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Penicillin-resistant pneumococci - potentials for modeling

Penicillin-resistant pneumococci - potentials for modeling. Prof. Karl Ekdahl KI/MEB and ECDC. About the bug. Streptococcus pneumoniae (pneumococcus) Gram-positive, encapsulated diplococcus Capsular swelling observed when reacted with type-specific antisera (Quellung reaction).

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Penicillin-resistant pneumococci - potentials for modeling

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  1. Penicillin-resistant pneumococci - potentials for modeling Prof. Karl Ekdahl KI/MEB and ECDC

  2. About the bug • Streptococcus pneumoniae (pneumococcus) • Gram-positive, encapsulated diplococcus • Capsular swelling observed when reacted with type-specific antisera (Quellung reaction)

  3. Electron micrograph of pneumococcus Surface capsular polysaccharide

  4. Polysaccharide capsule • Capsular polysaccharides: hydrophilic gels on organism surface • Most important virulence factor • Protects against phagocytosis by granulocytes and macrophages • Elicits a T-cell–independent (not boostable) immune response

  5. Pathogenesis • Colonisation of mucous membranes in respiratory tracts • Adhesion (bacterial adhesins) • Invasion of tissues if not defeated • Middle ear • Sinuses • Bronchi

  6. Important for modelling:Pneumococcal serotypes • Based on properties of capsular polysaccharides • Immunologically distinct and basis for classification • > 40 serogroups (e.g. group 19) • > 90 serotypes (e.g. types 19A, 19C, 19F) • No immunologic cross-reactivity between serogroups • Some cross-reactivity within some serogroups and some cross-protection • Geographical and temporal variation • Some more immunogenic than others

  7. % 20 15 10 Type 1 Type 3 Type 4 5 Type 6B Type 7F Type 9V Type 14 Type 23F 0 1997 1987 1992 IPD serotypes over time (Sweden)

  8. Important for modelling:Pneumococcal serotypes (II) • Children <5 y lack ability to mount antibody response to several serotypes • Such types (6B, 9V, 14, 19F, 23F) more dominating among young children = child serotypes • Account for the majority of carriage and disease in children • Explains high incidences of carriage and disease in the youngest • Child serotypes heavily linked to antibiotic resistance • Limited number of very successful international clones

  9. Pneumococcal vaccine Antibody response in young children

  10. Important for modelling:Capsular switch • Pnc very “promiscous bacteria” with excellent ability to exchange genetic material • Highly capable of switching serotype while retaining other properties (incl antibiotic resistance) • Likely frequent event (DCC outbreaks) • Survival mechanism • Often switches to other “child serotypes”: • 23F  19F • 9V  14

  11. About the disease • A major cause of morbidity and mortality worldwide • Over 1 million deaths annually due to pneumonia • Causes more deaths in young children in US than any other single microorganism • Incidence of infection varies globally • Age groups at highest risk for disease: • Infants and children < 2 years of age • Adults > 65 years of age • Pneumococcal disease frequently observed in children up to 5 years of age

  12. Clinical manifestations Otits media Sinusitis Endocarditis Peritonitis Arthritis Meningitis Pneumonia Pericarditis Septicemia Osteomyelitis

  13. Significant disease burden in children Disease severity Estimated number of cases per year (US) 1,400 Meningitis 17,000 Bacteremia Invasive Increases 71,000 Pneumonia Noninvasive 5–7 million Otitis media Prevalence MMWR. 1997;46:1-24.

  14. Etiology of acute otitis media(South Sweden)

  15. Acute otitis media • From colonisation to invasion of middle ear through the eustachian tube • Facilitated by previous viral infection • Mostly in young children with immature immune defence • Day-care centre (DCC) attendance and prior antibiotic treatment are risk factors

  16. Invasive pneumococcal disease (IPD) • Bacterial growth in normally sterile fluids • Blood (pneumonia, meningitis, endocarditis) • CSF (meningitis) • Joint fluids (artritis) • Pleural fluid (pleuritis) • Peritoneal fluid (peritonitis)

  17. Main clinical picture IPD(South Sweden) Pneumonia8% CFR Meningitis 18% CFR Septicemia29% CFR Others14% CFR

  18. Age-related incidence of IPD (Europe 2005)

  19. Incidence of invasive pneumococcal disease in children (US 1998) 250 200 150 Cases per 100,000 persons 100 50 0 0–5 6–11 12–17 18–23 24–35 36–47 48–59 5–9 yrs 10–19 yrs Age group (months)

  20. Seasonality IPD (Europe 2005)

  21. Important for modelling:Pneumococcal carriage • Asymptomatic carriage most common pneumococcal manifestation • Nasopharynx of young children most important reservoir of pnc • Ecological niche: carriage of one strain protects aginst carriage of other strains • First week critical: carriage or infection • Colonisations (carriage) is ”protective” of diseas • Younger children carrier for longer time • Distinct seasonality (same as for IPD)

  22. Åldersrelaterad bärartid Veckor

  23. Bärartid av pc-resistenta pneumokocker 28% 12% 6% Veckor

  24. Important for modelling:Role of day care centres (DCC) • 30-50% of (day care centre) DCC children are carriers during winter months • Rapid spread within DCCs • One dominating serotype in a DCC • Higher rates (same serotype) in siblings to DCC children • Increased risk of IPD • 2.63-fold risk in children 2–11 months of age • 2.29-fold risk in children 12–23 months of age • 3.28-fold risk in children 24–59 months of age Levine OS et al. Pediatrics. 1999;103:E28-E35.

  25. Carriage Rates Group Rate of carriage (%) Preschool children Up to 60 Grammar school children 35 High school students 25 Adults with children inhousehold 18–29 Adults without children in household 6 Black S, Shinefield H. Pediatr Ann. 1997;26:355-360.

  26. Antibiotic resistance • Papua New Guinea: First reports of pc resistance in 1969 - Pc resistance >30% already in 1980 • South Africa: First reports of multi-resistance in 1977 - Currently pc resistance ~40% • Alaska: Pc resistance >25% in 1987 • Spain: Pc resistance <7% in 1979 and >46% in 1993

  27. Streptococcus pneumoniae: patterns of penicillin non-susceptibility • Major resistance trends by serotype • Most frequently associated non-susceptible serotypes: 6B, 9V, 14, 19A, 19F, and 23F • Penicillin-susceptible strains may acquire resistance over time and become resistant to penicillin and other classes of drugs • Non-susceptible serotypes vary geographically over time, by antibiotic usage, age, and crowding • Non-susceptible strains are often resistant to other classes of antibiotics

  28. Others* 40 Macrolides and lincosamides Quinolones 35 Trimethoprim Tetracyclines 30 Cephalosporins 25 Penicillinase-resistant penicillins Narrow-spectrum penicillins 20 Broad- spectrum penicillins Defined daily dose per 1000 inhabitants per day 15 10 5 0 F rance Spain P o r tugal B elgium Luxem Italy Greece Finland Ireland UK Austria Sweden Netherland Germany Denmark *Includes sulphonamides, penicillinase-resistant penicillins, amphenicols, aminoglycosides, and glycopeptides. Cars O. et al. The Lancet 2001:357 ;1851-2 / Data provided by IMS Sales of antibiotics in the EU

  29. MIC (Mg/L) S (susceptible) <0.06 I (intermediate) 0.12-1.0 R (resistant) >2.0 Reportable in Sweden > 0.5 Penicillin-resistant pneumococci

  30. Antibiotic usage for acute otitis media by age (US) 5 4 3 Treated episodes of acute otitis media (millions) 2 1 0 < 1 1 2 3 4 5 6 7 8 9+ Age (years) 6 years and older = 16% (~ 4 million) of total episodes of otitis media treated with antibiotics. Levin. PDDA. 1997.

  31. Penicillin-resistant pneumococci (I+R)

  32. Important for modelling:Risk factors for resistance • Low age • DCC attendance (size of DCC group) • Consumption of antibiotics • Individual level • DCC level • Community level

  33. Child serotypes and resistance

  34. Risk factors for PRP-carriagein day-care centres Ab last 6 months Risk ratio 95% C.I. TMP/SMX 4.90 1,78 – 13.32 Cephalosporin 1.43 0.65 – 3.14 Erythromycin 1.38 0.72 – 2.63 PcV 1.09 0.82 – 1.45 Ampi-/amoxicillin 2.09 1.24 – 3.27 Any antibiotics 1.20 1.01 – 1.43

  35. Penicillin-binding proteins and-lactam resistance

  36. Important for modelling:PRP development (Baquero)

  37. PRP utveckling (Baquero) Slow introduction phase: Shift towards higher MIC through "selective" antibiotic pressure

  38. PRP utveckling (Baquero) Exponential growth phase: Spread of resistant strains independent of antibiotic pressure (though favoured by it)

  39. PRP utveckling (Baquero) Stationary phase: Resistance ~50%. "Herd immunity" against common serotypes and decreased ability for b-lactams to select for resistance

  40. Spread of international epidemic clones 23F 23F 23F 23F 23F

  41. Spread of serotype 9vSouthern Sweden 1. Malmö (0195) 8. Kävlinge (06-95) 2. Staffanstorp (03-95) 9. Trelleborg (08-95) 3. Vellinge (03-95) 10. Helsingborg (08-95) 4. Landskrona (04-95) 11. Burlöv (09-95) 5. Höganäs (04-95) 12. Lomma (10-95) 6. Lund (04-95) 13. Höör (12-95) 7. Eslöv (04-95) 14. Svalöv (01-96) 15. Svedala (02-96) 16. Skurup (03-96) 17. Bjuv (--) 18. Hörby (--) 19. Sjöbo (--) 20. Ystad (--) 5. (17). 10. 13. 14. 4. 7. (18). 8. 12. 6. 11. 2. (19). 1. 15. 3. (20). 16. 9.

  42. PRP and antibiotic consumption in children

  43. Basic reproductive rate for carriage of PRP in DCC (Southern Sweden)

  44. Rationale for Vaccination Against Streptococcus pneumoniae • Prevention of life-threatening and prevalent pneumococcal disease • Reduction of disease transmission • Reduction of carriage • Reduction of antibiotic resistance • Retention of antibiotic effectiveness

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