1、ANTIBIOTIC RESISTANT PATHOGENS:IMPACT AND CONTROLDavid Jay Weber,M.D.,M.P.H.Professor of Medicine,Pediatrics&EpidemiologyUniversity of North Carolina at Chapel Hill,USASOURCES OF SLIDESThanks are given to the following persons who provided slides for this lecturenWilliam Jarvis,CDCnMarin Kollef,Wash
2、ington Universitiy,St.LouisnChristopher Ohl,Wake Forest UniversitynJan Patterson,University of Texas,San AntonionMichael Pfaller,University of IowanLouis Rice,VA Medical Center,ClevelandIMPACT OF NOSOCOMIAL INFECTIONSIMPACT OF NOSOCOMIAL INFECTIONSIncidence=5-10%nIncidence rising with time2,000,000
3、patients develop a healthcare-associated infection each yearHealthcare-associated infections result in 90,000 deathCost estimated at$4.5 to$5.7 billion dollars per yearNOSOCOMIAL INFECTIONS IN THE UNITED STATESVariable19751995Admissions37,700,00035,900,000Patient-days299,000,000190,000,000Average le
4、ngth of stay7.95.3Inpatient surgical procedures18,300,00013,300,000Nosocomial infections2,100,0001,900,000Incidence of nosocomial infections(Number per 1000 patient-days)7.29.8Burke JP.NEJM 2003;348:651PREVALENCE:ICU(EUROPE)Study design:Point prevalence raten17 countries,1447 ICUs,10,038 patientsFre
5、quency of infections:4,501(44.8%)nCommunity-acquired:1,876(13.7%)nHospital-acquired:975(9.7%)nICU-acquired:2,064(20.6%)u Pneumonia:967(46.9%)u Other lower respiratory tract:368(17.8%)u Urinary tract:363(17.6%)u Bloodstream:247(12.0%)Vincent J-L,et al.JAMA 1995;274:639CHALLENGES IN THE PREVENTION AND
6、 MANAGEMENT OF HEALTHCARE-ASSOCIATED INFECTIONSChanging population of hospital patientsnIncreased severity of illnessnIncreased numbers of immunocompromised patientsnShorter duration of hospitalizationnMore and larger intensive care unitsGrowing frequency of antimicrobial-resistant pathogensnImporta
7、tion of antimicrobial-resistant pathogens from the community into the hospitalLack of compliance with hand hygieneReduced infection control resources nationwideFuture:Prion diseases,bioterrorism agents,gene therapy,xenotransplantationHEALTHCARE SYSTEM OF THE PASTTranquil GardensNursing HomeHomeCareA
8、cute CareFacilityOutpatient/AmbulatoryFacilityLong Term CareFacilityCURRENT HEALTHCARE SYSTEMTranquil GardensNursing HomeHomeCareAcute CareFacilityOutpatient/AmbulatoryFacilityLong Term CareFacilityCURRENT STATE OF HEALTHCARE EPIDEMIOLOGY IN ACUTE CARE HOSPITALSFewer hospitalsSmaller hospitalsMore a
9、nd larger intensive care unitsGreater patient severity of illnessMore immunocompromised patientsShorter staysFewer nurses?Fewer infection control personnel?MECHANISMS OF ANTIBIOTIC RESISTANCEIntrinsic resistanceAcquired resistancenAntibiotic modifying enzymes(e.g.,penicillin resistance in S.aureus)n
10、Target site alteration(e.g.,methicillin resistance in S.aureus)nPermeability barriers(e.g.,vancomycin tolerance in VISA)nEfflux pumps(e.g.,erythromycin resistance in S.pneumoniae)Mechanisms of ResistanceEliopoulos.Infectious Diseases.1992.IMPACT OF DRUG RESISTANT PATHOGENSInappropriate therapy with
11、worse outcomeProlonged hospitalizationnIncreased difficulty with placement in an extended care facilitynNeed of isolation precautions(may negatively impact on quality of patient care)Increased costHigher mortalityEMERGING DRUG RESISTANCE IN COMMUNITY PATHOGENSEMERGING RESISTANT PATHOGENS:COMMUNITYHI
12、V:Multiple agentsPneumococcus:Penicillin/cephalosporins,erythromycinGroup A streptococcus:ErythromycinMycobacterium tuberculosis:INH,rifampinNeisseria gonorrhoeae:Penicillin,quinolonesStaphyloccus aureus:OxacillinPlasmodium falciparum:Chloroquine,mefloquine,othersVAFeedlotsForeignDaycareCommunityHos
13、pitalsTertiaryHospitalsNursing HomesCommunityHomecareEnvironments Where Antibiotic Resistance Develops and Their RelationshipsAdapted from B.MurrayS.PNEUMONIAE:INCIDENCE,USMeningitis:3,000 casesBacteremia:50,000 casesPneumonia:500,000 casesOtitis media:7 million casesDeaths:20,000Source:Centers for
14、Disease Control.MMWR 1997;46(RR-8)02468101214161819881990199219941996199820002002%of Isolates Resistant to PenicillinYearBreiman RF,et al.JAMA.1994;271:1831-1835.Doern GV,et al.AAC.1996;40:1208-1213.Thornsberry C,et al.DMID.1997;29:249-257.Thornsberry C,et al.JAC.1999;44:749-759.Thornsberry C,et al.
15、CID 2002;34(S1):S4-S16.Karlowsky,et al.CID.2003;36:963-970.Sahm,et al.IDSA 2003,abstract 201.Data on file,Ortho-McNeil Pharmaceutical,Inc.In vitro activity does not necessarily correlate with clinical results.Trend for Penicillin-Resistant(MIC 2 mg/ml)S.pneumoniae in the US(1988-2002)PENICILLIN SUSC
16、EPTIBILITY65.0663.2556.4953.5252.037575.673.272.576.470.565.8304050607080199519961997199819992000year%susceptibilityNCUS,ABCUS,DoernCLINICAL SYNDROMES:STAPHYLOCOCCUS AUREUSSkinnPrimary pyodermas:Impetigo,folliculitis,furuncles,carbuncles,paronychia,cellulitisnToxin mediated syndromes:Toxic shock syn
17、drome(TSS),scalded skin syndrome(SSS)Systemic:Sepsis,bacteremia,endocarditisOrgan system:Meningitis,osteomyelitis,septic arthritis,paratitis,myositisEvolution of Antimicrobial Resistancein Gram-positive CocciVancomycin-resistantS.aureusCLASSIFICATION OF S.AUREUS RESISTANCE Type of S.aureusCommentOxa
18、cillin-susceptible(OSSA)Susceptible to oxacillin,nafcillin,cephalosporins,and -lactam inhibitor combinations.Borderline-resistant(BRSA)Borderline oxacillin MICs due to hyperproduction of -lactamase,abnormal PBPs,or heterogeneous mecA production.Oxacilin-resistant(ORSA)Oxacillin 4 ug/mL due to low af
19、finity PBP(PBP-2).Resistant to all penicillins,cephalosporins,carbapenems.Glycopeptide-intermediate(GISA)Vancomycin MIC 8-16 ug/mL;also intermediate to teicoplanin.Mechanism=thickened cell wall.Clinically resistant to vancomycin.Vancomycin-resistant(VRSA)Vancomycin MIC 32 ug/mL.Mechanism=vanA gene f
20、rom VRE E.faecalisORSA:Prevalence of co-resistance to other drugs,U.S.,1997-1999:020406080100MRSA with Co-ResistanceDiekema DJ et al.CID.2001;32:S114-S132.ORSA strains showed resistance to mean 3.5(median 3)additional drug classes36%89%93%79%26%24%CiprofloxacinTetracycline16%Increasing Prevalence of
21、 MRSA in S.aureus Bloodstream Infections01020304050607080CommunityNosocomial199719981999Diekema DJ et al.CID.2001;32:S114-S132.%MRSAUnited States,S aureus isolates(N=4405)EPIDEMIOLOGIC AND CLINICAL FEATURESCommunity-acquired strains demonstrate increased susceptibility to antibiotics and multiple cl
22、onal typesClinical features and epidemiologic features of community-acquired cases similar to healthcare associatednSkin and soft tissue infections predominateFamilial transmission of MRSA describedOutbreaks described(e.g.,high school wresting team)ANTIBIOTIC RESISTANCE IN THE COMMUNITY:FACTORS CONT
23、RIBUTING TO SPREAD IN THE COMMUNITYFactors contributing to spread of antibiotic resistancenSelection of antibiotic-resistance genesnIncrease in“high-risk”(immunodeficient)populationnProlonged survival of persons with chronic diseasesnCongregate facilities(e.g.,jails,day care centers)nLack of rapid,a
24、ccurate diagnostic tests to distinguish between viral and bacterial infectionsnIncreased use of antibiotics in animals&agriculture Source:Segal-Maurer S.ID Clin NA 1996;10:939-957.ANTIBIOTIC RESISTANCE:Physician practices contributing to inappropriate antibiotic useProviding antibacterial drugs to t
25、reat viral illnessesUsing inadequate diagnostic criteria for infections that may have a bacterial etiologyProviding expensive,broad-spectrum agents that are unnecessaryPrescribing antibiotics at an improper dose or durationANTIBIOTIC PRESCRIBING,CHILDRENDiagnosisOffice Visits(x1000)Antibiotic Prescr
26、iptions(x1000)%Total Antibiotic PrescriptionsOtitis media20,82016,15030URI14,0686,50912Pharyngitis7,4355,24610Bronchitis6,4184,6649Sinusitis3,2542,3564Nyquist A-C,et al.JAMA 1998;279:875ANTIBIOTIC PRESCRIBING,ADULTSDiagnosisOffice Visits(x1000)Antibiotic Prescriptions(x1000)%Total Antibiotic Prescri
27、ptionsSinusitis13,3697,49412Bronchitis10,2356,76211URI11,0335,84210Pharyngitis7,4125,6349UTI4,8582,7985Otitis media4,2262,0033Gonzoles R,et al.JAMA 1997;278:901FREQUENCY OF ANTIBIOTIC USEDiagnosisChildrenAdultCommon cold44%51%URI46%52%Bronchitis75%66%Streptococcus Pneumoniae:Regional Trends in Antib
28、iotic Resistance%NonsusceptibleData:B.Schwartz,Emerging Infections Program,CDC;ICAAC 98=regional range01020304050AtlantaBaltimoreConn.MetroTenn.MinneapolisPortlandSan Fran.RegionBeta-lactamMacrolide11.21.41.61.822.2Relative Risk0-2425-4950-7475-100%Antibiotic Use QuartileB-lactamsMacrolidesStreptoco
29、ccus Pneumoniae:Risk for Antibiotic Resistance is Greater with Increased Outpatient Antibiotic UseControlled for regionData:B.Schwartz,Emerging Infections Program,CDC;ICAAC 98Decreased Susceptibility of S.pneumoniae to Fluoroquinolones in Canada:Relationship of Resistance to Antibiotic Use00.511.522
30、.533.544.551988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998S.pneumo.with ReducedSusceptibility to Fluoroquinolones(%)0123456#of Prescriptions/100 Persons15-64 y.o 64 y.o#of Rx/100 persons Overall prevalence of FQRSP 1.0%No reduced susceptibility in children FQRSP prevalence higher in the elder
31、ly and in Ontario Highest FQ use in the elderly and in OntarioChen et.al.,NEJM 1999;341:233-9KEY NOSOCOMIAL PATHOGENSNational Nosocomial Infections Surveillance(NNIS)Report:ICU Infections 1986-19970204060Bloodstream InfectionCoNS*S.aureusEnterococcusC.albicansEnterobacterOther0204060PneumoniaP.aerug
32、inosaS.aureusEnterobacterK.pneumoniaeH.influenzaeOther0204060Surgical Site InfectionEnterococcusCoNS*S.aureusP.aeruginosaEnterobacterOtherPercentPercentPercentRISK FACTORS FOR HEALTHCARE-ASSOCIATED INFECTIONSHAZARDS IN THE ICUWeinstein RA.Am J Med 1991;91(suppl 3B):180SPREVALENCE:ICU(EUROPE)Study de
33、sign:Point prevalence raten17 countries,1447 ICUs,10,038 patientsFrequency of infections:4,501(44.8%)nCommunity-acquired:1,876(13.7%)nHospital-acquired:975(9.7%)nICU-acquired:2,064(20.6%)u Pneumonia:967(46.9%)u Other lower respiratory tract:368(17.8%)u Urinary tract:363(17.6%)u Bloodstream:247(12.0%
34、)Vincent J-L,et al.JAMA 1995;274:639RISK FACTORS FOR ICU ACQUIRED INFECTIONS00.511.522.5Trauma on AdmissionMechanical VentilationUrinary CatherizationStress Ulcer ProphylaxisCVP LinePA CatherizationOdds Ratio(1.01-1.43)(1.16-1.57)(1.20-1.60)(1.19-1.69)(1.51-2.03)(1.75-2.44)(95%CI)RISK FACTORS FOR IC
35、U ACQUIRED INFECTIONS010203040506070802114-207-135-63-41-2Length of Stay,dOdds Ratio(1.56-4.13)(5.51-14.70)(9.33-24.14)(19.43-48.67)(37.90-96.25)(48.18-120.06)(95%CI)EMERGING DRUG RESISTANCE IN NOSOCOMIAL PATHOGENSEMERGING RESISTANT PATHOGENS:HEALTH CARE FACILITIESStaphylococcus aureus:Oxacillin,van
36、comycin,linezolidEnterococcus:Penicillin,aminoglycosides,vancomycin,linezolid,dalfopristin-quinupristinEnterobacteriaceae:ESBL producers,carbapenemsCandida spp.:FluconazoleMycobacterium tuberculosis:INH,rifampinCurrent status of resistance in the ICU:(NNIS,2002 vs 19972001)Resistance(%)0102030405060
37、708090Vancomycin/EnterococciMethicillin/S.aureusMethicillin/CNS3rd Ceph/E.coli3rd Ceph/K.pneumoniaeImipenem/P.aeruginosaQuinolone/P.aeruginosa3rd Ceph/P.aeruginosa3rd Ceph/Enterobacter spp.+11+13+1+142+32+27+225Change in resistance(%)JanDec 200219972001(sd)Ceph=cephalosporin;NNIS=National Nosocomial
38、 Infections Surveillance System;CNS=coagulase-negative staphylococciNNIS.Am J Infect Control 2003;31:48198ORSA,SENTRY,1997-1999Diekema D,et al.CID 2001;32(S-2):S114ENTEROCOCCAL RESISTANCEIntrinsic ResistanceSemisynthetic penicillinsCephalosporinsClindamycinTrimethoprim-SulfamethoxazoleMonobactamsAmi
39、noglycosidesCarbapenems(E.faecium)AcquiredAminoglycosides(High Level)ChloramphenicolErythromycinPenicillinTetracyclineVancomycin and TeicoplaninLinezolidSynercid024681012145870758085899091929394FY97%VRE in ICU%VRE Non-ICUIncreasing VRE Over Time“PROBLEM”GRAM-NEGATIVE PATHOGENSP.aeruginosaESBL-produc
40、ing GNRnE.colinKlebsiella pneumoniaenEnterobacter spp.Acinetobacter spp.Stenotrophomonas maltophilaP.AERUGINOSA SUSCEPTIBILITYUS,1999(SENTRY)0.0%10.0%20.0%30.0%40.0%50.0%60.0%70.0%80.0%90.0%100.0%AmikacinTobramycinCiprofloxacinCeftazidimeCefepimePiperacillinMeropenemImipenemGales A,et al.CID 2001;32
41、(S-2);146What is an Extended-Spectrum -Lactamase(ESBL)?Variant of standard TEM and SHV-lactamasesResult of point mutations in TEM-1 and SHV-1 genesAlters active binding site of enzymeExtends spectrum of the mutated-lactamaseAllows effective hydrolyzation of third-generation cephalopsorinsTransmitted
42、 via plasmidsEvolution of -Lactamase Plasmid-Mediated TEM and SHV EnzymesAmpicillinTEM-1E.coliS.paratyphiTEM-1Reported in 28 gram-negativespeciesESBL in EuropeESBL inUnitedStates150 ESBLsworldwideThird-generation cephalosporinsESBLs Detection Methods:Inhibition by Clavulanic AcidANTIMICROBIAL RESIST
43、ANCE RATES-GNR,ICARE/AUR,JANUARY 1998 JUNE 20030.0%5.0%10.0%15.0%20.0%25.0%30.0%Quinolone-E.coliCef3-E.coliCef3-KlebsiellaCarbapenem-KlebsiellaCef3-Enterobacter%ResistantICUNon-ICU InpatientCDC.AJIC 2003;31:881-98.ACINETOBACTER SUSCEPTIBILITYUS&CANADA,1997-1999(SENTRY)0.0%10.0%20.0%30.0%40.0%50.0%60
44、.0%70.0%80.0%90.0%100.0%ImipenemMeropenemTicar/ClavPip/TazoCeftazidimeCefepimeCiprofloxacinGentamicinTobramycinAmikacinAll isolatesNosocomialisolatesGales AC,et al.Clin Infect Dis 2001;32(Suppl 2):S104-113STENOTROPHOMONAS RESISTANCEUS,1997-1999(SENTRY)0.0%10.0%20.0%30.0%40.0%50.0%60.0%70.0%80.0%90.0
45、%100.0%TetracyclineGatifloxacinCiprofloxacinTobramycinAmikacinCeftazidimePip/tazoTicar/clavTMP-SMXGales AC,et al.Clin Infect Dis 2001;32(Suppl 2):S104-113ANTIBIOTIC RESISTANCE IN HOSPITALS:FACTORS CONTRIBUTING TO SPREAD IN HOSPITALSGreater severity of illness of hospitalized patientsMore severely im
46、munocompromised patientsNewer devices and procedures in useIncreased introduction of resistant organisms from the communityIneffective infection control&isolation practices(pliance)Increased use of antimicrobial prophylaxisIncreased use of polymicrobial antimicrobial therapyHigh antimicrobial use in
47、 intensive care unitsSource:Shales D,et al.Clin Infect Dis 1997;25:684-99.PRINCIPLES OF ANTIBIOTIC RESISTANCE(Levy SB.NEJM,1998)1.Given sufficient time and drug use,antibiotic resistance will emerge.2.Resistance is progressive,evolving from low levels through intermediate to high levels.3.Organisms
48、resistant to one antibiotic are likely to become resistant to other antibiotics.4.Once resistance appears,it is likely to decline slowly,if at all.5.The use of antibiotics by any one person affects others in the extended as well as the immediate environment.FACTORS ASSOCIATED WITH RESISTANT PATHOGEN
49、SAll resistance is localHospital demographicsnSizenTeaching versus non-teachingnLocationCare in an intensive care unitDuration of hospitalization and use of an invasive medical device(central venous catheter,endotracheal tube for mechanical ventilation,urinary catheter)Prior antimicrobial useANTIMOC
50、ROBIAL RESISTANCE,US,1999-2000Diekema DJ,et al.Clin Infect Dis 2004;38:7885ANTIMOCROBIAL RESISTANCE,US,1999-2000Diekema DJ,et al.Clin Infect Dis 2004;38:7885ANTIMICROBIAL RESISTANCE RATES-GPC,ICARE/AUR,JANUARY 1998 JUNE 20030.0%10.0%20.0%30.0%40.0%50.0%60.0%70.0%80.0%Cefotax-PneumococcusPen-Pneumoco
