1. LATIN-AMERICAN MULTICENTRE STUDY ON ANTIBIOTIC RESISTANCE OF S
LATIN-AMERICAN MULTICENTRE STUDY ON ANTIBIOTIC RESISTANCE OF S. PNEUMONIAE ISOLATED FROM CHILDREN WITH SEVERE PNEUMONIA

2. A study by:
Research Group of the Collaborative Multicentre Study on Acute Respiratory Infections and Bacterial Resistance (CARIBE) *
* Cardoso M.R.A.; Agosti M.R.; Benguigui Y.; Berezin E.W.; Brandileone M.C.C.; Camargos P.; Cociglio R.; Coradin H.; Diaz M.E.R.; Feris J.M.; Ferrero F.; Grenon S.; Maggi R.S.; March M.F.B.P.; Martearena C.R.; Nascimento-Carvalho C.M.C.; Pascua C.F.; Regueira M.; Ruvinsky R.; Sanchez J.; Sant’Anna C.C.; Souza L.S.F.; Tagliaferri P.; Urbano C.
Sponsors:
Panamerican Health Organization (PAHO)
World Health Organization (WHO)

3. INTRODUCTION
Association between diminished susceptibility to penicillin of S. pneumoniae and severity of pneumonia is uncertain
No prospective study on drug-resistant S. pneumoniae X clinical outcome in Latin America

4. Dominican Rep.
Peru
Brazil
Argentina

5. OBJETIVES OF THE STUDY PRINCIPAL OBJECTIVE SECONDARY OBJECTIVES
penicillin resistant S. pneumoniae x the risk of clinical failure
SECONDARY OBJECTIVES
Rate of S. pneumoniae infection   
Prevalence of in vitro penicillin-resistant
S. pneumoniae
Risk factors associated with treatment failure

6. METHOD STUDY DESIGN SAMPLE SIZE RECRUITMENT OF PATIENTS
Multicentre prospective observational investigation
SAMPLE SIZE
196 isolates  RR  2.5 associated to risk factors for clinical
failure ( = 0.05 ; 1- = 0.80)
Isolation rate of 5%  3900 children  196 isolates
RECRUITMENT OF PATIENTS
Children hospitalised with severe pneumonia  WHO guidelines

7. METHOD INCLUSION CRITERIA Age from 3 to 59 months,
History of cough and/or difficult breathing,
Lower chest indrawing with or without presence of fast breathing,
Written informed consent from their mothers

8. METHOD EXCLUSION CRITERIA
Signs of very severe disease or very severe pneumonia
Severe malnutrition [weight for age (WAZ) < 3]
Other infections conditions requiring antibiotic therapy
Current measles or pertussis
Prior history of wheezing including physician diagnosed asthma
Known penicillin allergy
Evidence of pulmonary abscess or miliary tuberculosis
Known or clinically recognisable congenital heart disease
Known underlying disease
Known immunological disorder (including known HIV positive status)
Hospitalization in the previous 2 weeks
Prior enrolment in this observational study

9. METHOD OUTCOME MEASURES Clinical outcome Laboratory outcomes
treatment failure
Laboratory outcomes
prevalence of S. pneumoniae isolates
prevalence of penicillin-resistant S. pneumoniae

10. SUCCESS 48 h TREATMENT SCHEDULE Ampicillin IV 150 mg Penicillin
Children
meses
Children
meses
48 h
any time
dangerous signs
chest indrawing or
resp. rate increased by 10 br/min or
development of any dangerous sign
no chest indrawing
resp. rate either normal or not increased by 10
br/ min
no dangerous sign
Home treatment
amoxycillin 50 mg
failure
failure
change antibiotic
change antibiotic
SUCCESS

11. RESULTS
TABLE 1 - CHILDREN HOSPITALISED WITH SEVERE PNEUMONIA BY COUNTRY
COUNTRY n %
ARGENTINA
857
30.58
BRASIL
1071
38.21
PERU
235
8.38
DOMINICAN REPUBLIC
640
22.83
Total
2803
100.00

12. RESULTS COUNTRY isolates isolation rate ARGENTINA 107 12.49% BRAZIL
TABLE 2 - NUMBER OF ISOLATES AND ISOLATION RATE BY COUNTRY
COUNTRY
isolates
isolation rate
ARGENTINA
107
12.49%
BRAZIL
111
10.36%
PERU 7
3.07%
DOMINICAN REPUBLIC 67
10.47%
Total
292
10.42%

13. RESULTS n % blood 184 63.01 pleural fluid 105 35.96
TABLE 3 - NUMBER OF ISOLATES BY ORIGIN
ORIGIN n %
blood
184
63.01
pleural fluid
105
35.96
blood + pleural fluid 3
1.03
Total
292
100.00

14. RESULTS TABLE 4 - SEROTYPES IDENTIFIED IN THE STUDY (n=257) * Serotype% 14
50.97 1
10.12 6B
8.56 5
6.61 9V
3.89 6A
3.50 7F
2.72
Serotype %
19A
2.33 3
18C
1.95
19F
1.56
10A
23F
1.17
others
2.73
Total number of serotypes: 20
* 35 (12%) isolates without serotype identification

15. RESULTS 4 6B 9V 14 18C 19F 23F + 1 5 + 3 7F PCV-7 68.10% PCV-9 84.83%
PERCENTAGE OF SEROTYPES REPRESENTED IN THE
PNEUMOCOCCAL CONJUGATE VACCINES
4 6B 9V C 19F 23F + 1 5 F
PCV-7
68.10%
PCV-9
84.83%
PCV-11
89.88%
n=257

16. SEROTYPES MOST PREVALENT IN THE COUNTRIES
14: %
1: %
3: %
6A / 6B: 3%
(n=61)
Dominican Rep.
14: 44%
6B: 11%
1: 10%
5: 7%
(n=91)
Brasil
Peru
14: 43%
(n=7)
14: 44%
1: 13%
5: 10%
6B: 9%
(n=98)
Argentina

17. RESULTS TABLE 5 - PNEUMOCOCCAL RESISTANCE TO PENICILLIN (n=270) * n %
SUSCEPTIBILITY n %
susceptible
140
51.85
intermediate 70
25.93
resistant 60
22.22
Susceptible : MIC < 0.06 g/ml
Intermediate: 0.12 g/ml < MIC < 1.00 g/ml
Resistant : MIC > 2.00 g/ml
* 22 (7.53%) with unknown susceptibility

18. PNEUMOCOCCAL RESISTANCE TO PENICILLIN BY COUNTRY (n=270)
Dominican Rep.
S: 68.4%
I: %
R: %
Brasil
Peru
S: 57.1%
I: 14.3%
R: 28.6%
Argentina
S: 49.0%
I: 35.0%
R: 16.0%

19. RESULTS Total TABLE 6 – SEROTYPES MOST PREVALENT BY AGE GROUP (MONTHS)14 97
74% 34
26%
131
100%
6A / 6B 24
78% 7
22% 31 1 10
38% 16
62% 26 5
41%
59% 23 9V 9
90%
10% 19

20. RESULTS susceptible intermediate resistant Total
TABLE 7 – SUSCEPTIBILITY BY AGE GROUP (MONTHS)
SUSCEPTIBILITY
< 24 mo.
≥ 24 mo.
Total
susceptible 84
45% 56
68%
140
52%
intermediate 54
29% 16
20% 70
26%
resistant 50 10
12% 60
22%
n=188
n=82
n=270
p = 0.001

21. RESULTS TOTAL TABLE 8 – TREATMENT FAILURE BY ISOLATION FAILURE no 206
WITH ISOLATION
WITHOUT ISOLATION
TOTAL no
206
71%
2227
89%
2433
87%
yes 86
29%
284
11%
370
13%
292
100%
2511
2803
Treatment failure: local complication after 48h or general complication at any time
or change of antibiotic or intensive care unit or death

22. RESULTS TOTAL TABLE 9 – TREATMENT FAILURE BY ISOLATION FAILURE 5 40 45
WITH ISOLATION
WITHOUT ISOLATION
TOTAL
Local complication 5 40 45
General complication 2 11 13
Change of antibiotic 72
215
287
Intensive care unit 4 6 10
death 12 14

23. Multiple logistic regression analysis for treatment failure for all cases (n=2637)
Characteristics
Treatment failure
Anadjusted analysis
Adjusted analysis
p-value no
yes RR
95% CI
RRadj
Age (mo)
0.24
<12
835 85
1.00
12 |- 24
827
133
1.58
1.26
24 |- 36
344 70
2.00
1.51
36 |-48
190 27
1.40
1.01
≥ 48
110 16
1.43
1.24
Pleural effusion
<0.001
2051
221
255
4.00
1.89
General status
<0.0001
normal
1754
165
irritated
482
134
2.96
3.03
2.30 – 3.99
depressed 32
4.86
4.76
2.92 – 7.75
Consolidation
693 39
up to 1/3 of the lung
1212
132
1.94
1.20
more than 1/3
348
149
7.61
3.66
2.39 – 5.60
bilateral 53 11
3.69
2.22
1.04 – 4.73
Previous use of antibiotics
1807
225
499
106
1.71
1.68
1.28 – 2.20
S. pneumoniae isolation
0.017
2113
193 76
3.26
1.56
1.09 – 2.23

24. Multiple logistic regression analysis for treatment failure for cases with S. pneumoniae isolated (n=269)
Characteristics
Treatment failure
Anadjusted analysis
Adjusted analysis
p-value no
yes RR
95% CI
RRadj
Age (mo)
0.014
<12 73 14
1.00
12 |- 24 65 34
2.73
2.55
24 |- 36 25 20
4.17
3.65
36 |-48 16 5
1.63
1.30
≥ 48 3
1.12
0.81
Pleural effusion
0.028
104 24 89 52
2.53
2.17
General status
0.004
normal
139 39
irritated 44 30
2.43
2.68
depressed 10 7
2.49
3.10
Consolidation
0.59
up to 1/3 of the lung 84
1.90
1.85
more than 1/3 49
3.67
2.04
Previous use of antibiotics
0.89
151 58 42 18
0.59 – 2.09
0.95
S. pneumoniae susceptibility
0.71
susceptible 90 41
intermediate 47 19
0.82
full resistance 12
0.64
unknown 15 4
0.55

25. CONCLUSION
1. The data from different Latin American centres indicate that there is no influence of penicillin susceptibility upon the treatment failure of severe pneumonia in children. Penicillin is effective for pneumonia treatment even in infections due to non-susceptible strains.
2. S.pneumoniae was more frequently detected in children with severer infections.
3. The factors associated with treatment failure were: pleural effusion, consolidation in more than 1/3 of the lung, general status of the child, and previous use of antibiotics.