On the action of methotrexate and 6-Mercaptopurine on M. avium subspecies paratuberculosis

Greenstein, Robert J.; Su, Liya; Haroutunian, Vahrum; Shahidi, Azra; Brown, ST

doi:10.1097/00054725-200705005-00027

Cited by 23 publications

(47 citation statements)

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“…Human-origin (Crohn's disease patient) isolates of M. paratuberculosis tended to be more susceptible to 6-MP than were bovine-origin isolates (Table 4). These findings are comparable to those reported by Greenstein et al using the BACTEC 460 system for M. paratuberculosis in in vitro susceptibility studies (13,45). The growth-suppressive effects of 6-MP differed by mycobacterial species.…”

Section: Discussionsupporting

confidence: 91%

Thiopurine Drugs Azathioprine and 6-Mercaptopurine Inhibit Mycobacterium paratuberculosis Growth In Vitro

Shin

Collins

2008

Antimicrob Agents Chemother

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The in vitro susceptibility of human-and bovine-origin Mycobacterium paratuberculosis to the thioupurine drugs 6-mercaptopurine (6-MP) and azathioprine (AZA) was established using conventional plate counting methods and the MGIT 960 ParaTB culture system. Both 6-MP and AZA had antibacterial activity against M. paratuberculosis; isolates from Crohn's disease patients tended to be more susceptible than were bovine-origin isolates. Isolates of Mycobacterium avium, used as controls, were generally resistant to both AZA and 6-MP, even at high concentrations (>64.0 g/ml). Among rapidly growing mycobacteria, Mycobacterium phlei was susceptible to 6-MP and AZA whereas Mycobacterium smegmatis strains were not. AZA and 6-MP limited the growth of, but did not kill, M. paratuberculosis in a dose-dependent manner. Anti-inflammatory drugs in the sulfonamide family (sulfapyridine, sulfasalazine, and 5-aminosalycilic acid [mesalamine]) had little or no antibacterial activity against M. paratuberculosis. The conventional antibiotics azithromycin and ciprofloxacin, used as control drugs, were bactericidal for M. paratuberculosis, exerting their killing effects on the organism relatively quickly. Simultaneous exposure of M. paratuberculosis to 6-MP and ciprofloxacin resulted in significantly higher CFU than use of ciprofloxacin alone. These data may partially explain the paradoxical response of Crohn's disease patients infected with M. paratuberculosis to treatment with immunosuppressive thiopurine drugs, i.e., they do not worsen with anti-inflammatory treatment as would be expected with a microbiological etiologic pathogen. These findings also should influence the design of therapeutic trials to evaluate antibiotic treatments of Crohn's disease: AZA drugs may confound interpretation of data on therapeutic responses for both antibiotic-treated and control groups.

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Section: Discussionsupporting

confidence: 91%

Thiopurine Drugs Azathioprine and 6-Mercaptopurine Inhibit Mycobacterium paratuberculosis Growth In Vitro

Shin

Collins

2008

Antimicrob Agents Chemother

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“…23,24 These drugs could potentially affect the activity of antimicrobials when used together for treatment of CD. We assessed drug interactions in vitro by determining the FICI values of two-drug (6-mercaptopurine plus antimicrobial) combinations containing 6-mercaptopurine and one of the eight antibiotics that showed in vitro anti-MAP activity in our previous study.…”

Section: -Mercaptopurine -Antibiotic Combinationsmentioning

confidence: 99%

“…22 Interestingly, 6-mercaptopurine was recently shown to have anti-MAP activity in vitro. 23,24 The objectives of this work were to evaluate the actions of clarithromycin or 6-mercaptopurine with other anti-MAP agents and with each other on the in vitro growth of MAP.…”

Section: Introductionmentioning

confidence: 99%

Effects of interactions of antibacterial drugs with each other and with 6-mercaptopurine on in vitro growth of Mycobacterium avium subspecies paratuberculosis

Krishnan

Manning

Collins

2009

Journal of Antimicrobial Chemotherapy

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Objectives: Mycobacterium avium subspecies paratuberculosis (MAP) has been targeted for treatment with clarithromycin and rifamycin derivatives in numerous cases of Crohn's disease (CD). 6-Mercaptopurine and its pro-drug azathioprine are widely used as immunomodulators in the treatment of CD and have recently been shown to have anti-MAP activity in vitro. The objectives of the study were to evaluate the in vitro effects on MAP of (i) 6-mercaptopurine when combined with each of eight conventional antibacterial agents with in vitro anti-MAP activity and (ii) antibacterial combinations consisting of two drugs (clarithromycin combined with amikacin, rifampicin, ciprofloxacin or ethambutol) and three drugs (clarithromycin, rifabutin and clofazimine). Methods:The drug interaction effects on nine human isolates of MAP were determined by the chequerboard method adapted for the BACTEC TM MGIT TM 960 culture system and by calculation of the fractional inhibitory concentration index (FICI) for drug combinations.Results: Synergism (FICI 0.5) was observed between 6-mercaptopurine and azithromycin (seven isolates), clarithromycin, rifampicin, rifabutin (four isolates each) and ethambutol (two isolates). 6-Mercaptopurine was not antagonistic with any of the antibacterial agents tested. Among the combinations of two and three antibacterials tested, the clarithromycin/rifampicin combination was synergistic against four isolates, while all other combinations showed no interaction.Conclusions: This in vitro study suggests that 6-mercaptopurine may be synergistic with macrolides and rifamycin derivatives against MAP. The activity of clarithromycin against MAP seems to be enhanced by rifampicin.

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“…azathioprine, and their metabolites, e.g. 6-mercaptopurine, inhibit the growth of MAP in vitro [39] . It is possible that intracellular cell deficient (spheroplast) MAP may not replicate well despite immunosuppression [35] .…”

Section: Antimycobacterial Antibiotics For Crohn's Diseasementioning

confidence: 99%

Mycobacterium avium subspecies paratuberculosis and its relationship with Crohn’s disease

Mendoza

Lana²,

Dı́az-Rubio³

2009

WJG

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The hypothesis postulating that Mycobacterium avium paratuberculosis (MAP) is the cause of Crohn's disease (CD) has been circulating for many years. Advances in molecular techniques, such as polymerase chain reaction and culture methods, have enabled researchers to demonstrate that there is an association between MAP and CD. Recently, genome-wide association studies have identified novel susceptibility genes for CD, which are critical for generation of an adaptive immune response that is protective against intracellular pathogens, including M. tuberculosis infection. However, the role of MAP as a cause of CD suffered a setback with the report that administration of antimycobacterial therapy failed to lead to a sustained response in CD patients. Accordingly, this review sought neither to confirm nor refute this, but instead to survey recent literature on the role of MAP in CD.

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On the action of methotrexate and 6-Mercaptopurine on M. avium subspecies paratuberculosis

Cited by 23 publications

References 0 publications

Thiopurine Drugs Azathioprine and 6-Mercaptopurine Inhibit Mycobacterium paratuberculosis Growth In Vitro

Thiopurine Drugs Azathioprine and 6-Mercaptopurine Inhibit Mycobacterium paratuberculosis Growth In Vitro

Effects of interactions of antibacterial drugs with each other and with 6-mercaptopurine on in vitro growth of Mycobacterium avium subspecies paratuberculosis

Mycobacterium avium subspecies paratuberculosis and its relationship with Crohn’s disease

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