IMPORTANCE OF PENICILLINASE PRODUCTION FOR ACTIVITY OF PENICILLIN ALONE OR IN COMBINATION WITH SULBACTAM IN EXPERIMENTAL ENDOCARDITIS DUE TO METHICILLIN-RESISTANT STAPHYLOCOCCUS-AUREUS

The activity of penicillin, alone and in combination with sulbactam, a gainst a heterogeneously methicillin-resistant, penicillinase-producin g clinical isolate of Staphylococcus aureus and its penicillinase-nega tive derivative was investigated in vitro and in a rabbit experimental endocarditis model. Penicillin was significantly more effective than vancomycin against the penicillinase-negative derivative in vivo (P < 0.001), and it sterilized 25% of the vegetations. The combination of p enicillin and sulbactam exhibited an in vivo synergistic effect on the penicillinase-producing strain (P < 0.01) but did not produce any adv antage over treatment with vancomycin, even when a high dose of sulbac tam was used (100 mg/kg of body weight every 6 h). This combination wa s significantly less effective against the penicillinase-producing str ain than was penicillin alone against the penicillinase-negative deriv ative (P < 0.03). In addition, the most resistant subpopulation of the surviving bacteria, which grew on agar containing 16 mu g of methicil lin per ml, was detected in 5 of 6 animals treated with penicillin and a high dose of sulbactam against the penicillinase-producing strain c ompared with only 1 of 12 animals treated with penicillin alone agains t the penicillinase-negative derivative (P < 0.01). We conclude that p enicillin is highly effective against penicillinase-negative methicill in-resistant S. aureus and that penicillinase production, rather than methicillin resistance, appears to be the limiting factor for the acti vity of the penicillin-sulbactam combination against penicillinase-pro ducing, methicillin-resistant S. aureus.