1. Chapter 10: Restricting antibiotic use and optimizing dosing

2. Antibiotic resistance factors The two factors affecting antibiotic resistance: Amount of antibiotic used How we use it Antibiotic resistance correlates with human antibiotic use. Relationship between penicillin consumption and penicillin resistance in European countries. Out-patient sales are measured as defined daily dose (DDD). Misuse of antibiotics: Non-aderence to therapy (discontinue use once symptoms are eliminated) Old medications loose efficacy due to oxidation

3. Antibiotics are everywhere! Antibiotic use in humans is affected by multiple factors: Prescription vs. out-patient access Stewardship by physicians Cultural perceptions (cf. Box 10-2) Other factors: Agriculture Waste (water treatment plants, etc.)

4. Clinical resistance and resistant mutations are not the same Clinical resistance is a binary designation based on MIC values. That is, the pathogen is either resistant or not. However, within an infection, there is a distribution of mutants with varying degrees of antibiotic susceptibility. The clinical goal is to inhibit or eliminate enough of the infection that the body’s immune response can clear the rest. However, such an approach promotes the most resistant mutants.

5. Real world examples of the mutant selection window In a S. aureus infection, rabbits were treated with fluoroquinolone at concentrations inside the mutant selection window. After several days of treatment, the dominate, susceptible populations dropped by orders of magnitude, whereas growth of resistant mutants became obvious. In a few days, the resistant mutants dominated the population. Percentage (%) Antibiotic Resistance

6. Real world examples of the mutant selection window Resistance also developed during a human trial of TB patients. Patient noses where colonized by S. aureus. Rifampicin treatment for TB exposed the nasal infection to antibiotic. After 4 weeks of therapy, 53 of 58 (90%) patients had the S. aureus infection eliminated. Molecular strain typing indicated that the five remaining resistant infections were different strains, indicating that patient-to-patient transmission was not the source of resistance. Moreover, isolates from before and after rifampicin therapy indicated had identical DNA patterns, indicating resistance was acquired from the susceptible population before treatment.

7. The mutant selection window Q: Is this a good dosing strategy? Why or why not?

8. The mutant selection window Q: Is this better? Why or why not?

9. MPC is the MIC value of the most resistant mutant subpopulation

10. Combining MPC with PK/PD targets The logic used is to identify doses likely to restrict the emergence of resistance is the same as used to cure the infection, except that MPC is used as a dosing target. This approach would be straightforward if the MPC value of each isolate was some conserved multiple of MIC; however, this is not the case. As such, effective dosing based on MPC requires PK/PD measurements.

11. Bacteriostatic vs. lethal drugs Keeping antibiotic concentrations above MPC throughout therapy is suitable for bacteriostatic drugs. However, it is more stringent than necessary for drugs that kill bacteria because these antibiotics reduce the size of the mutant population. As such, the likelihood of the smaller subpopulation acquiring the resistance mutation. Fluoroquinolone concentrations restricted mutant amplification when above MPC for only 20% of the dosing interval.

12. Combination therapy can be used when MPC values are greater than MTC

13. Combination therapy restricts emergence of resistance When antibiotic resistance mutations are so protective that safe doses cannot maintain drug concentrations above MPC with a single agent, combination therapy can close the mutant selection window In this strategy, two or more compounds are sought that act independently. That is, a resistance mutant in one should not affect the other. When the concentrations of both exceed their respective MIC values, the pathogen must simultaneously acquire two resistant mutants for growth. Q: As an analogy, what is the probability of getting snake-eyes when rolling a pair of dice?

14. Pharmacokinetic mismatch If the concentration of one agent dips below its MIC value while the other agent is above its, that is the same as monotherapy wrt to the second agent.

15. Pharmacokinetic match In principle, the two compounds should have similar pharmacokinetics, rising above and falling below the the MIC at the same time.

16. Closing the mutant selection window: Consideration of resistance during drug discovery Option 1 Option 2 (preferred)