Comparison of Oral Amoxicillin with Placebo for the Treatment of World Health Organization-Defined Nonsevere Pneumonia in Children Aged 2-59 Months: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial in Pakistan

Hazir, T.; Nisar, Y. B.; Abbasi, S.; Ashraf, Y. P.; Khurshid, J.; Tariq, P.; Asghar, R.; Murtaza, A.; Masood, T.; Maqbool, S.

doi:10.1093/cid/ciq142

Cited by 101Pneumonia and Respiratory InfectionsAntibiotic Use and ResistancePleural and Pulmonary Diseases

Comparison of Oral Amoxicillin with Placebo for the Treatment of World Health Organization-Defined Nonsevere Pneumonia in Children Aged 2-59 Months: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial in Pakistan

Hazir, T., Nisar, Y. B., Abbasi, S., Ashraf, Y. P., Khurshid, J., Tariq, P., Asghar, R., Murtaza, A. +2 more·2011·Clinical Infectious Diseases

DOI 10.1093/cid/ciq142

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Abstract

Background world Health Organization (WHO) acute respiratory illness case management guidelines classify children with fast breathing as having pneumonia and recommend treatment with an antibiotic. There is concern that many of these children may not have pneumonia and are receiving antibiotics unnecessarily. This could increase antibiotic resistance in the community. The aim was to compare the clinical outcome at 72 h in children with WHO-defined nonsevere pneumonia when treated with amoxicillin, compared with placebo. Methods we performed a double-blind, randomized, equivalence trial in 4 tertiary hospitals in Pakistan. Nine hundred children aged 2-59 months with WHO defined nonsevere pneumonia were randomized to receive either 3 days of oral amoxicillin (45mg/kg/day) or placebo; 873 children completed the study. All children were followed up on days 3, 5, and 14. The primary outcome was therapy failure defined a priori at 72 h. Results in per-protocol analysis at day 3, 31 (7.2%) of the 431 children in the amoxicillin arm and 37 (8.3%) of the 442 in placebo group had therapy failure. This difference was not statistically significant (odds ratio [OR], .85; 95%CI, .50-1.43; P = .60). The multivariate analysis identified history of difficult breathing (OR, 2.86; 95% CI, 1.29-7.23; P = .027) and temperature >37.5°C 100°F at presentation (OR, 1.99; 95% CI, 1.37-2.90; P = .0001) as risk factors for treatment failure by day 5. Conclusion clinical outcome in children aged 2-59 mon…

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Self-citation
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Background
Antibiotic therapy versus no antibiotic therapy for children aged two to 59 months with WHO-defined non-severe pneumonia and wheeze.
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Background
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Background
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Background
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Antibiotic therapy versus no antibiotic therapy for children aged 2 to 59 months with WHO-defined non-severe pneumonia and wheeze.
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“Dealing with missing data We contacted the authors of two included trials (Awasthi 2008a; Hazir 2011), and the author of the trial awaiting classification (Jehan 2020) to obtain missing numerical outcome data.”
BackgroundMethodInfluential
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Tikmani, S. S., Muhammad, A. A., Shafiq, Y., Shah, S., Kumar, N., Ahmed, I., Azam, I., Pasha, O., & Zaidi, A. K. M. (2017) · Clinical Infectious Diseases · doi:10.1093/cid/ciw690 · Cited by 15
“Ambulatory Treatment of Fast Breathing in Young Infants • CID 2017:64 (15 January) • 185 for children presenting with only fast breathing pneumonia in older children aged 2–59 months [14].”
Causes of Fever in Outpatient Tanzanian Children
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A double blind community-based randomized trial of amoxicillin versus placebo for fast breathing pneumonia in children aged 2-59 months in Karachi, Pakistan (RETAPP)
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BackgroundInfluential
Rising Pediatric Morbidity and Mortality in the Developing World
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Esposito, S., Bianchini, S., Argentiero, A., Neglia, C., & Principi, N. (2020) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2020.1781091 · Cited by 13
Antimicrobial Therapy in Community-Acquired Pneumonia in Children
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Methods for conducting a double-blind randomized controlled clinical trial of three days versus five days of amoxicillin dispersible tablets for chest indrawing childhood pneumonia among children two to 59 months of age in Lilongwe, Malawi: a study protocol
Ginsburg, A., May, S., Nkwopara, E., Ambler, G., McCollum, E., Mvalo, T., Phiri, A., Lufesi, N., & Sadruddin, S. (2018) · BMC Infectious Diseases · doi:10.1186/s12879-018-3379-z · Cited by 10
C reactive protein-guided prescription of antibiotics for children under 12 years with respiratory symptoms in Kyrgyzstan: protocol for a randomised controlled clinical trial with 14 days follow-up
Isaeva, E., Bloch, J., Poulsen, A., Kurtzhals, J., Reventlow, S., Siersma, V., Akylbekov, A., Sooronbaev, T., Aabenhus, R. M., & Kjærgaard, J. (2023) · BMJ Open · doi:10.1136/bmjopen-2022-066806 · Cited by 9
Antibiotic Use and Outcomes Among Children Hospitalized with Suspected Pneumonia
Cotter, J., Florin, T., Moss, A., Suresh, K., Navanandan, N., Ramgopal, S., Shah, S. S., Ruddy, R., Kempe, A., & Ambroggio, L. (2022) · Journal of Hospital Medicine · doi:10.1002/jhm.13002 · Cited by 9
Serum Procalcitonin Levels in Children with Clinical Syndromes for Targeting Antibiotic Use at an Emergency Department of a Kenyan Hospital
Akech, S., Kinuthia, D. M. W., & Macharia, W. (2019) · Journal of Tropical Pediatrics · doi:10.1093/tropej/fmz027 · Cited by 7 · see citing works
“non-severe pneumonia cases may be safe [7].”
Establishment of childhood pneumonia cause in the era of pneumococcal conjugate vaccines.
Rhedin, S. (2016) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(16)30067-4 · Cited by 9 · see citing works
Systematic evaluation of non-inferiority and equivalence randomized trials of anti-infective drugs
Li, Y., He, Y., Sheng, Y., Wang, K., Wang, J., Huang, J., Yang, J., & Zheng, Q. (2013) · Expert Review of Anti-infective Therapy · doi:10.1586/14787210.2013.851600 · Cited by 10 · see citing works
Prevalence and factors related to antibiotic prescription in Benin: a school-based study.
Koura, K., Garcia, A., Todoégnon, B., Deloron, P., Cot, M., & Faucher, J. (2013) · Acta Tropica · doi:10.1016/j.actatropica.2013.04.004 · Cited by 9
Should fast breathing pneumonia cases be treated with antibiotics? The scientific rationale for revisiting management in Low and Middle income countries
Jehan, F., Nisar, M. I., Kerai, S. M., Brown, N., Ambler, G., & Zaidi, A. K. M. (2019) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2019.05.035 · Cited by 8 · see citing works
“This has generated substantial debate among experts (Hazir et al., 2011; Awasthi et al., 2008).”
Background
Antibiotics for Paediatric Community-Acquired Pneumonia: What is the Optimal Course Duration?
Kok, H., Chang, A. B., Fong, S., McCallum, G., Yerkovich, S., & Grimwood, K. (2025) · Pediatric Drugs · doi:10.1007/s40272-024-00680-4 · Cited by 7
“A Pakistan-based RCT randomised 873 children aged 2−59 months with WHO-defined non-severe CAP to receive either 3 days of low-dose oral amoxicillin (45 mg/kg/day) or placebo [50].”
Exploring how non-inferiority and equivalence are assessed in paediatrics: a systematic review
Aupiais, C., Zohar, S., Taverny, G., Roux, É. L., Boulkedid, R., & Alberti, C. (2018) · Archives of Disease in Childhood · doi:10.1136/archdischild-2018-314874 · Cited by 9 · see citing works
Evidence for short duration of antibiotic treatment for non-severe community acquired pneumonia (CAP) in children — are we there yet? A systematic review of randomised controlled trials
Ben-Shimol, S., Levy-Litan, V., Falup-Pecurariu, O., & Greenberg, D. (2014) · Pneumonia · doi:10.15172/pneu.2014.4/432 · Cited by 7
“All 7 trials from developing countries [7, 8, 9, 10, 23, 24, 25] evaluated children at the age of 2-59 months and used the WHO clinical definition for non-severe CAP, including tachypnoea (high respiratory rate adjusted for age) and excluding severe (defined as lower chest in-drawing) and very severe diseases.”
BackgroundMethodInfluential
The Effectiveness of Acceptance and Commitment Group Therapy on the Self-esteem of Girls With Visual Impairment.
Department of Psychology and Exceptional Child Education, F. O. B. S., Mirmohammadi, F., Pourmohamadreza-Tajrishi, M., Pediatric Neurorehabilitation Research Center, D. O. P. A. E. O. E. C., Dolatshahi, B., Department of Clinical Psychology, F. O. B. S., Bakhshi, E., & Department of Biostatistics and Epidemiology, F. O. R. S. (2022) · Journal of Rehabilitation · doi:10.32598/rj.22.4.3261.1 · Cited by 6 · see citing works
An Update on WHO Recommendations on Childhood Pneumonia and Diarrhea (2024)
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Variation in Antibiotic Treatment Failure Outcome Definitions in Randomised Trials and Observational Studies of Antibiotic Prescribing Strategies: A Systematic Review and Narrative Synthesis
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“For example, two double-blind randomized placebo-controlled trials comparing three days of oral amoxicillin with placebo for children aged 2 to 59 months with non-severe pneumonia in Pakistan used different criteria to ascertain their primary outcome of antibiotic treatment failure [3,4].”
BackgroundMethod
Performance of an artificial intelligence algorithm for interpreting lung sounds from children hospitalised with pneumonia in Malawi
Hoekstra, N. E., Chagomerana, M., Smith, Z. M., Kala, A., McLane, I., Verwey, C., Olson, D., Buck, W., Mulindwa, J., Gaudio, A., et al. (2025) · Journal of Global Health · doi:10.7189/jogh.15.04264 · Cited by 5
Can child pneumonia in low-resource settings be treated without antibiotics? A systematic review & meta-analysis
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Development of a prognostic risk score to aid antibiotic decision-making for children aged 2-59 months with World Health Organization fast breathing pneumonia in Malawi: An Innovative Treatments in Pneumonia (ITIP) secondary analysis
McCollum, E., Brown, S. P., Nkwopara, E., Mvalo, T., May, S., & Ginsburg, A. (2019) · PLoS ONE · doi:10.1371/journal.pone.0214583 · Cited by 5 · see citing works
Using a period incidence survey to compare antibiotic use in children between a university hospital and a district hospital in a country with low antimicrobial resistance: a prospective observational study
Thaulow, C., Blix, H., Eriksen, B. H., Ask, I. S., Myklebust, T., & Berild, D. (2019) · BMJ Open · doi:10.1136/bmjopen-2018-027836 · Cited by 5 · see citing works
“Treatments, n (% of all treatments) 110 (32) 32 (23) 78 (38) <0.”
Non-treatment of children with community health worker-diagnosed fast-breathing pneumonia in rural Malawi: exploratory subanalysis of a prospective cohort study
King, C., Colbourn, T., Mankhambo, L., Beard, J., Burgess, D. C. H., Costello, A., Izadnegahdar, R., Lufesi, N., Mwansambo, C., Nambiar, B., et al. (2016) · BMJ Open · doi:10.1136/bmjopen-2016-011636 · Cited by 5
“Recent evidence from South Asia suggests that treating fast-breathing pneumonia with a placebo has equivalent recovery rates to the recommended course of oral antibiotics, reporting a treatment failure (or non-recovery) rate of 8% with or without antibiotics.(14) Research is needed into the non-treatment of”
Background
Antibiotics usage in infants during the first 18 months of life in Benin: a population-based cohort study
Brembilla, A., Mauny, F., Garcia, A., Koura, K., Deloron, P., & Faucher, J. (2016) · European Journal of Clinical Microbiology and Infectious Diseases · doi:10.1007/s10096-016-2587-y · Cited by 5 · see citing works
An update on antimicrobial options for childhood community-acquired pneumonia: a critical appraisal of available evidence
Nascimento-Carvalho, C. M., Andrade, D. C., & Vilas‐Boas, A. (2015) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2016.1109633 · Cited by 5 · see citing works
“Two trials compared amoxicillin with placebo and found discordant results.[18,21] It is important to observe that both studies included patients diagnosed with CAP solely on clinical grounds (Table 4).”
Result
The remaining unsolved problems for rational antibiotic therapy use in pediatric community-acquired pneumonia
Esposito, S., Argentiero, A., Rebecchi, F., Fainardi, V., Pisi, G., & Principi, N. (2022) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2022.2028773 · Cited by 4
HOspitalised Pneumonia Extended (HOPE) Study to reduce the long-term effects of childhood pneumonia: protocol for a multicentre, double-blind, parallel, superiority randomised controlled trial
Chang, A., Fong, S., Yeo, T., Ware, R., McCallum, G., Nathan, A., Ooi, M., de Bruyne, J. D., Byrnes, C., Lee, B., et al. (2019) · BMJ Open · doi:10.1136/bmjopen-2018-026411 · Cited by 4 · see citing works
“However, the external validity of these studies is limited and biased towards equivalence where neither treatment will be effective as most subjects diagnosed with clinical pneumonia likely had bronchiolitis or viral ALRIs because: (1) over half of the subjects were infants, (2) 20% to 80% had wheeze, (3) chest X-rays…”
Background
Antibiotic Treatment of Nonsevere Pneumonia With Fast Breathing-Is the Pendulum Swinging?
Driscoll, A., & Kotloff, K. (2019) · JAMA pediatrics · doi:10.1001/jamapediatrics.2018.3846 · Cited by 4
Management of fever among under-fives and utility of malaria rapid diagnostic test under reduced malaria burden in Rufiji District, Southeastern Tanzania
Tarimo, D. S., Jani, B., & Killewo, J. (2015) · Asian Pacific Journal of Tropical Disease · doi:10.1016/s2222-1808(15)60946-x · Cited by 4 · see citing works
“In the absence of severe clinical signs which is defined by the WHO[40], the children could reasonably be sent home without antibiotic treatment[41,42].”
Background
Narrow-spectrum antibiotics are as effective as broad-spectrum antibiotics in the treatment of community-acquired pneumonia
Selby, A., Pettit, K., & Brown, N. (2015) · Archives of Disease in Childhood: Education & Practice Edition · doi:10.1136/archdischild-2015-308815 · Cited by 4
Chest radiography in children aged 2–59 months enrolled in the Innovative Treatments in Pneumonia (ITIP) project in Lilongwe Malawi: a secondary analysis
Mvalo, T., McCollum, E., Fitzgerald, E., Kamthunzi, P., Schmicker, R., May, S., Phiri, M., Chirombo, C., Phiri, A., & Ginsburg, A. (2022) · BMC Pediatrics · doi:10.1186/s12887-021-03091-3 · Cited by 3
Prospects for Molecular Point-of-Care Diagnosis of Lower Respiratory Infections at the Hospital‘s Doorstep
Cohen-Bacrie, S., & Halfon, P. (2012) · Future Virology · doi:10.2217/fvl.12.124 · Cited by 3 · see citing works
Circulating markers of neutrophil activation and lung injury in pediatric pneumonia in low-resource settings
Konrad, E. R., Soo, J., Conroy, A. L., Namasopo, S., Opoka, R. O., & Hawkes, M. (2022) · Pathogens and Global Health · doi:10.1080/20477724.2022.2160885 · Cited by 3 · see citing works
“…trial in Pakistan found that outcomes were no different in children with WHO-defined non-severe pneumonia who received antibiotics compared to placebo [11], suggesting that the currently used clinical criteria are not a good indicator of which patients are most likely to benefit from antibiotics.”
Result
Markers of pediatric respiratory distress predictive of poor outcome in low- and middle-income countries: a systematic review
Hedstrom, A. B., Arnim, A. O. V. S. A.-V., Grassia, K. L., & Nielsen, K. R. (2020) · Journal of Global Health Reports · doi:10.29392/001c.14136 · Cited by 2 · see citing works
The Combination of Salbutamol Nebulizer and Oral Procaterol to the Indonesian Children with Pneumonia
Darmawan, E., & Kusumawati, L. (2020) · doi:10.22034/ijps.2019.104391.1533 · Cited by 2
“65 [14] Hazir T, Nisar Y, Abbasi S, Ashraf YP, Khurshid J, Tariq P, Maqbool S.”
Background
Community-acquired pneumonia in children — a changing spectrum of disease
le Roux, D. M., & Zar, H. J. (2017) · Pediatric Radiology · doi:10.1007/s00247-017-3827-8 · Cited by 170 · see citing works
Comment on: Comparison of oral amoxicillin given thrice or twice daily to children between 2 and 59 months old with non-severe pneumonia: a randomized controlled trial.
Osowicki, J., Carr, J., Bryant, P., & Gwee, A. (2015) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dku398 · Cited by 2
Pulmonary infections and resistance to antibiotics: recent information
Torres, A., Niederman, M., Artigas, A., & Carlet, J. (2012) · Expert Review of Anti-Infective Therapy · doi:10.1586/eri.12.84 · Cited by 2
Non-inferiority designs comparing placebo to a proven therapy for childhood pneumonia in low-resource settings
May, S., Brown, S. P., Schmicker, R., Emerson, S., Nkwopara, E., & Ginsburg, A. (2019) · Clinical Trials · doi:10.1177/1740774519888460 · Cited by 1
The perks of prognostic biomarkers: A paradigm switch in the triage of sick febrile patients.
Bassat, Q. (2019) · Clinical Infectious Diseases · doi:10.1093/cid/ciz420 · Cited by 1
Outcome of children with ESBL-E. coli acute pyelonephritis treated with cephalosporins.
Vakkilainen, S., Pätäri-Sampo, A., & Saxén, H. (2018) · Journal of Infection · doi:10.1016/j.jinf.2018.03.009 · Cited by 1
The pattern of antibiotic administration for toddlers and infants with acute respiratory infections (Mashhad- Iran)
Sasan, M., Vakili, V., Nejat, S., & Khajedaluee, M. (2014) · doi:10.22038/ijn.2014.4145 · Cited by 1
“clinical outcome in these children is not different when treated with antibiotic (amoxicillin 45mg/kg/day) or placebo (12).”
Background
Oral amoxicillin for management of fast breathing or chest indrawing pneumonia without danger signs in children aged 2–59 months: a systematic review and meta-analysis
Pathak, B. G., Nisar, Y. B., Natchu, U. C. M., Manapurath, R., Thakur, A., Vats, P., Chandola, T. R., & Sinha, B. (2026) · Journal of Global Health · doi:10.7189/jogh.16.04209
“Awasthi et al . and Hazir et al . had given amoxicillin dosages ranging from 15 mg/kg/d to 54 mg/kg/d every eight hours for three days [ 27 , 28 ], and the trials after that, i.e .”
InfluentialSelf-citation
Effectiveness of amoxicillin and amoxicillin-clavulanate for the treatment of community-acquired pneumonia in adults and children: a systematic review and meta-analysis
Potter-Schwartz, L., Swe, M. M., Sharland, M., Bielicki, J., Cooper, B. S., & Lim, C. (2026) · BMJ Open · doi:10.1136/bmjopen-2025-112219
Effectiveness of amoxicillin and amoxicillin-clavulanate for the treatment of community-acquired pneumonia in adults and children: systematic review and meta-analysis
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“All of the placebo studies had a duration of oral amoxicillin treatment for three days with dosage between 31 mg/kg/day and 1000mg/day [18,22,25,27].”
Diagnosis of pneumonia in paediatric age group by comparing two modalities chest x-ray versus ultrasonography at tertiary care hospital
Chawda, V., Tollawala, P., Khasavat, S., Suthar, K., Shah, N. R., & Pandya, R. (2024) · IP International Journal of Medical Paediatrics and Oncology · doi:10.18231/j.ijmpo.2024.005
Clinical Profile, Radiological Resolution and Risk Factors Associated with Community Acquired Pneumonia: Correspondence
Chaudhary, N., & Shrestha, S. (2019) · Journal of Nepal Paediatric Society · doi:10.3126/jnps.v38i2.21755

Authors: Hazir, T., Nisar, Y. B., Abbasi, S., Ashraf, Y. P., Khurshid, J., Tariq, P., Asghar, R., Murtaza, A., Masood, T., & Maqbool, S.
Affiliations: Pakistan Institute of Medical Sciences (PK)
Benazir Bhutto Hospital (PK)
ORCID: Nisar, Y. B.
Murtaza, A.
Venue: Clinical Infectious Diseases
Publisher: Oxford University Press (OUP)
Published: 2010-12-28
Volume: 52
Issue: 3
Pages: 293-300
ISSN: 1058-4838 (ISSN-L)
1537-6591
DOI: 10.1093/cid/ciq142
OpenAlex: W2112972128
Cited by: 101
References: 0
Citations by year: 2026: 2 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 7 · 2021: 2 · 2020: 6 · 2019: 9 · 2018: 8 · 2017: 8 · 2016: 10 · 2015: 15 · 2014: 11 · 2013: 6 · 2012: 7
FWCI: 3.72
Type: journal article
Language: en
Open access: closed
Locations: Clinical Infectious Diseases (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Epidemiology › Pneumonia and Respiratory Infections
Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Antibiotic Use and Resistance
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pleural and Pulmonary Diseases
Keywords: pediatric pneumonia, oral amoxicillin, antibiotic use, treatment failure, risk factors for treatment failure, antibiotic resistance, rational antibiotic use
MeSH terms: Amoxicillin, Anti-Bacterial Agents, Child, Preschool, Double-Blind Method, Female, Humans, Infant, Male, Pakistan, Placebos, Pneumonia, Severity of Illness Index, Treatment Outcome, Treatment Failure

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Comparison of Oral Amoxicillin with Placebo for the Treatment of World Health Organization-Defined Nonsevere Pneumonia in Children Aged 2-59 Months: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial in Pakistan

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