Susceptibility Trends of Zoliflodacin against Multidrug-Resistant Neisseria gonorrhoeae Clinical Isolates in Nanjing, China, 2014 to 2018

Abstract

Previously, we reported potent activity of a novel spiropyrimidinetrione, zoliflodacin, against N. gonorrhoeae isolates from symptomatic men in Nanjing, China, collected in 2013. Here, we investigated trends of susceptibilities of zoliflodacin in 986 isolates collected from men between 2014 and 2018. N. gonorrhoeae isolates were tested for susceptibility to zoliflodacin and seven other antibiotics. Mutations in gyrA, gyrB, parC, parE and mtrR genes were determined by PCR and sequencing. The MICs of zoliflodacin ranged from ≤0.002 to 0.25 mg/L; the overall MIC50s and MIC90s were 0.06 mg/L and 0.125mg/L in 2018, increasing two-fold from 2014. However, the percent of isolates with lower zoliflodacin MICs declined in each year sequentially while the percent with higher MICs increased yearly (P≤0.00001). All isolates were susceptible to spectinomycin but resistant to ciprofloxacin (MIC ≥1 mg/L); 21.2% (209/986) were resistant to azithromycin (≥1 mg/L), 43.4% (428/986) were penicillinase-producing (PPNG), 26.9% (265/986) tetracycline-resistant (TRNG) and 19.4% (191/986) were multi-drug resistant (MDR) isolates. Among 202 isolates tested, all were quinolone resistant with double or triple mutations in gyrA; One hundred ninety three (193/202; 95.5%) also had mutations in parC. There were no D429N/A and/or K450T mutations in GyrB identified in the 143 isolates with higher zoliflodacin MICs; a S467N mutation in GyrB was identified in one isolate. We report that zoliflodacin continues to have excellent in vitro activity against clinical gonococcal isolates, including those with high-level resistance to ciprofloxacin, azithromycin and extended spectrum cephalosporins.

Pharmacodynamic Evaluation of Zoliflodacin Treatment of Neisseria gonorrhoeae Strains With Amino Acid Substitutions in the Zoliflodacin Target GyrB Using a Dynamic Hollow Fiber Infection Model

“…Thus, the GyrB S467N substitution appears to predispose to emergence of zoliflodacin resistance, despite not conferring resistance to zoliflodacin on its own. Fortunately, N. gonorrhoeae strains with GyrB S467N substitution appear to be very rare internationally ( https://pathogen.watch/collections/all?organismId=485 ; Le et al, 2021 ). Furthermore, the zoliflodacin-resistant SE600/18-D429N mutant suffered from a biofitness disadvantage and was outcompeted by the zoliflodacin-susceptible parent SE600/18 strain, which suggests that these zoliflodacin-resistant strains will be less effective at amplifying and spreading after emergence.…”

“…However, in static in vitro laboratory experiments zoliflodacin-resistant mutants have been selected; all containing substitutions of amino acids D429 or K450 of GyrB ( Alm et al, 2015 ; Foerster et al, 2015 ; Foerster et al, 2019 ; Jacobsson et al, 2021 ). No clinical isolate with amino acid substitution in GyrB K450 and only one single clinical isolate with a GyrB D429V substitution has been found ( Jacobsson et al, 2014 ; Alm et al, 2015 ; Unemo et al, 2015 ; Unemo et al, 2019 ; Bradford et al, 2020 ; Le et al, 2021 ; Adamson et al, 2021 ). Additionally, an isolate with a GyrB S467N substitution was selected previously in static in vitro experiments ( Alm et al, 2015 ) .…”

“…Zoliflodacin has a high in vitro activity against N. gonorrhoeae , including multi-drug-resistant clinical strains ( Jacobsson et al, 2014 ; Unemo et al, 2015 ; Unemo et al, 2019 ; Bradford et al, 2020 ). No clinical N. gonorrhoeae isolates with zoliflodacin resistance have been reported when international gonococcal populations from the last decade have been examined ( Jacobsson et al, 2014 ; Unemo et al, 2015 ; Unemo et al, 2019 ; Bradford et al, 2020 ; Le et al, 2021 ). However, in static in vitro laboratory experiments zoliflodacin-resistant mutants have been selected; all containing substitutions of amino acids D429 or K450 of GyrB ( Alm et al, 2015 ; Foerster et al, 2015 ; Foerster et al, 2019 ; Jacobsson et al, 2021 ).…”

“…This substitution did not alone cause zoliflodacin resistance as a first step mutation (zoliflodacin MIC of 0.25 mg/L), however it further increased the MIC of zoliflodacin as a second step mutation ( Alm et al, 2015 ). Rare clinical gonococcal isolates with a GyrB S467N substitution ( https://pathogen.watch/collections/all?organismId=485 ), e.g., 1 of 143 isolates with zoliflodacin MICs of 0.125–0.25 mg/L in Nanjing, China ( Le et al, 2021 ), and wild-type (susceptible) MICs of zoliflodacin have been found. However, the international prevalence of these strains is basically unknown.…”

Fascinating Molecular and Immune Escape Mechanisms in the Treatment of STIs (Syphilis, Gonorrhea, Chlamydia, and Herpes Simplex)

“…Additionally, studies revealed that the conventional therapeutic dose of 2 g does not induce cardiac arrhythmias and is well tolerated [ 137 ]. Although zoliflodacin maintains an excellent in vitro activity against clinical N. gonorrhoeae isolates, the rising potential to develop AMR led to further antibiotics research [ 138 ]. A 2021 study found that a single dose of MBX-4132, an acylaminooxadiazole that selectively inhibits ribosomal trans-translation, successfully cleared MDR N. gonorrhoeae infection in mice [ 139 ].…”