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.

Related blog posts:

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,

 

Toronto Consensus for Perianal Fistulizing Crohn’s Disease

A recent consensus report (AH Steinhart, R Panaccione et al. Inflamm Bowel Dis 2019; 1-13) provides updated guidelines for the management of perianal fistulizing Crohn’s disease (CD).

As an aside, the article starts off with an extremely lengthy disclosure (of financial interests) –more than 30 lines of extremely small font!

The scope of the problem:

  • About 21% of CD patients have developed perianal fistulizing disease by 10 yrs and 26% after 20 years.
  • This complication leads to significant morbidity/reduced quality of life and about 70% require surgical treatment during long-term followup.

The substance of the article are summarized in Table 4 and Figure 1. The recommendations all are considered to be based on either low quality of evidence or very low quality of evidence:

  • In those with active fistulizing disease, the authors recommend imaging (EUS or MRI)
  • In those with evidence of complicated fistulizing disease, “we suggest surgical consultation.”
  • In those with active fistulizing CD, “we suggest the use of antibiotic therapy for initial management.”
  • In those with active fistulizing CD, “we recommend the use of anti-TNF therapy” for induction and maintenance.
  • In those with active fistulizing CD, “when starting anti-TNF therapy, we suggest it be combined with thiopurine or methotrexate over monotherapy to optimize pharmacokinetic parameters.”
  • In those with active fistulizing CD, surgical management is recommended in those when there is an inadequate response to medical management.

Some additional pointers:

  • Early surgical consultation is recommended in setting of suspected clinical abscess (eg. pain, fever, leukocytosis).
  • The authors’ algorithm suggests that if early surgical intervention is not required, then patients should first receive antibiotics for initial symptom control, followed by imaging, and, if uncomplicated fistulizing disease on imaging, followed by anti-TNF therapy (with either MTX or thiopurine).  If complicated fistulizing disease, then surgical intervention may be needed prior to institution of anti-TNF therapy.
  • “The rate of fistula healing was 43% with medical therapy alone and 53% with combination surgical and medical therapy” based on a systematic review of 8 cohort studies.

My take: This article helps simplify/streamline the approach to this troubling complication.

Related blog posts:

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.

 

Shoshone, California

Can Therapeutic Drug Monitoring with Monotherapy Achieve Similar Results as Combination Therapy for IBD?

A recent retrospective study (S Lega et al. Inflamm Bowel Dis 2019; 25: 134-41) suggests that proactive therapeutic drug monitoring (pTDM) with infliximab (IFX) helps achieve similar outcomes as combination therapy (with immunomodulator) in patients with inflammatory bowel disease.

Before reviewing the key findings, it is important to emphasize a few crucial limitations/methods:

  • The study enrolled 83 patients; only 16 received were in the monotherapy pTDM group.
  • This was a retrospective study
  • The authors utilized TDM at week 10.  If the IFX level was <20 mcg/mL, the dose and frequency of infliximab were both adjusted. If the level was between 20 & 25, either the frequency was adjusted or no adjustment, and if the level was >25, then no adjustment in dosing was performed.

Key findings:

  • The frequency of infliximab discontinuation with mono therapy in those with pTDM was lower than in those with ‘standard of care’ TDM (P=0.04) but did not differ from patients receiving combination therapy
  • Overall 9 of the 83 patients (11%) discontinued IFX during the 1-year study

In the discussion, the authors suggest that week 14 TDM may be suboptimal as this is the first time patients have an 8-week interval.

My take: The jury is out with regard to whether pTDM can negate the need for combination therapy  –a prospective trial is needed; however, the idea of getting TDM a bit earlier is intriguing, particularly as it has been shown that a high percentage of pediatric patients are receiving an insufficient dose of infliximab (Is Standard Infliximab Dose Tool Low in Pediatrics?)

Related blog posts:

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.

View from Artist’s Drive, Death Valley

Management of Acute Severe Colitis

A recent review (KG Whatley, MJ Rosen. Inflamm Bowel Dis 2019; 25: 56-66) succinctly summarizes the contemporary medical management of acute severe ulcerative colitis (ASUC).

Figure 1 provides a useful initial checklist which includes the following:

  • PUCAI score
  • Labs/Imaging: CBC/d, CMP, CRP/ESR, Stool studies (culture/C diff), AXR
  • Pre-salvage labs: TB screen, Hep B serology, VZV serology if needing anit-TNF, TPMT if contemplating thiopurine, lipids if contemplating calcineurin inhibitor
  • Endoscopy: Consider Flex Sig (unsedated) with tissue for CMV PCR if not responding to 3 days of IV steroids
  • Thromboembolism prophylaxis: Low molecular weight heparin (adults, & high-risk pediatric patients), pneumatic compression (low-risk pediatric)
  • Nutrition plan
  • Corticosteroids: methylprednisolone 1-15. mg/kg (to max of 40-60 mg daily)

Each of these recommendations is discussed. For the flex sig recommendation, the authors note that a “full colonoscopy is not recommended due to risk of perforation.” With regard to CMV, the authors acknowledge the low quality of evidence to support antiviral treatment of CMV in this setting.  In addition, the authors suggest PCP prophylaxis in those who receive triple immunosuppression or in those receiving calcineurin inhibitors.

Figure 2 provides a handy algorithm for infliximab salvage therapy in the setting of ASUC:

  • If salvage therapy with infliximab is indicated (day 3-5 of IV steroids), the authors recommend 10 mg/kg dosing.  If there is no response after 3-5 days, repeat dosing is recommended.  If there is no response after an additional 3-5 days, colectomy is recommended.
  • If there is a response to infliximab, the algorithm recommends outpatient management. At time of the 3rd dose (week 5-6), the authors obtain an IFX level.  In those with a level <15, then dosing at 4 week maintenance is recommended; whereas in those 15 and above, every 8 week maintenance is recommended.

The authors discuss some potential emerging treatments. Recommendations from the authors with regard to surgery:

  • Most patients are best served with a subtotal colectomy/end ileostomy in preparation for future ileal pouch anal anastomosis
  • “Surgery should not be delayed to enhance nutrition or taper steroids.”

My take: This article summarizes current approaches with emphasis on not waiting a long time for salvage therapies and using early therapeutic drug monitoring to assist in dosing frequency.

Related blog posts:

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.

Death Valley

 

Experimental Use of FMT for Ulcerative Colitis

In a recent randomized, double-blind study (SP Costello et al. JAMA. 2019;321(2):156-164. doi:10.1001/jama.2018.20046), the use of fecal microbiota transplantation (FMT) was effective in 32% in inducing remission in adult patients with ulcerative colitis (UC).

Key Finding:  In this randomized clinical trial that included 73 adults with mild to moderately active ulcerative colitis, the proportion achieving steroid-free remission at 8 weeks was 32% with donor FMT vs 9% with autologous FMT, a significant difference

Abstract:

Importance  High-intensity, aerobically prepared fecal microbiota transplantation (FMT) has demonstrated efficacy in treating active ulcerative colitis (UC). FMT protocols involving anaerobic stool processing methods may enhance microbial viability and allow efficacy with a lower treatment intensity.

Objective  To assess the efficacy of a short duration of FMT therapy to induce remission in UC using anaerobically prepared stool.

Design, Setting, and Participants  A total of 73 adults with mild to moderately active UC were enrolled in a multicenter, randomized, double-blind clinical trial in 3 Australian tertiary referral centers between June 2013 and June 2016, with 12-month follow-up until June 2017.

Interventions  Patients were randomized to receive either anaerobically prepared pooled donor FMT (n = 38) or autologous FMT (n = 35) via colonoscopy followed by 2 enemas over 7 days. Open-label therapy was offered to autologous FMT participants at 8 weeks and they were followed up for 12 months.

Main Outcomes and Measures  The primary outcome was steroid-free remission of UC, defined as a total Mayo score of ≤2 with an endoscopic Mayo score of 1 or less at week 8. Total Mayo score ranges from 0 to 12 (0 = no disease and 12 = most severe disease). Steroid-free remission of UC was reassessed at 12 months. Secondary clinical outcomes included adverse events.

Results  Among 73 patients who were randomized (mean age, 39 years; women, 33 [45%]), 69 (95%) completed the trial. The primary outcome was achieved in 12 of the 38 participants (32%) receiving pooled donor FMT compared with 3 of the 35 (9%) receiving autologous FMT (difference, 23% [95% CI, 4%-42%]; odds ratio, 5.0 [95% CI, 1.2-20.1]; P = .03). Five of the 12 participants (42%) who achieved the primary end point at week 8 following donor FMT maintained remission at 12 months. There were 3 serious adverse events in the donor FMT group and 2 in the autologous FMT group.

Conclusions and Relevance  In this preliminary study of adults with mild to moderate UC, 1-week treatment with anaerobically prepared donor FMT compared with autologous FMT resulted in a higher likelihood of remission at 8 weeks. Further research is needed to assess longer-term maintenance of remission and safety.

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Golden Gulch Trail, Death Valley

 

ESPGHAN Position Paper: Biosimilars in Pediatric Inflammatory Bowel Disease

A recent position paper from ESPGHAN/Porto Group:

Full text: Use of Biosimilars in Pediatric Inflammatory Bowel Disease: An Updated Position Statement of the Pediatric IBD Porto Group of ESPGHAN. L de Riddler et al. JPGN 2019; 68: 144-53

Key points:

  • There are sufficient data (by extrapolation from different indications, adult data and limited pediatric data) to state that in children with IBD who are indicated for IFX treatment, CT-P13 is a safe and efficacious alternative to the originator IFX for
    induction, and maintenance, of remission. 97% agreement
  • A switch from the originator infliximab to CT-P13 may be considered in children with IBD in clinical remission, following at least 3 induction infusions. 84% agreement
  • Multiple switches (>1 switch) between biosimilars and reference drug or various biosimilars are not recommended in children with IBD, as data on interchangeability is limited and traceability of the drugs in case of loss of efficacy and/or safety signals may be compromised. 97% agreement
  • Physicians/institutions should keep records of brands and batch numbers of all biological medicines (including biosimilars) administered. 89% agreement

Related blog posts:

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.

IBD Update Feb 2019

Briefly noted:

B Feagan et al. Systematic review: efficacy and safety of switching patients between reference and biosimilar infliximab. Alim Pharm Ther 2019 Jan;49(1):31-40. “While available data have not identified significant risks associated with a single switch between reference and biosimilar infliximab, the studies available currently report on only single switches and were mostly observational studies lacking control arms. Additional data are needed to explore potential switching risks in various populations and scenarios.”

MP Pauly et al. Incidence of Hepatitis B Virus Reactivation and Hepatotoxicity in Patients Receiving Long-term Treatment with Tumor Necrosis Factor Antagonists. Clin Gastroenterol Hepatol 2018; 16: 1964-73. Using data from 8887 adults, this retrospective review found  “HBV reactivation iin 39% of patients who were HBsAg+ before therapy, but not in any patients who were HBsAg-negative and anti-HBc+ before therapy.”

D Lauritzen et al. Pediatric Inflammatory Bowel Diseases: Should We Be Looking for Kidney Abnormalities? Inflamm Bowel Dis 2018; 24: 2599-2605. In a cross-sectional cohort of 56 children with IBD, the authors found 25% “had either previously reported kidney disease or ultrasonographic signs of chronic kidney disease.” The authors note that plasma cystatin C is a useful biomarker for glomerular filtration as it less dependent on nutritional status; it is increased in the setteing of a decline in GFR.

L Pouillon et al. Mucosal Healing and Long-term Outcomes of Patients with Inflammatory Bowel Diseases Receiving Clinic-Based vs Trouhg Concentration-Based Dosing of Infliximab. Clin Gastroenterol Hepatol 2018; 16: 1276-83.  This retrospective study with patients who completed TAXIT maintenance phase found that patients who received trough-based infliximab dosing had a lower discontinuation rate of infliximab compared with clinic-based dosing (2 of 21 [10%]  vs. 10 of 27 [37%]).  However, both groups had >75% of patients able to continue infliximab for more than 3 years after the trial.

N Ouldali et al. Early Arthritis Is Associated With Failure of Immunosuppressive Drugs and Severe Pediatric Crohn’s Disease Evolution. Inflamm Bowel Dis 2018; 24: 2423-30. In this retrospective study with 272 patients with Crohn’s disease, 23.9% (n=65) developed arthritis and this was associated with failure of immunosuppressive drugs with OR of 6.9 after 2 years. In this study, immunosuppressive drugs refers to thiopurines and methotrexate.  By the completion of study, a much greater proportion of those with arthritis required biologic treatment (76% vs 32%, OR 4.3)