Paradoxical dose effect of continuously administered cloxacillin in treatment of tolerant Staphylococcus aureus endocarditis in rats

The efficacies of different doses of cloxacillin administered by continuous infusion were compared in the treatment of endocarditis in rats caused by a β-lactam tolerant strain of Staphylococcus aureus and its non-tolerant variant. In-vitro killing of the tolerant strain was maximal at a concentration near the MIC, while at higher concentrations the rate of killing gradually decreased, a paradoxical effect, not found for the non-tolerant strain. During treatment of endocarditis caused by a tolerant strain, the reduction of bacterial numbers in the infected vegetations decreased significantly with increasing doses of cloxacillin. Thus for the tolerant strain a paradoxical dose effect was also apparent in vivo