1. Antibiotic Approval Program on Patients’ Clinical Outcomes and Antibiotic Expenditures at Siriraj Hospital Pinyo Rattanaumpawan MD Patama Sutha MD Visanu Thamlikitkul MD Department of Medicine Faculty of Medicine Siriraj Hospital Mahidol University, Bangkok, Thailand

2. Siriraj Hospital Profile Tertiary Care University Hospital in Bangkok 2,300 Hospital Beds 2,300 Hospital Beds 2,600,000 Out-patients’ visits per year 2,600,000 Out-patients’ visits per year 100,000 In-patients per year 100,000 In-patients per year 1,400 Physicians (700 residents & clinical fellows) 1,400 Physicians (700 residents & clinical fellows) Faculty of Medicine Siriraj Hospital, Mahidol University

3. Background Thailand National List of Essential Medicines Thailand National List of Essential Medicines Drugs in category D should be approved by Drugs in category D should be approved by qualified specialists and DUE should be qualified specialists and DUE should be conducted to avoid inappropriate use and conducted to avoid inappropriate use and to promote appropriate use of such drugs to promote appropriate use of such drugs

4. Background Thailand National List of Essential Medicines Thailand National List of Essential Medicines Drugs in category D should be approved by Drugs in category D should be approved by qualified specialists and DUE should be qualified specialists and DUE should be conducted to avoid inappropriate use and conducted to avoid inappropriate use and to promote appropriate use of such drugs to promote appropriate use of such drugs Many antibiotics are listed in category D Many antibiotics are listed in category D including including  Piperacillin/Tazobactam  Imipenem  Meropenem very broad spectrum very broad spectrum last line therapy for last line therapy for resistant bacteria resistant bacteria very expensive very expensive

5. Background Cost of Piperacillin/Tazobactam, Imipenem Cost of Piperacillin/Tazobactam, Imipenem and Meropenem at Siriraj Hospital in 2006 and Meropenem at Siriraj Hospital in 2006 ~ $ 4,000,000 ~ $ 4,000,000

6. Background Cost of Piperacillin/Tazobactam, Imipenem Cost of Piperacillin/Tazobactam, Imipenem and Meropenem at Siriraj Hospital in 2006 and Meropenem at Siriraj Hospital in 2006 ~ $ 4,000,000 ~ $ 4,000,000 DUE of these 3 drugs in 2007 revealed that DUE of these 3 drugs in 2007 revealed that Inappropriate use at prescription ~ 10% Inappropriate use at prescription ~ 10% Inappropriate use at continued treatment Inappropriate use at continued treatment (2-3 days after initial prescription) ~ 50% (2-3 days after initial prescription) ~ 50%

7. Background Cost of Piperacillin/Tazobactam, Imipenem Cost of Piperacillin/Tazobactam, Imipenem and Meropenem at Siriraj Hospital in 2006 and Meropenem at Siriraj Hospital in 2006 ~ $ 4,000,000 ~ $ 4,000,000 DUE of these 3 drugs in 2007 revealed that DUE of these 3 drugs in 2007 revealed that Inappropriate use at prescription ~ 10% Inappropriate use at prescription ~ 10% Inappropriate use at continued treatment Inappropriate use at continued treatment (2-3 days after initial prescription) ~ 50% (2-3 days after initial prescription) ~ 50% Hospital administrators were concerned on Hospital administrators were concerned on inappropriate use and cost of these 3 drugs inappropriate use and cost of these 3 drugs

8. Background Siriraj Hospital decided to have antibiotic Siriraj Hospital decided to have antibiotic approval measure and DUE of these 3 drugs approval measure and DUE of these 3 drugs according to recommendation of Thailand according to recommendation of Thailand National List of Essential Medicines National List of Essential Medicines

9. Background Siriraj Hospital decided to have antibiotic Siriraj Hospital decided to have antibiotic approval measure and DUE of these 3 drugs approval measure and DUE of these 3 drugs according to recommendation of Thailand according to recommendation of Thailand National List of Essential Medicines National List of Essential Medicines Responsible physicians raised a concern on Responsible physicians raised a concern on negative effect of this measure on clinical negative effect of this measure on clinical outcomes for patients whose antibiotics are outcomes for patients whose antibiotics are changed or discontinued changed or discontinued

10. Background Siriraj Hospital decided to have antibiotic Siriraj Hospital decided to have antibiotic approval measure and DUE of these 3 drugs approval measure and DUE of these 3 drugs according to recommendation of Thailand according to recommendation of Thailand National List of Essential Medicines National List of Essential Medicines Responsible physicians raised a concern on Responsible physicians raised a concern on negative effect of this measure on clinical negative effect of this measure on clinical outcomes for patients whose antibiotics are outcomes for patients whose antibiotics are changed or discontinued changed or discontinued No solid evidence from literature to support No solid evidence from literature to support such negative effect such negative effect

11. Background Siriraj Hospital decided to have antibiotic Siriraj Hospital decided to have antibiotic approval measure and DUE of these 3 drugs approval measure and DUE of these 3 drugs according to recommendation of Thailand according to recommendation of Thailand National List of Essential Medicines National List of Essential Medicines Responsible physicians raised a concern on Responsible physicians raised a concern on negative effect of this measure on clinical negative effect of this measure on clinical outcomes for patients whose antibiotics are outcomes for patients whose antibiotics are changed or discontinued changed or discontinued No solid evidence from literature to support No solid evidence from literature to support such negative effect such negative effect Siriraj Hospital endorsed a study to convince Siriraj Hospital endorsed a study to convince responsible physicians on patients’ outcomes responsible physicians on patients’ outcomes

12. Objective To determine effectiveness of antibiotic To determine effectiveness of antibiotic approval measure on patients’ clinical approval measure on patients’ clinical outcomes and antibiotic expenditures outcomes and antibiotic expenditures

13. Methods Randomized controlled study in hospitalized Randomized controlled study in hospitalized adult patients who received piperacillin/ adult patients who received piperacillin/ tazobactam, imipenem and meropenem from tazobactam, imipenem and meropenem from August to November 2007 August to November 2007

14. Methods Randomized controlled study in hospitalized Randomized controlled study in hospitalized adult patients who received piperacillin/ adult patients who received piperacillin/ tazobactam, imipenem and meropenem from tazobactam, imipenem and meropenem from August to November 2007 August to November 2007 Once there was a prescription of any target Once there was a prescription of any target antibiotics, Pharmacy Department notified antibiotics, Pharmacy Department notified study team study team Study team allocated the target antibiotic Study team allocated the target antibiotic prescription to either control group or prescription to either control group or antibiotic approval group by simple antibiotic approval group by simple randomization randomization

15. Methods Control Group Patients received antibiotics according to Patients received antibiotics according to their physicians’ decision their physicians’ decision Study team observed patients’ clinical Study team observed patients’ clinical courses and outcomes until the patients left courses and outcomes until the patients left the hospital the hospital

16. Methods Antibiotic Approval Group Patients were assessed by infectious disease Patients were assessed by infectious disease specialist to determine if target antibiotics specialist to determine if target antibiotics were indicated according to predetermined were indicated according to predetermined criteria criteria

17. Predetermined Criteria Piperacillin/Tazo., Imipenem, Meropenem Confirmed or suspected P.aeruginosa infection Confirmed or suspected P.aeruginosa infection Infection due to pathogen resistant to Infection due to pathogen resistant to cephalosporins, aminoglycosides, quinolones Empiric therapy for neutropenic fever Empiric therapy for neutropenic fever Infection due to pathogen susceptible to other antibiotics but the patient is unable to receive such antibiotics Infection due to pathogen susceptible to other antibiotics but the patient is unable to receive such antibiotics

18. Predetermined Criteria Additional criteria for imipenem & meropenem Therapy of nosocomial infection which is not responding to other antibiotics Therapy of nosocomial infection which is not responding to other antibiotics Infection due to pathogen which is resistant to beta-lactam + beta-lactamase inhibitor Infection due to pathogen which is resistant to beta-lactam + beta-lactamase inhibitor Severe infection due to ESBL+ve pathogen Severe infection due to ESBL+ve pathogen

19. Methods Antibiotic Approval Group Patients were assessed by infectious disease Patients were assessed by infectious disease specialist to determine if target antibiotics specialist to determine if target antibiotics were indicated according to predetermined were indicated according to predetermined criteria criteria If target antibiotic was indicated, it was If target antibiotic was indicated, it was continued continued If target antibiotic was not indicated, study If target antibiotic was not indicated, study team suggested stopping or modifying it team suggested stopping or modifying it

20. Methods Antibiotic Approval Group Patients were assessed by infectious disease Patients were assessed by infectious disease specialist to determine if target antibiotics specialist to determine if target antibiotics were indicated according to predetermined were indicated according to predetermined criteria criteria If target antibiotic was indicated, it was If target antibiotic was indicated, it was continued continued If target antibiotic was not indicated, study If target antibiotic was not indicated, study team suggested stopping or modifying it team suggested stopping or modifying it Study team observed patients’ clinical Study team observed patients’ clinical courses and outcomes until the patients left courses and outcomes until the patients left the hospital the hospital

21. Clinical Outcomes Favorable outcomes : Cure & Improvement Favorable outcomes : Cure & Improvement Eradication of causative pathogens Eradication of causative pathogens Length of hospital stay Length of hospital stay Duration of fever Duration of fever Side effects of antibiotics Side effects of antibiotics Death due to infection Death due to infection Status at discharge Status at discharge

22. Antibiotic Consumption & Expenditure Duration of all antibiotics Duration of all antibiotics Duration of target antibiotics Duration of target antibiotics Total cost of all antibiotics Total cost of all antibiotics Total cost of target antibiotics Total cost of target antibiotics Defined Daily Dose (DDD) of all antibiotics DDD of target antibiotics DDD of target antibiotics

23. Methods Sample Size Non-inferiority study Non-inferiority study Favorable outcome in control gr. = 70% Favorable outcome in control gr. = 70% Favorable outcome in intervention group Favorable outcome in intervention group was < 5% of control group was < 5% of control group Type I error 5% and Type II error 20% Type I error 5% and Type II error 20% 500 prescriptions in each group 500 prescriptions in each group

24. Results 1,028 prescriptions of imipenem, meropenem, 1,028 prescriptions of imipenem, meropenem, piperacillin/tazobactam in 948 patients piperacillin/tazobactam in 948 patients 516 prescriptions (486 patients) - Control 516 prescriptions (486 patients) - Control 512 prescriptions (462 patients) - Intervention 512 prescriptions (462 patients) - Intervention

25. Characteristics of Patients Characteristic Control Intervention p (N=516) (N=512) Males52.9% 53.0% 0.9 Males52.9% 53.0% 0.9 Mean Age 62.1 y. 63.5 y. 0.2 Mean Age 62.1 y. 63.5 y. 0.2 Location of Patients Location of Patients Medical Wards 68.9% 70.8% 0.7 Medical Wards 68.9% 70.8% 0.7 Surgery Wards 25.1% 24.5% Surgery Wards 25.1% 24.5% Type of Infections Type of Infections CAI 18.0% 20.9% 0.2 CAI 18.0% 20.9% 0.2 HAI 82.0% 79.1% HAI 82.0% 79.1%

26. Characteristics of Patients Characteristic Control Intervention p (N=516) (N=512) Purpose of Antibiotic Usage Purpose of Antibiotic Usage Treatment 98.6% 98.6% 1 Treatment 98.6% 98.6% 1 Prophylaxis 1.4% 1.4% Prophylaxis 1.4% 1.4% Type of Target Antibiotic Type of Target Antibiotic Pip./Tazobac. 46.9% 44.5% 0.6 Pip./Tazobac. 46.9% 44.5% 0.6 Imipenem 35.4% 35.7% Imipenem 35.4% 35.7% Meropenem 17.6% 19.7% Meropenem 17.6% 19.7%

27. Inappropriate Prescriptions 42% of target antibiotic prescriptions were 42% of target antibiotic prescriptions were considered inappropriate

28. Compliance to Suggestions 42% of target antibiotic prescriptions were 42% of target antibiotic prescriptions were considered inappropriate 46% of inappropriate prescriptions were changed to more appropriate antibiotics 46% of inappropriate prescriptions were changed to more appropriate antibiotics according to suggestions

29. Compliance to Suggestions 42% of target antibiotic prescriptions were 42% of target antibiotic prescriptions were considered inappropriate 46% of inappropriate prescriptions were changed to more appropriate antibiotics 46% of inappropriate prescriptions were changed to more appropriate antibiotics according to suggestions 24% of inappropriate prescriptions were discontinued according to suggestions 24% of inappropriate prescriptions were discontinued according to suggestions (antibiotics were not needed)

30. Compliance to Suggestions 42% of target antibiotic prescriptions were 42% of target antibiotic prescriptions were considered inappropriate 46% of inappropriate prescriptions were changed to more appropriate antibiotics 46% of inappropriate prescriptions were changed to more appropriate antibiotics according to suggestions 24% of inappropriate prescriptions were discontinued according to suggestions 24% of inappropriate prescriptions were discontinued according to suggestions 22% of inappropriate prescriptions were changed to other inappropriate antibiotics not suggested by infectious disease specialist (non-compliance rate & squeezing the balloon) 22% of inappropriate prescriptions were changed to other inappropriate antibiotics not suggested by infectious disease specialist (non-compliance rate & squeezing the balloon)

31. Outcomes of Patients Clinical Outcome Control Intervention p (N=516) (N=512) Favorable Outcome 60.5% 68.9% <0.01 Eradicate Pathogens 50.2% 65.4% <0.01 Mean LOS 30.7 d. 30.4 d. 0.8 Mean Length Fever 11.0 d. 7.5 d. <0.01 Antibiotic Allergy 1.4% 0.4% 0.1 AAD 3.5% 4.9% 0.2 Death from Infection 35.4% 29.4% 0.05 Mean d. all ATB 16.4 d. 12.7 d. <0.01 Mean d. target ATB 9.3 d. 7.5 d. <0.01 Alive at Discharge 57.4% 55.6% 0.6

32. Outcomes of Patients Clinical Outcome Control Intervention p (N=516) (N=512) Favorable Outcome 60.5% 68.9% <0.01 Eradicate Pathogens 50.2% 65.4% <0.01 Mean LOS 30.7 d. 30.4 d. 0.8 Mean Length Fever 11.0 d. 7.5 d. <0.01 Antibiotic Allergy 1.4% 0.4% 0.1 AAD 3.5% 4.9% 0.2 Death from Infection 35.4% 29.4% 0.05 Mean d. all ATB 16.4 d. 12.7 d. <0.01 Mean d. target ATB 9.3 d. 7.5 d. <0.01 Alive at Discharge 57.4% 55.6% 0.6

33. Antibiotic Consumption & Expenditure Control Intervention (N=516) (N=512) Control Intervention (N=516) (N=512) Total Cost all ATB (m.$) 0.71 0.54 Total Cost target ATB (m.$) 0.34 0.28 All ATB/Episode ($) 1,238 967 Target ATB/Episode ($) 661 538 DDD all ATB 13,528 10,738 DDD target ATB 3,696 2,972 DDD all ATB/Episode 26.2 21.0 DDD target ATB/Episode 7.2 5.8

34. Antibiotic Consumption & Expenditure Control Intervention (N=516) (N=512) Control Intervention (N=516) (N=512) Total Cost all ATB (m.$) 0.71 0.54 Total Cost target ATB (m.$) 0.34 0.28 All ATB/Episode ($) 1,238 967 Target ATB/Episode ($) 661 538 DDD all ATB 13,528 10,738 DDD target ATB 3,696 2,972 DDD all ATB/Episode 26.2 21.0 DDD target ATB/Episode 7.2 5.8 Minimal “Squeezing the Balloon Effect”

35. Antibiotic Consumption & Expenditure Actual difference in antibiotic expenditures between antibiotic approval group and control group was $ 143,793 Actual difference in antibiotic expenditures between antibiotic approval group and control group was $ 143,793 Annual antibiotic cost savings from antibiotic approval program would be $ 862,704 if all prescriptions of target antibiotics were reviewed by infectious disease physicians Annual antibiotic cost savings from antibiotic approval program would be $ 862,704 if all prescriptions of target antibiotics were reviewed by infectious disease physicians

36. Conclusion Antibiotic approval program for imipenem, meropenem, piperacillin/tazobactam at Siriraj Hospital is an effective measure in reducing antibiotic consumption & expenditure without compromising patients’ clinical outcomes

37. Cost-Benefit of Antibiotic Approval Program If all prescriptions of target antibiotics are reviewed by infectious diseases physicians, hospital will have annual saving US $ 862,704 If all prescriptions of target antibiotics are reviewed by infectious diseases physicians, hospital will have annual saving US $ 862,704 Extra costs of DUE and antibiotic approval processes are not taken into account when aforementioned amount of cost savings is estimated Extra costs of DUE and antibiotic approval processes are not taken into account when aforementioned amount of cost savings is estimated Extra costs generated by DUE and antibiotic approval (personnel costs and additional costs for microbiologic investigations) are estimated as up to US $ 50,000 per year Extra costs generated by DUE and antibiotic approval (personnel costs and additional costs for microbiologic investigations) are estimated as up to US $ 50,000 per year DUE & antibiotic approval are cost-benefit DUE & antibiotic approval are cost-benefit

38. Prerequisite of Antibiotic Approval Program Antibiotic approval can be applied only to institutions where there are qualified infectious diseases physicians who are willing to take responsibility in approving restricted antibiotics and are able to continue providing suggestions regarding antibiotic prescription and management of infections Antibiotic approval can be applied only to institutions where there are qualified infectious diseases physicians who are willing to take responsibility in approving restricted antibiotics and are able to continue providing suggestions regarding antibiotic prescription and management of infections

39. Prerequisite of Antibiotic Approval Program Antibiotic approval can be applied only to institutions where there are qualified infectious diseases physicians who are willing to take responsibility in approving restricted antibiotics and are able to continue providing suggestions regarding antibiotic prescription and management of infections Antibiotic approval can be applied only to institutions where there are qualified infectious diseases physicians who are willing to take responsibility in approving restricted antibiotics and are able to continue providing suggestions regarding antibiotic prescription and management of infections Well trained clinical pharmacists should be able to perform approval Well trained clinical pharmacists should be able to perform approval

40. Implementations Study results were presented to hospital administrators in April 2008 Study results were presented to hospital administrators in April 2008 Siriraj Hospital informed all responsible physicians regarding the study results Siriraj Hospital informed all responsible physicians regarding the study results Antibiotic approval measure has been continued since May 2008 Antibiotic approval measure has been continued since May 2008

41. More Information Poster Number 291 Poster Number 291 American Journal of Infection Control American Journal of Infection Control 2010; 38: 38 - 43. 2010; 38: 38 - 43.

42. Antibiotic Approval Program on Patients’ Clinical Outcomes and Antibiotic Expenditures at Siriraj Hospital Pinyo Rattanaumpawan MD Patama Sutha MD Visanu Thamlikitkul MD Department of Medicine Faculty of Medicine Siriraj Hospital Mahidol University, Bangkok, Thailand

43. Characteristics of Patients Characteristic Control Intervention p (N=516) (N=512) Underlying Conditions of Patients Cardio-pulmonary 38.7% 54.1% <0.01 Malignancy 34.0% 42.0% 0.01 Liver Diseases 6.6% 11.7% 0.01 Renal Diseases 16.3% 22.3% 0.02 Neurological Dis. 15.4% 22.9% 0.01

44. Clinical Outcomes of Patients Different characteristics between 2 groups Different characteristics between 2 groups Multivariate analysis was performed Multivariate analysis was performed Factors associated with unfavorable outcome OR (95%CI) p OR (95%CI) p Control group patient 1.35 (1.03-1.76) 0.03 Control group patient 1.35 (1.03-1.76) 0.03 Pneumonia 2.36 (1.78-3.15) <0.01 Pneumonia 2.36 (1.78-3.15) <0.01

45. Impact of Antibiotic Approval Program on Antimicrobial Resistance Impact on antibiotic resistance of pathogens was not measured because patients allocated to both groups stayed in the same wards, and duration of study was only 4 months Impact on antibiotic resistance of pathogens was not measured because patients allocated to both groups stayed in the same wards, and duration of study was only 4 months Therefore, it would be unlikely to observe any changes in antibiotic resistance patterns Therefore, it would be unlikely to observe any changes in antibiotic resistance patterns of isolated pathogens either from patients or from environment There are many factors contributing to AMR There are many factors contributing to AMR

46. Subgroup Analysis in Microbiological Documented Infections Clinical OutcomeControlIntervention p (N=290) (N=323) Favorable Outcome 58.9% 65.6% 0.08 Eradicate Pathogen 50.2% 65.4% <0.01 Death (Infection) 37.9% 31.9% 0.1

47. Main Reasons for Non-Compliance Responsible physicians did not believe that patient was free of active infection according to infectious disease physician’s opinion Responsible physicians did not believe that patient was free of active infection according to infectious disease physician’s opinion Some surgeons believed that antibiotic prophylaxis should be continued until endotracheal tube was removed Some surgeons believed that antibiotic prophylaxis should be continued until endotracheal tube was removed Many responsible physicians were not certain that narrow spectrum antibiotics could replace target antibiotics that they initially gave to their patients, especially for the patients who were improving after receiving the target antibiotics Many responsible physicians were not certain that narrow spectrum antibiotics could replace target antibiotics that they initially gave to their patients, especially for the patients who were improving after receiving the target antibiotics

48. Different Rates of Comorbidity Infectious diseases physicians did not involve in care processes in control group whereas Infectious diseases physicians did not involve in care processes in control group whereas infectious diseases physicians continued supervising management of patients who received antibiotic approval Additional medical information was recorded, and additional microbiologic Additional medical information was recorded, and additional microbiologic investigations for diagnosis of infections and for assessment of microbiologic outcomes were made for antibiotic approval group

49. Different Rates ofComorbidity Different Rates of Comorbidity Differences in characteristics of patients would not favor outcomes of patients who received antibiotic approval because higher rates of having comorbidity that compromised clinical outcomes were observed more often in patients who received antibiotic approval Differences in characteristics of patients would not favor outcomes of patients who received antibiotic approval because higher rates of having comorbidity that compromised clinical outcomes were observed more often in patients who received antibiotic approval

50. Inappropriate Use of Target Antibiotics Prevalence of inappropriate use of target antibiotics in antibiotic approval group was 41.6% which was modestly less than 50% observed from a preliminary DUE period Prevalence of inappropriate use of target antibiotics in antibiotic approval group was 41.6% which was modestly less than 50% observed from a preliminary DUE period This might be due to each prescription of target antibiotics during study period was required to be accompanied with antibiotic order sheet that was filled in by responsible physician This might be due to each prescription of target antibiotics during study period was required to be accompanied with antibiotic order sheet that was filled in by responsible physician Therefore, some prescriptions of target antibiotics were cancelled earlier if responsible physicians thought that their prescriptions were obviously inappropriate Therefore, some prescriptions of target antibiotics were cancelled earlier if responsible physicians thought that their prescriptions were obviously inappropriate

51. Clinical Outcomes in Antibiotic Approval Patients in antibiotic approval group had better outcomes Patients in antibiotic approval group had better outcomes Infectious diseases physicians not only approved the use of target antibiotics, but they also recommended appropriate microbiologic investigations so that the site of infections and the causative agents became known Infectious diseases physicians not only approved the use of target antibiotics, but they also recommended appropriate microbiologic investigations so that the site of infections and the causative agents became known Antibiotics given to patients in antibiotic approval group could either be discontinued with certainty in patients with no infections or tailored to more specific antibiotics according to microbiologic results Antibiotics given to patients in antibiotic approval group could either be discontinued with certainty in patients with no infections or tailored to more specific antibiotics according to microbiologic results

52. Clinical Outcomes in Antibiotic Approval Patients in antibiotic approval group had better outcomes Patients in antibiotic approval group had better outcomes Many patients in control group who had no infections or had colonization or had infections with resistant pathogens, (e.g. MRSA) continued to receive target antibiotics leading to super-infections with organisms (e.g. MRSA, pandrug-resistant Acinetobacter spp, or Candida spp.) which were resistant to target antibiotics, resulting in unfavorable outcomes and mortality Many patients in control group who had no infections or had colonization or had infections with resistant pathogens, (e.g. MRSA) continued to receive target antibiotics leading to super-infections with organisms (e.g. MRSA, pandrug-resistant Acinetobacter spp, or Candida spp.) which were resistant to target antibiotics, resulting in unfavorable outcomes and mortality

53. Clinical Outcomes in Antibiotic Approval Although some baseline characteristics of patients in both groups were significantly different, the results of multivariate analysis showed that being a patient in control group and having pneumonia was significantly Although some baseline characteristics of patients in both groups were significantly different, the results of multivariate analysis showed that being a patient in control group and having pneumonia was significantly associated with unfavorable outcome This observation confirmed that a difference in favorable clinical outcomes was associated with antibiotic approval program because hospital-acquired pneumonia was a well- known factor associated with poor clinical This observation confirmed that a difference in favorable clinical outcomes was associated with antibiotic approval program because hospital-acquired pneumonia was a well- known factor associated with poor clinical outcome of hospitalized patients

54. Clinical Outcomes in Antibiotic Approval Length of hospital stay and patients’ survival at hospital discharge were not significantly different in either group because most of patients in both groups had chronic underlying diseases, and they were hospitalized because of these medical problems and died of such comorbidities Length of hospital stay and patients’ survival at hospital discharge were not significantly different in either group because most of patients in both groups had chronic underlying diseases, and they were hospitalized because of these medical problems and died of such comorbidities

55. Squeezing the Balloon Effect Consumption of antibiotics other than target antibiotics were also collected because physicians might shift from target antibiotics to other antibiotics if target antibiotics were not approved Consumption of antibiotics other than target antibiotics were also collected because physicians might shift from target antibiotics to other antibiotics if target antibiotics were not approved 22% of prescriptions in antibiotic approval group were changed to other antibiotics which were not recommended by infectious diseases physicians 22% of prescriptions in antibiotic approval group were changed to other antibiotics which were not recommended by infectious diseases physicians Nonetheless, DDD of the target antibiotics and all antibiotics as well as DDD of target antibiotics and all antibiotics per episode of infection in antibiotic approval group were much lower than those in control group Nonetheless, DDD of the target antibiotics and all antibiotics as well as DDD of target antibiotics and all antibiotics per episode of infection in antibiotic approval group were much lower than those in control group Therefore, ‘‘squeezing the balloon effect’’ found in our study was minimal Therefore, ‘‘squeezing the balloon effect’’ found in our study was minimal

56. Squeezing the Balloon Effect Consumption of antibiotics other than target antibiotics were also collected because physicians might shift from target antibiotics to other antibiotics if target antibiotics were not approved Consumption of antibiotics other than target antibiotics were also collected because physicians might shift from target antibiotics to other antibiotics if target antibiotics were not approved 21.6% of prescriptions in antibiotic approval group were changed to other antibiotics, such as cefepime, which were not recommended by infectious diseases physicians 21.6% of prescriptions in antibiotic approval group were changed to other antibiotics, such as cefepime, which were not recommended by infectious diseases physicians

57. Squeezing the Balloon Effect Nonetheless, DDD of the target antibiotics and all antibiotics as well as DDD of target antibiotics and all antibiotics per episode of infection in antibiotic approval group were much lower than those in control group Nonetheless, DDD of the target antibiotics and all antibiotics as well as DDD of target antibiotics and all antibiotics per episode of infection in antibiotic approval group were much lower than those in control group Therefore, the ‘‘squeezing the balloon effect’’ found in our study was minimal Therefore, the ‘‘squeezing the balloon effect’’ found in our study was minimal

58. Defined Daily Dose (DDD) DDD is a measure of assumedaverage DDD is a measure of assumed average maintenance dose per day for a drug used as maintenance dose per day for a drug used as a main indication in adults a main indication in adults

59. Defined Daily Dose (DDD) DDD (Amoxicillin 250 mg) = dose form of strength (250mg)*Quant. of amoxi. dispensed WHO assigned DDD for Amoxicillin (1000 mg) = 250*20 / 1000 = 5 DDD (Erythromycin 250 mg) = dose form of strength (250mg)*Quant. of erythro. dispensed WHO assigned DDD for erythromycin (500 mg) = 250*20 / 500 = 10

60. Antibiotic Consumption & Expenditure Antibiotic Approval Program Antibiotic Cost Saving Control - Intervention = 4.8 mB for 4 months Annual Antibiotic Cost Saving = 14.4 mB Antibiotic Cost Saving = 4.5 mB for 4 months if 516 prescriptions in the control group were reviewed by infectious diseases specialist

64. Methods Sample Size Non-inferiority study Non-inferiority study Favorable outcome in control gr. = 70% Favorable outcome in control gr. = 70% Favorable outcome in intervention group Favorable outcome in intervention group was < 5% of control group was < 5% of control group Type I error 5% and Type II error 20% Type I error 5% and Type II error 20% 500 prescriptions in each group 500 prescriptions in each groupStatistics Descriptive statistics, Chi-square/ Fisher’s Descriptive statistics, Chi-square/ Fisher’s exact test, Student t-test/ Mann-Whitney exact test, Student t-test/ Mann-Whitney U-test, multivariate analysis U-test, multivariate analysis