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)

Surface capsular polysaccharide Electron micrograph of pneumococcus

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

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

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

IPD serotypes over time (Sweden)

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

Pneumococcal vaccine Antibody response in young children

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

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

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

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

Etiology of acute otitis media (South Sweden)

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

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)

Main clinical picture IPD (South Sweden) Pneumonia 8% CFR Meningitis 18% CFR Septicemia 29% CFR Others 14% CFR

Age-related incidence of IPD (Europe 2005)

Incidence of invasive pneumococcal disease in children (US 1998) –56–1112–1718–2324–3536–4748–595–9 yrs10–19 yrs Age group (months) Cases per 100,000 persons

Seasonality IPD (Europe 2005)

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)

Åldersrelaterad bärartid Veckor

Bärartid av pc-resistenta pneumokocker Vecko r 28% 12% 6%

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.

Black S, Shinefield H. Pediatr Ann. 1997;26: GroupRate of carriage (%) Preschool childrenUp to 60 Grammar school children35 High school students25 Adults with children in household 18–29 Adults without children in household6 Carriage Rates

Antibiotic resistance Papua New Guinea: First reports of pc resistance in Pc resistance >30% already in 1980 South Africa: First reports of multi-resistance in Currently pc resistance ~40% Alaska: Pc resistance >25% in 1987 Spain: Pc resistance 46% in 1993

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

Sales of antibiotics in the EU

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

Antibiotic usage for acute otitis media by age (US) 6 years and older = 16% (~ 4 million) of total episodes of otitis media treated with antibiotics < Treated episodes of acute otitis media (millions) Age (years) Levin. PDDA

Penicillin-resistant pneumococci (I+R)

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

Child serotypes and resistance More exposed to antibiotics Resistance Comparative advantage Common in young children

Risk factors for PRP-carriage in day-care centres Ab last 6 monthsRisk ratio95% C.I. TMP/SMX4.901,78 – Ampi-/amoxicillin – 3.27 Any antibiotics – 1.43 Cephalosporin – 3.14 Erythromycin – 2.63 PcV – 1.45

Penicillin-binding proteins and  -lactam resistance

Important for modelling: PRP development (Baquero)

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

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

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

23F 23F 23F Spread of international epidemic clones

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 (--) (17) (18). (19) (20) Spread of serotype 9v Southern Sweden

PRP and antibiotic consumption in children

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

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

Old polysaccharide vaccines T cells-independent immune response  No immunological memory  No booster response  Non-immunogenic in young children  23 of 90 serotypes  Protects against invasive disease in adults  Questionable protection against pneumonia  No protection against otitis media  No effect on carriage  Commercially available since 1984

New protein-conjugated vaccines T cell-dependent immune response Immunological memory Booster response Immunogenic also in young children 7-11 of 90 serotypes Protects against invasive disease in all age groups (type-specific) Protects against AOM (type-specific) Effective against carriage Licensed in USA February 2000 & European approval February 2001

Important for modelling: Conjugate vaccine reduction of carriage Significant reduction of vaccine types No reduction in non-vaccine types Effect >1 year after vaccination Herd immunity

Important for modelling: Serotype replacement Seen in both carriage of disease To a large extent switch to non-vaccin types Regulated by competition between species  Increase in prevalence of serotypes present in population  Introduction of ”new” serotypes (previously unable to compete  Unmasking of subdominant types in an individual May result in a switch to more immunogenic types  Acquired immunity at an earlier age Replacement of other bacteria

Important for modelling: Vaccine effect on antibiotic resistance Reduction of antibiotics consumption (15-20% Israel) Reduction of carriage of antibiotic-resistant bacteria  Vaccine types = child serotypes = resistant types Herd immunity: decreased carriage in siblings Reduction of infection with antibiotic resistant bacteria But the bacteria will fight back  Serotype replacement to non-vaccine types  They will eventually also become resistant

Some important questions to be answered by modellers What is the relative importance of antibiotic consumption on individual, DCC and community level? Are there differences 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 ?