Keeping Concentrations Above MPC Restricts Mutant Amplification

By definition, antibiotic concentrations above MIC block susceptible cell growth; by analogy, concentrations above MPC should block mutant subpopulation growth, because MPC is the MIC of the least susceptible mutant subpopulation.^111,209 Experimentally, when antibiotic concentrations are kept above MPC throughout treatment, mutant subpopulation amplification is inhibited with cultured S. pneumoniae and fluoroquinolones,¹¹⁵ with cultured S. aureus and several antibiotics,^114,210 and with an S. aureus infection of rabbits treated with a fluoroquinolone.¹⁰⁵ These data support MPC serving as a drug concentration threshold for restricting emergence of resistance.¹¹⁰

Keeping antibiotic concentrations above MPC throughout therapy is suitable for bacteriostatic antibiotics. However, it is more stringent than necessary for antibiotics that kill cells having a resistance mutation, because these antibiotics reduce the size of the mutant subpopulation. A smaller subpopulation has a lower chance of acquiring the second resistance mutation needed for growth in the presence of antibiotic at the MPC. An experimental demonstration of this principle is seen during infection of rabbits with S. aureus. Fluoroquinolone concentrations restricted mutant amplification when above MPC for only 20% of the dosing interval.¹⁰⁵ At present, the effect of lethal activity on emergence of resistance must be determined empirically for each antibiotic-pathogen combination.