Chloramphenicol versus ampicillin plus gentamicin for community acquired very severe pneumonia among children aged 2-69 months in low resource settings:  multicentre randomised controlled trial (SPEAR study)

Background:  First line treatment for community acquired very severe pneumonia is injectable chloramphenicol followed by oral chloramphenicol according to WHO guidelines.  There is a lack of evidence on regimens other than chloramphenicol for treating this indication.

Objective:  To evaluate whether 10 days’ treatment with Injectable ampicillin plus gentamicin compared with chloramphenicol reduces treatment failure in children aged 2-59 months with community acquired very severe pneumonia in low resource settings.

Methods:  This study was a randomised, open-label design.  Patients were enrolled from inpatient wards of tertiary care hospitals in 7 different countries.  One group received ampicillin plus gentamicin, while the other group received chloramphenicol.  Those randomised to the ampicillin plus gentamicin arm received ampicillin 200 mg/kg/d in four doses every six hours, and gentamicin 7.5 mg/kg/d as in a single daily dose. Children randomised to the chloramphenicol arm received 75 mg/kg/d given in three doses every eight hours. The first dose of antibiotics were administered within two hours of enrollment.  Treatment duration was 10 days.  The primary outcome was treatment failure at five days.  The secondary outcomes were treatment failure at 48 hours and at 10 and 21 days.  Inclusion criteria included children aged 2-59 months; history of cough or difficulty breathing, or both; WHO defined very severe pneumonia; central cyanosis or inability to drink; and caregiver willingness to consent.  Exclusion criteria included wheezing, with history of three or more attacks, or known asthma; known heart disease; duration of present illness greater than 10 days; history of serious adverse reaction to any of the study drugs; previous enrollment in the study; admission to hospital for more than 24 hours within past 7 days; documented evidence of injectable antibiotic treatment for more than 24 hours before enrollment; stridor; known renal failure or not passed urine during past six hours; evidence of cerebral malaria; evidence of bacterial meningitis; clinical jaundice; residence of patient in an area where follow up was not possible; empyema or presence of pneumatoceles on chest radiograph.  Originally, a desired sample size of 1182 patients was determined.  Only 958 of those were randomised (479 to each treatment arm).  All children were included in the intent-to-treat analysis, bearing in mind that 5 children were lost to follow up in each group.  The power was 80%. 

Results:  For the primary outcome (treatment failure at five days), of the total 131 (13.6%) children who failed treatment by day 5, the cumulative rate was higher among those assigned to the chloramphenicol group (relative risk 1.43, 95% confidence interval 1.03 to 1.97).  For secondary outcomes (treatment failure at 48 hours and 10 and 21 days), by 48 hours after randomisation 87 (9.1%) children had failed treatment, consisting of 48% of the total cumulative number of treatment failures.  At this early time point an excess of children failed treatment in the chloramphenicol group (n=54) compared with the ampicillin plus gentamicin group (n=33; relative risk 1.6, 95% confidence interval 1.1 to 2.5).   Similarly, with the exception of persistence of very severe pneumonia, the cumulative total number of children who failed treatment through days 10 and 21 remained higher in the chloramphenicol group, and the distribution of reasons for this remained similar to those observed at day 5.

Strengths:  Confidence intervals were 95% and the alpha level was 5%.  There was a good account of patients during the study.  Compliance was 95%.

Weaknesses:  The intent-to-treat analysis could overestimate safety and underestimate efficacy of the treatments because of the number of dropouts.  Many of the subgroup analyses were not statistically significant, considering the confidence intervals of relative risk.  This study was open-label, furthermore the authors attempt to excuse non-blinding with claims that blinding was not possible; however, a double dummy could have been employed to disguise the treatment arms.

Conclusion:  The SPEAR trial gives readers a practical account of what the most likely outcomes would be if the methods were really applied to practice.  In reality there is non-compliance, unblinding, and variability from child to child.  Although the limitations (e.g. open-label) of this study are apparent, the authors come to an accurate conclusion.  Ampicillin plus gentamicin treatment would be more favorable for this population and this indication, given the risk of aplastic anemia with chloramphenicol therapy.  Yet, cost would likely be a consideration in this population of a low resource areas.

Asghar R, Banajeh S, Egas J, et. al.  Chloramphenicol versus ampicillin plus gentamicin for community acquired very severe pneumonia among children aged 2-59 months in low resource settings:  multicentre randomised controlled trial (SPEAR study).  BMJ 2008; 336; 80-84.

Prepared by:  Casey R. Watts, PharmD Candidate