Elsevier

The Lancet

Volume 364, Issue 9440, 25 September–1 October 2004, Pages 1141-1148
The Lancet

Articles
Oral amoxicillin versus injectable penicillin for severe pneumonia in children aged 3 to 59 months: a randomised multicentre equivalency study*

https://doi.org/10.1016/S0140-6736(04)17100-6Get rights and content

Summary

Background

Injectable penicillin is the recommended treatment for WHO-defined severe pneumonia (lower chest indrawing). If oral amoxicillin proves equally effective, it could reduce referral, admission, and treatment costs. We aimed to determine whether oral amoxicillin and parenteral penicillin were equivalent in the treatment of severe pneumonia in children aged 3–59 months.

Methods

This multicentre, randomised, open-label equivalency study was undertaken at tertiary-care centres in eight developing countries in Africa, Asia, and South America. Children aged 3–59 months with severe pneumonia were admitted for 48 h and, if symptoms improved, were discharged with a 5-day course of oral amoxicillin. 1702 children were randomly allocated to receive either oral amoxicillin (n=857) or parenteral penicillin (n=845) for 48 h. Follow-up assessments were done at 5 and 14 days after enrolment. Primary outcome was treatment failure (persistence of lower chest indrawing or new danger signs) at 48 h. Analyses were by intention-to-treat and per protocol.

Findings

Treatment failure was 19% in each group (161 patients, pencillin; 167 amoxillin; risk difference –0·4%; 95% CI –4·2 to 3·3) at 48 h. Infancy (age 3–11 months; odds ratio 2·72, 95% CI 1·95 to 3·79), very fast breathing (1·94, 1·42 to 2·65), and hypoxia (1·95, 1·34 to 2·82) at baseline predicted treatment failure by multivariate analysis.

Interpretation

Injectable penicillin and oral amoxicillin are equivalent for severe pneumonia treatment in controlled settings. Potential benefits of oral treatment include decreases in (1) risk of needle-borne infections; (2) need for referral or admission; (3) administration costs; and (4) costs to the family.

Introduction

Acute respiratory infection is one of the leading causes of morbidity and mortality in children under 5 years of age in developing countries, and is responsible for an estimated 1·9 million deaths in this age group every year.1, 2, 3 Bacterial infection has a far greater role as a cause of pneumonia in children in developing countries than it does in developed countries. One explanation for the higher mortality associated with acute respiratory infection in developing countries is the high prevalence of a bacterial cause. Researchers using lung aspiration have isolated Streptococcus pneumoniae and Haemophilus influenzae (as well as others), in up to 74% of patients with pneumonia in developing countries.4

Standard guidelines developed by WHO5 recommend that children with no lower chest wall indrawing who have fast breathing (⩾50 breaths per min in infants aged 2–11 months and ⩾40 breaths per min in those aged 12–59 months)—ie, with non-severe pneumonia—be treated at home with oral antibiotics, and those with lower chest wall indrawing (ie, severe pneumonia), be admitted and given parenteral antibiotics (benzylpenicillin or ampicillin). Application of these guidelines in developing countries has resulted in decreased mortality from acute respiratory infection.6, 7 However, admission required for administration of injectable treatment has several drawbacks. First, routine use of injectable antibiotics, either intravenously or intramuscularly, is associated with an increase in the risk of clinically significant morbidity, such as complications of abscess formation at the injection site and transmission of HIV, hepatitis, or other pathogens associated with use of contaminated needles. Second, injection needles and administration equipment are in short supply or periodically unavailable in some settings, preventing delivery of recommended treatment. Third, admission can substantially raise the cost of health care. Fourth, children who have to be referred for admission and injectable treatment might not be brought or be able to travel to hospital.

A recent trial in Pakistan showed that oral amoxicillin was effective in 82% of bacteraemic children with a clinical diagnosis of severe pneumonia.8 If oral amoxicillin proved as effective as injectable penicillin in the treatment of severe pneumonia, substantial improvements in access to appropriate care, nosocomial complications, iatrogenic infections, and costs could be achieved with its widespread use. Our aim was to do a multicentre equivalency study comparing oral amoxicillin with injectable penicillin in the treatment of WHO-defined severe pneumonia in children.

Section snippets

Patients

We undertook a randomised, non-blinded equivalency trial of oral amoxicillin and injectable penicillin in children aged 3–59 months with WHO-defined severe pneumonia,5 in the paediatric departments of tertiary-care facilities at nine international sites: Colombia, Ghana, India, Mexico, Pakistan, South Africa (two sites), Vietnam, and Zambia. Children presenting as emergencies with a history of coughing or difficulty breathing and lower chest indrawing were assessed for enrolment into the study.

Results

Participant accrual took place between May, 1999, and May, 2002. The Cape Town and Zambia centres ended recruitment in September, 1999, and July, 2000, respectively, both because of poor accrual from changes in the referral patterns. We randomly assigned 1702 participants to penicillin and amoxicillin (figure). 27 children aged between 2 and 3 months were mistakenly allocated but this protocol deviation was distributed evenly between both treatment groups, and these babies were included in the

Discussion

We have shown that oral amoxicillin and injectable penicillin are equally effective at 48 h and beyond. The 48-h treatment failure rate was similar to that of 18% Straus and colleagues reported with oral amoxicillin for the treatment of severe pneumonia.8 Although several baseline characteristics were predictive of treatment failure at 48 h, only infancy (age 3–11 months), severe tachypnoea, and hypoxaemia were predictive in the multivariable model, which is in accordance with the findings of

References (40)

  • World Health Organization. WHO Programme for the Control of Acute Respiratory Infections. Acute respiratory infections...
  • SA Qazi et al.

    Reduction in acute respiratory infection hospital mortality with standard ari case management. Islamabad, Pakistan: Federal ARI Cell, National ARI Control Programme, the Children' Hospital

    (1995)
  • KV Forrest et al.

    Manual of clinical microbiology

    (2003)
  • 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age

    MMWR Morb Mortal Wkly Rep

    (1994)
  • SA Qazi et al.

    Standard management of acute respiratory infections in a children's hospital in Pakistan: impact on antibiotic use and case fatality

    Bull World Health Organ

    (1996)
  • PC O'Brien

    Procedures for comparing samples with multiple endpoints

    Biometrics

    (1984)
  • PC O'Brien et al.

    A multiple testing procedure for clinical trials

    Biometrics

    (1979)
  • Clinical efficacy of 3 days versus 5 days of oral amoxicillin for treatment of childhood pneumonia: a multicentre double-blind trial

    Lancet

    (2002)
  • Catchup study group

    Clinical efficacy of co-trimoxazole versus amoxicillin twice daily for treatment of pneumonia: a randomised controlled clinical trial in Pakistan

    Arch Dis Child

    (2002)
  • F Shann et al.

    Clinical signs that predict death in children with severe pneumonia

    Pediatr Infect Dis J

    (1989)
  • Cited by (155)

    • Challenges in the diagnosis of paediatric pneumonia in intervention field trials: recommendations from a pneumonia field trial working group

      2019, The Lancet Respiratory Medicine
      Citation Excerpt :

      Although effective in informing treatment guidelines that largely reduced childhood mortality,21,32 use of the WHO definition could lead to reduced effect size and study power in field trials.21,29 In fact, severe pneumonia is less likely to be confused with another disease than non-severe pneumonia, and more accurately assess the efficacy of interventions against pneumonia.110–112 As pneumonia prevalence is highest in the first year of life, pneumonia outcome studies might find more cases with greater severity by focusing on a shorter follow-up period.

    • Complicated pneumonia in children

      2020, The Lancet
      Citation Excerpt :

      However, the clinical response in CCAP is slow, and patience is required before changing treatment. The duration of intravenous antibiotic therapy to prescribe is controversial, and oral antibiotic therapy should be started as soon as possible.130–132 A course of 2–3 weeks of intravenous antibiotic therapy is usually sufficient, often with a transition to oral therapy when fever has abated for at least 24–48 h, there is no respiratory distress or evidence of uncontrolled sepsis, the child is tolerating enteral feeds and has an improved mood and playfulness, and when inflammatory markers are reducing.133

    View all citing articles on Scopus
    *

    Contributors listed at end of report. See details of contributorship at http://image.thelancet.com/extras/03art8088webappendix.

    View full text