Comparison of 3 Days Amoxicillin Versus 5 Days Co-Trimoxazole for Treatment of Fast-breathing Pneumonia by Community Health Workers in Children Aged 2–59 Months in Pakistan: A Cluster-randomized Trial

Abstract

Background Globally, most deaths due to childhood pneumonia occur at the community level. Some countries are still using oral co-trimoxazole, despite a World Health Organization recommendation of oral amoxicillin for the treatment of fast-breathing pneumonia in children at the community level. Methods We conducted an unblinded, cluster-randomized, controlled-equivalency trial in Haripur District, Pakistan. Children 2–59 months of age with fast-breathing pneumonia were treated with oral amoxicillin suspension (50 mg/kg/day) for 3 days in 14 intervention clusters and oral co-trimoxazole suspension (8 mg trimethoprim/kg and 40 mg sulfamethoxazole/kg/day) for 5 days in 14 control clusters by lady health workers (LHW). The primary outcome was treatment failure by day 4 for intervention clusters and by day 6 for control clusters. The analysis was per protocol. Results Out of the 15 749 cases enrolled in the study, 9153 cases in intervention and 6509 cases in control clusters were included in the analysis. Treatment failure rates were 3.6% (326) in intervention clusters and 9.1% (592) in control clusters. After adjusting for clustering, the risk of treatment failure was lower in intervention clusters (risk difference [RD] -5.5%, 95% confidence interval [CI] -7.4–-3.7%) than in control clusters. Children with incomplete adherence had a small increase in treatment failure versus those with complete adherence (RD 2.9%, 95% CI 1.6–4.1%). No deaths or serious adverse events occurred. Conclusions A 3-day course of oral amoxicillin, administered by LHWs, is an effective and safe treatment for fast-breathing pneumonia in children 2–59 months of age. A shorter course of amoxicillin improves adherence to therapy, is low in cost, and puts less pressure on antimicrobial resistance. Clinical Trials Registration ISRCTN10618300.

Community case management of fast-breathing pneumonia with 3 days oral amoxicillin vs 5 days cotrimoxazole in children 2-59 months of age in rural Pakistan: A cluster randomized trial

“…The treatment failure rate in other studies for amoxicillin ranged 8%-23% and for cotrimoxazole ranged from 9.5%-39%. The only exceptions are two studies, one study conducted in Brazil by the PNEUMOPAC-Efficacy Study Group which treated fast breathing pneumonia cases with oral amoxicillin and the failure rate was 3% [ 27 ] and In the Haripur community-based study, treatment failure for amoxicillin was 3.6% and for cotrimoxazole was 9.1% [ 28 ] There are other two community-based studies in young infants (<60 days) conducted recently in which treatment failure rate in amoxicillin was comparable with this study, one study was conducted in Pakistan in which the treatment failure rate with 3-day amoxicillin was 2.6% vs 4.9% in the placebo group [ 29 ]. Similarly, in the multicountry trial conducted in rural Bangladesh, Ethiopia, India, and Malawi, the treatment failure with 7-day treatment with oral amoxicillin was 5.4% [ 30 ].…”

“…Another possible reason for the difference in treatment failure could be a single respiratory rate cut-off used in this study. As far as our knowledge is concerned, it was one of the first community-based trials for fast-breathing pneumonia along with a similar trial conducted at Haripur, Pakistan site at the same time with the same collaborating partners, trial design, inclusion, and exclusion criteria [ 28 ]. Almost all studies reported male dominance in fast-breathing pneumonia enrolment [ 12 , 13 , 22 - 24 ].…”

Antimicrobial Resistance in Pneumococcal Carriage Isolates from Children under 2 Years of Age in Rural Pakistan

“…In addition, many general practitioners and unlicensed health care providers prescribe broad spectrum antibiotics for mild, self-limiting illnesses ( 20 , 21 ).This in parallel with poor compliance by patients results in increasing antibiotic resistance ( 5 ). Thus, we see widespread nonsusceptibility to cotrimoxazole, which was once the mainstay of treatment for community management of pneumonia ( 22 , 23 ). We did not collect information on antibiotic prescription patterns as a part of our study; however, published literature from rural areas of Sindh report that 80% of the rural dwellers use antibiotics without prescription.…”

Clinical utility of a model‐based amoxicillin dosage regimen in neonates with early‐onset sepsis

“…However, excessive accumulation of amoxicillin may lead to seizures. [22][23][24] Despite the longstanding use of amoxicillin for sepsis therapy in neonates, amoxicillin dosage guidelines are still based mainly on expert opinion, leading to considerable intercentre variability in dosing recommendations. 25 Some studies have investigated amoxicillin pharmacokinetics (PK) of premature and term infants.…”

“…Amoxicillin, a semi‐synthetic antibiotic belonging to the subclass of aminopenicillins, is active against both Gram‐positive and Gram‐negative pathogens such as E. coli and S. agalactiae , 18–21 and generally considered safe. However, excessive accumulation of amoxicillin may lead to seizures 22–24 . Despite the longstanding use of amoxicillin for sepsis therapy in neonates, amoxicillin dosage guidelines are still based mainly on expert opinion, leading to considerable intercentre variability in dosing recommendations 25 .…”