1 / 19

Azithromycin and Metronidazole for Induction of Remission in Pediatric Crohn’s Disease

Azithromycin and Metronidazole for Induction of Remission in Pediatric Crohn’s Disease. Arie Levine Pediatric Gastroenterology Unit Wolfson Medical Center. CD – A Disorder of Bacterial Clearance?. Oxidative Burst NCF4 NCF2. Treatment. Darfeuille Michaud. Defect in Apoptosis ?.

abram
Download Presentation

Azithromycin and Metronidazole for Induction of Remission in Pediatric Crohn’s Disease

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Azithromycin and Metronidazole for Induction of Remission in Pediatric Crohn’s Disease Arie Levine Pediatric Gastroenterology Unit Wolfson Medical Center

  2. CD – A Disorder of Bacterial Clearance? Oxidative Burst NCF4 NCF2 Treatment Darfeuille Michaud

  3. Defect in Apoptosis ? • Defective apoptosis T cells (Bax/ BCL2 ratios ) • Defective apoptosis in dendritic cells with NOD2 mutations • Increased Survivin –HSP90( anti-apoptotic molecule) in mucosal T cells in Crohn’s disease • Apoptosis pharmoacogenetic indices predict response to therapy • Response to thiopurines correlated with apoptosis effect Ina et al. J Immunol 1999;163:1081–90 Zelinkova et al Inflamm Bowel Dis 2008 ;14:186-94 De Souza et al Gastroenterology 2012 Hlavaty et al Inflamm Bowel Dis 2007;13:372-9 Cosuetal JCC 2012 epub

  4. Genetic Defect Bacterial Clearance Bacterial Infiltration of the Epithelium Stimulation of the adaptive immune system Tissue damage enabling bacterial penetration + + Environment Unknown factors Defect of apoptosis of Activated T Cells Pathogenesis- Bacterial penetration cycle Abnormal regulation of the immune system Intestinal tissue damage

  5. Genetic Defect Bacterial Clearance Bacterial Infiltration of the Intestines Stimulation of the adaptive immune system Tissue damage enabling bacterial penetration + + Environment Unknown factors Defect of apoptosis of Activated T Cells Pathogenesis- Bacterial stimulation Interventions Abnormal regulation of the immune system Intestinal tissue damage

  6. Requirements for Ab Success with Bacterial Penetration Model • Decrease bacterial triggering through all 3 compartments ( refuges) • Luminal • Biofilm • Intracellular • Simultaneous apoptosis

  7. Azithromycin - Unique • Decreases bacterial triggering through all 3 compartments ( refuges) • Luminal • Biofilm • Intracellular • Promotes prolonged apoptosis of activated T cells • AIEC sensitive • Reduces epithelial permeability by up regulating Claudins Occludins and JAM A

  8. Pilot Data

  9. Pilot Data (Retrospective analysis) • All patients treated identically, all patients seen at week 0,4 and 8 weeks with PCDAI and CRP • Weeks 0-4 • Azithromycin 7.5-10 mg /kg /day 5 days a week (max 500mg)+ Metronidazole 15-20 mg/kg daily (max 1000 mg) • Weeks 4-8 • Azithromycin 7.5-10 mg /kg /day 3 days a week + Metronidazole 15-20 mg/kg daily • Primary end point remission ( PCDAI <7.5 without height or <10), variables associated with remission • Secondary end point was normalization of CRP at week 8 ( <0.5 mg/dL)

  10. Baseline Data- mean age 13.1 ± 3.9 yrs

  11. Results • PCDAI dropped from 28 ± 10 to 8.6 ± 8.3 • (P<0.001) • CRP declined from 3.2 ± 2.7 to 1.2 ± 2.6 mg/dL • (P=0.04) • ESR from 44 ± 19 to 26 ± 12 (P<0.001) • CRP wk 8 normal 54% of patients with elevated CRP baseline

  12. Hypothesis • We hypothesize that a 2-month antibiotic course of Azithromycin combined with Metronidazole is effective for inducing remission in active pediatric Crohns disease (CD). We also hypothesize that Azithromycin combined with Metronidazole is superior to the Metronidazole alone , and that remission will be accompanied by normalization of CRP in a high proportion of patients with active CD.

  13. Prospective Multicenter RCT BMRP Funded Trial-Comparing two arms over 8 weeks of therapy Group 1: Oral Metronidazole 10mg/kgX2/day (maximum 1000mg day) for 8 weeks + Oral Azithromycin 7.5 mg/kg once daily (maximum 500mg) 5 consecutive days a week for the first 4 weeks and 3 consecutive days a week for the last 4 weeks Group 2: Oral Metronidazole 10mg/kg X2/day (maximum 1000mg) for 8 weeks. N=70

  14. Inclusion Criteria: 1. Children 5-17 years of age. 2. Diagnosis of active Crohn's Disease. 3. Patients with a PCDAI≥10 ≤40 (mild to moderate disease). 4. Have involvement of the colon and/or terminal ileum.. 5. The CRP ≥ 0.6 mg/dL. 6. Duration of disease since diagnosis < 3 years.

  15. Endpoints Primary : Response rate at 8 weeks defined as a drop in PCDAI of at least 12.5 points (or remission without steroids, intention to treat principle) Secondary: 1. CS free remission rate at 8 weeks. 2. Normalization of CRP ( CRP ≤0.5 mg/dL) 3. Mean Fecalcalprotectin at 8 weeks . 4. CS free remission at 12 weeks

  16. Questions in a translational level • Fecal samples for microbiome at baseline 8 and 12 weeks • Does Microbiome predict response ? • Is response dependent on changing microbiome? *Analysis of Microbiome from samples and Bioinformatics will be performed in Boston.

  17. Importance • Clinical • Offer alternative therapy that does not require immune suppression • Does treating upstream event ( trigger for inflammation) early in disease change natural history • Translational • Can we identify a component in the microbiome which is present before therapy, changes in responders?

  18. Update • Sites in Boston, Edmonton, 6 sites in Europe • and 4 in Israel

  19. Crohn’s Disease: A Disease of Pathogenic ,Non- Pathogenic Bacteria ?

More Related