Antibiotic Resistance and Serotype
Replacement of pneumococcus in Post-PCV
era – What can we expect in South Asia?
Samir K Saha, Ph.D.
Child Health Research Foundation
&
Dhaka Shishu Hospital
PCV Introduction Status
Source: VIMS Report: Global Vaccine
2
Introduction, IVAC; October, 2013
Estimated IPD cases prevented among all ages,
United States 2001-2009
Age =>5
Age <5
40,000
Cases prevented
35,000
30,000
25,000
20,000
15,000
10,000
280,000 cases & 19,000 deaths prevented
5,000
0
2001
2002
2003
Pilishvili JID 2010 & CDC unpublished
2004
2005
2006
2007
2008
2009
Year
3
Some Limitations – Behavior of NVTs
IPD trends among Alaskan Native children <2 years
in the era of PCV7
4
Rates of invasive pneumococcal disease
among U.S. children <5 years, 1998-2009
Overall
PCV7 type
19A
Cases per 100,000
120
100
80
60
40
STEADY STATE?
PCV7
introduction
20
0
-76%
+284%
-100%
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Year
Moore, IDSA, 2009
5
Who is Responsible for Erosion of Our
Achievements?
Non-vaccine types – 19A?
Why 19A serotype is so special?
• Prevalent
• Clinically important
• Often highly and multiply resistant worldwide
• Not affected by PCV7
Are We Sure About 19A dynamics?
25
23
20
– Dramatic Increase
• All were Multi drug
resistant
15
10
8
5
0
• Serotype 19A in Korea
During Pre-PCV era
0
1991-1994 1995-1999 2000-2006
– Not increased in
Australian and some
other population
We are possibly near to the end of 19A
issues
• Further detail evidence from the countries
with higher disease burden
• Availability of PCV-13
• Possibility of extended protection of 19F
towards 19A
– Domingues et al. ISPPD 9 – Abst 0288
Impact of PCV on Antibiotic Resistance
FURTHER REWARD FROM PCV
Impact of PCV on Resistance of
Pneumococcus
Kyaw et al NEJM 2006;354:1455-83
Impact of PCV on Resistance of
Pneumococcus
Reduction in Antibiotic Use
• PCV contains most of the drug resistant strains
• Vaccination reduces these serotypes in
vaccinated and unvaccinated population
• Leads to reduction in prevalence of resistant
strains
• Finally, PCV is potentially contributing in
reducing use of antibiotics and emergence of
resistance
Dagan & Klugman. Lancet Infect Dis 2008; 8:785-95; Cohen et al PIDJ
2006;25:1001-7
PCV impact in reducing resistance –
has a caveat
Impact of PCV and antibiotic on prevalence of drug
resistant Pneumococcal carriage
PCV
Antibiotic in last 3 months
Carriage with PenR
Yes
No
4.8%
Yes
Yes
8.6%
No
No
10.3%
No
Yes
16.2%
Cohen R et al, PIDJ, 2006
MOVING TO SOUTH ASIA
PCV Introduction Status South
Asia
Country
Program type
Bangladesh
GAVI approved
Nepal
GAVI approved/approved with clarification
Sri Lanka
Non-GAVI planning introduction
Pakistan
Universal
Afghanistan
Universal
Bhutan
Non-GAVI planning introduction
Source: International Vaccine Access Center (IVAC), Johns Hopkins Bloomberg School of Public Health.
Vaccine Information Management System (VIMS). Accessed 3 Mar 2014.
Year of
Introduction
2014
2014
2016
2012
2013
2016
Ingredients for Hydrababadi Biryani
SOUTH ASIA HAS ALL THE INGREDIENTS
TO MAKE THE PCV OUTCOME COMPLEX
May have several 19As
DIVERSE SEROTYPES: >50
DIFFERENT SEROTYPES
Serotype causing IPD in Bangladesh 2000-2013
Total IPD N=1033 & detected serotype N=626
120
95%
110
90%
100
80%
90
80
67%
70
60
49%
40
99%
99%
Total IPD
Culture
Latex
ICT
PCR
1033
421
211
380
21
Serotype Detected
626 (61%)
32%
30
90%
80%
70%
60%
50%
40%
20%
18%
12%
10%
14
6B
18C
19F
23F
4
9V
1
5
7F
6A
19A
3
2
12A
45
8
38
24F
18A
20
12F
18F
10F
29
33
10A
21
34
23A
25F
33B
35F
6C
13
48
15A
15B
15F
16F
22F
33F
35B
7B
23
25
27
31
39
40
11A
11F
17F
28A
33C
35A
7%
PCV
7
100%
30%
23%
20
0
98%
43%
40%
50
10
97%
PCV
10
PCV
13
0%
Serotypes causing IPD in India, Nepal &
Sri Lanka
20
100
18
90
16
80
%
14
70
12
60
10
50
8
40
6
30
4
20
C
u
m
m
l
a
t
i
v
e
2
10
0
0
14
6A/B/C/D
19F
23F
9A/V
18A/B/C/F
4
1
5
7A/F
3
19A
15B/C
2
23A
8
47F
12A
22A/F
11A/D
25F
38
9N/L
13
15A
16
19B
20
39
10A
17F
19C
23B
24F
27
29
33C
33F
34
35,42
45
10F
11C
15
16A
16 F
24B
32
33
33B
35B
35C
% Vaccine Type
(n = 735)
PCV7
PCV10 PCV13
NVT
Vaccine Type
Data for the period of 2005-2013
Cummlative
South Asia is Close to Tell More About NVTs
- 19A and Beyond
• Bangladesh and Pakistan are introducing PCV10
• With available multiyear Pre-PCV data and
huge disease burden
• These countries will be in a good position to shed
light on PCV impacts
• Looking forward to be advocate for the next introducers
• Will be happy to volunteer for India – if ………..
Possibly God is still kind (by and large)
ANTIBIOTIC RESISTANCE IN
PNEUMOCOCCUS
Susceptibility of South AsianCotrimoxazole
Pneumococcus
Penicillin
100
80
60
40
20
0
100
80
60
40
20
0
I
100
I
R
Chlormphenicol
100
80
80
60
60
40
40
20
20
0
0
I
R
R
Erythromycin
I
R
Are We Missing Something for Impact Studies?
SEROTYPE SPECIFIC SUSCEPTIBILITY
Cotrimoxazole Susceptibility Among
Vaccine Types - Bangladesh
30
Susceptible
Intermediate
Resistant
4%
25
20
56%
11%
5%
45%
15
8%
10
5
58%
56%
78%
46%
22%
0
14
28%
46%
14%
28%
50%
18C
19F
36%
36%
23F
40%
25%
25%
50%
33%
4
6B
55%
50%
50%
50%
9V
25%
1
5
22%
44%
25%
34%
6A
7F
45%
100
19A
3
Susceptibility Penicillin Among Vaccine
Types - Bangladesh
30
Susceptible
Resistant
25
20
6%
15
29%
100%
8%
100%
10%
10
100%
11%
5
71%
92%
89%
90%
100%
100%
18C
19F
23F
4
100%
100%
0
14
94%
6B
9V
100%
1
5
6A
7F
19A
3
For Optimal Control
of IPD - Combined
efforts of PCV and
Antibiotic Use
⇑
vaccination
• Is the model going to work
in South Asia?
– Introduction of PCV
– Judicious use of Antibiotics
• Remote possibility
– Let’s take typhoid treatment
as a model
Select
antibiotics
⇓ antibiotic
use
Model of Ron and Keith
• MDR Reported from Bangladesh,
Typhoid MDR and Use
India and UK
of Antibiotic
80
% of Multidrug resistant strains
70
Hospital
71
60
56
Community
50
40
40
33
30
26
20
16
30
13
10
0
95
96
97
98
– Physicians started using third
generation Cephalosporin
– It was proved to be wrong
– The did not come back to the old
practice
– Good results…..
• Tried to help them more
– Hand to hand delivery of report with
minimal turn around time (24 hrs)
• Only 16% of Physicians switched
to 1st line drug despite the
evidence in hand
Saha et al Antimicrobial Agents Chemother 1995,
Saha et al J Clin Microbiol 2001
• MDR Reported from Bangladesh,
India and UK
Typhoid MDR and
Use of Antibiotic
80
% of Multidrug resistant strains
70
Hospital
71
60
56
Commun
ity
50
40
30
20
40
33
30
26
16
13
10
0
95 96 97 98
– Physicians started using third
generation Cephalosporin
– It was proved to be wrong
– The did not come back to the old
practice
– Good results…..Thank you Doctor!!
• Tried to help them more
– Hand to hand delivery of report with
minimal turn around time (24 hrs)
• Only 16% of Physicians switched
to 1st line drug despite the
evidence in hand
Saha et al Antimicrobial Agents Chemother 1995,
Saha et al J Clin Microbiol 2001
Antibiotic Use in India
Molecule growth trajectory in Bangladesh
Source: Bangladesh Pharmaceutical Index (BPI) by IMS
Note: 2013 data estimated, based on YTD Q2 performance
1,200.00
1,000.00
CEFRADINE
OFLOXACIN
800.00
LEVOFLOXACIN
CIPROFLOXACIN
600.00
CEFIXIME
CEFUROXIME
CEFUROXIME AXETIL
400.00
CEFTRIAXONE
200.00
2006
2007
2008
2009
2010
2011
2012
2013
Human Nasopharynx the Natural Habitat of
Pneumococcus
CARRIAGE WITH INVASIVE
POTENTIAL
6A
19F
6B
14
23F
9V
4
18C
7F
1
5
19A
3
15B
13
19B
11A
Non T
35B, 29
16F
10F
23B
35F
15C
34
24F
9L
6C
33B
17F
15A
21
20
36
35B
33F
28A
10B
29
35C, 42
7B
15F
33C
23A
9N
7C
10A
9A
48
22A
38
8
18F
12F
11C
11B
17A
40
39
35A
31
29, 35B, 42
28F
22F
2
12A
45
18A
10F
24
11F
23A
25F
-40
-20
PCV 10
PCV 13
Invasiveness of Carriage
Invasive Strain(N=298, 2007-2012)
Carriage Strain (N=432, 2005-2007 & 2009-2011)
Carriage
Invasive
Potential
Carriage Serotypes
>90%
Vaccine Types
Non Vaccine Types
1, 5 & 7F
2, 12A, 18A, 10F
80 - 90%
45, 8, 12F, 38
25 - 80% 14, 18C, 23F, 6B, 19A
0
Invasive
20, 7B, 10A, 33F, etc
25 - 50%
4, 19F, 6A, 9V
15A, 24F, 33B, 25F, etc.
<25%
3
15B, 19B, 10F, 6C, etc
20
40
60
Carriage
• Pneumococcal carriage the greatest sources of
resistance
– Children carry the resistant strains more and for
longer period of time
• South Asian children have all the ingredients to harbor
resistant strains
Carriage Rate of Pneumococcus – an
ongoing longitudinal study
80%
70%
60%
50%
40%
30%
20%
10%
0%
1
2
3
4
Visit number (Age in months)
5
6
This is Only Superficial View
MULTIDIMENSIONAL CHALLENGE
Multiple Carriage - Colonization
1000000
6A
12F
14
23A
100000
10000
1000
100
10
1
0
1
2
3
4
5
Age in Months
6
7
8
9
10
Thousands
Dynamics of Multiple Carriage
1000
1
10B
100
35A
Density
10
1
0.1
0.01
0.001
0
1
2
3
4
5
Visits
6
7
8
9
10
Promiscuity – A trick of
Pneumococcus to evade
vaccine and antibiotic
effect
• Naso-pharynx is an ideal
place for Pneumococcus to
transfer genetic material to
its nearest one and make it
smarter than us
Conclusion
• South Asian countries will be saving more lives then
the number of cases in US
• It will have challenges
– Lack of pre-data
– Diverse serotype
– Low vaccine coverage
• It is important to have all modalities in place to ensure
our clear understanding about the dynamics of
Pneumococcus, during the post PCV era
• Considering the lack of data well designed carriage
study should be considered seriously
Acknowledgement
I gratefully acknowledge
• Ron Dagan
• Thomas Cherian
• Cynthia Whitney
• Keith Klugman
• IVAC
• Last but not the least
my team member
Last but not the least
my team member