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

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)

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

Dominican Rep. Peru Brazil Argentina

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

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

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

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

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

SUCCESS 48 h TREATMENT SCHEDULE Ampicillin IV 150 mg Penicillin Children 3 - 23 meses Children 24 - 59 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

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

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%

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

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

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 14 18C 19F 23F + 1 5 + 3 7F PCV-7 68.10% PCV-9 84.83% PCV-11 89.88% n=257

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

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

PNEUMOCOCCAL RESISTANCE TO PENICILLIN BY COUNTRY (n=270) 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%

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

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

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

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

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 1.18 - 2.11 1.26 0.92 - 1.72 24 |- 36 344 70 2.00 1.42 - 2.81 1.51 1.04 - 2.18 36 |-48 190 27 1.40 0.88 - 2.21 1.01 0.62 - 1.67 ≥ 48 110 16 1.43 0.81 - 2.53 1.24 0.68 - 2.28 Pleural effusion <0.001 2051 221 255 4.00 3.08 - 5.21 1.89 1.34 - 2.67 General status <0.0001 normal 1754 165 irritated 482 134 2.96 2.30 - 3.79 3.03 2.30 – 3.99 depressed 32 4.86 3.11 - 7.60 4.76 2.92 – 7.75 Consolidation 693 39 up to 1/3 of the lung 1212 132 1.94 1.34 - 2.80 1.20 0.81 - 1.77 more than 1/3 348 149 7.61 5.23 - 11.07 3.66 2.39 – 5.60 bilateral 53 11 3.69 1.79 - 7.62 2.22 1.04 – 4.73 Previous use of antibiotics 1807 225 499 106 1.71 1.33 - 2.19 1.68 1.28 – 2.20 S. pneumoniae isolation 0.017 2113 193 76 3.26 2.43 - 4.38 1.56 1.09 – 2.23

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 1.35 - 5.53 2.55 1.19 - 5.43 24 |- 36 25 20 4.17 1.84 - 9.47 3.65 1.47 - 9.01 36 |-48 16 5 1.63 0.51 - 5.18 1.30 0.38 - 4.53 ≥ 48 3 1.12 0.28 - 4.41 0.81 0.18 - 3.59 Pleural effusion 0.028 104 24 89 52 2.53 1.45 - 4.43 2.17 1.08 - 4.38 General status 0.004 normal 139 39 irritated 44 30 2.43 1.35 - 4.36 2.68 1.41 - 5.09 depressed 10 7 2.49 0.89 - 6.98 3.10 0.99 - 9.65 Consolidation 0.59 up to 1/3 of the lung 84 1.90 0.52 - 6.96 1.85 0.46 - 7.54 more than 1/3 49 3.67 1.04 - 12.97 2.04 0.49 - 8.51 Previous use of antibiotics 0.89 151 58 42 18 0.59 – 2.09 0.95 0.48 - 1.91 S. pneumoniae susceptibility 0.71 susceptible 90 41 intermediate 47 19 0.46 - 1.70 0.82 0.39 - 1.70 full resistance 12 0.64 0.31 - 1.35 0.31 - 1.63 unknown 15 4 0.18 - 1.87 0.55 0.16 - 1.90

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.