In Vitro Activity of Fosfomycin Alone and in Combination with Ceftriaxone or Azithromycin against Clinical Neisseria gonorrhoeae Isolates

摘要

New therapeutic strategies are needed to combat the emergence of infections due to multidrug-resistant Neisseria gonorrhoeae. In this study, fosfomycin (FOS) was tested against 89 Neisseria gonorrhoeae isolates using the Etest method, showing MIC50/MIC(90)s of only 8/16 mu g/ml (range, <= 1 to 32 mu g/ml). FOS in combination with ceftriaxone (CRO) or azithromycin (AZT) was then evaluated using the checkerboard method for eight strains, including Neisseria gonorrhoeae F89 (CRO-resistant) and AZT-HLR (high-level AZT-resistant). All combinations that included FOS gave indifferent effects (fractional inhibitory concentration [FIC] index values, 1.2 to 2.3 for FOS plus CRO, 1.8 to 3.2 for FOS plus AZT). Time-kill experiments for FOS, CRO, AZT, and their combinations (at 0.5x, 1x, 2x, and 4x the MIC) were performed against Neisseria gonorrhoeae strain ATCC 49226, one Neisseria gonorrhoeae multi-antigen sequence typing (NG-MAST) sequence type 1407 (ST1407) strain, F89, and AZT-HLR. For all strains, at 24 h, the results indicated that (i) FOS was bactericidal at 2X the MIC, but after >24 h, there was regrowth of bacteria; (ii) CRO was bactericidal at 0.5x the MIC; (iii) AZT was bactericidal at 4x the MIC; (iv) CRO plus AZT was less bactericidal than was CRO alone; (v) FOS plus AZT was bactericidal at 2x the MIC; and (vi) CRO plus AZT and FOS plus CRO were both bactericidal at 0.5x the MIC, but FOS plus CRO had more rapid effects. FOS is appealing for use in the management of Neisseria gonorrhoeae infections because of its single and oral formulation. However, our results suggest it be used in combination with CRO. After the appropriate clinical trials are conducted, this strategy could be implemented for the treatment of infections due to isolates possessing resistance to CRO and/or AZT.