No evidence of reduced cephalosporin susceptibility of circulating strains of Neisseria gonorrhoeae in the Netherlands despite nearly a decade of recommending ceftriaxone monotherapy

Due to increasing antimicrobial resistance (AMR), ceftriaxone is the only remaining singledose antibiotic effective against Neisseria gonorrhoeae. To preserve this treatment option, guidelines have recommended combination therapy with azithromycin since 2012. The rationale was that azithromycin would eradicate isolates with reduced ceftriaxone susceptibility and thereby prevent the emergence of ceftriaxone resistance. However, no randomised controlled trials (RCTs) have assessed if combination therapy is superior to monotherapy for the treatment of gonorrhoea in terms of efficacy or emergence of AMR. Metaanalyses have found no difference in efficacy between monotherapy and dual therapy. In fact, increasing macrolide exposure may promote AMR acquisition. These considerations have led some guidelines to change back to recommending ceftriaxone monotherapy for uncomplicated gonorrhoea, and the 2020 European guidelines now include monotherapy as an alternative. Dutch guidelines are unusual in that, unlike the rest of Europe, they never recommended dual therapy; a single 500 mg intramuscular dose of ceftriaxone has been the preferred treatment for gonorrhoea since 2011. This policy allowed us to test whether between 2012 and 2019, the use of ceftriaxone monotherapy in the Netherlands was associated with lower ceftriaxone susceptibility in circulating strains of N. gonorrhoeae as compared with countries were dual therapy was recommended. We compared ceftriaxone, cefixime and azithromycin susceptibility of gonococcal isolates from the Netherlands with that of isolates from the remaining 26 European countries participating in European Gonococcal Antimicrobial Surveillance Programme between 2012 and 2019. For each antibiotic, we applied a mixedeffects linear regression model to estimate the association between the isolates’ logarithmically transformed minimum inhibitory concentration (MIC) and treatment policy in the country of collection (monotherapy in the Netherlands and dual therapy in the remaining countries). The model was adjusted for gender, mode of transmission, year of MIC reporting and countrylevel antibiotic consumption in the year before the isolate was collected. Antibiotic consumption data were derived from the European Surveillance of Antimicrobial Consumption Network. To account for residual confounding and for the longitudinal nature of the data, country of reporting was included as a random effect. Outcomes of the regression model were exponentiated to obtain ORs, which indicate change in geometric mean MIC. More than 20 000 isolates were included (table 1 and online supplemental table S1). The UK, the Netherlands and Spain contributed 9.9%, 9.4% and 8.3% of all MIC values, respectively (online supplemental figure S1). Antibiotic consumption in the Netherlands was among the lowest in Europe (online supplemental figure S2). The monotherapy policy in the Netherlands was not associated with the geometric mean MIC for ceftriaxone (OR 0.46, 95% CI 0.12 to 1.77) or cefixime (OR 0.52, 95% CI 0.17 to 1.57), but was associated with a lower geometric mean MIC for azithromycin compared with other countries (OR 0.59, 95% CI 0.35 to 0.98). These findings suggest that nearly a decade of ceftriaxone monotherapy in the Netherlands was not associated with reduced cephalosporin susceptibility of circulating N. gonorrhoeae isolates. There are limitations to our analysis, including those inherent to surveillance data and the possibility that healthcare providers may not follow national treatment guidelines. In addition, our analysis may have been insensitive to the impact of recently circulating strains with reduced cephalosporin susceptibility. In addition, Research Letter