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JAC Advance Access published online on July 26, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki270
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Received April 4, 2005
Revised June 27, 2005
Accepted June 30, 2005

Original article

In vitro and in vivo activity of combination antimicrobial agents on Haemophilus ducreyi

Josée E. Roy-Leon 1, Wallace D. Lauzon 1, Baldwin Toye 2, Neera Singhal 3, and D. William Cameron 4*

1 Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada
2 Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada; Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, Canada
3 Clinical Epidemiology Program, Ottawa Health Research Institute at The Ottawa Hospital, Ottawa, Canada
4 Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada; Clinical Epidemiology Program, Ottawa Health Research Institute at The Ottawa Hospital, Ottawa, Canada

* To whom correspondence should be addressed.
D. William Cameron, E-mail: bcameron{at}ohri.ca


  Abstract

Objectives: Development of single dose antibiotic treatments for chancroid has been followed by drug-resistant Haemophilus ducreyi in endemic areas. We examined the activity and interactions of antimicrobial agents and combinations against H. ducreyi.

Methods: We evaluated the in vitro susceptibility of three virulent strains of H. ducreyi to ceftriaxone, azithromycin, rifabutin and streptomycin, and each two-drug combination by the agar dilution method. We then tested each two-antibiotic combination for activity by the chequerboard method. Lastly, we chose the antibiotic combination with the lowest fractional inhibitory concentration index (FICI) and tested combined sub-therapeutic doses, the highest doses which had no effect alone on lesion healing compared with controls, for in vivo interaction in the temperature-dependent rabbit model of H. ducreyi infection.

Results: Each H. ducreyi strain was susceptible in vitro to each antibiotic and two-antibiotic combination, and combined ceftriaxone and streptomycin had the lowest FICI at 0.63. In five treated animals versus three untreated controls, combined sub-therapeutic doses of ceftriaxone (0.05 mg/kg) and streptomycin (10 mg/kg) reduced mean (SD) duration of culture positivity from 7.3 (1.1) to 2.6 (1.7) days (P < 0.001), time to 50% reduction in lesion size from 9.7 (1.5) to 5.8 (0.8) days (P < 0.005), and time to resolution of ulcer from 11.7 (2.3) to 6.6 (1.7) days (P < 0.05).

Conclusions: Ceftriaxone and streptomycin have in vivo synergic interaction against H. ducreyi lesions in the temperature-dependent rabbit model of infection. Antibiotic combinations may be evaluated clinically as single-dose therapy for chancroid.

Keywords: antimicrobial interactions; chancroid; H. ducreyi; synergy.
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