Indications
Cefepime is a broad-spectrum fourth-generation cephalosporin antibiotic primarily indicated for the treatment of pneumonia caused by susceptible bacterial strains. It is also widely used for empirical therapy in febrile neutropenic patients. In adults, cefepime addresses both uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and complicated intra-abdominal infections when combined with metronidazole, all due to susceptible bacterial agents. Furthermore, cefepime, in conjunction with enmetazobactam, is effective in treating complicated urinary tract infections.
Pharmacodynamics
This antibiotic exhibits significant activity against a variety of Gram-negative and Gram-positive bacteria. Its Gram-negative targets include Enterobacter species, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa. Among Gram-positive bacteria, it is effective against methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Viridans group streptococci. Cefepime distinguishes itself from third-generation cephalosporins with enhanced Gram-negative coverage and notable stability against hydrolysis by plasmid- and chromosome-mediated beta-lactamases. Additionally, it is a poor inducer of type 1 beta-lactamases, offering an advantage in treating infections resistant to third-generation cephalosporins. Its time-dependent antibacterial activity is supported by studies in animal models showing that efficacy correlates with the time plasma concentration exceeds the minimum inhibitory concentration (MIC) of pathogens. Cefepime's ability to penetrate the inflamed blood-brain barrier is noteworthy, although its interference with γ-aminobutyric acid (GABA) pathways can result in some neurotoxic side effects.
Absorption
Upon administration, cefepime displays different pharmacokinetic profiles depending on the route. In a study involving healthy adult male volunteers given intravenous doses of 500 mg, 1 g, and 2 g, the peak plasma concentrations (Cmax) observed were 39.1, 81.7, and 163.9 μg/mL, respectively, with respective AUC values of 70.8, 148.5, and 284.8 h·μg/mL. Intramuscular administration of the same doses resulted in lower peak plasma levels of 13.9, 29.6, and 57.5 μg/mL, and corresponding AUC values of 60, 137, and 262 h·μg/mL, with time to peak concentration (Tmax) occurring around 1.4, 1.6, and 1.5 hours. Cefepime does not accumulate in the body when administered in clinically relevant doses over a nine-day period, and it demonstrates linear pharmacokinetics between doses of 250 mg and 2 g. In pediatric patients receiving an intramuscular dose of 50 mg/kg, the absolute bioavailability was recorded at 82.3%.
Metabolism
Cefepime undergoes minimal hepatic metabolism, with less than 1% being metabolized in the liver. Its primary metabolic pathway involves conversion to N-methylpyrrolidine (NMP), followed by rapid oxidation to produce a more stable compound, NMP-N-oxide, which is the predominant metabolite of cefepime. Minor metabolites include NMP and the 7-epimer of cefepime. The oxidation of NMP to NMP-N-oxide is likely mediated by flavin-containing mixed-function oxygenase.
Mechanism of Action
Cefepime operates as a bactericidal cephalosporin, sharing a mode of action with other beta-lactam antibiotics. It effectively targets bacterial cell wall synthesis by binding to and inhibiting transpeptidases, specifically penicillin-binding proteins (PBPs), which play a crucial role in the final stages of synthesizing the peptidoglycan layer. This inhibition leads to the lysis and subsequent death of susceptible microorganisms. Cefepime exhibits a broad spectrum of in vitro activity, encompassing both Gram-positive and Gram-negative bacteria. It demonstrates a strong affinity for PBP-3 and PBP-1 in Escherichia coli and Pseudomonas aeruginosa, as well as PBP-2 in Escherichia coli and Enterobacter cloacae.
