Antibiotic Approval Program on Patients’ Clinical Outcomes and Antibiotic Expenditures at Siriraj Hospital Pinyo Rattanaumpawan MD Patama Sutha MD Visanu

Antibiotic Approval Program on Antibiotic Approval Program on

Patients’ Clinical Patients’ Clinical

Outcomes and Outcomes and

Antibiotic Expenditures Antibiotic Expenditures

at Siriraj Hospital at Siriraj Hospital

Pinyo Rattanaumpawan MD Pinyo Rattanaumpawan MD Patama Sutha MD Patama Sutha MD Visanu Thamlikitkul MDVisanu Thamlikitkul MD

Department of Medicine Department of Medicine Faculty of Medicine Siriraj Hospital Faculty of Medicine Siriraj Hospital

Mahidol University, Bangkok, ThailandMahidol University, Bangkok, Thailand

Siriraj Hospital ProfileSiriraj Hospital Profile

• Tertiary Care University Hospital in Tertiary Care University Hospital in BangkokBangkok

• 2,300 Hospital Beds2,300 Hospital Beds

• 2,600,000 Out-patients’ visits per year 2,600,000 Out-patients’ visits per year

• 100,000 In-patients per year100,000 In-patients per year

• 1,400 Physicians (700 residents & 1,400 Physicians (700 residents & clinical fellows)clinical fellows)

Faculty of Medicine Siriraj Hospital, Mahidol Faculty of Medicine Siriraj Hospital, Mahidol UniversityUniversity

BackgroundBackground• Thailand National List of Essential Thailand National List of Essential

MedicinesMedicines Drugs in category D should be Drugs in category D should be

approved by approved by

qualified specialists and DUE should be qualified specialists and DUE should be

conducted to avoid inappropriate use conducted to avoid inappropriate use

and and

to promote appropriate use of such to promote appropriate use of such

drugsdrugs

BackgroundBackground• Thailand National List of Essential Thailand National List of Essential

MedicinesMedicines Drugs in category D should be Drugs in category D should be

approved by approved by

qualified specialists and DUE should be qualified specialists and DUE should be

conductedconducted to avoid inappropriate use to avoid inappropriate use

and and

to promote appropriate use of such to promote appropriate use of such

drugsdrugs Many antibiotics are listed in category Many antibiotics are listed in category

D D

including including Piperacillin/TazobactamPiperacillin/Tazobactam Imipenem Imipenem Meropenem Meropenem

•very broad very broad spectrumspectrum

•last line therapy last line therapy for for

resistant bacteriaresistant bacteria

•very expensivevery expensive

BackgroundBackground• Cost of Piperacillin/Tazobactam, Cost of Piperacillin/Tazobactam,

Imipenem Imipenem

and Meropenem at Siriraj Hospital in and Meropenem at Siriraj Hospital in

2006 2006

~ $ 4,000,000~ $ 4,000,000


Imipenem Imipenem


2006 2006

~ $ 4,000,000~ $ 4,000,000• DUE of these 3 drugs in 2007 revealed DUE of these 3 drugs in 2007 revealed

that that Inappropriate use at prescription ~ Inappropriate use at prescription ~

10%10% Inappropriate use at continued Inappropriate use at continued

treatment treatment

(2-3 days after initial prescription) ~(2-3 days after initial prescription) ~

50%50%


Imipenem Imipenem


2006 2006

~ $ 4,000,000~ $ 4,000,000• DUE of these 3 drugs in 2007 revealed DUE of these 3 drugs in 2007 revealed

that that Inappropriate use at prescription ~ Inappropriate use at prescription ~

10%10% Inappropriate use at continued Inappropriate use at continued

treatment treatment

(2-3 days after initial prescription) ~(2-3 days after initial prescription) ~

50%50%• Hospital administrators were concerned Hospital administrators were concerned

on on

inappropriate use and cost of these 3 inappropriate use and cost of these 3

drugsdrugs

BackgroundBackground• Siriraj Hospital decided to have Siriraj Hospital decided to have antibioticantibiotic approval measure and DUE of these 3 approval measure and DUE of these 3 drugsdrugs according to recommendation of according to recommendation of Thailand Thailand National List of Essential MedicinesNational List of Essential Medicines

BackgroundBackground• Siriraj Hospital decided to have Siriraj Hospital decided to have antibioticantibiotic approval measure and DUE of these 3 approval measure and DUE of these 3 drugsdrugs according to recommendation of according to recommendation of Thailand Thailand National List of Essential MedicinesNational List of Essential Medicines Responsible physicians raised a Responsible physicians raised a concern onconcern on negative effect of this measure on negative effect of this measure on clinicalclinical outcomes for patients whose antibiotics outcomes for patients whose antibiotics areare changed or discontinuedchanged or discontinued

BackgroundBackground• Siriraj Hospital decided to have Siriraj Hospital decided to have antibioticantibiotic approval measure and DUE of these 3 approval measure and DUE of these 3 drugsdrugs according to recommendation of according to recommendation of Thailand Thailand National List of Essential MedicinesNational List of Essential Medicines Responsible physicians raised a Responsible physicians raised a concern onconcern on negative effect of this measure on negative effect of this measure on clinicalclinical outcomes for patients whose antibiotics outcomes for patients whose antibiotics areare changed or discontinuedchanged or discontinued No solid evidence from literature to No solid evidence from literature to support support such negative effectsuch negative effect

BackgroundBackground• Siriraj Hospital decided to have Siriraj Hospital decided to have antibioticantibiotic approval measure and DUE of these 3 approval measure and DUE of these 3 drugsdrugs according to recommendation of according to recommendation of Thailand Thailand National List of Essential MedicinesNational List of Essential Medicines Responsible physicians raised a Responsible physicians raised a concern onconcern on negative effect of this measure on negative effect of this measure on clinicalclinical outcomes for patients whose antibiotics outcomes for patients whose antibiotics areare changed or discontinuedchanged or discontinued No solid evidence from literature to No solid evidence from literature to support support such negative effectsuch negative effect Siriraj Hospital endorsed a study to Siriraj Hospital endorsed a study to convince convince responsible physicians on patients’ responsible physicians on patients’ outcomesoutcomes

ObjectiveObjective• To determine effectiveness of antibiotic To determine effectiveness of antibiotic approval measure on patients’ clinical approval measure on patients’ clinical outcomes and antibiotic expendituresoutcomes and antibiotic expenditures

MethodsMethods• Randomized controlled study in Randomized controlled study in hospitalized hospitalized adult patients who received adult patients who received piperacillin/ piperacillin/ tazobactam, imipenem and tazobactam, imipenem and meropenem frommeropenem from August to November 2007August to November 2007

MethodsMethods• Randomized controlled study in Randomized controlled study in hospitalized hospitalized adult patients who received adult patients who received piperacillin/ piperacillin/ tazobactam, imipenem and tazobactam, imipenem and meropenem from meropenem from August to November 2007August to November 2007 Once there was a prescription of any Once there was a prescription of any targettarget antibiotics, Pharmacy Department antibiotics, Pharmacy Department notifiednotified study teamstudy team Study team allocated the target Study team allocated the target antibioticantibiotic prescription to either control group orprescription to either control group or antibiotic approval group by simple antibiotic approval group by simple randomizationrandomization

MethodsMethodsControl Group Control Group • Patients received antibiotics according Patients received antibiotics according to to their physicians’ decisiontheir physicians’ decision• Study team observed patients’ clinical Study team observed patients’ clinical courses and outcomes until the patients courses and outcomes until the patients left left the hospital the hospital

MethodsMethodsAntibiotic Approval GroupAntibiotic Approval Group• Patients were assessed by infectious Patients were assessed by infectious

disease disease

specialist to determine if target specialist to determine if target

antibioticsantibiotics

were indicated according to were indicated according to

predetermined predetermined

criteria criteria

Predetermined CriteriaPredetermined Criteria

Piperacillin/Tazo., Imipenem, MeropenemPiperacillin/Tazo., Imipenem, Meropenem • Confirmed or suspected Confirmed or suspected P.aeruginosa P.aeruginosa

infectioninfection• Infection due to pathogen resistant to Infection due to pathogen resistant to

cephalosporins, aminoglycosides, cephalosporins, aminoglycosides,

quinolonesquinolones• Empiric therapy for neutropenic feverEmpiric therapy for neutropenic fever• Infection due to pathogen susceptible Infection due to pathogen susceptible

to other antibiotics but the patient is to other antibiotics but the patient is

unable to receive such antibioticsunable to receive such antibiotics

Predetermined CriteriaPredetermined Criteria

Additional criteria forAdditional criteria for imipenem & imipenem &

meropenemmeropenem• Therapy of nosocomial infection which Therapy of nosocomial infection which

is not responding to other antibioticsis not responding to other antibiotics• Infection due to pathogen which is Infection due to pathogen which is

resistant to beta-lactam + beta-resistant to beta-lactam + beta-

lactamase inhibitorlactamase inhibitor• Severe infection due to ESBL+ve Severe infection due to ESBL+ve

pathogenpathogen

MethodsMethodsAntibiotic Approval GroupAntibiotic Approval Group• Patients were assessed by infectious Patients were assessed by infectious disease disease specialist to determine if target specialist to determine if target antibioticsantibiotics were indicated according to were indicated according to predetermined 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, If target antibiotic was not indicated, study study team suggested stopping or modifying team suggested stopping or modifying itit

MethodsMethodsAntibiotic Approval GroupAntibiotic Approval Group• Patients were assessed by infectious Patients were assessed by infectious disease disease specialist to determine if target specialist to determine if target antibioticsantibiotics were indicated according to were indicated according to predetermined 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, If target antibiotic was not indicated, study study team suggested stopping or modifying team suggested stopping or modifying itit• Study team observed patients’ clinical Study team observed patients’ clinical courses and outcomes until the patients courses and outcomes until the patients left left the hospital the hospital

Clinical OutcomesClinical Outcomes• Favorable outcomes : Cure & Favorable outcomes : Cure &

ImprovementImprovement• Eradication of causative pathogensEradication of causative pathogens• Length of hospital stay Length of hospital stay • Duration of feverDuration of fever• Side effects of antibioticsSide effects of antibiotics• Death due to infection Death due to infection • Status at dischargeStatus at discharge

Antibiotic Consumption & Antibiotic Consumption & ExpenditureExpenditure

• Duration of all antibioticsDuration of all antibiotics

• Duration of target antibioticsDuration of target antibiotics

• Total cost of all antibioticsTotal cost of all antibiotics

• Total cost of target antibioticsTotal cost of target antibiotics

• Defined Daily Dose (DDD) of all Defined Daily Dose (DDD) of all

antibiotics antibiotics

• DDD of target antibioticsDDD of target antibiotics

MethodsMethodsSample SizeSample Size• Non-inferiority studyNon-inferiority study Favorable outcome in control gr. = Favorable outcome in control gr. =

70%70% Favorable outcome in intervention Favorable outcome in intervention

group group

was was << 5% of control group 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 group500 prescriptions in each group

ResultsResults

• 1,028 prescriptions of imipenem, 1,028 prescriptions of imipenem,

meropenem,meropenem,

piperacillin/tazobactam in 948 patients piperacillin/tazobactam in 948 patients 516 prescriptions (486 patients) - 516 prescriptions (486 patients) -

Control Control 512 prescriptions (462 patients) - 512 prescriptions (462 patients) -

Intervention Intervention

Characteristics of PatientsCharacteristics of PatientsCharacteristic Control Characteristic Control Intervention p Intervention p (N=516) (N=516) (N=512) (N=512) • MalesMales 52.9%52.9% 53.0% 53.0% 0.9 0.9 • Mean Age 62.1 y. 63.5 y. Mean Age 62.1 y. 63.5 y. 0.2 0.2

• Location of Patients Location of Patients Medical Wards 68.9% 70.8% Medical Wards 68.9% 70.8% 0.7 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% CAI 18.0% 20.9% 0.2 0.2 HAI 82.0% 79.1%HAI 82.0% 79.1%

Characteristics of PatientsCharacteristics of PatientsCharacteristic Control Intervention Characteristic Control Intervention p p (N=516) (N=516) (N=512)(N=512)• Purpose of Antibiotic Usage Purpose of Antibiotic Usage Treatment 98.6% 98.6% Treatment 98.6% 98.6%

1 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% Pip./Tazobac. 46.9% 44.5%

0.6 0.6 Imipenem 35.4% 35.7% Imipenem 35.4% 35.7%

Meropenem 17.6% 19.7%Meropenem 17.6% 19.7%

Inappropriate PrescriptionsInappropriate Prescriptions• 42% of target antibiotic prescriptions 42% of target antibiotic prescriptions were were considered inappropriateconsidered inappropriate

Compliance to SuggestionsCompliance to Suggestions• 42% of target antibiotic prescriptions 42% of target antibiotic prescriptions were were considered inappropriateconsidered inappropriate 46% of inappropriate prescriptions 46% of inappropriate prescriptions were changed to more appropriate were changed to more appropriate antibiotics antibiotics according to suggestionsaccording to suggestions

Compliance to SuggestionsCompliance to Suggestions• 42% of target antibiotic prescriptions 42% of target antibiotic prescriptions were were considered inappropriateconsidered inappropriate 46% of inappropriate prescriptions 46% of inappropriate prescriptions were changed to more appropriate were changed to more appropriate antibiotics antibiotics according to suggestionsaccording to suggestions 24% of inappropriate prescriptions 24% of inappropriate prescriptions were discontinued according to were discontinued according to suggestionssuggestions(antibiotics were not needed)(antibiotics were not needed)

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

Outcomes of PatientsOutcomes of PatientsClinical Outcome Control Clinical Outcome Control Intervention p Intervention p (N=516) (N=516) (N=512) (N=512) Favorable Outcome 60.5% Favorable Outcome 60.5% 68.9% <0.01 Eradicate Pathogens 68.9% <0.01 Eradicate Pathogens 50.2% 65.4% <0.01 50.2% 65.4% <0.01Mean LOS 30.7 d. 30.4 Mean LOS 30.7 d. 30.4 d. 0.8d. 0.8 Mean Length Fever 11.0 d. Mean Length Fever 11.0 d. 7.5 d. <0.01 7.5 d. <0.01 Antibiotic Allergy 1.4% 0.4% Antibiotic Allergy 1.4% 0.4% 0.1 0.1AAD 3.5% AAD 3.5% 4.9% 0.24.9% 0.2 Death from Infection 35.4% Death from Infection 35.4% 29.4% 0.05 Mean d. all ATB 29.4% 0.05 Mean d. all ATB 16.4 d. 12.7 d. <0.01 Mean d. 16.4 d. 12.7 d. <0.01 Mean d. target ATB 9.3 d. 7.5 d. <0.01target ATB 9.3 d. 7.5 d. <0.01 Alive at Discharge 57.4% Alive at Discharge 57.4% 55.6% 0.655.6% 0.6

Outcomes of PatientsOutcomes of PatientsClinical Outcome Control Clinical Outcome Control Intervention p Intervention p (N=516) (N=516) (N=512) (N=512) Favorable Outcome 60.5% Favorable Outcome 60.5% 68.9% <0.01 Eradicate Pathogens 68.9% <0.01 Eradicate Pathogens 50.2% 65.4% <0.01 50.2% 65.4% <0.01Mean LOS 30.7 d. 30.4 Mean LOS 30.7 d. 30.4 d. 0.8d. 0.8 Mean Length Fever 11.0 d. Mean Length Fever 11.0 d. 7.5 d. <0.01 7.5 d. <0.01 Antibiotic Allergy 1.4% 0.4% Antibiotic Allergy 1.4% 0.4% 0.1 0.1AAD 3.5% AAD 3.5% 4.9% 0.2 4.9% 0.2 Death from Infection 35.4% Death from Infection 35.4% 29.4% 0.05 Mean d. all ATB 29.4% 0.05 Mean d. all ATB 16.4 d. 12.7 d. <0.01 Mean d. 16.4 d. 12.7 d. <0.01 Mean d. target ATB 9.3 d. 7.5 d. <0.01target ATB 9.3 d. 7.5 d. <0.01 Alive at Discharge 57.4% Alive at Discharge 57.4% 55.6% 0.655.6% 0.6


Control Control Intervention Intervention (N=516) (N=512)(N=516) (N=512)Total Cost all ATB (m.$) 0.71 Total Cost all ATB (m.$) 0.71 0.54 0.54 Total Cost target ATB (m.$) 0.34 Total Cost target ATB (m.$) 0.34 0.280.28All ATB/Episode ($) 1,238 All ATB/Episode ($) 1,238 967 Target ATB/Episode ($) 661 967 Target ATB/Episode ($) 661 538 538DDD all ATB 13,528 DDD all ATB 13,528 10,738 10,738 DDD target ATB 3,696 DDD target ATB 3,696 2,9722,972DDD all ATB/Episode 26.2 DDD all ATB/Episode 26.2 21.0 21.0 DDD target ATB/Episode 7.2 DDD target ATB/Episode 7.2 5.85.8


Control Control Intervention Intervention (N=516) (N=512)(N=516) (N=512)Total Cost all ATB (m.$) 0.71 Total Cost all ATB (m.$) 0.71 0.54 0.54 Total Cost target ATB (m.$) 0.34 Total Cost target ATB (m.$) 0.34 0.280.28All ATB/Episode ($) 1,238 All ATB/Episode ($) 1,238 967 Target ATB/Episode ($) 661 967 Target ATB/Episode ($) 661 538 538DDD all ATB 13,528 DDD all ATB 13,528 10,738 10,738 DDD target ATB 3,696 DDD target ATB 3,696 2,9722,972DDD all ATB/Episode 26.2 DDD all ATB/Episode 26.2 21.0 21.0 DDD target ATB/Episode 7.2 DDD target ATB/Episode 7.2 5.85.8

Minimal “Squeezing the Balloon Minimal “Squeezing the Balloon Effect”Effect”


• Actual difference in antibiotic Actual difference in antibiotic

expenditures between antibiotic approval expenditures between antibiotic approval

group and control group was $ 143,793group and control group was $ 143,793• Annual antibiotic cost savings from Annual antibiotic cost savings from

antibiotic approval program would be $ antibiotic approval program would be $

862,704 if all prescriptions of target 862,704 if all prescriptions of target

antibiotics were reviewed by infectious antibiotics were reviewed by infectious

disease physiciansdisease physicians

ConclusionConclusion

Antibiotic approval program for Antibiotic approval program for

imipenem, meropenem, imipenem, meropenem,

piperacillin/tazobactam at Siriraj piperacillin/tazobactam at Siriraj

Hospital is an effective measure in Hospital is an effective measure in

reducing antibiotic consumption & reducing antibiotic consumption &

expenditureexpenditure without compromising without compromising

patients’ clinical outcomespatients’ clinical outcomes

Cost-Benefit of Antibiotic Approval Cost-Benefit of Antibiotic Approval ProgramProgram

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

Prerequisite of Antibiotic Approval Prerequisite of Antibiotic Approval ProgramProgram

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

Prerequisite of Antibiotic Approval Prerequisite of Antibiotic Approval ProgramProgram

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

ImplementationsImplementations• Study results were presented to Study results were presented to

hospital administrators in April 2008hospital administrators in April 2008• Siriraj Hospital informed all responsible Siriraj Hospital informed all responsible

physicians regarding the study results physicians regarding the study results • Antibiotic approval measure has been Antibiotic approval measure has been

continued since May 2008continued since May 2008

More InformationMore Information

• Poster Number 291Poster Number 291

• American Journal of Infection Control American Journal of Infection Control

2010; 38: 38 - 43.2010; 38: 38 - 43.

Antibiotic Approval Program on Antibiotic Approval Program on

Patients’ Clinical Patients’ Clinical

Outcomes and Outcomes and

Antibiotic Expenditures Antibiotic Expenditures

at Siriraj Hospital at Siriraj Hospital

Pinyo Rattanaumpawan MD Pinyo Rattanaumpawan MD Patama Sutha MD Patama Sutha MD Visanu Thamlikitkul MDVisanu Thamlikitkul MD

Department of Medicine Department of Medicine Faculty of Medicine Siriraj Hospital Faculty of Medicine Siriraj Hospital

Mahidol University, Bangkok, ThailandMahidol University, Bangkok, Thailand

Characteristics of PatientsCharacteristics of PatientsCharacteristic Control Characteristic Control Intervention p Intervention p (N=516) (N=516) (N=512) (N=512)

Underlying Conditions of Patients Underlying Conditions of Patients

Cardio-pulmonary 38.7% 54.1% Cardio-pulmonary 38.7% 54.1%

<0.01 <0.01 Malignancy 34.0% Malignancy 34.0%

42.0% 0.01 Liver Diseases 42.0% 0.01 Liver Diseases

6.6% 11.7% 0.01 Renal 6.6% 11.7% 0.01 Renal

Diseases 16.3% 22.3% Diseases 16.3% 22.3%

0.02 Neurological Dis. 15.4% 0.02 Neurological Dis. 15.4%

22.9%22.9% 0.010.01

Clinical Outcomes of PatientsClinical Outcomes of Patients

• Different characteristics between 2 Different characteristics between 2

groupsgroups• Multivariate analysis was performedMultivariate analysis was performed

Factors associated with unfavorable Factors associated with unfavorable

outcome outcome

OR (95%CI) OR (95%CI)

pp

Control group patient 1.35 (1.03-1.76) Control group patient 1.35 (1.03-1.76)

0.03 0.03

Pneumonia 2.36 (1.78-Pneumonia 2.36 (1.78-

3.15) <0.013.15) <0.01

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

Subgroup Analysis inSubgroup Analysis inMicrobiological Documented Microbiological Documented

InfectionsInfections

Clinical OutcomeClinical Outcome ControlControl Intervention Intervention pp

(N=290) (N=323)(N=290) (N=323)

Favorable Outcome 58.9% 65.6% Favorable Outcome 58.9% 65.6% 0.08 0.08

Eradicate Pathogen 50.2% 65.4% Eradicate Pathogen 50.2% 65.4% <0.01 <0.01

Death (Infection) 37.9% 31.9% Death (Infection) 37.9% 31.9% 0.1 0.1

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

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

Different Rates ofDifferent Rates of ComorbidityComorbidity • Differences in characteristics of Differences in characteristics of patients would not favor outcomes of patients would not favor outcomes of patients who received antibiotic approval patients who received antibiotic approval because higher rates of having because higher rates of having comorbidity that compromised clinical comorbidity that compromised clinical outcomes were observed more often in outcomes were observed more often in patients who received antibiotic approvalpatients who received antibiotic approval

Inappropriate Use of Target Inappropriate Use of Target AntibioticsAntibiotics

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

Clinical Outcomes in Antibiotic Clinical Outcomes in Antibiotic ApprovalApproval

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


• Patients in antibiotic approval group Patients in antibiotic approval group had better outcomeshad better outcomes• Many patients in control group who had Many patients in control group who had no infections or had colonization or had no infections or had colonization or had infections with resistant pathogens, (e.g. infections with resistant pathogens, (e.g. MRSA) continued to receive target MRSA) continued to receive target antibiotics leading to super-infections antibiotics leading to super-infections with organisms (e.g. MRSA, pandrug-with organisms (e.g. MRSA, pandrug-resistant resistant AcinetobacterAcinetobacter spp, or spp, or CandidaCandida spp.) which were resistant to target spp.) which were resistant to target antibiotics, resulting in unfavorable antibiotics, resulting in unfavorable outcomes and mortalityoutcomes and mortality


• Although some baseline characteristics Although some baseline characteristics of patients in both groups were of patients in both groups were significantly different, the results of significantly different, the results of multivariate analysis showed that being a multivariate analysis showed that being a patient in control group and having patient in control group and having pneumonia was significantlypneumonia was significantlyassociated with unfavorable outcomeassociated with unfavorable outcome• This observation confirmed that a This observation confirmed that a difference in favorable clinical outcomes difference in favorable clinical outcomes was associated with antibiotic approval was associated with antibiotic approval program because hospital-acquired program because hospital-acquired pneumonia was a well-known factor pneumonia was a well-known factor associated with poor clinicalassociated with poor clinicaloutcome of hospitalized patientsoutcome of hospitalized patients


• Length of hospital stay and patients’ Length of hospital stay and patients’ survival at hospital discharge were not survival at hospital discharge were not significantly different in either group significantly different in either group because most of patients in both groups because most of patients in both groups had chronic underlying diseases, and had chronic underlying diseases, and they were hospitalized because of these they were hospitalized because of these medical problems and died of such medical problems and died of such comorbiditiescomorbidities

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

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

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

Defined Daily Dose (DDD)Defined Daily Dose (DDD) • DDD is a measure of assumedDDD is a measure of assumed average average maintenance dose per day for a maintenance dose per day for a drugdrug used asused as a main indication in adultsa main indication in adults

Defined Daily Dose (DDD)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


Antibiotic Approval ProgramAntibiotic Approval ProgramAntibiotic Cost Saving Antibiotic Cost Saving Control - Intervention = 4.8 mB for 4 Control - Intervention = 4.8 mB for 4 months Annual Antibiotic Cost months Annual Antibiotic Cost Saving = 14.4 mBSaving = 14.4 mB

Antibiotic Cost Saving = 4.5 mB for 4 Antibiotic Cost Saving = 4.5 mB for 4 months if 516 prescriptions in the months if 516 prescriptions in the control group were reviewed by control group were reviewed by infectious diseases specialistinfectious diseases specialist

MethodsMethodsSample SizeSample Size• Non-inferiority studyNon-inferiority study Favorable outcome in control gr. = Favorable outcome in control gr. = 70%70% Favorable outcome in intervention Favorable outcome in intervention group group was was << 5% of control group 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 group500 prescriptions in each groupStatisticsStatistics• Descriptive statistics, Chi-square/ Descriptive statistics, Chi-square/ Fisher’s Fisher’s exact test, Student t-test/ Mann-exact test, Student t-test/ Mann-Whitney Whitney U-test, multivariate analysis U-test, multivariate analysis

Documents

Antibiotic Approval Program on Patients’ Clinical Outcomes and Antibiotic Expenditures at Siriraj Hospital Pinyo Rattanaumpawan MD Patama Sutha MD Visanu