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Cefepime

Cefepime: A Fourth-Generation Cephalosporin in the Fight Against Resistant Infections

Introduction

The rising challenge of antibiotic resistance has pushed the medical field to rely on more potent and broad-spectrum antibiotics. Among these, Cefepime, a fourth-generation cephalosporin, stands out for its broad antibacterial spectrum, including activity against many resistant Gram-negative organisms. Approved by the FDA in 1996, Cefepime has since become a mainstay in hospitals worldwide, particularly for serious infections and as empirical therapy in high-risk patients.

Overview of Cefepime

  • Class: Fourth-generation cephalosporin

  • Brand Names: Maxipime, generics

  • Route of Administration: Intravenous (IV) or intramuscular (IM)

  • Chemical Formula: C19H24N6O5S2

  • Molecular Weight: 480.56 g/mol

Cefepime was developed to overcome some of the limitations of earlier cephalosporins, particularly their susceptibility to beta-lactamase-mediated resistance.

Mechanism of Action

Like all beta-lactam antibiotics, Cefepime exerts its bactericidal effect by inhibiting bacterial cell wall synthesis. It binds to penicillin-binding proteins (PBPs), preventing the cross-linking of the peptidoglycan layer, which leads to cell lysis and death.

Cefepime is particularly resistant to many beta-lactamases, including AmpC-type enzymes that often render third-generation cephalosporins like cefotaxime or ceftazidime ineffective.

Spectrum of Activity

Cefepime has a broad spectrum, covering both Gram-positive and Gram-negative organisms, including many drug-resistant strains.

Gram-Positive Bacteria

  • Staphylococcus aureus (MSSA)

  • Streptococcus pneumoniae

  • Streptococcus pyogenes

  • Enterococcus faecalis (limited activity)

Gram-Negative Bacteria

  • Escherichia coli

  • Klebsiella pneumoniae

  • Enterobacter cloacae

  • Citrobacter freundii

  • Serratia marcescens

  • Proteus mirabilis

  • Pseudomonas aeruginosa

  • Haemophilus influenzae

  • Neisseria gonorrhoeae

Anaerobes

  • Limited coverage; not reliable for anaerobic infections

Cefepime’s robust Pseudomonas activity is one of its defining features and a key reason for its use in intensive care units.

Pharmacokinetics and Pharmacodynamics

Parameter Value
Bioavailability (IV/IM) 100%
Peak Plasma Level 30–60 minutes (IV)
Half-Life ~2 hours
Protein Binding ~20%
Elimination Renal (85% unchanged)
Volume of Distribution ~18 L

Cefepime demonstrates time-dependent killing, and maintaining serum concentrations above the MIC is crucial for efficacy. Renal excretion is the primary route of elimination, making dosage adjustment essential in renal impairment.

Formulations and Dosage

Cefepime is available as a powder for injection that can be reconstituted for IV or IM use.

Typical Adult Dosing

  • 1–2 g IV every 8–12 hours

  • For Pseudomonas infections or neutropenic fever: 2 g IV every 8 hours

Pediatric Dosing

  • 50 mg/kg every 8–12 hours

  • Maximum dose: 6 g/day

Dosage must be adjusted in patients with renal dysfunction, as accumulation can increase the risk of neurotoxicity.

Clinical Indications

Cefepime is approved and widely used for several serious bacterial infections, especially in hospital settings:

1. Febrile Neutropenia

  • Empiric monotherapy

  • Broad Gram-negative and Pseudomonas coverage

2. Hospital-Acquired Pneumonia (HAP)

  • Effective against nosocomial pathogens, including P. aeruginosa

3. Complicated Intra-Abdominal Infections (in combination with metronidazole)

  • Covers aerobic organisms; metronidazole adds anaerobic coverage

4. Urinary Tract Infections

  • Especially complicated or catheter-associated UTIs

5. Skin and Soft Tissue Infections

  • Particularly in diabetic foot infections or postoperative wounds

6. Sepsis and Bacteremia

  • Empirical treatment of bloodstream infections, especially if multi-drug resistant organisms are suspected

7. Meningitis

  • Penetrates the cerebrospinal fluid (CSF) effectively

  • Used in cases involving Gram-negative organisms

Clinical Efficacy

Numerous clinical trials have confirmed Cefepime’s efficacy across multiple infection types. Key findings include:

  • Comparable or superior to ceftazidime in treating Gram-negative infections

  • Effective as monotherapy in febrile neutropenia, reducing the need for combination therapy

  • Useful in empiric treatment while awaiting culture results due to its wide coverage

Adverse Effects

Cefepime is generally well tolerated, though side effects may occur, particularly in patients with renal impairment.

Common Side Effects

  • Rash

  • Diarrhea

  • Injection site reactions

  • Nausea

Serious Adverse Effects

  • Neurotoxicity: Encephalopathy, confusion, seizures—especially in renal dysfunction

  • Clostridioides difficile-associated diarrhea (CDAD)

  • Hypersensitivity reactions, including anaphylaxis

  • Hematologic: Thrombocytopenia, leukopenia (rare)

Proper dosing adjustments in renal impairment are crucial to avoid neurotoxicity, which is dose-dependent.

Drug Interactions

Cefepime has minimal drug-drug interactions. However:

  • Loop diuretics and aminoglycosides may increase the risk of nephrotoxicity when used concurrently.

  • Probenecid can reduce renal excretion of Cefepime, though not commonly co-prescribed.

Use in Special Populations

Renal Impairment

  • Dose reduction required

  • Monitor closely for signs of CNS toxicity

Hepatic Impairment

  • No dose adjustment necessary

Pregnancy and Lactation

  • Pregnancy Category B

  • Appears safe; minimal data in lactation but low milk transfer

Geriatrics

  • Increased risk of neurotoxicity; careful dosing required

Resistance Patterns and Mechanisms

While Cefepime is more stable against AmpC beta-lactamases, resistance is emerging, especially in ESBL-producing and carbapenem-resistant organisms.

Mechanisms of Resistance

  • Beta-lactamase production (ESBLs, AmpC, carbapenemases)

  • Porin loss or modification

  • Efflux pumps

Resistant Organisms

  • ESBL-producing Enterobacteriaceae

  • Acinetobacter baumannii

  • Stenotrophomonas maltophilia

  • Carbapenemase-producing Klebsiella pneumoniae

Despite resistance concerns, Cefepime retains activity against many multidrug-resistant Gram-negative bacteria, making it a valuable tool in empirical therapy.

Cefepime in Antimicrobial Stewardship

Due to its broad-spectrum nature, Cefepime is included in many hospital stewardship programs with caution. Guidelines recommend:

  • De-escalation once pathogen sensitivity is known

  • Avoidance in uncomplicated or community-acquired infections unless necessary

  • Renal dosing vigilance to avoid toxicity

Overuse contributes to selection pressure and resistance, so stewardship policies encourage judicious use of Cefepime.

Comparative Table: Cefepime vs. Other Cephalosporins

Feature Cefepime Ceftazidime Ceftriaxone Cefotaxime
Generation 4th 3rd 3rd 3rd
Pseudomonas Coverage Yes Yes No No
Beta-Lactamase Stability High Moderate Low Low
CNS Penetration Good Moderate Good Good
Dosing Frequency Q8–12h Q8h Q24h Q8h

Role in Empirical Therapy

Cefepime is a popular choice in empirical regimens for:

  • Neutropenic fever

  • Sepsis of unknown origin

  • Suspected Pseudomonas infections

  • Nosocomial pneumonia

In many cases, Cefepime serves as the “go-to” agent until cultures identify the causative organism and narrow-spectrum therapy is feasible.

Recent Developments and Research

Cefepime is being studied in combination with beta-lactamase inhibitors like zidebactam and taniborbactam to enhance its utility against resistant pathogens.

Fixed-Dose Combinations Under Development

  • Cefepime-taniborbactam

  • Cefepime-zidebactam

These combinations aim to combat ESBLs and even some carbapenemase-producing strains, potentially extending Cefepime’s utility in the coming years.

Patient and Healthcare Provider Considerations

  • Monitor renal function closely, especially in older adults

  • Be alert for neurological symptoms during prolonged use

  • Educate on completing the course even if symptoms improve

  • Use microbiologic culture and sensitivity testing to guide therapy

Conclusion

Cefepime is a powerful fourth-generation cephalosporin with a broad spectrum of action, excellent stability against beta-lactamases, and proven efficacy in a wide range of serious infections. Its place in modern medicine is secure, particularly for hospital-acquired infections, neutropenic fever, and sepsis.