of Antibiotic Resistance - ReAct


of Antibiotic Resistance - ReAct

The Global Public Health Threatof Antibiotic ResistanceAndreas Heddini, MD, PhD

Patients withpneumoniaand bacteriain bloodPenicillinPenicillinincreased thechance of survivalfrom 10% to 90%% surviingDagarUntreated

Discovery of antibiotics• Enormous medical gains– Reduced morbidity andmortality due to bacterialinfections– A requirement for modernhealth care• Larger surgicalinterventions• Treatment of theimmunosuppressed,including cancer patients• Transplantations• Neonatal care

To the Congress in 1969:The time has cometo close the bookon infectiousdiseases…..William H. StewartSurgeon General 1965-69

A Global ChallengeAntibiotics are losing their effectiveness ata pace that was unforeseen just 5-10 years agoThe drug development pipeline is virtually emptyfrom antibiotics with a novel mechanism of action

The Current Paradox:AntibioticResistanceDrugDevelopmentMorbidityMortalityCosts

Use - Rational andIrrationalAccess, quality,marketing, financingSpread of resistantbacteriaPoor hygiene andsanitation in hospitals andthe community, travelAntibioticResistanceLack of newantibioticsScientific hurdlesLow return of investment

60 years of antibiotic use….Millions of tons.........ResistanceOverconsumptionNew antibioticsMarketing

The dwindling antibiotic pipeline...TrimetoprimStreptograminsQuinolonesChloramphenicol LincosamidesTetracyclinesMacrolidesGlycopeptidesSulphonamidesAminoglycosidesPenicillinsLipopeptidesOxazolidinones1930´s 1940´s 1950´s 1960´s 1970’s 1980´s 1990´s 2000´s

The survival of the fit

Bacteria can develop resistanceagainst all antibiotics• Cause• Spontaneuous mutations• Transfer of genetic information between bacteria• Selection• Under the pressure of antibiotics resistant bacteria are selected• Spread• Resistant bacteria• Epidemic strains (outbreaks)• Endemic situation

What happens during antibiotictreatment?• Empirical treatment• Based on experience and previous knowledge –educated guess – treatment often started beforeconfirmation of diagnosis• Aim• To eliminate or quell presumed pathogen• Side effects• Affects the normal bacterial flora• Selects the bacteria, which have aqcuired/have naturalresistance to the antibiotic

“It is not difficult to make microbes resistant to penicillin ….…. The time may come when penicillin can be bought by anyone inthe shops. Then there is the danger that the ignorant man may easilyunderdose himself and by exposing his microbes to non-lethalquantities of the drug make them resistant.”Alexander Fleming's Nobel Lecture, 1945

Illegal OTC antibiotic sale in the EUAthens, Greece (174 pharmacies)2008:-100% of all visited pharmacies soldAmoxicillin/clavulanic acid OTC- 53% sold Ciprofloxacin OTC, despite extrarestrictions for fluoroquinolone prescriptionsPlachouras et al. Euro Surveill. 2010

Bacteria with agenetic mechanismfor antibiotic resistance•Spontaneous mutation•Transfer of resistance genesAntibioticsSelection

Bacteria with agenetic mechanismfor antibiotic resistance•Spontaneous mutation•Transfer of resistance genesAntibioticsSelectionSpreadCrowding TravelPoor hygiene &infection controlFood-chain

Bacteria with agenetic mechanismfor antibiotic resistance•Spontaneous mutation•Transfer of resistance genesAntibioticsSelectionSpreadCrowding TravelPoor hygiene &infection controlFood-chainIncreasing resistance in hospitalsand the community

The more we use them, the more welose them…Albright et al. EID 2004;10(3):514-7

A Global ProblemWorldwide spread of the 23F clone of penicillinresistant pneumococciUSAMexicoColombiaU. KFrance•ThailandKoreaJapanTaiwanSingaporeArgentina Brazil S. Africa

ESBL (CTX-M) producing Enterobacteriaceae2001-2002EndemicitySporadic reports2007EndemicitySporadic reports2005

Orphanage in Bamako,MaliESBL colonized 100% ofthe children and 63%, ofthe adult staff studied.Tandé et al. Emerg Infect Dis. 2009 Mar;15(3):472-4.Mumhibili hospital,TanzaniaThe mortality rate fromGram-negativebloodstream infectionwas 43 %, more thandouble that of malaria..Blomberg et al. BMC Infect Dis. 2007 May 22;7:43.

Antibiotic susceptibility proportions for NDM-1-positiveEnterobacteriaceae isolated in the UK and IndiaUK (n=37) Chennai (n=44) Haryana (n=26)Imipenem 0% 0% 0%Meropenem 3% 3% 3%Piperacillin-taz 0% 0% 0%Cefotaxime 0% 0% 0%Ceftazidime 0% 0% 0%Cefpirome 0% 0% 0%Aztreonam 11% 0% 8%Ciprofloxacin 8% 8% 8%Gentamicin 3% 3% 3%Tobramycin 0% 0% 0%Amikacin 0% 0% 0%Minocycline 0% 0% 0%Tigecycline 64% 56% 67%Colistin 89% 94% 100%From Kumarasamy et al. Lancet Infect Dis 2010

Rolain et al. Clin Microb Inf 2010Spread of NDM-1

Newborn infections, pneumonia anddiarrhea acocunt for almost 40% of all childdeaths globallyBlack et al (Lancet 2010)

The UN Millenium Goals and antibioticresistance…Goal 4: Reduce child mortalityGoal 5: Improve maternal health

Modern medicine is not possiblewithout effective antibioticsHip replacementOrgan transplantsCancer chemotherapyCare of preterm babies

Nor is fundamental health care…

Neonatal sepsis and antibioticresistance – does it matter?

Case Fatality Rates (Neonatal sepsis)OrganismSTAPHYLOCOCCUSAUREUSSusceptibilityResistant Sensitive15.4 % 3.5 %%KLEBSIELLA 22.8 % 16.1 %ENTEROBACTER 28.0 % 21.6 %ACINETOBACTER &PSEUDOMONAS42.7 % 14.0 %ESCHERICHIA COLI 44.0 % 26.7 %Zulfiqar Bhutta presentation at ReActconference Sep 2010

Mortality outcomes are worse inneonates with resistant infections(Tanzania)60503694091Death (%)3020149585523PositiveNegative101510Culture Gram Reaction ESBL MRSAParameterKayange M et al, BMC Pediatrics 2010

Childhood pneumonia – are weovertreating?• Double-blind, randomized trial in 4 tertiaryhospitals in Pakistan• 900 children aged 2–59 months with WHOdefined non-severe pneumonia were randomizedto receive either 3 days of oral amoxicillin orplacebo;• Clinical outcome in children aged 2–59 monthswith WHO-defined non-severe pneumonia is notdifferent when treated with an antibiotic orplacebo.Hazir et al. Clin Infect Dis. Feb 2011

Loss of first line drugs increases drugcostsSource: WHO Policy Perspective 2005, adapted from WHO Model Formulary,WHO Clinical Guidelines and Management Sciences for Health’s 2004International Drug Price Indicator Guide (slide courtesy: David Heymann)

The tip of the icebergICUHospitalCommunityEcology


Preserving antibiotics – what dowe do while waiting for newdrugs?

There will be no magic bulletsolution to the problem ofantibiotic resistance

Looking ahead• Economic development ->increased consumption!• Antibiotics (azithromycin andclindamycin) proposed to beused for ”vaccination”againstmalaria - > how to balancehealth benefits?• Effects of antibiotics in theenvironment and in the foodchain– keep separate!

Action is needed now• People are dying from bacterial infectionsbecause the lack of effective therapy• Antibiotic resistance is causingsignificant costs for health care• The market driven system for researchand development of new antibiotics isfailing

Strategies for the management ofAntibiotic ResistanceSurveillanceMonitor:ResistancepatternsAntibioticuseDecreasethe need forantibioticsReducediseaseincidencepreventspread ofbacteriaUseantibioticsproperlyImprovediagnosticsand useNonmedicalusageEnvironment,food, plantsetc.CoordinatenationalactivitiesKnowledgeeducation,informationresearchInternationalcollaboration

Health systems perspective

Antibiotic resistance is not onedisease - crosscuttingPneumoniaSepsisMeningitisSTDsWound infectionsGynecological infectionsAntibiotic Resistance

A fine balanceGlobal need ofeffectiveantibioticsImmediatebenefit to theindividualButler C et al. JAC 2001;48:435–440Rational use of antibiotics

Managing antibiotic resistanceProlong the lifespan of existing drugs• Rational Use• Better diagnostics• Combinations?Prevent the spread of resistant bacteria• Improved hygiene• Infection control• Hospital structureDevelopment of new antibiotics• New financial models required!

Rational use of antibiotics• More restrictive use• Where there is need• But…• Also an issue of access• Not at least in low-income countries

Adapted from Källander 2005Access vs. Excess

In some cases, the medicinecabinet is already empty“ Almost half of the sampled sepsispatients could not be treated withavailable antibiotics due to resistanceagainst these medicines – a majorityof these patients were newborns.A significant number of these babies died. Ten years agothese lives could have been saved, but today theremaining treatment options are way too costly for mostparents.”Dr Florence Najjuka, Makerere, Ugandaat ReAct WHA briefing, WHO Geneva 2009

Access• Will increased access per se lead to betterhealth outcomes?• What about quality?WHO/TDR, A. Crump

R&D for new antibiotics• Desperate need fornew classes ofantibiotics• Better diagnosticmethods – rapiddiagnostic tests• Vaccines

Simulation studies: Most lives saved from reducingdisease burden accrue to Africa, while other regionsbenefit from reducing overuse

Issues• Difficult to introduce a new diagnostic in apopulation that self-treats unless thesensitivity is high enough (~95%) to ensurethat the overall number of individual livessaved is positive• The benefit of any diagnostic test for severeALRI depends on access to effective hospitalcare.

Study conclusion - diagnostics• ALRI contributes annually to the deaths of >2million children aged

Antimalarial prescriptions forfebrile patients• Patients presenting to outpatient departments in northeast Tanzania withvarying level of malaria transmission• 2,425 Patients for whom a malaria test was requested were randomised tomicroscopy or rapid tests• Outcome: proportion of malaria negative patients prescribed Antimalarial drugsMicroscopyN = 1204Rapid testN = 1193174 +(14%)1.030 -(86%)188 +(16%)1.005 -(84%)Antimalarialsprescribed98% 51% 99% 54%Reyburn et al BMJ 2007

Currently 37 sites in 19 countries24 sites in Africa9 sites in Asia1 site in OceaniaOver 2,000,000 peopleunder surveillance

Prospective monitoring of demographic and health eventsInterventiontrials(randomised)Capturing episodes ofdisease and hospitaladmissionVerbal autopsyfor cause ofdeathMeasure characteristics ofenvironment or householdmembers (e.g. SES, vaccines,HIV, nutrition)Health and DemographicSurveillance System (HDSS)

INDEPTH cross-site research - 1• Mortality levels, patterns, and trends• Causes of death in developing countries• Model life tables• Malaria transmission and mortality• Health equity studies• Migration and urbanization• Sexual and Reproductive Health

INDEPTH cross-site research - 2• NCD risk factor studies in Asia• Adult health and Aging• Climate Change and Health• Intervention trials platform– Effects of ART scale-up on mortality andhealth systems– Phase IV – Effectiveness and SafetyStudies of antimalarias (INESS)• Antibiotic resistance

Surveillance in Low-IncomeCountries• ”Don’t let the best be the enemy of the good!”• Sentinel surveillance• Work with available structures• Few pathogens• Start!

Innovation and R&D for novelantibioticsMany new initiatives targeted to address this healthconcern have been launched, notably in the area ofR&D of new antibioticsNeed for global measures that ensure that newstrategies and/or health technologies are applicable,accessible and affordable also in low- and middleincome countries

Challenges in low-incomecountries• High background mortality and morbidity ofbacterial disease• Rising incomes – greater access to antibiotics• Yet many patients do not have access toeffective antibiotics• Increasing levels of resistance to first linedrugs• Second line drugs may be unaffordable tomany low-income families

Policy options• Encourage physician only prescribing?• Scale up rapid diagnostic tests?• Improve surveillance?• Reduce incentives for over prescribing• Improve access to quality medicines• Pneumoccocal and HiB vaccination• Improve hospital infection control

Antibiotics – a finiteresource

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