Does Cephalexin Cover Enterobacter cloacae?
No, cephalexin does not provide reliable coverage against Enterobacter cloacae and should not be used to treat infections caused by this organism.
Microbiologic Evidence Against Cephalexin Use
The FDA label for cephalexin explicitly states that it "is not active against most strains of Enterobacter spp." 1
First-generation cephalosporins like cephalexin have poor activity against Enterobacter species due to chromosomally encoded AmpC β-lactamases that mediate resistance to cephalothin, cefazolin, cefoxitin, and most penicillins 2
Guidelines specifically warn against using third-generation cephalosporins for Enterobacter species "because of the documented high frequency of resistance developing on therapy," making first-generation agents like cephalexin even more inappropriate 3
Mechanism of Resistance
Enterobacter cloacae possesses inducible chromosomal AmpC β-lactamases that can be expressed at high levels through mutation, conferring resistance to first- and second-generation cephalosporins 2
Even when an isolate initially appears susceptible, resistance can emerge during therapy through derepression of these chromosomal enzymes—a phenomenon well-documented with Enterobacter infections 2
AmpC enzymes in Enterobacter mediate resistance to cephalothin, cefazolin, cefoxitin, most penicillins, and β-lactamase inhibitor–β-lactam combinations 2
Appropriate Treatment Options for Enterobacter cloacae
For Susceptible Isolates (Non-Carbapenem-Resistant)
Carbapenems (meropenem 1 g IV three times daily, imipenem/cilastatin 0.5 g IV three times daily) are the most reliable choice for multidrug-resistant Enterobacter infections 3
Fourth-generation cephalosporin cefepime (1-2 g IV every 12 hours) may be used when the isolate is confirmed susceptible and ESBL production is absent, though resistance can still develop 3
Recent data show cefepime resistance in E. cloacae complex at approximately 10%, significantly higher than in other Enterobacteriaceae 4
For Carbapenem-Resistant Isolates
Newer β-lactam/β-lactamase inhibitor combinations show excellent activity (>95%): ceftazidime/avibactam (2.5 g IV three times daily), imipenem/relebactam, and meropenem/vaborbactam (2 g IV three times daily) 5, 4
Ceftolozane/tazobactam has lower activity (~80%) against Enterobacter species and should be reserved for Pseudomonas coverage 4
Critical Clinical Pitfalls
Never use first- or second-generation cephalosporins (including cephalexin, cefazolin, cefuroxime) for Enterobacter infections, as they lack adequate activity and resistance is nearly universal 3
Avoid third-generation cephalosporins as monotherapy due to the high frequency of resistance emergence during treatment 3
Always obtain culture and susceptibility testing before initiating therapy, as Enterobacter resistance patterns are unpredictable and vary by institution 3
Even when cefepime appears susceptible in vitro, clinical failures have been reported, particularly in patients previously exposed to third-generation cephalosporins 3
Historical Context
- Infections caused by Enterobacter cloacae resistant to even third-generation cephalosporins have been encountered for decades, with proper surgical procedures and appropriate antibiotic selection being essential to prevent rapid resistance development 6