In Switzerland, N. gonorrhoeae strains with decreased susceptibility to third-generation cephalosporins are emerging. We observed increasing rates of cefixime resistant strains, with a prevalence of 11% between 2007 and 2012. Moreover, ceftriaxone MICs are rising. The proportion of isolates with elevated ceftriaxone MIC was 2.2% between 2007 and 2012.
Our findings are in line with the worldwide documented decrease in cephalosporin susceptibility of N. gonorrhoeae. In the European Gonococcal antimicrobial susceptibility surveillance project (Euro-GASP), 9% of isolates displayed decreased susceptibility to cefixime (MIC ≥0.25 mg/L) in 2010. Cefixime resistance rates were >5% in 11 of 21 European countries, and >15% in 5 countries, including Austria, Denmark, Slovenia, Spain and Cyprus
. In the United States the percentage of cefixime resistant isolates (MIC ≥0.25 mg/L) increased from 0.1% in 2006 to 1.4% in 2011
. The rise was most pronounced in the West with resistance rates of 17% in Hawaii and 6.4% in San Diego, California, in 2011
These are in vitro data and clinical cephalosporin resistance has not yet been defined due to the fact that so far there have been too few documented treatment failures in order to establish a clear relationship between MIC and clinical treatment failure. In a recently published Canadian cohort study the rate of clinical treatment failure associated with isolates of N. gonorrhoeae with a cefixime MIC of ≥0.12 mg/L was 25.0% compared to 1.9% of isolates with a cefixime MIC of <0.12 mg/L
In 2008, we isolated one strain with a MIC for ceftriaxone of 0.25 mg/L. No decreased susceptibility to ceftriaxone (MIC ≥0.25 mg/L) was detected from 2004 to 2010 among Euro-GASP isolates. However, in correspondence to our data, ceftriaxone MICs increased from 2009 onwards
. In the United States the percentage of isolates with elevated ceftriaxone MICs (≥0.125 mg/L) rose slightly from 0% in 2006 to 0.4% in 2011
. As displayed for cefixime, no threshold for resistance to ceftriaxone in N. gonorrhoeae has been defined yet. Increasing MICs for cephalosporins, however, may precede the emergence of resistance.
We found high ciprofloxacin resistance rates of N. gonorrhoeae, with 72.7% in 2012. Our data demonstrates that during the 1990s and early 2000s, when ciprofloxacin was first choice for treatment, fluoroquinolone-resistant isolates emerged, and rapidly increased after 2000, correlating with the observation in other countries around the world
[24–26]. By 2007, in the United States, and even earlier in other regions, including Europe and Australia, fluoroquinolones were no longer recommended for the treatment of gonococcal infections
[27, 28]. In Europe, ciprofloxacin resistance was 53% (MIC ≥1 mg/L) in 2010
, and 13.3% in the United States in 2011 (≥1 mg/L)
The World Health Organization (WHO) recommends discontinuation of empirical use of an antibiotic once 5% of locally acquired gonococcal isolates are resistant
. The high rates of strains with decreased cefixime susceptibility and first isolates with elevated MICs for ceftriaxone shown by our data, support the recommendation of dual therapy for gonococcal infections with ceftriaxone plus either azithromycin or doxycycline. Combination regimens have been adopted as strategies for the treatment of other bacterial infections in the context of multidrug resistance development. The oral cephalosporin, cefixime, should no longer be used as first-line treatment.
In light of identified strains with decreased ceftriaxone susceptibility, health-care providers need to be vigilant for treatment failures, even in patients treated with recommended antibiotic regimens. In persons treated with alternative regimens, such as cefixime, test of cure is recommended. Continued local surveillance of gonococcal antimicrobial susceptibility is important. Due to the widespread use of nucleic acid amplification testing, culture for N. gonorrhoeae with antimicrobial susceptibility testing is not routinely done in clinical practice.
To the best of our knowledge, this is the first report on cephalosporin susceptibility testing of N. gonorrhoeae in Switzerland. Longitudinal data on antimicrobial resistance in gonococci over a period of more than two decades was assessed. Nevertheless, the study has several limitations. The level of coverage was relatively low, attributed in a large part to the low number of gonococcal cultures taken routinely in clinical practice. The samples were not systematically collected within a sentinella system, which may result in selection of specimens with a higher resistance rate. Not all strains were tested for cephalosporins, which particularly concerns isolates obtained before 2006. However, the subset of 20-30% of all isolates stored, none showed decreased susceptibility for cefixime and ceftriaxone. It is therefore unlikely that we missed a relevant resistance signal. Finally, the isolates were not tested for azithromycin.