Abstract
The use of antibiotics in Crohn’s disease has recently been studied and our group has shown previously the efficacy and safety of RMAT in an open clinical trial. Forty-two Crohn’s patients, who were serologically positive with the p35 and p36 serologic markers specific for Mycobacterium avium ss. paratuberculosis (MAP), were chosen for treatment with Rifabutin and Macrolide Antibiotic Therapy (RMAT). The RMAT medications included 250 mgm 1 po bid clarithromycin and 150 mgm 1 po bid rifabutin and 200 mgm po bid of a probiotic containing equal amounts of Lactobacillus acidophilus and Lactobacillus rhamnosus. These patients were followed serologically and clinically each month. The serial blood samples were stored to measure, at a later date, the quantitative antibody response to MAP. 7 patients withdrew from the study since they were unable to tolerate medications. The 35 remaining patients were assessed to determine their overall response to treatment. The period of treatment ranged from 6 months to 22 months with the average treatment period being 8.5 months. 77.1% (27/35) of the patients reached a sustained state of clinical remission while being off all other Crohn’s medications, such as immunosuppresants and corticosteroids. The majority of these patients had acute presentations of Crohn’s disease when placed on RMAT. 5 patients also had documented endoscopic healing correlating with treatment response. 8.6% (3/35) of patients noticed significant improvements but were still using Crohn’s medications with RMAT. 14.3% (5/35) were non-responders noticing no marked improvement while on RMAT. 16.7% (7/42) of patients were unable to tolerate the RMAT medications and withdrew from the study within two months of treatment noticing no improvements. These findings add further evidence to support the role of RMAT in the treatment of Crohn’s disease in patients serologically positive for MAP. A large multicenter clinical trial is needed to further explore these findings.
 

RMAT CLINICAL TRIAL RESULTS

RMAT	Patients	Percent (%)
Responders	27	27/35 (77.1%)
Partial Responders	3	3/35 (8.6%)
Non-Responders	5	5/35 (14.3%)
Withdrawal	7	7/42 (16.7%)

Background
Refractory Crohn’s Disease and the Role of Antibiotics

Therapeutic options in refractory Crohn’s disease are limited. Although wide spread use of immunosuppressants has reduced the number of intractable cases, patients not responding to this therapy often become dependent on Corticosteroids and as a result, eventually undergo debilitating surgical resections. 

Antibiotics have been found to resolve secondary complications due to abscess and fistulae formation associated with abnormal bacterial colonization. Antibiotics have also been used as curative therapies directed against proposed etiological agents. 

Although studies have shown a general therapeutic role of antibiotics, these studies have had mixed results most likely due to study design, use of inappropriate antibiotics, brevity of treatment durations, and lack of evidence for the presence of an etiologic agent.1 

To effectively treat CD patients with antibiotics, it is necessary to stratify patients based on evidence that supports the presence of an etiologic agent. 

Association of Crohn’s Disease with Mycobacterium avium ss. Paratuberculosis

MAP is the etiologic agent that causes Johne’s disease, a chronic inflammatory bowel condition in animals, such as ruminants and primates. 

There are a number of histological similarities between CD and Johne’s disease.2 

MAP has been suspected as a possible etiological agent of CD. The association of CD and MAP has been strengthened by cumulative studies. 

Studies have isolated MAP from CD tissue3,4,5 and lymph nodes6. A recent study has isolated and cultured MAP from CD breast milk and CD resected tissue.7,8 

Stratification of CD patients with p35 and p36 recombinant clones

MAP recombinant antigens (p35 and p36) individually and combined have been shown to have a statistically significant difference in reactivity between Crohn’s disease-positive serum and serum samples from controls (Ulcerative colitis and healthy controls).9 

The recombinant clones p35 and p36 express 35- and 36 kDa proteins, respectively, and were identified from a previously constructed expression genomic library of MAP.10 

p35 encoding gene expresses a 35K protein that reacts well with sera from Johne’s animals11 while the p36 encoding gene has been sequenced (AF048899) and expresses a protein that is considered a Mycobacterium-genus specific antigen.12 

Treatment Strategies for Mycobacterium avium ss. Paratuberculosis

Once there is evidence to support a possible MAP infection, combination antibiotic therapy can be tailored to eradicate mycobcateria both intracellularly and extracellularly. 

The combination of clarithromycin and rifabutin have been shown to produce additive effect against both intra-cellular and extra-cellular replication of Mycobacterium avium.13 

Two-year outcome study using rifabutin and macrolide antibiotic therapy (RMAT) demonstrated that 93.5% of CD patients treated went into clinical remission.14