Antibiotics for the treatment of Crohn's disease

What is Crohn's disease?

Crohn's disease (CD) is an inflammatory disorder that can affect any segment of the gastrointestinal tract from the mouth to the anus. Common symptoms of CD include fever, diarrhea, abdominal pain and weight loss. CD is characterized by periods of relapse when people experience symptoms and periods of remission when the symptoms stop.

What are antibiotics?

Antibiotics are medications used to treat bacterial infections. Antibiotics are designed to target specific bacterial populations and have different mechanisms of action to stop a bacterial population from growing or eradicate the bacteria.

What is the purpose this study?

Antibiotics are commonly used for managing patients with CD because the inflammatory process in the bowel was believed to be triggered by a specific bacterial pathogen. Elimination of this bacterial target would allow the inflammatory process to resolve. However, current clinical guidelines do not recommend use of antibiotic agents to induce or maintain clinical remission in patients with CD because there is no definitive evidence to suggest a benefit to using antibiotics in this way.

How was this study performed?

A systematic review of current literature was performed to determine whether antibiotic therapy is effective to induce or maintain remission in CD. An electronic search of several databases was performed and studies that met our inclusion criteria were selected for further evaluation. Statistical analyses were performed to determine which specific antibiotics had an overall benefit.

What were the results?

Several antibiotics, including ciprofloxacin, metronidazole, clarithromycin, rifaximin and cotrimoxazole, have been studied in CD. Most of the included studies were small in size. When we pooled antibiotics as a class, these drugs provided a modest benefit over placebo (i.e. a fake drug such as a sugar pill) for induction of remission and improvement of CD symptoms. For example, remission rates were 45% (253/542) in participants who received antibiotics compared to 36% (82/231) in participants who received placebo. We rated the quality of evidence supporting this outcome as high. Few studies assessed the use of antibiotics for maintenance of remission in CD. The impact of antibiotics on preventing relapse in CD is uncertain. Antibiotics do not appear to increase the risk of side effects when compared to placebo. Common side effects reported in the studies included gastrointestinal upset, upper respiratory tract infection, abscess formation, headache, change in taste and paraesthesia (pins and needles in the extremities). Serious side effects were not well reported in the studies and the impact of antibiotics on the risk of serious side effects is uncertain.

Conclusions

Moderate to high quality evidence suggests that any benefit provided by antibiotics in active CD is likely to be very modest. High quality evidence suggests that there is no increased risk of side effects with antibiotics compared to placebo. The effect of antibiotics on the risk of serious side effects is uncertain. The effect of antibiotics on preventing relapse in CD is uncertain. Thus, no firm conclusions regarding the benefits and harms of antibiotics for maintenance of remission in CD can be drawn. More research is needed to determine the harms and benefits of antibiotic therapy in CD.

Authors' conclusions: 

Moderate to high quality evidence suggests that any benefit provided by antibiotics in active CD is likely to be modest and may not be clinically meaningful. High quality evidence suggests that there is no increased risk of adverse events with antibiotics compared to placebo. The effect of antibiotics on the risk of serious adverse events is uncertain. The effect of antibiotics on maintenance of remission in CD is uncertain. Thus, no firm conclusions regarding the efficacy and safety of antibiotics for maintenance of remission in CD can be drawn. More research is needed to determine the efficacy and safety of antibiotics as therapy in CD

Read the full abstract...
Background: 

Several antibiotics have been evaluated in Crohn's disease (CD), however randomised controlled trials (RCTs) have produced conflicting results.

Objectives: 

To assess the efficacy and safety of antibiotics for induction and maintenance of remission in CD.

Search strategy: 

We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register and Clinicaltrials.gov database from inception to 28 February 2018. We also searched reference lists and conference proceedings.

Selection criteria: 

RCTs comparing antibiotics to placebo or an active comparator in adult (> 15 years) CD patients were considered for inclusion.

Data collection and analysis: 

Two authors screened search results and extracted data. Bias was evaluated using the Cochrane risk of bias tool. The primary outcomes were failure to achieve clinical remission and relapse. Secondary outcomes included clinical response, endoscopic response, endoscopic remission, endoscopic relapse, histologic response, histologic remission, adverse events (AEs), serious AEs, withdrawal due to AEs and quality of life. Remission is commonly defined as a Crohn's disease activity index (CDAI) of < 150. Clinical response is commonly defined as a decrease in CDAI from baseline of 70 or 100 points. Relapse is defined as a CDAI > 150. For studies that enrolled participants with fistulizing CD, response was defined as a 50% reduction in draining fistulas. Remission was defined as complete closure of fistulas. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. We calculated the mean difference (MD) and corresponding 95% CI for continuous outcomes. GRADE was used to assess the certainty of the evidence.

Main results: 

Thirteen RCTs (N = 1303 participants) were eligible. Two trials were rated as high risk of bias (no blinding). Seven trials were rated as unclear risk of bias and four trials were rated as low risk of bias. Comparisons included ciprofloxacin (500 mg twice daily) versus placebo, rifaximin (800 to 2400 mg daily) versus placebo, metronidazole (400 mg to 500 mg twice daily) versus placebo, clarithromycin (1 g/day) versus placebo, cotrimoxazole (960 mg twice daily) versus placebo, ciprofloxacin (500 mg twice daily) and metronidazole (250 mg four time daily) versus methylprednisolone (0.7 to 1 mg/kg daily), ciprofloxacin (500 mg daily), metronidazole (500 mg daily) and budesonide (9 mg daily) versus placebo with budesonide (9 mg daily), ciprofloxacin (500 mg twice daily) versus mesalazine (2 g twice daily), ciprofloxacin (500 mg twice daily) with adalimumab versus placebo with adalimumab, ciprofloxacin (500 mg twice daily) with infliximab versus placebo with infliximab, clarithromycin (750 mg daily) and antimycobacterial versus placebo, and metronidazole (400 mg twice daily) and cotrimoxazole (960 mg twice daily) versus placebo. We pooled all antibiotics as a class versus placebo and antibiotics with anti-tumour necrosis factor (anti-TNF) versus placebo with anti-TNF.

The effect of individual antibiotics on CD was generally uncertain due to imprecision. When we pooled antibiotics as a class, 55% (289/524) of antibiotic participants failed to achieve remission at 6 to 10 weeks compared with 64% (149/231) of placebo participants (RR 0.86, 95% CI 0.76 to 0.98; 7 studies; high certainty evidence). At 10 to 14 weeks, 41% (174/428) of antibiotic participants failed to achieve a clinical response compared to 49% (93/189) of placebo participants (RR 0.77, 95% CI 0.64 to 0.93; 5 studies; moderate certainty evidence). The effect of antibiotics on relapse in uncertain. Forty-five per cent (37/83) of antibiotic participants relapsed at 52 weeks compared to 57% (41/72) of placebo participants (RR 0.87, 95% CI 0.52 to 1.47; 2 studies; low certainty evidence). Relapse of endoscopic remission was not reported in the included studies. Antibiotics do not appear to increase the risk of AEs. Thirty-eight per cent (214/568) of antibiotic participants had at least one adverse event compared to 45% (128/284) of placebo participants (RR 0.87, 95% CI 0.75 to 1.02; 9 studies; high certainty evidence). The effect of antibiotics on serious AEs and withdrawal due to AEs was uncertain. Two per cent (6/377) of antibiotic participants had at least one adverse event compared to 0.7% (1/143) of placebo participants (RR 1.70, 95% CI 0.29 to 10.01; 3 studies; low certainty evidence). Nine per cent (53/569) of antibiotic participants withdrew due to AEs compared to 12% (36/289) of placebo participants (RR 0.86, 95% CI 0.57 to 1.29; 9 studies; low certainty evidence) is uncertain. Common adverse events in the studies included gastrointestinal upset, upper respiratory tract infection, abscess formation and headache, change in taste and paraesthesia

When we pooled antibiotics used with anti-TNF, 21% (10/48) of patients on combination therapy failed to achieve a clinical response(50% closure of fistulas) or remission (closure of fistulas) at week 12 compared with 36% (19/52) of placebo and anti-TNF participants (RR 0.57, 95% CI 0.29 to 1.10; 2 studies; low certainty evidence). These studies did not assess the effect of antibiotics and anti-TNF on clinical or endoscopic relapse. Seventy-seven per cent (37/48) of antibiotics and anti-TNF participants had an AE compared to 83% (43/52) of anti-TNF and placebo participants (RR 0.93, 95% CI 0.76 to 1.12; 2 studies, moderate certainty evidence). The effect of antibiotics and anti-TNF on withdrawal due to AEs is uncertain. Six per cent (3/48) of antibiotics and anti-TNF participants withdrew due to an AE compared to 8% (4/52) of anti-TNF and placebo participants (RR 0.82, 95% CI 0.19 to 3.45; 2 studies, low certainty evidence). Common adverse events included nausea, vomiting, upper respiratory tract infections, change in taste, fatigue and headache

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