Oral Antibiotics For Refractory Inflammatory Bowel Disease

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.

Link to abstract: Efficacy of Combination Antibiotic Therapy for Refractory Pediatric Inflammatory Bowel Disease

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

Outcomes:

  • 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

Implications:

  • 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.

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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.

Heart-shaped Cactus, Joshua Tree National Park

Joshua Tree National Park. This image selected since this article discusses a ‘bridge’ therapy,

 

Do these antibiotics make me look fat?

There has been a lot of interest and conflicting reports about whether antibiotics contribute to obesity.  Another interesting study on this theme:

  • ET Rogawski et al. JPGN 2017; 65: 350-6. 

The authors followed 1954 children twice weekly from birth to 2 years of age as part of the MAL-ED study.  There were 8 study sites, including in Bangladesh, India, Brazil, Pakistan, Nepal, South Africa, Peru, and Tanzania. Key finding:

  • Antibiotic use before 6 months of age was associated with increased weight from 6 months to 2 years of age.
  • Antibiotic use after 6 months did not affect growth.

The authors speculate: “If treatment of infections were the main mechanism, we would expect antibiotic exposure after 6 months to also have an impact.” Thus, they conclude that effects on the microbiome are likely a more important explanation.

My take (borrowed from te authors):  “Antibiotic use in low-resource settings” can improve growth, though the long-term consequences are not known.  In high-income settings, weight gain secondary to antibiotic exposure is more likely to be detrimental.

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Patient T-shirt

 

Do antibiotics contribute to obesity? Not in recent study

There have been studies suggesting that antibiotics at a young age promote obesity and other studies that have NOT found an association. A recent study (JAMA Pediatr. 2017;171(2):150-156. doi:10.1001/jamapediatrics.2016.3349could not find an effect of chronic prophylactic antibiotics.

Link: Weight Gain and Obesity in Infants and Young Children Exposed to Prolonged Antibiotic Prophylaxis

From Abstract:

Design, Setting, and Participants  Secondary analysis of data from the Randomized Intervention for Children With Vesicoureteral Reflux Study, a 2-year randomized clinical trial that enrolled participants from 2007 to 2011. All 607 children who were randomized to receive antibiotic (n = 302) or placebo (n = 305) were included. Children with urinary tract anomalies, premature birth, or major comorbidities were excluded from participation.

Interventions  Trimethoprim-sulfamethoxazole or placebo taken orally, once daily, for 2 years.

Results  Participants had a median age of 12 months (range, 2-71 months) and 558 of 607 (91.9%) were female. Anthropometric data were complete at the 24-month visit for 428 children (214 in the trimethoprim-sulfamethoxazole group and 214 in the placebo group). Weight gain in the trimethoprim-sulfamethoxazole group and the placebo group was similar (mean [SD] change in weight-for-age z score: +0.14 [0.83] and +0.18 [0.85], respectively; difference, −0.04 [95% CI, −0.19 to 0.12]; P = .65). There was no significant difference in weight gain at 6, 12, or 18 months or in the prevalence of overweight or obesity at 24 months (24.8% vs 25.7%; P = .82). Subgroup analyses showed no significant interaction between weight gain effect and age, sex, history of breastfeeding, prior antibiotic use, adherence to study medication, or development of urinary tract infection during the study.

My take: Whether antibiotics could contribute to obesity is not entirely clear –even the possibility could encourage better stewardship of antimicrobials.

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