Treatment of Enterobacter cloacae Urinary Tract Infection
Cefepime sensitivity for E. cloacae is unreliable and should not be used as first-line therapy, particularly if the isolate is ESBL-producing or has elevated MICs within the susceptible range; carbapenems are the preferred treatment for serious E. cloacae infections.
Cefepime Sensitivity Concerns for E. cloacae
Resistance Mechanisms Compromise Cefepime Efficacy
First and second-generation cephalosporins are generally not effective against Enterobacter infections, and third-generation cephalosporins are not recommended due to increased likelihood of resistance, particularly for E. cloacae 1.
Fourth-generation cephalosporins (cefepime) can be used only if Extended-Spectrum beta-lactamase (ESBL) is absent 1.
One-third of E. cloacae bloodstream isolates produce SHV-type ESBLs in addition to hyperproducing AmpC-type beta-lactamases, resulting in cefepime MIC₉₀ of 64 μg/ml for ESBL-producing strains versus 0.5 μg/ml for non-ESBL producers 2.
Critical MIC Considerations
For cephalosporin-resistant Enterobacter spp. infections, patients with higher cefepime MIC in the susceptible dose-dependent category (4-8 μg/ml) had significantly higher mortality with cefepime (5 of 7,71.4%) compared to carbapenem therapy (2 of 11,18.2%) 3.
Cefepime-susceptible dose-dependent (SDD) isolates are independently associated with 30-day mortality in multivariate analysis 3.
Two-thirds of ESBL-producing E. cloacae isolates would be incorrectly classified as susceptible to cefepime using standard breakpoints, and phenotypic ESBL detection methods are generally unreliable with these isolates 2.
Recommended Antibiotic Treatment Algorithm
For Non-Carbapenem-Resistant E. cloacae UTI
Step 1: Obtain susceptibility testing and assess resistance patterns
If ESBL-negative and cefepime MIC ≤2 μg/ml: Cefepime may be considered, though carbapenems remain safer 3, 4.
If ESBL-positive or cefepime MIC 4-8 μg/ml (SDD range): Use carbapenems as first-line therapy 3.
Step 2: Carbapenem selection for multidrug-resistant E. cloacae
Meropenem or Imipenem are effective against E. cloacae and E. aerogenes 1.
For complicated UTI: Meropenem-vaborbactam 4 g IV q8h or imipenem-cilastatin-relebactam 1.25 g IV q6h 1.
For Carbapenem-Resistant E. cloacae (CRE)
First-line options for CRE-UTI:
Ceftazidime-avibactam 2.5 g IV q8h (weak recommendation, very low quality evidence) 1.
Meropenem-vaborbactam 4 g IV q8h or imipenem-cilastatin-relebactam 1.25 g IV q6h (weak recommendation, low quality evidence) 1.
Alternative options:
Plazomicin 15 mg/kg IV q12h for complicated UTI (weak recommendation, very low quality evidence) 1.
Single-dose aminoglycoside for simple cystitis due to CRE (weak recommendation, very low quality evidence) 1.
Fosfomycin for complicated UTI without septic shock 1.
For carbapenem-resistant Enterobacter, treatment options include polymyxins, tigecycline, fosfomycin, and carbapenems used in a double carbapenem regimen 1.
Critical Pitfalls to Avoid
Do Not Rely on Standard Susceptibility Reporting
Phenotypic ESBL detection methods are unreliable for E. cloacae, leading to false susceptibility reports for cefepime 2.
Request specific MIC values rather than categorical interpretation (S/I/R), as MICs within the "susceptible" range (4-8 μg/ml) predict treatment failure 3.
Avoid Cefepime in High-Risk Scenarios
Never use cefepime for critically ill patients with E. cloacae bacteremia 3.
Avoid cefepime if prior cephalosporin exposure or hospital-acquired infection, as these increase ESBL prevalence 2, 5.
Do not use cefepime empirically in settings with high ESBL prevalence (>30% of E. cloacae isolates) 2.
Geographic and Institutional Considerations
CTX-M-type ESBLs are increasingly prevalent and confer cefepime resistance; 32% of E. cloacae isolates in some hospital studies carry blaCTX-M genes 5.
Seven out of 9 isolates carrying group 1 blaCTX-M genes were resistant or intermediate to cefepime 5.
When Cefepime May Be Acceptable
Cefepime can be considered only when ALL of the following criteria are met:
- Confirmed ESBL-negative by molecular testing 1.
- Cefepime MIC ≤2 μg/ml 3.
- Non-critically ill patient with uncomplicated UTI 6, 4.
- No prior cephalosporin exposure 2, 5.
- Community-acquired infection in low ESBL prevalence setting 2.
Even when these criteria are met, carbapenems remain the safer choice for E. cloacae infections given the mortality data 3.