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Randomized Trial of Amoxicillin for Pneumonia in Pakistan.

ABSTRACT: BACKGROUND:The World Health Organization (WHO) recommends oral amoxicillin for patients who have pneumonia with tachypnea, yet trial data indicate that not using amoxicillin to treat this condition may be noninferior to using amoxicillin. METHODS:We conducted a double-blind, randomized, placebo-controlled noninferiority trial involving children at primary health care centers in low-income communities in Karachi, Pakistan. Children who were 2 to 59 months of age and who met WHO criteria for nonsevere pneumonia with tachypnea were randomly assigned to a 3-day course of a suspension of amoxicillin (the active control) of 50 mg per milliliter or matched volume of placebo (the test regimen), according to WHO weight bands (500 mg every 12 hours for a weight of 4 to <10 kg, 1000 mg every 12 hours for a weight of 10 to <14 kg, or 1500 mg every 12 hours for a weight of 14 to <20 kg). The primary outcome was treatment failure during the 3-day course of amoxicillin or placebo. The prespecified noninferiority margin was 1.75 percentage points. RESULTS:From November 9, 2014, through November 30, 2017, a total of 4002 children underwent randomization (1999 in the placebo group and 2003 in the amoxicillin group). In the per-protocol analysis, the incidence of treatment failure was 4.9% among placebo recipients (95 of 1927 children) and 2.6% among amoxicillin recipients (51 of 1929 children) (between-group difference, 2.3 percentage points; 95% confidence interval [CI], 0.9 to 3.7). Results were similar in the intention-to-treat analysis. The presence of fever and wheeze predicted treatment failure. The number needed to treat to prevent one treatment failure was 44 (95% CI, 31 to 80). One patient (<0.1%) in each group died. Relapse occurred in 40 children (2.2%) in the placebo group and in 58 children (3.1%) in the amoxicillin group. CONCLUSIONS:Among children younger than 5 years of age with nonsevere pneumonia, the frequency of treatment failure was higher in the placebo group than in the amoxicillin group, a difference that did not meet the noninferiority margin for placebo. (Funded by the Joint Global Health Trials Scheme [of the Department for International Development, Medical Research Council, and Wellcome] and others; RETAPP ClinicalTrials.gov number, NCT02372461.).

SUBMITTER: Jehan F

PROVIDER: S-EPMC7244232 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFirst dose oral co-trimoxazole and referral are recommended for WHO-defined severe pneumonia. Difficulties with referral compliance are reported in many low-resource settings, resulting in low access to appropriate treatment. The objective in this study was to assess whether community case management by lady health workers (LHWs) with oral amoxicillin in children with severe pneumonia was equivalent to current standard of care.MethodsIn Haripur district, Pakistan, 28 clusters were randomly assigned with stratification in a 1:1 ratio to intervention and control clusters by use of a computer-generated randomisation sequence. Children were included in the study if they were aged 2-59 months with WHO-defined severe pneumonia and living in the study area. In the intervention clusters, community-based LHWs provided mothers with oral amoxicillin (80-90 mg/kg per day or 375 mg twice a day for infants aged 2-11 months and 625 mg twice a day for those aged 12-59 months) with specific guidance on its use. In control clusters, LHWs gave the first dose of oral co-trimoxazole (age 2-11 months, sulfamethoxazole 200 mg plus trimethoprim 40 mg; age 12 months to 5 years, sulfamethoxazole 300 mg plus trimethoprim 60 mg) and referred the children to a health facility for standard of care. Participants, carers, and assessors were not masked to treatment assignment. The primary outcome was treatment failure by day 6. Analysis was per protocol with adjustment for clustering within groups by use of generalised estimating equations. This study is registered, number ISRCTN10618300.FindingsWe assigned 1995 children to treatment in 14 intervention clusters and 1477 in 14 control clusters, and we analysed 1857 and 1354 children, respectively. Cluster-adjusted treatment failure rates by day 6 were significantly reduced in the intervention clusters (165 [9%] vs 241 [18%], risk difference -8·9%, 95% CI -12·4 to -5·4). Further adjustment for baseline covariates made little difference (-7·3%, -10·1 to -4·5). Two deaths were reported in the control clusters and one in the intervention cluster. Most of the risk reduction was in the occurrence of fever and lower chest indrawing on day 3 (-6·7%, -10·0 to -3·3). Adverse events were diarrhoea (n=4) and skin rash (n=1) in the intervention clusters and diarrhoea (n=3) in the control clusters.InterpretationCommunity case management could result in a standardised treatment for children with severe pneumonia, reduce delay in treatment initiation, and reduce the costs for families and health-care systems.FundingUnited States Agency for International Development (USAID).

Project description:BackgroundPneumonia is the leading cause of mortality in under-five children and most of these deaths occur in South-East Asia and Africa. Fast breathing pneumonia if not treated can progress to lower chest indrawing pneumonia. Treatment recommendation by the World Health Organization (WHO) for fast-breathing pneumonia includes oral amoxicillin and cotrimoxazole (as an alternative). Due to limited access to health care facilities and skilled health care workers, many children are unable to receive antibiotics. Algorithm-based community case management of pneumonia through trained community health workers has resulted in a decline in morbidity and mortality in low- and middle-income countries (LMIC).MethodsIt was a cluster-randomized, unblinded, community-based trial conducted in the Matiari district of Sindh province, Pakistan. Lady Health Workers (LHWs) were trained in assessing, classifying, and managing fast-breathing pneumonia cases (Respiratory rate of >50 breaths/min) at home with oral amoxicillin for three days and with co-trimoxazole for five days in the intervention and control arms respectively. Children with fast-breathing pneumonia were screened by LHWs and were validated by the study by Community Health Workers (CHWs) within 48 hours. They were followed by the LHWs on days 2, 4, and 14 in intervention and on days 2, 6, and 14 in the control arm. Primary treatment failure was assessed on day 4 in intervention and day 6 in the control arm. A severe pneumonia trial was registered with ClinicalTrials.gov, number NCT01192789.ResultsFrom February 2008 to March 2010, a total of 5876 children were enrolled by Lady Health Workers as fast breathing pneumonia. On validation visits of the CHWs, 728 (12%) children were excluded. A total of 4984 children were analysed as per protocol: 2480 in intervention and 2504 in control. There were 72 (2.9%) primary treatment failures in the intervention arm as compared to 102 (4%) in the control arm with a risk difference of -0.94 (-2.84%, 0.96%). Secondary treatment failures were almost equal in both arms (4 vs 7 cases). No deaths or serious adverse events were recorded.ConclusionsThis study shows that amoxicillin can be as effective as cotrimoxazole to treat fast-breathing pneumonia cases at the domiciliary level.RegistrationNCT01192789.

Project description:ContextEvidence to support antibiotic treatment for acute rhinosinusitis is limited, yet antibiotics are commonly used.ObjectiveTo determine the incremental effect of amoxicillin treatment over symptomatic treatments for adults with clinically diagnosed acute rhinosinusitis.Design, setting, and participantsA randomized, placebo-controlled trial of adults with uncomplicated, acute rhinosinusitis were recruited from 10 community practices in Missouri between November 1, 2006, and May 1, 2009.InterventionsTen-day course of either amoxicillin (1500 mg/d) or placebo administered in 3 doses per day. All patients received a 5- to 7-day supply of symptomatic treatments for pain, fever, cough, and nasal congestion to use as needed.Main outcome measuresThe primary outcome was improvement in disease-specific quality of life after 3 to 4 days of treatment assessed with the Sinonasal Outcome Test-16 (minimally important difference of 0.5 units on a 0-3 scale). Secondary outcomes included the patient's retrospective assessment of change in sinus symptoms and functional status, recurrence or relapse, and satisfaction with and adverse effects of treatment. Outcomes were assessed by telephone interview at days 3, 7, 10, and 28.ResultsA total of 166 adults (36% male; 78% with white race) were randomized to amoxicillin (n = 85) or placebo (n = 81); 92% concurrently used 1 or more symptomatic treatments (94% for amoxicillin group vs 90% for control group; P = .34). The mean change in Sinonasal Outcome Test-16 scores was not significantly different between groups on day 3 (decrease of 0.59 in the amoxicillin group and 0.54 in the control group; mean difference between groups of 0.03 [95% CI, -0.12 to 0.19]) and on day 10 (mean difference between groups of 0.01 [95% CI, -0.13 to 0.15]), but differed at day 7 favoring amoxicillin (mean difference between groups of 0.19 [95% CI, 0.024 to 0.35]). There was no statistically significant difference in reported symptom improvement at day 3 (37% for amoxicillin group vs 34% for control group; P = .67) or at day 10 (78% vs 80%, respectively; P = .71), whereas at day 7 more participants treated with amoxicillin reported symptom improvement (74% vs 56%, respectively; P = .02). No between-group differences were found for any other secondary outcomes. No serious adverse events occurred.ConclusionAmong patients with acute rhinosinusitis, a 10-day course of amoxicillin compared with placebo did not reduce symptoms at day 3 of treatment.Trial registrationclinicaltrials.gov Identifier: NCT00377403.

Project description:The World Health Organization (WHO) recommends intravenous (IV) ampicillin and gentamicin as first-line therapy to treat severe pneumonia in children under five years of age. Ampicillin needs to be administered at a six-hourly interval, which requires frequent nursing intervention and bed occupancy for 5-7 days, limiting its utility in resource-poor settings. We compared the efficacy of IV amoxicillin over IV ampicillin, which is a potential alternative drug in treating severe pneumonia in children between 2-59 months. We conducted an unblinded, randomized, controlled, non-inferiority trial in the Dhaka hospital of icddr,b from 1 January 2018 to 31 October 2019. Children from 2-59 months of age presenting with WHO defined severe pneumonia with respiratory danger signs were randomly assigned 1:1 to either 50 mg/kg ampicillin or 40 mg/kg amoxicillin per day with 7.5 mg/kg gentamicin. The primary outcome was treatment failure as per the standard definition of persistence of danger sign(s) of severe pneumonia beyond 48 h or deterioration within 24 h of therapy initiation. The secondary outcomes were: (i) time required for resolution of danger signs since enrolment, (ii) length of hospital stay, (iii) death during hospitalization, and (iv) rate of nosocomial infections. Among 308 enrolled participants, baseline characteristics were similar among the two groups. Sixty-two (20%) children ended up with treatment failure, 21 (14%) in amoxicillin, and 41 (27%) in ampicillin arm, which is statistically significant (relative risk [RR] 0.51, 95% CI 0.32-0.82; p = 0.004). We reported 14 deaths for serious adverse events, 4 (3%) and 10 (6%) among amoxicillin and ampicillin arm, respectively. IV amoxicillin and IV gentamicin combination is not inferior to combined IV ampicillin and IV gentamicin in treating severe pneumonia in under-five children in Bangladesh. Considering the less frequent dosing and more compliance, IV amoxicillin is a better choice for treating children with severe pneumonia in resource-limited settings.

Project description:ImportancePneumonia is the leading infectious killer of children. Rigorous evidence supporting antibiotic treatment of children with nonsevere fast-breathing pneumonia in low-resource African settings is lacking.ObjectiveTo assess whether treatment with placebo for nonsevere fast-breathing pneumonia is substantively less effective than 3 days of treatment with amoxicillin.Design, setting, and participantsThis double-blind, 2-arm, randomized clinical noninferiority trial with follow-up of 14 days screened 1343 HIV-uninfected children aged 2 to 59 months with nonsevere fast-breathing pneumonia at outpatient departments of hospitals in Lilongwe, Malawi, Africa, between June 2016 and June 2017.InterventionsPlacebo or amoxicillin dispersible tablets administered twice daily for 3 days.Main outcomes and measuresThe primary end point was the proportion of children failing treatment by day 4 with a relative noninferiority margin of 1.5 times the failure rate in the amoxicillin group. Primary analyses were performed based on the intention-to-treat principle. Planned secondary analyses included treatment failure or relapse by day 14.ResultsIn total, 1126 children were randomized to 3 days of amoxicillin (n = 564) or placebo (n = 562) therapy. Baseline demographic and clinical characteristics were similar between the groups. For the entire study population, the mean (SD) age was 21.3 (15.1) months, and 601 (53.4%) were female. After an interim analysis, the data safety monitoring board stopped the study because children receiving amoxicillin had a 4.0% (22 of 552 with outcome data) treatment failure rate by day 4, whereas children receiving placebo had a 7.0% (38 of 543) treatment failure rate (adjusted relative risk, 1.78; 95% CI, 1.07%-2.97%; adjusted absolute difference, 3.0%; 95% CI, 0.4%-5.7%). Among children with known day 14 outcomes, 56 of 552 (10.1%) receiving amoxicillin and 64 of 543 (11.8%) receiving placebo had either treatment failure by day 4 or relapse by day 14 (relative risk, 1.16; 95% CI, 0.83%-1.63%; absolute difference, 1.6%; 95% CI, -2.1% to 5.4%). There were no deaths.Conclusions and relevanceIn HIV-uninfected children aged 2 to 59 months in a malaria-endemic region of Malawi, placebo treatment of nonsevere fast-breathing pneumonia was significantly inferior to treatment with amoxicillin. However, by day 4, approximately 93% of children receiving placebo were without treatment failure, and there was no significant difference between groups in treatment failure or relapse by day 14. The number of children with nonsevere fast-breathing pneumonia that needed amoxicillin treatment for 1 child to benefit was 33.Trial registrationClinicalTrials.gov Identifier: NCT02760420.

Project description:Pneumonia is the leading cause of child mortality under five years of age worldwide. For pneumonia with chest indrawing in children aged 3-59 months, injectable penicillin and hospitalization was the recommended treatment. This increased the health care cost and exposure to nosocomial infections. We compared the clinical and cost outcomes of a seven day treatment with oral amoxicillin with the first 48 h of treatment given in the hospital (hospital group) or at home (home group).We conducted an open-label, multi-center, two-arm randomized clinical trial at six tertiary hospitals in India. Children aged 3 to 59 months with chest indrawing pneumonia were randomized to home or hospital group. Clinical outcomes, treatment adherence, and patient safety were monitored through home visits on day 3, 5, 8, and 14 with an additional visit for the home group at 24 h. Clinical outcomes included treatment failure rates up to 7 days (primary outcome) and between 8-14 days (secondary outcome) using the intention to treat and per protocol analyses. Cost outcomes included direct medical, direct non-medical and indirect costs for a random 17% subsample using the micro-costing technique.1118 children were enrolled and randomized to home (n = 554) or hospital group (n = 564). Both groups had similar baseline characteristics. Overall treatment failure rate was 11.5% (per protocol analysis). The hospital group was significantly more likely to fail treatment than the home group in the intention to treat analysis. Predictors with increased risk of treatment failure at any time were age 3-11 months, receiving antibiotics within 48 h prior to enrolment and use of high polluting fuel. Death rates at 7 or 14 days did not differ significantly. (Difference -0.0%; 95% CI -0.5 to 0.5). The median total treatment cost was Rs. 399 for the home group versus Rs. 602 for the hospital group (p < 0.001), for the same effect of 5% failure rate at the end of 7 days of treatment in the random subsample.Home based oral amoxicillin treatment was equivalent to hospital treatment for first 48 h in selected children of chest indrawing pneumonia and was cheaper. Consistent with the recent WHO simplified guidelines, management with home based oral amoxicillin for select children with only fast breathing and chest-indrawing can be a cost effective intervention.ClinicalTrials.gov NCT01386840, registered 25th June 2011 and the Indian Council of Medical Research REFCTRI/2010/000629.

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Randomized Trial of Amoxicillin for Pneumonia in Pakistan.

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