Submit Manuscript

International Journal of Pharmacology

Year: 2012 | Volume: 8 | Issue: 7 | Page No.: 596-613
Facebook Twitter Digg Reddit Linkedin StumbleUpon E-mail
Review Article

A Comprehensive Review of Antibiotics in Clinical Trials for Inflammatory Bowel Disease

A.H. Abdolghaffari, S. Nikfar, H.R. Rahimi and M. Abdollahi

ABSTRACT

Although, positive role of special bacteria in induction of Inflammatory Bowel Disease (IBD) including Ulcerative Colitis (UC) and Crohn’s Disease (CD) have been demonstrated in several studies but the consensus on etiology of IBD and beneficial effect of antibiotics has not been reached yet. And, also, no well-designed clinical trials in this regard have been done yet. This review focuses on various clinical trials which have been done in according to beneficial use of antibiotics in UC and CD from 1978 to date. For this purpose, all electronic databases such as PubMed, Scopus, Google Scholar and Cochrane library were searched. The results of clinical trials suggested that metronidazole, ciprofloxacin or the combinations of these antibiotics are effective in CD. However, ciprofloxacin is the first choice, because it has good coverage on gram negative and anaerobic bacterium which plays an important role in CD. However, there is a controversy on the use of antibiotics in UC and the efficacy of them in long-term treatment of UC is still in doubt. Various antibiotics such as anti-tuberculosis, macrolides (clarithromycin), fluoroquinolones, 5-nitroimidazoles, rifaximin, rifamycin derivatives (rifampin), aminoglycosides (tobramycin), rifabutin, clofazimine, tetracyclines (tetracycline and doxycycline) and vancomycin have been under attention of researchers in the recent years. Furthermore, other antibiotics with lower cost and adverse effects, effectiveness and availability are the third generation of cephalosporins and gentamicin and also penicillin or clindamycin that should be evaluated in future studies.
PDF Abstract XML References Citation
Received: August 15, 2012;   Accepted: August 30, 2012;   Published: December 31, 2012

INTRODUCTION

Inflammatory bowel diseases: Inflammatory Bowel Diseases (IBD), including Crohn’s Disease (CD) and Ulcerative Colitis (UC) are characterized by gastrointestinal (GI) inflammation and some extra-intestinal indicators such as liver complications, arthritis, skin manifestations and eye problems (Williams et al., 2008). Site and nature of the inflammatory changes are the main differences between CD and UC (Table 1), in which CD can attack any portion of the GI tract from mouth to anus (skip lesions) and affect the whole bowel wall but a majority of the cases start in the terminal ileum, while, UC is restricted to the mucosa and epithelial lining of the gut, colon and the rectum (Walsh et al., 2011).

IBD considered in the past in the developed countries but their prevalence within developing countries has been increasing in the recent years. Also, if the prevalence of CD and UC is quite similar in developed countries such as North America, South America, Europe, Australia and New Zealand, however, there may be differences in developing countries such as Pakistan and India in which much less extra intestinal disease with both UC and CD has been reported. In Pakistan, few patients have perianal or fistulizing disease, however, the age of presentation of CD in India is a decade later than in the West, colonic involvement is also more common and fistulization appears less common in India (Bernstein et al., 2010). The incidence of IBD peaks in two age groups: mainly the third decade, with a smaller peak in the seventh decade.

Table 1: Summary of the main differences between ulcerative colitis (UD) and Crohn’s disease (CD)
Image for - A Comprehensive Review of Antibiotics in Clinical Trials for Inflammatory Bowel Disease

In adults, the prevalence of CD is higher among women but equal in both genders for UC (Kappelman et al., 2007). Furthermore, the incidence of CD varies from 0.7 to 14.6 individuals per 100,000 inhabitants, whereas the prevalence of UC varies from 1.5-24.5 individuals per 100,000 inhabitants. About 1.4 million people in the United States (US) suffer from IBD (Carbonnel et al., 2009; Lakatos, 2006). Therefore, different treating guideline should be considered in various around of the world that needs further studies.

IBD can induce significant intestinal signs including diarrhea typically having blood and mucus, abdominal pain, vomiting and weight loss (Bernstein et al., 2010). Therefore, IBD patients are usually incapable to do their daily works, common relations and experiences (Al-Qabandi et al., 2011). Although, the etiology of IBD still remains unknown but the role of genetic, environment, immune response dysregulation, intestinal microbes and Oxidative Stress (OS) have been already demonstrated (Bernstein et al., 2010; Rezaie et al., 2007; Salari and Abdollahi, 2009). Some studies suggest that infection is the main etiology but distinctive microbes have not been isolated yet (Krisner, 1988). It has been suggested that CD parallels with Johne’s disease in cattle which is due to Mycobacterium avium subspecies Paratuberculosis (MAP). However, today this hypothesis is not acceptable because MAP is not the only bacterium that is associated with CD and other bacterial strains including Yersinia enterocolitica, Chlamydia trachomatis, Listeria and cell wall deficient pseudomonas are also important (Dalziel, 1913; Sartor, 2005). These organisms as a cause for IBD are still challenging and the evidences are poor but it is still believed that CD and UC are resulted from an irregular immunological reaction to gut microbiota in susceptible host (Abraham and Cho, 2009). It has been demonstrated that the concentration of intestinal microbes in IBD is higher than normal and increases progressively with the severity of the disease (Rahimi et al., 2007a). This is important that bowel inflammation does not occur without change in gut bacterial flora as proved in experimental models of colitis (Sellon et al., 1998). In the healthy gut, there is a cooperative connection between the host and the gut bacterial flora in which exposure leads to down-regulation of inflammatory genes and inhibiting the immune response of the gut to other pathogens (Hanauer, 2006). Metronidazole, ciprofloxacin or their combinations are commonly used by most clinicians as first-line treatment in patients with perianal disease, in combination with surgical drainage of abscesses (Baumgart, 2012). Therefore, the beneficial role of antibiotics in IBD has been discussed in this review. For this purpose, databases of PubMed, Google Scholar and Scopus were searched from 1978 to February 2012 for clinical trials conducted on UC and CD patients. The search terms were inflammatory bowel disease, IBD, ulcerative colitis, UC, Crohn’s disease, CD, antibiotic, antimicrobial agents, antiparasitic agents, antimycobacterials agents, β-lactams, penicillins, cephalosporins, ketolides, carbapenems, tetracyclines, macrolides, aminoglycosides, nitroimidazoles and fluroquinolones. The search strategy was limited to clinical trials and English language.

Pathophysiology of IBD: The pathology of CD is characterized by an intermittent inflammation and skips lesions of transmural bowel wall that can develop to fibrosis, strictures and fistulas. Though, these lesions can occur in any area of the GI tract, they usually take place within the ileum. UC is restricted to the colon and rectum and it involves inflammation of the bowel wall mucosa and submucosa and the lesions can range as far as the cecum (Walsh et al., 2011).

While the etiology of IBD is not well known, however, the role of genetic predisposition, environmental triggers, bacteria, Oxidative Stress (OS) and dysregulation of the immune response cannot be ignored (Rezaie et al., 2007; Hanauer, 2006; Danese et al., 2004). Studies have determined that genetic background can predispose a subset of IBD patients to the progress of disease (Mathew and Lewis, 2004). Studies on genome have discovered more than 40 susceptibility loci for IBD, some of them are distinct for UC or CD and some of them are linked with both (Hakonarson and Grant, 2009). The IBD1 gene encoding the protein NOD2 (also called CARD15) in CD, OCTN1/2 within the IBD5 locus in CD and UC, ATG16L in CD, IRGM1 in CD and IL23R in CD and UC can be noted (Mayer, 2010). Studies have indicated that defects in NOD2 or OCTN1/2 affect the ability of the host to restrict and eliminate microbes that gain access to gut tissue (Mathew and Lewis, 2004). Interestingly inflammation and lesions generally occur in intestinal regions with the highest bacterial concentration and the patients with IBD typically have greater numbers of adherent bacteria compared to normal subject (Rahimi et al., 2007a; Thompson-Chagoyan et al., 2005). Intestinal lamina propria contains intestinal epithelia and inflammatory cells which make available an innate immune protection for the GI tract that equilibrates the requirement for immune tolerance of microbiota with the defense against microbial pathogens. Dysfunction at the epithelial border (for example disturbed mucus layer, imperfect tight junctions) may cause failure of tolerance. This dysfunction can trigger innate immune cells, causing them to secrete several cytokines and chemokines to the host commensal microbiota (Abraham and Cho, 2009; Mayer, 2010). It is thought that other immunological factors downstream antigen recognition including over-activity of effector lymphocytes and pro-inflammatory cytokines, failure of regulatory lymphocytes and anti-inflammatory cytokines to control inflammation and resistance of T-cells to apoptosis (Bamias et al., 2005). Several studies have demonstrated that Toll-like Receptors (TLRs) represent key mediators of innate host defense in the intestine, involved in maintaining mucosal as well as commensal homeostasis. Recent studies in various experimental models of colitis have helped to reveal the mechanistic importance of TLR dysfunction in IBD pathogenesis. It has been demonstrated that environment, genetics and host immunity form a multidimensional and highly interactive regulatory triad controls TLR function in the intestinal mucosa. Imbalance between these factors may promote aberrant TLR signaling, significantly contributing to acute and chronic intestinal inflammatory processes in IBD (Cario, 2010).

Drugs used in the treatment of IBD: Medical treatment of IBD is rapidly developing with introduction of new biological agents that are likely to modify future therapeutic approaches (Walsh et al., 2011). Main objectives of current drug treatments are to maintain the patient in remission and ameliorate the disease’s secondary effects, rather than modifying or reversing the underlying pathogenic mechanism (Pithadia and Jain, 2011).

Many drugs and drug classes are available to manage both UC and CD, including 5-amino salicylate (5-ASA) (Nikfar et al., 2009; Rahimi et al., 2009a), corticosteroids (Rahimi et al., 2007b), immunosuppressive agents and anti tumor necrosis factor (TNF-α) (Rahimi et al., 2007c; Nikfar et al., 2010a; Amini-Shirazi et al., 2009), antioxidants (Ebrahimi et al., 2008; Khoshakhlagh et al., 2007), probiotics (Rahimi et al., 2008a; Elahi et al., 2008; Nikfar et al., 2010b), antibiotics (Loftus et al., 2008; Feagan et al., 2007) and some herbal medicines as supplemental therapy (Rahimi et al., 2009b; Rahimi et al., 2010; Abdolghaffari et al., 2010; Hasani-Ranjbar et al., 2009).

For management of mild to moderate IBD, salicylates are used although they are not without adverse effects. For management of moderate to severe IBD, glucocorticoides and immunosuppressive drugs are usually used (Rahimi et al., 2009b). New biological agents target TNF and adhesion proteins for inflammatory cell translocation. However, anti-TNF therapy may increase the risk of infection (Rutgeerts et al., 2009; Lakatos and Miheller, 2010; Nikfar et al., 2010b) and thus must be used with many caution and as the last options. Antibiotics are recommended in CD patients with perianal disease and fistulas and also in the treatment of C difficile infection (Prantera and Scribano, 2009). Although, antibiotics are often recommended to induce remission in mild to moderate CD, they are also effective for handling fistulas, bacterial overgrowth, abdominal abscesses and infections around the anus and genital areas (Pithadia and Jain, 2011).

Intestinal microflora can be changed by administering antibiotics and prebiotics that contain three species of Bifidobacterium, 4 species of Lactobacillus and Streptococcus salivarius (Prantera and Scribano, 2009; Travis et al., 2006) or probiotics (beneficial bacteria) or the combination of these methods (synbiotics). Studies support the protective role of probiotics and prebiotics in IBD or its complications (Salari et al., 2012; Ghasemi-Niri et al., 2011; Hedin et al., 2010; Nikfar et al., 2008; Rahimi et al., 2008b; Alivanis et al., 2010; Jamalifar et al., 2011) and even in irritable bowel syndrome (Hosseini et al., 2012) and therefore, they can be more effective in combination to antibiotics.

Generally, we can divide the treatment and management of IBD into five steps:

• Administration of oral aminosalicylate including sulfasalazine, mesalamine, balsalazide and olsalazine
• Antibiotics including ciprofloxacin, metronidazole, antituberculosis therapy, macrolides, fluoroquinolones, 5-nitroimidazoles and rifaximin (alone or in combination) can be used. However, the adverse effects of antibiotics including nausea, anorexia, diarrhea and monilial (candidal) infections, peripheral neuropathy (mostly observed with metronidazole) should be concerned in each individual
• Administration of corticosteroids such as intravenous (i.v.) methylprednisolone oral or rectal budesonide (Alivanis et al., 2010; Li et al., 2008) can be considered
• Administration of immune modifiers including 6-mercaptopurine or azathioprine (1-2 mg kg-1 day-1), infliximab (5 mg kg-1 at 0, 2 and 6 weeks, followed by 5 mg kg-1 every 8 weeks thereafter), adalimumab and natalizumab should be considered (Ford et al., 2011; Lichtenstein et al., 2006) with adequate care
• Administration of methotrexate (12.5-25 mg week-1, p.o. or IM), thalidomide (50-300 mg day-1, p.o.) and IL-11 (1 mg week-1, SC) in CD and cyclosporine A (i.v., 2-4 mg kg-1 day-1) butyrate enema (rectal, 200 mL day-1) and heparin (SC, 20,000 U day-1) in UC (Lichtenstein et al., 2006) should be considered

The common bacteria in IBD: Several studies have shown differences in bacterial diversity between healthy individuals and IBD patients. Overall the result of these studies have shown evidence for a decline in bacterial diversity, an increase in fungal and a decrease in methanogen diversity in GI tract of IBD patients but they could not identify specific bacterial or fungal communities for this disease yet (Scanlan and Marchesi, 2008; Franke et al., 2008; Frank et al., 2007; Kuehbacher et al., 2006; Ott et al., 2008; Scanlan et al., 2008). Increase of Enterobacteria in patient with IBD has been previously shown (Kotlowski et al., 2007). Mycobacterium avium subsp. paratuberculosis, Chlamydia pneumoniae, Saccharomyces cerevisiae, Clostridium difficile, Campylobacter jejuni and adherent invasive Escherichia coli (E. coli) have all been shown to be potentially infectious organisms in the development of IBD (Reiff and Kelly, 2010; Berg et al., 2012; O’Hara et al., 2012). Other bacteria which have a positive role in induction of IBD in patients are indicated in Table 2. Some studies have shown that an increase in mucosal populations of adherent invasive E. coli which were found prevalent in CD is the strongest evidence of a specific pathogen in human IBD (Sasaki et al., 2007; Rhodes, 2007; Darfeuille-Michaud et al., 2004).

Commensal microorganisms live with their hosts and are essential for development of a healthy gut. The role of commensal bacteria is to facilitate digestion, absorption and storage of nutrients as well as protection against pathogen colonization through competition for nutrients, secretion antimicrobial substances and micro-niche exclusion. In addition, commensal bacteria promote angiogenesis and development of the intestinal epithelium and have been shown necessary for normal development and function of the immune system (Artis, 2008). Overactive immune response towards commensal bacteria causes initiation and development of IBD. In fact, microbial balance is crucial to protect against bad gram negative pathogens, such as E. coli and Pseudomonas (Reiff and Kelly, 2010). Consequently, strong evidence from animal models recommends that the development of IBD is impossible in the presence of normal enteric flora (Triantafillidis et al., 2011).

Application of antibiotics in IBD: Most of studies that have indicated the role of special bacteria in induction of IBD, are not well designed. Most of existing clinical trials had small sample size (16 to 213 subjects), short duration (2 to 24 weeks) and methodological bias. In patients with IBD, the rate of Bacteroides, Escherichia coli and Enterococci increase in the bowel while Lactobacilli and Bifidobacteria decrease that necessitate use of antibiotics (Triantafillidis et al., 2011; Pithadia and Jain, 2011).

Some studies demonstrated that a decrease in mucosal peptide antibiotics (defensins) could be involved in the pathogenesis of IBD. Defensins are antimicrobial peptides made at a range of epithelial exteriors that their highest function is to retain equilibrium between protection from pathogens and tolerance to normal flora. It has been advised that diminished expression of defensins compromises host immunity resulting in inflammation. This deficiency may be due to change in the intracellular transcription of NF-κB and the intracellular peptidoglycan receptor NOD2. The beneficial effect of antibiotics in CD patients exhibits the theory of the presence of weakened mucosal antibacterial motion. Although recent studies suggest that defensin deficiency might be a result of mucosal surface damage in inflammatory course, it still needs to be clarified by further studies (Triantafillidis et al., 2011; Wehkamp et al., 2005; Ramasundara et al., 2009; Fellerman et al., 2003).

Generally, antibiotic can be used in IBD for numerous aims including as an assistant in the company of other medicines for handling of active IBD, as a management for a definite impediment of CD and as prophylaxis for disease relapse in postoperative CD (Triantafillidis et al., 2011). The conditions that use of antibiotics cannot be declined include (C. difficile and so forth) (Sartor, 2004):

• Phlegmon of intra-abdominal, hepatic or perianal abscesses and inflammation
• Fistulae (perianal, enteroenteric, enterocolonic, enterocutaneous and enterovesical)
• Anal fissures
• Small intestinal bacterial overgrowth secondary to strictures, loss of ileocecal valve, enteroenteric and enterocolonic fistulae
• Postoperative infections
• Toxic megacolon
• Secondary infections

Table 2: Possible bacterium which has a positive role in IBD
Image for - A Comprehensive Review of Antibiotics in Clinical Trials for Inflammatory Bowel Disease
AM: Amikacin, GM: Gentamicin, CTX: Cotrimoxazol, AMP: Ampicillin, MTZ: Metronidazole, VCM: Vancomycin, RFX: Rifaximin, FDX: Fidaxomicin, CDAD: Clostridium difficile associated diarrhea, ND: Not determined, ERM: Erythromycin, RFB: Rifabutin, MAP: Mycobacterium avium subspecies paratuberculosis, DOX: Doxycycline, CLR: Clarithromycin, TE: Tetracycline, AZ: Azathioprine, AMG: Aminoglycoside, AMC: Amoxicillin-clavulanic acid, FQ: Fluoroquinolones, CTX: Ceftriaxone, CAM: Chloramphenicol, CIP: Ciprofloxacin, CL: Clindamycin, PEN: Penicillin, NRF: Norfloxacin, CET: Cephalotin, AMX: Amoxicillin

Mechanisms of action of antibiotics in IBD include (Sartor, 2004):

• Reduction of luminal and adherent mucosal bacterial foci
• Selective elimination of pathogenic luminal bacteria
• Reduction of tissue invasion, microabscesses and secondary bacterial proliferation adjacent to mucosal ulcers and fistulae
• Reduction of bacterial translocation and systemic dissemination of possible bacteria

The use of antibiotics as principal or adjuvant treatment of UC and CD is still debated. Even though the systemic use of antibiotics against IBD can act against enteric commensal bacteria but controlled clinical trials support use of these agents (Sartor, 2004).

Diverse factors may be measured in IBD clinical trials include CD activity index (CDAI) and Serum Orosomucoid (SO) which can be measured to estimate the improvement of disease activity (mean CDAI; 217; range, 160-305) (Colombel et al., 1999). Other factors include median pre-treatment Harvey Bradshaw index (HBI) (9; range 5-16) and median serum C-reactive protein (CRP) (21.5 mg L-1; range <5-117) and production of provocative cytokines (Leiper et al., 2000).

Antibiotics in CD; current clinical trials: In recent times, several clinical trials have been published on the use of broad-spectrum antibiotics in CD patients. The antibiotic used so far in patients with CD include metronidazole, rifaximin, clarithromycin, ciprofloxacin, clofazimine and anti-tuberculosis drugs. Ciprofloxacin and metronidazole or their combination are considered as standard for prompting remission in CD while ciprofloxacin is the first choice because it has good coverage on gram negative and anaerobic bacteria such as E. coli (Sreedhar et al., 2008). A systematic review and meta-analysis of Randomized Controlled Trials (RCTs) by Khan et al. (2011) showed the benefit of antibiotics in treatment of IBD. They were effective in both remission of active CD (Relative Risk (RR) of active disease not in remission was 0.85) and conservation of CD (RR of relapse was 0.62) (Khan et al., 2011). Anti-tuberculosis, macrolides, fluroquinolones, 5-nitroimidazoles, rifaximin and rifamycin derivatives were tested in this study (Khan et al., 2011). Cotrimoxazole and tetracycline are other antibiotics were also used for CD (Triantafillidis et al., 2011).

As we mentioned in Table 3, rifaximin as a rifamycin analog with a broad spectrum of activity in form of rifaximin-extended intestinal release has been used in CD and the results showed improvement in remission as CDAI reduced. Also metronidazole was used in CD as monotherapy or in combination with ciprofloxacin and cotrimoxazole in several clinical trials successfully and led to remission and decrease of CDAI. Results of the clinical trials demonstrated that ciprofloxacin is an effective drug in a proportion of patients with active CD mainly located in the colon. Clarithromycin as a broad-spectrum antibiotic has been used in CD but it was found ineffective in active CD. It is notable that use of clarithromycin in combination with rifabutin has been good in decreasing CDAI. Although, it has been shown that antituberculosis compounds are ineffective in CD but rifabutin in combination with clofazimine and clarithromycin reduced inflammation in CD.

Further clinical trial studies about antibiotic therapy in CD are summarized in Table 3.

Antibiotics in UC; current clinical trials: In comparison to CD, there are a few studies about the advantageous of antibiotics in UC where they seem ineffective for long-term treatment (Table 1) in spite of implicating of bacteria such as Enterococci, Peptostreptococci and Enterobacteria which live on the lining of the bowel being involved in UC. The failure of antibiotics may possibly return to poor identification of involved bacteria in UC and unsuitable pick of antibiotics. Nevertheless, most of studies have reported the benefit of ciprofloxacin, metronidazole and tobramycin in UC (Mantzaris et al., 1994, 2004; Madden et al., 1994; Chiba et al., 2011).

As we mentioned in Table 4, use of amoxicillin in combination with tetracycline and metronidazole in UC improved clinical symptoms, reduced Clinical Activity Index (CAI) and retained disease in remission. Furthermore, use of amoxicillin with clavulanic reduced production of inflammatory cytokines. Ciprofloxacin has been investigated in patients with UC with diverse results and needs further studies but in overall it seems effective. Rifaximin was also studied in patients with UC and showed no significant differences in clinical efficacy however it improved stool frequency, rectal bleeding and sigmoidoscopic score.

Table 3: Summary of clinical trials of antibiotic therapy in CD
Image for - A Comprehensive Review of Antibiotics in Clinical Trials for Inflammatory Bowel Disease
RFX-EIR: Rifaximin-extended intestinal release, PO: Per oral, IV: Intravenous, N: Number of patients, AMX: Amoxicillin, TE: Tetracycline, MTZ: Metronidazole, CIP: Ciprofloxacin, MTX: Methotrexate, 5-ASA: Aminosalicylates, CS: Cyclosporin, IFX: Infliximab, AZ: Azathioprine, 6-MP: 6-mercaptopurine, ND: Not determined, MMF: Mycophenolate mofetil, PDN: Prednisolone, BUD: Budesonide, RFX: Rifaximin, CLR: Clarithromycin, OLZ: Olsalazine, NAG: N-acetyl glucosamine, BS: Bismuth subcitrate, RFB: Rifabutin, CFZ: Clofazimine, MP: Methylprednisolone, MO: microorganism, ETB: Ethambutol, HBI: Harvey Bradshaw index, CDAI: Crohn’s disease activity index, RFP: Rifampicin, CLO: Clofazimine, INH: Isoniazid, DDS: Dapsone, FA: Fusidic acid (an antibiotic with T-cell specific immunosuppressive effects similar to those of cylosporin): VN: Vivonex, FM: Framycetin, COL: Colistin, NYS: Nystatin, SSZ: Sulfasalazine, CTX: Cotrimoxazol

Table 4: Summary of clinical trials of antibiotic therapy in UC
Image for - A Comprehensive Review of Antibiotics in Clinical Trials for Inflammatory Bowel Disease
PO: Per oral, IV: Intravenous, N: Number of patients, SD: Study design, AMX: Amoxicillin, TE: Tetracycline, MTZ: Metronidazole, CAI: Clinical activity index, CIP: Ciprofloxacin, PDN: Prednisolone, HCT: Hydrocortisone, SSZ: Sulfasalazine, RFX: Rifaximin, AMC: Amoxicillin-clavulanic acid, MP: Methylprednisolone, BMZ: betamethasone, OLZ: Olsalazine, TOB: Tobramycin, VCM: Vancomycin, MIP-1: Macrophage inflammatory protein-1, CRP: C-reactive protein, IL: interleukin, HBT: HBT (hydrogen breath test) is a simple and non-invasive test for clinical diagnosis of IBD patients which is performed after a short period of fasting (typically 8–12 hours), EC: enteric-coated

Investigations demonstrated that use of metronidazole in UC in conjunction with corticosteroids produced no better results when compared with placebo plus corticosteroids in inducing remission. It was reported that use of metronidazole in combination with tobramycin showed no significant improvement in remission rate.

Further clinical trials about antibiotic therapy in UC are summarized in Table 4.

CONCLUSIONS

Taking collectively, undesirable effects of aerobic and anaerobic bacteria in etiology of IBD cannot be neglected (Artis, 2008) and thus it is not surprising to see usefulness of antibiotics in active UC or CD and also in relapsing quiescent CD (Pineton de Chambrun et al., 2008). Antibiotics when used with 5-ASAs or corticosteroids or probiotics or immunosuppressive showed better effects than monotherapy. Metronidazole, ciprofloxacin, anti tuberculosis or the combinations of these antibiotics seem effective in CD. In UC, concurrent use of amoxicillin, tetracycline and metronidazole keeps patients in remission much better than monotherapy. New antibiotics such as anti-tuberculosis, macrolides clarithromycin, fluroquinolones, 5-nitroimidazoles, rifaximin, rifamycin derivatives (rifampin), aminoglycosides (tobramycin), rifabutin, clofazimine, tetracyclines (tetracycline and doxycycline) and vancomycin have shown some benefits in UC and CD. Up to now, most of supports go to use of ciprofloxacin and metronidazole. Rifaximin has also received good supports in management of CD. Regarding pharmacoeconomics essentials, low cost and toxicity antibiotics such as first to third generation of cephalosporin and gentamicin (effective against E. coli) or penicillin and clindamycin (effective against C. difficile) should be trailed in future trials. The final point is that the debate on the use of antibiotics in IBD still remains and need further well-designed studies to help identify which patients need antibiotic or antibiotic combination and if yes, what is the preferred compound with what dosage and duration of treatment.

ACKNOWLEDGMENT

This paper is the outcome of an in-house financially non-supported study.

REFERENCES

  1. Abdolghaffari, A.H., A. Baghaei, F. Moayer, H. Esmaily and M. Baeeri et al., 2010. On the benefit of Teucrium in murine colitis through improvement of toxic inflammatory mediators. Human Exp. Toxicol., 29: 287-295.
    CrossRef
  2. Abraham, C. and J.H. Cho, 2009. Inflammatory bowel disease. N. Engl. J. Med., 361: 2066-2078.
    PubMed
  3. Afdhal, N.H., A. Long, J. Lennon, J. Crowe and D.P. O'Donoghue, 1991. Controlled trial of antimycobacterial therapy in Crohn's disease. Clofazimine versus placebo. Dig. Dis. Sci., 36: 449-453.
    PubMed
  4. Alivanis, P., G. Aperis, F. Lambrianou, A. Zervos, C. Paliouras, N. Karvouniaris and A. Arvanitis, 2010. Reversal of refractory sulfasalazine-related renal failure after treatment with corticosteroids. Clin. Ther., 32: 1906-1910.
    CrossRef
  5. Al-Qabandi, W.A., E.K Buhamrah, K.A Hamadi, S.A. Al-Osaimi, A.A. Al-Ruwayeh and J. Madda, 2011. Inflammatory bowel disease in children, an evolving problem in Kuwait. Saudi J. Gastroenterol., 17: 323-327.
    CrossRefPubMed
  6. Ambrose, N.S., R.N. Allan, M.R. Keighley, D.W. Burdon, D. Youngs, P. Barnes and J.E. Lennard-Jones, 1985. Antibiotic therapy for treatment in relapse of intestinal Crohn's disease: A prospective randomized study. Dis. Colon Rectum., 28: 81-85.
    CrossRef
  7. Amini-Shirazi, N., A. Hoseini, A. Ranjbar, A. Mohammadirad, N. Yasa and M. Abdollahi, 2009. Inhibition of tumor necrosis factor and nitrosative/oxidative stresses by Ziziphora clinopoides (Kahlioti); A molecular mechanism of protection against dextran sodium sulfate-induced colitis in mice. Toxicol. Mech. Methods, 19: 183-189.
    CrossRefPubMedDirect Link
  8. Arnold, G.L., M.R. Beaves, V.O. Pryjdun and W.J. Mook, 2002. Preliminary study of ciprofloxacin in active Crohn's disease. Inflamm. Bowel Dis., 8: 10-15.
    CrossRef
  9. Artis, D., 2008. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat. Rev. Immunol., 8: 411-420.
    CrossRefDirect Link
  10. Bamias, G., M.R. Nyce, S.A. De La Rue and F. Cominelli, 2005. New concepts in the pathophysiology of inflammatory bowel disease. Ann. Intern. Med., 143: 895-904.
    PubMed
  11. Baumgart, D.C., 2012. Crohn's Disease and Ulcerative Colitis From Epidemiology and Immunobiology to a Rational Diagnostic and Therapeutic Approach. Springer, New York, USA., ISBN-13: 978-1461409977.
  12. Berg, A.M., C.P. Kelly and F.A. Farraye, 2012. Clostridium difficile infection in the inflammatory bowel disease patient. Inflamm. Bowel Dis., (In Press).
    CrossRef
  13. Bernstein, C.N., M. Fried, J.H. Krabshuis, H. Cohen and R. Eliakim et al., 2010. World gastroenterology organization practice guidelines for the diagnosis and management of IBD in 2010. Inflamm. Bowel Dis., 16: 112-124.
    CrossRef
  14. Blichfeldt, P., J.P. Blomhoff, E. Myhre and E. Gjone, 1978. Metronidazole in Crohn's disease: A double blind cross-over clinical trial. Scand. J. Gastroenterol., 13: 123-127.
    PubMed
  15. Borody, T.J., S. Bilkey, A.R. Wettstein, S. Leis, G. Pang and S. Tye, 2007. Anti-mycobacterial therapy in Crohn's disease heals mucosa with longitudinal scars. Dig. Liver Dis., 39: 438-444.
    CrossRefPubMed
  16. Bottone, E.J., 1997. Yersinia enterocolitica: The charismacontinues. Clin. Microbiol. Rev., 10: 257-276.
    PubMed
  17. Burillo, A. and E. Bouza, 2010. Chlamydophila pneumoniae. Infect. Dis. Clin. North Am., 24: 61-71.
    CrossRef
  18. Burke, D.A., A.T. Axon, S.A. Clayden, M.F. Dixon, D. Johnston and R.W. Lacey, 1990. The efficacy of tobramycin in the treatment of ulcerative colitis. Aliment. Pharmacol. Ther., 4: 123-129.
    CrossRefPubMed
  19. Carbonnel, F., P. Jantchou, E. Monnet and J. Cosnes, 2009. Environmental risk factors in Crohn's disease and ulcerative colitis: An update. Gastroenterol. Clin. Biol., 33: S145-S157.
    CrossRef
  20. Cario, E., 2010. Toll-like receptors in inflammatory bowel diseases: A decade later. Inflamm. Bowel Dis., 16: 1583-1597.
    CrossRef
  21. Casellas, F., N. Borruel, M. Papo, F. Guarner, M. Antolin, S. Videla and J.R. Malagelada, 1998. Antiinflammatory effects of enterically coated amoxicillin-clavulanic acid in active ulcerative colitis. Inflamm. Bowel Dis., 4: 1-5.
    CrossRefPubMed
  22. Chapman, R.W., W.S. Selby and D.P. Jewell, 1986. Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut, 27: 1210-1212.
    CrossRef
  23. Chiba, T., K. Sato, Y. Toya, K. Endo and Y. Abiko et al., 2011. Serial changes in cytokine expression in irritable bowel syndrome patients following treatment with calcium polycarbophil. Hepatogastroenterology, 58: 1527-1530.
    PubMedDirect Link
  24. Colombel, J.F., M. Lemann, M. Cassagnou, Y. Bouhnik and B. Duclos et al., 1999. A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn's disease. Am. J. Gastroenterol., 94: 674-678.
    CrossRefPubMed
  25. Dalziel, T.K., 1913. Chronic interstitial enteritis. Br. Med. J., 2: 1068-1070.
    Direct Link
  26. Danese, S., M. Sans and C. Fiocchi, 2004. Inflammatory bowel disease: The role of environmental factors. Autoimmun. Rev., 3: 394-400.
    CrossRef
  27. Darfeuille-Michaud, A., J. Boudeau, P. Bulois, C. Neut and A.L. Glasser et al., 2004. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease. Gastroenterology, 127: 412-421.
    CrossRef
  28. Dejaco, C., M. Harrer, T. Waldhoer, W. Miehsler, H. Vogelsang and W. Reinisch, 2003. Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn's disease. Aliment. Pharmacol. Ther., 18: 1113-1120.
    CrossRefPubMed
  29. Dickinson, R.J., H.J. O'Connor, I. Pinder, I. Hamilton, D. Johnston and A.T. Axon, 1985. Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis. Gut, 26: 1380-1384.
    PubMed
  30. Elahi, B., S. Nikfar, S. Derakhshani, M. Vafaie and M. Abdollahi, 2008. On the benefit of probiotics in the management of pouchitis in patients underwent ileal pouch anal anastomosis: A meta-analysis of controlled clinical trials. Dig. Dis. Sci., 53: 1278-1284.
    CrossRefPubMedDirect Link
  31. Epstein, L. and Y. Golan, 2012. Fidaxomicin, a new treatment for Clostridium difficile infections. Drugs Today, 48: 101-108.
    PubMed
  32. Ebrahimi, F., H. Esmaily, M. Baeeri, A. Mohammadirad, S. Fallah and M. Abdollahi, 2008. Molecular evidences on the benefit of N-acetylcysteine in experimental colitis. Central Eur. J. Biol. 3: 135-142.
    CrossRefDirect Link
  33. Feagan, B.G., W.J. Sandborn, S. Hass, T. Niecko and J. White, 2007. Health-related quality of life during natalizumab maintenance therapy for Crohn's disease. Am. J. Gastroenterol., 102: 2737-2746.
    PubMed
  34. Fellerman, K., J. Wehkamp, K.R. Herrlinger and E.F. Stange, 2003. Crohn's disease: A defensin deficiency syndrome?. Eur. J. Gastroenterol. Hepatol., 15: 627-634.
    PubMed
  35. Ford, A.C., W.J. Sandborn, K.J. Khan, S.B. Hanauer, N.J. Talley and P. Moayyedi, 2011. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am. J. Gastroenterol., 106: 644-659.
    PubMed
  36. Frank, D.N., A.L. Amand, R.A. Feldman, E.C. Boedeker, N. Harpaz and N.R. Pace, 2007. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl. Acad. Sci., 104: 13780-13785.
    PubMed
  37. Franke, A., T. Balschun, T.H. Karlsen, J. Sventoraityte and S. Nikolaus et al., 2008. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet., 40: 1319-1323.
    PubMed
  38. Ghasemi-Niri, S.F., A.H. Abdolghaffari, S. Fallah-Benakohal, M. Hosseinpour-Feizi and P. Mahdaviani et al., 2011. On the benefit of whey-cultured Lactobacillus casei in murine colitis. J. Physiol. Pharmacol., 62: 341-346.
    PubMed
  39. Gionchetti, P., F. Rizzello, A. Ferrieri, A. Venturi and C. Brignola et al., 1999. Rifaximin in patients with moderate or severe ulcerative colitis refractory to steroid-treatment: A double-blind, placebo-controlled trial. Dig. Dis. Sci., 44: 1220-1221.
    PubMed
  40. Goodgame, R.W., K. Kimball, S. Akram, E. Ike, C.N. Ou, F. Sutton and D. Graham, 2001. Randomized controlled trial of clarithromycin and ethambutol in the treatment of Crohn's disease. Aliment. Pharmacol. Ther., 15: 1861-1866.
    PubMed
  41. Greenbloom, S.L., A.H. Steinhart and G.R. Greenberg, 1998. Combination ciprofloxacin and metronidazole for active Crohn's disease. Can. J. Gastroenterol., 12: 53-56.
    PubMed
  42. Gui, G.P.H., P.R.S. Thomas, M.L.V. Tizard, J. Lake, J.D. Sanderson and J. Hermon-Taylor, 1997. Two-year-outcomesanalysis of Crohn'sdiseasetreated with rifabutin and macrolideantibiotics. J. Antimicrob. Chemother., 39: 393-400.
    Direct Link
  43. Hakonarson, H. and S.F. Grant, 2009. Genome-wide association studies in type 1 diabetes, inflammatory bowel disease and other immune-mediated disorders. Semin. Immunol., 21: 355-362.
    PubMed
  44. Hanauer, S.B., 2006. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm. Bowel Dis., 1: S3-S9.
    PubMed
  45. Hasani-Ranjbar, S., B. Larijani and M. Abdollahi, 2009. A systematic review of the potential herbal sources of future drugs effective in oxidant-related diseases. Inflamm. Allergy Drug Targets, 8: 2-10.
    CrossRefPubMedDirect Link
  46. Hedin, C.R., M. Mullard, E. Sharratt, C. Jansen and J.D. Sanderson et al., 2010. Probiotic and prebiotic use in patients with inflammatory bowel disease: A case-control study. Inflamm. Bowel Dis., 16: 2099-2108.
    PubMed
  47. Hosseini, A., S. Nikfar and M. Abdollahi, 2012. Probiotics use to treat irritable bowel syndrome. Expert Opin. Biol. Ther.
    CrossRefDirect Link
  48. Inoue, S., H. Nakase, M. Matsuura, S. Ueno and N. Uza et al., 2007. Open label trial of clarithromycin therapy in Japanese patients with Crohn's disease. J. Gastroenterol. Hepatol., 22: 984-988.
    PubMed
  49. Jamalifar, H., H. Rahimi, N. Samadi, A. Shahverdi and Z. Sharifian et al., 2011. Antimicrobial activity of different Lactobacillus species against multi- drug resistant clinical isolates of Pseudomonas aeruginosa. Iran J. Microbiol., 3: 21-25.
    PubMed
  50. Kappelman, M.D., S.L. Rifas-Shiman, K. Kleinman, D. Ollendorf, A. Bousvaros, R.J. Grand and J.A. Finkelstein, 2007. The prevalence and geographic distribution of Crohn's disease and ulcerative colitis in the United States. Clin. Gastroenterol. Hepatol., 5: 1424-1429.
    CrossRefPubMed
  51. Khan, K.J., T.A. Ullman, A.C. Ford, M.T. Abreu and A. Abadir et al., 2011. Antibiotic therapy in inflammatory bowel disease: A systematic review and meta-analysis. Am. J. Gastroenterol., 106: 661-673.
    CrossRefPubMedDirect Link
  52. Khoshakhlagh, P., M. Bahrololoumi-Shapourabadi, A. Mohammadirad, L. Ashtaral-Nakhai, B. Minaie and M. Abdollahi, 2007. Beneficial effect of phosphodiesterase-5 inhibitor in experimental inflammatory bowel disease: Molecular evidence for involvement of oxidative stress. Toxicol. Mech. Methods, 17: 281-288.
    CrossRef
  53. Koch, T.R., 2007. Treatment of Crohn's disease with an antibiotic regimen directed against mycobacterium avium paratuberculosis. http://clinicaltrials.gov/ct2/show/NCT00513552.
  54. Koda-Kimble, M.A., L.Y. Young, W.A. Kradjan, B.J. Guglielmo, B.K. Alldredge and R.L. Corelli, 2009. Applied Therapeutics: The Clinical Use of Drugs. 9th Edn., Wolters Kluwer Health/Lippincott Williams and Wilkins, Philadelphia.
  55. Kotlowski, R., C.N. Bernstein, S. Sepehri and D.O. Krause, 2007. High prevalence of Escherichia coli belonging to the B2+D phylogenetic group in inflammatory bowel disease. Gut, 56: 669-675.
    PubMed
  56. Krisner, J.B., 1988. Historical aspects of infl ammatory bowel disease. J. Clin. Gastroenterol., 10: 286-297.
    PubMed
  57. Kuehbacher, T., S.J. Ott, U. Helwig, T. Mimura and F. Rizzello et al., 2006. Bacterial and fungal microbiota in relation to probiotic therapy (VSL No. 3) in pouchitis. Gut, 9: 833-841.
    Direct Link
  58. Lakatos, P.L., 2006. Recent trends in the epidemiology of inflammatory bowel diseases: Up or down?. World J. Gastroenterol., 12: 6102-6108.
    Direct Link
  59. Lakatos, P.L. and P. Miheller, 2010. Is there an increased risk of lymphoma and malignancies under anti-TNF therapy in IBD?. Curr. Drug Targets, 11: 179-186.
    PubMed
  60. Langholz, E., J. Brynskov, K. Bendtzen, M. Vilien and V. Binder, 1992. Treatment of Crohn's disease with fusidic acid: An antibiotic with immunosuppressive properties similar to cyclosporin. Aliment. Pharmacol. Ther., 6: 495-502.
    PubMed
  61. Leiper, K., A.I. Morris and J.M. Rhodes, 2000. Open label trial of oral clarithromycin in active Crohn's disease. Aliment Pharmacol. Ther., 14: 801-806.
    PubMed
  62. Leiper, K., K. Martin, A. Ellis, A.J. Watson, A.I. Morris and J.M. Rhodes, 2008. Clinical trial: Randomized study of clarithromycin versus placebo in active Crohn's disease. Aliment Pharmacol. Ther., 27: 1233-1239.
    PubMed
  63. Li, C.Y., B.L. Zhang, C.X. Chen and Y.M. Li, 2008. OMOM capsule endoscopy in diagnosis of small bowel disease. J. Zhejiang Univ. Sci. B., 9: 857-862.
    PubMed
  64. Lichtenstein, G.R., M.T. Abreu, R. Cohen and W. Tremaine, 2006. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology, 130: 935-939.
    PubMed
  65. Lobo, A.J., D.A. Burke, G.M. Sobala and A.T. Axon, 1993. Oral tobramycin in ulcerative colitis: Effect on maintenance of remission. Aliment Pharmacol. Ther., 7: 155-158.
    PubMed
  66. Loftus, E.V., B.G. Feagan, J.F. Colombel, D.T. Rubin and E.Q. Wu et al., 2008. Effects of adalimumab maintenance therapy on health-related quality of life of patients with Crohn's disease: Patient-reported outcomes of the CHARM trial. Am. J. Gastroenterol., 103: 3132-3141.
    PubMed
  67. Madden, M.V., A.S. McIntyre and R.J. Nicholls, 1994. Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis. Dig. Dis. Sci., 39: 1193-1196.
    PubMed
  68. Maeda, Y., S.C. Ng, P. Durdey, C. Burt and J. Torkington et al., 2010. Randomized clinical trial of metronidazole ointment versus placebo in perianal Crohn's disease. Br. J. Surg., 97: 1340-1347.
    PubMed
  69. Mantzaris, G.J., A. Hatzis, P. Kontogiannis and G. Triadaphyllou, 1994. Intravenous tobramycin and metronidazole as an adjunct to corticosteroids in acute, severe ulcerative colitis. Am. J. Gastroenterol., 89: 43-46.
    PubMed
  70. Mantzaris, G.J., E. Archavlis, P. Christoforidis, D. Kourtessas and P. Amberiadis et al., 1997. A prospective randomized controlled trial of oral ciprofloxacin in acute ulcerative colitis. Am. J. Gastroenterol., 92: 454-456.
    PubMed
  71. Mantzaris, G.J., K. Petraki, E. Archavlis, P. Amberiadis, D. Kourtessas, A. Christidou and G. Triantafyllou, 2001. A prospective randomized controlled trial of intravenous ciprofloxacin as an adjunct to corticosteroids in acute, severe ulcerative colitis. Scand. J. Gastroenterol., 36: 971-974.
    PubMed
  72. Mantzaris, G.J., M. Sfakianakis, E. Archavlis, K. Petraki, A. Christidou, A. Karagiannidis and G. Triadaphyllou, 2004. A prospective randomized observer-blind 2-year trial of azathioprine monotherapy versus azathioprine and olsalazine for the maintenance of remission of steroid-dependent ulcerative colitis. Am. J. Gastroenterol., 99: 1122-1128.
    PubMed
  73. Maragkoudakis, S., S.R. Poulidaki, E. Papadomanolaki, G. Alevraki, M. Papadogianni, N. Oikonomou and P. Fanourgiakis, 2011. Empiric antimicrobial therapy and infectious diarrhea. Do we need local guidelines?. Eur. J. Int. Med., 22: 60-62.
    PubMed
  74. Mathew, C.G. and C.M. Lewis, 2004. Genetics of inflammatory bowel disease: Progress and prospects. Hum. Mol. Genet., 13: R161-R168.
    CrossRefPubMed
  75. Mayer, L., 2010. Evolving paradigms in the pathogenesis of IBD. J. Gastroenterol., 45: 9-16.
    PubMed
  76. Nikfar, S., H. Mirfazaelian and M. Abdollahi, 2010. Efficacy and tolerability of immunoregulators and antibiotics in fistulizing crohn's disease: A systematic review and meta-analysis of placebo-controlled trials. Curr. Pharm. Des., 16: 3684-3698.
    CrossRef
  77. Nikfar, S., M. Darvish-Damavandi and M. Abdollahi, 2010. A review and meta-analysis of the efficacy of antibiotics and probiotics in management of pouchitis. Int. J. Pharmacol., 6: 826-835.
    CrossRefDirect Link
  78. Nikfar, S., R. Rahimi, A. Rezaie and M. Abdollahi, 2009. A Meta-Analysis of the efficacy of sulfasalazine in comparison with 5-aminosalicylates in the induction of improvement and maintenance of remission in patients with ulcerative colitis. Dig. Dis. Sci., 54: 1157-1170.
    CrossRefPubMed
  79. Nikfar, S., R. Rahimi, F. Rahimi, S. Derakhshani and M. Abdollahi, 2008. Efficacy of probiotics in irritable bowel syndrome: a meta‐analysis of randomized, controlled trials. Dis. Colon Rectum., 51: 1775-1780.
    PubMed
  80. Nomura, T., T. Ohkusa, I. Okayasu, T. Yoshida and M. Sakamoto et al., 2005. Mucosa-associated bacteria in ulcerative colitis before and after antibiotic combination therapy. Aliment Pharmacol. Ther., 21: 1017-1027.
    PubMed
  81. O'Hara, J.R., T.D. Feener, C.D. Fischer and A.G. Buret, 2012. Campylobacter jejuni disrupts protective Toll-like receptor 9 signaling in colonic epithelial cells and increases the severity of dextran sulfate sodium-induced colitis in mice. Infect. Immun., 80: 1563-1571.
    PubMed
  82. Ohkusa, T., K. Kato, S. Terao, T. Chiba and K. Mabe et al., 2010. Newly developed antibiotic combination therapy for ulcerative colitis: A double-blind placebo-controlled multicenter trial. Am. J. Gastroenterol., 104: 1820-1829.
    PubMed
  83. Ohkusa, T., T. Nomura, T. Terai, H. Miwa and O. Kobayashi et al., 2005. . Effectiveness of antibiotic combination therapy in patients with active ulcerative colitis: A randomized, controlled pilot trial with long-term follow-up. Scand. J. Gastroenterol., 40: 1334-1342.
    PubMed
  84. Ott, S.J., T. Kuhbacher, M. Musfeldt, P. Rosenstiel and S. Hellmig et al., 2008. Fungi and inflammatory bowel diseases: Alterations of composition and diversity. Scand. J. Gastroenterol., 43: 831-841.
    PubMed
  85. Pineton de Chambrun, G., J.F. Colombel, D. Poulain and A. Darfeuille-Michaud, 2008. Pathogenic agents in inflammatory bowel diseases. Curr. Opin. Gastroenterol., 24: 440-447.
    PubMed
  86. Pithadia, A.B. and S. Jain, 2011. Treatment of Inflammatory Bowel Disease (IBD). Pharmacol. Rep., 63: 629-642.
    PubMed
  87. Prantera, C. and M.L. Scribano, 2009. Antibiotics and probiotics in inflammatory bowel disease: Why, when and how. Curr. Opin. Gastroenterol., 25: 329-333.
    PubMed
  88. Prantera, C., A. Kohn, R. Mangiarotti, A. Andreoli and C. Luzi, 1994. Antimycobacterial therapy in Crohn's disease: Results of a controlled, double-blind trial with a multiple antibiotic regimen. Am. J. Gastroenterol., 89: 513-518.
    PubMed
  89. Prantera, C., F. Zannoni, M.L. Scribano, E. Berto, A. Andreoli, A. Kohn and C. Luzi, 1996. An antibiotic regimen for the treatment of active Crohn's disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin. Am. J. Gastroenterol., 91: 328-332.
    PubMed
  90. Prantera, C., H. Lochs, M. Campieri, M.L. Scribano, G.C. Sturniolo, F. Castiglione and M. Cottone, 2006. Antibiotic treatment of Crohn's disease: Results of a multicentre, double blind, randomized, placebo-controlled trial with rifaximin. Aliment. Pharmacol. Ther., 23: 1117-1125.
    PubMed
  91. Prantera, C., H. Lochs, M. Grimaldi, S. Danese and M.L. Scribano et al., 2012. Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn's disease. Gastroenterology, 142: 473-481.
    PubMed
  92. Rahimi, R., S. Nikfar and M. Abdollahi, 2007. Meta-analysis technique confirms the effectiveness of anti-TNF-alpha in the management of active ulcerative colitis when administered in combination with corticosteroids. Med. Sci. Monit., 13: 13-18.
    PubMedDirect Link
  93. Rahimi, R., S. Nikfar and M. Abdollahi, 2007. Do anti-tumor necrosis factors induce response and remission in patients with acute refractory Crohns disease? A systematic meta-analysis of controlled clinical trials. Biomed. Pharmacother., 61: 75-80.
    CrossRefDirect Link
  94. Rahimi, R., S. Nikfar, A. Rezaie and M. Abdollahi, 2007. A meta‐analysis of antibiotic therapy for active ulcerative colitis. Dig. Dis. Sci., 52: 2920-2925.
    CrossRefDirect Link
  95. Rahimi, R., S. Nikfar, F. Rahimi, B. Elahi, S. Derakhshani, M. Vafaie and M. Abdollahi, 2008. A meta-analysis on the efficacy of probiotics for maintenance of remission and prevention of clinical and endoscopic relapse in Crohn's disease. Dig. Dis. Sci., 53: 2524-2531.
    CrossRefPubMed
  96. Rahimi, R., S. Nikfar, A. Rezaie and M. Abdollahi, 2008. A meta‐analysis of the benefit of probiotics in maintaining remission of human ulcerative colitis: Evidence for prevention of disease relapse and maintenance of remission. Arch. Med. Sci., 4: 185-190.
    Direct Link
  97. Rahimi, R., M.R. Shams-Ardekani and M. Abdollahi, 2010. A review of the efficacy of traditional Iranian medicine for inflammatory bowel disease. World J. Gastroenterol., 16: 4504-4514.
    CrossRefPubMed
  98. Rahimi, R., S. Mozaffari and M. Abdollahi, 2009. On the use of herbal medicines in management of inflammatory bowel diseases: A systematic review of animal and human studies. Dig. Dis. Sci., 54: 471-480.
    CrossRefDirect Link
  99. Rahimi, R., S. Nikfar, A. Rezaie and M. Abdollahi, 2009. Comparison of mesalazine and balsalazide in induction and maintenance of remission in patients with ulcerative colitis: A meta-analysis. Dig. Dis. Sci., 54: 712-721.
    CrossRef
  100. Ramasundara, M., S.T. Leach, D.A. Lemberg and A.S. Day, 2009. Defensins and inflammation: The role of defensins in inflammatory bowel disease. J. Gastroenterol. Hepatol., 24: 202-208.
    CrossRefPubMedDirect Link
  101. Reiff, C. and D. Kelly, 2010. Inflammatory bowel disease, gut bacteria and probiotic therapy. Int. J. Med. Microbiol., 300: 25-33.
    PubMed
  102. Rezaie, A., R.D. Parker and M. Abdollahi, 2007. Oxidative stress and pathogenesis of inflammatory bowel disease: An epiphenomenon or the cause. Dig. Dis. Sci., 52: 2015-2021.
    CrossRefPubMed
  103. Rhodes, J.M., 2007. The role of Escherichia coli in inflammatory bowel disease. Gut, 56: 610-612.
    PubMed
  104. Ruiz-Bolivar, Z., M.C. Neuque-Rico, A.K. Carrascal-Camacho, R.A. Poutou-Pinales and S. Mattar, 2011. Antimicrobial susceptibility of Listeria monocytogenes food isolates from different cities in Colombia. Foodborne Pathogens Dis., 8: 913-919.
    CrossRefDirect Link
  105. Rutgeerts, P., S. Vermeire and G. Van Assche, 2009. Biological therapies for inflammatory bowel diseases. Gastroenterology, 136: 1182-1197.
    PubMed
  106. Salari, P., S. Nikfar and M. Abdollahi, 2012. A meta-analysis and systematic review on the effect of probiotics in acute diarrhea. Inflamm. Allergy Drug Targets, 11: 3-14.
    PubMed
  107. Salari, P. and M. Abdollahi, 2009. Current opinion in the pharmaceutical management of irritable and inflammatory bowel diseases: Role of ATP. Rec. Pat. Endoc. Metab. Immune Drug Disc., 3: 69-75.
    CrossRef
  108. Sartor, R.B., 2004. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: Antibiotics, probiotics and prebiotics. Gastroenterology, 126: 1620-1633.
    CrossRefPubMedDirect Link
  109. Sartor, R.B., 2005. Does Mycobacterium avium subspecies paratuberculosis cause Crohn's disease?. Gut, 54: 896-898.
    CrossRefPubMedDirect Link
  110. Sasaki, M., S.V. Sitaraman, B.A. Babbin, P. Gerner-Smidt and E.M. Ribot et al., 2007. Invasive Escherichia coli are a feature of Crohn's disease. Lab. Invest., 87: 1042-1054.
    PubMed
  111. Sato, K., T. Chiba and T. Ohkusa, 2009. Serial changes of cytokines in active ulcerative colitis: Effects of antibiotic combination therapy. Hepatogastroenterology, 56: 1016-1021.
    PubMed
  112. Saverymuttu, S., H.J. Hodgson and V.S. Chadwick, 1985. Controlled trial comparing prednisolone with an elemental diet plus non-absorbable antibiotics in active Crohn's disease. Gut, 26: 994-998.
    PubMed
  113. Scanlan, P.D. and J.R. Marchesi, 2008. Micro-eukaryotic diversity of the human distal gut microbiota: Qualitative assessment using culture-dependent and-independent analysis of faeces. ISME J., 2: 1183-1193.
    PubMed
  114. Scanlan, P.D., F. Shanahan and J.R. Marchesi, 2008. Human methanogen diversity and incidence in healthy and diseased colonic groups using mcrA gene analysis. BMC Microbiol., 8: 79-79.
    PubMed
  115. Selby, W., P. Pavli, B. Crotty, T. Florin and G. Radford-Smith et al., 2007. Two-year combination antibiotic therapy with clarithromycin, rifabutin and clofazimine for Crohn's disease. Gastroenterology, 132: 2313-2319.
    PubMed
  116. Sellon, R.K., S. Tonkonogy, M. Schultz, L.A. Dieleman and W. Grenther et al., 1998. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun., 66: 5224-5231.
    PubMed
  117. Shaffer, J.L., S. Hughes, B.D. Linaker, R.D. Baker and L.A. Turnberg, 1984. Controlled trial of rifampicin and ethambutol in Crohn's disease. Gut, 25: 203-205.
    PubMed
  118. Shafran, I. and L.K. Johnson, 2005. An open-label evaluation of rifaximin in the treatment of active Crohn's disease. Curr. Med. Res. Opin., 21: 1165-1169.
    PubMed
  119. Shafran, I., L. Kugler, F.A. El-Zaatari, S.A. Naser and J. Sandoval, 2002. Open clinical trial of rifabutin and clarithromycin therapy in Crohn's disease. Dig. Liver Dis., 34: 22-28.
    PubMed
  120. Steinhart, A.H., B.G. Feagan, C.J. Wong, M. Vandervoort and S. Mikolainis et al., 2002. Combined budesonide and antibiotic therapy for active Crohn's disease: A randomized controlled trial. Gastroenterology, 123: 33-40.
    PubMed
  121. Sreedhar, S., C.L. Roberts, C.A. Hart, H.M. Martin, S.W. Edwards, J.M. Rhodes and B.J. Campbell, 2008. Replication of colonic crohn's disease mucosal Escherichia coli isolates within macrophages and their susceptibility to antibiotics. Antimicrobial Agents Chemother., 52: 427-434.
    CrossRef
  122. Sutherland, L., J. Singleton, J. Sessions, S. Hanauer and E. Krawitt et al., 1991. Double blind, placebo controlled trial of metronidazole in Crohn's disease. Gut, 32: 1071-1075.
    PubMed
  123. Swift, G.L., E.D. Srivastava, R. Stone, R.D. Pullan and R.G. Newcombe et al., 1994. Controlled trial of anti-tuberculous chemotherapy for two years in Crohn's disease. Gut, 35: 363-368.
    PubMed
  124. Teasley, D.G., D.N Gerding, M.M. Olson, L.R. Peterson and R.L. Gebhard, M.J. Schwartz and J.T. Jr. Lee, 1983. Prospective randomized trial of metronidazole versus van comycin for Clostridium-difficile-associateddiarrhoea and colitis. Lancet, 2: 1043-1046.
    PubMed
  125. Terao, S., K. Yamashiro, I. Tamura, T. Hirano, T. Ohkusa and K. Kato, 2011. Antibiotic combination therapy for steroid withdrawal in steroid-dependent ulcerative colitis. Digestion, 83: 198-203.
    PubMed
  126. Thia, K.T., U. Mahadevan, B.G. Feagan, C. Wong and A. Cockeram et al., 2009. Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn's disease: A randomized, double-blind, placebo-controlled pilot study. Inflamm. Bowel Dis., 15: 17-24.
    CrossRefPubMed
  127. Thomas, G.A., G.L. Swift, J.T. Green, R.G. Newcombe and C. Braniff-Mathews et al., 1998. Controlled trial of antituberculous chemotherapy in Crohn's disease: A five year follow up study. Gut, 42: 497-500.
    PubMed
  128. Thompson-Chagoyan, O.C., J. Maldonado and A. Gil, 2005. Aetiology of Inflammatory Bowel Disease (IBD): Role of intestinal microbiota and gut-associated lymphoid tissue immune response. Clin. Nutr., 24: 339-352.
    CrossRefPubMed
  129. Travis, S.P., E.F. Stange, M. Lemann, T. Oresland and Y. Chowers et al., 2006. European evidence based consensus on the diagnosis and management of Crohn's disease: Current management. Gut, 55: 16-35.
    PubMed
  130. Triantafillidis, J.K., E. Merikas and F. Georgopoulos, 2011. Current and emerging drugs for the treatment of inflammatory bowel disease. Drug Des. Devel. Ther., 5: 185-210.
    PubMed
  131. Turunen, U.M., M.A. Farkkila, K. Hakala, K. Seppala and A. Sivonen et al., 1998. Long-term treatment of ulcerative colitis with ciprofloxacin: A prospective, double-blind, placebo-controlled study. Gastroenterology, 115: 1072-1078.
    PubMed
  132. Uehara, T., K. Kato, T. Ohkusa, M. Sugitani, Y. Ishii, N. Nemoto and M. Moriyama, 2010. Efficacy of antibiotic combination therapy in patients with active ulcerative colitis, including refractory or steroid-dependent cases. J. Gastroenterol. Hepatol., 25: S62-S66.
    CrossRefPubMed
  133. Ursing, B., T. Alm, F. Barany, I. Bergelin and K. Ganrot-Norlin et al., 1982. A comparative study of metronidazole and sulfasalazine for active Crohn's disease: The cooperative Crohn's disease study in Sweden. II. Result. Gastroenterology, 83: 550-562.
    PubMed
  134. Walsh, A., J. Mabee and K. Trivedi, 2011. Inflammatory bowel disease. Prim. Care., 38: 415-432.
    PubMed
  135. Wehkamp, J., K. Fellermann and E.F. Stange, 2005. Human deficins in Crohn's disease. Chem. Immunol. Allergy, 86: 42-54.
    PubMed
  136. West, R.L., C.J. van der Woude, B.E. Hansen, R.J. Felt-Bersma, A.J. van Tilburg, J.A. Drapers and E.J. Kuipers, 2004. Clinical and endosonographic effect of ciprofloxacin on the treatment of perianal fistulae in Crohn's disease with infliximab: A double-blind placebo-controlled study. Aliment. Pharmacol. Ther., 20: 1329-1336.
    PubMed
  137. West, R.L., C.J. van der Woude, H.P. Endtz, B.E. Hansen and M. Ouwedijk et al., 2005. Perianal fistulas in Crohn's disease are predominantly colonized by skin flora: Implications for antibiotic treatment? Dig. Dis. Sci., 50: 1260-1263.
    PubMed
  138. Williams, H., D. Walker and T.R. Orchard, 2008. Extraintestinal manifestations of inflammatory bowel disease. Curr. Gastroenterol. Rep., 10: 597-605.
    PubMed
  139. Yoon, J.E., W.K. Kim, J.S. Lee, K.S. Shin and T.S. Ha, 2011. Antibiotic susceptibility and imaging findings of the causative microorganisms responsible for acute urinary tract infection in children: A five-year single center study. Korean J. Pediatr., 54: 79-85.
    PubMed
  140. Zar, F.A., S.R. Bakkanagari, K.M. Moorthi and M.B. Davis, 2007. A comparison of vancomycin and metronidazole for the treatment of Clostridiumdifficile-associateddiarrhea, stratified by disease severity. Clin. Infect. Dis., 45: 302-307.
    PubMed

Leave a Comment

Your email address will not be published. Required fields are marked *