Elsevier

The Lancet

Volume 352, Issue 9124, 25 July 1998, Pages 270-274
The Lancet

Articles
Antimicrobial resistance and clinical effectiveness of co-trimoxazole versus amoxycillin for pneumonia among children in Pakistan: randomised controlled trial

https://doi.org/10.1016/S0140-6736(97)10294-XGet rights and content

Summary

Background

Co-trimoxazole is widely used in treatment of paediatric pneumonia in developing countries, but drug resistance may decrease its effectiveness. We studied the effectiveness of co-trimoxazole compared with that of amoxycillin in pneumonia therapy, and assessed the clinical impact of co-trimoxazole resistance.

Methods

We recruited 595 children, aged 2–59 months, with non-severe or severe pneumonia (WHO criteria) diagnosed in the outpatient wards of two urban Pakistan hospitals. Patients were randomly assigned on a 2:1 basis co-trimoxazole (n=398) or amoxycillin (n=197) in standard WHO doses and dosing schedules, and were monitored in study wards. The primary outcome was inpatient therapy failure (clinical criteria) or clinical evidence of pneumonia at outpatient follow-up examination.

Findings

There were 92 (23%) therapy failures in the co-trimoxazole group and 30 (15%) in the amoxycillin group (p=0·03)—26 (13%) versus 12 (12%) among children with non-severe pneumonia (p=0·856) and 66 (33%) versus 18 (18%) among those with severe pneumonia (p=0·009). For patients with severe pneumonia, age under 1 year (p=0·056) and positive chest radiographs (p=0·005) also predicted therapy failure. There was no significant association between antimicrobial minimum inhibitory concentration and outcome among bacteraemic children treated with co-trimoxazole.

Interpretation

Co-trimoxazole provided effective therapy in non-severe pneumonia. For severe, life-threatening pneumonia, however, co-trimoxazole is less likely than amoxycillin to be effective.

Introduction

In developing countries, 3·5 million children die each year from acute respiratory infections (ARI).1 To reduce the death-rate due to ARI in countries where diagnostic and laboratory support are limited, WHO has developed a standard case-management strategy that uses simple clinical signs to diagnose pneumonia, with empirical antimicrobial treatment for children found to have the disease.

In 1989, the Ministry of Health in Pakistan inaugurated a national case-management programme to control ARI mortality; co-trimoxazole, a WHO-approved antimicrobial agent, was recommended for outpatient treatment of pneumonia. This policy was subsequently questioned when a local study found that 43% of Haemophilus influenzae and 31% of Streptococcus pneumoniae isolates from the blood of children with pneumonia showed high-level in-vitro resistance to co-trimoxazole (minimum inhibitory concentration ≥4/76 organism-specific standard dilutions).2, 3 Nonetheless, proponents argued for the continued use of co-trimoxazole on the basis that no correlation between in-vitro susceptibility to co-trimoxazole and clinical outcome for pneumonia had ever been established, in addition to which co-trimoxazole had in 1993 been shown to be effective (91% of 95 cases resolved) in another local study, in outpatients with non-severe pneumonia.4 And, of course, to change the national recommendations for pneumonia therapy would be difficult and costly. We undertook a clinical trial to assess the effectiveness of co-trimoxazole in comparison with amoxycillin for non-severe pneumonia and severe pneumonia, and to examine the association between in- vitro co-trimoxazole susceptibility and clinical response.

Section snippets

Patients

This study was approved by the institutional review boards of the Pakistan Ministry of Health, Centers for Disease Control and Prevention (Atlanta), and WHO (Geneva).

We evaluated for enrolment in the study all children aged 2–59 months who presented as outpatients with cough or breathing difficulty to either the Rawalpindi General Hospital or the Children's Hospital (Pakistan Institute of Medical Sciences). Study physicians used standard WHO ARI algorithms to diagnose and classify children with

Results

Between November, 1991, and April, 1992, 595 children were enrolled. Nine (1·5%) children did not complete the inpatient phase, and seven (1·2%) patients completed the inpatient phase but were not available for follow-up examination (figure). Baseline characteristics of the children are given in table 1. Radiographic evidence of pneumonia was present in 153 (26·3%) of the 580 children for whom radiographs were available. S pneumoniae or H influenzae were isolated from blood of 146 (24·5%)

Discussion

On the basis of results from field studies, WHO has identified and endorsed several antimicrobial drugs to treat pneumonia.9, 10 Of these, co-trimoxazole is particularly favoured not only because it has in-vitro activity against both S pneumoniae and H influenzae11– the principal causative agents of severe paediatric pulmonary infections in developing countries–but also because it is easy to administer, inexpensive, and widely available. The cost of a course of co-trimoxazole for a 1-year-old

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