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1、Penicillin-resistant pneumococci-potentials for modelingProf.Karl EkdahlKI/MEB and ECDCAbout the bugStreptococcus pneumoniae(pneumococcus)Gram-positive,encapsulated diplococcusCapsular swelling observed when reacted with type-specific antisera(Quellung reaction)Surface capsular polysaccharideElectro
2、n micrograph of pneumococcusPathogenesisColonisation of mucous membranes in respiratory tractsAdhesion(bacterial adhesins)Invasion of tissues if not defeatedMiddle earSinusesBronchi Important for modelling:Pneumococcal serotypesBased on properties of capsular polysaccharidesImmunologically distinct
3、and basis for classification 40 serogroups(e.g.group 19)90 serotypes(e.g.types 19A,19C,19F)No immunologic cross-reactivity between serogroupsSome cross-reactivity within some serogroups and some cross-protectionGeographical and temporal variationSome more immunogenic than othersImportant for modelli
4、ng:Pneumococcal serotypes(II)Children 5 y lack ability to mount antibody response to several serotypesSuch types(6B,9V,14,19F,23F)more dominating among young children=child serotypesAccount for the majority of carriage and disease in childrenExplains high incidences of carriage and disease in the yo
5、ungestChild serotypes heavily linked to antibiotic resistanceLimited number of very successful international clonesPneumococcal vaccine Antibody response in young childrenAbout the diseaseA major cause of morbidity and mortality worldwideOver 1 million deaths annually due to pneumoniaCauses more dea
6、ths in young children in US than any other single microorganismIncidence of infection varies globallyAge groups at highest risk for disease:Infants and children 65 years of agePneumococcal disease frequently observed in children up to 5 years of ageSignificant disease burden in childrenOtitis mediaP
7、neumoniaBacteremiaMeningitisDisease severityNoninvasiveInvasiveEstimated number of cases per year(US)57 million71,00017,0001,400PrevalenceIncreasesMMWR.1997;46:1-24.Etiology of acute otitis media(South Sweden)Invasive pneumococcal disease(IPD)Bacterial growth in normally sterile fluidsBlood(pneumoni
8、a,meningitis,endocarditis)CSF(meningitis)Joint fluids(artritis)Pleural fluid(pleuritis)Peritoneal fluid(peritonitis)Main clinical picture IPD(South Sweden)Pneumonia8%CFRMeningitis18%CFRSepticemia29%CFROthers14%CFRAge-related incidence of IPD(Europe 2005)Incidence of invasive pneumococcal disease in
9、children(US 1998)0501001502002500561112171823243536474859 59 yrs1019 yrsAge group(months)Cases per 100,000 personsSeasonality IPD(Europe 2005)ldersrelaterad brartidVeckorBrartid av pc-resistenta pneumokockerVeckor28%12%6%Black S,Shinefield H.Pediatr Ann.1997;26:355-360.GroupRate of carriage(%)Presch
10、ool childrenUp to 60Grammar school children35High school students25Adults with children inhousehold 1829Adults without children in household6Carriage RatesAntibiotic resistancePapua New Guinea:First reports of pc resistance in 1969-Pc resistance 30%already in 1980South Africa:First reports of multi-
11、resistance in 1977-Currently pc resistance 40%Alaska:Pc resistance 25%in 1987Spain:Pc resistance 46%in 1993 Streptococcus pneumoniae:patterns of penicillin non-susceptibilityMajor resistance trends by serotypeMost frequently associated non-susceptible serotypes:6B,9V,14,19A,19F,and 23FPenicillin-sus
12、ceptible strains may acquire resistance over time and become resistant to penicillin and other classes of drugsNon-susceptible serotypes vary geographically over time,by antibiotic usage,age,and crowdingNon-susceptible strains are often resistant to other classes of antibioticsSales of antibiotics i
13、n the EUCars O.et al.The Lancet 2001:357;1851-2/Data provided by IMS0510152025303540F ranceSpain P ortugal B elgiumLuxemItalyGreece FinlandIrelandUKAustriaGermanySwedenDenmarkNetherlandOthers*Macrolides and lincosamidesQuinolonesTrimethoprimTetracyclinesCephalosporinsPenicillinase-resistant penicill
14、insNarrow-spectrum penicillinsBroad-spectrum penicillins*Includes sulphonamides,penicillinase-resistant penicillins,amphenicols,aminoglycosides,and glycopeptides.Defined daily dose per 1000 inhabitants per dayPenicillin-resistant pneumococciMIC(Mg/L)S(susceptible)2.0Reportable inSweden 0.5Antibiotic
15、 usage for acute otitis media by age(US)6 years and older=16%(4 million)of total episodes of otitis media treated with antibiotics.0123451 year after vaccinationHerd immunityImportant for modelling:Serotype replacementSeen in both carriage of diseaseTo a large extent switch to non-vaccin typesRegula
16、ted by competition between speciesIncrease in prevalence of serotypes present in populationIntroduction of”new”serotypes(previously unable to competeUnmasking of subdominant types in an individualMay result in a switch to more immunogenic typesAcquired immunity at an earlier ageReplacement of other
17、bacteriaImportant for modelling:Vaccine effect on antibiotic resistanceReduction of antibiotics consumption(15-20%Israel)Reduction of carriage of antibiotic-resistant bacteriaVaccine types=child serotypes=resistant typesHerd immunity:decreased carriage in siblingsReduction of infection with antibiot
18、ic resistant bacteriaBut the bacteria will fight backSerotype replacement to non-vaccine typesThey will eventually also become resistant Some important questions to be answered by modellersWhat is the relative importance of antibiotic consumption on individual,DCC and community level?Are there diffe
19、rences in ability between antibiotics to select for resistance?Is there a threshold level of community antibotic consumption,critical for the spread of epidemic clones?If so would it be different for different serotypes/clones?Why clonal spread for some pneumo-cocci,but not for others?Is antibiotic resistance reversible in PRP given the importance of clones in the epidemiology?How will the new conjugated vaccines affect the ecology(serotype distribution)in high,medium and low prevalence settings?Are these vaccines the solution to the problem with antibiotic resistance?Alternative solution?