Enterobacter
Enterobacter species, particularly Enterobacter cloacae and Enterobacter aerogenes, are important nosocomial pathogens responsible for various infections, including bacteremia, lower respiratory tract infections, skin and soft tissue infections, urinary tract infections (UTIs), endocarditis, intra-abdominal infections, septic arthritis, osteomyelitis, and ophthalmic infections.
Risk factors for nosocomial Enterobacter species infections include hospitalization of greater than 2 weeks, invasive procedures in the past 72 hours, treatment with antibiotics in the past 30 days, and the presence of a central venous catheter. Specific risk factors for infection with nosocomial multidrug-resistant strains of Enterobacter species include the recent use of broad-spectrum cephalosporins or aminoglycosides and ICU care.
These "ICU bugs" cause significant morbidity and mortality, and infection management is complicated by multiple antibiotic resistance. Enterobacter species possess inducible beta-lactamases, which are undetectable in vitro but are also responsible for resistance during treatment. Physicians treating patients infected with these bacteria are advised to avoid certain antibiotics, particularly third-generation cephalosporins, because resistant mutants can quickly appear. The crucial first step is appropriate identification of the bacteria. Antibiograms must be interpreted with respect to the different resistance mechanisms and their respective frequency, as is reported for bacteria belonging to this genus, even if the resistance mechanisms have not been detected by routine in vitro antibiotic susceptibility testing.
Pathophysiology
Enterobacter species rarely cause disease in a healthy individual. This opportunistic pathogen, similar to other members of the Enterobacteriaceae family, possesses an endotoxin known to play a major role in the pathophysiology of sepsis and its complications.
Although community-acquired infections are occasionally observed, nosocomial infections are, by far, the most frequent. Patients most susceptible to acquiring Enterobacter infections are those who stay in the hospital, especially the ICU, for prolonged periods. Other major risk factors include the prior use of antimicrobial agents, concomitant malignancy (especially hemopoietic and solid organ malignancies) hepatobiliary disease, ulcers of the upper gastrointestinal tract, use of foreign devices such as intravenous catheters, and serious underlying conditions such as burns, mechanical ventilation, and immunosuppression.
The source of infection may be endogenous via colonization of the skin, gastrointestinal tract, or urinary tract or exogenous resulting from the ubiquitous nature of these bacteria. Multiple reports have incriminated the hands of personnel, endoscopes, blood products, devices for monitoring intra-arterial pressure, and stethoscopes as sources of infection. Outbreaks have been traced to various common sources: total parenteral nutrition solutions, isotonic saline solutions, albumin, digital thermometers, and dialysis equipment.
Enterobacter species contain a subpopulation of organisms that produce a beta-lactamase at low-levels. Once exposed to broad-spectrum cephalosporins, the subpopulation of beta-lactamase–producing organisms predominate. Thus, an infection that appears sensitive to cephalosporins at the time of diagnosis may quickly develop into a resistant infection during therapy. Imipenem and cefepime have a more stable beta-lactam ring against the lactamase produced by resistant strains of Enterobacter.
Causes
* Enterobacter is a gram-negative bacillus belonging to the Enterobacteriaceae family. Other members of this family include Klebsiella, Escherichia, Citrobacter, Serratia, Salmonella, Shigella species, and many others. Enterobacteriaceae are the most frequent bacterial isolates recovered from clinical specimens. These bacteria have an outer membrane that contains, among other things, lipopolysaccharides from which lipid-A plays a major role in sepsis. Lipid-A, also known as endotoxin, is the major stimulus for the release of cytokines, which are the mediators of systemic inflammation and its complications.
* In the microbiology laboratory, colonies of Enterobacteriaceae appear large, dull-gray, and dry or mucoid on sheep blood agar. All Enterobacteriaceae are glucose fermenters and, consequently, are able to grow in aerobic and anaerobic atmospheres.
* MacConkey agar is a lactose-containing medium that is selective for nonfastidious gram-negative bacilli such as Enterobacteriaceae. Using the enzymes beta-galactosidase and beta-galactoside permeases, the most frequently encountered species of Enterobacter strains activate the pH indicator (neutral red) included in MacConkey agar, giving a red stain to the growing colonies. Klebsiella and Enterobacter may appear similar as mucoid colonies but can be readily differentiated by a few specific tests. In contrast to Klebsiella, Enterobacter organisms are motile, usually ornithine decarboxylase-positive, and urease-negative.
* Many different species comprise the genus Enterobacter. For some, no evidence exists to date that proves they can cause human infections. The most frequently isolated species are E cloacae and E aerogenes, followed by E sakazakii, which produces a characteristic yellow pigment. Other species rarely encountered in the clinic include Enterobacter asburiae, Enterobacter gergoviae, Enterobacter taylorae, Enterobacter hormaechei, and Enterobacter cancerogenus. Enterobacter agglomerans has been removed from the genus Enterobacter and renamed Pantoea agglomerans.
Treatment:
Medicine: Antimicrobial therapy is indicated in virtually all infections caused by Enterobacter species.With few exceptions, the major classes of antibiotics used to manage infections with these bacteria are the beta-lactams, the quinolones, the aminoglycosides, and TMP-SMZ.
The choice of appropriate antimicrobial agents is complicated by the fact that the majority of bacteria in this genus are either very resistant to these agents or can develop resistance during antimicrobial therapy. When this occurs, consultation with experts in infectious diseases and microbiology are usually indicated. Newer options include tigecycline. Although it is not indicated specifically for pneumonia or bloodstream infections caused by Enterobacter species, it has excellent in vitro activity against these gram-negative bacilli.
E cloacae, E aerogenes, and most of the others are resistant to the narrow-spectrum penicillins that traditionally have good activity against other Enterobacteriaceae such as E coli (eg, ampicillin, amoxicillin) and to first-generation and second-generation cephalosporins (eg, cefazolin, cefuroxime). They also are usually resistant to cephamycins such as cefoxitin. Resistance to third-generation cephalosporins (eg, ceftriaxone, cefotaxime, ceftazidime) and to extended-spectrum penicillins (eg, ticarcillin, azlocillin, piperacillin) is variable but can develop during treatment. The activity of the fourth-generation cephalosporins (eg, cefepime) is fair, and, for the carbapenems (eg, imipenem, meropenem, ertapenem), activity is excellent. However, resistance has been reported, even to these agents.
·[FONT="] [/FONT]The bacteria designated by the acronym SERMOR-PROVENF (SER = Serratia, MOR = Morganella, PROV = Providencia, EN = Enterobacter, F = freundii for Citrobacter freundii) have similar, although not identical, chromosomal beta-lactamase genes that are inducible. With Enterobacter, the expression of the gene AmpC, is repressed, but derepression can be induced by beta-lactams. Of these inducible bacteria, mutants with constitutive hyperproduction of beta-lactamases can emerge at a rate between 105 and 108. These mutants are highly resistant to most beta-lactam antibiotics and are considered stably derepressed.
·[FONT="] [/FONT]These beta-lactamases are from the functional group 1 and molecular class C in the Bush-Jacoby-Medeiros classification of beta-lactamases. They are not inhibited by beta-lactamase inhibitors (eg, clavulanic acid, tazobactam, sulbactam). Ampicillin and amoxicillin, first- and second-generation cephalosporins, and cephamycins are strong AmpC beta-lactamase inducers. They are also rapidly inactivated by these beta-lactamases; thus, resistance is readily documented in vitro.
·[FONT="] [/FONT]Third-generation cephalosporins and extended-spectrum penicillins, although labile to AmpC beta-lactamases, are weak inducers. Resistance is expressed in vitro only with bacteria that are in a state of stable derepression (mutant hyperproducers of beta-lactamases). However, the physician must understand that organisms considered susceptible by in vitro testing can become resistant during treatment by the following sequence of events: (1) induction of AmpC beta-lactamases, (2) mutation among induced strains, (3) hyperproduction of AmpC beta-lactamases by mutants (stable derepression), and (4) selection of the resistant mutants (the wild type sensitive organisms being killed by the antibiotic).
·[FONT="] [/FONT]For unknown reasons, extended-spectrum penicillins are less selective than third-generation cephalosporins. The in-therapy resistance phenomenon occurs less frequently with carboxy, ureido, or acylaminopenicillins. This phenomenon has been well documented as a cause of treatment failure with pneumonia and bacteremia; however, the phenomenon is rare with UTIs.
·[FONT="] [/FONT]Carbapenems are strong AmpC beta-lactamase inducers, but they remain very stable to the action of these beta-lactamases. As a consequence, no resistance to carbapenems, either in vitro or in vivo, can be attributed to AmpC beta-lactamases.
·[FONT="] [/FONT]The fourth-generation cephalosporins are relatively stable to the action of these beta-lactamases; consequently, they retain moderate activity against the mutant strains of Enterobacter, hyperproducing AmpC beta-lactamases.
·[FONT="] [/FONT]More recently, the production of extended-spectrum beta-lactamases (ESBLs) has been documented. Usually, these ESBLs are TEM1-derived or SHV1-derived enzymes, and they have been reported since 1983 in K pneumoniae, Klebsiella oxytoca, and E coli. Bush et al classify these ESBLs in group 2be and in molecular class A in their beta-lactamase classification. The location of these enzymes on plasmids favors their transfer between bacteria of the same and of different, genera. Many other gram-negative bacilli may also possess such resistant plasmids.
·[FONT="] [/FONT]Among Enterobacter, reports indicate that E aerogenes has been the most frequent carrier of ESBL. Unlike the AmpC beta-lactamases, these enzymes are encoded by plasmid DNA and do not possess a molecular mechanism of induction or stable derepression. They are inactivated by the beta-lactamase inhibitors and remain susceptible to cefoxitin (testing cefoxitin is then a useful tool to help differentiate AmpC beta-lactamases from ESBLs).
·[FONT="] [/FONT]Bacteria-producing ESBLs should be considered resistant to all generations of cephalosporins, all penicillins, and to the monobactams such as aztreonam, even if the in vitro susceptibilities are in the sensitive range according to the CLSI breakpoints. In the past, the CLSI has cautioned physicians regarding the absence of a good correlation with susceptibility when its breakpoints are applied to ESBL-producing bacteria.
·[FONT="] [/FONT]In 1999, this committee published guidelines for presumptive identification and for confirmation of ESBL production by Klebsiella and E coli guidelines that are often applied to other Enterobacteriaceae. From the above, one can conclude that, when a bacterium of the genus Enterobacter produces ESBL(s) (more than 1 ESBL can be produced by the same bacteria), it does so in addition to the AmpC beta-lactamases that are always present, either in states of inducibility or in states of stable derepression. With stable derepressed mutants, ESBL is almost impossible to detect unless molecular methods such as polymerase chain reaction (PCR) or isoelectric focusing (IEF) electrophoresis are used. For inducible strains, no recommendations have been issued by the CLSI for the detection of ESBL (ie, if PCR and IEF electrophoresis are not readily available).
·[FONT="] [/FONT]Carbapenems are the only reliable beta-lactam drugs for the treatment of severe Enterobacter infections, and fourth-generation cephalosporins are a distant second choice. The association of an extended-spectrum penicillin with a beta-lactamase inhibitor remains a controversial issue for therapy of ESBL-producing organisms.
·[FONT="] [/FONT]Resistance to carbapenems is rare but has been reported for imipenem in strains of E cloacae with a high MIC. The beta-lactamases implicated were NMC-A and IMI-1, both molecular class A and functional group 2f carbapenemases, which are inhibited by clavulanic acid and then able to hydrolyze all the beta-lactams not associated with a beta-lactamase inhibitor.
·[FONT="] [/FONT]Hyperproduction (stable derepression) of AmpC beta-lactamases associated with some decrease in permeability to the carbapenems may also cause resistance to these agents.
* Aminoglycosides
*
o Aminoglycoside resistance is relatively frequent and varies widely among centers.
o As with other members of Enterobacteriaceae, this resistance results from the production of different aminoglycoside-inactivating enzymes.
* Quinolones and TMP-SMZ
*
o Resistance to fluoroquinolones is relatively rare.
o Resistance to TMP-SMZ is more frequent.
Surgical Care
Surgical care is indicated as for other sources of infection: drainage or debridement of abscesses, infected collections, or osteomyelitic foci.
In some instances, the clinician must consider this option instead of percutaneous drainage with CT-scan guidance. The severity of the infection and the size of the collection to be drained are among the parameters to consider when choosing the best option for the patient.
For endocarditis, valvular replacement is also indicated, particularly when emboli or intractable heart failure is present.
Consultations
This opportunistic pathogen causes severe and frequently life-threatening infections that can originate in virtually any body compartment. Infection warrants consultation with many different subspecialists.
* Consultation with an infectious diseases specialist helps in the selection of antimicrobial agents, taking into account the multiple mechanisms of resistance to different classes of antimicrobial agents and the lack of correlation between crude in vitro susceptibility results and true clinical efficacy for most of the beta-lactams.
* Intensive care specialists, when appropriate, can help in the management of severe sepsis or septic shock.
* General internal medicine and/or medical subspecialists (eg, cardiologists, gastroenterologists, nephrologists, rheumatologists, pulmonologists) may be helpful.
* Surgeons may help with the drainage of infected collections, if indicated.
* Consult neonatologists for neonatal sepsis and, possibly, general pediatricians or pediatric subspecialists (including pediatric surgeons).
* Radiologists and nuclear medicine physicians may help select the best imaging study according to patient's specific problems and (radiologists) may be needed to perform percutaneous drainage of infected collections.