Fourth-generation cephalosporins: A review of in vitro activity, pharmacokinetics, pharmacodynamics and clinical utility

Abstract

Antimicrobial resistance to antibiotics is a significant problem in the treatment of serious nosocomial infections. Antibiotic therapy is often empiric, until a specific pathogen and its antibiotic susceptibility are known, after which time adjustments in initial therapy may be made as necessary. The increasing prevalence of Gram-positive bacteria as a cause of serious nosocomial infections, together with the increasing incidence of resistance among Gram-negative bacilli, require the use of compounds with broad-spectrum antimicrobial activity. The third-generation cephalosporins are widely used for empiric therapy but their effectiveness has been limited by the increasing prevalence of strains of Enterobacteriaceae and Pseudomonas spp. that produce derepressed AmpC β-lactamases. The fourth-generation cephalosporins are structurally related to the third-generation cephalosporins but, in addition, they possess a quaternary ammonium group at the C-3′ position. They are zwitterionic compounds, which facilitates rapid penetration through the outer membrane of Gram-negative bacteria. This, together with their low affinity for clinically important β-lactamases, results in potent activity against many Gram-negative pathogens, including strains producing derepressed class I (AmpC) β-lactamase, resistant to most third-generation cephalosporins. In addition, some fourth-generation cephalosporins exhibit excellent activity in vitro against Gram-positive bacteria, including methicillin-susceptible staphylococci, penicillin-resistant pneumococci and viridans group streptococci. Among the fourth-generation cephalosporins, only cefpirome and cefepime are widely available. A review of clinical studies published to date indicates that they are potentially useful as a first line empiric therapy for serious infections, including severe community-acquired and nosocomial pneumonia, bacteremia, febrile episodes in neutropenic patients and meningitis.