Essential Anti-infectives:Essential Anti-infectives:Neglected Tropical Diseases andNeglected Tropical Diseases and

Other InfectionsOther Infections

William R BowieWilliam R BowieDivision of Infectious DiseasesDivision of Infectious Diseases

UBC and VGHUBC and VGH

Objectives and OutlineObjectives and Outline

Overview of neglected tropical diseases andOverview of neglected tropical diseases andinfections in resource poor countriesinfections in resource poor countries

Review Impacts and drivers of such infectionsReview Impacts and drivers of such infections Summarize current issues with respect to Summarize current issues with respect to anti-anti-

infectivesinfectives, particularly , particularly antibacterialsantibacterials Review needs for mitigationReview needs for mitigation Review some success storiesReview some success stories

Diseases of Particular Interest and ImpactDiseases of Particular Interest and Impact

Neglected tropical diseasesNeglected tropical diseases Diarrheal Diarrheal diseasesdiseases Respiratory infectionsRespiratory infections Other common infectionsOther common infections MalariaMalaria TuberculosisTuberculosis

WHO Neglected Tropical DiseasesWHO Neglected Tropical Diseases

((http://www.who.http://www.who.int/neglected_diseases/diseases/en/int/neglected_diseases/diseases/en/))•• Buruli Buruli UlcerUlcer•• Chagas Chagas disease(American disease(American trypanosomiasistrypanosomiasis))•• Dengue/dengue Dengue/dengue haemorrhagic haemorrhagic feverfever•• Dracunculiasis Dracunculiasis (guinea-worm disease)(guinea-worm disease)•• FascioliasisFascioliasis•• Human African Human African trypanosomiasistrypanosomiasis•• LeishmaniasisLeishmaniasis•• LeprosyLeprosy•• Lymphatic filariasisLymphatic filariasis•• OnchocerciasisOnchocerciasis•• SchistosomiasisSchistosomiasis•• Soil transmitted Soil transmitted helminthiasishelminthiasis•• SnakebiteSnakebite•• TrachomaTrachoma•• YawsYaws

Hotez PJ et al. NEJM 2007;357:1018-1027

Hotez PJ et al. NEJM 2007;357:1018-1027

Hotez PJ et al. NEJM 2007;357:1018-1027

Numbers of Deaths Due to CommonNumbers of Deaths Due to CommonInfections in Children Re-framedInfections in Children Re-framed

~ 5 million/yr~ 5 million/yr 13,700/day13,700/day 570/hr570/hr

If 3000 deaths on 9/11 = 5.26 hours of daily child deathsIf 3000 deaths on 9/11 = 5.26 hours of daily child deaths More children die from infection in 2 hours than allMore children die from infection in 2 hours than all

known deaths from SARSknown deaths from SARS ? 20 minutes of total human avian influenza deaths? 20 minutes of total human avian influenza deaths All known pH1N1 deaths = 1 dayAll known pH1N1 deaths = 1 day

Relevance to Antimicrobial ResistanceRelevance to Antimicrobial Resistance For 5 of the 6 leading infectious diseases killersFor 5 of the 6 leading infectious diseases killers

–– acute respiratory infections, HIV/AIDS, acute respiratory infections, HIV/AIDS,diarrheal diarrheal diseases, tuberculosis and malaria -diseases, tuberculosis and malaria -rates of antimicrobial resistance are sufficientlyrates of antimicrobial resistance are sufficientlyhigh that many previously effective drugs are nohigh that many previously effective drugs are nolonger reliably active, and for some of thelonger reliably active, and for some of theinfections, the number of effective options hasinfections, the number of effective options hasrapidly fallenrapidly fallen

Major Issues with Infections: Societal/equityMajor Issues with Infections: Societal/equity

Malnutrition (macro- and micro-nutrients)Malnutrition (macro- and micro-nutrients) Failure of primary prevention (vaccines, hygiene,Failure of primary prevention (vaccines, hygiene,

sanitation etc)sanitation etc) Unequal or limited access to health and otherUnequal or limited access to health and other

servicesservices Inadequate scientific understanding Inadequate scientific understanding ––

epidemiology and resistance with relevantepidemiology and resistance with relevantsyndromic or other management guidelinessyndromic or other management guidelines

Inadequate Inadequate diagnositic diagnositic support, infection controlsupport, infection control

Major Issues with Anti-infectives: DrugMajor Issues with Anti-infectives: DrugRelatedRelated

Lack of access or consistent access to effectiveLack of access or consistent access to effectivedrugsdrugs

Inappropriate use of effective drugsInappropriate use of effective drugs Use of inappropriate drugsUse of inappropriate drugs Counterfeit drugsCounterfeit drugs Antimicrobial resistanceAntimicrobial resistance Lack of development of new drugsLack of development of new drugs

Additional Issues with Antimicrobial UseAdditional Issues with Antimicrobial Use

HCP behaviorsHCP behaviors Incorrect dosing and durationsIncorrect dosing and durations Use when infecting strains are known to be or likely to beUse when infecting strains are known to be or likely to be

resistantresistant Use of Use of anti-infectives anti-infectives when other approaches are more effectivewhen other approaches are more effective

((esp diarrheal esp diarrheal diseases)diseases) Reliance on drugs instead of appropriate surgical or infectionReliance on drugs instead of appropriate surgical or infection

control techniquescontrol techniques

Patient behaviorsPatient behaviors Not taking as prescribedNot taking as prescribed Using someone elseUsing someone else’’s (s (esp esp medicine cabinet)medicine cabinet) Using when prescribed for another indicationUsing when prescribed for another indication

Outdated drugOutdated drug

Patient Barriers to Access/UsePatient Barriers to Access/Use

Access to health careAccess to health care CostCost AvailabilityAvailability Social stigmaSocial stigma MarginalizationMarginalization GenderGender PrejudicePrejudice IgnoranceIgnorance Other belief systemsOther belief systems Fear of Western medicineFear of Western medicine

Additional Issues in Tropical ClimatesAdditional Issues in Tropical Climates

Poor storage conditionsPoor storage conditions High temperatureHigh temperature High humidityHigh humidity Lack of rotation of stock (drugs go out of date)Lack of rotation of stock (drugs go out of date)

Factors in Selection of Essential MedicinesFactors in Selection of Essential Medicines

Disease prevalenceDisease prevalence Evidence of efficacyEvidence of efficacy Evidence of safetyEvidence of safety Comparative cost-effectivenessComparative cost-effectiveness

Essential Medicines: Problematic Areas forEssential Medicines: Problematic Areas forAnti-infectivesAnti-infectives

Antimicrobial resistanceAntimicrobial resistance Changing epidemiology (and resistance)Changing epidemiology (and resistance)

Data acquired elsewhere or even in the same area atData acquired elsewhere or even in the same area ata different time may not apply well or at all in a locala different time may not apply well or at all in a localareaarea

Use impacts not only the individual, but also theUse impacts not only the individual, but also thecontacts, and the environmentcontacts, and the environment

New therapies, even if initially effective ones that couldNew therapies, even if initially effective ones that couldbe made available in resource poor settings, may onlybe made available in resource poor settings, may onlyprovide a transient benefit because resistance develops,provide a transient benefit because resistance develops,often quicklyoften quickly

Factors in Selection of Essential Medicines:Factors in Selection of Essential Medicines:Problems with Problems with Anti-infectivesAnti-infectives: Neglect re: Neglect re

Lack of DataLack of Data Disease prevalence (and etiology if a syndrome)Disease prevalence (and etiology if a syndrome)

Usually poorly knownUsually poorly known If pathogen(s) known, antimicrobial susceptibility dataIf pathogen(s) known, antimicrobial susceptibility data

are rarely knownare rarely known Evidence of efficacyEvidence of efficacy

Rarely known in the resource poor situationRarely known in the resource poor situation Evidence of safetyEvidence of safety

Likely can extrapolate from other settingsLikely can extrapolate from other settings Comparative cost-effectivenessComparative cost-effectiveness

Data usually lacking, Data usually lacking, esp esp if AMRif AMR

Neglect in Efficacy DataNeglect in Efficacy Data

Essential medicine recommendationsEssential medicine recommendations Largely first line used in Largely first line used in syndromic syndromic managementmanagement Resistance to them likely high, but generally unknownResistance to them likely high, but generally unknown Would be expected that use would often not beWould be expected that use would often not be

effective for many conditions (diarrhea, sepsis)effective for many conditions (diarrhea, sepsis) Second/third line choicesSecond/third line choices

More costlyMore costly Still promote resistanceStill promote resistance No evidence that have better actual outcomeNo evidence that have better actual outcome Despite cost, could be more cost-effectiveDespite cost, could be more cost-effective

Counterfeit or Substandard AntimicrobialsCounterfeit or Substandard Antimicrobials

Counterfeit = Counterfeit = mislabelled mislabelled with respect to identitywith respect to identityand/or sourceand/or source

Substandard = inadequate drug quantity orSubstandard = inadequate drug quantity orqualityquality

Problems with all pharmaceutical productsProblems with all pharmaceutical products In developing countries, biggest problem is withIn developing countries, biggest problem is with

anti-infectivesanti-infectives, , esp esp antibiotics and anti-parasiticantibiotics and anti-parasiticagentsagents

CountryCountry’’s capacity to restrict dangerous drugss capacity to restrict dangerous drugsdepends heavily on its wealthdepends heavily on its wealth

Kelesidis K et al. Journal of Antimicrobial Chemotherapy 2007;60:214-236

Counterfeit or Substandard AntimicrobialsCounterfeit or Substandard Antimicrobials

WHO estimates that up to 10% of worldWHO estimates that up to 10% of world’’sspharmaceutical trade consists of fakespharmaceutical trade consists of fakes 25% of trade in developing countries25% of trade in developing countries

Extensive implications for patients and AMR ifExtensive implications for patients and AMR iffalsely conclude that an inexpensive agent isfalsely conclude that an inexpensive agent isineffectiveineffective Drives use of more expensive or more toxicDrives use of more expensive or more toxic

drugs, and likely heightens risk of AMRdrugs, and likely heightens risk of AMRbecause they are usually more broadly activebecause they are usually more broadly active

Kelesidis K et al. Journal of Antimicrobial Chemotherapy 2007;60:214-236

Mitigation OpportunitiesMitigation Opportunities

Local society and countryLocal society and country PreventionPrevention Access to health servicesAccess to health services

More effective use of what is availableMore effective use of what is available Management protocols appropriate for localManagement protocols appropriate for local

conditionsconditions Judicious and correct useJudicious and correct use

International effortsInternational efforts Low cost genericsLow cost generics New vaccine, drug and diagnostics developmentsNew vaccine, drug and diagnostics developments Global programsGlobal programs

Mitigation Opportunities: Local Society andMitigation Opportunities: Local Society andCountryCountry

PreventionPrevention Nutrition Nutrition –– food and nutrients food and nutrients Access to services Access to services –– food, water, sanitation, housing, food, water, sanitation, housing,

educationeducation Effective use of vaccinesEffective use of vaccines

Access to health servicesAccess to health services General careGeneral care Rehydration Rehydration protocolsprotocols

Combine efforts in programs to create synergiesCombine efforts in programs to create synergies Education, sanitation, water, vaccine programs,Education, sanitation, water, vaccine programs,

animal health, mass campaignsanimal health, mass campaigns

Mitigation Opportunities: More Effective UseMitigation Opportunities: More Effective Useof What We Haveof What We Have

Management protocols appropriate for localManagement protocols appropriate for localconditionsconditions Basic diagnostic capabilities for care andBasic diagnostic capabilities for care and

baseline studies (including AMR)baseline studies (including AMR) Syndromic Syndromic management where possiblemanagement where possible

(based on local epidemiology and resistance)(based on local epidemiology and resistance) Potentially nontraditional delivery systemsPotentially nontraditional delivery systems

Judicious and correct useJudicious and correct use Correct therapeutic regimen(s)Correct therapeutic regimen(s) Correctly taken (dose, time, duration)Correctly taken (dose, time, duration)

Mitigation Opportunities: International andMitigation Opportunities: International andTransnational EffortsTransnational Efforts

Low cost genericsLow cost generics Potentially made locally with adequatePotentially made locally with adequate

precautionsprecautions Equitable accessEquitable access New vaccine, drug and diagnosticsNew vaccine, drug and diagnostics

developmentsdevelopments Global programsGlobal programs

Science Base for Infectious DiseasesScience Base for Infectious DiseasesResearch in the 21Research in the 21stst Century Century

Genomics and Genomics and Host immunity, diagnostics, new drugHost immunity, diagnostics, new drugproteomicsproteomics targets, vaccines, drug resistance,targets, vaccines, drug resistance,

pathogenesispathogenesisSynthetic chemistrySynthetic chemistry Drug design, high-throughput screeningDrug design, high-throughput screening

/robotics/roboticsComputer/mathComputer/math Drug design, predictive models ofDrug design, predictive models of

modelingmodeling transmissiontransmissionMolecular Molecular epidemiolepidemiol Pathogen virulence, transmission patternsPathogen virulence, transmission patternsGenetic epidemiologyGenetic epidemiology Host susceptibilityHost susceptibilityInformation technologyInformation technology All encompassingAll encompassing

Fauci Fauci AS, AS, Clin Inf Dis Clin Inf Dis 2001;32:675-6852001;32:675-685

Human Ingenuity in Response toHuman Ingenuity in Response toNew InfectionsNew Infections

Effective, easily administered vaccinesEffective, easily administered vaccines Rapid, sensitive, specific diagnostic testsRapid, sensitive, specific diagnostic tests Effective treatments that eradicate or at leastEffective treatments that eradicate or at least

suppress infectionsuppress infection Computer based programs that take data to look forComputer based programs that take data to look for

trends and outbreakstrends and outbreaks Focus on systems and complexityFocus on systems and complexity

BUTBUT Society in any country may not accept the cost ofSociety in any country may not accept the cost of

new innovations, and they are not typically used ornew innovations, and they are not typically used oruniversally available in low income countriesuniversally available in low income countries

To what extent do technical bio-medicalTo what extent do technical bio-medicalsolutions contribute to improving globalsolutions contribute to improving global

health?health? PositivesPositives

Advances in diagnostics, vaccines, therapies (but lessAdvances in diagnostics, vaccines, therapies (but lessso for ID), understanding, communicationso for ID), understanding, communication

Biggest impact is with vaccines (Biggest impact is with vaccines (ie ie prevention), andprevention), anddistribution of low cost innovations (impregnated beddistribution of low cost innovations (impregnated bednets, use of oral nets, use of oral rehydrationrehydration))

NegativesNegatives Most are very expensive to develop and/or useMost are very expensive to develop and/or use Extensive human and financial resources are focusedExtensive human and financial resources are focused

on technical solutions, but there would be higheron technical solutions, but there would be higherimpact dealing with distribution and equityimpact dealing with distribution and equity

Examples of Good International EffortsExamples of Good International Efforts

Millennium Development GoalsMillennium Development Goals Millennium Ecosystem AssessmentMillennium Ecosystem Assessment Commission on Social Determinants of HealthCommission on Social Determinants of Health Stop TB PartnershipStop TB Partnership Malaria Eradication Programs (Roll Back Malaria)Malaria Eradication Programs (Roll Back Malaria) HIV/AIDS initiativesHIV/AIDS initiatives Access to Essential Medicines effortsAccess to Essential Medicines efforts Neglected Tropical Diseases initiativesNeglected Tropical Diseases initiatives Vaccine InitiativesVaccine Initiatives

Molyneux DH. Lancet 2010;375:3-4

Liese B et al. Lancet 2010;375:67-76

Liese B et al. Lancet 2010;375:67-76

Key MessagesKey Messages

At global level, infections are a symptom orAt global level, infections are a symptom orindication of inequality in terms of distribution ofindication of inequality in terms of distribution ofresources, risks and opportunitiesresources, risks and opportunities

High rates of infection and under 5 years of ageHigh rates of infection and under 5 years of agemortality closely parallel every major indicator ofmortality closely parallel every major indicator ofinequality or access to servicesinequality or access to services

Improvements in nutrition, water security,Improvements in nutrition, water security,sanitation, food security, more equitablesanitation, food security, more equitabledistribution of wealth and access to adequatedistribution of wealth and access to adequatehealth services have led to dramatic decreaseshealth services have led to dramatic decreasesin rates of infectious diseasesin rates of infectious diseases

Future ChallengesFuture Challenges

Sustainability even of successful programsSustainability even of successful programs Champions, turmoil (political and others), lossChampions, turmoil (political and others), loss

of interest as disease comes under controlof interest as disease comes under control Resistance to drugs usedResistance to drugs used Stovepipe programsStovepipe programs World economicsWorld economics Climate change (extremes, and long termClimate change (extremes, and long term

trends)trends) NutritionNutrition

Liese B et al. Lancet 2010;375:67-76