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Pseudomonas aeruginosa and Other Pseudomonas Species
Pseudomonas species are ubiquitous gram-negative bacteria capable of inhabiting a wide variety of diverse environments, including soil, water, plants, insects, and animals. Among all Pseudomonas species, P. aeruginosa is the most important species affecting humans and is responsible for serious debilitating and life-threatening infections.
P. aeruginosa infections were noted in the literature in the 1800s when physicians began to report a “condition” causing a blue-green discoloration on bandages and associated with a “peculiar” odor. The cause of the discoloration was first characterized by Fordos in 1869, who extracted the blue crystalline pigment called pyocyanin. In 1882, Gessard verified “the parasitic origin of this phenomenon” using Pasteur's cultures and isolated the organism, which was originally called Bacillus pyocyaneus. Initially, this pathogen was regarded as “a curiosity without any influence upon human pathology,” and “old surgeons looked upon blue pus on their dressings as rather a favorable sign.” In 1894, Williams provided one of the first reviews of case reports of B. pyocyaneus infections. He described septic patients with “hemorrhagic spots of a port-wine color” and pustules, with recovery of the organism from these skin lesions. Subsequently, more case reports of infections caused by B. pyocyaneus appeared in the literature. In the 1940s, Haynes provided detailed microbiologic characteristics of P. aeruginosa that would distinguish it from Pseudomonas fluorescens. During the Vietnam War, P. aeruginosa was recorded as one of the three most common wound pathogens. By the mid-1990s, P. aeruginosa became of great concern as a pathogen associated with burn infections and war-related wounds. P. aeruginosa is now considered to be of most concern because it causes a variety of infections associated with considerable morbidity and mortality, usually occurring among immunocompromised hosts. Furthermore, single-drug and multidrug resistance rates are particularly high for this pathogen, which severely limits the therapeutic options available to treat infected patients.
Microbiology
The pseudomonads are aerobic gram-negative, motile rods. They are ubiquitous in soil, water, plants, and animals and have numerous important ecologic roles ( Fig. 219.1 ). The German botanist Walter Migula first used the term Pseudomonas, which is derived from the Greek pseudo, meaning “false”, and monas, meaning “unit”. Although the etymology was never explained, it has been postulated that Migula created this name because the bacteria resembled the cells of nonflagellate Monas in size and motility. P. aeruginosa is an obligate aerobic rod-shaped bacterium measuring 0.5 to 1.0 µm in width and 1 to 3 µm in length. It grows as a single bacterium, although it can occur in short chains. It grows on many types of culture media, forming smooth round colonies with a characteristic grapelike or “corn-taco” odor and green-blue coloration. The coloration is due to the production of pyocyanin (blue) and pyoverdin (green). This distinct color explains the species name of “ aeruginosa, ” a Latin word meaning “verdigris” or “copper rust.” Some strains produce other pigments, including pyorubin (dark red) and pyomelanin (black). Isolates from patients with cystic fibrosis (CF) may have a distinct mucoid appearance. P. aeruginosa is oxidase positive and grows at 37°C to 42°C. Growth at 42°C allows differentiation from other Pseudomonas species, including P. fluorescens and P. putida. Identification of P. aeruginosa is based on colony morphology, coloration, oxidase positivity, and growth at 42°C.
Strains of P. aeruginosa can produce an extracellular polysaccharide, referred to as alginate. Overproduction of this substance leads to the formation of a mucoid colony phenotype, which is usually present among isolates recovered from patients with CF and other chronic infections. Isolates recovered from the environment or those causing nosocomial infections are usually nonmucoid.
The Pseudomonas aeruginosa Genome
The P. aeruginosa genome is large (over 6 million base pairs) and complex. In contrast to other large bacterial genomes, the Pseudomonas genome does not contain an abundance of gene duplication events but instead contains numerous distinct gene families. This finding explains the great genetic and functional diversity of this pathogen.
The genome is composed of a relatively invariable core genome, which contains 90% of the total genome and includes the conserved gene sequences that encode metabolic and pathogenic factors present in the majority of P. aeruginosa strains. The accessory genome is highly variable and includes genes found only in certain P. aeruginosa strains. The genetic elements in the accessory genome result in distinct P. aeruginosa phenotypes, with niche-specific adaption. These genetic elements include virulence factors, resistance genes, and genes encoding specific catabolic pathways that allow persistence in harsh environments (pollutants, pesticides).
Pseudomonas aeruginosa and the Human Microbiota
The Human Microbiome Project, established by the National Institutes of Health, has begun to characterize the human microbial communities colonizing healthy individuals, using 454 FLX Titanium platform pyrosequencing of 16S ribosomal RNA genes. Analysis of the human microbiota among 242 healthy adults from five major body areas (oral cavity and oropharynx, stool, vagina, nares, and skin [inner elbows and behind the ears]) revealed that P. aeruginosa was completely absent from both the skin and nares and that Pseudomonas species (not identified at the species level) were present in miniscule abundance in the stool and oral cavity, although more abundant in the latter. These data suggest that P. aeruginosa is not a common bacterium that inhabits the human microbiota among healthy hosts.
Alterations in the microbiome lead to a decrease in colonization resistance (increasing colonization with antimicrobial-resistant bacteria) and a decrease in resilience (the microbiome's ability to recover). The absence or near absence of P. aeruginosa in the healthy human microbiome strongly suggests that for detectable long-term colonization to occur, a perturbation of the microbiome is necessary. Antimicrobial agents, other medications (e.g., anticholinergics), gastrointestinal diseases, and diet may be some of the necessary factors required for P. aeruginosa colonization.
Virulence Factors
An abundance of virulence factors have been identified among various P. aeruginosa strains. These factors are either present on the bacterial cell surfaces or are secreted ( Table 219.1 ). The majority of virulence factors, however, have been identified in cell lines or animal models and therefore their role in human disease has not been clearly established. Major virulence factors are discussed in the following sections. Virulence factors associated with CF are discussed in Chapter 71 .
TABLE 219.1
Virulence Factors of Pseudomonas aeruginosa and Their Role in Pathogenesis
| VIRULENCE FACTOR | ROLE IN PATHOGENESIS |
|---|---|
| Pili and flagella | Attachment to host cells, motility, biofilm formation |
| Type I secretion system (alkaline protease) | Delivery of toxins to extracellular spaces |
| Type II secretion system (elastase, exotoxin A, phospholipase A, protease IV) | Cytotoxicity, inflammation, colonization |
| Type III secretion system (exotoxins S, T, U, and Y) | Tissue injury |
| Endotoxin (lipopolysaccharide) | Resisting host innate defenses |
| Alginate | Antiphagocytic activity, resists opsonic killing |
| Pyocyanin | Tissue damage, inhibition of lymphocyte proliferation |
| Pyoverdin | Binds iron |
| Quorum-sensing molecules | Cell-to-cell communication regulating virulence and biofilm formation |
Pili
Pili allow the bacteria to adhere to cell surfaces, are involved in biofilm formation, and mediate motility. Five pilA alleles have been identified (groups I to V) among P. aeruginosa strains. Type IV pili (T4P) has been extensively investigated. This group of pili is unique in that its members can mediate motility independent of flagella. Many P. aeruginosa T4P-expressing strains exhibit “twitching motility,” a jerky movement with an estimated velocity of approximately 1 mm/h (equivalent to 500 cell lengths per hour, assuming the average length of a P. aeruginosa cell is 2 µM). The functions of twitching motility include biofilm formation and exploration of surfaces. Given their role in adherence, T4P are deployed during the early stages of acute infection. Production of pili is frequently lost in chronic infections, such as CF, with selection of strains with other phenotypes better suited for that environmental niche.
P. aeruginosa possesses a single polar flagellum, which plays an important role in motility, colonization, and biofilm formation, similar to pili.
Type I and II Secretion Systems
The type I secretion system (T1SS) secretes toxins in a one-step process into extracellular spaces. The most important toxin studied in the T1SS is alkaline protease, which inhibits fibrin formation and promotes dissemination of P. aeruginosa. Secretion of toxins by type II secretion system (T2SS) is a two-step process whereby toxins are synthesized as precursor proteins and then cleaved. Toxins excreted by this system include exotoxin A, phospholipase C, protease IV, and elastase, which mediate cytotoxic effects and inflammatory processes and promote colonization.
Type III Secretion Systems
The type 3 secretion system (T3SS) is a complex secretory system that directly injects exotoxins into the cell cytoplasm. Four proteins have been identified. Exotoxin U (ExoU) is a phospholipase, which induces apoptosis as well as causes necrosis of phagocytes and parenchymal cells. Exotoxin Y (ExoY) is an adenylate cyclase, which may disrupt the barrier function of pulmonary endothelial cells. Exotoxins T and S (ExoT and ExoS) are bifunctional proteins that affect target cell growth by inhibiting DNA synthesis and inducing changes in the cytoskeleton and cellular morphology, thus affecting adherence. Although all strains harbor T3SS genes, only a few are capable of secreting these effector proteins under the conditions tested. The expression of the T3SS in P. aeruginosa isolates may confer a worse clinical outcome among humans than nonexpressors.
Quorum-Sensing Molecules
Quorum sensing (QS) allows cell-to-cell communication and involves signaling molecules called autoinducers. The usual steps of QS involve the production of autoinducers followed by their active or passive release into the environment. These autoinducers are then recognized by specific receptors, resulting in changes in gene regulation. This complex signaling network allows the “community” of P. aeruginosa bacteria to react to different signals and thereby adapt to different niches. There are three QS systems present in P. aeruginosa isolates: two are referred to as the LuxI/LuxR-type QS circuits, and the third is referred to as the Pseudomonas quinolone signal system. These QS systems control the expression of virulence factors, including elastase, exotoxin A, and proteases.
QS also controls biofilm formation (see Chapter 71 ). Biofilms are a type of growth mode that results in clusters of bacterial colonies, encased in a biopolymer matrix, that attach to surfaces. Biofilms are predominantly formed on implantable devices or during chronic infections, such as osteomyelitis and CF. One of the main functions of biofilms is to reduce the efficacy of antimicrobial agents by impeding the agents’ ability to reach the bacteria.
Other Virulence Factors
A variety of other virulence factors produced by P. aeruginosa have been described. Endotoxin, or lipopolysaccharide, is a virulence factor located on the outer portion of the outer membrane and provides resistance to host defenses. Pyoverdins are siderophores that compete with host proteins for iron chelation. Pyocanin reacts with oxygen to form oxygen radicals, causing tissue damage, and inhibits both lymphocyte proliferation and cilia function. Lastly, alginate is an extracellular polysaccharide, which has antiphagocytic activity and resists killing by opsonization. It is a scavenger of free radicals that are released by macrophages and inhibits neutrophil chemotaxis and complement activation. Its secretion results in a mucoid morphology seen on culture plates.
Epidemiology
P. aeruginosa is implicated in both community- and hospital-acquired infections, although it is much more common in the latter. In the United States, P. aeruginosa is the 6th most common pathogen implicated in all hospital-acquired infections, as reported in 2016 by the National Healthcare Safety Network (NHSN). It is the second most common pathogen associated with ventilator-associated pneumonia and ranks third among causes of catheter-associated urinary tract infections. P. aeruginosa is the 5th most common pathogen causing surgical site infections and 10th most common pathogen causing catheter-related bloodstream infections (BSIs). Patients at high risk for P. aeruginosa hospital-acquired infections include those admitted to an intensive care unit (ICU) and those with burns, neutropenia, or CF. These patient populations are discussed in this section and also in Chapter 71 .
Rates of P. aeruginosa implicated in infections in long-term acute care hospitals (LTACHs) are even higher than rates reported from hospital settings. LTACHs are defined as health care facilities that are accredited as acute care hospitals with an average annual length of stay of at least 25 days for Medicare patients, as per the Centers for Medicare and Medicaid Services. Patients admitted to these LTACHs usually require prolonged care after hospitalization, including hemodialysis, mechanical ventilation, intravenous medication, and wound care. In contrast to the hospital setting, P. aeruginosa is the most common cause of catheter-associated urinary tract infections and ventilator-associated pneumonia in LTACHs. Even when rates of P. aeruginosa infections in LTACHs are compared with those from ICUs, P. aeruginosa is still a more frequent pathogen implicated in LTACH infections. For example, in 2010, 19% of catheter-associated urinary tract infections in patients in LTACHs were caused by P. aeruginosa compared with 9% to 12% of those occurring in ICUs. Ventilator-associated pneumonia caused by P. aeruginosa was also more frequent in LTACHs (35%) compared with that occurring in ICUs (17%–20%). The higher occurrence of P. aeruginosa infections is likely due to an older, more debilitated patient population with excessive health care exposure.
Transmission Dynamics of Pseudomonas aeruginosa and Reservoirs
Acquisition of P. aeruginosa can occur both exogenously and endogenously. Exogenous acquisition occurs through contaminated hands of health care workers and environmental surfaces. An in-depth epidemiologic study characterized the exogenous transmission of multidrug-resistant (MDR) P. aeruginosa in six ICUs. The investigators obtained cultures from hands, gloves, and gowns of health care workers during routine patient care activities, surveillance cultures from patients, and environmental samples from sinks, bedrails, vital sign monitors, supply carts, door handles, intravenous pumps, ventilators, and floors. Molecular typing, using pulsed-field gel electrophoresis, was performed to determine clonal relatedness among strains. In that study, MDR Acinetobacter species were the most common pathogens to contaminate health care workers’ gloves and hands, occurring among 33% of interactions between health care workers and patients. P. aeruginosa was the second most common MDR pathogen to contaminate health care workers, which occurred during 17.4% of health care worker–patient interactions. Independent risk factors associated with health care worker contamination were presence of environmental contamination, duration in patients’ room greater than 5 minutes, performing a physical examination, and contact with the mechanical ventilator. Environmental contamination was also very common: P. aeruginosa was recovered from 22% of rooms. This study and many others emphasize that exogenous transmission plays a major role in the nosocomial acquisition of P. aeruginosa and that environmental contamination is central to its transmission to patients and health care workers.
Endogenous acquisition of a resistant strain of P. aeruginosa is defined as colonization with an antimicrobial-susceptible strain that subsequently becomes resistant primarily through antimicrobial selective pressure within the host. A study of imipenem-resistant P. aeruginosa transmission demonstrated that, among events that could be determined, endogenous acquisition accounted for 19% of identified acquisition events and that exogenous acquisition accounted for 31% of events.
As outlined earlier, environmental reservoirs contribute substantially to the spread of P. aeruginosa. The most common sites either have high moisture or humidity or are water related ( Table 219.2 ). In the hospital setting, outbreaks of P. aeruginosa have been linked predominantly to water sources, including potable water, showerheads, and sinks (see Table 219.2 ). Other sources have included health care workers’ artificial or long nails, intraocular lens solution, ultrasound transmission gel during transesophageal echocardiography, retained tissue in surgical instruments, and soap dispensers. The ability of P. aeruginosa to form biofilms on surfaces increases its ability to survive on inanimate surfaces and makes it difficult to eradicate. Biofilms are microbial communities held together by structural polysaccharides (slime), which attach strongly to surfaces. Biofilms produced by P. aeruginosa lead to antimicrobial tolerance and impede eradication by environmental cleaning agents.
TABLE 219.2
Environmental Reservoirs of Pseudomonas aeruginosa
| Hospital Reservoirs of P. aeruginosa |
| Sinks, taps, showerheads |
| Potable water |
| Respiratory therapy equipment |
| Flower vases, ice makers |
| Hydrotherapy pools |
| Cleaning equipment (mops, buckets) |
| Bronchoscopes, endoscopes |
| Resuscitators |
| Water baths |
| Multidose vials |
| Community Reservoirs of P. aeruginosa |
| Home humidifiers |
| Whirlpools, hot tubs, spas |
| Swimming pools |
| Water-damaged homes |
True community-acquired infections among people without any prior exposure to a health care setting are rare. The rarity of community-acquired infections reflects the fact that P. aeruginosa is not part of the healthy human microbiota and that colonization occurs predominantly after hospitalization and antimicrobial exposure. Community-acquired infections, however, have been reported, including outbreaks from contaminated community reservoirs and among intravenous drug users. As with the hospital setting, water-related reservoirs are the main sources of P. aeruginosa in the community and include whirlpools, hot tubs, contact lenses, home humidifiers, water-damaged houses, swimming pools, loofah sponges, and even holy water. Contaminated recreational water, however, is among the most common sources of P. aeruginosa outbreaks. A review of outbreaks associated with recreational water, from 1971 to 2000, identified P. aeruginosa as the second most frequent causative pathogen, after Cryptosporidium species. P. aeruginosa was implicated in 36 outbreaks during the study period, with most of the outbreaks associated with whirlpool baths, hot tubs, and swimming pools. The main presentation is that of a superficial folliculitis that is pruritic and maculopapular and progresses to vesiculopustular within hours to days after exposure. It remits spontaneously. Conjunctivitis and otitis externa were also reported. Common nonmedical terms associated with community-acquired P. aeruginosa infections include “hot tub rash,” “swimmer's ear,” and “hot hand-foot syndrome” (see “Skin and Soft Tissue Infections,” later).
Food products may also be sources of P. aeruginosa in both community and hospital settings, because this pathogen has been isolated in a variety of vegetables, including lettuce, mushrooms, and carrots, and is present in soil. A definitive link between the presence of P. aeruginosa in vegetables and subsequent colonization or infection, however, has not been clearly established. Nevertheless, it is plausible that ingestion of P. aeruginosa –contaminated raw vegetables by high-risk individuals, including neutropenic patients and other immunocompromised hosts and those with decreased gastric acidity or oropharyngeal invasive devices, may increase the risk for colonization.
Antimicrobial Resistance
P. aeruginosa possesses a plethora of different resistance mechanisms. It is therefore not surprising that rates of antimicrobial resistance and multidrug resistance are among the highest in these organisms compared with other common human pathogens. Of even greater concern is the paucity of novel antimicrobial agents being developed to combat P. aeruginosa infections. The US Food and Drug Administration (FDA), however, approved ceftolozane-tazobactam in 2014. It has enhanced affinity for P. aeruginosa penicillin-binding proteins and appears to be unaffected by loss of porin channels or upregulation of efflux pumps. Over 80% of isolates resistant to ceftazidime or meropenem retain susceptibility to this novel agent. Currently, it is approved for use in urinary tract and intraabdominal infections, and several reports suggest that it may also be useful for treating other severe infections caused by MDR P. aeruginosa with confirmed susceptibility to ceftolozane-tazobactam (see Chapter 21 ).
Rates of antimicrobial resistance among P. aeruginosa hospital isolates recovered from different types of health care–associated infections in the United States in 2014, as reported by the NHSN, were as follows: aminoglycosides, 7% to 21%; extended-spectrum cephalosporins, 10% to 27%; fluoroquinolones, 12% to 33%; carbapenems, 8% to 28%; and piperacillin ± tazobactam, 7% to 19%. Multidrug resistance, defined as resistance to three or more of these antimicrobial classes, was present among 4% to 20% of isolates. Similarly to previous reports, isolates from ventilator-associated pneumonia had the highest rates, and those from surgical site infections had the lowest rates.
The 2016 Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net) reported rates of P. aeruginosa resistance to piperacillin ± tazobactam, ceftazidime, fluoroquinolones, aminoglycosides, and carbapenems. Overall, resistance rates to ceftazidime increased from 2013 to 2016. Conversely, the mean percentages of resistance for fluoroquinolones, aminoglycosides, and carbapenems significantly decreased over the same period of time, whereas resistance to piperacillin ± tazobactam remained stable. In 2016, 33.9% of isolates were resistant to one or more of the five antimicrobial classes, 13.6% were resistant to three or more, and 4.4% were resistant to all five classes. Resistance rates to three or more groups of antimicrobials varied considerably between European countries, with lowest percentages reported from Iceland, Denmark, Luxembourg, the United Kingdom, the Netherlands, and Norway (<3%) and highest percentages from Bulgaria and Romania (36%–49%). Percentages of single-drug resistance among P. aeruginosa isolates obtained from Latin America and the Asia-Pacific rim range from 23% to 41%.
In the United States in 2010, resistance rates in LTACH units were reported to be even higher than in ICUs. For example, MDR P. aeruginosa was more common among patients with catheter-associated urinary tract infections in LTACHs (25%) compared with those occurring in patients in ICUs (12%). Similarly, rates of multidrug resistance in patients with catheter-associated BSI were higher among those in LTACHs (16%) than those in ICUs (2%–9%).
Resistance Mechanisms
P. aeruginosa harbors numerous resistance mechanisms that either decrease penetration to the target site, alter the target site, or inactivate the antimicrobial agent using bacterial enzymes. These mechanisms can be broadly categorized as intrinsic, acquired, or adaptive, with overlap between categories.
Intrinsic Resistance
Decreased Permeability of the Outer Membrane
The semipermeable outer membrane of P. aeruginosa allows important nutrients to enter the cell through channels present on the cell membranes called porins. Numerous antimicrobial agents, including β-lactams, aminoglycosides, tetracyclines, fluoroquinolones, and carbapenems, enter the bacterial cell through these porins. Several families of porins have been characterized, including OprF, OprD, OprM, and TonB. Although OprF is a major porin in the outer cell membrane, allowing transport of large substrates, its role in antimicrobial resistance has not been definitively proven because loss of OprF porins in mutant strains does not alter antimicrobial penetration. Among the remaining three families, OprD has been the most studied. This channel allows entry of carbapenems but not of other β-lactams. Loss of OprD, however, may not have an equal impact on minimal inhibitory concentration increases for all carbapenems equally. Lastly, some porins in the family of OprM are presumed to be part of efflux systems and are discussed in the next section.
Not all antimicrobial agents use porins to enter the cell but instead decrease cell membrane stability by binding to lipopolysaccharides on the outer cell membrane. Examples of such agents include aminoglycosides and polymyxins.
Efflux Pumps
As the name implies, efflux pumps actively pump antimicrobial agents out of the bacteria. These pumps confer resistance to the great majority of antimicrobial agents (with the exception of polymyxins) and are the predominant systems for multidrug resistance among P. aeruginosa . Five superfamilies of efflux pumps have been identified, of which the resistance-nodulation-division (RND) family is among the most common. MexAB-OprM and MexXY-OprM efflux systems of the RND family confer intrinsic multidrug resistance to numerous antimicrobial agents, including fluoroquinolones, aminoglycosides, β-lactams, tetracyclines, tigecycline, and chloramphenicol. MexAB-OprM also confers resistance to meropenem but not imipenem, thus explaining differences in susceptibility patterns among different carbapenems. Similarly, the MexXY-OprM efflux system removes cefepime but not ceftazidime.
Antimicrobial-Modifying Enzymes
The majority of antimicrobial-modifying enzymes are acquired on plasmids and are discussed later in the chapter, with the exception of AmpC, a chromosomally encoded inducible cephalosporinase. AmpC confers resistance to all β-lactams except fourth-generation cephalosporins and carbapenems. When AmpC is overproduced, through mutations, resistance may also be conferred to these antimicrobial classes. Therapeutic failure due to the emergence of resistance during appropriate therapy can occur in over 50% of patients, especially those with serious P. aeruginosa infections and those with neutropenia or CF.
Acquired Resistance
Acquired resistance genes predominantly confer resistance to β-lactams and aminoglycosides. Extended-spectrum β-lactamases (ESBLs) are plasmid mediated and confer resistance to penicillins, narrow- and extended-spectrum cephalosporins, aztreonam, and sometimes carbapenems. ESBL-producing P. aeruginosa strains have rapidly spread worldwide. ESBL families identified in P. aeruginosa include PER, VEB, GES, TEM, SHV, and CTX-M enzymes. GES-type enzymes also extend their activity to carbapenems. These enzymes have been recovered from isolates from China, South Africa, Brazil, and France. Oxacillinase β-lactamases (OXAs) can either be narrow spectrum or broad spectrum and are weakly inhibited by clavulanic acid. Carbapenemase-hydrolyzing oxacillinases, which can be either acquired or naturally occurring, have also been identified in P. aeruginosa isolates, although less frequently than in Acinetobacter species. Resistance to carbapenems can also occur via metallo-carbapenemases and include the Verona integron-encoded metallo-β-lactamase (VIM), IMP, and New Delhi metallo-β-lactamase (NDM) families. These enzymes are of great concern because they are active against penicillins and cephalosporins as well as carbapenems. VIM-type isolates were first reported in P. aeruginosa isolates recovered in Italy in 1997 and subsequently spread into members of the Enterobacteriaceae, especially Klebsiella pneumoniae. Isolates with NDM enzymes may also carry aminoglycoside and fluoroquinolone resistance genes and remain susceptible only to colistin and polymyxin B. Another enzyme active against carbapenems, present in P. aeruginosa isolates, is the K. pneumoniae carbapenemase (KPC) type. KPC-producing strains were first identified in Colombia and have since spread to Puerto Rico, China, and the United States, and most recently Brazil. Carbapenem-resistant isolates, regardless of the mechanism of resistance, result in serious infections. A longitudinal study from 1989 to 2006 demonstrated that rates of imipenem-resistant P. aeruginosa isolates increased from 13% to 20% and that infections caused by these resistant pathogens were associated with higher in-hospital mortality. Prior exposure to carbapenems increased the risk for imipenem-resistant P. aeruginosa infection by almost eightfold.
Aminoglycoside-Modifying Enzyme
Aminoglycoside-modifying enzymes are carried on multiple different genetic mobile elements, such as plasmids, transposons, and integrons. They confer resistance to all aminoglycosides, although, in general, amikacin may be less susceptible to these enzymes. The most common aminoglycoside-modifying enzymes are aminoglycoside nucleotidyltransferase (2′)-I, which confers resistance to gentamicin and tobramycin, and aminoglycoside acetyltransferase (6′)-II, which also confers resistance to netilmicin.
Treatment of Pseudomonas aeruginosa Infections
Treatment of P. aeruginosa infections, especially BSIs, centers around the controversy of monotherapy versus combination therapy. A few earlier studies support the use of combination therapy since mortality rates were lower when two antimicrobial agents, instead of a single agent, were used to treat BSI caused by P. aeruginosa. The main limitation of these studies is that in many the monotherapy study arm consisted of only an aminoglycoside, which is suboptimal for the treatment of P. aeruginosa BSI. In a meta-analysis, which also concluded that combination therapy is superior to monotherapy, four of the five included studies used aminoglycosides in the monotherapy study arm. There are numerous other limitations with older studies that support the use of combination therapy, including lack of double blinding and randomization, different sources of BSI, retrospective lack of adjustment for time to start of appropriate antimicrobial therapy, and duration of follow-up. Confounding by indication, whereby the severely ill patients receive combination therapy, is another limitation of studies addressing this issue. Another reason that is often cited for supporting combination therapy is the potential synergy between the two antimicrobial agents, usually a β-lactam and an aminoglycoside. Although in vitro and animal studies show benefit of this combined regimen, clinical studies have provided conflicting data. Preventing the emergence of antimicrobial resistance is another reason often cited for supporting the use of combination therapy, but there are minimal data to support this statement. Administering the appropriate dose, at the correct frequency and for the optimal duration, is likely more important in preventing the emergence of resistance than combination therapy. Prompt initiation of the appropriate antimicrobial agents is also key to a successful outcome, as is removal of invasive devices if implicated.
Overall, the great majority of more recent studies do not show a survival benefit between combination therapy and monotherapy for definitive therapy. However, the main conclusion by most investigators is that large randomized clinical trials are needed to definitively answer the question of efficacy between combination therapy and monotherapy.
Use of combination therapy should be strongly considered in the severely ill patient for the empirical treatment of P. aeruginosa BSI, especially in those health care institutions with patients with a high rate of multidrug resistance. Using combination therapy will thus ensure that at least one antimicrobial agent is effective against the infecting P. aeruginosa strain. Deescalating to a single antimicrobial agent, once antimicrobial susceptibility profiles are available, should then be considered. Narrowing to a single agent is especially relevant when the combination therapy includes an aminoglycoside, because this regimen is associated with increased nephrotoxicity. Other adverse events that are more likely to occur with combination therapy, compared with monotherapy, include an increased risk for Clostridioides difficile (formerly Clostridium difficile ) infection, further alterations in the protective effects of the human microbiota against colonization by other MDR organisms, and fungal infections.
Antimicrobial agents effective against P. aeruginosa and appropriate doses are listed in Table 219.3 . Polymyxins (colistin, polymyxin B) should be reserved for MDR P. aeruginosa, when other alternatives are not available, because this class of agents is inferior to other available antipseudomonal agents. Emergence of resistance during treatment has been documented for K. pneumoniae BSI and likely also occurs for P. aeruginosa infections. High-dose continuous infusion of β-lactams has also been successfully used in the treatment of BSI caused by MDR P. aeruginosa. Moriyama and associates reported three patients infected with MDR P. aeruginosa strains who were successfully treated with a continuous infusion of ceftazidime (6.5–16.8 g/day) or aztreonam (8.4 g/day) and tobramycin. The rationale behind this approach is that antibacterial activity of β-lactams depends on the time that the antimicrobial concentration is above the minimal inhibitory concentration of the bacteria. Using continuous infusion ensures that the concentration of the β-lactam will be above the minimal inhibitory concentration for the entire dosing interval, whereas intermittent dosing may cause the concentration to fall below the minimal inhibitory concentration. Future clinical studies, however, are required to further validate this treatment regimen.
TABLE 219.3
Intravenous Antimicrobial Agents Effective Against Pseudomonas aeruginosa
| ANTIMICROBIAL AGENT | INTRAVENOUS DOSE |
|---|---|
| Penicillins Plus β-Lactamase Inhibitor | |
| Ticarcillin-clavulanate | 3.1 g q4h |
| Piperacillin-tazobactam | 4.5 g q6h or 3.375 g q4h |
| Broad-Spectrum Cephalosporins ± β-Lactamase Inhibitor | |
| Ceftazidime | 2 g q8h |
| Cefepime | 2 g q8–12h |
| Ceftolozane-tazobactam | 1.5g q8h |
| Ceftazidime-avibactam | 2.5 g q8h |
| Fluoroquinolones | |
| Ciprofloxacin | 400 mg q8h |
| Levofloxacin | 750 mg q24h |
| Carbapenems | |
| Imipenem | 500 g q6h |
| Meropenem | 1–2 g q8h |
| Doripenem | 500 mg q8h |
| Monobactam | |
| Aztreonam | 2 g q8h |
| Aminoglycosides | |
| Tobramycin | 2 mg/kg loading dose, then 1.7 mg/kg q8h or 4–7 mg/kg q24h |
| Gentamicin | As for tobramycin |
| Amikacin | 7.5 mg/kg q12h or 15 mg/kg q24h |
For a review of novel antimicrobials with potential activity, refer to Wright et al.
Novel antipseudomonal agents are reviewed in detail by Wright and colleagues. Several studies indicate that ceftolozane-tazobactam and ceftazidime-avibactam are effective in the treatment of MDR– P. aeruginosa BSI and other infections, although resistance can develop even with short courses of therapy. The combination of ceftazidime and the novel non–β-lactam β-lactamase inhibitor avibactam has been approved for the treatment of complicated urinary tract infections and intraabdominal infections. The addition of avibactam to ceftazidime allows this combination to inhibit Ambler class A β-lactamases (including KPC), AmpC β-lactamases, and OXA-type Ambler class D β-lactamases, making this drug an excellent therapeutic option for infections caused by MDR gram-negative bacteria, including P. aeruginosa. The recommended dose for patients with normal renal function is 2 g of ceftazidime and 500 mg of avibactam every 8 hours. Resistance to ceftazidime-avibactam among P. aeruginosa has been described, with higher rates among MDR isolates involving efflux mechanisms or metallo-carbapenemases.
Infections Caused by Pseudomonas aeruginosa
Bloodstream Infections
Update: Duration of Therapy for Pseudomonas aeruginosa Bloodstream Infections
BSIs are among the most serious infections caused by P. aeruginosa, with mortality rates reaching 60%. The nationwide Surveillance and Control of Pathogens of Epidemiological Importance (SCOPE), which included data from 49 US hospitals, reported that from 1995 to 2002 the incidence of P. aeruginosa nosocomial BSI was 2.1 per 10,000 hospital admissions. P. aeruginosa was the third most common gram-negative bacteria causing nosocomial BSI and accounted for 4.3% of all cases. In the ICUs, P. aeruginosa was the fifth most common isolate implicated in BSI, accounting for 4.7% of all cases, and was the seventh most common isolate in non-ICU wards, accounting for 3.8% of cases. Outside the United States, P. aeruginosa is implicated in even more cases of nosocomial BSI. In a surveillance study that collected data from 16 Brazilian hospitals from 2007 to 2010 and used the same methodology as the SCOPE study, 8.9% of all nosocomial BSI were caused by P. aeruginosa.
Risk factors for P. aeruginosa BSI include immunodeficiency, prior hospitalization, previous antimicrobial exposure, advanced age, prior surgery, and invasive devices. Many of these risk factors represent an association with BSI, irrespective of the implicated pathogen.
Mortality rates for nosocomial BSI caused by P. aeruginosa are among the highest. The great majority of reported crude mortality percentages from large surveillance studies range from 39% to 60%. These percentages are similar to those caused by Candida species. Some studies, however, report lower mortality rates, ranging from 12% to 30%. The large range in mortality rates from different studies reflects the multitude of factors that affect outcomes associated with BSI. For P. aeruginosa BSI, advanced age, high Acute Physiology and Chronic Health Evaluation II (APACHE II) score, sepsis, poor functional status, polymicrobial bacteremia, and inappropriate initial antimicrobial therapy have all been associated with an increased risk for mortality.
Multidrug resistance is also a risk factor for increased mortality. Rates of mortality in infections due to MDR P. aeruginosa strains are twofold to threefold higher compared with non-MDR strains. Because inappropriate initial empirical therapy is a major contributor to these higher mortality rates, combination therapy for empirical treatment is warranted when multidrug resistance rates are high (see later).
The predominant distinguishing feature of P. aeruginosa BSI is the occurrence of ecthyma gangrenosum. Although not pathognomonic for P. aeruginosa, the presence of these characteristic skin lesions should raise high suspicion for this pathogen (see “ Skin and Soft Tissue Infections ” later).
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