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JAC Advance Access originally published online on September 16, 2009
Journal of Antimicrobial Chemotherapy 2009 64(5):1018-1023; doi:10.1093/jac/dkp339
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

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

Manju Y. Krishnan, Elizabeth J. B. Manning and Michael T. Collins*

Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706-110, USA

Received 9 July 2009; returned 18 August 2009; revised 24 August 2009; accepted 24 August 2009

* Corresponding author. Tel: +1-608-262-8457; Fax: +1-608-265-6463; E-mail: mcollin5{at}wisc.edu

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 BACTECTMMGITTM960 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.

Keywords: drug combination , FIC , immunomodulator , antibiotics , susceptibility , paratuberculosis , Crohn's disease


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