Research

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 doi: https://doi.org/10.1136/bmj.39421.435949.BE (Published 10 January 2008) Cite this as: BMJ 2008;336:80
  1. Rai Asghar, professor1,
  2. Salem Banajeh, professor2,
  3. Josefina Egas, microbiologist3,
  4. Patricia Hibberd, professor4,
  5. Imran Iqbal, professor5,
  6. Mary Katep-Bwalya, consultant6,
  7. Zafarullah Kundi, FRCP professor1,
  8. Paul Law, associate professor7,
  9. William MacLeod, assistant professor8,
  10. Irene Maulen-Radovan, professor9,
  11. Greta Mino, professor10,
  12. Samir Saha, professor11,
  13. Fernando Sempertegui, director3,
  14. Jonathon Simon, director8,
  15. Mathuram Santosham, professor7,
  16. Sunit Singhi, professor12,
  17. Donald M Thea, professor8,
  18. Shamim Qazi, medical officer13
  19. for the SPEAR (Severe Pneumonia Evaluation Antimicrobial Research) Study Group
  1. 1Rawalpindi General Hospital, Rawalpindi, Pakistan
  2. 2Al-Sabeen Hospital, Sana’a, Yemen
  3. 3Corporacion Ecuatoriana de Biotecnologia, Quito, Ecuador
  4. 4Clinical Research Institute, New England Medical Center Tufts University, Boston, USA
  5. 5Nishter Hospital, Multan, Pakistan
  6. 6University Teaching Hospital, Lusaka, Zambia
  7. 7Department of International Health, Johns Hopkins Bloomberg University, Baltimore, USA
  8. 8Center for International Health and Development, Boston University School of Public Health, Boston, MA 02118, USA
  9. 9Instituto Nacional de Pediatria, Division de Investigacíon, Mexico City, Mexico
  10. 10Children’s Hospital, Guayaquil, Ecuador
  11. 11Dhaka Shishu Hospital, Dhaka, Bangladesh
  12. 12Post Graduate Institute of Medical Education and Research, Chandigarh, India
  13. 13Department of Child and Adolescent Health and Development, World Health Organization, Geneva, Switzerland
  1. Correspondence to: D M Thea dthea{at}bu.edu
  • Accepted 5 November 2007

Abstract

Objective To evaluate whether five 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.

Design Open label randomised controlled trial.

Setting Inpatient wards within tertiary care hospitals in Bangladesh, Ecuador, India, Mexico, Pakistan, Yemen, and Zambia.

Participants Children aged 2-59 months with WHO defined very severe pneumonia.

Intervention Chloramphenicol versus a combination of ampicillin plus gentamicin.

Main outcome measures Primary outcome measure was treatment failure at five days. Secondary outcomes were treatment failure defined similarly among all participants evaluated at 48 hours and at 10 and 21 days.

Results More children failed treatment with chloramphenicol at day 5 (16% v 11%; relative risk 1.43, 95% confidence interval 1.03 to 1.97) and also by days 10 and 21. Overall, 112 bacterial isolates were obtained from blood and lung aspirates in 110 children (11.5%), with the most common organisms being Staphylococcus aureus (n=47) and Streptococcus pneumoniae (n=22). In subgroup analysis, bacteraemia with any organism increased the risk of treatment failure at 21 days in the chloramphenicol group (2.09, 1.41 to 3.10) but not in the ampicillin plus gentamicin group (1.12, 0.59 to 2.13). Similarly, isolation of S pneumoniae increased the risk of treatment failure at day 21 (4.06, 2.73 to 6.03) and death (5.80, 2.62 to 12.85) in the chloramphenicol group but not in the ampicillin plus gentamicin group. No difference was found in treatment failure for children with S aureus bacteraemia in the two groups, but the power to detect a difference in this subgroup analysis was low. Independent predictors of treatment failure by multivariate analysis were hypoxaemia (oxygen saturation <90%), receiving chloramphenicol, being female, and poor immunisation status.

Conclusion Injectable ampicillin plus gentamicin is superior to injectable chloramphenicol for the treatment of community acquired very severe pneumonia in children aged 2-59 months in low resource settings.

Trial registration Current Controlled Trials ISRCTN39543942.

Footnotes

  • Contributors: RA, SB, GJB, OF, PH, II, CL, MK-B, WM, MS, S Singhi, DMT, and SQ conceived and designed the study and developed the protocol. DMT, SQ, and MS monitored the study. S Saha, Muhammad Ruhul Amin, Muhammad Hanif, PL, FS, JE, GM, S Singhi, Pallab Ray, Akashdeep, IM-R, Sandra Villagómez Martínez, II, Jameel ur Rehman Naeem, Ismaeel Shafeeu, ZK, RA, SB, Abdul Hakeem Bawazeer, Abdul Hakeem Al-Silwi, and MK-B implemented the study and collected data. SB, JE, PH, PL, WM, GM, S Saha, S Singhi, DMT, and SQ analysed the data and prepared the manuscript. PH and WM managed and coordinated the data and carried out the statistical analysis.

  • We thank the following from the participating sites: Ruth Flor, Patricia Parrales, Sebastian Prado, Norma Villamar, Nelson Nieto, and Brenda Mosquera (Ecuador); Lata Kumar and Shailesh Mehta (India); Patricia Arzate (Instituto Nacional De Pediatria, Mexico); Maximilliano Gonzalez and Lilliana Martinez (Juarez Hospital, Mexico); Fatum Maktari, Amin Mohi-El-din, and Basil Maktari (Yemen). Steering committee: S Saha (Bangladesh); FS (Ecuador); S Singhi (India); IM-R (Mexico); II (Pakistan); ZK (Pakistan); SB (Yemen); MK-B (Zambia); SQ (Switzerland); DMT, BM, and JS (Boston, United States); MS (Baltimore, United States); PH (Boston, United States). Data safety monitoring board: Ted Colton (Boston University School of Public Health); Elizabeth Barnett (Boston University Medical Center); Christopher Duggan (Boston Children’s Hospital and Harvard School of Public Health).

  • Funding: Department of Child and Adolescent Health and Development, WHO; Center of International Health and Development, Boston University; and Johns Hopkins Bloomberg School of Public Health, Baltimore (USAID grant No HRN-A-00-96-90010-00).

  • Competing interests: None declared.

  • Ethical approval: This study was approved by the institutional ethical review committees at all study institutions, plus Boston University School of Public Health, Johns Hopkins University Bloomberg School of Public Health, and WHO. A data safety monitoring board reviewed cumulative data once a year. O’Brien Fleming stopping rules were used twice to determine the safety and utility of continuing the study.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Accepted 5 November 2007
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