Antimicrobial Resistance in Developing Countries Anı´bal de J. Sosa Denis K. Byarugaba l l Carlos F. Ama´ bile-Cuevas Po-Ren Hsueh l l Samuel Kariuki Iruka N. Okeke l Editors Antimicrobial Resistance in Developing Countries Foreword by Thomas F. O’Brien Introductory Preface by the Editors Guest Preface by Stuart B. Levy 1 3 Editors Anı´baldeJ.Sosa DenisK.Byarugaba AllianceforthePrudentUse DepartmentofVeterinaryMedicine ofAntibiotics(APUA) MakerereUniversity TuftsUniversity Kampala,Uganda Boston,MAUSA [email protected] [email protected] CarlosF.Ama´bile-Cuevas Po-RenHsueh Fundacio´nLusaraparala DepartmentofLaboratoryMedicineand Investigacio´nCientı´fica InternalMedicine MexicoCity,Mexico NationalTaiwanUniversityHospital [email protected] Taipei,Taiwan,R.O.C [email protected] SamuelKariuki IrukaN.Okeke KenyaMedicalResearch DepartmentofBiology Institute(KEMRI),Nairobi, HaverfordCollege Kenya Haverford,PA,USA [email protected] [email protected] ISBN978-0-387-89369-3 e-ISBN978-0-387-89370-9 DOI10.1007/978-0-387-89370-9 SpringerNewYorkDordrechtHeidelbergLondon LibraryofCongressControlNumber:2009920952 #SpringerScienceþBusinessMedia,LLC2010 Allrightsreserved.Thisworkmaynotbetranslatedorcopiedinwholeorinpartwithoutthewritten permissionofthepublisher(SpringerScienceþBusinessMedia,LLC,233SpringStreet,NewYork, NY10013,USA),exceptforbriefexcerptsinconnectionwithreviewsorscholarlyanalysis.Usein connectionwithanyformofinformationstorageandretrieval,electronicadaptation,computer software,orbysimilarordissimilarmethodologynowknownorhereafterdevelopedisforbidden. Theuseinthispublicationoftradenames,trademarks,servicemarks,andsimilarterms,evenifthey arenotidentifiedassuch,isnottobetakenasanexpressionofopinionastowhetherornottheyare subjecttoproprietaryrights. Printedonacid-freepaper SpringerispartofSpringerScienceþBusinessMedia(www.springer.com) Foreword Avoiding infection has always been expensive. Some human populations escaped tropical infections by migrating into cold climates but then had to procure fuel, warm clothing, durable housing, and crops from a short growing season. Waterborne infections were averted by owning your own well or supporting a community reservoir. Everyone got vaccines in rich countries,whilepeopleinothersgotthemlaterifatall. Antimicrobialagentsseemedatfirsttobeanexception.Theydidnotneedto bedeliveredthroughacoldchainandtoeveryone,asvaccinesdid.Theyhadto begivenonlytoinfectedpatientsandoftenthenasrelativelycheapinjectables orpillsoffashelfforonlyafewdaystogetastonishingcures.Antimicrobials notonlywerebetterthanmostotherinnovationsbutalsoreachedmoreofthe world’speoplesooner. The problem appeared later. After each new antimicrobial became widely used, genes expressing resistance to it began to emerge and spread through bacterialpopulations.Patientsinfectedwithbacteriaexpressingsuchresistance genesthenfailedtreatmentandremainedinfectedordied.Growingresistance toantimicrobialagentsbegantotakeawaymoreandmoreofthecuresthatthe agentshadbrought. It then proved to be much more resource-intensive to keep patients from becominginfectedwithandfailingtreatmentfordrug-resistantbacteriathanit had been to deliver the drugs that had caused the problem. Resource-limited countriesthathadmanagedtomakeantimicrobialsavailabletotheirinfected patientscouldnotaffordtodoallthethingsthatwerethenneededtomanage theantimicrobialresistancethatresulted. Antimicrobial resistance seems a function of how many bacteria have been exposed to antimicrobials, for example, so treat only infections that antimi- crobialscureforaslong,butonlyaslong,asneeded.Treatinganinfectinggerm withadrugitresistsnotonlyfailsbutalsomakesthatresistantgermspread,so treatonlywiththedrugthatcanstillkillit.Resistantgermsspreadtoothers,so identifythemandinterrupttheirspread. Eachofthesewaystocontrolresistancecostsmuchmorethanithadcostto distribute the boxes of pills and injectables that had begun the resistance. Expensive microbiology laboratories in rich countries test whether the germ v vi Foreword infectinganypatientisofakindthatantimicrobialagentskill,andifsowhich agentcouldstillkillit.Thosecountriesthenmakethatagentpromptlyavailable bykeepingubiquitouscostlystocksofallagents. Adequate housing and support for personal hygiene may also minimize interpersonal exchange of resistant bacteria in communities of developed countries, and clean water limits their ingestion. Many developed countries feed large amounts of resistance-selecting antimicrobials to food animals, however,buttheydobantheirresidualsinfoodortheirusetopreservefood. Lessisknownabouttheseindevelopingcountries Inbothrichandpoornations,resistantbacteriacausetheirmostfrequent, costly, and deadly infections in hospitals and intensive care units. In the rich nations,however,disposableitemscomeintruckloadsfromwarehousestohelp nurses,andwell-organizedinfectioncontrolteamsslowthespreadofresistant bacteria between private rooms, while the poorer struggle with shortages of reusableitemsandonehand-washingsinkforanopenward. Further promoting resistance in resource-limited countries is a cruel underlying inequity. They have more of the infections that richer countries have, e.g., pneumococcal, AIDS, meningococcal, trauma-related, tuberculosis, shigellosis,plusmanytheydonothave,suchastyphoid,malaria,andcholera. These require more valid antimicrobial use and also elicit more inadvertent misusebycomplicatingdiagnosis,thusmakingresistanceworse. In a developed country, a sick febrile patient has prompt laboratory testing andcompiledlocaltestresultstopredictdiagnosisandbesttherapyimmediately, withconfirmationoradjustmentinafewdays.Inanundevelopedcountry,there willbe fewer or no tests or compiledresults,fewer antimicrobialsavailable for oftenblindtherapyofmorepossiblediagnosesandsomorechanceoftreatment failureandfurtherspreadofresistance. Forallofthesereasons,themanagementofantimicrobial resistance inthe resource-limitedworld faces specialchallenges and appears to need tools that arelessresource-intensivethanthosethathaveevolvedinthedevelopedworld. Affordable strategies and tools to manage antimicrobial resistance in less- resourced regions may need special effort to develop, but possible examples canbeconsidered. Microbiology laboratories in developed countries, for example, using supply-intensive instruments and highly trained and salaried staff for a huge menuoftests,becomethemodelofexcellence.Attemptstoduplicatethemina developing country, however, may deplete the pool of trained professionals, outrunsupplysources,andpricetestssohighthatfewpatientscanaffordthem andtheybecome,afterall,largelyunused. An alternative model might be developed in which a limited set of inexpensiveessentialtestsusingacommonlistofsuppliescouldbeperformed by less-extensively but specifically trained workers supported by a web-based supportandoversightsystem.Thiswouldnotreplaceanycurrentlyfunctioning laboratoriesbutsupplementthematthenextlowertierofmedicalfacilitiesthat nowhavenolaboratories. Foreword vii Similarly,growthoftheInternetmayprovidecheapwaystoprovideupdated information on currently prevalent infections and their drug resistances, as locally compileddata now doindevelopedcountries, and useittoupdateand disseminate treatment guidelines. Every microbial test result that can be produced in a resource-limited country should be captured and analyzed to helpoverviewitsproblemsandupdateresponsestothem. Eachofthetoolsnowusedtocontrolantimicrobialresistancemightthusbe reviewedwithdevelopingworldcaregiverstoexplorewaysinwhichtheycould bemodifiedtobecost-effectiveintheircircumstances.Mightnothospitalsthat cannot afford a team of infection control nurses, for example, have access to specialtrainingmaterialsandinformationsupporttohelptheirexistingnursing staffcarryoutsomeoftheirfunctions? Such a rethinking of the tools and strategies for controlling antimicrobial resistance to improve their application in the resource-limited world will not happenspontaneously.Itwillrequireconcertedandfundedeffortbyspecialists frombothworlds.Gainingsupportforitmayprovedifficult,moreover,since thewholeproblemofantimicrobialresistancehasrepeatedlyslippedfromthe attentionofpublichealthandotherfundingagencies. The first step in such a needed initiative is to recognize that antimicrobial resistanceisadifferentandmoredeadlyprobleminthedevelopingworldandto elaborateindetailalloftheaspectsofthatproblem.Thatiswhatthisbookdoes andwhyitisimportant.Itcanbeseenasbothaninformativeworkandabasis foraction. Boston,Massachusetts ThomasF.O’Brien Introduction This book was mainly compiled while we quietly celebrated the 80th anniversaryofthediscoveryofpenicillin,afactthatformallyinauguratedthe ‘‘era of antibiotics’’ and it will become available during the celebration of the 150th anniversary of Darwin’s On the Origin of Species (and the 200th anniversary of Darwin himself). These two milestones remind us, on the one hand, that we have been witnesses to the evolution of bacteria and other microorganisms from mostly susceptible to mostly resistant to drugs and, on the other, how little to heart even those of us who are not blinded by superstitionhavetaken thebasicnotions ofgeneticchangeandselection. But in addition to the formidable evolutionary forces behind resistance, and the equallyformidableneglectinputtingourknowledgeofittowork,developing countrieshavetodealwithawidevarietyofpeculiarconditionsthatfosterthe emergenceandspreadofresistantgerms.Theseaggravatingfactorsrangefrom malnutrition to lack of medical services and inadequate medical training and then to counterfeit drugs and incompetent governments. These traits are not exclusivetopoorcountries,butcoalesceintheworstpossiblewayshere.There isanexceptionalneedforrigorousdataonthescaleandspreadofantimicrobial resistance,aswellasforeffectivemeansforsharingthedataandusingitasan evidence base for effective containment strategies. In developing countries where resistance is a prime issue, data are least available, evidence is rarely collated, and containment interventions have been poorly implemented. Indeed, the validity of many proposed interventions in developing countries remainsuntested. In putting together this book, we tried to assemble an overview of the magnitude,causes,consequences,andpossibleactionsonmicrobialresistance indevelopingcountries.Ifthebookappearsbrief,itisbecauseweknowlittle about this particular side of the problem, as one of the main features of poor countriesisinsufficientscientificandmedicalresearch,andofopportunitiesto publishthescarcefindingsin‘‘international’’scientificjournals,whichroutinely dismiss papers from developing countries because results are ‘‘only of local interest’’.Therefore,inadditiontopresentinginformationandideas,thebook explicitly highlights gaps that represent opportunities for research and policy innovation. High among our priorities has been to obtain data and critique ix x Introduction fromscholarswhoworknotonbutindevelopingcountriesandtoincludeinput from a variety of geographic regions. The picture that emerges, although incomplete, allows the reader to assess the current and emerging threats, the distinct issues that influence the evolution of resistance, the main problems caused by resistance, and the potential avenues to tackle at least some of this complexpanorama. Preface Theproblemofantimicrobialresistanceknowsnoboundaries.Drug-resistant microbesofallkindscanmoveamongpeopleandanimals,fromonecountryto another—withoutnotice.Fromtheearlystagesofidentifyinganddiscovering antibiotic resistance, the problem was clearly severe in developing countries where drug availability was limited and resistance was high. However, it has been in the developed world, with its abundant resources, where resistance has been more vigorously studied. Therefore, it is of some interest that out of a 1981 meeting in the Dominican Republic, where representatives from developing as well as industrialized countries assembled, came an Antibiotic MisuseStatementdeclaringtheconsequencesofinappropriateuseofantibiotics, namely the emergence and spread of antibiotic resistance. The response to the widecirculationofthestatementledtotheestablishmentoftheAllianceforthe PrudentUseofAntibiotics(APUA).Thisinternationalorganizationcontinues today, 27 years later, to champion increased awareness and appropriate antimicrobial use so as to curtail drug resistance and ‘‘preserve the power of antibiotics.’’APUAfosterspartnershipsandcommunicationsamongpeoplein bothdevelopedanddevelopingcountriestoimproveantibioticaccessibilityand reverseresistance. This book, edited by Drs. Anibal Sosa and Denis Byarugaba and their associateeditors,isuniqueinfocusingonantimicrobialresistanceasitrelates toandthreatensdevelopingcountries.Itiscuriousthatithastakenthislongto produce a book dedicated to antibiotic resistance in developing parts of the world.Onecanask‘‘why?’’sinceresistanceisandhasbeensocommonthere.In fact,whereasresistancehasbeenaddressedforthepastfourdecadesbyexperts intheindustrializedworld,studiesdescribingtheproblemandthepublichealth situation in the developing world have lagged behind. Although we have learned much from studies of the genetics and molecular biology of the problem from investigations in industrialized countries, it is in developing countrieswheremorestudiesandeffortsareneeded.With travelencouraging thetransportofmicrobes,theinformationinthisbookwillhavewide-sweeping benefit, not only for developing countries but also for the world at large. Surveillanceofresistanceandthepreventionofresistanceneedattentionona worldwidebasis.Improvingantibioticuserequiresaglobaleffort. xi