Efficacy of oxacillin and ampicillin-sulbactam combination in experimental endocarditis caused by beta-lactamase-hyperproducing Staphylococcus aureus

Abstract

Optimal therapy of infections caused by borderline oxacillin-susceptible, 3-lactamase-hyperproducing Staphylococcus aureus has not been established. We used a rat model of aortic valve endocarditis to examine efficacies of antibiotic regimens against a borderline oxacillin-susceptible strain as compared with a fully susceptible S. aureus strain. Animals were treated with oxacillin alone or in combination with sulbactam or with ampicillin-sulbactam combinations at two dose levels. Infections caused by the borderline susceptible and fully susceptible strains responded equally wel to oxacillin alone, with residual bacterial titers in vegetations falling to 4.8 ± 1.6 and 4.4 ± 1.7 (mean ± standard deviation) log,0 CFU/g, respectively. Addition of sulbactam to oxacillin (1:2) did not enhance the efficacy of oxacillin against either strain in the animal model. A high-dose regimen of ampicillin-sulbactam (2:1) yielding mean (+ standard deviation) levels in serum of 16.8 ± 7.4 and 9.5 ± 1.1 ,ug/ml, respectively, proved equally effective against both strains (bacterial titers, 6.6 log1o CFU/g).However, at lower doses (8.3 + 2.6 and 5.9 ± 2.4 ,ug/ml), the combination showed greater efficacy against the fully susceptible strain, with residual titers of 7.1 + 2.0 versus 9.0 + 1.6 log1o CFU/g (P < 0.05). In vitro studies revealed that the ,B-lactamase inhibitor sulbactam was also a potent inducer of staphylococcal P-lactamase at clinically relevant concentrations. Based on this short-term in vivo therapy study, oxacillin would be predicted to be clinically effective in the therapy of infections caused by borderline oxacillin-susceptible strains of S. aureus, while the combination of ampicillin with sulbactam appears to be inferior to oxacillin alone against such infections.In 1986, McDougal and Thornsberry (8) described isolates of Staphylococcus aureus displaying borderline susceptibility to antistaphylococcal penicillins. These strains were inhibited by methicillin and oxacillin at concentrations of 4 and 2 p,g/ml, respectively, and were characterized by the production of large amounts of P-lactamase. Addition of a f-lactamase inhibitor such as clavulanic acid or sulbactam restored activities of the penicillins to levels which inhibit fully methicillin-susceptible S. aureus strains. Such strains appear to be distinct from those demonstrating chromosomally mediated intrinsic ,-lactamase resistance, which has been associated with the presence of a low-affinity penicillinbinding protein, termed PBP 2a or 2' (5). To differentiate borderline susceptible strains from the latter group of intrinsically resistant organisms further, they have also been called acquired-resistant strains (7,8). Whether infections caused by borderline susceptible staphylococcal isolates would respond to ,B-lactams as well as infections caused by fully susceptible strains, or whether these isolates should be considered the same as intrinsically resistant strains for clinical and therapeutic purposes, is unclear and remains to be determined.In this study...

Activity of ampicillin-sulbactam and oxacillin in experimental endocarditis caused by beta-lactamase-hyperproducing Staphylococcus aureus

“…We speculated that these results may have been influenced to a large degree by the striking ability of sulbactam to induce 1-lactamase production in BOSSA strains and to a much lower extent in OSSA strains, a phenomenon which we demonstrated in vitro (12). This hypothesis was supported by the observation that addition of sulbactam to oxacillin tended to antagonize the in vivo activity of the latter against both strains, although the differences observed did not reach statistical significance.…”

“…Inhibition of such isolates required methicillin and oxacillin concentrations of 4 and 2 ,ug/ml, respectively, but full susceptibility could be restored by combination of an antistaphylococcal penicillin with a ,B-lactamase inhibitor such as clavulanic acid or sulbactam. In a previous study, we examined the in vivo activities of ampicillin-sulbactam and oxacillin in a rat model of experimental endocarditis caused by such a borderline oxacillin-susceptible S. aureus (BOSSA) strain in comparison with endocarditis caused by a fully oxacillin-susceptible S. aureus (OSSA) strain (12). We found that oxacillin was equally effective against BOSSA and OSSA strains, reducing bacterial densities in cardiac vegetations from more than 1010 CFU/g to between io4 and io CFU/g.…”

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

“…BSSA strains generally belong to phage group 94/96, possess a unique 17.2-kb plasmid, and produce generous amounts of the type A variant of staphylococcal P-lactamase (4,28). Infections by these strains generally are responsive to therapy with the penicillinase-resistant penicillins (25,37). BSSA strains exhibit very rapid degradation of ampicillin ( …”

Analysis of Borderline Oxacillin-Resistant Staphylococcus aureus (BORSA) Strains Isolated in Tunisia

“…It has been proposed by some authors that there is no apparent reason for BORSA strains to be considered resistant to all other ␤-lactams (5,18,22). Therefore, infections caused by these strains can probably be safely and effectively treated with ␤-lactam antibiotics, including cloxacillin, or with the use of a ␤-lactam-␤-lactamase inhibitor combination (16,26,27). However, other authors have demonstrated that oxacillin has not been effective against BORSA strains (8,23).…”