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 "m utant prevention concentration" (MPC) because no resistant colony is recove red even when >10(10) cells are plated. Resistant mutants are selected excl usively 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 sele ction window can be reduced in a variety of ways, including adjustment of a ntibiotic structure and dosage regimens. The window can be closed to preven t mutant selection through combination therapy with greater than or equal t o2 antimicrobial agents if their normalized pharmacokinetic profiles superi mpose at concentrations that inhibit growth. Application of these principle s could drastically restrict the selection of drug-resistant pathogens.