)
●Stenotrophomonas maltophilia – Infections with P. aeruginosa appear to promote colonization and coinfection with S. maltophilia. In a mouse model, coinfection with P. aeruginosa and S. maltophilia resulted in higher S. maltophilia counts from bronchoalveolar lavage and lung tissue specimens than S. maltophilia monoinfection, likely because the two organisms formed well-integrated biofilms [129].
Acute invasive P. aeruginosa infections — P. aeruginosa possesses an array of virulence factors implicated in acute infections [130]. These include secreted products; exotoxins A, S, and U; elastase; alkaline protease; cytotoxins; phospholipase C; and phenazines [131-133]. Cell-bound organelles (such as pili and flagella) and membrane-bound lipopolysaccharide (LPS, endotoxin) have also been implicated in virulence.
There is no single product that explains the organism's ability to cause disease and death. In an in vitro study, biofilm formation and distribution of virulence genes did not appear to differ between VAP and non-VAP isolates, although VAP isolates were less virulent in an in vivo model [134].
A reasonable synthesis of the experimental work in this area is that different virulence factors play a role at different stages in the pathogenesis of invasive infections.
Invasion — P. aeruginosa requires an intact flagellum and motility to exert its maximum invasive effect in some animal models of infection. Strains lacking flagella are less capable of causing bacteremia and pneumonia in neonatal mice [135] and of disseminating from burn wounds [136,137].
The relative importance of the motility function of flagella and a possible proinflammatory role of flagellin were examined in a lung model of acute P. aeruginosa infection [138]. The findings suggested that flagellin is involved in early mortality, while loss of motility alone did not appear to affect virulence. Thus, the decreased virulence in strains lacking flagella in the neonatal mouse model cited above is more likely due to the absence of flagellin [135]. (See "Pseudomonas aeruginosa pneumonia".)
Lipopolysaccharide and toxins — After invasion, lipopolysaccharide (LPS) probably plays a role in disease similar to that proposed for other gram-negative pathogens. LPS protects the organism from the activity of complement in the bloodstream and triggers cytokine pathways, leading to sepsis and septic shock. (See "Pathophysiology of sepsis".)
In addition to LPS, it has been proposed that the elaboration of toxins after invasion is responsible for some of the tissue damage. The role of toxins in the disease process has been difficult to determine, as there are no data incriminating a specific toxin, such as is found with diphtheria toxin or the staphylococcal and streptococcal shock toxins. In addition, mutants of P. aeruginosa lacking many of these toxins remain virulent.
Thus, although toxins are probably not needed for the major disease syndromes encountered in most patients with P. aeruginosa infections, they may play a role in some localized infections, such as in the eye [139] or lung [119,140], and contribute to the severity of disease. This potential effect was illustrated in a study of P. aeruginosa strains isolated from 108 consecutive patients with lower respiratory or systemic infection [140]. Infection with a P. aeruginosa strain expressing the type III secreted toxins (TTSS; eg, ExoS, ExoT, ExoU, ExoY, or PcrV) was associated with a sixfold greater risk of death compared with infection with a strain that did not express these proteins (odds ratio 6.2). ExoU, which disrupts the integrity of the lipid membrane, is associated with cytotoxicity, severe lung epithelial injury, and bacterial dissemination. The severity of lung epithelial injury and the risk of bacterial dissemination into the circulation correlate with the ExoU phenotype in different P. aeruginosa strains [141]. ExoY induces edema and might elicit amyloid cytotoxins that subvert the endothelial amyloid host defense; in has been associated with end-organ dysfunction in ventilated patients with P. aeruginosa lung infection [142].
Expression of these type III secreted toxins is associated with higher mortality in patients with P. aeruginosa bacteremia as well [120].
The degree of infection may be limited by host factors. Experimental data suggest that host ubiquitin ligase Cbl-b limits P. aeruginosa dissemination mediated by the secreted toxin ExoT [143]. Ubiquitination leads to proteasomal degradation of the toxin.
Investigational interventions based on pathogenesis — Part of the impetus for studies of pathogenesis in P. aeruginosa infections is interest in the development of a vaccine to prevent infection in susceptible hosts or new antimicrobials for treatment of the organism. No vaccines or new antibiotics have yet resulted from this work, but development of vaccines against type III secretion system proteins [144], LPS [145], and flagella [146] continues. Quorum sensing (QS), a regulation mechanism that dictates the expression of some virulence factors and biofilm formation was recently investigated as a potential therapeutic modality; some FDA-approved medications (eg, sitagliptin, allopurinol) have shown ability to inhibit this mechanism in in vivo studies [147,148]. Other research has focused on phage therapy [149], neutralizing antibodies against exotoxins [150], and live attenuated vaccines from Francisella or Salmonella strains, but these interventions remain experimental and incompletely studied [151,152]. Although vaccine candidates against outer-membranes OprF-OprI conjugates initially yielded promising results in healthy volunteers as well as burn patients [153,154], they unfortunately were not able to reduce infection rate despite displaying a significant immunogenic effect [155]. Plasmapheresis to remove inhibitory antibodies has also been explored [156]. Public availability of the Pseudomonas genome sequence may provide further insights into the mechanisms of pathogenesis of P. aeruginosa infections and help investigators discover new genetic targets that can be exploited for vaccine or therapeutic development [157].
SUMMARY AND RECOMMENDATIONS
●Environmental niche – Pseudomonas aeruginosa, a nonfermenting gram-negative bacillus, is prevalent in the environment, particularly in water, which can serve as a reservoir for infection. (See 'Introduction' above.)
●Microbiology – Certain features are characteristic of P. aeruginosa grown on culture and help confirm its identification. These include a sweet grape-like odor, elaboration of green pigment, and oxidase-positivity. (See 'Microbiology' above.)
●Epidemiology – P. aeruginosa is a common cause of nosocomial pneumonia, urinary tract infection, and surgical site infection. It has become a less frequent cause of bacteremia in patients with neutropenia in most parts of the world. It remains the most important pathogen in patients with cystic fibrosis. P. aeruginosa is also associated with certain community-acquired infections following particular exposures (eg, water, puncture wounds, injection drug use). (See 'Epidemiology' above.)
●Cystic fibrosis – In patients with cystic fibrosis, chronic colonization with P. aeruginosa is associated with a downregulation of virulence factors and expression of a mucoid phenotype that likely protects against phagocytosis and opsonization. P. aeruginosa may also promote Staphylococcus aureus colonization in the lungs of patients with cystic fibrosis. (See 'Chronic infection in cystic fibrosis' above.)
●Resistance – P. aeruginosa can develop resistance to antibiotics through a number of mechanisms, including expression of beta-lactamases or efflux pumps and downregulation of outer membrane porins. (See 'Antimicrobial resistance' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel Sexton, MD, who contributed to earlier versions of this topic review.
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