In an adult without β‑lactam allergy, when should I use cefepime versus meropenem for serious Gram‑negative infections such as hospital‑acquired pneumonia, urinary tract infection, or intra‑abdominal infection?

Cefepime vs Meropenem for Serious Gram-Negative Infections

For serious Gram-negative infections in hospitalized adults, meropenem should be preferred over cefepime when treating critically ill patients with sepsis/septic shock, healthcare-associated infections, known ESBL colonization, recent antibiotic exposure, or suspected multidrug-resistant pathogens including Pseudomonas aeruginosa, Enterobacter species, or ESBL-producing organisms. 1, 2

Clinical Decision Algorithm

Use Meropenem (First-Line) When:

• Critically ill patients with sepsis or septic shock requiring empiric broad-spectrum coverage 1
• Healthcare-associated infections (onset >48 hours after admission or ≤30 days post-surgery) 1
• Known colonization with ESBL-producing Enterobacteriaceae within the last 3 months 1, 3
• Recent antibiotic exposure (third-generation cephalosporins, fluoroquinolones, or piperacillin-tazobactam in the last 3 months) 3
• Suspected or documented ESBL-producing organisms (E. coli, Klebsiella pneumoniae) 2
• AmpC-hyperproducing organisms (Enterobacter, Citrobacter, Serratia marcescens) that may develop resistance during cephalosporin therapy 1
• Hospital-acquired or ventilator-associated pneumonia with risk factors for MDR pathogens 1
• Complicated intra-abdominal infections requiring anaerobic coverage (meropenem provides complete anaerobic coverage without metronidazole) 4, 1
• Febrile neutropenia in high-risk patients 5, 6

Cefepime May Be Acceptable When:

• Community-acquired infections in non-critically ill patients without recent healthcare exposure 4
• Fully susceptible organisms documented on culture (E. coli, Proteus mirabilis, Klebsiella species without ESBL production) 1
• Uncomplicated urinary tract infections or mild-to-moderate infections in patients without sepsis 7, 8
• Community-acquired pneumonia of moderate severity without risk factors for resistance 8

Key Evidence Supporting Meropenem Superiority

The IDSA guidelines explicitly state that MDR gram-negative organisms treated with cephalosporins (including cefepime) have worse clinical outcomes compared to carbapenems, even when organisms appear susceptible in vitro. 1 This is particularly critical because treatment failure rates with cephalosporins for ESBL-producing organisms can reach 20-40% despite in vitro susceptibility. 1

• Meropenem maintains 96.0% susceptibility against all gram-negative isolates in U.S. surveillance programs 1
• Gram-negative bacteremias carry 18% mortality compared to 5% for gram-positive organisms, making appropriate initial therapy critical 1
• For ESBL-producing infections, meropenem 1g IV every 8 hours is recommended as first-line monotherapy in critically ill patients 2

Spectrum Differences That Matter Clinically

Meropenem Advantages:

• Complete anaerobic coverage eliminates need for metronidazole in intra-abdominal infections 4, 1
• Reliable activity against ESBL-producing Enterobacteriaceae 2, 5
• Stable against AmpC β-lactamases produced by Enterobacter, Citrobacter, and Serratia 1
• Maintained activity against many resistant strains of Pseudomonas aeruginosa 1, 5
• Lower seizure risk than imipenem, making it suitable for CNS infections 5, 6

Cefepime Limitations:

• Not reliable for ESBL-producing organisms despite potential in vitro susceptibility 4, 2
• Risk of resistance development during therapy with AmpC-hyperproducing organisms 1
• Requires addition of metronidazole for anaerobic coverage in intra-abdominal infections 4
• Should not be used for 3rd-generation cephalosporin-resistant Enterobacteriaceae 4

Dosing Recommendations

Meropenem:

• Standard: 1g IV every 8 hours 2
• Critically ill/high MIC organisms: 2g IV every 8 hours as 3-hour extended infusion 1
• Therapeutic drug monitoring recommended in critically ill patients to achieve plasma concentrations >4× MIC for ≥40% of dosing interval 1

Cefepime:

• Standard: 1-2g IV every 8-12 hours 7, 8
• Nosocomial pneumonia: 2g IV every 8 hours 8

Critical Pitfalls to Avoid

• Do not rely on cefepime for ESBL-producing organisms despite in vitro susceptibility – clinical failure rates are unacceptably high 1, 2
• Do not use cefepime empirically in healthcare-associated infections without ruling out ESBL or AmpC-hyperproducing organisms 4, 1
• Avoid extended use of cephalosporins in settings with high ESBL prevalence due to selective pressure and resistance emergence 4
• Do not use cefepime monotherapy for complicated intra-abdominal infections – requires metronidazole for anaerobic coverage 4

De-escalation Strategy

Once culture and susceptibility results are available, de-escalation from meropenem to cefepime or narrower agents is appropriate and recommended when:

• Fully susceptible organism documented without ESBL production 1
• No AmpC-hyperproducing organisms identified 1
• Clinical improvement demonstrated 4
• Source control achieved in intra-abdominal infections 4

De-escalation is associated with lower mortality rates in ICU patients and is a key antimicrobial stewardship practice. 4

Special Considerations

Intra-Abdominal Infections:

• Plasma and peritoneal concentrations of cefepime are similar, so dose increases are probably not required 4
• Increased doses of meropenem may be required to reach adequate peritoneal concentrations in severe infections 4
• Prolonged or continuous infusions of beta-lactams should be considered for critically ill patients 4

Carbapenem-Resistant Organisms:

• For carbapenem-resistant Enterobacteriaceae (CRE), newer agents like meropenem-vaborbactam, ceftazidime-avibactam, or imipenem-cilastatin-relebactam are required 4, 1
• For metallo-β-lactamase producers, cefiderocol or combination therapies may be needed 1