Cefepime: a reappraisal in an era of increasing antimicrobial resistance

Abstract

Cefepime is a 'fourth-generation' cephalosporin with an in vitro extended-spectrum of activity against Gram-negative and Gram-positive pathogens. Cefepime is approved for the treatment of moderate-to-severe infections, such as pneumonia, uncomplicated and complicated urinary tract infections, skin and soft-tissue infections, intra-abdominal infections and febrile neutropenia. In this article, we provide a critical review of pharmacodynamics, clinical management, pharmacokinetics, metabolism, pharmacodynamic target analyses, clinical efficacy, safety and tolerability of cefepime after more than a decade of clinical use. Keywordscephalosporin; ESBL; extended-spectrum β-lactamase; susceptibility Cefepime is a 'fourth-generation' cephalosporin with an in vitro extended-spectrum of activity against Gram-negative and Gram-positive pathogens. Cefepime was introduced into clinical practice in 1994 and is approved for the treatment of moderate-to-severe infections, such as pneumonia, uncomplicated and complicated urinary tract infections (UTIs), skin and softtissue infections, intra-abdominal infections and febrile neutropenia.In the past 15 years, we have observed an increased occurrence of multidrug-resistant Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii and Staphylococcus aureus in the community, long-term care and hospital settings, posing serious problems in the choice of an appropriate antibiotic treatment [1,2]. In this article, we provide a critical reappraisal of cefepime after more than a decade of clinical experience. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript ChemistryThe chemical structure of cefepime is represented in Figure 1. As shown, cefepime is a zwitterionic oxymino β-lactam with an amino-thiazole side chain. Pharmacodynamics Mechanism of actionCefepime, similar to other β-lactams, inhibits bacterial cell wall biosynthesis by covalent attachment to penicillin-binding proteins (PBPs) and impedes the final transpeptidation step of peptidoglycan synthesis. Bacteria exposed to a concentration of cefepime above their MIC lyse due to the combined inhibition of PBPs and ongoing activity of cell wall autolytic enzymes (autolysis and murein hydrolases) [3].Unlike other extended-spectrum cephalosporins, the methylpyrrolidinium group of cefepime confers a zwitterionic charge that enhances bactericidal activity by rapid penetration through the porin channels in the outer membrane of Gram-negative pathogens [4,5]. In addition, in vitro studies and clinical observations suggest that cefepime may select for resistance at a lower rate than other extended-spectrum cephalo sporins [6,7]. For example, in vitro development of resistance to cefepime versus other β-lactams (i.e., cefpirome, ceftazidime, cefotaxime, piperacillin and imipenem) in P. aeruginosa was evaluated. Stepwise resistance was assessed by serial passage of colonies located nearest to the inhibition zone. The lowest frequencies of spontaneous resistance mutations were found with cefepime and i...

Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms

“…It is important to use existing antibiotics effectively whenever possible, using pharmacokinetics (PK) and pharmacodynamics (PD) analyses. Cefepime (CFP), a fourth-generation cephalosporin, is widely used to treat infections caused by GNB in both adult and pediatric patients (13,14). Several studies have shown the effectiveness and safety of CFP in treating urinary tract and lower respiratory infections in children (15,16).…”

Cephalosporin resistant bacterial strains isolated from respiratory infections

“…Keywords: cephalosporins, resistance, respiratory, infections in ambulatory care, but also parenterally, as an alternative to the amoxicillin -clavulanic acid or amoxicillin -sulbactam combinations [3,4]. It is often the case that the infectious agent is not isolated, hence no antibiogram is performed.…”

In Vivo Evolution of CMY-2 to CMY-33 β-Lactamase in Escherichia coli Sequence Type 131: Characterization of an Acquired Extended-Spectrum AmpC Conferring Resistance to Cefepime

“…In general, ESBLs are inhibited by the commercially available ␤-lactamase inhibitors but hydrolyze well the fourth-generation cephalosporin cefepime (FEP). On the other hand, AmpCs are not inhibited by inhibitors and do not hydrolyze FEP (1,(3)(4)(5). Therefore, FEP is suggested for the treatment of infections caused by AmpC producers (6)(7)(8).…”