The Dynamic Epidemiology of Streptococcus pneumoniae.

Joshua P. Metlay, MD, PhD

Division of General Internal Medicine

University of Pennsylvania

Presented at the 41st Annual Symposium

“Global Movement of Infectious Pathogens and Improved Laboratory Detection”

Eastern PA Branch-American Society for Microbiology

November 17, 2011

Thomas Jefferson University, Philadelphia

Outline

• Introduction to pneumococcal disease

• Secular trends

–Antimicrobial drug resistance (macrolides)

–Serotype replacement

• Geographic patterns

Survival from pneumococcal bacteremia 1952-1962

Penicillin Resistance in S. pneumoniae United States 1979-2000

1979-1994: CDC Sentinel Surveillance Network

1995-2002: CDC Active Bacterial Core Surveillance (ABCs) /Emerging Infections Program

Sentinel ABCs

The Delaware Valley Hospital Network

• Hospital based reporting of cases of pneumococcal bacteremia

• Established in 2001

• Centralized susceptibility testing

• 48 hospitals in the 5 county region of Southeastern Pennsylvania

• 3.7 million population

• 400 annual cases

Participating hospitals in the Delaware Valley

Emerging Infectious Diseases 2001

Risk Factors for Pneumococcal Bacteremia

Characteristic Cases per 100,000 95% CI

Age

18-49 8.3 7.5 – 9.2

50-64 15.9 14.4 – 17.6

65-79 26.4 26.4 – 29.5

80+ 59.4 52.7 – 67

Race

White 13.7 12.9 – 14.7

African American 26.4 24.2 – 28.9

Time Trends

Pneumococcal Conjugate Vaccine

• Seven valent conjugate vaccine licensed in February 2000

• 4, 6B, 9V, 14, 18C, 19F, 23F

• Widespread use by June 2000.

• 2,4, 6, 13-15 month immunization schedule

• Efficacy for otitis media, invasive disease, pneumonia.

• Reduction in carriage of vaccine serotypes

Temporal trends in risk of invasive pneumococcal disease: children

Temporal trends in risk of invasive pneumococcal disease: adults

What is Herd Immunity?

Picture courtesy of Dr. C. Whitney

Early Successes with Vaccination R

ate

of

VT

IP

D p

er 1

00

,00

0 p

op

ula

tion

Indirect effect:

65% decrease

CDC. MMWR 2005; 54: 893-7.

Direct effect:

94% decrease

Vaccination of children reduces risk of disease in adults

0

20

40

60

80

100

Any child vaccinated Youngest child

vaccinated

%

Cases

Controls

Vaccine. 2006

Archives of IM 2010

CLSI Breakpoints 2011

Drug MIC (ug/mL)

Interpretive Standard

S I R

Penicillin (Meningitis) ≤ 0.06 0.12-1 ≥ 2

Penicillin (Non-meningitis) ≤ 2 4 ≥ 8

Erythromycin ≤0.25

0.5 ≥ 1

Genotype Year

2001-2

(n=55)

2002-3

(n=41)

2003-4

(n =42)

2004-5

(n=57)

2005-6

(n=84)

2006-7

(n=93)

2007-8

(=89)

p-value

mefA+ermB- 72.7% 70.7% 52.4% 50.9% 40.5% 44.1% 34.8% <.0001

mefA-ermB+ 20.0% 26.8% 26.2% 36.8% 40.5% 31.2% 46.1% .01

ermB+mefA

+

1.8% 0.0% 9.5% 10.5% 17.9% 23.7% 19.1% <.0001

23S rRNA

(A2059G)

3.6% 2.4% 7.1% 0.0% 1.2% 1.1% 1.1% .17

[1]

Macrolide Resistance Genotypes

Emerging Macrolide Resistance

PCV-13

• Introduction of PCV-13 in 2000

• Coverage of PCV-7 serotypes:

–4,6B,9V,14,18C,19F,23F

• Additional serotypes:

–1,3,5,6A,7F,19A

Pediatric Carriage of Pneumococcal Serotypes 2008-2010

0

2

4

6

8

10

12

14

16

18

20

2008 2009 2010

% o

f i

sola

tes

YEAR

6C

35B

19A

11A

15C

23B

23A

15A

21

15B like

16F

22F

15B

Spatial Trends

“Everything is related to everything else, but near things are more related than distant things’’

Tobler’s First Law of Geography

Pneumococcal Case Distribution

Disease risk varies by neighborhood

Significant hot spots exist

Why are there clusters of disease?

• Small area outbreaks from highly virulent clones – Pathogen Hypothesis

• Neighborhood level exposures influence risk of transmission – Vector Hypothesis

• Heterogenous population distribution – Host Hypothesis

PFGE Analysis of Pneumo Isolates

Genetic clustering vs. geographic clustering

Children as Vectors

Huang CID 2005

Child Exposure is Associated with Reduced Risk of Disease

Characteristic Cases per 100,000 95% CI

# of children in home

0 21.5 20.3 – 22.8

1 8.3 6.8 – 9.9

2+ 3.3 2.6 – 4.2

Archives of Internal Med 2010

Key Points

• Overall risk of pneumococcal disease has declined but new serotypes are emerging

• Emerging serotypes are primarily multidrug resistance, reflecting selection of MDR clones and expansion of previously low prevalence serotypes

• Variation in disease risk likely reflects host factors, but vector and pathogen factors are rapidly changing in pneumococcal disease.

Thanks • Robert Austrian

• Lou Bell

• Catherine Berjohn

• Charlie Branas

• Linda Crossette

• Chris Czaja

• Paul Edelstein

• Kristen Feemster

• Neil Fishman

• James Flory

• Marshall Joffe

• Ebb Lautenbach

• Yimei Li

• Zhenying Liu

• Russell Localio

• Mat Macdonald

• Irv Nachamkin

• Samir Shah

• Justine Shults

• Tony Smith