INTERPLAY OF CELL-WALL BARRIER AND BETA-LACTAMASE ACTIVITY DETERMINES HIGH-RESISTANCE TO BETA-LACTAM ANTIBIOTICS IN MYCOBACTERIUM-CHELONAE

We calculated the target access index, which reflects the probability that a drug will reach its target at an effective concentration, and the predictive MICs of cephaloridine, cephalothin, and cefazolin for Mycobacterium chelonae from the drug concentrations inhibiting the binding of benzylpenicillin to penicillin-binding proteins, the permeability coefficients, and the beta-lactamase properties. Despite a low level of beta-lactamase activity and because of a very effective permeability barrier, the target access indices were very low, e.g., 100 times lower than for penicillinase-producing Escherichia coli. The predicted MICs were within one to three twofold dilutions of the experimentally determined values (which ranged between 512 and greater-than-or-equal-to 2,048-mu-g/ml). These results demonstrate that the interplay of the cell wall barrier and beta-lactamase activity determines high resistance of M. chelonae to beta-lactam antibiotics.