Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies

Studies with fluoroquinolones have led to a general method for restricting the selection of antibiotic-resistant mutants. The strategy is based on the use of antibiotic concentrations that require cells to obtain 2 concurrent resistance mutations for growth. That concentration has been called the "mutant prevention concentration" (MPC) because no resistant colony is recovered even when >10(10) cells are plated. Resistant mutants are selected exclusively within a concentration range (mutant selection window) that extends from the point where growth inhibition begins, approximated by the minimal inhibitory concentration, up to the MPC. The dimensions of the mutant selection window can be reduced in a variety of ways, including adjustment of antibiotic structure and dosage regimens. The window can be closed to prevent mutant selection through combination therapy with > or =2 antimicrobial agents if their normalized pharmacokinetic profiles superimpose at concentrations that inhibit growth. Application of these principles could drastically restrict the selection of drug-resistant pathogens.