A recent retrospective study (J Breton et al. Inflamm Bowel Dis 2019; https://doi.org/10.1093/ibd/izz006) currently available online in advance of publication is likely to influence current practice in children with refractory inflammatory bowel disease (IBD). Thanks to Ben Gold for sharing this reference.
Here are some of the details:
- There were 63 patients who met inclusion criteria.
- 27 (43%) with colonic (n=18) or ileocolonic (n=9) Crohn’s disease (CD)
- 23 (36.5%) with ulcerative colitis
- 13 (21% classified with IBD-U.
- 34 (54%) were corticosteroid-refractory or dependent
- 62/63 with previous or present loss of response or primary nonresponse to anti-tumor necrosis factor (anti-TNF) therapy
- 48 (76.2%) were receiving anti-TNF therapy at time of antibiotic initiation
- Of the 37 with available anti-TNF trough, 23 (62.%) were considered therapeutic (IFX ≥5, or ADA ≥7.5)
- Medical refractoriness “was defined by corticosteroid resistance, as shown by no or partial response to more than 7 days of hgih-dose corticosteroids (≥ 1 mg/kg/day prednisone equivalent) or primary nonresponse or loss of response to a biologic”
Antibiotic regimens: A=Amoxicillin, D =Doxycycline, M =Metronidazole, C= Ciprofloxacin, V= vancomycin. Antibiotic therapy was based on previous study which used ADM. A =50 mg/kg/day divided TID to max 500 mg/dose; D =4 mg/kg/day divided BID to max 100 mg/dose; M 15 mg/kg/day divided TID to max of 250 mg/dose. In children <8 yrs, C =20 mg/kg/day divided BID to max of 250 mg. Vancomycin 125 mg/dose QID in <8 y and 250 mg/dose QID in ≥8 yo could be added as a 4th drug and Gentamicin cold be substituted in those with a drug allergy.
- 45% ADM
- 8% ADMV
- 8% CMV
- 8% AMV
- 8% ACM
- 6% ADV
- 17% Other
Improvement with Regimen:
- Median PUCAI dropped from 55 at baseline to 10 (P<0.0001) by 3 weeks ± 1 week after antibiotic initiation
- 40 (63.5%) experienced a clinical response with a change in PUCAI of ≥20 points
- 25 (39.7%) entered clinical remission, including 6 who achieved corticosteroid-free remission
- Other markers of improvement: increased median hemoglobin (10.7–>11.6), Improved median CRP (1.1 –> 0), improved median ESR (38 –>21)
- Use of doxycycline (OR 0.25) and high PUCAI ≥ 65 (OR 0.2) were both associated with a much lower odds of clinical remission
- Among the 25 entering clinical remission, 13 (65%) had successful rescue of current anti-TNF therapy, 6 were transitioned to another biologic (vedolizumab or ustekinumab)
- No serious adverse drug-related toxicities were evident. No cases of Clostridium difficile. One patient had a vaginal yeast infection
- The authors interpret their findings as indicating that antibiotics could serve as an effective rescue therapy in some and potentially rescue anti-TNF therapy in patients with refractory disease.
- The discussion speculates that improvement is related to microbial modulation as dysbiosis “may play a causative role in perpetuating inflammation”
- In those placed on antibiotics, the authors state that “clinical response should be assessed frequently and therapy discontinued if no improvement is documented within 1 week”
Safety and Antibiotic Choice:
- While there were no safety signals evident in this study over 1 year, the long-term risks of using antibiotics is uncertain. For example, with ciprofloxacin, a fluoroquinolone, there is a well-recognized risk of permanent damage to tendons/joints (link to FDA update) and fluoroquniolones increase the risk of aortic tear/rupture. Because aortic rupture is rare, this increased risk represents a very low absolute risk.
- The authors indicate that doxycycline, used in 45%, had a much lower response rate. This makes the choice of antibiotic regimen uncertain –none of the other regimens were used in more than 8%.
- Given the retrospective nature, it is unclear whether some of the improvement could be related to additional time for the adjunctive/non-antibiotic treatments to work. Though, the authors found that the effect of antibiotics seemed to be independent of therapy optimization.
My take: This is an important study for children with limited treatment options in the setting of refractory disease and may act to salvage current anti-TNF treatment or facilitate a bridge to an alternative treatment. Though, the optimal antibiotic regimen in this setting is unclear.
Related blog posts:
- IBD Reviews: Role of Antibiotics and Data on Biomarkers “We have recently begun considering oral vancomycin and gentamicin as sole first-line therapy in the rare form of infantile (ie <2 years of age) mild to moderate IBD, with promising success…this is merely investigational” at this time. (Ref: Lev-Tzion R et al. Digestion 2017; 95: 310-13).
- Management of Acute Severe Colitis
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.