JAC Advance Access originally published online on July 26, 2005
Journal of Antimicrobial Chemotherapy 2005 56(3):552-558; doi:10.1093/jac/dki270
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In vitro and in vivo activity of combination antimicrobial agents on Haemophilus ducreyi
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; 3 Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, Canada; 4 Clinical Epidemiology Program, Ottawa Health Research Institute at The Ottawa Hospital, Ottawa, Canada
Received 4 April 2005; returned 12 May 2005; revised 27 June 2005; accepted 30 June 2005
* Corresponding author. University of Ottawa at The Ottawa Hospital, Box 228, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. Tel: +1-613-737-8923; Fax: +1-613-737-8925; E-mail: bcameron{at}ohri.ca
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