文献类型：期刊文献

英文题名：Bacitracin enhances ceftriaxone susceptibility of the high-level ceftriaxone-resistant gonococcal FC428 clone

作者：Gu, Yuhua[1,2];Song, Shuaijie[1,2];Zhu, Qingrui[1,2];Jiao, Ruilin[1,2];Lin, Xu'ai[1,2];Yang, Fan[1,2,3];van der Veen, Stijn[1,2,4,5]

机构：[1]Zhejiang Univ, Dept Microbiol, Hangzhou, Peoples R China;[2]Zhejiang Univ, Sch Med, Dept Dermatol, Sir Run Run Shaw Hosp, Hangzhou, Peoples R China;[3]Shaoxing Univ, Coll Med, Shaoxing, Peoples R China;[4]Zhejiang Univ, Collaborat Innovat Ctr Diag & Treatment Infect Di, Affiliated Hosp 1, Sch Med,State Key Lab Diag & Treatment Infect Dis, Hangzhou, Peoples R China;[5]Zhejiang Prov Key Lab Microbial Biochem & Metab, Hangzhou, Peoples R China

年份：2023

卷号：11

期号：6

外文期刊名：MICROBIOLOGY SPECTRUM

收录：SCI-EXPANDED(收录号：WOS:001107383600011)、、Scopus(收录号：2-s2.0-85180014763)、WOS

基金：MOST vertical bar National Natural Science Foundation of China (NSFC) 82272382 Stijn van der Veen; MOST vertical bar National Natural Science Foundation of China (NSFC) 82150610507 Stijn van der Veen; MOST vertical bar National Natural Science Foundation of China (NSFC) 82072320 Stijn van der Veen

语种：英文

外文关键词：Neisseria gonorrhoeae; FC428; bacitracin; ceftriaxone; antimicrobial synergy; FICI; dual therapy

外文摘要：Neisseria gonorrhoeae is a multidrug-resistant bacterial pathogen for which ceftriaxone mono-antimicrobial therapy and ceftriaxone plus azithromycin dual-antimicrobial therapy are the only remaining effective therapies. However, ceftriaxone efficacy is threatened by the global dissemination of the high-level ceftriaxone-resistant FC428 clone, while azithromycin has in recent years been removed from the recommended dual therapy in some countries as a result of increasing (high-level) azithromycin resistance. Inclusion of an alternative second antimicrobial could be an effective strategy to protect ceftriaxone from (further) resistance development. In this study, we investigated gonococcal susceptibility to bacitracin and determined its synergistic anti-gonococcal activity with ceftriaxone. Gonococcal susceptibility to bacitracin was investigated for 449 contemporary clinical isolates using the agar dilution method. Bacitracin displayed consistent activity against the N. gonorrhoeae strain collection, with a minimum inhibitory concentration (MIC) range of 2-32 mg/L and a MIC90 of 32 mg/L. Furthermore, bacitracin was bactericidal in time-kill assays, particularly against the tested FC428-associated isolate, which showed 10(5)-fold inactivation after 8 hours of exposure to a 4x MIC dose. Importantly, bacitracin and ceftriaxone displayed synergistic activity, with a fractional inhibitory concentration index <= 0.5 for the majority of tested strains. Finally, spot assays showed strong synergistic activity against the FC428-associated isolates, with up to 200-fold reduced plating efficacy for bacitracin combined with ceftriaxone compared with ceftriaxone only. In conclusion, bacitracin shows synergistic anti-gonococcal activity with ceftriaxone and might therefore be an interesting candidate for inclusion in a dual-antimicrobial therapy with ceftriaxone. IMPORTANCE Ceftriaxone-based antimicrobial therapies for gonorrhea are threatened by waning ceftriaxone susceptibility levels and the global dissemination of the high-level ceftriaxone-resistant gonococcal FC428 clone. Combination therapy can be an effective strategy to restrain the development of ceftriaxone resistance, and for that purpose, it is important to find an alternative antimicrobial to replace azithromycin, which has recently been removed in some countries from the recommended ceftriaxone plus azithromycin dual-antimicrobial therapy. Ideally, the second antimicrobial should display synergistic activity with ceftriaxone. We hypothesized that bacitracin might display synergistic activity with ceftriaxone because of their distinct mechanisms targeting bacterial cell wall synthesis. In this study, we showed that bacitracin indeed displays synergistic activity with ceftriaxone against Neisseria gonorrhoeae. Importantly, strains associated with the FC428 clone appeared to be particularly susceptible to the bacitracin plus ceftriaxone combination, which might therefore be an interesting dual therapy for further in vivo testing.