Azithromycin and metronidazole versus metronidazole-based therapy for the induction of remission in mild to moderate paediatric Crohn’s disease : a randomised controlled trial

Levine, Arie; Kori, Michal; Kierkus, J.; Boneh, Rotem Sigall; Sładek, Małgorzata; Escher, Johanna C.; Wine, Eytan; Yerushalmi, Baruch; Dias, Jorge Amil; Shaoul, Ron; Wauters, Gigi Veereman; Boaz, Mona; Abitbol, Guila; Bousvaros, Athos; Turner, Dan

doi:10.1136/gutjnl-2017-315199

Cited by 32 publications

(27 citation statements)

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“…Recent studies reported superior outcomes for MET plus AZ, as compared to MET alone. 13,14 AZ penetrates multiple intestinal compartments 15,16 and enables targeting of adherent and invasive E. coli (AIEC) strains and other bacteria that have been associated with CD at disease onset in children. 9,[17][18][19] Consistent with previous reports, we observed reduced abundances of ASV 4 (Escherichia/Shigella) in the MET+AZ group, but increased abundances in the MET group, which may reflect activity of azithromycin against this taxon in our cohort.…”

Section: Discussionmentioning

confidence: 99%

“…A complete description of the study design, laboratory and analysis methods, and primary outcomes was published previously. 13 Additional inclusion criteria, besides age and disease activity, included at least one elevated inflammatory marker above normal values (C-reactive protein, CRP; erythrocyte sedimentation rate, ESR; or calprotectin) and disease duration since diagnosis < 3 years. Exclusion criteria included presence of a stool pathogen (based on bacterial culture, parasite study, or Clostridium difficile toxin assay), involvement of the proximal ileum or jejunum (L4b as per Paris classification), unclassified IBD, fibrostenotic disease (defined as strictures with prestenotic dilatation), internal or perianal fistulizing disease, prominent extraintestinal manifestations (e.g., arthritis, uveitis and sclerosing cholangitis), known allergy to either metronidazole or azithromycin, prolonged QTc at baseline, or steroid use during the 7 days prior to enrollment.…”

Section: Methodsmentioning

confidence: 99%

“…12 Metronidazole (MET) is one of the most commonly prescribed antibiotics in the treatment of pediatric CD, but recent studies reported superior outcomes for the combination of MET plus Azithromycin (AZ), as compared to MET alone. 13,14 AZ is especially promising in the treatment of IBD, as it penetrates multiple intestinal compartments, including the intestinal lumen, biofilms in the mucus layer, as well as macrophages. 15,16 The use of AZ might improve treatment of various pathogens implicated in CD, such as adherent and invasive E. coli (AIEC) strains.…”

Section: Introductionmentioning

confidence: 99%

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Treatment-Specific Composition of Gut Microbiota Is Associated with Disease Remission in a Pediatric Crohn’s Disease Cohort

Sprockett

Fischer

Boneh

et al. 2018

Preprint

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We investigated the impact of metronidazole and metronidazole plus azithromycin on the gut microbiota in pediatric Crohn's disease. Disease remission was associated with a treatment-specific microbiota configuration, and could be predicted based on pre-antibiotic microbiota profiles.3 Abstract Background: The beneficial effects of antibiotics in Crohn's disease (CD) depend in part on the gut microbiota but are inadequately understood. We investigated the impact of metronidazole (MET) and metronidazole plus azithromycin (MET+AZ) on the microbiota in pediatric CD, and the use of microbiota features as classifiers or predictors of disease remission.Methods: 16S rRNA-based microbiota profiling was performed on stool samples from 67 patients in a multinational, randomized, controlled, longitudinal, 12-week trial of MET vs.MET+AZ in children with mild to moderate CD. Profiles were analyzed together with disease activity, and then used to construct Random Forest models to classify remission or predict treatment response.Results: Both MET and MET+AZ significantly decreased diversity of the microbiota and caused large treatment-specific shifts in microbiota structure at week 4. Disease remission was associated with a treatment-specific microbiota configuration. Random Forest models constructed from microbiota profiles pre-and during antibiotic treatment with metronidazole accurately classified disease remission in this treatment group (AUC of 0.879, 95% CI 0.683, 0.9877; sensitivity 0.7778; specificity 1.000, P < 0.001). A Random Forest model trained on preantibiotic microbiota profiles predicted disease remission at week 4 with modest accuracy (AUC of 0.8, P = 0.24). Conclusions:MET and MET+AZ antibiotic regimens in pediatric CD lead to distinct gut microbiota structures at remission. It may be possible to classify and predict remission based in part on microbiota profiles, but larger cohorts will be needed to realize this goal.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Treatment-Specific Composition of Gut Microbiota Is Associated with Disease Remission in a Pediatric Crohn’s Disease Cohort

Sprockett

Fischer

Boneh

et al. 2018

Preprint

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“…Cardiac toxicity was only studied or reported in eight studies (six prospective, one retrospective, and one case report). Among prospective studies, five RCTs and one prospective cohort study reported 79 cardiac adverse events (Table 4) [35][36][37][38][39][40]. One prospective study where children received weekly azithromycin for 6 months reported statistically significant QT prolongation [35].…”

Section: Cardiac Toxicitymentioning

confidence: 99%

Safety of azithromycin in pediatrics: a systematic review and meta-analysis

Zeng

Choonara

et al. 2020

Eur J Clin Pharmacol

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Purpose To evaluate the toxicity of azithromycin in neonates, infants, and children. Methods A systematic review was performed for relevant studies using Medline (Ovid), PubMed, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, and International Pharmaceutical Abstracts. We calculated the pooled incidence of adverse drug reactions (ADRs) associated with azithromycin based on prospective studies (RCTs and prospective cohort studies) and analyzed the risk difference (RD) of ADRs between azithromycin and placebo or other antibiotics using meta-analysis of RCTs. Results We included 133 studies with 4243 ADRs reported in 197,675 neonates, infants, and children who received azithromycin. The safety of azithromycin as MDA in pediatrics was poorly monitored. The main ADRs were diarrhea and vomiting. In prospective non-MDA studies, the most common toxicity was gastrointestinal ADRs (938/1967; 47.7%). The most serious toxicities were cardiac (prolonged QT or irregular heart beat) and idiopathic hypertrophic pyloric stenosis (IHPS). Compared with placebo, azithromycin did not show increased risk ADRs based on RCTs (risk difference − 0.17 to 0.07). The incidence of QT prolonged was higher in the medium-dosage group (10-30 mg/kg/day) than that of low-dosage group (≤ 10 mg/kg/day) (82.0% vs 1.2%). Conclusion The safety of azithromycin as MDA needs further evaluation. The most common ADRs are diarrhea and vomiting. The risk of the most serious uncommon ADRs (cardiac-prolonged QT and IHPS) is unknown.

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“…Metronidazol kezelés, melyet az elmúlt 10-15 évben alkalmaztak, hatékony lehet a vastagbelet, ill. végbélnyílás körüli területet érintő gyulladás esetén, valamint csökkenti annak a valószínűségét, hogy a betegség újból kialakuljon a műtéti eltávolítás után. Az azitromicin és metronidazol kombinált terápiában, a CRP és a calprotectin szintjét szignifikánsan csökkentette, az enyhe és közepes CD betegségben, gyermekeknél, azonban idősebb betegeknél mellékhatásként QT szakasz megnyúlást okozhat [109] . Az utóbbi időben a ciprofloxantin eredményességét is igazolták [110] .…”

Section: Antibiotikumok Probiotikumokunclassified

Terápiás lehetőségek kísérletes vastagbélgyulladásos patkánymodellben

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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

Abstract: NCT01596894.

Cited by 32 publications

References 50 publications

Treatment-Specific Composition of Gut Microbiota Is Associated with Disease Remission in a Pediatric Crohn’s Disease Cohort

Treatment-Specific Composition of Gut Microbiota Is Associated with Disease Remission in a Pediatric Crohn’s Disease Cohort

Safety of azithromycin in pediatrics: a systematic review and meta-analysis

Terápiás lehetőségek kísérletes vastagbélgyulladásos patkánymodellben

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