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Azithromycin and metronidazole versus metronidazole-based therapy for the induction of remission in mild to moderate paediatric Crohn’s disease : a randomised controlled trial
  1. Arie Levine1,2,
  2. Michal Kori3,
  3. Jarek Kierkus4,
  4. Rotem Sigall Boneh1,
  5. Malgorzata Sladek5,
  6. Johanna C Escher6,
  7. Eytan Wine7,
  8. Baruch Yerushalmi8,9,
  9. Jorge Amil Dias10,
  10. Ron Shaoul11,
  11. Gigi Veereman Wauters12,
  12. Mona Boaz13,14,
  13. Guila Abitbol15,
  14. Athos Bousvaros16,
  15. Dan Turner17
  1. 1 Pediatric Gastroenterology and Nutrition Unit, Wolfson Medical Center, Holon, Israel
  2. 2 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
  3. 3 Pediatric Day Care Unit, Kaplan Medical Center, Rehovot, Israel
  4. 4 Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
  5. 5 Department of Pediatrics, Gastroenterology and Nutrition, Jagiellonian University Medical College, Cracow, Poland
  6. 6 Department of Pediatric Gastroenterology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands
  7. 7 Division of Pediatric Gastroenterology, Department of Pediatrics, University of Alberta, Edmonton, Canada
  8. 8 Pediatric Gastroenterology Unit, Soroka University Medical Center, Beersheba, Israel
  9. 9 Faculty of Health Sciences, Ben-Gurion University of the Negev, Negev, Israel
  10. 10 Department of Pediatrics, S. Joao Hospital, Porto, Portugal
  11. 11 Pediatric Gastroenterology Unit, Ruth Children’s Hospital, Rambam Medical Center, Brussels, Belgium
  12. 12 Pediatric Gastroenterology Unit, University Hospital UZ Brussels, Brussels, Belgium
  13. 13 Department of Nutrition School of Health Sciences, Ariel University, Ariel, Israel
  14. 14 Epidemiology and Research Unit, E. Wolfson Medical Center, Holon, Israel
  15. 15 Pediatric Gastroenterology Lab, The Juliet Keidan Institute of Paediatric Gastroenterology, Hepatology, and Nutrition, Shaare Zedek Medical Center, Jerusalem, Israel
  16. 16 Division of Gastroenterology and Nutrition, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  17. 17 The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel
  1. Correspondence to Professor Arie Levine, Pediatric Gastroenterology and Nutrition Unit, Wolfson Medical Center, Holon 58100, Israel; alevine{at}


Objective Crohn’s disease (CD) pathogenesis associated with dysbiosis and presence of pathobionts in the lumen, intracellular compartments and epithelial biofilms. Azithromycin is active in all three compartments. Our goal was to evaluate if azithromycin-based therapy can improve response and induce remission compared with metronidazole alone in paediatric CD.

Design This blinded randomised controlled trial allocated children 5–18 years with 10<Pediatric Crohn’s Disease Activity Index (PCDAI)≤40 to azithromycin 7.5 mg/kg, 5 days/week for 4 weeks and 3 days/week for another 4 weeks with metronidazole 20 mg/kg/day (group 1) or metronidazole alone (group 2), daily for 8 weeks. Failures from group 2 were offered azithromycin as open label. The primary end point was response defined by a decrease in PCDAI>12.5 or remission using intention to treat analysis.

Results 73 patients (mean age 13.8±3.1 years) were enrolled, 35 to group 1 and 38 to group 2. Response and remission rates at week 8 were identical 23/35 (66%) in group 1 and 17/38 (45%) and 15/38 (39%) in group 2 (P=0.07 and P=0.025, respectively). The needed to treat for remission was 3.7. Faecal calprotectin declined significantly in group 1 (P=0.003) but not in group 2 (p=0.33), and was lower at week 8 (P=0.052). Additional therapy was required in 6/35(17%) from group 1 versus 16/38(42%) in group 2 (P=0.027) by week 8. Among 12 failures in group 2, open-label azithromycin led to remission in 10/12 (83%).

Conclusions The combination of azithromycin and metronidazole failed to improve response but was superior for induction of remission and reduction in calprotectin.

Trial registration number NCT01596894.

  • crohn’s disease
  • inflammatory bowel disease
  • paediatric
  • antibiotics
  • therapy
  • azithromycin
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  • Contributors AL: design of study, grant, patient enrolment and preparation of manuscript; DT: design of the study and patient enrolment. RSB: data collection and analysis and study management; AB: study organisation; MB:statistical analysis; GA: cal protection analysis; MC, JK, MS, JE, EW, BY, JAD,RS, GVW: patient recruitment.

  • Funding This study was supported by a grant from the Broad Medical Research Program of the Broad Foundation (BMRP IBD-337) to AL.

  • Competing interests None declared.

  • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

  • Ethics approval Ethical committees of all participating institutions.

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

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