Medicine.Past,PresentandFuture.ANTIBIOTICSProfessorAnthonyCoatesMedicalMicrobiologyDepartmentofCellularandMolecularMedicine,StGeorges,UniversityofLondon.MicrobeskilleachotherwithantibioticsTheyhavedevelopedself-defencemechanisms:1.Non-multiplyingstate2.Biofilm3.GeneticresistanceThesearchforantibioticsbeginsBacterialgeneticresistancetoantibioticsbeginstoneutralisethebeneficialeffects.1945, in an interview with The New York Times, Fleming warned that the misuse of penicillin could lead to selection of resistant forms of bacteria The solution: Make new antibiotics to replace the old ones to which resistance has emerged. Antibioticdevelopment1929-72TheAntibioticParadox,StuartLevy,NewYork,PlenumPress,1992,4THEPRESENTAntibioticresistanceisrising80706050403020100199019952000 2003PercentofResistantStrainMRSAQRPSEMRSPN/VREPRSPNMRSA = methicillin resistant Staphylococcus aureusVRE = vancomycin resistant enterococciMRSPN = macrolide resistant Streptococcus pneumoniaePRSPN = penicillin resistant Streptococcus pneumoniaeQRPSE = quinolone resistant Pseudomonas aeruginosaThenumberofnewantibioticswhichreachthemarketisfallingLife-or-deathCrisis:TheBacteriaarewinningEmergenceofresistanceisoutpacingtheintroductionofnewantibiotics(2003Daptomycin;2004none;2005Tygacil)Nonewagentsinclinicaldevelopmentagainstmulti-drugresistantgram-negativesegPseudomonas aeruginosa, Acinetobacter sppWhyhasthepharmaceuticalindustryreduceditsproductionofnewantibiotics?ResistanceemergestooquicklyandreducestheeffectivelifeofanantibioticToolittleprofitBigBiologyhasfailedtoproducenewantibioticsIncreasedcostsduetomoreregulationegECLitigationfearsGovernmentrestrictionsonuse(Keepinreserve)AntibioticuseintodaysworldAmoxilandAugmentin25%ofallpresciptionsMorethan$1billionsalesperyearforAugmentin,Klacid,ZithromaxandLevaquin.(IMSHealth,IMSMidas,www.imshealth.com/globalinsights)THEFUTUREInternationalresponsetotheglobalspreadofantimicrobialresistanceImprovestandardsofantimicrobialprescribingandsoprolongthelifeofexistingantimicrobialsVaccinesPreventionbyimprovedinfectioncontrolLimitedimpactsofarProductionofnewantibioticsGlaxoSmithKlinehastwoindevelopmentJohnsonandJohnsonactivePfizeractiveNovartishaveenteredantibioticR&D(PersonalCommunication,HallsGA,medicalmarketingservices,ghallsbtconnect.com)ProductClassSpectrumIv/oralIndicationsPhaseCompany (Licensor)Quinupristin/dalfopristin streptograminGram-positive (excluding E. faecalis)IvVRE, cSSTIs, bloodstream infections MarketedKing Pharmaceuticals (Sanofi-aventis)Gatifloxacin FluoroquinoloneBroad-spectrum Iv and oralcommunity-acquired RTIs SSTIs UTIsMarketed Bristol-Myers Squibb/ Grunenthal (Kyorin)Iv and oralAcute otitis media (paediatric)Discontinued Linezolid Oxazolidinone Gram-positive Iv and oralRTIs SSTIs VRE Bloodstream infections MarketedPharmacia Telithromycin Ketolide Gram-positive, Respiratory tract infection pathogens oralcommunity-acquired RTIsMarketedAventisErtapenemCarbapenemBroad-spectrum (excluding non-fermenters)IvCAP, intra-abdominal infection, acute gynae infections USA + Europe. cSSTI, cUTI USAMarketedMerck & Co Moxifloxacin FluoroquinoloneBroad-spectrum Iv and oralRTIs,Marketed; BayercSSTIsApproved in EU & USAintra-abdominal infectionsFiledGemifloxacin FluoroquinoloneBroad-spectrum Iv and oralAECB; mild-moderate CAP Oral Marketed; iv late-pre-clinical USA Oscient(LG Chemical)5-day treatment of CAP; acute bacterial sinusitis Phase III complete USA; filing expected by end 2005community-acquired RTIs Pre-reg EUCo-marketing partner not yet announcedDaptomycin lipopeptideGram-positive Iv (oral development discontinued)cSSTIsMarketed USA, filed EUCubist USA; Chiron Europe and ROW (Lilly)Bacteraemia/endocarditis Pre-reg USATigecycline (GAR 936)Glycylcycline Gram-positive, Gram-negative and anaerobesIvcSSTI, HAP, CAP, intra-abdominal infections, cUTI, VRE, Marketed USA; filed EU WyethDalbavancin Glycopeptide Gram-positive Iv; once-weekly cSSTI, Filed USA Vicuron CeftobiproleCephalosporin Gram-positive (including MRSA) + Gram-negative IvcSSTI, HAP, catheter-related bacteraemia (and probably CA P)Phase III; FDA fast tracked for HAP/VAPBasilea Pharmaceutica/J&J (Roche)TelavancinGlycopeptideGram-positive (including MRSA)Iv cSSTI and HAPPhase III; FDA fast trackedTheravanceDoripenem (S-4661)CarbapenemBroad -spectrum, including resistant Gram-negativesIvcUTI. cIAI, HAP/VAPPhase III; FDA fast tracked for HAP/VAPJ&J (Shionogi)Garenoxacin Des F(6) quinoloneBroad-spectrum Iv and oralcommunity-acquired RTIs SSTIs UTIs; intra-abdominal infection Phase III Schering Plough (Toyama)AR-100DiaminopyrimidineGram-positive (including MRSA), Respiratory tract infection pathogens IVMRSA, RTIs, SSTIsIV Phase III; oral Phase I Arpida Ltd (Roche)Ramoplanin Glycolipo-depsipeptideGram-positive Oral non-absorbedPrevention of VRE bacteraemia in neutropenic patients Discontinued Oscient (Vicuron)C. difficile-associated diarrhoea Phase II/IIIRO4908463 (R1558/CS-023)Carbapenem Gram-positive including MRSA and Gram-negative including P. aeruginosaIv CAP; nosocomial bacterial infectionsCAP Phase IIRoche (Sankyo)CX-0903 (PPI-0903/TAK-599)Cephalosporin(Resistant) Gram-positive + Gram-negative IvcSSTI, HAP, CAPPhase I completed; Phase II cSSTI planned Q2 2005Cerexa (Peninsula/Takeda)DX-619Des F(6) quinoloneGram-positive and Gram-negative (excluding P. aeruginosa)Iv and orallife- threatening infections caused by MDR Gram+Iv Phase IOral pre-clinical DaiichiWCK 771 FluoroquinoloneGram-positiveIv and oral cSSTIPhase I WockhardtGSK-565154Pleuromutilin (new class)susceptible and resistant Gram positive & Gram negative RTI pathogens; and multi-resistant MRSA (inc. VRSA)oralRTIsPhase I GlaxoSmithKline LBM415Deformylase inhibitorGram-positive and Respiratory tract pathogens iv and oralcommunity-acquired RTIsPhase I (but to be replaced by new molecule due Phase I Q4 2005) Novartis (Vicuron)AZD2563 Oxazolidinone Gram-positive Iv and oralRTIs SSTIs VRE Bloodstream infections Discontinued AstraZeneca Faropenem penemBroad-spectrum OralRTIs SSTIsDiscontinued BayerOritavancin Glycopeptide Gram-positive IvcSSTI, HAP bloodstream infections Discontinued InterMune (Lilly)ABT-773 ketolideGram-positive, Respiratory tract infection pathogens Iv and oralcommunity-acquired RTIsDiscontinued AbbottBB 83698Deformylase inhibitorGram-positive Respiratory tract infection pathogens iv and oralcommunity-acquired RTIsDiscontinued British BiotechROW=restofworld;CAP=community-acquiredpneumonia;cSSTI=complicatedskinandskinstructureinfections;VAP=ventilator-associatedpneumoniaRef:PersonalCommunicationHallsGA,medicalmarketingservices,34LedboroughLane,Beaconsfield,BucksHP92DD,UK;ghallsbtconnect.comMethodsofgenerationofnewantibioticsAnewapproach:developantibioticswhichkillnon-multiplyingbacteriaSurviveveryhighconcentrationsofantibioticsSourceofcontinuinginfectionMayberesponsibleforemergenceofgeneticresistanceAntibioticDieMultiplyingNon-MultiplyingSurviveMultiplyingClinical Disease 012345678905101520253035404550Concentrations of Drugs (ug/ml)Log CFU/mlAugmentinLevofloxacin AzithromycinLinezolidHT31HT42Staphylococcusaureusstationaryphase 01234567801020304050607080Concentrations of Drugs (ug/ml)Log CFU/mlVancomycinHT31HT42MethicillinresistantS.aureusstationaryphaseNewantimicrobialagentswhichkillnon-multiplyingbacteriaPotentialUseincombinationwithanti-multiplyingcompoundsWillshortenthedurationofchemotherapyMayreducetheemergenceofresistanceConclusionsPastAntibioticshaverevolutionisedmedicineandhavesavedmillionsoflivesPresentIncreasingbacterialresistanceandfallingantibioticproductionisreducingtheefficacyofantibioticsFutureAcontinuoussupplyofnewantibioticsisneeded,withactivityagainstnon-multiplyingbacteriaAcknowledgementsYanminHuClivePage*AnthonyCoatesStGeorges,UniversityofLondon;*SacklerInstitute,KingsCollege,London.MRCCooperativeGrant(5year),BurtonProgrammeGrant(5year),EuropeanCommission(3year),HelperbyTherapeuticsplc.