Antibiotic Resistance of S. pneumoniae in Children with Severe Pneumonia in Latin America

1. LATIN-AMERICAN MULTICENTRE STUDYON 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. Brazil Argentina Peru

5. OBJETIVES OF THE STUDY • PRINCIPAL OBJECTIVE • 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 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 • treatment failure • Laboratory outcomes • prevalence of S. pneumoniae isolates • prevalence of penicillin-resistant S. pneumoniae

10. TREATMENT SCHEDULE Ampicillin IV 150 mg Penicillin 200.000 u Children 24 - 59 meses Children 3 - 23 meses 48 h any time • no chest indrawing • resp. rate either normal or not increased by 10 • br/ min • no dangerous sign chest indrawing or resp. rate increased by 10 br/min or development of any dangerous sign dangerous signs Home treatment amoxycillin 50 mg failure failure change antibiotic change antibiotic SUCCESS

11. RESULTS TABLE 1 - CHILDREN HOSPITALISED WITH SEVERE PNEUMONIA BY COUNTRY

12. RESULTS TABLE 2 - NUMBER OF ISOLATES AND ISOLATION RATE BY COUNTRY

13. RESULTS TABLE 3 - NUMBER OF ISOLATES BY ORIGIN

14. RESULTS TABLE 4 - SEROTYPES IDENTIFIED IN THE STUDY (n=257) * Total number of serotypes: 20 * 35 (12%) isolates without serotype identification

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

16. SEROTYPES MOST PREVALENT IN THE COUNTRIES 14: 74% 1: 7% 3: 5% 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. Susceptible : MIC < 0.06 g/ml Intermediate: 0.12 g/ml < MIC < 1.00 g/ml Resistant : MIC > 2.00 g/ml RESULTS TABLE 5 - PNEUMOCOCCAL RESISTANCE TO PENICILLIN (n=270) * * 22 (7.53%) with unknown susceptibility

18. PNEUMOCOCCAL RESISTANCE TO PENICILLIN BY COUNTRY (n=270) S: 30.8% I: 18.4% R: 50.8% Dominican Rep. S: 68.4% I: 22.4% R: 9.2% Brasil Peru S: 57.1% I: 14.3% R: 28.6% Argentina S: 49.0% I: 35.0% R: 16.0%

19. RESULTS TABLE 6 – SEROTYPES MOST PREVALENT BY AGE GROUP (MONTHS)

20. RESULTS TABLE 7 – SUSCEPTIBILITY BY AGE GROUP (MONTHS) n=82 n=270 n=188 p = 0.001

21. RESULTS TABLE 8 – TREATMENT FAILURE BY ISOLATION Treatment failure: local complication after 48h or general complication at any time or change of antibiotic or intensive care unit or death

22. RESULTS TABLE 9 – TREATMENT FAILURE BY ISOLATION

23. Multiple logistic regression analysis for treatment failure for all cases (n=2637)

24. Multiple logistic regression analysis for treatment failure for cases with S. pneumoniae isolated (n=269)

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.