• ANTIBIOTIC RESISTANCE
• GONORRHOEA
• NEISSERIA GONORRHOEA
• URETHRITIS
• GAY MEN

Resistance to third generation cephalosporin-resistant Neisseria gonorrhoeae (NG) is of great concern for public health globally. Gonorrhoea therapy failures with cefixime (oral) and, rarely, the more potent ceftriaxone (injectable) have been verified in many countries around the world,1 and gonococcal strains with higher level of ceftriaxone resistance have been isolated in Japan, France and Spain.2–4 Until 2013, cefotaxime 1g intramuscularly was recommended for gonorrhoea treatment in the guidelines for Dutch general practitioners (GPs). No treatment failures with this antibiotic have been previously documented. Herein, the first verified gonorrhoea treatment failure with a third generation cephalosporin, cefotaxime, in the Netherlands is described.

In November 2012 (day 1), a 28-year-old man characterised as MSM (men having sex with men) presented to his GP with urethral discharge and dysuria, and urethritis was clinically suspected. A urine sample for nucleic acid amplification test (NAAT) detecting Chlamydia trachomatis and NG was sent to a routine laboratory and he was treated with azithromycin 1g orally because of suspected chlamydial infection. On day 6, he returned with unresolved symptoms; however, NAAT results were not yet available. A urethral culture was performed and the patient was treated with ciprofloxacin 500 mg orally. Cultures were done using GC medium (Oxoid) with LCAT (Lincomycin, Colistin, Amphotericin B and Trimethoprim) supplement (Oxoid), Vitox (Oxoid) and NAD (1 mg/L). Identification of NG was done by MALDI-ToF. On day 9, a positive NG culture was reported to the physician and the NAAT (Strand Displacement Amplification, BD Viper platform) for C. trachomatis was negative. The patient, whose symptoms had persisted, was treated with 1g cefotaxime intramuscularly, according to the Dutch guidelines for GPs. The NAAT of the initial sample for NG was positive, but this result was only available on day 12, since the laboratory had requested confirmatory NAAT testing. On day 12, the presentations persisted and a repeat new urethral culture was positive for NG. The patient denied having any sexual contacts since cefotaxime treatment was administered and test-of-cure cultivation on day 12. Treatment with ceftriaxone 500 mg intramuscularly was given and the symptoms were resolved on day 15, when the patient was contacted by telephone, and on day 20, when the patient visited the physician’s office. The patient refused to provide a subsequent test-of-cure sample.

The gonococcal isolates obtained pretreatment and post-treatment with cefotaxime were indistinguishable with multi-locus sequence typing (MLST ST1901), NG multi-antigen sequence typing (NG-MAST ST1407), NG multiple-locus variable-number tandem-repeat analysis and serovar determination (Bpyust). Using Etest on chocolate agar plates, the isolates showed in vitro resistance to cefotaxime (minimum inhibitory concentration (MIC) =0.25 mg/L) and ciprofloxacin (MIC>32 mg/L), and intermediate susceptibility to azithromycin (MIC=0.5 mg/L) (http://www.eucast.org/clinical_breakpoints), and a clearly increased MIC of ceftriaxone (0.064 mg/L) and cefixime (0.125 mg/L). As reference strains, WHO strains G, K, L, M, O and P were used.5 The penA, mtrR (including the promoter sequence) and porB (for detection of the penB resistance determinant) genes were sequenced as previously described.6 Both isolates contained a mosaic penA gene, type XXXIV,1 ,3 as well as an A-deletion in promoter of mtrR and the G120K and A121N amino acid alterations in penB. These mutations have been associated with resistance against cephalosporins.6

Successful treatment of NG with cephalosporins depends on the duration of the serum concentration of unbound antibiotic above the MIC of the strain. Due to the shorter half-life of cefotaxime of 1.3 h in comparison with ceftriaxone (7 h) after intramuscular injection, in combination with differences in protein binding, the time of unbound antibiotic over MIC of this strain will be 7.8 h after injection of 1g cefotaxime intramuscularly, but 35 h after 500 mg ceftriaxone intramuscularly.7 ,8 Accordingly, cefotaxime is no longer recommended for empiric treatment of NG in the Dutch GP guidelines and instead ceftriaxone is now recommended, which is in accordance with treatment guidelines for NG.9 In the Netherlands, ceftriaxone replaced cefotaxime in the Public Health treatment guidelines in 2007; however, the guidelines for Dutch GPs did not implement this replacement until 2013. Ciprofloxacin treatment, initially given to this patient, is outdated.

This report describes the first verified gonorrhoea treatment failure with a third generation cephalosporin, cefotaxime, in the Netherlands. The MLST ST1901, NG-MAST ST1407 multidrug-resistant gonococcal clone, with decreased susceptibility or resistance to third generation cephalosporins and resulting in treatment failures is widely spread in Europe, including the Netherlands, and basically worldwide.1 ,10 Accordingly, therapeutic failures with cefotaxime might have occurred more frequently than realised, particularly when the current case belonged to a high-frequency transmitting population (MSM).