title: Determination of in vitro synergy for dual antimicrobial therapy against resistant Neisseria gonorrhoeae using Etest and agar dilution.
abstract: In response to antimicrobial resistance of Neisseria gonorrhoeae to last-resort extended-spectrum cephalosporins, combination therapy of azithromycin+ceftriaxone is now recommended. Dual therapy can be effective to treat monoresistant strains as well as multidrug-resistant strains, preferably employing the effect of in vitro synergy. As reports on in vitro synergy of azithromycin+ceftriaxone in N. gonorrhoeae are conflicting, in this study an evaluation of this combination was performed using a cross-wise Etest method and agar dilution. Synergy was defined as a fractional inhibitory concentration index (FICI) of ≤0.5. To identify other dual treatment options for gonorrhoea, in vitro synergy was evaluated for 65 dual antimicrobial combinations using Etest. Azithromycin, cefixime, ceftriaxone, colistin, ertapenem, fosfomycin, gentamicin, minocycline, moxifloxacin, rifampicin, spectinomycin and tigecycline were screened for synergy in all possible combinations. No synergy or antagonism was found for any of the 65 combinations. The geometric mean FICI ranged from 0.82 to 2.00. The mean FICI of azithromycin+ceftriaxone was 1.18 (Etest) and 0.55 (agar dilution). The difference between both methods did not result in a difference in interpretation of synergy. Ceftriaxone-resistant strain F89 was tested in all combinations and no synergy was found for any of them. Most importantly, the ceftriaxone minimum inhibitory concentration of F89 was not decreased below the breakpoint with any concentration of azithromycin.
authors.affiliation: STI Outpatient Clinic, Cluster of Infectious Diseases, Public Health Service Amsterdam, PO Box 2200, 1000 CE Amsterdam, The Netherlands; Department of Dermatology, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, The Netherlands.
authors.forename: Carolien M
authors.initials: CM
authors.lastname: Wind
authors.affiliation: STI Outpatient Clinic, Cluster of Infectious Diseases, Public Health Service Amsterdam, PO Box 2200, 1000 CE Amsterdam, The Netherlands; Department of Dermatology, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, The Netherlands; Center for Infection and Immunology Amsterdam (CINIMA), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Henry J C
authors.initials: HJ
authors.lastname: de Vries
authors.affiliation: Public Health Laboratory, Cluster of Infectious Diseases, Public Health Service Amsterdam, PO Box 2200, 1000 CE Amsterdam, The Netherlands; Department of Medical Microbiology, Onze Lieve Vrouwe Gasthuis General Hospital, PO Box 95500, 1090 HM Amsterdam, The Netherlands. Electronic address: avdam@ggd.amsterdam.nl.
authors.forename: Alje P
authors.initials: AP
authors.lastname: van Dam
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D006069:Gonorrhea / Q000188:drug therapy / Q000382:microbiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae / Q000187:drug effects* / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents
keywords: Antimicrobial susceptibility; Azithromycin; Ceftriaxone; Combination therapy; Gonorrhoea; In vitro synergy