Vol. 36, No. 12
0066-4804/92/122577-07$02.00/0 Copyright © 1992, American Society for Microbiology
Continuous Infusion of 13-Lactam Antibiotics
WILLIAM A. CRAIG' 2.3* AND STEVEN C. EBERT3V4 Department of Medicine1 and School of Pharmacy,3 University of Wisconsin, Madison, Wisconsin 53792; Department of Medicine,William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 537052; and Department of Pharmacy, Meriter Hospital, Madison, Wisconsin 537154
Over 40 years ago, several investigators attempted to establish the optimal dosage regimens of penicillin G for the treatment of infections caused by common gram-positive bacteria. In a variety of streptococcal infection models inanimals, they showed that the total dose of drug required to cure infection was significantly less if the drug was administered in multiple doses at frequent intervals than if it was administered as a single dose or as multiple doses at widely spaced intervals (18, 20, 37). The aggregate time that active penicillin concentrations were maintained, rather than the magnitude of the concentration,appeared to be the important determinant of efficacy against these infections. As a result, repository formulations of penicillin G, designed to maintain continuous levels of the drug in plasma and tissues for protracted time periods, were used extensively in the early years of penicillin therapy. Studies with penicillin also demonstrated that removal of staphylococci and streptococci from penicillinexposure is not followed by immediate bacterial regrowth (19, 21, 59). Rather, a lag phase or recovery period, which can last for several hours, is observed. This persistent suppression of bacterial growth supported the development of the intermittent dosing regimens for ,B-lactam antibiotics that are currently used in clinical practice. The goal of a dosage regimen for each individual 3-lactam is toprevent the drug-free interval between doses from being long enough for the bacterial pathogen to resume growth (17). Although these intermittent dosage regimens seem to work reasonably well in clinical practice, we do not know whether we are overdosing or even underdosing patients with most drugs. The increasing number of immunocompromised patients and the rising incidence of gram-negativebacillary infections have added impetus to the development of dosage regimens that will achieve the most benefit with the least amount of drug. During the past decade, many of the issues about dosing regimens raised by the early penicillin studies have been investigated for newer antimicrobial agents and for pathogens such as gram-negative bacilli. The results of those studies as well as theavailability of improved intravenous drug delivery systems for both the hospital and the outpatient settings have rekindled interest in the continuous infusion of ,-lactam antibiotics. This minireview summarizes current knowledge on the pharmacodynamic properties of 13-lactam antibiotics and their pharmacokinetics, therapeutic efficacies, and adverse effects when administered by continuous intravenousinfusion.
RATIONALE FOR CONTINUOUS INFUSION OF 13-LACTAM ANTIBIOTICS
The pharmacodynamic properties of antimicrobial agents refer to the relationships between drug concentration and drug activity or toxicity. The major pharmacodynamic parameters used to characterize antimicrobial activity are the MIC and MBC. However, the MIC and MBC reflect only the net drug effects over a fixed time ofincubation. The time course of antimicrobial activity is more accurately described by parameters such as the pattern of bactericidal activity and the presence or absence of persistent inhibitory effects on growth following drug exposure (11, 27, 75). It is these latter characteristics of ,-lactam antibiotics that provide most of the rationale for continuous infusion of these drugs. Bactericidal...