Enterobacter Infections Treatment & Management
- Author: Susan L Fraser, MD; Chief Editor: Michael Stuart Bronze, MD more...
Antimicrobial therapy is indicated in virtually all Enterobacter infections.
With few exceptions, the major classes of antibiotics used to manage infections with these bacteria include the beta-lactams, carbapenems, the fluoroquinolones, the aminoglycosides, and TMP-SMZ. Because most Enterobacter species are either very resistant to many agents or can develop resistance during antimicrobial therapy, the choice of appropriate antimicrobial agents is complicated. Consultation with experts in infectious diseases and microbiology is usually indicated. In 2006, Paterson published a good review of resistance among various Enterobacteriaceae. Ritchie et al (2009) published a good discussion regarding antibiotic choices for infection encountered in the ICU.
Newer options include tigecycline. Although not indicated specifically for Enterobacter pneumonia or bloodstream infections, tigecycline has excellent in vitro activity against these gram-negative bacilli.[24, 25, 26] In one laboratory study of multidrug-resistant gram-negative bacilli, tigecycline maintained a low MIC against all of the organisms. Older options might include intravenous administration of polymyxin B or colistin, drugs that are rarely used, even in large medical centers, and for which standard susceptibility criteria are not available. A study of 89 carbapenem nonsusceptible Enterobacteriaceae isolates from China showed that polymyxin B was much more active than tigecycline.
With rare exceptions, E cloacae, E aerogenes, and most other Enterobacter species 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. Initial resistance to third-generation cephalosporins (eg, ceftriaxone, cefotaxime, ceftazidime) and extended-spectrum penicillins (eg, ticarcillin, azlocillin, piperacillin) varies but can develop during treatment. The activity of the fourth-generation cephalosporins (eg, cefepime) is fair, and the activity of the carbapenems (eg, imipenem, meropenem, ertapenem, doripenem) is excellent. However, resistance has been reported, even to these agents.
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.
AmpC beta-lactamases are cephalosporinases 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 but may emerge rapidly in vivo. Jacoby (2009) recently published a good discussion about the emerging importance of AmpC beta-lactamases.
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 with 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).
For unknown reasons, extended-spectrum penicillins are less selective than third-generation cephalosporins. The in-therapy resistance phenomenon is less common with carboxy, ureido (eg, piperacillin), 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.
The fourth-generation cephalosporins are relatively stable to the action of AmpC beta-lactamases; consequently, they retain moderate activity against the mutant strains of Enterobacter, hyperproducing AmpC beta-lactamases.
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. However, Enterobacter species can develop resistance to carbapenems via other mechanisms. The New Delhi metallo-beta-lactamase (NDM-1) has affected Enterobacter species around the world.[30, 31, 32]
The production of extended-spectrum beta-lactamases (ESBLs) has been documented in Enterobacter. Usually, these ESBLs are TEM1 -derived or SHV1 -derived enzymes, and they have been reported since 1983 in Klebsiella 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.
Among Enterobacter species, reports indicate that E aerogenes has been the most common 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).
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.
In 1999, the CLSI 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).
Carbapenems are the most 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.
Resistance to carbapenems is rare but has been reported and is considered an emerging clinical threat posed by Enterobacter species, as well as by other Enterobacteriaceae.[30, 31] The beta-lactamases first implicated in imipenem resistance 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.
Hyperproduction (stable derepression) of AmpC beta-lactamases associated with some decrease in permeability to the carbapenems may also cause resistance to these agents. In vitro low-level ertapenem resistance was not associated with resistance to imipenem or meropenem, but high-level ertapenem resistance predicted resistance to the other carbapenems.
Metallo-beta-lactamases cause resistance across the carbapenem class, are transmissible, and have been associated with clinical outbreaks in hospitals worldwide. In one reported outbreak of 17 cases of infection (2 due to Enterobacter species), molecular studies demonstrated presence of a gene belonging to bla(VIM-1) cluster. KPC-type carbapenemases have emerged in New York City. The new NDM-1 carbapenemase has already rapidly spread to many countries.
Aminoglycoside resistance is relatively common and varies widely among centers.
As with other members of Enterobacteriaceae, this resistance results from the production of different aminoglycoside-inactivating enzymes.
Quinolones and TMP-SMZ
Resistance to fluoroquinolones is relatively rare but may be high in some parts of the world.
Resistance to TMP-SMZ is more common.
Colistin and polymyxin B
These drugs are being used more frequently to treat serious infection caused by multidrug-resistant organisms, sometimes as monotherapy or in combination with other antibiotics. Clinical experience, including documentation of success rates and attributable mortality is broadening.[36, 37] Heteroresistance to colistin was demonstrated in a few Enterobacter isolates collected from ICU patients and was best identified using broth microdilution, agar dilution, or E-test methods. Polymyxin B was not as active against Enterobacter species as it was against other Enterobacteriaceae but did demonstrate an MIC50 of less than or equal to 1, with 83% of Enterobacter isolates considered susceptible. One recent in vitro study documented a colistin MIC90 of 2 mcg/mL or less in more than 90% of Enterobacter isolates from Canada.
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 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 in patients with emboli or intractable heart failure.
Enterobacter species cause severe and frequently life-threatening infections that can originate in virtually any body compartment. Enterobacter 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, as well as with debridement of necrotic tissues.
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.
A microbiologist can provide valuable assistance by educating clinicians regarding the correct interpretation of susceptibility testing with this organism.
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