Significant increase in azithromycin “resistance” and susceptibility to ceftriaxone and cefixime in Neisseria gonorrhoeae isolates in 26 European countries, 2019
Authors: Day Michaela J. , Jacobsson Susanne , Spiteri Gianfranco , Kulishev Carina , Sajedi Noshin , Woodford Neil , Blumel Benjamin , van der Werf Marieke J. , Amato-Gauci Andrew J. , Unemo Magnus , Cole Michelle J. ,   The Euro-GASP network, Eder Claudia , Pleininger Sonja , Huhlescu Steliana , de Baetselier Irith , Hunjak Blaženka , Blažić Tatjana Nemeth , Maikanti-Charalampous Panagiota , Pieridou Despo , Zákoucká Hana , Žemličková Helena , Hoffmann Steen , Cowan Susan , Peetso Rita , Viktorova Jelena , Ndeikoundam Ndeindo , Bercot Beatrice , Sampo Anu Patari , Kirjavainen Vesa , Buder Susanne , Jansen Klaus , Miriagou Vivi , Balla Eszter , Dudás Mária , Sigmundsdóttir Guðrún , Asmundsdottir Lena Ros , Saab Sinead , Crowley Brendan , Carannante Anna , Stefanelli Paola , Pakarna Gatis , Mavcutko Violeta , Cassar Robert , Barbara Christopher , Vella Francesca , Van Dam Alje , Linde Ineke , Caugant Dominique , Kløvstad Hilde , Mlynarczyk-Bonikowska Beata , Borrego Maria-José , Pavlik Peter , Klavs Irena , Kustec Tanja , Vazquez Julio , Diaz Asuncion , Torreblanca Raquel Abad , Velicko Inga , Unemo Magnus , Fifer Helen , Templeton Kate 
Published: June 2022

Abstract
Background
The European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) performs annual sentinel surveillance of Neisseria gonorrhoeae susceptibility to therapeutically relevant antimicrobials across the European Union/European Economic Area (EU/EEA). We present the Euro-GASP results from 2019 (26 countries), linked to patient epidemiological data, and compared with data from previous years.

Methods
Agar dilution and minimum inhibitory concentration (MIC) gradient strip methodologies were used to determine the antimicrobial susceptibility (using EUCAST clinical breakpoints, where available) of 3239 N. gonorrhoeae isolates from 26 countries across the EU/EEA. Significance of differences compared with Euro-GASP results in previous years was analysed using Z-test and the Pearson's χ2 test was used to assess significance of odds ratios for associations between patient epidemiological data and antimicrobial resistance.

Results
European N. gonorrhoeae isolates collected between 2016 and 2019 displayed shifting MIC distributions for; ceftriaxone, with highly susceptible isolates increasing over time and occasional resistant isolates each year; cefixime, with highly-susceptible isolates becoming increasingly common; azithromycin, with a shift away from lower MICs towards higher MICs above the EUCAST epidemiological cut-off (ECOFF); and ciprofloxacin which is displaying a similar shift in MICs as observed for azithromycin. In 2019, two isolates displayed ceftriaxone resistance, but both isolates had MICs below the azithromycin ECOFF. Cefixime resistance (0.8%) was associated with patient sex, with resistance higher in females compared with male heterosexuals and men-who-have-sex-with-men (MSM). The number of countries reporting isolates with azithromycin MICs above the ECOFF increased from 76.9% (20/26) in 2016 to 92.3% (24/26) in 2019. Isolates with azithromycin MICs above the ECOFF (9.0%) were associated with pharyngeal infection sites. Following multivariable analysis, ciprofloxacin resistance remained associated with isolates from MSM and heterosexual males compared with females, the absence of a concurrent chlamydial infection, pharyngeal infection sites and patients ≥ 25 years of age.

Conclusions
Resistance to ceftriaxone and cefixime remained uncommon in EU/EEA countries in 2019 with a significant decrease in cefixime resistance observed between 2016 and 2019. The significant increase in azithromycin “resistance” (azithromycin MICs above the ECOFF) threatens the effectiveness of the dual therapy (ceftriaxone + azithromycin), i.e., for ceftriaxone-resistant cases, currently recommended in many countries internationally and requires close monitoring.