Abstract
The number of cases of gonorrhoea in the USA and worldwide caused by Neisseria gonorrhoeae is increasing (555 608 reported US cases in 2017, and 87 million cases worldwide in 2016). Many countries report declining in vitro susceptibility of azithromycin, which is a concern because azithromycin and ceftriaxone are the recommended dual treatment in many countries. We aimed to identify strain types associated with decreased susceptibility to azithromycin. We did a genomic analysis of N gonorrhoeae isolates obtained by the US Gonococcal Isolate Surveillance Project. Isolates were whole-genome sequenced based on decreased susceptibility to azithromycin (minimal inhibitory concentration [MIC] ≥2 μg/mL, using agar dilution antibiotic susceptibility testing) and geographical representation. Bioinformatic analyses established genomic diversity, strain population dynamics, and antimicrobial resistance profiles. 410 isolates were sorted into more than 20 unique phylogenetic clades. One predominant persistent clade (consisting of 97 isolates) included the most isolates with azithromycin MICs of 2 μg/mL or higher (61 of 97 [63%] vs 59 of 311 [19%]; p<0·0001) and carried a mosaic mtr (multiple transferable resistance) locus (68 of 97 [70%] vs two of 313 [1%]; p<0·0001). Of the remaining 313 isolates, 57 (18%) had decreased susceptibility to azithromycin (MIC ≥4 μg/mL), which was attributed to 23S rRNA variants (56 of 57 [98%]) and formed phylogenetically diverse clades, showing various levels of clonal expansion. Reduced azithromycin susceptibility was associated with expanding and persistent clades harbouring two well described resistance mechanisms, mosaic mtr locus and 23S rRNA variants. Understanding the role of recombination, particularly within the mtr locus, on the fitness and expansion of strains with decreased susceptibility has important implications for the public health response to minimise gonorrhoea transmission. US Centers for Disease Control and Prevention (CDC), CDC Combating Antibiotic Resistant Bacteria initiative, Oak Ridge Institute for Science Education, US Department of Energy/CDC/Emory University, National Institutes of Health, and Biomedical Laboratory Research and Development Service of the US Department of Veterans Affairs.
Highlights
Neisseria gonorrhoeae, a Gram-negative diplococcus, is the causative agent of gonorrhoea
The rates of reported cases of gonorrhoea in the USA have increased by 75·2% between 2009 and 2017, from a historic low of 98·1 cases per 100 000 population in 2009 to 170·6 cases per 100 000 population reported in the USA in 2017.1 Global prevalence and incidence of gonorrhoea is high,[2] with an estimated 87 million cases worldwide in 2016.3 N gonorrhoeae was identified as an urgent-level antibiotic resistance threat by the US Centers for Disease Control and Prevention (CDC) in 2013,4 and again in 2019.5 The CDC currently recommends dual therapy with azithromycin and ceftriaxone for first-line treatment of uncomplicated gonorrhoea.[6]
We aimed to extend our understanding of N gonorrhoeae genetic diversity, variation in strain prevalence, and antibiotic resistance determinants beyond previously published data for surveillance isolates obtained by Gonococcal Isolate Surveillance Project (GISP) in 2000–1318 and 2014–16.21 We did a surveillance-based genome analysis of GISP isolates from 2017 to identify strains and antibiotic resistance profiles associated with the overall increase in proportion of isolates with decreased susceptibility to azithromycin (MIC ≥2 μg/mL) in the USA
Summary
A Gram-negative diplococcus, is the causative agent of gonorrhoea. The long half-life of azithromycin (serum t1/2 68 h) might increase the risk of selection for resistance through prolonged subinhibitory intracellular and extracellular concentrations.[7] Reduced susceptibility of gonococci to azithromycin was reported in the 1990s, and azithromycin has not been recommended as a monotherapy, growing reports of decreased azithromycin susceptibility are being monitored worldwide.[8,9,10,11,12,13] Azithromycin was recommended to be used in dual therapy with ceftriaxone in 2015,6 to function as a shield to potentially delay the emergence of resistance to ceftriaxone, the last remaining antimicrobial option This recommendation was modelled after combination anti microbial therapy for prevention of resistance used for other infectious diseases such as tuberculosis.[14]
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