In vitro and in vivo activity of amoxicillin and penicillin G alone or combined with a penicillinase inhibitor (clavulanate) were tested against five isogenic pairs of methicillin-resistant Staphylococcus aureus (MRSA) producing or not producing penicillinase. Loss of the penicillinase plasmid caused an eight times or greater reduction in the MICs of amoxicillin and penicillin G (from ⩾64 to 8 µg/ml), but not of the penicillinase-resistant drugs methicillin and cloxacillin (⩾64 µg/ml). This difference in antibacterial effectiveness correlated with a more than 10 times greater penicillin-binding protein 2a affinity of amoxicillin and penicillin G than of methicillin and a ⩾90% successful amoxicillin treatment of experimental endocarditis due to penicillinasenegative MRSA compared with cloxacillin, which was totally ineffective (P < .001). Amoxicillin was also effective against penicillinase-producing parent MRSA, provided it was combined with clavulanate. Penicillinase-sensitive β-lactam antibiotics plus penicillinase inhibitors might offer a rational alternative treatment for MRSA infection
