Gut microbiota and inflammatory bowel disease: the role of antibiotics in disease management.

C L I N I C A L F O C U S : P A I N M A N A G E M E N T, R A R E D I S E A S E S , A N D A L L E R G I E S

Gut Microbiota and Inflammatory Bowel Disease: The Role of Antibiotics in Disease Management

Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.

DOI: 10.3810/pgm.2014.07.2779

David H. Kerman, MD 1 Amar R. Deshpande, MD 2 Assistant Professor of Clinical Medicine, Division of Gastroenterology, University of Miami Miller School of Medicine, Miami, FL; 2 Assistant Professor of Medicine, Division of Gastroenterology, University of Miami Miller School of Medicine, Miami, FL 1

Abstract: Imbalances in the composition and number of bacteria in the gut microbiota have been implicated in inflammatory bowel disease (IBD), and modulation of the gut microbiota by probiotics and antibiotics in IBD has been an active area of research, with mixed results. This narrative review summarizes the findings of relevant publications identified using the PubMed database. Although antibiotics have been associated with an increased risk of IBD development and flares, several meta-analyses demonstrate that antibiotics are efficacious for the induction of remission and treatment of flares in patients with IBD. Data supporting their use include a large number of antibiotic studies in Crohn’s disease and evidence suggests antibiotics are efficacious in both Crohn’s disease and ulcerative colitis, although there are fewer studies of the latter. For Crohn’s disease, antibiotics have been shown to be useful for the induction of remission and in the postoperative management of patients undergoing surgery. Additionally, patients with fistulizing disease, particularly perianal, can benefit from antibiotics administered short term. Both antimicrobials and probiotics have been shown to be useful for the treatment of pouchitis. Additional randomized controlled trials are needed to further elucidate the role of bacteria in IBD and to better inform clinicians about appropriate antibiotic therapies. Keywords: antibiotics; inflammatory bowel disease; probiotics; ulcerative colitis; Crohn’s disease

Normal Human Gut Microbiota

Correspondence: David H. Kerman, MD, Division of Gastroenterology, University of Miami Miller School of Medicine, PO Box 016960 (D-49), Miami, FL 33101. Tel: 305-243-8644 Fax: 305-243-3762 E-mail: [email protected]

The human gut microbiota is established at birth and is primarily determined by mode of delivery. Following birth by vaginal delivery, the bacterial landscape of a newborn most resembles that of the mother’s vaginal bacterial community (eg, Lactobacillus), whereas babies delivered by cesarean section are populated by bacteria commonly found on the skin of their mothers (eg, Staphylococcus).1 Bacterial composition of the gut microbiota early in life is influenced by diet (ie, breast-feeding vs formula feeding) and undergoes change within the first few months, with normal healthy infants maintaining relatively stable types of nonpathogenic commensal bacterial organisms, including Bifidobacteria, γ-Proteobacteria, Enterobacteriaceae, and Lactobacilli, that play an important role in normal gastrointestinal (GI) function (eg, motility, digestion, immunity).2–5 With time, the gut microbiota of unrelated infants become more similar, and by age 3 years begins to have a profile characteristic of the gut microbiota of adults.6 The microbiota of a healthy individual is generally stable over time, with the composition of the gut microbiota driven, in part, by geographic location and environmental factors (eg, smoking, diet).7–12 However, rapid (ie, within 1 to 2 days), temporal shifts in the gut microbiota can occur dependent on

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David H. Kerman and Amar R. Deshpande

consumption of diet, especially in individuals with reduced microbial complexity.13,14

healthy gut microbiomes, compared with patients with UC and CD in remission.26

The Role of Gut Microbiota in the Gut Immune System and Inflammatory Bowel Disease

Factors Affecting the Gut Microbiota

Imbalances in gut microbiota are associated with human disease, including celiac disease, allergic disorders, and inflammatory bowel disease (IBD).15–17 Inflammatory bowel disease, which includes a spectrum of diseases ranging from ulcerative colitis (UC) to Crohn’s disease (CD), is a chronic, relapsing disease characterized by dysregulated inflammation of the GI mucosa, with a complex etiology associated with genetic, environmental, immunologic, microbial, and dietary factors.11,18,19 Ulcerative colitis invariably involves the rectum and can advance proximally to involve the entire colon. Crohn’s disease primarily involves the distal ileum and colon, but inflammation can affect any part of the digestive tract.18 In a majority of patients, these diseases are characterized by alternating periods of disease flare and remission, whereas some patients have continuous disease activity.18 Animal studies have demonstrated the role of immune dysregulation in the pathogenesis of IBD. In one study, consumption of diets high in fat altered the gut bacterial composition of wild-type mice, and increased the rate of onset and incidence of colitis in interleukin (IL)-10–deficient mice but not wild-type mice.20 Another study showed that, unlike their wild-type counterparts, IL-10–deficient mice raised in specific pathogen environments spontaneously developed colitis.21 Colonization of IL-10–deficient mice with commensal bacterial species Enterococcus faecalis or Escherichia coli also led to the development of chronic colitis, indicating that aberrant immune responses play an important role in chronic GI inflammation.22 Thus, environmental factors such as diet and the enteric bacteria appear to interact with the immune system to play a role in the development of IBD in animal models. Similar to the differences observed in wild-type and immune-deficient mice, the gut microbiota of patients with IBD were found to differ from those of healthy individuals, as well as in patients without IBD in a general gastroenterology clinic.23,24 Further, the diversity and number of bacteria have been found to differ between regions of inflammation and noninflammation in the gut mucosa of patients with active UC and CD, and from patients without IBD.25 Also, patients with active UC and CD have decreased levels of Firmicutes, especially Faecalibacterium prausnitzii, bacteria which are commonly found in 8

Modulation of the gut microbiota early in life may influence the risk of disease in the future. The association between antibiotics and the risk of developing IBD has been established by a number of groups. A significant association with CD, but not UC, was demonstrated in children who were prescribed antibiotics within 2 years of their IBD diagnosis.27 Otitis media in children, a surrogate marker for antibiotic use, was significantly associated with a 2.8-fold increased risk of a diagnosis of IBD, with a diagnosis by the age of 1 year increasing the risk approximately 2- to 3-fold for a diagnosis of CD or UC, respectively.28 These findings corroborated those of a retrospective cohort study of children with IBD. Children exposed to antibiotics by the age of 1 year had a 5.5-fold increased risk for developing IBD, with each additional course of antibiotics (defined as continuous exposure with , 3 days interruption) and each additional week of exposure to antibiotics associated with a 6% and 1% increased risk for IBD, respectively.29 Finally, similar to findings in children, there was a significant association between the use of antibiotics and the diagnosis of adult-onset IBD within 2 years, with risk increasing in a dose-dependent manner.30 In addition to antibiotic use, other factors associated with increased risk of CD that also alter the gut microbiome include smoking, use of nonsteroidal anti-inflammatory drugs or oral contraceptives, appendectomy, consumption of animalderived proteins, and stress or depression.31 Interestingly, smoking and appendectomy are associated with decreased risk of UC, whereas the use of nonsteroidal anti-inflammatory drugs or postmenopausal hormones, consumption of dietary arachidonic acid or linoleic acid, and stress or depression are associated with increased risk of UC. Smoking significantly decreased the abundance of the bacteria Anaerostipes, a member of the Firmicutes phylum, by . 60%.32 Treatments for IBD, such as mesalamines, decreased levels of Escherichia and Shigella but increased levels of Enterococcus. However, whether dysregulation of the gut microbiome by these environmental factors is important for the pathophysiology of IBD remains to be elucidated. Not surprisingly, modulation of the gut microbiota in patients with IBD has been the focus of clinical research, with studies yielding mixed results (Table 1).33–41 Probiotics have been evaluated as a treatment for patients with IBD,

© Postgraduate Medicine, Volume 126, Issue 4, July/August 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Antibiotics in IBD

Table 1. Summary of Clinical Studies With the Probiotic VSL#3 in Patients With IBD Disease

Study Design

UC

RCT, DB, PC in children VSL#3 (weight-based dosing with newly diagnosed range, 450–1800 × 109 33 UC bacteria/d; n = 14) or placebo (n = 15) for 1 y OL, MC in adults with VSL#3 (1800 × 109 active UC refractory bacteria/2 sachets) bid for to mesalamine34 6 wks (N = 34)


UC

Dosing, n

UC

RCT, DB, PC, MC in adults with relapsing mild-to-moderate UC35

VSL#3 (1800 × 109 bacteria/2 sachets) bid (n = 71) or placebo (n = 73) for 8 wks

UC

RCT, DB, PC, MC in adults with mild-tomoderate active UC36

VSL#3 (1800 × 109 bacteria/2 sachets; n = 77) bid or placebo (n = 70) for 12 wks

UC

RCT, MC in adults with mild-to-moderate active UC37

VSL#3 (300 × 109 bacteria/g) 3 g/d plus balsalazide 2.25 g (n = 30), balsalazide 4.5 g/d (n = 30), or mesalazine 2.4 g/d (n = 30) VSL#3 (5 × 1011 cells/g) 3 g bid (n = 20) for 12 mo VSL#3 (300 × 109 bacteria/g) 6 g qd (n = 20) or placebo (n = 16) for 1 y

UC

OL in adults with UC in remission38 Recurrent or RCT, PC, MC in adults refractory pouchitis with recurrent or refractory pouchitis39 Prevention of pouchitis

RCT, DB, PC in adults who underwent ileostomy closure41

VSL#3 (900 × 109 bacteria) 3 g qd (n = 20) or placebo (n = 20) for 1 y

Chronic relapsing pouchitis

RCT, DB, PC of adults with chronic relapsing pouchitis40

VSL#3 (300 × 109 bacteria/g) 3 g bid (n = 20) or placebo (n = 20) for 9 mo

Primary Efficacy Outcome

Safety

92.8% of patients in VSL#3 group No AEs reported in remission at 1 y vs 36.4% in placebo group (P , 0.001)a 53% of patients in remission at 6 wksb

No AEs reported except increased bloating in 29% of patients, which did not lead to withdrawal from study 63.1% of patients in VSL#3 Mild AEs (eg, dizziness, flu-like group had . 50% decrease in symptoms, abdominal bloating, UCDAI score at wk 8 vs 40.8% fever, unpleasant taste) in 11.2% in placebo group (P = 0.031) of patients receiving VSL#3 and 12.3% of patients receiving placebo 32.5% of patients in VSL#3 group AEs reported included abdominal had $ 50% decrease in UCDAI bloating and discomfort in score at wk 6 vs 10% in placebo 14 patients (18.2%), with 7 of group (P = 0.001) these patients also experiencing an unpleasant taste Remissionc at 8 wks: balsalazide No severe AEs in balsalazide + VSL#3 (PP, 85.7%; ITT, 80%), groups; 2 patients receiving balsalazide (PP, 80.8%; ITT, 70%); mesalazine withdrew from study mesalazine (PP, 72.7%; ITT, due to AEs 53.3%); P value (ITT) , 0.02 75% in remission at 1 yd Mild constipation in 3 patients 85% of patients receiving VSL#3 in remission at 1 y vs 6% of patients receiving placebo (P , 0.0001)e Pouchitis was prevented in 90% and 60% of patients receiving VSL#3 vs placebo, respectively, after 1 y of treatmentf 85% of patients treated with VSL#3 in remission at 9 mo vs 0% receiving placebo P , 0.001)g

1 patient receiving VSL#3 withdrew from the study (abdominal cramps, vomiting, diarrhea) No AEs reported

No AEs reported

Remission defined as sustained decrease in the LCAI to # 2 after steroid treatment. Remission defined as UCDAI score # 2. c Remission defined as patient functional assessment ratings of normal bowel movements and lack of rectal bleeding. d Remission defined as no visible blood in stools and # 2 bowel movements per day. e Remission defined as a clinical PDAI score # 2 and an endoscopic PDAI score # 1. f Pouchitis defined as total PDAI $ 7. g Relapse defined as an increase of $ 2 points in the clinical portion of the PDAI. Abbreviations: AE, adverse event; DB, double-blind; IBD, inflammatory bowel disease; ITT, intent-to-treat; LCAI, Lichtiger colitis activity index; MC, multicenter; OL, open label; PC, placebo-controlled; PDAI, pouchitis disease activity index; PP, per protocol; RCT, randomized controlled trial; UC, ulcerative colitis; UCDAI, ulcerative colitis disease activity index. a

b

including a randomized, controlled trial of Lactobacillus reuteri in children with mild-to-moderate UC. Children receiving L. reuteri enemas for 8 weeks experienced a significant decrease (improvement) in the Mayo Disease Activity Index (DAI) compared with baseline (3.2 ± 1.3 vs 8.6 ± 0.8, respectively; P , 0.01), whereas children receiving placebo experienced no significant change from baseline. Further, 100% of patients receiving L. reuteri

achieved clinical response (ie, decrease of $ 2 points in DAI), and 31% achieved clinical remission (ie, final DAI score of , 2 points) compared with 53% (P , 0.01) and 0% (P , 0.05) of patients receiving placebo, respectively.42 No serious adverse events (AEs) were reported during the study. Conversely, a randomized, placebo-controlled trial of children with CD treated with Lactobacillus rhamnosus strain GG for up to 2 years reported no difference in median




time to relapse (Lactobacillus vs placebo, 11.6 months vs 12.8 months; P = 0.37) with a similar percentage of patients experiencing AEs in each group (18% vs 21%, respectively; P = 0.78).43 Various studies highlight the inconsistency in study design and clinical end points that limit comparison among studies.44–57 Data generally cannot be compared due to the variability in probiotic formulations administered, the differences in dosing regimens and modes of administration, and the generally small size of patient populations evaluated. In patients with mild-to-moderate UC, even when administered the same dose of the probiotic VSL#3, comparisons are limited by the differences in the duration of treatment and time points assessed as well as variability in how end points were defined.35,36,40 Overall, treatment with VSL#3 has been shown to be effective for the prevention of pouchitis (Table 1).33–41 Although modulation of the gut microbiota by probiotics has shown some favorable results, more research is needed.

Methods

This narrative review discusses the role of antibiotics in the management of IBD, and includes English-language articles identified using the PubMed database through September 2013. Search terms included antibiotic, bacteria, CD, Crohn’s disease, gut flora, fistulizing, flares, IBD, inflammatory bowel disease, luminal, microbiome, pathophysiology, perianal, probiotic, pouchitis, UC, and ulcerative colitis. Search results were reviewed and relevant publications were selected. References within individual articles were also used to identify publications for inclusion.

Discussion Antibiotics for the Management of IBD

Although there are data suggesting that the use of antibiotics may increase the risk for IBD, evidence also supports the important role of antibiotics in the management of patients with IBD (Figure 1). The treatment paradigm for patients with CD and UC includes the use of corticosteroids to induce remission and mesalamines, immunomodulators, and biologics for both the induction and maintenance of remission. Antibiotics represent a specific strategy for unique situations and are generally thought of as a bridge to a more permanent maintenance medication. Results of a recent meta-analysis showed that significant clinical improvement occurred in patients with CD following treatment with broad-spectrum antibiotics compared with placebo (56.1% vs 37.9%, respect ively; odds ratio [OR], 1.35; 95% CI, 1.16–1.58).58,59 Another meta-analysis found that treatment with nitroimidazoles 10

(eg, metronidazole), clofazimine, or ciprofloxacin was beneficial for patients with CD, with ORs of 3.54 (95% CI, 1.94–6.47), 2.86 (95% CI, 1.67–4.88), and 11.3 (95% CI, 2.6–48.8), respectively.60 Antibiotics were also effective in UC, inducing remission in a higher percentage of patients compared with placebo (64.2% vs 47.5%, respectively; OR, 2.17; 95% CI, 1.54–3.05).59

Antibiotics for the Postoperative Management of CD

Although surgical rates have decreased since the 1980s, it is estimated that approximately 40% of patients with CD will undergo surgery within 5 years of diagnosis.61,62 The converse is true in children; 1 study reported that intestinal resections in children have increased between 1997 and 2009, possibly due to an increase in diagnoses of pediatric IBD.63 A recent comprehensive literature review of 83 articles published between 1966 and 2011 reported clinical recurrence rates postsurgery ranged from 20% to 45% and from 34% to 61% at 5 and 10 years, respectively.64 One year after surgery, the mean rates for clinical recurrence were 26% for referral centers and 28% for randomized controlled trials, whereas the mean rates for endoscopic recurrence were 75% and 54%, respectively.64 There was a positive correlation between the severity of disease measured endoscopically 6 months after surgery and the rate of clinical recurrence at 5 years.65 The gut microbiota appears to play a role in disease recurrence following surgery; patients with disease recurrence were found to have a less stable microbiota over time.66 Indeed, surgical biopsies of patients without recurrence had a microbiota profile most similar to biopsies from patients without IBD.66 Also, bacterial counts were significantly increased in the neoterminal ileum of patients with CD following surgical resection.67 Treatment with antibiotics is thought to decrease gut lumen bacterial overgrowth, and believed to reduce pain and diarrheal symptoms by suppressing gut flora.59 However, patients with CD who used antibiotics had a shorter time to first surgery compared with patients with CD who did not (hazard ratio = 5.2; 95% CI, 3.4–8.1); although these data provide further evidence supporting the role of gut bacteria in CD, it is possible that surgery is a surrogate marker for more severe disease requiring more intensive medical intervention, including antibiotics.62 Gut bacteria clearly appear to play a role in disease recurrence. A number of conventional systemic antibiotics have been evaluated in patients with CD for the prevention of clinical or endoscopic recurrence following surgical resection, with mixed results (Table 2).68–72 Ciprofloxacin had no


Antibiotics in IBD


Figure 1. Efficacy of antibiotics for the treatment of IBD.

Rifaximin-EIR is an investigational drug. Abbreviations: EIR, extended intestinal release; IBD, inflammatory bowel disease. a

effect on clinical recurrence rates but decreased endoscopic recurrence rates compared with placebo, whereas metro nidazole, either alone or in combination with azathioprine, decreased both clinical and endoscopic recurrence rates compared with placebo. Ornidazole decreased both clinical

and endoscopic recurrence rates compared with placebo, although treatment was associated with a greater number of AEs, including GI intolerance, paresthesias, abnormal liver chemistries, and metallic taste. Further, long-term use may be limited by concerns related to the risk of the development


12 1 y: 25% 2 y: 43% 3 y: 50%

54 wks: 7.9% 54 wks: 37.5% 54 wks: 0.0046 3 mo: 34.4% 2 y: 29.7% 2 y: 45% 2 y: 0.17 12 mo: 53.6% 3 y: 45.9% 3 y: 47.5% 3 y: 0.53

3 mo: 58.8% 12 mo: 78.8%

Most common AEs reported in metronidazole group were metallic taste, GI intolerance, and paresthesias of limbs; paresthesias of limbs was most common AE in placebo group 12 AEs reported in metronidazole group vs 7 AEs in placebo group

Most common AEs reported in both groups were abdominal pain and joint pain 21 AEs reported in metronidazole group vs 7 AEs in placebo group

Overall, 36 AEs reported in 19 patients (ciprofloxacin, n = 10, vs placebo, n = 9)

Safety

Most commonly reported AEs were lymphopenia (azathioprine), paresthesias (metronidazole), or GI intolerance (placebo/azathioprine) 3 mo: 0.11 Most commonly reported AEs in 12 mo: 0.048 metronidazole plus azathioprine group were headache, metallic taste, and arthralgia vs metallic taste and WBC , 4000 in the metronidazole plus placebo group 3 mo: 0.047 Significantly more AEs with ornidazole vs placebo 12 mo: 0.037 (68.4% vs 30.0%, respectively; P = 0.0007). Most common AEs with ornidazole were abnormal liver tests, paresthesias, and GI intolerance vs fatigue and GI intolerance with placebo

6 mo: 0.19 12 mo: 0.15

, 0.578

P value

b

a

Patients received metronidazole plus azathioprine. Patients received metronidazole plus placebo. Abbreviations: AE, adverse event; DB, double-blind; GI, gastrointestinal; MC, multicenter; NS, not significant; PC, placebo-controlled; RCT, randomized controlled trial; WBC, white blood cells.

RCT, DB, PC of ornidazole 500 mg bid (n = 38) or placebo (n = 40) for 54 wks72

3 mo: 34.3%a 3 mo: 52.6%b 12 mo: 43.7%a 12 mo: 69.0%b

6 mo: 44% 12 mo: 56%

6 mo: 50%

Placebo

RCT, PC, MC of metronidazole 250 mg tid (or ornidazole 500 mg bid) with either azathioprine 100 mg or 150 mg/d (n = 40), or placebo (n = 41) for 3 mo71

6 mo: 33%

Antibiotic

Endoscopic Recurrence Rates

6 mo: 28%a 12 mo: 36%a

NS

, 1.000

P value

RCT, DB, PC of metronidazole tid (total dose, 15–20 mg/kg/d) in combination with azathioprine 2–2.5 mg/kg/d (n = 25) or placebo (n = 25) for 3 mo70

1 y: 7% 2 y: 24% 3 y: 31%

RCT, DB, PC of metronidazole 20 mg/kg/d (n = 30) or placebo (n = 30) for 3 mo69

Placebo 24 wks: 18%

Antibiotic

Clinical recurrence rates

RCT, DB, PC, MC of ciprofloxacin 500 mg bid (n = 17) 24 wks: 18% or placebo (n = 16) for 6 mo68

Study Design and Treatment Dosing and Duration

Table 2. Summary of Clinical Studies Evaluating Antibiotics for the Postoperative Management of Patients With Crohn’s Disease




Antibiotics in IBD

of bacterial resistance to antibiotics and development of Clostridium difficile infection, as well as the knowledge that diversity of the gut microbiome may be altered up to 4 years in some patients following short-term treatment with antibiotics.68,70,72–74


Antibiotics for the Induction of Remission of CD

In addition to the postsurgical management of patients with CD, antibiotics may be efficacious for the induction of remission of CD. A pooled analysis of 10 randomized controlled trials showed that antibiotics provided a significant benefit for inducing remission compared with placebo in patients with active CD (relative risk, 0.85; 95% CI, 0.73–0.99; P = 0.03).75 Although significant benefit was noted, the findings led to a weak recommendation from the authors given the heterogeneity of treatments.75 Indeed, induction of clinical remission of CD with antibiotics has yielded mixed findings in a number of independent studies, with only a small number of studies demonstrating significant differences between antibiotics and placebo (Table 3); again, these studies all had differences in duration of treatment (from 4 weeks to 6 months), with different antibiotics used in a number of combinations.76–85 Results of a retrospective study of patients receiving the nonsystemic antibiotic rifaximin, both in traditional and extended intestinal release forms, showed that rifaximin induced remission and response compared with placebo.83,84,86 In contrast with systemic antibiotics, which are associated with a greater percentage of AEs than placebo (eg, abdominal pain, nausea, vomiting, vaginal candidiasis, dizziness, and taste disturbance),77–79,81 rifaximin had fewer disturbances mostly limited to the GI tract (eg, nausea, flatulence).83,84 Although antibiotics have demonstrated efficacy in patients with CD, exposure to antibiotics in children with newly diagnosed CD has been shown to be associated with dysbiosis of the gut microbiome.87 Dysbiosis may allow for the proliferation of less protective bacterial species in the gut.88 However, further research is needed to determine the extent to which dysbiosis is associated with specific antibiotics and their respective dosing and length of treatment.

Role of Antibiotics in Fistulizing/Perianal Disease

Patients with CD commonly develop fistulae, with symptoms including rectal pain; continual drainage from the perianal region, vagina, and abdominal wall; and recurrent urinary tract infections.89 Complex fistulae occur in 80% of patients with fistulizing disease, and approximately half of

all fistulae that develop are located in the perianal region.89,90 Antibiotics are the most commonly prescribed medication for the treatment of fistulae (44%) and, although data from clinical trials are limited, antibiotics are considered appropriate therapy.89,90 In patients with fistulae randomized to treatment with metronidazole, ciprofloxacin, or placebo for 10 weeks, remission (defined as closure of all draining fistulae at week 10) was reported in 0%, 30%, and 12.5%, and perianal fistulae were improved (ie, $ 50% decrease from baseline in number of openly active draining fistulae) in 14.3%, 40%, and 12.5% of patients, respectively.91 However, AEs occurred in 100%, 70%, and 62.5% of patients receiving metronidazole, ciprofloxacin, or placebo, respectively. The most commonly reported AEs were an unpleasant taste, cold symptoms, and abscesses or open fistulae. In patients with CD-related fistulae, antibiotics used as part of a treatment regimen that included standard immunosuppressive therapies (ie, thiopurines and anti–tumor necrosis factor agents) have been evaluated.92 In 1 study, approximately half (54%) of patients with fistulae treated with antibiotics alone (ie, ciprofloxacin, metronidazole, or both) experienced response, defined as a $ 50% decrease from baseline in the number of draining fistulae following 8 weeks of treatment.93 Concomitant azathioprine significantly increased response rates (including complete response, defined as fistula closure or absence of draining fistulae) at 20 weeks compared with antibiotics alone (48% vs 15%, respectively; P = 0.03). In a study evaluating ciprofloxacin alone and in combination with infliximab, clinical response was similar between ciprofloxacin 500 mg twice daily (9%, 1 patient) and placebo (15%, 2 patients) after 6 weeks of treatment.92 The addition of infliximab (5 mg/kg infusion at weeks 6, 8, and 12) to therapy increased clinical response rates to 91% in the ciprofloxacin group compared with 62% in the placebo group at week 8 (P = 0.17), with similar results at week 12. Although data suggest that antibiotics alone may be efficacious for the treatment of fistulizing disease, antibiotics in combination with standard immunosuppressive therapy may provide greater response.

Role of Antibiotics in CD Flares

Although there is a paucity of data regarding the use of antibiotics in patients experiencing CD flares, the limited data available suggest the potential utility of antibiotics in these patients. A medical records review identified an association between use of antibiotics and decreased incidence of flare in patients with CD (adjusted OR, 0.78; 95% CI, 0.64–0.96;


14

Metronidazole 250 mg bid or tid and ciprofloxacin 200 mg tid (n = 7)80 Metronidazole 500 mg bid and ciprofloxacin 500 mg bid in combination with budesonide 9 mg qd (n = 66) or placebo in combination with budesonide 9 mg qd (n = 68)81 8 wks

4 wks

Partial remission in 71% ND of patients Metronidazole 500 mg bid 0.55 and ciprofloxacin 500 mg bid in combination with budesonide vs placebo in combination with budesonide (33% vs 38%, respectively)

Metronidazole 20 mg/kg/d NS or 10 mg/kg/d vs placebo (27% or 36% vs 25%)

16 wks

0.02

Antibiotics vs placebo at 16 wks (66% vs 50%, respectively)

Clarithromycin vs placebo 1.00 at 12 wks (26% vs 27%)

Ciprofloxacin vs placebo 3 mo: , 0.001 at 3 mo (61.0% vs 71.0%) 6 mo: , 0.001 and 6 mo (58.0% vs 71.1%)

P value

2y

3 mo

Clarithromycin Clarithromycin 1 g qd (n = 19) or placebo (n = 22)77

Clarithromycin 250 mg qd for wk 1, 250 mg bid for wks 2 and 3, and 750 mg qd from wk 4; rifabutin 150 mg qd for wk 1, 300 mg qd for wks 2 and 3, and 450 mg qd from wk 4; clofazimine 50 mg qd (n = 102) or placebo (n = 111)78 Metronidazole Metronidazole 20 mg/kg/d (n = 30) or 10 mg/kg/d (n = 33), or placebo (n = 36)79

6 mo

Treatment Induction of Duration Clinical Remission

Ciprofloxacin Ciprofloxacin 500 mg bid (n = 28) or placebo (n = 19)76

Study Drug, n

P value

Not evaluated

Safety

Most common AEs that differed significantly between antibiotic and placebo groups included taste disturbance (27% vs 0%, respectively), dizziness/lightheadedness (21% vs 6%, respectively), diarrhea (20% vs 6%, respectively), vaginitis (17% vs 3%, respectively), and glossitis/oral candidiasis (14% vs 0%)

6 and 8 patients receiving metronidazole and placebo, respectively, withdrew from the study due to AEs. AEs in the metronidazole group included intestinal perforation, thrombocytopenic purpura, headache; similar incidence of nausea, vomiting, abdominal pain, and hypoesthesia/paresthesia in 2 groups, rash or arthralgia in the placebo group Only reported AE was slight taste disturbance

A greater percentage of patients receiving clarithromycin completed treatment vs patients receiving placebo (63% vs 45%, respectively). Clarithromycin AEs leading to study withdrawal: CD flare, lack of efficacy, abdominal pain, nausea and vomiting; perianal abscess and altered taste sensation reported in patients completing treatment. Placebo AEs leading to study withdrawal: worsening CD and vomiting Between wks 16 AEs more common with antibiotic treatment vs placebo Antibiotics vs placebo $ 1 included vaginal candidiasis (4.0% vs 0.8%, respectively), relapse between wks 16 and and 52: 0.054 abdominal distention (3.4% vs 0.8%, respectively), urine 52 (39% vs 56%), at wk 104 Wk 104: 0.14 discoloration (2.8% vs 0.3%, respectively), abnormal (26% vs 43%), and at wk 156 Wk 156: 0.54 liver function and myalgia (both AEs, 2.3% vs 0.3%, (59% vs 50%) respectively)

Maintenance of Clinical Remission

Table 3. Summary of Clinical Studies Evaluating Antibiotics for the Induction and Maintenance of Clinical Remission in Patients With Crohn’s Disease




AEs reported included dapsone (anemia) and clofazimine (increase in skin pigmentation); no AEs reported with rifampicin or ethambutol

b

a

Most common AEs included headache (6%), symptoms of CD (6%), nausea (4%), flatulence (2%), nasopharyngitis (2%), and fever (2%)

Overall, 41% of patients reported $ 1 AE

Antimicrobial combination vs placebo (86% and 94%, respectively)c

Antimicrobial combination vs placebo (58% and 24%, respectively)

Wk 14: NS, 0.03, NS, respectively

Wk 24: Rifaximin-EIR 1200 mg, 800 mg, 400 mg vs placebo (32%, 45%, 38% vs 29%, respectively)c Wk 24: NS, 0.02, NS, respectively

Rifaximin-EIR 1200 mg, 800 mg, 400 mg vs placebo

Wk 14: Rifaximin-EIR 1200 mg, 800 mg, 400 mg vs placebo (39%, 51%, 45% vs 35%, respectively)b

Overall, 88 AEs occurred in 38 patients, with GI disorders (eg, flatulence, nausea) the most commonly reported AEs

NS

Rifaximin-EIR 1200 mg, 800 mg, 400 mg vs placebo (47%, 62%, 54% vs 43%, respectively)a

AEs associated with antibiotic treatment included severe pseudomembranous colitis, abdominal pain, nausea, and antibiotic-associated diarrhea

Rifaximin-EIR 800 mg qd NS or bid vs placebo (32% or 52% vs 33%, respectively)

ND

66% of patients achieved clinical remission

P = 0.005 for rifaximin-EIR 800 mg vs placebo. P = 0.03 for rifaximin-EIR 800 mg vs placebo. c Percentage of patients in each treatment group achieving remission in the induction phase of the study and entering the maintenance phase of the study.85 Abbreviations: AE, adverse event; CD, Crohn’s disease; EIR, extended intestinal release; GI, gastrointestinal; ND, not determined; NS, not significant.

12 wks Rifaximin-EIR 800 mg qd (n = 25) or bid (n = 29) or placebo (n = 29)84 Rifampicin Rifampicin 600 mg qd, ethambutol 9 mo 15 mg/kg qd, dapsone 100 mg for 6 d/wk, and clofazimine 100 mg every 2 d (n = 22) or placebo (n = 18)85

Metronidazole 15–20 mg/kg/d (divided 8 wks dose) in combination with azithromycin 7.5–10 mg/kg/d up to 500 mg/d qd for 5 consecutive days per wk for 4 wks, followed by 3 times/wk for 4 wks (n = 32)82 Rifaximin-EIR 12 wks Rifaximin-EIR 1200 mg (n = 99), 800 mg (n = 98), 400 mg (n = 104) bid, or placebo (n = 101)83


Antibiotics in IBD



P = 0.019).94 A second study showed that a comparable percentage of patients experiencing mild-to-moderate CD flare receiving either ciprofloxacin 500 mg twice daily or mesalamine 2 g twice daily achieved complete remission (ie, Crohn’s Disease Activity Index # 150 and a decrease in Crohn’s Disease Activity Index . 75) following 6 weeks of treatment (56% vs 55%, respectively).95 Although further clinical trials are needed, antibiotics appear to have efficacy in the treatment of patients with CD flares.


Role of Antibiotics in UC Flares and Maintenance of Remission

Overall, the data regarding the use of antibiotics in patients with UC are limited compared with data available for CD. A medical record–based study demonstrated that antibiotic use was not associated with flare in patients with UC in remission (adjusted OR, 0.96; 95% CI, 0.82–1.12; P = 0.581), and furthermore, use of antibiotics did not appear to aggravate symptoms of UC.94 Another study reported that a greater percentage of patients with UC randomized to treatment with ciprofloxacin in combination with prednisone and mesalamine for 6 months had a clinical response (no treatment failure [ie, moderate to severe activity in $ 2 segments of the colon]) compared with patients not receiving antibiotics (79% vs 56%, respectively; P = 0.02).96 These limited data provide some evidence for the potential benefit of antibiotics in patients with UC; however, additional studies are needed before substantive conclusions can be drawn.

Antibiotics and Pouchitis

Patients with chronic refractory disease for which medical therapy offers little to no relief of symptoms often undergo surgery, including total proctocolectomy with ileal pouch–anal anastomosis. One potential complication is the development of pouchitis, characterized by increased stool frequency, rectal bleeding, abdominal cramping, rectal urgency, and tenesmus.97 The microbial composition of the ileal pouch differs greatly from normal gut microbiota, with an increase in Proteobacteria and a decrease in Bacteroidetes and Firmicutes; it is also associated with a decrease in microbial diversity when compared with patients with uninflamed pouches.98,99 Although the role of the gut microbiota in pouchitis is an active area of investigation, it is clear that bacteria play an important role. Short-term antibiotic treatment is recommended for the management of pouchitis, although the evidence for this recommendation is limited, and the results of most clinical studies are based on small sample sizes.97,100,101 A systematic review of randomized controlled 16

trials concluded that ciprofloxacin was more effective than metronidazole in patients with acute pouchitis.100 Results of a number of small clinical studies suggest that rifaximin either alone or in combination with systemic antibiotics is also efficacious for pouchitis.102–104 A randomized, double-blind, placebo-controlled trial showed that a greater percentage of patients with active pouchitis treated with rifaximin achieved clinical remission (ie, pouchitis DAI score , 7 points and a 3-point decrease from baseline in the pouchitis DAI score) compared with placebo (25% vs 0%, respectively; P = 0.211) over a 4-week period.102 In addition, rifaximin has been shown to be useful in prevention of recurrence of pouchitis in patients who have responded to antibiotic therapy and then stayed on maintenance rifaximin therapy.103 Thus, efficacy of both systemic antibiotics and rifaximin has been shown in the treatment of pouchitis.

Conclusion

The role of the gut microbiota in human health and disease has been well established. Imbalances in the composition, number, and diversity of bacteria normally found in the gut appear to play a role in IBD. Thus, modulation of the gut microbiota has been examined in a number of clinical trials of patients with IBD. Clinical studies of probiotics have yielded mixed results, and although many studies have demonstrated efficacy and safety, comparisons between studies are limited by inconsistencies in study design, clinical end points, and the variety of probiotic formulations and dosing regimens assessed. Antibiotics have shown efficacy for the treatment and management of patients with IBD, especially those with CD. Although exposure to antibiotics, especially in childhood, has been associated with increased risk of developing IBD, antibiotics are effective for the postoperative management of patients with CD, induction of remission of CD, and treatment of patients with fistulizing disease. Again, the strength of the evidence is limited by study design and differences in dosing regimens across studies. There are limited data supporting the use of antibiotics in patients with UC. Conventional systemic antibiotics are associated with a number of AEs and concern for drug resistance, both of which limit their long-term use. Additional studies are necessary to fully evaluate the role of probiotics and antibiotics in the shortterm and long-term management of IBD. This is an area of active research, demonstrated not only by the 5 registered trials of antibiotics and 3 registered trials of probiotics currently recruiting patients in the United States, but also by the increase in basic research.105 Future randomized controlled


Antibiotics in IBD

studies that include larger patient populations with more standardized regimens are needed to compare the efficacy of different antibiotic treatment strategies. These studies, in combination with data from mechanistic studies examining the role of bacteria in IBD, will better guide clinical practice in the optimal management and treatment of patients with IBD.


Acknowledgments

Technical editorial and medical writing assistance was provided under the direction of the authors by Sophie Bolick, PhD, Synchrony Medical Communications, LLC, West Chester, PA. Funding for this support was provided by Salix Pharmaceuticals, Inc., Raleigh, NC.

Conflicts of Interest Statement

David H. Kerman, MD, and Amar R. Deshpande, MD, have no conflicts of interest to declare.

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