Cefotaxime optimal dosage in adult patients. A reappraisal

Cefotaxime, a third generation cephalosporin, is used throughout the world over a wide range of doses. The purpose of this paper is to discuss the rationale for determination of the optimal dosage and of adequate modes of administration. Among the factors determining in vivo activity, the most important are: (1) the time dependence of the antibacterial effect of cephalosporins, (2) the limited effect of increasing the drug concentration in contact with the bacteria and (3) the absence of a significant post-antibiotic effect. Combined with the rather short elimination half-life of cefotaxime, these factors argue for the use of a unitary dose of 1g in adult patients and for a 6- or 8-hour interval between doses. Information obtained from various animal models of infection are discussed. Clinical and bacteriological studies published in the international literature report a high rate of cure (between 80 and 100%) according to the type of infection and to the criteria of efficacy, with daily doses ranging from 2 to 4g bid or qid. The results obtained with the lowest doses are detailed, particularly for infections permitting the use of a low dosage. The necessity for increasing the dose is discussed in the following situations: (1) in specific infections requiring high local drug concentrations such as meningitis and endocarditis, (2) against micro-organisms exhibiting moderate susceptibility to cefotaxime (MIC greater than or equal to 1 mg/L) and (3) in immunocompromised patients. It is now well established that third generation cephalosporins have to be combined with other antimicrobial agents (e.g. aminoglycosides) for the treatment of patients with infections caused by bacteria able to become resistant. For susceptible strains, it has not been established that a synergistic effect of cefotaxime with another agent allows a reduction of the dosage of each member of the combination.