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.

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