Intervensions and Strategies to Improve the Use of Antimicrobials in Developing Countries

WHO/CDS/CSR/DRS/2001.9ORIGINAL: ENGLISHDISTRIBUTION: GENERAL

World Health Organization

Interventions andstrategies to improvethe use of antimicrobialsin developing countriesDrug Management Program

Copies can be obtained from the CDS Information Resource CentreWorld Health Organization, 1211 Geneva 27, Switzerland

fax: +41 22 791 42 85 email: [email protected]

WHO/CDS/CSR/DRS/2001.9ORIGINAL: ENGLISHDISTRIBUTION: GENERAL

Interventions andstrategies to improvethe use of antimicrobialsin developing countries:a reviewDrug Management ProgramManagement Sciences for HealthArlington, VA, United States of America

World Health Organization

A BAC

KGRO

UND D

OCUM

ENT F

OR

THE W

HO GL

OBAL

STRA

TEGY

FOR C

ONTA

INME

NT OF

ANTIM

ICROB

IAL

RESIS

TANC

E

Acknowledgement

The World Health Organization wishes to acknowledge the support of the United States Agency for Inter-national Development (USAID) in the production of this document.

Contributors to this report included Ama de Graft-Aikins, International Network for Rational Use ofDrugs Ghana; John Chalker, Global Technical Leadership Coordinator, Rational Pharmaceutical Manage-ment Plus Project; David Lee, Technical Deputy Director, Drug Management Program (DMP) of Manage-ment Sciences for Health; and Maria Miralles, Research and Evaluation Manager, DMP. This documentwas produced under the terms of cooperative agreement number HRN-A-92-00059-13.

World Health Organization 2001

This document is not a formal publication of the World Health Organization (WHO), and all rights are reserved by the Organiza-tion. The document may, however, be freely reviewed, abstracted, reproduced and translated, in part or in whole, but not for sale orfor use in conjunction with commercial purposes.

The views expressed in documents by named authors are solely the responsibility of those authors.

The designations employed and the presentation of the material in this document, including tables and maps, do not imply theexpression of any opinion whatsoever on the part of the secretariat of the World Health Organization concerning the legal status ofany country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines onmaps represent approximate border lines for which there may not yet be full agreement.

The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended byWHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietaryproducts are distinguished by initial capital letters.

Designed by minimum graphicsPrinted in Switzerland

Contents

iii

WHO/CDS/CSR/DRS/2001.4 DRUG RESISTANC IN MALARIA

Abbreviations and acronyms iv

Background 1

1. Introduction 2

2. Objectives 4

3. Methodology 53.1 Search strategy 53.2 Criteria for methodological adequacy 53.3 Measuring study effects and effect size 6

4. Results 74.1 Overview of results 7

Table 1. Interventions across geographical areas and study settings 8Table 2. Distribution of studies by type of intervention and design 8Table 3a. Studies by identified categories and subcategories of intervention types 9Table 3b. Studies by identified categories and subcategories of intervention types 9Table 3c. Studies by identified categories and subcategories of intervention types 10Table 4. Distribution of studies by targeted health care providers, health

problems, and practices 10Table 5. Percentage magnitude of improvement by type of intervention concentrating

on the following outcomes: use of antimicrobials, dose of antimicrobials,under-5 mortality rate 11

4.2 Analysis of results 114.2.1 Types of interventions tested 114.2.2 Targets of interventions: health care providers, health problems, and practices 124.2.3 Outcomes measured 124.2.4 Impacts of interventions 13

4.3 Evaluating the effectiveness of intervention strategies 134.3.1 Educational interventions 134.3.2 Combined managerial and educational approaches 144.3.3 Managerial approaches 154.3.4 Economic interventions 15

5. Discussion 165.1 Effectiveness of different types of interventions 165.2 Neglected issues 17

5.2.1 Settings 175.2.2 Conditions 175.2.3 Cost-effectiveness 17

5.3 Limitations of this review 17

6. Conclusion 19

Appendix 1. Characteristics of intervention studies 20

Bibliography 29

iv

Abbreviations and acronyms

AB antibioticARCH Applied Research for Child Health [Project]ARI acute respiratory infectionC control groupCCM community case managementCHWs community health workersDx diagnosisE experimental groupEDP essential drugs programHCs health centresICIUM International Conference on Improving the Use of MedicinesINRUD International Network for Rational Use of DrugsNIS Newly Independent StatesPHC primary health carePP&C pre-, post-measurements with comparisonRCT randomized control trialsRPM Rational Pharmaceutical Management [Project]Rx prescriptionRxg prescribingSTDs sexually transmitted diseasesSTGs standard treatment guidelinesTS&C time series with comparisonTS-C time series without comparisonTx treatmentUSAID United States Agency for International DevelopmentUSP United States PharmacopeiaUTI urinary tract infectionsWHO/DAP World Health Organization Action Programme on Essential Drugs

INTERVENTIONS AND STRATEGIES TO IMPROVE THE USE OF ANTIMICROBIALS IN DEVELOPING COUNTRIES WHO/CDS/CSR/DRS/2001.9

1WHO/CDS/CSR/DRS/2001.9 INTERVENTIONS AND STRATEGIES TO IMPROVE THE USE OF ANTIMICROBIALS IN DEVELOPING COUNTRIES

Background

Use of Medicines (ICIUM). The conference iden-tified key topics for research on improving prescrib-ing and dispensing practices, improving communityuse of medicines, and developing effective phar-maceutical policies and regulations. Also recognizedwas the need for innovative interventions to im-prove malaria case management and well-designedinterventions in hospitals and private sector settings.

In 1998 RPM received funds from the UnitedStates Agency for International Development(USAID), through the global initiative to slow theemergence of antimicrobial resistance, to conducta technical review that would refine and updatecurrent knowledge of the effectiveness of interven-tions aimed at the use of antimicrobials. Thisactivity is within the mandate of RPMs technicalleadership programme. The partners for this activ-ity are INRUD Ghana and the Harvard UniversityDrug Policy Group.

This review serves as a springboard to furtherwork on interventions to improve the use ofantimicrobials. To the extent that there are stillmany gaps in our understanding of the determi-nants of drug use in general and antimicrobials inparticular, our understanding of why some inter-ventions appear to be more effective than others isalso not complete. More rigorous design, imple-mentation, and follow-up of intervention researchcan greatly assist in closing these gaps. Health careplanners, managers, and practitioners can benefitgreatly from this information by quickly identify-ing the most appropriate strategies to improve druguse in their contexts and expect reasonable improve-ments in the use of antimicrobials, and, ultimately,a reduction in the rates of resistance.

A significant force driving the spread of antimicro-bial resistance is the inappropriate use ofantimicrobials in primary care and hospital settings.This is related to overprescribing as well as inap-propriate selection and dosing of antibiotics byhealth care providers, unfettered access to anti-microbials by consumers, and a failure to adhere toclinically desirable treatment regimens. Conse-quently, interventions focusing on health provid-ers have been widely recommended andimplemented. These include educational interven-tions that aim to change behaviour by changingpeoples knowledge (e.g. formal education, semi-nars, training, distribution of literature, academicdetailing), managerial interventions that aim toguide behaviour (e.g. formulary lists, treatmentguidelines, clinical supervision systems, audit, andfeedback), and regulatory interventions that definewhat is required and legal (e.g. professional licens-ing, registration, practice laws). However, not allthe proposed interventions have been rigorouslytested to determine their impact on the use ofantimicrobials. Hence, it is likely that manylessons learned already, both positive and negative,are being repeated, some at a cost that must bequestioned in light of the results.

Some efforts have been made to promote refine-ment of the state-of-the-art of drug use interven-tion research in general. In 1997 the RationalPharmaceutical Management (RPM) Project, theApplied Research for Child Health (ARCH)Project, the International Network for Rational Useof Drugs (INRUD), the United States Pharmaco-peia (USP), and the WHO Action Programme onEssential Drugs (WHO/DAP) cosponsored theFirst International Conference on Improving the


2

1. Introduction

Inappropriate drug use is characterized by anyof the following: overprescription (prescribing drugswhen none are needed clinically); omission (whenrequired drugs for certain conditions are not pre-scribed); the use of inappropriate dosages (too highor too low); incorrect duration (too short or toolong); incorrect selection (mismatch between or-ganisms); unnecessary expense (the selection ofnewer and more expensive drugs when older,cheaper drugs are clinically adequate); and unnec-essary risk (use of injections or intravenous anti-biotics when oral forms would be suitable).Participants in drug use decisions include not onlyclinically trained health care providers, and author-ized and other dispensers, but also consumers whoengage in self-initiated purchasing of drugs with-out contact with prescriber or dispenser and theuse of drugs left over from previous treatments. Forantimicrobials, these characteristics of inappropri-ate drug use cause particular concern for the devel-opment of resistance.

There is a strong correlation between inappro-priate prescribing and inappropriate self-medica-tion (Greenhalgh, 1987), but generally drug usewithin these groups is rooted in a complex andmultilayered mix of medical, psychosocial, cultural,economic, and even geopolitical factors. Within thiscomplex, a number of factors have been associatedwith suboptimal use of antibiotics, particularlywithin the context of prescribing and dispensinghealth care provider groups. These include (1) in-sufficient prescriber knowledge about differentialdiagnosis, the kinds of conditions treatable withantibiotics and appropriate therapies for bacterialinfections; (2) patient demands and preferences fortreatment, sometimes real, sometimes based onmisperceptions by health providers; (3) fear of lossof economic incentives due to patient dissatisfac-tion arising from non-response to perceived patientdemands; (4) fear of negative clinical outcomes inthe absence of therapy; (5) influence of social andcultural norms or opinion leaders on practice; (6)promotional pressures of pharmaceutical compa-nies; and (7) wish to maximize profits. To a lesser

The use of antimicrobials1 has contributed to thedramatic fall in morbidity from communicable andinfectious diseases over the last 50 years globally(e.g. UNIDO, 1980; WHO, 1988, 1996; Kuninet al., 1990; Richardson, 1992), as to increasinglyhigh levels of expenditure on and consumption ofantimicrobials. A substantial proportion of thetotal drug budget in many countries is dedicatedto antibiotics and they are often the largest singlegroup of drugs purchased in developing countries.However, despite the vast advancements broughtabout since the development of antibiotics andantimicrobials, their widespread availability and usehave had several negative implications on globalhealth care, among these the inappropriate use byhealth care providers and consumers and the in-crease of drug resistance. The primary economicimplication of resistance on the diminishing effi-cacy of antibiotic treatment includes the need torely on more expensive drugs that may be practi-cally unaffordable for most primary health careprogrammes.

In developing countries, relatively high levels ofavailability and consumption have led to dispro-portionately higher incidence of inappropriate useand greater levels of resistance compared to devel-oped countries (WHO, 1988, 1996). Surveys onantibiotic use in these settings show antibiotics pre-scribed in 35 to 60% of clinical encounters althoughappropriate in less than 20% (Trostle, 1996). Arecent comparative analysis of inappropriate pre-scribing by physicians and other professional per-sonnel in 12 developing countries also highlightedan unnecessarily high proportion (25 to 75%) ofpatients receiving antibiotics during clinical visits(Hogerzeil et al., 1993). These indicate the con-tinuing need to curb the irrational, or inappropri-ate, use of antimicrobial agents and to identifyeffective interventions to improve drug use.

1 The terms antimicrobial and antibiotic are often used inter-changeably. Antibiotics are natural substances that inhibitthe growth of bacteria or kill them directly. In practice,though, most commercial antibiotics have been chemicallyaltered or enhanced, producing antimicrobials.


extent, inadequate drug supply infrastructure, in-appropriate or outdated treatment guidelines, lackof access to correct clinical information, and workenvironment factors also contribute in varyingmeasure to inappropriate use of antibiotics by pre-scribers and dispensers. Attempts to improve anti-biotic use should aim to identify the key factorsthat promote overuse, such as those describedabove, and develop interventions that address theidentified factors.

Despite the volume of studies that describe in-appropriate drug use in general, and antimicrobialdrug use in particular, there is relatively little knownabout effective strategies to improve the use ofantimicrobials in the developing country context.A recent study evaluated strategies to improve gen-eral medication use in primary care in 56 develop-ing countries (Ross-Degnan et al., 1997). Althoughthis review did not concentrate on antimicrobialdrug use, it did show that the most common prac-

tice addressed by the interventions was the prescrib-ing of antibiotics, with 76% of the studies focus-ing directly or indirectly on improving antibioticuse. The desired outcome for most of the studiesreviewed was typically a reduction in unnecessaryprescribing of antibiotics, although in interventionsthat sought to improve compliance with treatmentguidelines of specific diseases such as acute respira-tory infections, an increase in the prescribing of apreferred antibiotic was the desired outcome.

This paper aims to follow up on the above-ref-erenced review by focusing specifically on evaluat-ing interventions aimed at improving antimicrobialuse in developing countries. It is hoped that theunderstanding gained through this exercise will notonly identify gaps in our knowledge about the ef-fectiveness of interventions, but also serve as a guidein the development of research agendas and appli-cations of results to address antimicrobial use inthese regions.


4

2. Objectives

aimed to identify the interventions that appear tobe most effective in improving antimicrobialprescribing and dispensing and other outcomes ofantimicrobial use by health care providers, and toassess their level of impact. Finally, it aimed toidentify critical gaps in current knowledge aboutinterventions and on measuring their impact onantimicrobial use specifically in developing coun-try settings.

The overall objective of this review was to surveypublished and unpublished interventions to im-prove the use of antimicrobials in developing coun-tries and evaluate the evidence of their effectiveness.Within this general aim were three specific objec-tives. First, the review set out to select interven-tions that meet minimum methodological criteriafor validity in study design and compare their ex-periences in terms of settings, target conditions andpopulations, and outcome measures. Second, it


3. Methodology

current selection of 36 studies using the followinginclusion criteria:

Studies from the following geographical areas:Africa, Asia, Latin America, and the Newly In-dependent States and Eastern Europe

Studies targeted at public and private sectorhealth care providers, which were divided intothree main categories: (1) clinically trainedhealth providers, which included physicians andother authorized prescribers such as nurses, clini-cal officers, medical aides, and health workers;(2) authorized dispensers, which included phar-macists and counter attendants; and (3) otherdispensers such as drug sellers and variety store-keepers

Studies focusing on antibiotic use on the fol-lowing target conditions: respiratory infections(otitis media, pharyngitis, sinusitis, no-pneumo-nia cough/bronchitis, pneumonia, and purulentrhinitis/common cold), gastrointestinal condi-tions (acute watery diarrhoea, such as choleraand non-cholera, and bloody diarrhoea), skininfections, hospital infections (systemic prophy-laxis, wound infections), fever, genitourinaryinfections (urinary tract infections [UTI], andsexually transmitted diseases [STDs])

Studies using the following study designs:randomized control trials (RCT), before andafter measurements with a comparison group(PP&C), and time series with or without a com-parison group (TS&C, TS-C)

3.2 Criteria for methodological adequacy

The stated study designs were preselected for anumber of reasons. Generally within the contextof the experimental design, the RCT is the idealparadigm for providing valid scientific evidence.This is because it has the strength of eliminatingconfounding variables by the process ofrandomization. However RCTs and experimentaldesigns are often not feasible when studying

3.1 Search strategy

A database of published and unpublished interven-tion studies on improving antimicrobial use byhealth care providers in developing countries wasgenerated using three main search strategies. First,a search was conducted for abstracts, posters, jour-nal articles, reports, reviews, and newslettersreporting interventions to improve the use of anti-microbial drugs by health care providers. The searchwas conducted on the WHO/DAP website, thecomputerized INRUD database, and the pro-gramme and abstract book of ICIUM. Next, asearch on general medical health literature was con-ducted using the computerized retrieval systemMEDLINE (19661999). The search was for arti-cles with the keywords antimicrobial, antibiotic,antibiotic use, or those that referred to the nameof any individual antibiotic. The initial collectionwas then limited to articles about drug utilization,or prescribing, and those whose title implied anintervention because of the use of action words likereducing, improving, and so on. Establishedcanned strategies aimed at accomplishing suchscreens were used in this selection process. Pen-ultimately, the search was limited to articles fromAfrica, Latin America, and Asia.1 Finally materialsof interest, especially from the Newly IndependentStates (NIS) and Eastern Europe, were requestedfrom individual researchers and organizationsknown to be involved in research on improving theuse of drugs. These were identified through RPMcontacts in the NIS, including the Russian Federa-tion, the Republic of Moldova, Ukraine, and Hun-gary, in addition to the MEDLINE and INRUDbibliographical searches. Data were extracted byone researcher only, and the authors were notapproached.

This initial broad collection of studies on anti-microbial use was then narrowed down to the

1 These included countries not on the Organization for Eco-nomic Cooperation and Development list of industrializedcountries for 1998.


6

human groups. In real-life settings it is oftenimpossible to assign people at random to two groupsor to maintain a control group. Therefore experi-mental designs are often replaced by quasi-experimental designs. With these designs at leastone characteristic of a true experiment is missingeither randomization or the use of a separate con-trol group. However it always includes manipula-tion of an independent variable that serves as theintervention. Studies that use strong quasi-experimental designs such as before and after stud-ies with control groups and time series studies withor without comparison groups are generally con-sidered to be adequate for guiding policy (Campbelland Stanley, 1963; Cook and Campbell, 1979;Varkevisser et al., 1991).

3.3 Measuring study effects andeffect size

Five main outcome measures were identified forassessing change in antibiotic use: changes in healthcare provider knowledge of antibiotic use (diagno-sis, therapy), changes in prescribing and adminis-tration of antibiotics, changes in clinical outcome,changes in patient factors (satisfaction, improvedknowledge on illness and drugs, changes in mor-tality, duration or severity of illness), and changesin cost of antibiotic use.

The interventions included in this review tookplace in different countries and health settings, useddifferent approaches and methodologies, targeteddifferent audiences and practices, and measureddifferent outcomes. In order to evaluate the rela-tive effectiveness of these different interventionstrategies it was important to develop a metric forcomparing effect sizes across studies that took intoaccount the heterogeneity of study dynamics. Asystematic process for summarizing relative effectsizes in all included studies was therefore developed.

This involved firstly outlining all the outcomesidentified by authors as the targets for their inter-vention(s). In order to indicate the magnitude of

effects of an intervention, the outcome measureswithin this outlined group for which the studyachieved a significant positive change were identi-fied (e.g. reduction in antibiotic prescribing, in-crease in number of cases treated according to atreatment guideline, or a reduction in disease-spe-cific mortality). All outcome measures were thenconverted to a scale where positive change wasindicated by positive numbers.

The procedure for calculating effect size de-pended on how study outcomes were measured.Generally, outcome measures reported within thestudies were expressed as percentages (e.g. percent-age of patients receiving an injection), mortalityrates (e.g. deaths per 1000 live births in childrenunder five), performance scores (e.g. a knowledgeindex), or numerical scores (e.g. number of casestreated according to a treatment guideline). Foroutcomes measured as percentages, effect size wascomputed as the relative gain in the interventiongroup, calculated as the net difference between thepercentage improvement in the intervention groupand the percentage improvement in the compari-son group.1 For outcomes measured as mortalityrates, performance scores, or numerical scores, thechanges before and after intervention were con-verted into percentages by dividing the absolutechanges (post-intervention) by baseline values.2

For studies using time series or repeated meas-ures without comparison groups, effect size wascalculated as percentage improvement between thestable pre-intervention percentage and the stablepost-intervention percentage; short-term shifts inpercentage immediately before or after an interven-tion were discounted as transitory effects.

It is important to note that the taxonomy of in-terventions used in this study was developed byMSH and is used in many developing countries.However, in other parts of the world studies tendto use the taxonomy developed by the EffectivePractice and Organization of Care (EPOC) groupof the Cochrane Collaboration.

1 Effect size = (%POST%PRE)intervention

(%POST%PRE)

control

2 Effect size = ((%POST%PRE) / PRE)intervention

) ((%POST%PRE) / PRE)

control )


4. Results

one in which prescribers are persuaded by pro-viding information or knowledge for them(Managing Drug Supply, 1997, p. 466). The edu-cational intervention may be face-to-face inter-ventions, trainings, seminars, workshops, orprovision of written material. A managerial in-tervention is one in which prescribers are guidedin the decision-making process. This guidancemay take the form of providing standard treat-ment guidelines, limited procurement lists,supervisory and monitoring visits, and so on. Amixed educational and managerial interventionprovides both guidance and persuasion. Lastly,an economic intervention provides a differenteconomic incentives environment.

The categories for these interventions aredescribed in Table 2 and then subcategorizedwith results in Tables 3a, 3b, and 3c. The distri-bution of interventions per category is 13educational interventions, 18 combinationeducational/managerial interventions, fourmanagerial interventions, and one economic in-tervention strategy. In addition, two of the com-bined managerial and educational interventionshad a purely managerial intervention as well.

5. The studies targeted three main groups of healthcare providers: (1) prescribers, which includedphysicians and paramedics (e.g. nurses, clinicalofficers, trained community health workers); (2)dispensers, including pharmacists and counterattendants, and other dispensers such as drugsellers and general or variety storekeepers; and(3) populations within communities. Table 4presents the distribution of studies by targetedhealth care providers, health conditions, andpractices. Twenty-two of the studies targetedphysicians, 25 targeted paramedics, nine targetedcommunity health workers, two targeted phar-macists and drug sellers, and 11 targeted thecommunity.

6. There were three main health conditions targetedby the studies: 18 targeted acute respiratory in-fections (ARI), 13 targeted gastrointestinal con-

1 Despite an active search for published and unpublishedinterventions to improve use of antibiotics in EasternEurope and the Newly Independent States, none werefound that met the study criteria.

4.1 Overview of results

There were 36 studies meeting the inclusion crite-ria. A comprehensive summary of results outliningthe characteristics of all selected interventions andtheir key measured outcomes is presented inAppendix 1. Each study in Appendix 1 has anumber in the first column. This number is usedfor reference in the tables. An overview of resultsindicates the following:

1. The selected studies were distributed over threegeographical regions: Asia, Africa, and LatinAmerica.1 The majority of studies (20) reviewedwere carried out in Asia. Distribution of remain-ing studies in Africa and Latin America was 10and 6, respectively. The majority of studies werecarried out in the early to mid-1990s. Threestudies (one Latin American and two African)were carried out in the 1980s.

2. The majority of studies (31) were conducted inpublic primary health care (PHC) facilities, ofwhich 11 were also carried out in the commu-nity. Three studies were carried out in hospitalsand two in private sector pharmacy/drugstoresettings. Table 1 presents the distribution of stud-ies across geographical areas and study settings.

3. In terms of methodology employed, 12 studieswere randomized controlled trials (RCTs), 16were pre-post-measurements with a comparisongroup studies (PP&C), and the remaining eightwere time series studies, of which three employedcomparison groups (TS&C) and five did not(TS-C) (Table 2).

4. The types of interventions tested were brokendown into four main categories: (1) educational,(2) combined educational and managerial, (3)managerial, and (4) an economic intervention.The definition of an educational intervention is


8

ditions (particularly diarrhoea), and six workedwith malaria. Three studies investigated otherspecific health conditions, namely hypertensionand urinary tract infections, in addition to themain ones. Six studies focused on health workerpractices (such as injection and rational drug use)across a broad range of health conditions (Table4).

7. Outcomes measured by the studies fell into fivecategories: changes in health providers knowl-edge of antibiotic use, prescribing and adminis-tration practices, dispensing practice, patientfactors, and drug costs. One study focused on

the cost of drugs as the main outcome measure.The outcomes focused on here for the sake ofimproved antimicrobial use are percentage ofchange in antibiotic use, percentage of changein correct dose prescribed, under-five mortalityrates, and malaria prevalence.

8. Thirty-one of the 36 studies reported the resultsof the intervention. Twelve studies reported atleast one large impact (>30% improvement in atargeted outcome relative to control), 12 re-ported moderate impact (1030% improve-ment), and seven had very low or no impact(


TABLE 3B. STUDIES BY IDENTIFIED CATEGORIES AND SUBCATEGORIES OF INTERVENTION TYPES

Educational and managerial Reference Nos. Results Prevalenceinterventions methods malaria

Antibiotic use


10

TABLE 3C. STUDIES BY IDENTIFIED CATEGORIES AND SUBCATEGORIES OF INTERVENTION TYPES

Managerial interventions Reference number Total number Effect

Reduction AB use Following STG

STG 24 1 [6%]

STG plus discussion 19 1 [-10%]

STG plus discussion, plus audit and review 19 1 [-24%]

Audit and review 33, 35 2 [dk], [dk]

Supervision, audit, and review 32 1 [ns] [14%]

Surveys, audit supervision, making plans 34 1 [-32%]

Economic interventions Reference number Total number Effect

Reduction AB use Following STG

Change from flat fee to item fee 36 1 [-7%]

Note: Brackets show results of equivalent intervention.ns non-significant at 95% level.dk dont know.

TABLE 4. DISTRIBUTION OF STUDIES BY TARGETED HEALTH CARE PROVIDERS, HEALTH PROBLEMS, AND PRACTICES

Intervention targets: Health conditions and health care provider practices

ARI Diarrhoea Malaria Other specific General health Practices***Intervention targets: conditions* conditions**Health care providers [18] [13] [6] [3] [6] [6]

PRESCRIBERS

Physicians [22] 11 10 4 3 5 6(2,4,7,8,11,14, (2,3,5,6,10,13, (2,14,24,33) (14,16,33) (1,31,32,34,36) (24,31,32,

16,19,26,30,32) 14,18,24,30) 34,35,36)

Paramedics [25] 10 6 5 3 6 6(2,7,8,14,15,16, (2,3,13,14,24,30) (2,9,14, 24,33) (14,16,33) (1,17,31, (24, 31,32,

21,26,27,30) 32,34,36) 34,35,36)

CHWs [9] 7 1 1 0 0 0(15,21,25,26, (22) (20)

27,28,29)

DISPENSERS

Pharmacists [1] 0 1 0 0 0 0(12)

Drug sellers/ 1 2 0 0 0 0storekeepers [2] (23) (12,23)

USERS

Community [11] 8 2 1 0 0 1(4,15,21,25,26, (10,22) (20) (17)

27,28,29)

Notes: 1. Number inside ( ) denotes reference number of study in Appendix I targeting different health care providers, health conditions, andhealth provider practices.

2. Number in [ ] in column headings denotes total number of studies that targeted ARI, diarrhoea, malaria, other specific conditions,general health conditions, and practices. Number in [ ] in far left column indicates total number of studies that targeted physicians,paramedics, CHWs, pharmacists, drug sellers/storekeepers, and the community.

* Lack of appetite, urinary tract infection, hypertension, trivial infections.** AB use, prescribing for all conditions.*** Health worker performance, drug-selling behaviour.

11

WHO/CDS/CSR/DRS/2001.9 INTERVENTIONS AND STRATEGIES TO IMPROVE THE USE OF ANTIMICROBIALS IN DEVELOPING COUNTRIES

4.2 Analysis of results

Throughout this analysis, numbers in parenthesesdenote the reference number of the relevant study.The studies that these reference numbers refer tocan be found in Appendix 1.

4.2.1 Types of interventions tested

The classification of the interventions was basedon the predominant strategy they employed toinfluence the use of antibiotics by health care pro-viders. It is important to note that while this sys-tem presented homogenized categories ofintervention studies (e.g. educational or manage-rial) each intervention had distinct characteristics.For example, while interventions may have appliedthe same intervention modalities (a training semi-nar, or development of treatment guidelines) theywere likely to have applied different study designsand varying levels of timeframe, intensity, or so-phistication. Several interventions, both within andbetween intervention group types, applied variedmultiple strategies. However, classifying the inter-ventions by predominant strategy used enabled aclear presentation of the range of tested strategiesaimed at improving the use of antibiotics. The dis-tribution of studies by type of intervention andstudy design is presented in Table 2. The distribu-tion of studies by primary intervention type andsubcategories of interventions with degree of effectis presented in Table 3ac. As many studies em-ployed multiple interventions, the number of in-terventions is greater than the number of studies.

Educational interventions were tested in 13 stud-

ies (Table 3a). Within these 13 studies there were10 intervention groups that had a single interven-tion, of which eight were some kind of trainingcourse, seminar, or workshop. One single interven-tion was community education and one the distri-bution of a newsletter. In addition there were 18strategies used in combination with each other.Trainings were combined with community educa-tion (4) as well as media coverage and peer review(10). Face-to-face education was combined withinteractive workshops and newsletters (3). Semi-nars and trainings were combined with a newslet-ter (1, 12), and newsletters were combined withinteractive workshops and trainings were combinedwith peer review (2, 6, 10, 11).

Eighteen studies involved some combination ofeducational and managerial strategy and were thuscategorized separately (see Tables 2 and 3b). Ten ofthese had a community case management approachfor improving the treatment of pneumonia (ninestudies) and malaria (one study). Overall standardtreatment guidelines (STGs) and supervision werethe most common interventions: five studies com-bined providing STGs with training (19, 23, 24,25, 31), one had a consensual STG building exer-cise alone (14), whereas another combined that withsupervision, training, mass education, and condi-tional supply of drugs and equipment (17). Threestudies had STGs and mass education, one com-bining with printed material (15) and two com-bining with training (25, 26). Supervision wascombined with training in five (21, 22, 27, 28, 30)and with an STG in addition (18), and with drugsin addition (20). One combined regulations with

TABLE 5. PERCENTAGE MAGNITUDE OF IMPROVEMENT BY TYPE OF INTERVENTION CONCENTRATING ON THE FOLLOWINGOUTCOMES: USE OF ANTIMICROBIALS, DOSE OF ANTIMICROBIALS, UNDER-5 MORTALITY RATE

Greatest effect change in outcome measure

Types of Excluded Total no.intervention 50% results of studies

Educational 3 5 1 2 1 0 1 13(1,9 ,10) (2,3,4,7,13) (8) (5,6) (11) (12)

Educational/ 3 2 3 2 2 4 2 18Managerial (14,24,31) (23,27) (15,22,28) (21,29) (20,26) (17,18,19,25) (16,30)

Managerial [1] 1 [1] 1 0 0 2 4 [2](24) (32) (19) (34) (33,35)

Economic 1 1(36)

Total effect change 7 [1] 8 4 [1] 5 3 4 5 36 [2]by intervention type

Notes: [ ] includes studies that have been categorized under a different section as well. Numbers in italics and parentheses refer to studies asnumbered in Appendix 1.


12

advocacy and training (16). Thus of the 18 studyinterventions in this section, 14 used STGs and 11used supervision as managerial interventions com-bined with 16 using some form of training.

Four studies and two interventions in other stud-ies used purely managerial interventions (Tables 2and 3c). Audit and review was the most commonintervention. It was used alone in two (33, 35),combined with supervision in one (32), and usedin addition to surveys and planning in one (34)and with STGs and discussion in another (19).STGs (24) with discussions (19) made up theothers.

The final category of interventions reviewed waseconomic. Only one study fell under this category(36). It focused mainly on the impact of differen-tial drug pricing on prescribing practices and onpatients ability to remember dosing schedulesaccording to the number of dispensed drug items.Although this may be considered to be a manage-rial intervention, because the intervention wasgeared less on guiding behaviour and more on pro-viding incentives for behaviour change, it is worth-while considering this as a separate category.

4.2.2 Targets of interventions: Health careproviders, health problems, and practices

The interventions targeted a broad range of healthcare providers and three major health problems.Some studies targeted health care providers prac-tices, such as injection use or polypharmacy, acrossa range of different health problems.

Physician practices were the predominant focusin a majority of the studies (n=22), while the prac-tices of paramedics such as nurses and clinical of-ficers were the target of 25 studies (Table 4). Ninestudies targeted some type of community worker,such as village health workers or midwives. Thedispensing practices of pharmacists and counterattendants were the subjects studied in one study,while practices of other dispensers such as com-munity drug sellers and storekeepers were studiedin another. Lastly, in addition to targeting healthcare providers, five studies focused on the healthand drug use behaviours of communities at whichthe interventions were targeted.

Overall, 17 studies focused on the treatment ofARI, 14 on diarrhoea, and six on malaria. Onlythree studies addressed other specific health condi-tions in addition to one or more of the aforemen-tioned health problems. These were namelyhypertension (14), urinary tract infection (16), and

trivial infections (33). In addition, six focused ongeneral health conditions and health worker prac-tices.

The most common practice addressed by all thestudies was the prescribing of antibiotics in thetreatment of ARI, diarrhoea, and malaria. The de-sired outcome was a change in inappropriate pre-scribing of antibiotics. In all cases other than forARI, the desired outcome was a reduction in use aswell as in two studies an improvement in dose (2,17). However, for ARI, very often the goal was toincrease the use of antibiotics in children suspectedof having pneumonia. The effectiveness of thesewas measured by looking at the total under-fivemortality rate in seven (15, 21, 25, 26, 27, 28, 29)and antibiotic use in two (18, 31).

Other prescribing practices including polyphar-macy and the use of injections also received someattention, but as they were not directly concernedwith antimicrobials we will not consider them fur-ther here.

Other important prescribing practices influenc-ing the rational use of drugs, such as the choice ofappropriate classes of drugs, of appropriate drugswithin a therapeutic class, or the cost-effectivenessof prescribing were not addressed in the studies re-viewed.

4.2.3 Outcomes measured

The principal outcomes of interest in the majorityof studies were prescribing practices in antibioticuse. Twenty-five of the studies focused on improve-ment in health care providers prescribing practicesof antibiotics as the major targeted outcome. Onefocused on the cost of the drugs (30), one on treat-ment according to STGs without measuring anti-biotics in particular as well (32), and another lookedat various prescribing parameters (16) (Appendix1).

Changes in patient outcomes were the secondmost frequent focus of studies. Of the eight studiesthat measured this, seven focused on reducing childmortality due to ARI (15, 21, 24, 26, 27, 28, 29)and one collected outcome data on the prevalenceof malaria in the community (20). All of these stud-ies used community case management approaches.

The remaining study, apart from prescribingindicators, targeted patient knowledge on dosingschedules of dispensed drugs (36).

Although the majority of interventions werepredominantly or partly educational, improvementin knowledge, an implicit consequence of training

13


or education, was not a major outcome measuretargeted by studies. Specific gains in knowledge byhealth care providers were measured in only six ofthe studies. Diagnostic skill, another crucial inter-mediate factor influencing appropriate prescribingpractice and arising from improved knowledge, waslargely ignored by studies that explicitly measuredimproved knowledge.

Dispensing practices were the foci of two stud-ies. These studies concentrated on changes in dis-pensers knowledge of diarrhoea and ARI treatment(12, 23). Neither of these studies examined theimpact of improved dispensing practices on patientoutcomes. Improved knowledge and motivation,as well as clinically effective use of drugs, have beenidentified as some of the crucial changes in patientoutcomes arising from appropriate dispensingencounters (Ross-Degnan et al., 1997).

4.2.4 Impacts of interventions

The overall impacts of the interventions on improv-ing at least one targeted outcome was high (Table5). Of the studies reviewed, 31 reported results fromwhich evaluation of impacts could be made: 12reported at least one large impact with relevance toantimicrobials (>30% improvement) after imple-mentation of interventions, 12 reported moderateimpacts (1030%), and seven of the interventionshad very low impact (


14

Five studies reported reduction of antibiotic useby between 10 and 20% (2, 3, 4, 7, 13). Three ofthem (2, 7, 13) had single training, face-to-faceeducation, or interactive workshop interventions,and two had combinations with a newsletter orcommunity education.

Two reported reductions of around 7% (1, 10).They used newsletters and group seminars in onecase and intensive community education and doc-tor training in another. In study 1, Agunawela etal. tested the distribution of five newsletters on fivedifferent issues on proper antibiotic use with andwithout training seminars for prescribers. Both in-terventions had small but nonsignificant positiveimpacts on antibiotic use. In study 10, Paredes-Solari et al. used media-oriented approaches (video,market broadcasts) and printed educational mate-rials targeted at the community, in addition to face-to-face visits and dissemination of educationalmaterials for physicians to educate both groups ondiarrhoea treatment. These approaches had mini-mal impact on general drug use for diarrhoea andantibiotic use specifically. Subsequent focus groupswith medical officers highlighted possible reasonsfor the ineffectiveness of the study, including thefailure of the training to address key issues such asmisunderstandings about drug efficacy or patientpreference for injections.

Three showed little effect (2, 9, 12), even thoughone used a multimethod workshop, one carried outin-service training, and one trained private phar-macists. In study 2, they used multimethod train-ing covering standard treatment guidelines for ARI,diarrhoea, and malaria. This width may have beenthe reason for the minimal impact in antibiotic use,although they achieved an impact on improvingdosage.

Five studies with moderate impacts focused ona single health problem; either ARI (4, 8) or diar-rhoea (3, 10, 13).

One study compared multimethod refreshertraining and community education with just re-fresher training, or just community education (4).Researchers found that reductions in communityantibiotic use were twice as large (18.8%) with thecombined strategy compared to just retraining(8.8%), whereas community education alone hadminimal impact.

Another study (Santoso, 1996) compared face-to-face education with a seminar. The face-to-faceshowed a greater change in antibiotic use (17%versus 10%) but the opposite was true for antidiar-rhoeal use where the greater change was in the semi-

nar group. This may, however, be explained by thehigher initial level of use.

4.3.2 Combined managerial and educationalapproaches

Eighteen of the studies were categorized as testingcombined educational and managerial interventions(see Table 3b and Appendix 1).

Ten of them, as stated before, used a commu-nity case management (CCM) approach where bothhealth workers and the community were targeted.The predominant focus of these studies using CCMintervention strategies was the reduction of child-hood mortality due to ARI and malaria throughthe training of community health workers (CHWs),other health providers, and the community. Thetwo that measured percentage of antibiotic useshowed dramatic increases +85% and +49% inchildren (studies 19 and 31, respectively). Of theseven that measured child mortality, four showedresults over 30% (15, 25, 26, 29), two between 25and 30% (21, 28), and one of 13% (27). The studythat concentrated on malaria prevalence showed aneffect of 48% reduction (20).

The remaining eight studies, apart from the 10mentioned above, showed varied results. Threeshowed great effect. One with a combination ofmany different methods (consensus STGs, super-vision, trainings, mass education, and conditionalprovision of drugs and equipment showed a 22%decline in antibiotic prescription and a 69% im-provement in antibiotic dose (17). Another (22)by combining a multimethod workshop for CHWsand the community with follow-up supervisionattained a 29% decrease in antibiotic use. Study18 concentrated on diarrhoea treatment and dis-semination of printed STGs and achieved a largedrop in antibiotic use (64%).

For three other intervention studies, consensualSTGs (14) or STGs with training plus or minussupervision (23, 24) were not very effective. Thefirst (23) was dealing with private drug sellers, whohave a strong economic motive to not prescriberationally, and the second (24) tested three strate-gies within three intervention groups for dissemi-nation of new STGs to health facilities in sixdistricts. The first strategy focused on simple dis-semination of the STG booklet during a visit tocollect data to measure the WHO drug use indica-tors. The second combined the dissemination ofthe booklet with follow-up feedback of baselineperformance data and targeted training on identi-

15


fied problems; and the third combined dissemina-tion of the manual with feedback, training, andadditional monthly supervisory visits over a six-month period. Across all 16 indicators tested, in-cluding prescribing practice, antibiotic use, andpercentage treated according to STGs, the follow-ing results were found: simple dissemination hadno effect, targeted on-site training had consistentpositive effects on performance, and supervisionsometimes resulted in additional improvement. Thebehaviours upon which supervision seemed to havean impact were those that were observable andquantifiable during supervisory visits, such as con-sulting and dispensing times, or adequacy of druglabelling.

The successful interventions almost all includedregular supervision and other administrative/mana-gerial strategies such as drug supply management.Most CCM interventions reviewed here also shareda number of characteristics with successful train-ing interventions such as a focus on a single healthproblem, multimethod and multisession trainingapproaches, and practical skills orientation. Thesestrategies were also typically reinforced throughconcurrent community and health worker educa-tion.

4.3.3 Managerial approaches

Managerial approaches actually all included someeducational work, sometimes through feedback andsometimes through participatory formulations ofSTGs. One of the managerial studies (34) reporteda large reduction in injection use (56%) and a largereduction in antibiotic use (32%). Their interven-tion involved surveys, audit, supervision, and in-cluding the medical staff in making plans. In themanagerial arm of study 19, the effect of introduc-

ing an STG with discussion showed a 10% reduc-tion, but when audit and review were added thereduction increased to 24%.

The studies reporting the largest impacts (ofimproving at least one outcome measure by over50%) focused predominantly on improving exist-ing public sector supervisory systems (32, 34). In(32), Kafle and colleagues, for example, developedimproved guidelines for supervision and monitor-ing, which were then used by district and publichealth officers within their various district healthposts. The results of supervision and monitoringwere incorporated into audits and feedback to pre-scribers. This strategy yielded a moderate impactof a 19.8% increase of cases treated according tothe STGs. The average consulting time was in-creased by over 50%. In an innovative variation ofthe supervisory strategy, one study in Indonesiaimplemented a self-monitoring system in whichhealth centre staff, trained and facilitated initiallyby district staff, sampled their own prescriptionrecords on a monthly basis (Sunartono et al., 1995).The data gathered were then used to track threesimple drug use indicators, namely number of drugsprescribed, percentage antibiotic use, and percent-age injection use. Over an 18-month period, thenumber of drugs per prescription declined by 26%,antibiotic use was reduced by 32%, and injectionuse declined by 56%.

4.3.4 Economic interventions

Only one study reviewed has looked at the effectof charging mechanisms on prescribing practices.Holloway and Gautam (1997) showed that charg-ing by banded items moderately reduces the fre-quency of prescribing antibiotics and injectionscompared to charging a flat fee.


16

5. Discussion

ers are participatory and interactive. The strat-egy that seems to achieve low impact on prac-tice, when used alone, is the use of individualinvolvement in the development and definitionof treatment norms.

Thirdly, supervision or performance monitor-ing using indicators or simple protocols in com-bination with audit and feedback of performanceindicators to prescribers has proved to be highlyeffective in improving specific practices. Com-bining these approaches with the peer group de-velopment of new guidelines or theimprovement of existing ones, or active dissemi-nation of guidelines through staff training, hasalso resulted in considerable improvement incompliance with treatment guidelines. Overallsome ongoing activity such as supervision, datafeedback, or peer review is needed to sustain theintervention effect.

A strategy that has consistently failed to causemeasurable improvements in behaviour is thesimple dissemination of printed clinical guide-lines or unbiased drug information.

Finally, the community case management ap-proach has produced clear evidence of effective-ness in reducing child mortality from ARI ordiarrhoea. The combination of single healthproblem focus, multimethod, and multisessiontraining approaches with simultaneous supervi-sion and drug supply management and concur-rent community and health worker educationhas the practical advantage of addressing themultiple dynamics of child health and childhooddiseases. A critical issue that was neglected byall but one of the studies using the CCM ap-proach is the impact of the approach on healthcare providers prescribing practice, particularlywith the treatment of ARI, and the implicationof this on their treatment of other health prob-lems or on long-term patterns of communityantibiotic use. Since the desired outcome of thecompliance with WHO ARI guidelines (usedby all the studies) was an increase in the pre-

It is remarkable the few numbers of acceptable stud-ies performed in this area. Only 36 studies werefound covering all developing countries. Consid-ering the huge problems with antibiotic use in de-veloping countries and the variety of conditions andsettings, it is clear that our level of knowledge isnot great. However, from these studies we can drawsome conclusions about effectiveness of differentstrategies.

5.1 Effectiveness of different types ofinterventions

Based on the results of the review, a number of as-sertions can be made about interventions that areeffective in improving antimicrobial use by healthcare providers in developing countries, as well asthose that have proved ineffective.

Firstly, educational/training interventions,whether conducted in large or small groups, cansuccessfully improve targeted antibiotic prescrib-ing outcomes by an average of 20% or more, ifthey are well designed. The characteristics oftraining strategies that have the greatest impacton outcome measures include use of multipletraining modalities (such as lectures, group prob-lem-solving, role playing, and practical skillsorientation); repeated sessions; single problemfocus; on-site training; and use of opinion lead-ers or district-level staff as trainers. However,where measured, these improvements are notnecessarily sustainable over time.

Secondly, the use of group process approachesamong health workers has great potential forimproving prescribing practices. Strategies thatencourage peer review and peer group commit-ment to treatment standards, preferably devel-oped by target group or continuing groupinvolvement in peer monitoring, appear to cre-ate and sustain change. The group process ap-proach also appears to have a moderate impacton drug use behaviours within patient and com-munity groups when group process encountersbetween community members and health work-

17


scribing of preferred antibiotics, could compli-ance with ARI treatment guidelines lead to in-creased prescribing and use of antibiotics forother conditions and encourage the developmentof antibiotic resistance? The possibility of suchcarry-over effects demands examination.

5.2 Neglected issues

5.2.1 Settings

The majority of studies were carried out in publichealth settings, leaving private sector practicesvirtually unexamined.

Drug sellers. More than 80% of people whensick use drug sellers or pharmacists but only two ofthese studies address drug shops. Of the two stud-ies that did concentrate on private pharmacies,Podhipak et al (12) with an educational interven-tion showed very small changes whereas Kafle (23)showed some positive effect.

Hospital inpatients. Only three studies addressedhospitals directly. Given the volume and cost ofantimicrobials used in inpatient settings, and therisk of the development of resistant organisms, thedearth of hospital-based studies is remarkable. Thedevelopment of multiple drug resistance to suchbacteria as Pseudomonas, Streptococcus aureus, Ente-rococci, and Staphylococcus aureus is a cause of seri-ous infections in hospitalized patients. Treatingantimicrobial-resistant infections generally requiresthe use of more expensive or more toxic drugs andcan result in longer hospital stays. Alternatives cannot only be more expensive but can also not beapproved for use in special populations, such aschildren, rendering management of an otherwisecommon infection difficult.

Private sector doctors in outpatient settings. Nostudies addressed this part of the health sector.

Patient and community use. Apart from the com-munity case management interventions for ARI,in the relatively rare occurrence that drugs are pre-scribed correctly in the right dose we know noth-ing of the compliance of the public in taking theprescribed drugs.

In particular we have no examples of case stud-ies to find the determinants of poor use and anyexamples of interventions to change this. Thus verylittle is known about whether and under what cir-cumstances interventions directed at prescribers anddispensers and changes in their practices result inbetter patient outcomes.

Dispensing encounters, for example, have beenidentified as crucial mediums for educating patients

and motivating them to use drugs in clinically ef-fective ways (Ross-Degnan et al., 1997). In thiscontext, it would be useful to know how improvedcommunication from dispensers influences inter-mediate patient variables such as knowledge aboutdisease and treatment, satisfaction with treatment,and eventual compliance with recommendedtherapy.

These points only serve to highlight gaps in thesample of studies, emphasizing their narrow focuson a few types of inadequate use outcome meas-ures.

5.2.2 Conditions

The majority of studies focused on three healthconditions: ARI, diarrhoea, and malaria. Althoughit is recognized that these are a major cause of deathin children, other important conditions for whichantimicrobials are used include tuberculosis, hepa-titis B, various sexually transmitted diseases, andAIDS. In fact, by 1990, nearly every commonpathogenic bacterial species had developed varyingdegrees of antimicrobial resistance. Knowledge ofall the conditions for which antibiotics may be usedmay contribute to the development of strategies toimprove diagnosis and disease management, as wellas the development of guidelines and other inter-ventions.

5.2.3 Cost-effectiveness

With the exception of one study that highlightedthe cost-effectiveness of the small group trainingover the formal seminar (Santoso, 1996), none ofthe studies assessed the cost-effectiveness of theirinterventions. In order to select among differentpossible strategies for improving similar antibioticuse problems as well as justifying the use of a par-ticular intervention strategy over another within thehealth system, data on cost-effectiveness is essen-tial. The development of simple standardized ap-proaches can aid the collection of data oncost-effectiveness and the selection of other feasi-ble and relevant effectiveness measures.

5.3 Limitations of this review

While this review has highlighted the relativestrengths and weaknesses of selected interventionsand their impacts on antimicrobial use, it is im-portant to note that like the majority of literaturereviews, it has a number of methodological limita-tions.


18

Firstly, this collection of intervention strategiesis not exhaustive, despite intensive attempts to cre-ate a comprehensive database of relevant studies.The exclusive focus on studies obtained fromMEDLINE and only two key institutional archivesnecessarily excludes studies reported or publishedin other contexts.

Secondly, the availability and quality of evalua-tion studies on activities targeted at improving an-timicrobial use affect the proportions that end upin reviews such as these. Generally, the impacts ofcountless activities such as training courses, devel-opment of drug formularies and bulletins, and drugsupply improvements are not known because theyare often not evaluated. For those that get evalu-ated, a substantial number of attempts employ in-adequate research designs that affect the validity offindings. This review set a specified inclusion cri-teria for research designs based on knowledge onmethodologically accepted designs. While this strat-egy was used to obviate the more comprehensiveprocess of reviewing all studies and then evaluat-ing the evidence of only those with acceptable de-signs, it resulted in the exclusion of studies thatmay well have provided critical background andsupplementary information on the research area.

Furthermore the more comprehensive process mayhave had the advantage of building a strong docu-mented case for evaluating only studies with ac-ceptable designs, by highlighting the failings ofmethodologically inadequate studies. Ten studiesthat matched all inclusion criteria except for ap-propriate research design were excluded from thefinal selection process for this review.

Finally, conducting a comparative analysis ofinterventions with diverse objectives, strategies, andoutcomes is a problematic process. The majorityof selected interventions in this review are multidi-mensional and the process of homogenizing dis-tinct modalities into broad categories (communitycase management or group process) for the pur-poses of comparison presents problems for com-prehensive analysis. Furthermore, while thedevelopment of a metric to compare effect sizesacross studies is helpful, it is a technically and con-ceptually limiting way of measuring the absolutemagnitude or the importance of studies document-ing multiple impacts.

Limitations notwithstanding, this review hashighlighted critical information on interventionsto improve the use of antibiotics by health care pro-viders in developing countries.

19


6. Conclusion

The issues of antimicrobial misuse are of globalconcern, not least because of the spreading anddeveloping resistance of most common bacteria tomost inexpensive generic antibiotics. Therefore,methods to improve their use in a sustainable andcost-effective way are of crucial importance.

However, exploring interventions to improveantimicrobial use is, in fact, exploring methodsapplicable to the wider issues of rational drug usefor acute care drugs. This review has shown thatthe same lessons are learned and therefore we needto build on the work already done. The major find-ings of this paper are not essentially different from

the review of all interventions for all drug use pre-pared for the International Conference on Improv-ing Use of Medicines (Ross-Degnan, 1997).

Answers are urgently needed to the crucial ques-tion: If I am a manager in a health area, what inter-ventions can I use to improve antibiotic use? Thisreview has helped answer that in some respects, butnot in others. Within the public sector there are arange of possibilities, although issues of cost-effec-tiveness have not been addressed. However, in theprivate sector, the community, private pharmacies,and hospitals, there is almost no information and aclear need for further research exists.


20

Reference Target Target Intervention Outcomeand number Region Design group condition Setting Sample size (characteristics) measures Size of effect

EDUCATIONAL INTERVENTIONS

Angunawela Asia RCT Prescribers AB use for Public sector: 15 OPDs E1.5 newsletters on 5 % AB use E1: 31.5%24.1%= -7.4%et al. all conditions OPDs in PHC (2 IG,1 CG): different issues on(1991) units 43 prescribers proper AB use,

(E1-12,E2-16, E2.reinforced by group E2:38.8%31.5%= -7.3%C-15) seminar (1 3-hr session (C:32.2%31.8%=-0.4%)

1 per 7-8) (E2)

Bexell et al. Africa RCT Prescribers, Pre-scribing Public sector: 16 PHC : 2-day multimethod Correct drug E: 52.5%69% = 16.5%(1996) physicians, practice re PHC facilities 8E, 8C training seminars: given C: 43%57% = 14%

clinical malaria, (Lusaka, 26 prescribers group self-audit, caseofficers diarrhoea Zambia) in each group studies, individual Correct E: 43% 57% = 14%

& ARI homework, group dosage given C: 41% 38% = -3%work, lectures

Use of anti- E: 48.9%49.1%= +0.2%biotics C: 46.6%48.5%= +1.9%

Use of E: 11.9%12.6%= +0.7%2 injections C: 13.1%11.2%= -1.9%

Gani et al. Asia PP&C Prescribers, Acute Public 95 Prescribers Workshop on clinical % AB E:46%28% = + 18%(1995) physicians, diarrhoea health 37E from management and prescribed C: 32%32% = 0%

paramedics centres 3 districts communication. Distri-58C from 5 bution of leaflets and % ORS E: 35%53% = +18%districts scientific literature for prescribed C: 51%48% = -3%

face-to-face encoun-3 ters with physicians

Gonzales Latin RCT Prescribers ARI Health 4 health areas Area A (E1): refresher % AB use in E1: 26.6%7.8% = -18.8%Ochoa et al. America (physicians) clinics (A,B,C,D): training programme community(1996) community 10 clinics per & comm. ed. for mild ARI

areaArea B (E2): refresher E2: 20.6%11.7% = -8.8%trainingArea C (E3): comm. ed. E3: 11.4%12.3% = +0.9%

4 Area D (C): control C: 19.6%20.3% = + 0.7%

Guiscafre Latin PP&C MDs Diarrhoea 2 PHCs 69 MDs (36E; Workshop using active % use of E: 76.3%40.6% = -35.7%et al. America 33C) participative edu- antibiotics(1988) cating techniques

% use of E: 33.5%62.3% = +28.8%restrictivediets

5 % use of ORT E: 53.5%88.3% = +34.8%

Gutierrez Latin PP&C Physicians Diarrhoea PHC units of 40 physicians 1. Baseline study of % AB use E: 78.8%39.3% = -39.5%et al. America Min. of (20E, 20C) Rxg practices of MDs(1994) Health & 2. Multimethod % use of E: 47.3%12.4% = -34.9%

Social Security training workshop restrictive(Mexico City) 3. Post-workshop diets

evaluation4. Peer review to % ORT use E: 31.4%58.4% = +27%

discuss Tx behaviour6 of MDs

Appendix 1Characteristics of intervention studies

21




5. Mid-term evaluation % cases treat- (after workshop) at 2 months ed according E: 31.3%60.5% = +29.2%

6. Long-term to algorithm (after peer review committee) evaluation at 6, 12, E: 31.3%76.5% = +45.2% and 18months

[no modification of Rxgbehaviour or cases Txdaccording to algorithm in C

6 (contd) throughout study]

Hugh and Latin TS-C MDs, ARI Public health Physicians at MDs trained to % AB use E: 48.8%31.4% = -17.4%Corrales America paramedics centres at each health facilitate process of(1996) municipal centre in 5 improving ARI diagnosis7 level municipalities and Tx in municipalities

Naivalulevu Asia TS Prescribers, ARI Public sector: All health Training workshops on % AB use for At 3 months:(1990) physicians, all health facilities ARI case management ARI 43%22% = -21%

paramedics centres in (~2000 ARIWestern cases) At 9 months:regional 43%37% = -6%

8 division

Ofori-Adjei Africa PP&C Medical Malaria Public 60 MAs In service training in % use of E1:17.0%15.9%= -1.1%and Arhinful assistants health 20 with early malaria treatment chloroquine E2:16.9%15.6%= -1.3%(1996) (MAs) centres training E1; using case histories (CQ) injection C: 19.9%18.3%= 1.6%

20 with later and case presentationstraining E2; % of std. E1: 191%203 = +12%20 with no WHO CQ dose E2: 198%169% = -29%

9 training C for 2-year-old C: 185%135% = -50%

Paredes- Latin PP&C Physicians, Diarrhoea Periurban 2 periurban Intensive community Drug use for E: 43.1%33.3% = -9.8%Solari et al. America community area in areas intervention (video, diarrhoea (all C: 48.8%41.95 = -6.9%(1996) Lima, Peru market broadcasts, cases)

print materials), plusface-to-face visits, % AB use E: 25.5%17.9% = -7.6%booklets, & Rx pads (all cases) C: 29.3%21.4% = -8.9%for MDs

Drug use for E: 94.6%84.9% = -9.7%diarrhoea C: 92.4%91.9% = -0.5%(case seeing

10 MD)

Perez-Cuevas Latin PP&C MDs ARI Public PHC 4 Mexican Workshop (1wk 2hr % AB use S/E: 85.248.1% = -37.1%et al. America facilities Social Security daily sessions) using S/C: 97.1%86.5% = -10.6%(1996) Institute [I] interactive educational (6 month I/E: 68.8%49.1% =19.7%

(32E; 36C) techniques co-facilita- follow-up) I/C: 95.7%96.9% =+1.2%14 Min. of ted by physicianHealth [S] instructors who % following S/E: 35.7%40.9% = +5.2%(33E; 18C) received 1wk training, STG S/C: 30.5%31.0% = +0.5%

followed by peer review (18 month I/E: 30.0%54.2% =+24.2%11 follow-up) I/C: 19.0%21.0% =+12.0%

Podhipak Asia PP&C Pharmacists, Diarrhoea Private sector 3 subdistricts 3-hour training course % changes in Results NS although aet al. drug sellers drugstores (300 for pharmacists pharmacists standard effective % change(1993) (Bangkok) drugstores) (educational material and drug indicated some practices

E: 120 type-1 w/ follow-up call for sellers Rxg showed slight yet favourableDS, 60 type-2 non-attendees) ORS, antibio- change in sample groups.DS tics and anti- Antibiotics and anti-C: 50 type-1 Educational material diarrhoeal diarrhoeal drug uses wereDS, 60 type-2 by mail w/ follow-up drugs for slightly changedDS call for drug sellers diarrhoea and (unfavourably in some

12 dysentery instances)


22



Santoso Asia RCT MDs, Diarrhoea District 90 HCs in 6 1. Face-to-face small % antimi- E1:77.4%60.4%=-17.0%(1996 paramedics health districts. group intervention crobial use E2: 82.3%72.3%= -10%

cenres 30 face-to-face on appropriate diar- C: 82.6%79.3% = -3.3%int.; 30 formal rhoeamanagementseminar; 30 C 2. Two hr seminars on % antidiar- E1: 20.3%12.5%= -7.8%

same subject rhoeal use E2: 48.5%27% = -21.5%C: 21.1%20.7% = -0.4%

Change in E1: 4.797.55levels of E2: 4.377.44knowledge C: no datare diarrhoea

13 Tx

EDUCATIONAL / MANAGERIAL

Agyepong Africa RCT Physicians, Malaria, ARI, PHC facilities 30 urban PHC Develop consensus Tx % AB use E: 53.4 %61.7 % =+8.3%et al. paramedics diarrhoea, facilities norms in workshops C: 43.4%61.0% =+17.6%(1996) hypertension (15E, 15C) with staff of each H

facility facilitated by % injection E: 45.4%41.7% = -3.7%experts use C: 43.4%46.8%=[+5.4%]

% generic E: 75.2%84.0% = +8.8%14 drug Rxg C: 83.5%82.1% = -1.4%

Bang et al. Asia PP&C Paramedics, Pneumonia Public sector: 2 PH centres Mass education on Pneumonia- Post: E - 8.09 C - 17.5(1990) village health PH centres within conti- childhood pneumonia specific child-

workers, tradi- (Gadchi-roli, guous area of and case management, hoodtional birth India) 120 villages training to aid recog- mortalityattendants nition of childhood (rate/1000)

pneumonia and Tx w/co-trimoxazole Infant Post: E - 89 C - 121

mortality(rate/1000)

Total under- Post: E - 28.5 C - 40.715 five mortality

Carandang Asia TS+C Prescribers ARI, UTI Private and 10 govt Point 1: Advocacy, (1) Av No. (1) higher in private hosps.et al. public hospitals, education, and distri- drugs/case (2) and (3) w/ respect to both(1997) hospitals 10 private bution of information (2) % Rx ARI and UTI increased during

(Metro tertiary and generic drugs advocacy, monitoring andManila, secondary Point 2: Full implemen- (3) % drugs sanctions but declined overPhilippines) hospitals tation with penalties in EDL timehigher in govt hosps.

(4) % drug No variation in (4) betweenPoint 3: Period of Rxd as single type of hosp, but higher insustainability/levelling agent ARI. Results NS.

16 off

Chalker and Asia TS Health Antibiotic Public PHC 217 PHC HWs retrained and % patients 67.7%45.3 = -22.4%Phuong workers prescribing facilities facilities in assisted in making receiving(1997) (Commune 12 districts STGs and short EDLs antibiotics

health (pop 1.6stations) million) plus regular supervision % patients 29.9%98.4% = +68.5%

by district staff receivingadequate AB

17 doses

Chowdhury Asia RCT Prescribers, Diarrhoea Public sector 18 THCs E1. Dissemination of % treated E1: 29.3%91.1% =+61.8%et al. physicians Thana health (72 doctors; printed STG for diar- according to E2: 22.8%95.3% = +72.5%(1995) complexes 4/THC) rhoea management STG C: 31.1%85.5% = +54.7%

(THC) E1 (STG), and treatmentE2 (STG and E2. Brief small groupsmall group trainingtraining), C

ORS corners set up in % receiving E1: 70.1%8.9% = -61.2%all THCs during inter- antibiotics E2: 65.0%1.1% = -63.9%

18 vention period. C: 66.3%15.3% = -51.0%

23




Chowdhury, Asia PP&C Physicians ARI Thana E (1 THC) ARI case management Average no. E: 3.482.10 = +1.38et al. (sub-district) C (1 THC) [auditing and analysing drugs used C: 3.68% [post](1996) health of prescriptions for ARI

complexes served by the doctors] % prescribers E: 7.0%94% = +87%following STG C: 9.0% [post]

Antibiotic E: 10.0%95.0% = +85%use C: 9.8% [post]

Prescribers E: 55.0%93.0% = +38%using drugs C: 57.0% [post]from EDL

Generic E: 51.5%81.0% = +29.5prescribing C: 48% [post]

Mortality E: 10%1.6% = -8.4%19 rate C: 12.0% [post]

Delacollete Africa PP&C CHWs, Malaria Rural E (13 000 pop; Malaria case manage- Mean prev. E: 14374 = -48.3%et al. community health 12 CHWs) ment (training CHWs, acute malaria C: 121109 = -9.9%(1996) zone C (14000 pop) drug supply,

supervision) % untreated E: 31%24% = -7%20 cases C: 20%28% = +8%

Fauveau Asia PP&C Paramedics, ARI Rural sub- E: 1/2 district ARI case management ARI< 5 E: 4.73.2 = -31.9%et al. CHWs district (110 CHWs) (training of CHWs and mortality rate C: 6.56.1 = -6.2%(1992) C: 1/2 district paramedic supervisors, (/1000)

bi-weekly home visits,home Tx, referral) ARI< 1 E: 13.09.1 = -31.5%

mortality rate C: 15.516.0 = +3.2%21 (/1000)

Hetta and Africa TS-C CHWs, Diarrhoea Community All CHWs in 2 4-day multimethod % sulfona- E: 51%22% = -29%Lundstrom community rural rural health (drama, audio demos, mide use(1984) districts districts flipcharts, handbills,

educational demos) % ORS use E: 50%72% = +22%on Tx / prevention ofdiarrhoea

plus follow up22 supervision

Kafle Asia PP&C Drug retailers Diarrhoea, District drug 352 retailers (1) Small group face- Referral Diarrhoea:(1998) ARI retail shops from 12 to-face training [E1] practices E3: 5.85.0 = -0.8

(Nepal) districts, C: 2.311.3 = +94 study groups plus reinforcement ARI:E1,E2,E3,C material [E2] E1: 15.527.0 = +11.5

C: 4.616.3 =+ 11.7(2) Audit feedback viamail [E3] Dispensing Diarrhoea:

practices: E1= 58.339.2 = -19.1% antimi- C= 59.330.0 = 29.3crobial ARI:dispensed E1: 15.527.0 = +11.5

E2: 18.628.8 = +10.2E3: 17.522.2 = +4.7C: 31.517.5 = -14

Knowledge E2: 5.838.4= 32.6(of severe C: 15.121.0 = 5.9dehydrationin diarrhoea)

(of severe E1: 42.863.1 = +20.3ARI- C: 51.146.5 = +4.6

23 pneumonia) [NS results not shown].


24



Kafuko et al. Africa RCT Prescribers, Diarrhoea, 126 district E1: 42 HUs Dissemination of # drugs Rxd E1: 2.372.45 = +3.4%(1996) physicians, malaria, health units E2: 29 HUs national standard E2: 2.352.09 = -11.1%

paramedics Rxg and (HUs) from E3: 14 HUs treatment guidelines E3: 2.392.14 = -10.5%dispensing 4 regions of C: 42 HUs alone (E1) C: 2.452.45 = -0.0%for all Ugandaconditions plus timely feedback % cases E1: 51.657.8 = + 6.2%

and target training of given E2: 51.750.7 = - 1%health workers (E2); antibiotics E3: 54.354.3 = 0.0%

C: 5358 = +5.0%plus 6 month supportsupervision (E3) % treated E1: 24.8 %32.3% = +7.5%

according to E2: 24.0%52.0% = +28.0%NSTGs E3: 21.4%55.2% = +33.8%

24 C: 24.8%29.9% = + 5.1%

Khan et al. Asia PP&C CHWs ARI Community 38 villages ARI case management ARI < 5 E1: 8.64.0 = -53.5%(1990) (31 E1, 7C training workshops, mortality C: 14.414.5 = +1.5%

which crossed rate (/1000)over in year 2 plus community edu- E2: 14.56.5 = -55.2%

25 as E2) cation through CHWs.

Lucero et al. Asia TS+C Physicians, ARI Public 8 munici- 3 bi-annual ARI case All cause E: 18.59.5 = -48.6%(1994) paramedics, sector, palities management training < 5 mortality C: 16.512.5 = -24.2

CHWs PHC. E: 4 munici- workshops rate (/1000Communities palities person-yr)on island of C: 4 munici- plus communityBohol palities education through

CHWs (and assisting26 midwives)

Mtango Africa RCT CHWs, ARI Community 72 villages ARI case management Pneumonia E1 post = 32.429.2et al. paramedics (36 E, 36 C programme (training < 5 mortality C/E2 post 4035.0 = -12.8%(1986) which crossed CHWs, household visits rate (/1000)

over as E2 [6-8 wks], home Tx,during phase II referral, training HCof inter- and dispensary workersvention) to strengthen services

27 at referral level)

Pandey Asia TS+C CHWs ARI Commu- 18 subdistricts ARI case management All cause RR in yr 3 = 0.72 = -28%et al. (pneumonia) nities, programme (CHW < 5 mortality(1991) households small group training, rate (/1000)

with childrenunder 5 (in household visits every Pneumonia RR in yr 3 = 0.70 = -30%Jumla 2 wks, home Tx,

25




approach, integrated supervisory guidelines on drug use/manage-

30 (contd) ment indicators)

Wieden- Africa RCT Prescribers Prescribing Public sector 20 health New STGs distributed % injections 30%32.7% = 2.7%mayer practices facilities facilities via introductory and % AB Rxd 38.3%35.3% = 3%(1996) (10 E; 10 C) continuing education % AB Rxd in

workshops for in- childrenservice charges.


26


MANAGERIAL INTERVENTIONS

Sunartono Asia TS-C MDs, Injection Public 29 public 1. Monthly survey of Change inet al. paramedics antibiotic health health centres cases on 3 prescri- prescribing:(1995) use, poly- centre bing indicators

pharmacy 2. Monthly observation % use of 76%20% = -56% of paramedics injections clinical encounters by managers % use of 63%31% = -32%

3. Monthly interviews antibiotics with patients

4. Monthly discussion % use of 4.2%3.1% = -1.1% about findings polyphar-

Develop and imple- macyment process formonthly self-monitor-ing of Rxg practice

34 indicators

Thuo Africa PP&C Prescribers Rational Inpatient Not clearly E: feedback on analysis No. of anti- Tables unhelpful(1997) drug use care settings stated of treatment records biotics per

(hospitals) patientC: participatorydiscussions No. of

injections35 per patient

ECONOMIC INTERVENTIONS

Holloway Asia PP&C Prescribers, Rational Public PHC 30 health Baseline: all districts 1. INRUD/and Gautam community drug use facilities posts (HPs) charged flat fee WHO Rxg(1997) (Eastern and 3 hospitals covering full course of indicators:

Nepal) in 3 districts. all drugs a. No. items DE1: 2.6 1.8 = -0.8E1(9HPs, E1: 1-band item fee per Rx DE1: 2.5 2.0 = -0.51Hosp) E2: 2-band item fee DC: 2.7 2.7 = 0E2 (10HPs, C-flat fee1 Hosp) b. % Rx w/ DE1: 56.8 49.7 = -7.1%C (11 HPs, ABs DE2: 53.5%46.2% =-7.3%1 Hosp) DC: 57.6%65.7% =+8.1

c. % Rx w/ DE1: 6.9%14.2%=-2.7% injections DE2: 25.2%15%=-10.2%

DC: 22.5%19.8%=-2.7%

d. % Rx con- DE1: 1.5% 48.7%= +17.1% forming DE2: 31.2% 47.7% = +16.5 to STG DC: 23.5% 26.2% = +2.7%

2.% patients 1 item: E1-76%; E2-78%; C-74%able to 2 items: E1-65%; E2-54%;remember C-66%dosing 3 items: E1-36%; E2-34%;schedules C-48%per numberof dispensed

36 items

AB antibiotic; ARI acute respiratory infection; CG control group; CHWs community health workers; DS drugstore; Dx diagnosis; ED essential drugs;EDL essential drugs list; EDP essential drugs programme; EG experimental group; H health; HCs health centres, health posts, etc.; IG intervention group;NS non-significant; OPD outpatient department; ORS oral rehydration salts; Paramedics nurses, clinical officers, medical assistants, etc.; Rx prescription;Rxg prescribing; STG standard treatment guideline; Tx treatment.

27


References for the intervention studies

1. Angunawela I, Diwan V, Tomson G. Experimentalevaluation of the effects of drug information onantibiotic prescribing: A study in outpatient care inan area of Sri Lanka. International Journal of Epide-miology 1991;20(2):558564.

2. Bexell A et al. Improving drug use through continu-ing education: a randomized controlled trial inZambia. Journal of Clinical Epidemiology 1996;49:355357.

3. Gani L, Tangkilisan A, Pujilestari L. An educationalapproach to improve management of diarrhoeal dis-ease in children among the public physicians in Jakarta.Report, Applied Diarrhoeal Diseases ResearchProject, 1995.

4. Gonzales Ochoa EL et al. Prescription of antibioticsfor mild acute respiratory infections in children.Bulletin of the Pan American Health Organization1996;30(2):106117.

5. Guiscafre H et al. Evaluation of the strategy designedto promote changes in the prescription pattern oforal hydration, antibiotics and restrictive diets byfamily physicians. Archivos de Investigacion Medica1998; 19:395.

6. Gutierrez GH et al. Changing prescribing patterns:evaluation of an educational strategy for acutediarrhea in Mexico City. Medical Care 1994;32(5):436446.

7. Hugh M, Corrales G. Capacitacion gerencial sobreel manejo de infeccion respiratoria aguda. Proyectode servicios de salud decentralizados (SSD) MINSAUSAID. Informe preliminar, Analisis de la CGIRA,January 1996.

8. Naivalulevu L. Training for rational drug use (pre-scription of antibiotics for coughs and colds in Fijihas been greatly reduced since health staff partici-pated in training workshops). ARI News 1990:18.

9. Ofori-Adjei D, Arhinful DK. Effect of training onthe clinical management of malaria by medicalassistants in Ghana. Social Science and Medicine1996;42(8):11691176.

10. Paredes Solari PB et al. Intervention trial to decreasethe inappropriate use of drugs during childhood diar-rhoea. Preliminary Report for Applied DiarrhealDiseases Research Project, Lima, Peru, June 1996.

11. Perez-Cuevas R et al. Improving physician prescrib-ing patterns to treat rhinopharyngitis. Interventionstrategies in two health systems of Mexico. SocialScience and Medicine 1996;42(8):11851194.

12. Podhipak AW et al. Impact of an educational pro-gram on the treatment practices of diarrheal diseasesamong pharmacists and drug sellers. Southeast AsianJournal of Tropical Medicine and Public Health1993;24:3239.

13. Santoso B. Small group intervention vs. formal semi-nar for improving appropriate drug use. Social Sci-ence and Medicine 1996;8:11631168.

14. Agyepong I et al. The impact of group development oftreatment norms on prescribing at PHC levels in thegreater Accra Region. Final Report for the Ministryof Health, Greater Accra Region and Centre forClinical and Tropical Pharmacology, University ofGhana Medical School, 1996.

15. Bang AT et al. Reduction in pneumonia mortalityand total childhood mortality by means of commu-nity-based intervention trial in Gadchiroli, India.Lancet 1990;336:201206.

16. Carandang ED et al. Impact of the implementation ofthe Philippine generic law on prescribing for acute res-piratory and urinary tract infection in twenty metroManila hospitals. ICIUM program and abstract book,1997.

17. Chalker J, Phuong NK. Combating the growth of re-sistance to antibiotics. Antibiotic dose as an indicatorfor rational drug use. ICIUM program and abstractbook, 1997.

18. Chowdhury AKA et al. Impact of standard treatmentguidelines and small group training on prescribing fordiarrhoea in under-five children in Thana HealthComplexes in Bangladesh. Report, International Net-work for Rational Use of Drugs, 1995.

19. Chowdhury AKA et al. Effect of standard treatmentguidelines with or without audit on prescribing for acuterespiratory infections in government health facilities inBangladesh. Report, International Network for theRational Use of Drugs, 1996.

20. Delacollete CP, van der Stuyft P, Molima K. Usingcommunity health workers for malaria control:Experience in Zaire. Bulletin of the World HealthOrganization 1996;74(4):423430.

21. Fauveau V et al. Impact on mortality of a commu-nity-based programme to control acute lower respi-ratory tract infections. Bulletin of the World HealthOrganization 1992;70(1):109116.

22. Hetta OM, Lundstrom KJ. Training rural health stafffor oral rehydration therapy in Southern Sudan.Tropical Doctor 1984;14:151154.

23. Kafle KK. Impact of action-oriented training and/ormailed print material on retailer practices: safe dispens-ing, correct advice and appropriate referral for diar-rhoea, ARI and pregnancy. Study Report, Kathmandu,Nepal, 1998.

24. Kafuko JM Zirabmuzaale C, Bagenda D. Rationaldrug use in rural health units of Uganda: effect of na-tional standard treatment guidelines on rational druguse. Report for UNICEF Uganda, August 1996.

25. Khan AJ et al. Acute respiratory infection in chil-dren: a case management intervention in AbbattabadDistrict, Pakistan. Bulletin of the World HealthOrganization 1990;68:577585.


28

26. Lucero M et al. Field studies on the ARI case man-agement in the Philippines. JAMA Southeast Asia1994; Supplement:7376.

27. Mtango FD et al. Acute respiratory infections inchildren under five years. Control project inBagamoyo District, Tanzania. Transactions of theRoyal Society of Tropical Medicine and Hygiene1986;80(6):851858.

28. Pandey MR et al. Reduction in total under-fivemortality in western Nepal through community-based antimicrobial treatment of pneumonia. Lan-cet 1991;338:993997.

29. Reddaiah VP et al. Effectiveness of ARI control strat-egy on under five mortality. Indian Journal ofPediatrics 1991;58(1):123130.

30. Widyastuti SI et al. The impact of problem-based ra-tional drug use training on prescribing practices, costreallocations and savings in primary care facilities.

Documents

Intervensions and Strategies to Improve the Use of Antimicrobials in Developing Countries