Clinical studies of cefotaxime administered every 8 and 12 h have demonstrated comparable clinical and microbiologic success when compared to traditional 6-h regimens. This phenomena may be explained, in part, by the pharmacokinetic and pharmacodynamic properties of cefotaxime and the antimicrobially active metabolite desacetyl-cefotaxime. Although cefotaxime levels cannot be maintained above the bacterial minimum inhibitory concentration (MIC) for all infecting pathogens with extended dosing intervals, concentrations of desacetyl-cefotaxime remain above the effective concentration for a variety of organisms throughout the extended interval. Cefotaxime dosage adjustment may be accomplished in nonimmunocompromised patients with infections outside the central nervous system including uncomplicated urinary tract and lower respiratory infections. Infections caused by bacteria with MIC90 values ≤1 μg/ml usually respond to 8- or 12-h dosage intervals. Less susceptible organisms with MIC90 values between 2 and 8 μg/ml, such as Serratia marcescens, may initially require cefotaxime administered every 6 or 8 h. Extended intervals should be avoided or used cautiously in patients that are neutropenic, immunocompromised, or hypermetabolic. Upon evidence of clinical and microbiologic response, therapy may be continued with alternative stepdown therapy.