1. Use of AMR Surveillance Data to Develop Infectious Diseases Standard Treatment Guidelines in Developing Countries Use of AMR Surveillance Data to Develop Infectious Diseases Standard Treatment Guidelines in Developing Countries. Sosa A., Stelling J., O’Brien T., Traub F., Travers K., Hodges Myerson A.

2. Problem Statement: Antimicrobial resistance (AMR) has spread across regions and continents, resulting in increased morbidity, mortality, and costs. Often, the use of practical clinical guidelines in the management of key infectious diseases in the developing world is hampered by the lack of reliable antimicrobial surveillance data. When minimum requirements for AMR surveillance are met, data obtained from Antimicrobial Susceptibility Testing (AST) are essential to provide more effective therapy and minimize treatment failures.

3. Definition of Surveillance Definition of Surveillance. Surveillance is defined as the ongoing and systematic collection, analysis and interpretation of outcome-specific data essential to the planning, implementation, and evaluation of public health practice, closely integrated with the timely dissemination of these data to those who need to know. The final link of the surveillance chain is the application of these data to the control and prevention of human disease and injury. Source: Australia Communicable Diseases Intelligence - Vol 27 No 4, December 2003

4. Benefits of AMR Surveillance Benefits of AMR Surveillance.  characterization of disease etiologies and resistance trends  prompt identification and investigation of new threats in resistance  guidance to policy-makers in developing therapy recommendations  guidance to public health authorities in responding to outbreaks of community and hospital outbreaks of resistant organisms  evaluation of the impact of therapy and infection control interventions on infection rates and cure rates  strengthening of laboratory capacity and national communicable disease infrastructure through a process of continuous quality improvement

5. Limitations of AMR Surveillance Limitations of AMR Surveillance.  In sentinel and designed studies often expensive and labor-intensive with significant concerns for long- term sustainability  laboratory data could be flawed and mislead intervention strategies  epidemiological biases (representative of patients and samples)  need to set up internal and external quality assurance  translating data “in-vitro” to “in-vivo”  it requires trained personnel and standard protocol

6. Objectives: To develop a guide to help the National Standard Treatment Guideline (STG) committee to utilize AMR surveillance data to write and update STGs. The incorporation of surveillance data into STGs produces: 1)Better resource allocation of drugs by identifying inappropriate antimicrobials; 2)Appropriate access to essential antimicrobials; 3)Prudent use of antimicrobials by practitioners.

7. Setting: Developing country with minimum AMR surveillance system in place.

8. Design (1): Design (1): Qualitative analysis. The country’s AMR Surveillanceinfrastructure and specific disease environment were analyzed through: 1)Assessment of country AST and Quality Control Systems; 2)Assessment of the AMR surveillance country system; 3)Definition of AMR Alert Thresholds for key pathogens; 4)Definition of disease-specific therapy thresholds;

9. Design (2): 5) Assessment of regional and global AMR surveillance data for same key pathogens; 6) Assessment of health care infrastructure for drug procurement, transport, storage and delivery; 7) Application of WHO Bacterial Infections Guide.

10. Intervention: Production of a guide using local AMR data to inform the process of writing and updating the country’s STGs for the most prevalent bacterial infections responsible for ARI, diarrheal disease and sexually transmitted infections (STIs) in developing countries.

11. Outcome Measures: 1)Better understanding of the use of AMR data; 2)Better access and use of antimicrobials; 3)Reduction in the rate of increase of AMR in key pathogens. Study Funding Study Funding: USAID via Management Sciences for Health

12. Resistance alert thresholds The maximum allowable prevalence of resistant bacteria isolated from a group of patients that does not pose an unacceptable risk to general human health population receiving the drug of choice. Thresholds for Action in a Specific Setting Defined *5% resistance for N. gonorrhoeae *Beta lactamase producing meningococcus *1% resistance for Rx of meningitis *First pen-resistant Strep pyogenes Undefined (most) ?Multi-drug resistant TB ?% John Tapsall

13. The maximum allowable severity of certain disease-specific symptoms and signs that does not require antimicrobial treatment. Example: Severity of dehydration in Cholera Disease-specific thresholds

14. Empirical selection of an antibiotic in non- outbreak Vibrio cholerae infections in Nepal at the sub-health and health posts PatientEntry Sub-health & health posts Questions Is patient a child, an adult or a pregnant woman or a pregnant woman? Available ATBs TMP-SMX Tetracycline Chloramphenicol Benzyl Penicillin Child Adult TMP-SMX Tetracycline or TMP-SMP or Chloramphenicol TMP-SMP or Tetracycline if pregnancy  3 months Pregnant Woman Doxycline or Ciprofloxacin (both contraindicated in pregnancy) WHO PRESCRIBING GUIDE FOR BACTERIAL INFECTIONS Action Threshold Severity of dehydration Alert threshold V. cholereae Resistance Prevalence TMP-SMX  20% Chloramphenicol  20% Tetracycline  10% ChildPregnant WomanAdult If available at the post, Erythromycin

15. Empirical selection of an antibiotic in non- outbreak Vibrio cholerae infections in Nepal at the district level PatientEntry District Level Questions Is patient a child, an adult or a pregnant woman? Child Adult TMP-SMX Tetracycline or TMP-SMP or Chloramphenicol TMP-SMP or Tetracycline if pregnancy  3 months Pregnant Woman Doxycline or Ciprofloxacin (both contraindicated in pregnancy) WHO PRESCRIBING GUIDE FOR BACTERIAL INFECTIONS Action Threshold Severity of dehydration Alert threshold V. cholereae Resistance Prevalence TMP-SMX  20% Chloramphenicol  20% Tetracycline  10% ChildPregnant WomanAdult If available at the post, Erythromycin Available ATBs Amoxicillin,TMP-SMX, Tetracycline, Chloramphenicol, Benzyl Penicillin, Cloxacillin, Erythromycin, Ciprofloxacin, Gentamicin, Metronidazole, Rifampicin, Streptomycin, Ethambutol, Sulfaacetamide, Doxycycline, Nitrofurantoin

16. Empirical selection of an antibiotic in non- outbreak Vibrio cholerae infections in Nepal at the national level PatientEntry District Level Questions Is patient a child, an adult or a pregnant woman? Child Adult TMP-SMX Tetracycline or TMP-SMP or Chloramphenicol TMP-SMP or Tetracycline if pregnancy  3 months Pregnant Woman Doxycline or Ciprofloxacin (both contraindicated in pregnancy) WHO PRESCRIBING GUIDE FOR BACTERIAL INFECTIONS Action Threshold Severity of dehydration Alert threshold V. cholereae Resistance Prevalence TMP-SMX  20% Chloramphenicol  20% Tetracycline  10% ChildPregnant WomanAdult If available at the post, Erythromycin Available ATBs Amoxicillin,TMP-SMX, Tetracycline, Chloramphenicol, Benzyl Penicillin, Cloxacillin, Erythromycin, Ciprofloxacin, Gentamicin, Metronidazole, Rifampicin, Streptomycin, Ethambutol, Sulfaacetamide, Doxycycline, Nitrofurantoin, Cefotaxime

17. Discussion: Discussion: issues to be considered (1) 1.What are the challenging methodological issues?  Dealing with the inherent biases in the bacterial samples collected for AST, whether they are geographical, economic, medical, demographic, clustered around one time or outbreak.  Defining alert thresholds  Defining disease-specific therapy thresholds

18. Discussion: Discussion: issues to be considered (2) 2.Which methods questions should be included in a future research agenda?  Assessing the effect of losses-to-follow-up when evaluating the effect of STG implementation on treatment success/failure rates.  Another methodological issue to consider in the future development of STGs is that of observation bias: will prescribers alter their practice based solely on their participation in a study?

19. Selected References: 1.Wachter, D., M. Joshi, and B. Rimal,. Tropical Medicine and International Health, 1999. 4(11): p. 782-788. 2.Rehana, H.S., M.A. Nagarani, and M. Rehan, Indian Journal of Pharmacology, 1998. 30: p. 175- 180. 3.Kafle, K., et al., Community drug use in Nepal. 1997. 4.Nair, G., A. Hossain, and M. Rahman, 2002, ICCDR,B Center for Health & Population Research: Dakar, Bangladesh. 5.Stelling, J.M. and T.F. O'Brien. Clin Infect Dis, 1997. 24 Suppl 1: p. S157-68. 6.Nepal, M.o.H., Standard Treatment Schedules for Health Posts & Sub-Health Posts. 1999, Bagbazar, Kathmandu. 7.Ashkenazi, S., et al., J. Antimicrob. Chemother., 2003. 51(2): p. 427-429. 8.Honma, Y., et al., FEMS Immunol Med Microbiol, 2001. 32(1): p. 43-6. 9.Jesudason, M.V., V. Balaji, and C.J. Thomson. Indian J Med Res, 2002. 116: p. 96-8. 10.WHO, Model Prescribing Information. Drugs used for bacterial infections. 2001, World Health Organization: Geneva, Switzerland 11.Tapsall, J., Expert Opin Pharmacother, 2002. 3(2): p. 147 - 157. 12.MMWR, 2002. 51(46): p. 1041-1044. 13.WHO. Commun Dis Intell, 2001. 25(4): p. 274-6. 14.APUA. April 2003. Framework for Use of Antimicrobial Resistance Surveillance in the Development of Standard Treatment Guidelines.

20. Acknowledgment: Allison Hodges Myerson, M.Sc., M.A., APUA Research Coord. Thomas O’Brien, MD., WHO Collaborating Centre for Surveillance of Antibiotic Resistance, Boston John Stelling, MD, MPH., WHO Collaborating Centre for Surveillance of Antibiotic Resistance, Boston Karin Travers, ScD., APUA Research Manager Flora Traub, MPP, APUA International Coord. G. B. Nair, ICCDR, Bangladesh Anowar Hossain, ICCDR, Bangladesh Motiur Rahman, ICCDR, Bangladesh

21. Alliance for the Prudent Use of Antibiotics (APUA) 75 Kneeland Street Boston, MA 02111, USA www.apua.org Thank You! Anibal Sosa, MD. anibal.sosa@tufts.edu