In vitro antimicrobial combination testing of and evolution of resistance to the first-in-class spiropyrimidinetrione zoliflodacin combined with six therapeutically relevant antimicrobials for Neisseria gonorrhoeae

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Foerster, SunnivaWHO Collaborating Centre for Gonorrhoea and other STIs, Swedish Reference Laboratory for STIs, Faculty of Medicine and Health, Örebro University, Örebro, Sweden (author)

In vitro antimicrobial combination testing of and evolution of resistance to the first-in-class spiropyrimidinetrione zoliflodacin combined with six therapeutically relevant antimicrobials for Neisseria gonorrhoeae

Article/chapterEnglish2019

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2019-09-05
Oxford University Press,2019
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LIBRIS-ID:oai:DiVA.org:oru-78560
https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-78560URI
https://doi.org/10.1093/jac/dkz376DOI

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Language:English
Summary in:English

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Funding Agencies:Global Antibiotic Research & Development Partnership (GARDP) Örebro County Council Research Committee, Örebro, Sweden Foundation for Medical Research at Örebro University Hospital, Örebro, Sweden
OBJECTIVES: Resistance in Neisseria gonorrhoeae to all gonorrhoea therapeutic antimicrobials has emerged. Novel therapeutic antimicrobials are imperative and the first-in-class spiropyrimidinetrione zoliflodacin appears promising. Zoliflodacin could be introduced in dual antimicrobial therapies to prevent the emergence and/or spread of resistance. We investigated the in vitro activity of and selection of resistance to zoliflodacin alone and in combination with six gonorrhoea therapeutic antimicrobials against N. gonorrhoeae.METHODS: The international gonococcal reference strains WHO F (WT) and WHO O, WHO V and WHO X (strains with different AMR profiles) were examined. Zoliflodacin was evaluated alone or combined with ceftriaxone, cefixime, spectinomycin, gentamicin, tetracycline, cethromycin or sitafloxacin in chequerboard assays, time-kill curve analysis and selection-of-resistance studies.RESULTS: Zoliflodacin alone or in combination with all six antimicrobials showed rapid growth inhibition against all examined strains. The time-kill curve analysis indicated that tetracycline or cethromycin combined with zoliflodacin can significantly decrease the zoliflodacin kill rate in vitro. The frequency of selected zoliflodacin-resistance mutations was low when evaluated as a single agent and further reduced for all antimicrobial combinations. All resistant mutants contained the GyrB mutations D429N, K450T or K450N, resulting in zoliflodacin MICs of 0.5-4 mg/L.CONCLUSIONS: Zoliflodacin, alone or in combination with sexually transmitted infection therapeutic antimicrobials, rapidly kills gonococci with infrequent resistance emergence. Zoliflodacin remains promising for gonorrhoea oral monotherapy and as part of dual antimicrobial therapy with low resistance emergence potential. A Phase III trial evaluating efficacy and safety of zoliflodacin for uncomplicated gonorrhoea treatment is planned in 2019.

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Drusano, GeorgeInstitute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, FL, USA (author)
Golparian, Daniel,1984-Örebro universitet,Institutionen för medicinska vetenskaper,WHO Collaborating Centre for Gonorrhoea and other STIs, Swedish Reference Laboratory for STIs(Swepub:oru)degn (author)
Neely, MichaelChildren's Hospital of Los Angeles, Department of Pediatrics, Division of Infectious Diseases, University of Southern California, CA, USA (author)
Piddock, Laura J. V.Global Antibiotic Research & Development Partnership (GARDP), Geneva, Switzerland (author)
Alirol, EmilieGlobal Antibiotic Research & Development Partnership (GARDP), Geneva, Switzerland (author)
Unemo, Magnus,1970-Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,WHO Collaborating Centre for Gonorrhoea and other STIs, Swedish Reference Laboratory for STIs(Swepub:oru)muo (author)
WHO Collaborating Centre for Gonorrhoea and other STIs, Swedish Reference Laboratory for STIs, Faculty of Medicine and Health, Örebro University, Örebro, SwedenInstitute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, FL, USA (creator_code:org_t)

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In:Journal of Antimicrobial Chemotherapy: Oxford University Press74:12, s. 3521-35290305-74531460-2091

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