zithromax and Crohn-Disease

Early relapse in Crohn's disease (CD) is associated with a more severe disease course. The microbiome plays a crucial role, yet strategies targeting the microbiome are underrepresented in current guidelines. We hypothesise that early manipulation of the microbiome will improve clinical response to standard-of-care (SOC) induction therapy in patients with a relapse-associated microbiome profile. We describe the protocol of a pilot study assessing feasibility of treatment allocation based on baseline faecal microbiome profiles.. This is a 52-week, multicentre, randomised, controlled, open-label, add-on pilot study to test the feasibility of a larger multicontinent trial evaluating the efficacy of adjuvant antibiotic therapy in 20 paediatric patients with mild-to-moderate-CD (10

Topics: Anti-Bacterial Agents; Azithromycin; Bayes Theorem; Child; Crohn Disease; Humans; Induction Chemotherapy; Metagenome; Metronidazole; Microbiota; Multicenter Studies as Topic; Pilot Projects; Randomized Controlled Trials as Topic; Recurrence; Remission Induction; RNA, Ribosomal, 16S

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.. This blinded randomised controlled trial allocated children 5-18 years with 1012.5 or remission using intention to treat analysis.. 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%).. The combination of azithromycin and metronidazole failed to improve response but was superior for induction of remission and reduction in calprotectin.. NCT01596894.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Crohn Disease; Drug Therapy, Combination; Female; Gastrointestinal Microbiome; Humans; Induction Chemotherapy; Male; Metronidazole; Treatment Outcome

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.. 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.. 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 before and during antibiotic treatment with metronidazole accurately classified disease remission in this treatment group (area under the curve [AUC], 0.879; 95% confidence interval, 0.683-0.9877; sensitivity, 0.7778; specificity, 1.000; P < 0.001). A random forest model trained on pre-antibiotic microbiota profiles predicted disease remission at week 4 with modest accuracy (AUC, 0.8; P = 0.24).. 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.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Crohn Disease; Drug Therapy, Combination; Female; Gastrointestinal Microbiome; Humans; Male; Metronidazole; Remission Induction; RNA, Ribosomal, 16S; Treatment Outcome

Topics: Acne Vulgaris; Acute Generalized Exanthematous Pustulosis; Adult; Azathioprine; Azithromycin; Clobetasol; Crohn Disease; Drug Substitution; Female; Gastrointestinal Agents; Glucocorticoids; Humans; Infliximab; Remission Induction; Skin; Treatment Outcome

Crohn's disease (CD) is characterized by an aberrant response to the gut microbiota. We aimed to assess whether azithromycin based therapy is effective in inducing remission in CD, due to its effect in inducing apoptosis and efficacy against biofilms and intracellular bacteria.. Retrospective analysis of patients treated with an 8 week course of combined azithromycin and metronidazole. Patients were included if they had active CD defined as pediatric CD activity index (PCDAI) ≥ 10, and were not receiving any other medication for inducing remission in active disease. PCDAI score and CRP were recorded at baseline and 8 weeks thereafter.. Thirty two patients (mean age 13.1 ± 3.9, mean duration of disease 0.65 years) were included, of whom 21 (66%) entered clinical remission (PCDAI<10) after 8 weeks of treatment. The mean age at treatment and duration of disease did not differ between patients entering remission and those unresponsive to therapy. CRP, normalized in 54% of patients with elevated CRP at baseline. Factors associated with lack of response were a more severe disease (reflected by higher PCDAI and CRP values at baseline), presence of arthritis and extensive disease (ileocolonic, or prominent upper intestinal disease).. An 8 week course of azithromycin and metronidazole therapy may be effective in inducing clinical remission in mild-moderate luminal CD in children and young adults.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Anti-Infective Agents; Azithromycin; Blood Sedimentation; C-Reactive Protein; Child; Crohn Disease; Drug Therapy, Combination; Female; Hemoglobins; Humans; Male; Metronidazole; Remission Induction; Retrospective Studies; Serum Albumin; Severity of Illness Index; Treatment Outcome; Young Adult

Topics: Antibodies, Monoclonal; Atovaquone; Azithromycin; Babesiosis; Crohn Disease; Female; Gastrointestinal Agents; Humans; Infliximab; Middle Aged; Treatment Outcome

There is increasing evidence that Escherichia coli organisms are important in Crohn's disease (CD) pathogenesis. In CD tissue they are found within macrophages, and the adherent-invasive CD ileal E. coli isolate LF82 can replicate inside macrophage phagolysosomes. This study investigates replication and antibiotic susceptibility of CD colonic E. coli isolates inside macrophages. Replication of CD colonic E. coli within J774-A1 murine macrophages and human monocyte-derived macrophages (HMDM) was assessed by culture and lysis after gentamicin killing of noninternalized bacteria and verified by electron microscopy (EM). All seven CD colonic isolates tested replicated within J774-A1 macrophages by 3 h (6.36-fold +/- 0.7-fold increase; n = 7 isolates) to a similar extent to CD ileal E. coli LF82 (6.8-fold +/- 0.8-fold) but significantly more than control patient isolates (5.2-fold +/- 0.25-fold; n = 6; P = 0.006) and E. coli K-12 (1.0-fold +/- 0.1-fold; P < 0.0001). Replication of CD E. coli HM605 within HMDM (3.9-fold +/- 0.7-fold) exceeded that for K-12 (1.4-fold +/- 0.2-fold; P = 0.03). EM showed replicating E. coli within macrophage vacuoles. Killing of HM605 within J774-A1 macrophages following a 3-h incubation with antibiotics at published peak serum concentrations (C(max)) was as follows: for ciprofloxacin, 99.5% +/- 0.2%; rifampin, 85.1% +/- 6.6%; tetracycline, 62.8% +/- 6.1%; clarithromycin, 62.1% +/- 5.6% (all P < 0.0001); sulfamethoxazole, 61.3% +/- 7.0% (P = 0.0007); trimethoprim, 56.3% +/- 3.4% (P < 0.0001); and azithromycin, 41.0% +/- 10.5% (P = 0.03). Ampicillin was not effective against intracellular E. coli. Triple antibiotic combinations were assessed at 10% C(max), with ciprofloxacin, tetracycline, and trimethoprim causing 97% +/- 0.0% killing versus 86% +/- 2.0% for ciprofloxacin alone. Colonic mucosa-associated E. coli, particularly CD isolates, replicate within macrophages. Clinical trials are indicated to assess the efficacy of a combination antibiotic therapy targeting intramacrophage E. coli.

Topics: Animals; Anti-Bacterial Agents; Cell Line; Cells, Cultured; Colon; Crohn Disease; Culture Media; Escherichia coli; Humans; Macrophages; Mice; Microbial Sensitivity Tests; Monocytes; Mucous Membrane

The in vitro susceptibility of human- and bovine-origin Mycobacterium paratuberculosis to the thioupurine drugs 6-mercaptopurine (6-MP) and azathioprine (AZA) was established using conventional plate counting methods and the MGIT 960 ParaTB culture system. Both 6-MP and AZA had antibacterial activity against M. paratuberculosis; isolates from Crohn's disease patients tended to be more susceptible than were bovine-origin isolates. Isolates of Mycobacterium avium, used as controls, were generally resistant to both AZA and 6-MP, even at high concentrations (> or =64.0 microg/ml). Among rapidly growing mycobacteria, Mycobacterium phlei was susceptible to 6-MP and AZA whereas Mycobacterium smegmatis strains were not. AZA and 6-MP limited the growth of, but did not kill, M. paratuberculosis in a dose-dependent manner. Anti-inflammatory drugs in the sulfonamide family (sulfapyridine, sulfasalazine, and 5-aminosalycilic acid [mesalamine]) had little or no antibacterial activity against M. paratuberculosis. The conventional antibiotics azithromycin and ciprofloxacin, used as control drugs, were bactericidal for M. paratuberculosis, exerting their killing effects on the organism relatively quickly. Simultaneous exposure of M. paratuberculosis to 6-MP and ciprofloxacin resulted in significantly higher CFU than use of ciprofloxacin alone. These data may partially explain the paradoxical response of Crohn's disease patients infected with M. paratuberculosis to treatment with immunosuppressive thiopurine drugs, i.e., they do not worsen with anti-inflammatory treatment as would be expected with a microbiological etiologic pathogen. These findings also should influence the design of therapeutic trials to evaluate antibiotic treatments of Crohn's disease: AZA drugs may confound interpretation of data on therapeutic responses for both antibiotic-treated and control groups.

Topics: Animals; Azathioprine; Bacteriological Techniques; Cattle; Cattle Diseases; Colony Count, Microbial; Crohn Disease; Culture Media; Humans; Immunosuppressive Agents; Mercaptopurine; Microbial Sensitivity Tests; Mycobacterium avium subsp. paratuberculosis; Paratuberculosis; Reagent Kits, Diagnostic