Borderline susceptibility to methicillin in Staphylococcus aureus: a new mechanism of resistance?

Staphylococcus aureus strains with borderline levels of susceptibility or resistance to antistaphylococcal penicillinase-resistant penicillins (PRPs) were initially reported as neither heteroresistant nor multiply resistant organisms, producing large amounts of beta-lactamase, and becoming fully susceptible to PRPs in the presence of beta-lactamase inhibitors. This borderline susceptibility or low-level resistance was suggested to be due to beta-lactamase hyperproduction: according to this hypothesis, the staphylococcal beta-lactamase, when hyperproduced, would succeed in partially hydrolyzing methicillin and related PRPs. However, later studies demonstrated that borderline PRP susceptibility cannot be explained soley on this basis, beta-lactamase hyperproduction being neither sufficient nor necessary to determine the borderline phenotype. Intrinsic mechanisms have also been reported to be associated with some borderline PRP susceptible S. aureus strains. The more recent discovery of a PRP-hydrolyzing beta-lactamase (methicillinase) produced, in addition to the conventional penicillinase, by borderline S. aureus strains suggests that this second, more specific beta-lactamase is more likely to be responsible for the borderline phenotype than an increased amount of the penicillinase. The slow kinetics of PRP hydrolysis by methicillinase is consistent with its association with reduced susceptibility rather than true resistance to PRPs. The combined effect of methicillinase plus penicillinase on some common substrates might explain the increased beta-lactamase activity often observed in borderline S. aureus strains.