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Despite intensive investigations, Crohn's disease remains a medical enigma with no defined etiology or pathogenic mechanism. As a result, most treatments are only supportive in nature and often take on the course of "lets see what happens". While this approach may not be scientifically sound, it is certainly medically acceptable and more treatments have been developed or discovered by this method than not.
When it comes to antimicrobials, these agents are seeing increased use, although they have not received the attention they deserve. The term antimicrobial is preferred to the more commonly used antibiotic because many chemotherapeutic agents are antimicrobial but not true antibiotics.
There are many reasons why antimicrobials should be used in Crohn's disease. The gastrointestinal tract, from mouth to anus, contains a delicately balanced population of bacterial flora which function symbiotically with the host to aid in digestion, metabolism, and absorption of nutrients. Normal gut motility and bacterial population dynamics maintain that delicate balance. Each species of microbe occupies its own niche within the gastrointestinal tract, depending on their preferred environment. Whenever that balance is upset, and the population dynamics are altered, gastrointestinal disturbances will result. Most disturbances go undetected and/or are readily resolved, while others require medical intervention.
Crohn's disease patients, just by the nature and characteristics of the disease, cannot support a normal bacteria population. The formation of deep crypts in Crohn's disease allows microbes to establish microenvironments within these crypts and colonize the mucosa completely isolated from the general floral population of the gastrointestinal tract. Inflammation also impedes normal peristalsis and the mucosal barrier, thereby providing additional opportunities for abnormal colonization. Add to these conditions, surgical intervention and the continuous influx of a variety of chemotherapeutic agents, and its becomes difficult to imagine that a normal bacterial flora can be maintain in Crohn's disease. Several studies have supported the finding that Crohn's disease patients have an altered bacterial flora 1,2, and this is not surprising.
Thus, clinical, pathologic, and experimental evidence support the notion that an abnormal bacterial flora exists in Crohn's disease and that a normal floral population cannot be maintained. It is a small jump to suggest that this abnormal flora and colonization causes complications, either primary, secondary, or coincidentally, in the clinical and pathological condition observed in Crohn's disease. It is also a small jump to suggest that antimicrobial agents should have a therapeutic role in Crohn's disease. What is perhaps most puzzling is considering the vast array of antimicrobials available today, how few have been evaluated in Crohn's disease and how rapidly therapeutic failures are accepted.
Regardless of the therapeutic approach, the problem of patient population plaques all studies on Crohn's disease. Epidemiologic studies suggest that as many as 20% of Crohn's disease patients do not have Crohn's disease 3 and represent a 20% variable or error in the interpretation of data. There is also increasing support for the notion that Crohn's disease does not represent a single disease entity, but several idiopathic conditions grouped together. If we are to accept either or both of these conditions, without the ability to separate Crohn's disease into distinct subgroup populations other than by crude methods, e.g., small bowel, large bowel, etc., we need to interpret the data more loosely than with a more defined disease entity. A chemotherapeutic study that is a failure may not be a complete failure if therapeutic benefit was achieved within a subpopulation of patients, even if that subpopulation cannot be defined.
The use of antimicrobials in Crohn's disease has taken 2 separate forms or approaches in recent years. One is the use of antimicrobials to resolve secondary complications associated with abnormal bacterial colonization such as abscess formation, fistulas, etc., and are supportive in nature. The other use of antimicrobials has been directed against specific agents proposed to be etiologic agents in Crohn's disease and are curative in nature. These 2 approaches are completely different and require distinct objectives, study designs, interpretations, and end-points. As such, they are discussed separately.
The use of antimicrobials as supportive therapy is far easier to perform and evaluate than those used in a curative nature. Since the treatment is supportive and generally directed toward secondary complications, evaluations can be more subjective and employ such clinical parameters as CDAI, SI, and others. The study end-point and objective are limited to achieving clinical improvement, i.e., the patient feeling better.
Of the vast array of antimicrobials available, metronidazole has been the most frequently and extensively studied in Crohn's disease. Metronidazole is a synthetic nitroimidazole compound that has both antimicrobial and immunosuppressant activity. Antimicrobial activity is primarily associated with the nitro group attached to the imidazole ring, which is active against most anaerobic bacteria. The imidazole role also has immunomodulary activity and interferes with various aspects of cellular immunity, although the precise mechanisms of action are not clear.
Interest in metronidazole was sparked by the study of Ursing and Kamme 4 in 1975. These investigators reported a beneficial effect in 5 patients with large bowel Crohn's disease when treated with metronidazole in an uncontrolled trial. Since that time, several studies have evaluated metronidazole in the treatment of Crohn's disease including controlled, double-blinded, crossover, and double-blinded multi-centered controlled trials (Table I). Although trial results are not in complete agreement, most have demonstrated a beneficial effect of metronidazole in the treatment of active Crohn's disease, particularly those with colonic or ileocolonic involvement.
Although metronidazole does not significantly alter the overall course or disease outcome, it clearly serves its purpose of supportive therapy in resolving some of the complications in a majority of patients with active disease. The drug is well tolerated, even at the high doses used in Crohn's disease, and although the carcinogenic and mutagenic effects observed in laboratory animals is of concern 19, no data exists to support an increased risk of carcinogenic or mutagenic effects in humans 20.
Other antimicrobials have been evaluated in only a limited fashion in Crohn's disease (Table I). Ciprofloxacin, a fluoroquinalone that affects primarily gram-negative bacteria and some gram-positive anaerobes, has shown beneficial effects in some trials15-18. Sulfasalazine was compared to metronidazole in a double-blinded cross-over trial in active Crohn's disease, with no difference in efficacy observed between the two therapies10,11. Extended use (>1 mo.) of broad spectrum antibiotics, such as ampicillin and tetracycline, has also been evaluated in an uncontrolled trial, but the data are too unreliable to draw any conclusive findings.6 Treatment of patients with vancomycin in a double-blinded controlled trial for 7-days as adjunct therapy, failed to show any significant difference from placebo controls.12
Non-absorbable antimicrobials (framycetin, colistin, nystatin), in conjunction with an elemental diet, has also been evaluated in comparison to prednisolone, with the conclusion that non-absorbable antimicrobials are as effective as steroid therapy 13; however, since elemental diet alone has been shown to be effective in active Crohn's disease and proposed as a primary therapy, the results of non-absorbable antimicrobials are inconclusive. Other antimicrobials have been evaluated based on individual physician and clinical experiences, but except for an occasional case report, these treatments remain undocumented and the subject of "barroom talk".
In this issue of the Italian Journal of Gastroenterology and Hepatology, Prantera et al 18 evaluates the effects of the 2 most promising agents, metronidazole and ciprofloxacin, alone and in combination, in a retrospective trial. Although this report contradicts some data from previous studies (e.g., metronidazole was found effective in both colonic and ileal disease and reduced efficacy of ciprofloxacin in colitis), it corroborates previous studies in supporting a role for antimicrobials in the general chemotherapeutic treatment of Crohn's disease patients. Perhaps the most significant aspect of the study by Prantera et al, is their evaluation of combined antimicrobial therapy.
Combined antimicrobial therapy is the mainstay of therapy for most "difficult-to-treat" infectious agents and, whether primary or secondary, complication or coincidence, Crohn's disease has an infectious component. Few would argue that Crohn's disease is "difficult-to-treat". Whether combined drug therapy represents synergy against a specific bacterial agent, reduction in overall bacterial populations and colonization, prevention or circumvention of bacterial resistance, or simply preventative therapy for the complications of long-term antimicrobial therapy (e.g. C. difficile), combined antimicrobial therapy has generally been found to be more effective than single drug use. Why is it not implemented more frequently by the medical community remains a mystery.
The second approach to the use of antimicrobial treatment in Crohn's disease has been their use against specific infectious agents proposed to be primary etiologic agents. This approach is curative and therefore should have entirely different objectives, study design, data analysis, and end-points than a supportive approach. Unfortunately, most studies have followed the same methodology as the supportive approach, leading to an inconclusive study. A curative study needs to employ objective data - subjective evaluations, including CDAI, SI and others, have no significance or relevance in a curative therapeutic study. If a specific agent is being targeted, antimicrobials known to be effective against that agent need to be employed. Recent examples with multiple-drug resistant Mycobacterium tuberculosis nicely illustrate that quite effectively: treatment with up to 5 anti-tuberculous drugs offered no therapeutic benefit to patients. 21 Trials need also to define objective end-points and understand the many complications and expected pitfalls that may occur during prolonged treatment.
Crohn's disease, since its earliest descriptions, has been found to be clinically and pathologically almost indistinguishable from primary intestinal tuberculosis and similar to paratuberculosis in animals. Treatment protocols need to consider treatment pitfalls from these other diseases when considering end-points or failures. Surgical intervention is a required adjunct therapy in hyperplastic intestinal tuberculosis 22 - surgical intervention should not be considered a therapeutic failure or end-point in Crohn's disease. Healing of severely and chronically inflamed tissues often leads to fibrotic healing and disease characteristics may change to fibrostenotic resulting in obstruction. While these are often viewed as drug or treatment failures, they rather may simply represent a normal healing process of a chronic disease state. Treatment of chronic infectious diseases, like tuberculosis, often results in clinical worsening before improvement is noted; a "storm before the calm". These "storms" are often considered failures if not considered within the context of therapy complications, particularly in the absence of objective data collection. A CDAI, clinical and subjective, could certainly show a detrimental effect of treatment even while the patient was improving objectively.
Treatment duration is also an issue that is largely neglected in curative trials. An inflammatory condition that has taken years to develop cannot be expected to be resolved in a few short months. Antimicrobials, which are effective only against actively growing organisms, cannot be expected to work rapidly against a slow-growing organism. Antimicrobial response is much faster against a microbe such as Escherichia coli with a generation time of 20 minutes as compared to Mycobacterium leprae with a generation time of 20 days. Treatment of these chronic infectious diseases, particularly mycobacterial, require years of therapy to resolve lesions and obtain a curative state. Patients with lepromatous leprosy require 1-2 years of aggressive antimicrobial therapy with 3 or more drugs in combination followed by a lifetime of dapsone maintenance. To this date, it is unclear if lepromatous leprosy is ever really cured. Chronic infection with Mycobacterium avium in non-immunocompromised patients requires treatment with up to 5 antimicrobials all in combination for up to 5-years before clinical improvement is achieved 23. This aggressive and extended treatment is not curative, but limited to clinical improvement. A curative therapy trial for Crohn's disease lasting 6-9 months or less cannot be expected to be a success.
Current interest in the use of antimicrobials in a curative approach stems from the lingering hypothesis that Crohn's disease, or a subgroup thereof, is caused by Mycobacterium paratuberculosis, an organism that causes a similar disease in ruminant animals. It is not the purpose if this paper to review or comment on the data supporting or refuting this theory and readers are referred to other publications for additional information 24. What is perhaps most interesting about this hypothesis is its failure to die. Throughout the history of Crohn's disease, a variety of infectious agents have been proposed, only to be dismissed after a few short years. It has been over 15-years since this animal pathogen, M. paratuberculosis, was reported to be isolated from Crohn's disease patient's 24 and yet the theory remains alive today despite efforts to kill it. If nothing else, that alone gives it credibility.
Efforts using antimicrobial agents in a curative approach based on the hypothesis that Crohn's disease is caused by M. paratuberculosis, or other mycobacterial infection, have largely been disappointing (Table II). Although the literature is littered with case reports and non-peer reviewed articles suggesting efficacy, good clinical trials have not been performed. Of all the trials that have been reported, all suffer from one or more of the following deficiencies: 1) the lack of objective data; 2) inappropriate drug choices; 3) short duration; 4) inappropriate failure designations; 5) non-defined patient selection; and 6) uncontrolled.
The first reported trial using anti-mycobacterial agents in Crohn's disease was by a group of French scientists, Paris et al, in 1975 25 and then again in 1978 26. In this uncontrolled trial, rifampicin alone or combined with isoniazid, ethambutol, and streptomycin were evaluated. Although not a cure, a positive response was elicited including improvement in overall health, disappearance of intestinal symptoms, and closure of fistulae. The first double-blinded controlled trial employing mycobacterial chemotherapeutic agents was reported by Shaffer et al27 in 1984. Although reported as a failure of chemotherapy, it was largely a failure of study design. This study evaluated rifampin and ethambutol versus sulfasalazine and steroids alone. Of the 27 patients enrolled in this 2-year double-blinded cross-over trial, 13 were withdrawn before completion due to noncompliance, surgical intervention, or adverse reactions. Of the remaining 14 patients that completed the trial, 4 required surgery, 5 were withdrawn due to poor compliance, and 5 were withdrawn due to drug side effects. The authors concluded that there was no difference in clinical parameters between the two treatments.
Wirotsko et al 28 in 1984 reported on their evaluation of rifampin in the treatment of ocular lesions in Crohn's disease. This uncontrolled trial noted improvement of uveitis and intestinal disease with exacerbation of both conditions upon withdrawal. Hampson et al 29 evaluated rifampin in combination with ethambutol, isoniazid, pyrazinamide and clofazimine in an uncontrolled trial of 20 patients. During the 9-month course of treatment, about 50% of the patients went into remission and did not require continued steroid maintenance.
Afdhal et al 30 treated 49 patients with corticosteroids and clofazimine or steroids and placebo and although 58% of patients went into remission, rates were not significantly different from the placebo group. Rutgeerts et al 31 treated 16 patients with rifabutin and ethambutol in an uncontrolled trial. Of the 4 patients that completed a 6-month treatment regimen and of the 5 that completed a 12-month treatment, none achieved endoscopic improvement.
Prantera et al 32 performed a controlled, double-blinded trial using a 9-month regimen of ethambutol, clofazimine, dapsone and 1-day dose of rifabutin versus placebo in 40 patients with Crohn's disease. Although a significant difference in remission rates was noted in the treatment group versus placebo, there was no substantial evidence of endoscopic or radiologic healing.
Most recently, Gui et al 33 reported on a 2-year uncontrolled trial using rifabutin and macrolide antibiotics (clarithromycin or azithromycin) in 52 patients with severe Crohn's disease. Of the 46 patients that continued in the trial, there was significant improvement in clinical parameters after 6 and 24-months, improvement of inflammatory parameters, reduction or withdrawal from steroids, and remission in the majority of patients.
Other trials are currently in progress by several investigators claiming beneficial effects; but to date, these studies remain unpublished and must be categorized along with case reports, abstracts, and other non-peer-reviewed information.
Based on other infections, a curative chemotherapeutic therapy might be expected to follow a natural clinical course in which: 1) there is an immediate beneficial period from broad-spectrum action of the antimicrobial (supportive therapy); 2) a quiescent period as secondary complications are prevented and lesions begin to resolve ("the calm before the storm"); 3) worsening of the clinical state as lesions become fibrotic with stenosis of the lumen ("the storm"); 4) surgical intervention to resolve stenotic lesions; 5) gradual resolution of disease state ("the calm after the storm"); and 6) curative state (Figure 1). To achieve this course, therapy would likely need to consist of at least 3 antimicrobials known to have activity against the specific target microbe for at least 1-2 years, followed by single drug maintenance therapy for at least an additional 2-years. Biopsy, radiology, IS900 detection, and other objective determinations need to be performed 30 days prior to therapy, and at times 0, 3 mo., 6 mo., 1 yr., 2 yr., and 3 yrs post-treatment at a minimum. Such a treatment regime, conducted in a double-blinded placebo controlled trial is the only approach that can provide the data to determine if antimicrobial therapy can be curative or not. Unfortunately, these studies are very expensive to conduct properly and to date, have not been performed.
Whether the objective and approach of therapy is supportive or curative, antimicrobial therapy has a role in the treatment of Crohn's disease. What remains to be determined are the best drug(s) to be employed and for how long. Of the vast array of antimicrobials available on the market today, less than a handful have been evaluated, and of these, even fewer has been evaluated appropriately. One must wonder why?
After almost 25 years of antimicrobial use in Crohn's disease, and the apparent general acceptance that antimicrobials have a therapeutic role 34,35, essentially the same antimicrobials are being evaluated. We have progressed little. Until the medical community makes a decision to invest in the exploration of antimicrobial therapy and evaluate the vast array of available antimicrobials, such treatments will remain experimental or at the whim of the individual physician rather than accepted practice in the treatment of Crohn's disease. The time is long past over due.
FIGURE 1. Proposed clinical and pathological course of a curative treatment in Crohn's disease.
A patient receiving chemotherapeutic antimicrobial therapy that was curative in nature would be expected to undergo a clinical and pathological course in which: 1) there was an early period of remission caused by the broad spectrum action of antimicrobials on secondary complications, i.e., supportive therapy; 2) a period of clinical worsening as chronic inflammatory lesions become fibrotic in nature, often times requiring surgical intervention due to stenosis, i.e., relapse ; 3) followed by a gradual resolution of the inflammatory process, i.e., second period of remission, leading to the curative state. Time course would likely be 2 to 4 years.
|Year||Investigators||Antimicrobial||Type of Trial|
|1976||Ursing & Kamme4||metronidazole||Uncontrolled|
|1978||Blichfedt et al5||Metronidazole||Double-blind crossover|
|1978||Moss et al6||Broad spectrum||Uncontrolled|
|1980||LaMont & Trnka7||Vancomycin||Uncontrolled|
|1980||Berstein et al8||Metronidazole||Uncontrolled|
|1982||Brandt et al9||Metronidazole||Uncontrolled|
|1982||Ursing et al 10
Rosen et al 11
|Metronidazole vs. sulfazalazine||Double-blind crossover|
|1985||Dickenson et al12||Vancomycin||Double blind placebo|
|1991||Sutherland et all4||Metronidazole||Controlled Double-blind multi-center|
|1996||Prantera et al 16||Metronidazole & Ciproflaxacin||Randomized controlled|
|1998||Greenbloom 17||Ciproflaxacin & metronidazole||Open/uncontrolled|
|1998||Prantera et al 18||Metronidazole & Ciproflaxacin||Retrospective|
*Abstracts, case reports, notes, and non-peer-reviewed publications are excluded.
|Year||Investigators||Antimicrobial||Type of Trial|
|1975-1978||Paris et al 25,26||Rifampin + Others||Uncontrolled|
|1984||Shaffer et al 27||Rifampin + ethambutol||Double bind crossover|
|1987||Wirostko et al 28||Rifampin||Uncontrolled|
|1989||Hampson et al 29||Rifampin + ethambutol + isonaizid + pyrazinamide + clofazimine||Uncontrolled|
|1991||Afdhal et al 30||Clofazimine||Double blind placebo|
|1992||Rutgeerts 31||Rifampin + Ethambutol||Placebo controlled|
|1994||Prantera et al 32||Ethambutol + clofazimine + dapsone + rifampin||Double bind controlled|
|1997||Gui et al 33||Rifabutin + clarithromycin or azithromycin||uncontrolled|
*Abstracts, case reports, notes, and non-peer-reviewed publications are excluded.
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