1、Is Resistance Futile?Donald E LowUniversity of TorontoOntario Agency for Health Protection and PromotionAchievements in Public Health Control of infectious diseases Sanitation and Hygiene Vaccination Antibiotics MMWR 1999 48(29);621Antibiotics:the epitome of a wonder drug The introduction of antibio
2、tics in the 1940s converted illness into a strictly technical problem:virtual elimination of infectious disease as a significant factor in social life.Burnet FM.Natural history of infectious disease.2nd ed.Cambridge:Cambridge University Press,1953 Prevalence of Isolates of Multidrug-Resistant Gram N
3、egative Rods Recovered Within The First 48 h After Admission to the Hospital Pop-Vicas and DAgata CID 2005;40:1792-8.MRSADeLeo and Chambers JCI 2009 adapted from Klevens et al.JAMA I2007Hospital settingCarbapenemases(KPCs)CommunityS.pneumoniaeCommunity Associated MRSAFluoroquinolone resistant E.coli
4、Multi-drug resistant GCClinical CaseA 73 yo M with no travel hxLaparoscopic right radical nephrectomy for a hypernephroma with post-op pneumoniaEmpirically treated with various antimicrobials including the carbapenems Cultures found MDR K.pneumoniae,initially reported as AmpC-and ESBL-containingDied
5、 with pneumonia and respiratory failureS Krajden,Roberto Melano,and Dylan R.Pillai DrugMIC(m mg/mL)CLSI breakpointsAmpicillin16RCephalothin16RCefoxitin16RTobramycin8RAmikacin32ICeftriaxone32RCiprofloxacin2RMeropenem4SCarbapenemases Ability to hydrolyze penicillins,cephalosporins,monobactams,and carb
6、apenemsResilient against inhibition by all commercially viable-lactamase inhibitors KPC(K.pneumoniae carbapenemase)KPCs are the most prevalent of this group of enzymes,found mostly on transferable plasmids in K.pneumoniaeSubstrate hydrolysis spectrum includes cephalosporins,such as cefotaxime.KPCs h
7、ave transferred to Enterobacter spp.and in Salmonella sppStreptococcus pneumoniaelMost important pathogen in mild-to-moderate RTIs1 lGreatest morbidity2lGreatest mortality2Streptococcus pneumoniae1File TM Jr.Lancet.2003;362:1991-2001;2Bartlett JG,et al.Clin Infect Dis.2000;31:347-382;Canadian Bacter
8、ial Surveillance Network,Feb 2009*Oral breakpoints usedCanadian Bacterial Surveillance Network,Feb 2009lNP carriage 15%19 mos 10%after age of 10 3%in adultslInvasive and mucosal infection involves NP colonization with concurrent viral respiratory infection Kadioglu A.,et al.Nat Rev Micro 2008Pneumoc
9、occal VaccineslAlthough the 23-valent vaccine is immunogenic in adults and children older than 5 years,young children(2 years)have a severely impaired antibody response to polysaccharide vaccinationPPV23426B89V9N1410A18C11A19F12F23F15B117F5207F22F333F19AIntroduction of pneumococcal vaccines,Ontariol
10、Oct 1996 PPV23 program for adults Increased coverage from?2%to 35%in adultsInvasive pneumococcal disease,elderlyMetropolitan Toronto,1995-2000Pediatric invasive pneumococcal diseaseMetropolitan Toronto,1995-2000PCV7PPV234426B6B89V9V9N141410A18C18C11A19F19F12F23F23F15B117F522F7F33F319APneumococcal va
11、ccinesMMWR Feb 2008Invasive Pneumococcal Disease in Children 5 Years After Conjugate Vaccine Introduction,1998-2005lThe overall incidence of IPD among children aged 5 years declined from 99 cases/100,000 during 1998-1999 to 23 cases/100,000 in 2005Introduction of pneumococcal vaccines,OntariolOct 19
12、96 PPV23 program for adults Increased coverage from?2%to 35%in adultslDec 2001 PCV7 licensed Gradual increase in use in children(to about 1 dose per child,or 4 doses for 20%of children)lJan 2005 provincial PCV7 program No catch-up;start with birth cohortPediatric invasive pneumococcal diseaseMetropo
13、litan Toronto,1995-2007Invasive pneumococcal disease,elderlyMetropolitan Toronto,1995-2001Rates of penicillin and amoxicillin resistance Canada:1988-2008Canadian Bacterial Surveillance Network,March 2008Most Common MDR SPN Serotypes0510152025303523A15A6A19A9V146B23F19FPre-PCV7(1995-2001)%MDR SPNSero
14、typeVS0510152025303523A15A6A19A9V146B23F19FPre-PCV7(1995-2001)Post-PCV7(2006-2007)%MDR SPNSerotypeMost Common MDR SPN SerotypesP0.0001P=0.0009P0.0001P0.0001VSWorldwide Prevalance of MRSAAmong S.aureus IsolatesGrundmann H et al.Lancet 2006;368:874.MRSA in Canada,1995-2005Source:CNISPCommunity-Associa
15、tedMRSA Sports participants Inmates in correctional facilities Military recruits Children in daycare Native Americans,Alaskan Natives,Pacific Islanders Men who have sex with men Hurricane evacuees in shelters Foal watchers Rural crystal methamphetamine users First Outbreaks of CA-MRSAUdo EE et al.Ge
16、netic analysis of community isolates of methicillin-resistant Staphylococcus aureus in Western Australia.J.Hosp.Infect.1993US(1999)CDC.Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureusMinnesota and North Dakota,MMWR 1999Mulvey MR et al.Community-associated Met
17、hicillin-resistant Staphylococcus aureus,Canada EID 2005Worldwide(2000)Vandenesch F et al.Community-Acquired Methicillin-Resistant Staphylococcus aureus Carrying Panton-Valentine Leukocidin Genes:Worldwide Emergence EID 2003Emergence of CA-MRSA CanadaSimore A et al.Canadian Nosocomial Infection Surv
18、eillance Program CMRSA7(USA400)CMRSA10(USA300)Current Treatment Options for CA-MRSA InfectionMoellering RC CID 2008Community-acquired antibiotic resistance in urinary isolates from adult women in Canada 15%of E.coli isolates from adult women resistant to TMP-SMX Fluoroquinolone-resistant E coli was
19、7%10%of E coli isolates were fluoroquinolone-resistant in women older than 65 years of ageMc Isaac WJ et al.Can J Infect Dis Med Microbiol.2006Quinolone-resistant Neisseria gonorrhoeae infections in Ontario Isolates referred to the OPHL between 2002 and 2006FQ-R increased from 4.0%in 2002 to 27.8%in
20、 2006 FQ-R strains were more resistant to penicillin(p0.001);tetracycline(p0.001)and erythromycin(p0.001)All isolates were susceptible to cefixime,ceftriaxone,azithromycin and spectinomycinOta K et al.Can Med Ass J In PresslReducing colonization and infectionlReducing volume of antimicrobial uselWhe
21、n decision made to treat Use right drug Right dose Right durationReducing infection Reducing volume of antimicrobial use When decision made to treat Use right drug Right dose Right durationThe average excess age-specific numbers of outpatient visits and courses of antibiotics per 100 children per ye
22、ar Neuzil KM et al.NEJM 2000The Effect of Influenza on Hospitalizations,Outpatient Visits,and Courses of Antibiotics in Children Reducing colonization and infection Reducing volume of antimicrobial use When decision made to treat Use right drug Right dose Right durationSource:Verispan PDDA 2004Numbe
23、r of common office visits(millions)Source:SDI,FANDxRx.Based on all tablets/capsule antibiotics for the 52 weeks ending April 6,2005Telithromycin(Ketek)is indicated for acute exacerbations of chronic bronchitis,acute bacterial sinusitis and mild-to-moderate community-acquired pneumoniaUsage of antibi
24、otics in Europe vs.pneumococcal penicillin I/R 1997Felmingham et al.J Antimicrob Chemother 2000;45:191201Cars et al.Lancet 2001;357:1851185338.532.528.826.7241813.58.90102030405060FranceSpainPortugalBelgiumItalyUKGermanyNetherlandsDDD/1000/dayDI/RSP%*1996 data Reducing colonization and infection Red
25、ucing volume of antimicrobial use When decision made to treat Use right drug Right dose Right durationMultivariate Analysis of Risk Factors0123456-lactam w/in 3 monthsAlcoholismNoninvasivedisease 5 y 65 yOdds Ratio Other Considerations Immunosuppression Including steroids Multiple medical comorbidit
26、ies Exposure to day care child Exposure to any antibioticClavo-Sanchez AJ et al.Clin Infect Dis.1997;24:1052-1059.Harwell JI,Brown RB.Chest.2000;117:530-541.Vanderkooi OG et al.Clin Infect Dis.2005;40:1288-1297.Risks for Penicillin Resistancein PneumococcusPrevalence of Erythromycin Resistance Among
27、 Pneumococci by Prior Macrolide UseP=.02P=.004Vanderkooi OG et al.Clin Infect Dis.2005;40:1288-1297.P .0010102030405060No AntibioticErythromycin Clarithromycin AzithromycinRate of Macrolide Resistance in Infecting Isolates(%)Relative Risk for Infection With Fluoroquinolone-Resistant Pneumococci by P
28、rior Antibiotic UseVanderkooi OG et al.Clin Infect Dis.2005;40:1288-1297.02468101214161820No Prior AntibioticPrior Antibiotic(not fluoroquinolone)Prior FluoroquinoloneLevoofloxacin resistant(%)*P.001Fluoroquinolone PD ProfileFree AUC/MICLevofloxacin500 mgLevofloxacin750 mgGemifloxacin320 mgMoxifloxa
29、cin400 mg40(13-21)(24-40)(72-120)Resistance Prevention AUC/MIC100Efficacy AUC/MIC35206080100120140(41-69)Moran G.J Emerg Med.2006;30:377-387.10035WHO statement 2000The most effective strategy against antibiotic resistance is:“to unequivocally destroy microbes”“thereby defeating resistance before it starts”WHO Overcoming Antimicrobial Resistance,2000Canadian Bacterial Surveillance Network,Jan 2009%ResistantResistance Isnt Futile
