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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)
Electron micrograph of
pneumococcus
Surface
capsular
polysaccharide
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)
%20
15
10
Type 1
Type 3
Type 4
Type 6B
Type 7F
Type 9V
Type 14
Type 23F
5
0
1987
1992
1997
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
Clinical manifestations
Meningitis
Otits media
Pneumonia
Sinusitis
Pericarditis
Endocarditis
Septicemia
Peritonitis
Osteomyelitis
Arthritis
Significant disease burden in children
Estimated number
of cases per year (US)
Disease severity
Bacteremia
1,400
17,000
Increases
Invasive
Meningitis
71,000
Noninvasive
Pneumonia
5–7 million
Otitis media
Prevalence
MMWR. 1997;46:1-24.
Etiology of acute otitis media
(South Sweden)
Pneumokocker
Haemophilus influenzae
Moraxella catarrhalis
Virus
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)
25
Cases/100,000
20
15
10
5
0
00-04
05-14
15-24
25-44
Age groups
45-64
65+
Cases per 100,000 persons
Incidence of invasive pneumococcal
disease in children (US 1998)
250
200
150
100
50
0
0–5
6–11
12–17
18–23
24–35 36–47
Age group (months)
48–59 5–9 yrs 10–19 yrs
Seasonality IPD
(Europe 2005)
1400
1200
Number of cases
1000
800
600
400
200
0
01
02
03
04
05
06
07
Month
08
09
10
11
12
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
1,2
<1 år
1-2 år
3-4 år
5-6 år
7-18 år
>18 år
1
0,8
0,6
0,4
0,2
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20 >20
Veckor
Bärartid av pc-resistenta pneumokocker
1
0,9
Samtliga
0,8
Indexfall
0,7
0,6
Kontaktfall
0,5
0,4
0,3 28%
0,2
12%
0,1
6%
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20 >20
Vecko
r
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.
Carriage Rates
Group
Rate of carriage (%)
Preschool children
Up to 60
Grammar school children
35
High school students
25
Adults with children in
household
18–29
Adults without children
in household
6
Black S, Shinefield H. Pediatr Ann. 1997;26:355-360.
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
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
Others*
40
Macrolides and lincosamides
Quinolones
35
Trimethoprim
Tetracyclines
30
Cephalosporins
25
Penicillinase-resistant penicillins
Narrow-spectrum penicillins
20
Broad- spectrum penicillins
15
10
5
0
France
Spain Portugal Belgium Luxem
Italy
Greece Finland Ireland
UK
Austria
Sweden
Germany
Netherland
Denmark
*Includes sulphonamides, penicillinase-resistant penicillins, amphenicols, aminoglycosides, and glycopeptides.
Cars O. et al. The Lancet 2001:357 ;1851-2 / Data provided by IMS
Penicillin-resistant pneumococci
MIC (Mg/L)
S (susceptible)
I (intermediate)
R (resistant)
Reportable in
Sweden
<0.06
0.12-1.0
>2.0
> 0.5
Treated episodes of
acute otitis media (millions)
Antibiotic usage for acute otitis media
by age (US)
5
4
3
2
1
0
<1
1
2
3
4
5
6
Age (years)
6 years and older = 16% (~ 4 million) of total
episodes of otitis media treated with
antibiotics.
7
8
9+
Levin. PDDA. 1997.
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
Common
in young
children
Comparative
advantage
More exposed
to antibiotics
Resistance
Risk factors for PRP-carriage
in day-care centres
Ab last 6 months
TMP/SMX
Ampi-/amoxicillin
Any antibiotics
Cephalosporin
Erythromycin
PcV
Risk ratio
4.90
2.09
1.20
1.43
1.38
1.09
95% C.I.
1,78 – 13.32
1.24 – 3.27
1.01 – 1.43
0.65 – 3.14
0.72 – 2.63
0.82 – 1.45
Penicillin-binding proteins and
-lactam resistance
Frekvens (%)
Important for modelling:
PRP development (Baquero)
ÅR
Frekvens (%)
PRP utveckling (Baquero)
Slow introduction
phase:
Shift towards higher MIC
through "selective"
antibiotic pressure
ÅR
Frekvens (%)
PRP utveckling (Baquero)
Exponential growth
phase:
Spread of resistant
strains independent of
antibiotic pressure
(though favoured by it)
ÅR
PRP utveckling (Baquero)
Frekvens (%)
Stationary phase:
Resistance ~50%.
"Herd immunity"
against common
serotypes and
decreased ability
for b-lactams to
select for resistance
ÅR
Spread of international epidemic
clones
23F
23F
23F
23F
23F
Spread of serotype 9v
Southern Sweden
1. Malmö (0195)
2. Staffanstorp (03-95)
3. Vellinge (03-95)
4. Landskrona (04-95)
5. Höganäs (04-95)
6. Lund (04-95)
7. Eslöv (04-95)
5.
(17).
10.
13.
14.
4.
7.
(18).
8.
12.
11.
6.
2.
(19).
1.
15.
3.
9.
16.
(20).
8. Kävlinge (06-95)
9. Trelleborg (08-95)
10. Helsingborg (08-95)
11. Burlöv (09-95)
12. Lomma (10-95)
13. Höör (12-95)
14. Svalöv (01-96)
15. Svedala (02-96)
16. Skurup (03-96)
17. Bjuv (--)
18. Hörby (--)
19. Sjöbo (--)
20. Ystad (--)
PRP and antibiotic consumption in
children
PRP/1000 barn och dag
12
10
8
6
4
2
0
0
10
20
DDD/1000 barn och dag
30
Basic reproductive rate for carriage of
PRP in DCC (Southern Sweden)
2,0
25 barn
20 barn
15 barn
10 barn
5 barn
1,8
1,6
1,4
1,2
1,0
0,8
0,6
0,4
0,2
6 dec
6 nov
6 okt
6 sep
6 aug
6 jul
6 jun
6 maj
6 apr
6 mar
6 feb
6 jan
0,0
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 ?