Antibiotic exposure as a risk factor for emergence of resistance: the influence of concentration

Summary, 78S 2. Introduction, 78S 3. Pharmacodynamic principles, 79S 4. Mutation and resistance, 80S 4.1 Mutation frequency and sequential mutations, 80S 4.2 Mutant prevention concentrations, 80S 4.3 Combination therapy, 81S 5. Bactericidal vs bacteriostatic activity, 81S 6. Other factors – host interaction, 82S 7. 4‐Fluoroquinolones (4FQs), 82S 8. Aminoglycosides, 82S 9. β‐Lactams, 82S 9.1 Pharmacodynamic principles, 82S 9.2 Bactericidal rate, concentration and inoculum effects, 83S 9.3 Induction of β‐lactamases, 83S 9.4 Conclusions, 83S 10. Glycopeptides, 83S 11. Macrolides and sub‐MIC concentrations, 83S 12. New directions, 83S 12.1 Bioavailability, 83S 12.2 Targeted therapy, 84S 13. Conclusions, 84S 14. References, 84S Evolution of antibiotic resistance (AR) is increasingly perceived as a major clinical problem. The use of bactericidal antibiotics may protect against this, to some extent, by eradication of the pathogen, but the borders between cidal and inhibitory activity in the patient are often blurred. In addition, there are clinical reasons why eradication of the pathogen may not always be desirable. Antibiotic dosing schedules are currently driven by the perception that T > MIC and AUIC are the main predictors of outcome for time‐dependent and concentration‐dependent antibiotics, respectively. In the context of protecting against development of resistance in the pathogen however, peak antibiotic concentration and the concept of mutant prevention concentrations may be more important. The role of post‐antibiotic and sub‐MIC effects is more conjectural. Considerations of mechanisms of resistance and their relationship to antibiotic dosing schedules will also be highlighted. Lastly, the relevance of all this to the development of resistance in the normal bacterial flora will be discussed.