Efficacy of prophylaxis with beta-lactams and beta-lactam-beta-lactamase inhibitor combinations against wound infection by methicillin-resistant and borderline-susceptible Staphylococcus aureus in a guinea pig model

Abstract

Although some beta-lactams and beta-lactam-beta-lactamase inhibitor combinations exhibit activity against methicillin-resistant Staphylococcus aureus, there remains the concern that therapeutic failures may result from the selection of resistant subpopulations. The prophylactic use of these antibiotics in clean surgery, however, may prove adequate since wound infections arise from the inoculation of small numbers of bacteria. In this clinical setting, heterogeneity in the phenotypic expression of beta-lactam resistance may facilitate antibiotic efficacy. Similarly, beta-lactamase-mediated resistance in S. aureus is dependent on inoculum size, and it may be possible to prevent infection from small inocula with relatively labile beta-lactams. To test this hypothesis, antibiotics were administered to guinea pigs as prophylaxis against infection by two methicillin-resistant strains and one borderline-susceptible strain. Following prophylaxis with sulbactam or placebo, inoculation of only a dozen or fewer bacteria had a 50% probability of creating an abscess (50% infective dose [ID50]). The efficacy of ampicillin was similar to that of cefazolin, exhibiting moderate activity against the borderline-susceptible strain (ID50s, greater than 300 bacteria) and minimal activity against the methicillin-resistant strains (ID50s, fewer than 100 bacteria). Coadministration of sulbactam with ampicillin or cefazolin yielded better results than the beta-lactam alone for five of six strain-beta-lactam combinations, including an 80-fold increase in the efficacy of ampicillin-sulbactam compared with that of ampicillin for one methicillin-resistant strain (ID50s, 2,017 and 25 bacteria, respectively). Prophylaxis with beta-lactams, especially beta-lactam-beta-lactamase inhibitor combinations, reduces the risk of wound infection by beta-lactam-resistant S. aureus.