Why is cefepime not recommended as first-line treatment for a urinary tract infection caused by gram-negative bacilli?

Cefepime is Not Recommended for UTIs Caused by Gram-Negative Bacilli

Cefepime should not be used for urinary tract infections caused by gram-negative bacilli, particularly those producing extended-spectrum β-lactamases (ESBLs), due to very low certainty of evidence and a conditional recommendation against its use by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). 1

Reasons for Avoiding Cefepime in UTIs

Efficacy Concerns

• The ESCMID specifically suggests against using cefepime for third-generation cephalosporin-resistant Enterobacterales (3GCephRE) infections with a conditional recommendation based on very low certainty evidence 2
• Studies show variable results depending on resistance mechanisms, with higher mortality sometimes reported with cefepime for ESBL infections 2
• Even when isolates appear susceptible to cefepime in vitro, clinical outcomes may be inferior:
  • A 2023 study found that empiric cefepime was associated with longer time to clinical stability compared to meropenem for bloodstream infections caused by ceftriaxone-resistant Enterobacterales, even when the isolates were cefepime-susceptible 3

MIC-Dependent Failure

• Higher mortality has been observed with cefepime when minimum inhibitory concentrations (MICs) are elevated, even within the susceptible dose-dependent category 2
• In one study, mortality was higher with cefepime in a small subgroup of patients with higher cefepime MICs (5 of 7 versus 2 of 11, p=0.045) 2

Better Alternatives Available

• For severe UTIs or bacteremia, carbapenems (imipenem or meropenem) are strongly recommended with moderate certainty evidence 2, 1
• For non-severe UTIs, multiple superior options exist:
  • Piperacillin-tazobactam, amoxicillin-clavulanic acid, or quinolones (if susceptible) are conditionally recommended 2, 1
  • Cotrimoxazole is recommended for non-severe complicated UTI 1
  • Aminoglycosides (for short durations) or IV fosfomycin are recommended for complicated UTI without septic shock 2, 1

Treatment Algorithm for UTIs Caused by Gram-Negative Bacilli

For Severe UTIs/Bacteremia:

1. First choice: Carbapenems (imipenem or meropenem) 2, 1
2. Alternative for non-septic shock: Ertapenem 2, 1

For Complicated UTIs without Septic Shock:

1. First choice: IV fosfomycin (with caution in patients with heart failure risk) 1
2. Alternative: Aminoglycosides for short-duration therapy (<7 days) 1
3. Other options: Beta-lactam/beta-lactamase inhibitor combinations (BLBLIs) like piperacillin-tazobactam 1

For Non-Severe/Uncomplicated UTIs:

1. First choices: Piperacillin-tazobactam, amoxicillin-clavulanic acid, or quinolones (if susceptible) 2, 1
2. Alternative: Cotrimoxazole (if susceptible) 1
3. For uncomplicated lower UTI: Fosfomycin trometamol 3g single oral dose 1

Common Pitfalls to Avoid

• Relying on in vitro susceptibility alone: Cefepime may appear active in vitro against some ESBL-producing organisms, but clinical outcomes may still be inferior 3
• Ignoring MIC values: Even when isolates are technically susceptible to cefepime, elevated MICs within the susceptible range correlate with worse outcomes 2
• Prolonged aminoglycoside use: Risk of nephrotoxicity increases after 7 days of aminoglycoside therapy 1
• Overlooking antibiotic stewardship: Reserve carbapenems when possible to prevent further resistance development 1

Special Considerations

• Step-down therapy: Once patients are stabilized, consider switching to oral agents based on susceptibility testing 2, 1
• Heart failure risk: Avoid IV fosfomycin in patients with predisposing factors for heart failure due to an 8.6% risk 1
• Renal impairment: Adjust dosing of aminoglycosides and monitor renal function 1

While older studies suggested potential utility of cefepime in UTIs 4, 5, current guidelines and more recent evidence strongly support avoiding cefepime for infections caused by ESBL-producing or third-generation cephalosporin-resistant gram-negative bacilli 2, 1, 3.