Impact of the antibiotic dosage schedule on efficacy in experimental endocarditis

Abstract

The animal model of endocarditis provides a reliable and reproducible model of acute infection and appears appropriate for studying the parameters involved in the in vivo efficacy of antibiotic therapy. The following points are discussed: (i) beta-lactam antibiotics exhibit a time-dependent bactericidal effect which explains the importance of t1/2 beta in the determination of dosing intervals and the need for large unitary doses for increasing efficacy through extending the period of serum levels greater than MIC (ii). The impact of unitary doses and dosing intervals of aminoglycosides on their in vivo synergism with beta-lactams has been investigated in Escherichia coli and streptococcal infections. Once- daily dosing of netilmicin appears very synergistic with ceftriaxone on E. coli, and the aminoglycoside has a significant dose effect. Conversely, divided doses are necessary to exhibit full synergistic effect with penicillin G on E. faecalis. Different patterns of in vivo synergism can therefore be individualized (iii). The rapid bactericidal effect of quinolones and their in vivo post-antibiotic effect allowing large intervals between doses have been investigated with ciprofloxacin (iv). The importance of t1/2 beta on the in vivo effect of glycopeptides is illustrated by data comparing teicoplanin and vancomycin. It is concluded that in vitro killing rate within 3 h is the major factor interfering with the dose interval, followed by t1/2 beta which is of major importance for those drugs whose bactericidal effect is time-dependent. These parameters appear to have a similar importance in experimental endocarditis to that in other experimental models. However, infected vegetations represent a particular focus of infection incorporating heterogeneity of antibiotic distribution, high density of bacteria and reduced metabolic activity of microorganisms. These factors may explain the lack of in vivo postantibiotic effect observed with some antibiotics, correspondingly shorter dosage intervals in endocarditis than in other types of infections and a need for high unitary doses.