Approach Considerations
Investigate and attempt to eliminate all potential sites of infection (ie, attain good "source control"). For instance, an identified abscess should be drained, or an infected joint should prompt surgical consultation for drainage. Remove any potentially infected invasive devices, such as intravenous or urinary catheters.
Medical Care
Antimicrobial therapy is indicated in virtually all Enterobacter infections. Considerations for empirical therapy include an assessment regarding potential resistance to antibiotics, the infection site, anticipated achievable tissue concentrations of antibiotic, and predicted antibiotic adverse effects.
With few exceptions, the major classes of antibiotics used to manage infections with the E cloacae complex 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 clinical infectious diseases and microbiology is usually indicated, in addition to infectious disease pharmacists. In 2006, Paterson published a good review of resistance among various Enterobacteriaceae. [32] Ritchie et al (2009) published a good discussion regarding antibiotic choices for infection encountered in the ICU. [33]
Newer options include tigecycline, eravacycline, ceftazidime/avibactam, meropenem-vaborbactam, and plazomicin [34] , aztreonam in combination with ceftazidime-avibactam [35] , and the recently FDA approved cefidericol. [36]
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.
Emerging strategies to combat and treat ESKAPE pathogens including Enterobacter include consideration for combination antibiotics, phage therapy, antimicrobial peptides, silver nanoparticles and photodynamic light therapy. [37]
Beta-lactams
With rare exceptions, E cloacae complex 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 and may emerge rapidly in vivo. Jacoby (2009) published a good discussion about the emerging importance of AmpC beta-lactamases. [38]
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, it occurs rarely with UTIs. [39]
The fourth-generation cephalosporin cefepime is relatively stable to the action of AmpC beta-lactamases; consequently, it retains moderate activity against the mutant strains of Enterobacter, hyperproducing AmpC beta-lactamases. Nevertheless, resistance has been reported to develop when this antibiotic was used to treat Enterobacter infections.
Ceftazidime-avibactam was initially approved in 2015 for the treatment of complicated intra-abdominal infections (cIAI) when given with metronidazole and complicated urinary tract infections (cUTI) due to susceptible organisms including E cloacae. It was subsequently approved for hospital-acquired and ventilator-associated pneumonia. It was also approved in March 2019 for treatment in children older than 3 months with cIAI (given with metronidazole) and cUTI. This antibiotic has been shown both in vitro and in vivo to have activity against multidrug-resistant E cloacae isolates. [40, 41]
Ceftaroline, a "fifth generation" cephalosporin with activity against S aureus and other staphylococci, including methicillin-resistant isolates, has activity and resistance potential against E cloacae complex isolates similar to those of third-generation cephalosporins. Ceftolozane-tazobactam had reliable activity against only wild-type E cloacae complex isolates, but not against ESBL or AmpC-overproducing strains. [42] Therefore, neither of these antibiotics would be considered useful for empirical treatment of serious Enterobacter infections.
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. [43, 44, 45]
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. [46] 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.
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.
The CLSI has 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, additional ESBL and carbapenemase detection laboratory methods have been published by the CLSI. [47]
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 (e.g. piperacillin-tazobactam) remains a controversial issue for therapy of ESBL-producing organisms. [48]
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. [43, 44] 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.
In August 2017, meropenem/vaborbactam was FDA approved for complicated urinary tract infections (cUTI) caused by carbapenem-resistant Enterobacteriaceae (CRE). The novel carbapenem/beta-lactamase inhibitor meropenem/vaborbactam (Vabomere) specifically addresses carbapenem-resistant Enterobacteriaceae (CRE) (eg, E coli, K pneumoniae) by inhibiting the production of enzymes that block carbapenem antibiotics, one of the more powerful classes of drugs in the antibiotic arsenal. Bacteria that produce the K pneumoniae carbapenemase (KPC) enzyme are responsible for a large majority of CRE infections in the United States.
The approval was based on data from a phase 3 multicenter, randomized, double-blind, double-dummy study, TANGO-I (n=550) in adults with cUTI, including those with pyelonephritis. The primary endpoint was overall cure or improvement and microbiologic outcome of eradication (defined as baseline bacterial pathogen reduced to < 104 CFU/mL). Data showed about 98.4% of patients treated with intravenous meropenem/vaborbactam exhibited cure/improvement in symptoms and a negative urine culture result, compared with 94.3% of patients treated with piperacillin/tazobactam. About one week posttreatment, approximately 77% of patients treated with meropenem/vaborbactam had symptom resolution and a negative urine culture result, compared with 73% of patients treated with piperacillin/tazobactam. [49]
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. [50]
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. [51] KPC-type carbapenemases have emerged in New York City. [32] The new NDM-1 carbapenemase has already rapidly spread to many countries. [15]
Aminoglycosides
Aminoglycoside resistance is relatively common and varies widely among centers. Amikacin and the new aminoglycoside plazomicin may have better activity than gentamicin or tobramycin but are not usually administered to persons with renal compromise owing to the high potential for toxicity.
Quinolones and TMP-SMZ
Resistance to fluoroquinolones is becoming more common and may be very high in some parts of the world. When susceptibility to fluoroquinolones is demonstrated, ciprofloxacin and levofloxacin have somewhat better activity than moxifloxacin.
Resistance to TMP-SMZ is more common, and it should be selected only when the susceptibility report is available from the microbiology laboratory and other drugs (eg, carbapenems) are not available for therapy.
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. [52, 53] 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. [54] 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. [55] One recent in vitro study documented a colistin MIC90 of 2 mcg/mL or less in more than 90% of Enterobacter isolates from Canada. [56] A study of 89 carbapenem-nonsusceptible Enterobacteriaceae isolates from China showed that polymyxin B was much more active than tigecycline. [57]
Tigecycline and eravacycline
Although not indicated specifically for Enterobacter pneumonia or bloodstream infections, tigecycline showed excellent in vitro activity against these gram-negative bacilli. [58, 59, 60] In one laboratory study of multidrug-resistant gram-negative bacilli, tigecycline maintained a low MIC against all of the organisms. [61]
Eravacycline is a new fluorocycline antibiotic in the tetracycline class. It is similar to tigecycline, but with expanded activity. [62, 63] It was approved by the FDA in 2018 for the treatment of intra-abdominal infections caused by susceptible organisms, including E cloacae. Clinical data are not yet extensive but are growing. Neither tigecycline nor eravacycline has FDA approval for use in patients younger than 18 years.
Cefidericol
Cefiderocol is a first in its class injectable siderophore cephalosporin that combines a catechol-type siderophore and cephalosporin core with side chains similar to cefepime and ceftazidime. This structure and its unique mechanism of action confer enhanced stability against hydrolysis by many beta-lactamases, including extended spectrum beta-lactamases such as CTX-M, and carbapenemases such as KPC, NDM, VIM, IMP, OXA-23, OXA48-like, OXA-51-like and OXA-58. Cefiderocol’s spectrum of activity encompasses both lactose fermenting and non-fermenting Gram-negative pathogens, including carbapenem-resistant Enterobacterales. [37, 64]
Cefiderocol has received US Food and Drug Administration approval for the treatment of patients 18 years of age or older with complicated urinary tract infections and pyelonephritis caused by susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.
It received approval in 2022 for the treatment of patients 18 years of age or older with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.
Surgical Care
Surgical care is indicated as for other sources of infection: drainage or debridement of abscesses, infected collections, or osteomyelitic foci. [35]
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.
Consultations
Enterobacter species cause severe and frequently life-threatening infections that can originate in virtually any body compartment. Enterobacter infection may warrant 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 infectious disease clinicians and pediatric surgeons).
Radiologists and nuclear medicine physicians may help select the best imaging study according to patient's specific problems. Interventional 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 and selection of further testing, when indicated.
Pharmacists, in particular those who have specialty training in Infectious Diseases pharmaceuticals and prescribing practices are often invaluable resources when treating patients with complicated, resistant infections due to Enterobacter species.
Complications
Rapid development of new resistance is one of the most difficult complication challenges in treating patients with Enterobacter infections. The clinician must always be aware of this potential, remain alert to signs of worseing or relapsing infection in the patient, and prepared to alter antibiotic therapy when indicated.
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Radiograph of an open right tibial fracture in a 21-year-old male marine who was wounded when an improvised explosive device detonated while he was on patrol in Iraq.
