Should we change the recommendations related to antibiotic drug dosage/drug duration?

1. Should we change the recommendations related to antibiotic drug dosage/drug duration? Workshop on Economic Epidemiology Makerere University August, 2009 Patricia Geli Rolfhamre

2. Acknowledgements Ramanan Laxminarayan, Resources for the Future David L. Smith, Resources for the Future Simon Levin, Princeton University Michael Dunne, Advisory committee “Extending the Cure”

3. Agenda • How are antibiotic guidelines developed? • Are we basing all dosing regimens on TB experience? • How can the guidelines be improved? • Consequences v. benefit of different guidelines • Conclusions and take home message

4. A drug to cure bacterial infections Second most widespread drug after analgesics: Majority of the population will take antibiotics at some time in their lives

5. Development of drug dose/duration guidelines Relationships between drug dose/duration and therapeutic efficacy – only beginning to be understood for many antibiotics Introduction of first antibiotic for clinical use 1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s

6. Development of drug dose/duration guidelines Relationships between drug dose/duration and therapeutic efficacy – only beginning to be understood for many antibiotics Is leading to dramatic changes in drug dose/duration recommendations Then: Three smaller doses per day Now: Single large daily dose Ex: Aminoglycosides 1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s

7. Development of drug dose/duration guidelines Historically designed to achieve: - maximal treatment efficacy - minimal toxicity

8. Development of drug dose/duration guidelines Historically designed to achieve: - maximal treatment efficacy - minimal toxicity BUT... Resistance not considered!

9. Resistance comes fast... J. Davies, 1997

10. ...is still growing ICU Patients Non-ICU Patients Source: NNIS DATA, Clinics Chest Med. 20:303-315

11. The Paradox “Selective pressure comes from a combination of overuse in many parts of the world, particularly for minor infections, misuse due to lack of access to appropriate treatment and underuse due to lack of financial support to complete treatment courses” Cited from: World Health Organization (2009),  Community-Based Surveillance of Antimicrobial Use and Resistance in Resource-Constrained Settings

12. From individuals to public health: DOTS for TB Treatment and prevention of resistance in individuals = key public health measure

13. This works for TB – but is it sound for other infections?

14. When and why do we treat? 50% of all consumption for respiratory tract infections (RTI) Most common symptoms: otitis media sore throats sinusitis,...

15. Duration v. benefit of treatment Many RTI symptoms are likely to be caused by viruses, i.e. no benefit of antibiotic treatment Even if bacterial, recent clinical evidence suggests that shorter drug durations can be equally effective as longer ones For acute otitis media (middle ear infection), the second most common infection after the common cold, 3 days has been shown to be as effective as 10 days

16. S. aureus “Normal” flora 1014 -1015 bacteria (or 1-2 kg) totally in the human body S. pneumoniae H. influenzae N. meningitidis E. coli, Klebsiella Enterobacter Enterococcus faecium

17. Normal flora: Consequences • Treatment exerts selection on “innocent bystanders” • Most of the harm done by use of a drug may be on species OTHER than the target of treatment • Most of the exposure of a given • species to a given drug may be • due to treatment of OTHER • infections

18. Normal flora: Consequences Resistance is contagious! It will continue to spread even after infection has been cleared

19. How can we investigate this further?

20. Traditional pharmacokinetic/ pharmacodynamic models Pharmacokinetics: what the body does to the drug Pharmacodynamics: what the drug does to the body Our knowledge comes mostly from experimental trials Immune responses NOT considered!

21. Pharmacokinetics/ Pharmacodynamics Antibiotic concentration # Bacteria R Growth R Time

22. Emergence and selection of resistance Antibiotic concentration # Bacteria R Selection of R S Selective Window (SW) Growth R Growth S Time in SW

23. Traditional pharmacokinetic/ pharmacodynamic models Sensitive population Resistant population R S

24. Incorporating the immune response Sensitive population Sensitive population Resistant population S R S I Immune response

25. Possible pathogen dynamics Unregulated bacterial dynamics: Commensal bacteria that uses body as a habitat Regulated bacterial dynamics: Bacteria and the immune response settles an equilibrium Self-limiting dynamics: Bacterial populations are reduced below a cut-off value (<1) and infection is successfully limited

26. Unregulated bacterial dynamics: the TB example Time symptoms Resistance selection Selective Window (SW) Time Time

27. Regulated bacterial dynamics: the normal flora example Time symptoms Resistance selection Selective Window (SW) Time Time

28. Regulated v. self-limiting dynamics Resistance selection self-limiting dynamics Resistance selection regulated dynamics Time symptoms Selective Window (SW) Time Time Time

29. Regulated v. self-limiting dynamics Optimal dosing for treatment ≠ optimal to prevent resistance! Resistance selection self-limiting dynamics Resistance selection regulated dynamics Time symptoms Selective Window (SW) Time Time Time

30. Consequences v. benefit of treatment for unregulated bacteria For unregulated and regulated bacterial dynamics, high concentrations for long durations are required to clear bacteria Time for clearance of TB does not exert selection in normal flora, because the two key agents in the three drug combination therapy for TB are not active against any other micro-organisms

31. Consequences v. benefit of treatment for self-limiting infections Self-limiting infections are successfully cleared with “shorter” duration of therapy Shorter durations with therapy exert less selection of resistance in normal flora, but give slightly longer duration of symptoms

32. Consequences v. benefit of treatment for self-limiting infections Does the gain of treating the patient outweigh the risk related to resistance development? Some studies have reported a low, but increased incidence in number of complications from countries with lower prescribing for AOM

33. Conclusions One size does NOT fit all! We need to broaden the concept of selection of resistance when devising optimal dosing strategies – both for guidelines for future and existing antibiotics

34. Alternative strategies to save our antibiotics for the next generation?

35. Webale! Thank you! Tack!