Is cefuroxime effective against Citrobacter freundii complex infections?

Cefuroxime Effectiveness Against Citrobacter freundii Complex

Cefuroxime is NOT effective against Citrobacter freundii complex and should not be used for these infections. Multiple lines of evidence demonstrate that C. freundii exhibits intrinsic resistance to second-generation cephalosporins like cefuroxime, with most isolates resistant to first, second, and third-generation cephalosporins 1.

Evidence Against Cefuroxime Use

FDA Label and In Vitro Data

• While the FDA label for cefuroxime lists Citrobacter spp. as having in vitro MICs at or below susceptible breakpoints in at least 90% of isolates, it explicitly states "the efficacy of cefuroxime in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials" 2.
• This critical caveat means cefuroxime lacks proven clinical efficacy despite theoretical in vitro activity 2.

Clinical Resistance Patterns

• A comprehensive surveillance study from 1987-1998 demonstrated that C. freundii isolates were consistently resistant to second-generation cephalosporins, with susceptibility rates declining over time 1.
• The study confirmed that most C. freundii isolates showed resistance to anti-pseudomonal penicillins, first, second, and third-generation cephalosporins 1.

Recommended Treatment Options

For Susceptible Strains

Fourth-generation cephalosporins or carbapenems are the preferred agents:

• Cefepime, cefpirome, imipenem, and meropenem remain the most active agents against C. freundii 1.
• Third-generation cephalosporins like ceftriaxone have demonstrated clinical success in documented cases, including neonatal C. freundii meningitis 3.
• Cefotaxime shows remarkable potency against C. freundii, inhibiting >90% of isolates at ≤0.5 mcg/mL 4.

For Carbapenem-Resistant Strains

• Ceftazidime-avibactam or meropenem-vaborbactam should be first-line treatment for KPC-producing carbapenem-resistant Enterobacterales, which includes C. freundii 5.
• Imipenem-relebactam or cefiderocol may be considered as alternatives 5.

Critical Clinical Pitfalls

Avoid Second-Generation Cephalosporins

• Do not use cefuroxime, cefoxitin, or other second-generation cephalosporins for C. freundii infections 6, 1.
• Even when in vitro testing suggests susceptibility, clinical efficacy is unproven and resistance is common 2, 1.

Resistance Development Risk

• C. freundii can develop resistance during therapy, particularly with ceftazidime-avibactam, through KPC-2 mutations (D179Y, D176Y) 7.
• These mutations may be present in only 11% of sequencing reads, making detection challenging 7.
• The resistance phenotype can be reversible in the absence of selective pressure, complicating treatment decisions 7.

Combination Therapy Considerations

• For MBL-producing strains, use ceftazidime-avibactam plus aztreonam rather than monotherapy 5.
• Combination therapy is NOT recommended for infections susceptible to newer beta-lactam/beta-lactamase inhibitor combinations when used as monotherapy 5, 6.