Failure of 500 mg of ceftriaxone to eradicate pharyngeal gonorrhoea, Australia

Sir, Over time Neisseria gonorrhoeae has developed resistance to a wide range of antimicrobials, including cephalosporins, limiting treatment options.1 We report a case of persistent pharyngeal N. gonorrhoeae despite administration of 500 mg of ceftriaxone by intramuscular injection, a dose exceeding that currently recommended in some countries for gonorrhoea. We obtained informed consent from the index patient to publish this report. A homosexual man presented to a Melbourne clinic in 2010 (day 0) complaining of anal discomfort. His regular male partner had been diagnosed with gonorrhoea and therefore he was given 500 mg of ceftriaxone by intramuscular injection. Both rectal and pharyngeal swabs grew N. gonorrhoeae. On day 22, a repeat pharyngeal swab grew N. gonorrhoeae. He returned on day 34. A third pharyngeal swab was taken before he was given 2 g of azithromycin. N. gonorrhoeae was again isolated. He reported that he had not had any sexual contact since his first visit. Pharyngeal and rectal swabs taken on day 41 were negative for N. gonorrhoeae on culture and by Abbott m2000 real-time PCR testing. The patient's regular male partner presented to a general practitioner with conjunctival and urethral gonorrhoea confirmed by nucleic acid amplification testing (NAAT) and was treated with cefalexin, doxycycline and amoxicillin. Pharyngeal and rectal swabs for culture and urine NAAT for N. gonorrhoeae taken 2 months later were negative. He reported that the last time he had sex was with his regular partner and that this was prior to day 0 above. Isolates were identified as N. gonorrhoeae based on Gram's stain, oxidase, carbohydrate utilization reactions and the MicroTrak®N. gonorrhoeae Culture Confirmation Test (Trinity Biotech) and confirmed by porA pseudogene and opa gene PCR assays. MICs were determined by agar plate dilution using the method of the Australian Gonococcal Surveillance Programme (AGSP)2 and Etests (AB bioMérieux). For all four isolates and all antimicrobials, the MIC values fell within one dilution of each other. The MIC values obtained and the AGSP interpretive categories were as follows: ceftriaxone, 0.03–0.06 mg/L (decreased susceptibility); ciprofloxacin, 8–16 mg/L (resistant); penicillin, 1–2 mg/L (less susceptible); spectinomycin, ≤64 mg/L (susceptible); and azithromycin, 0.25–0.5 mg/L (susceptible). The rectal and pharyngeal isolates from day 0 and the pharyngeal isolates from days 22 and 34 were examined by PFGE. Indistinguishable PFGE patterns were obtained for all four isolates. N. gonorrhoeae multi-antigen sequence typing (NG-MAST) of isolates from day 0 and day 22 identified them as sequence type (ST) 1407. The isolate from day 34 was ST4950. ST4950 contains a 3 base duplication in the por allele compared with ST1407, most likely due to a DNA replication error of the original ST1407 isolate in situ. Partial sequencing of the penA and porB genes revealed that all four isolates contained a mosaic penicillin-binding protein 2 type XXXIV and porB1b alterations G101K/A102N. N. gonorrhoeae was isolated from pharyngeal cultures taken 22 and 34 days after 500 mg of ceftriaxone. The day 22 isolate was indistinguishable from the day 0 isolate when compared by PFGE and NG-MAST. The day 34 isolate was also indistinguishable by PFGE, but was of a different, yet closely related, NG-MAST type. These findings, together with the reported absence of sexual activity, suggests the failure of 500 mg of ceftriaxone to eradicate pharyngeal N. gonorrhoeae. While re-infection could explain the results, the index patient and partner reported sexual abstinence following treatment. All four isolates showed decreased susceptibility to ceftriaxone with an MIC value of 0.03–0.06 mg/L. According to the AGSP the ceftriaxone MIC range 0.06–0.125 mg/L corresponds to decreased susceptibility and this is the highest MIC category reported for ceftriaxone. In 2010, in Australia, 4.8% of isolates tested had an MIC of ceftriaxone in this range.3 Higher ceftriaxone MIC values (0.125–0.25 mg/L) have been reported elsewhere,4 but not in Australia. These higher MIC values could in part be attributed to the use of EUCAST criteria elsewhere, based on a different MIC methodology. The isolates were NG-MAST type ST1407 (or the closely related ST4950), which is a clone of N. gonorrhoeae with decreased susceptibility to extended-spectrum cephalosporins that has disseminated globally4 and was associated with genital gonorrhoea treatment failure using 400 mg of cefixime.5 The isolates also harboured a mosaic penicillin-binding protein 2 type XXXIV and porB1b alterations G101K/A102N, recognized contributors to cephalosporin resistance.4 While the high ceftriaxone MICs for the above isolates would have contributed to pharyngeal treatment failure for the index patient, it should be noted that isolates with such MICs are increasingly being found in pharyngeal samples, but with only one other report of treatment failure at the 500 mg dose reported from Sweden.6–9 This case may represent a threshold of antimicrobial activity based on dose, site and isolate MIC.9 While treatment failure may be possible, it may not necessarily occur readily under these conditions. Nevertheless, with rising ceftriaxone MICs9 further treatment failures, both genital and extragenital, would seem inevitable. The laboratory work in this report was undertaken by MDUPHL, funded by the Department of Health Victoria. None to declare. We wish to thank Leonie Horvath, Hua Yi Li and Samantha Tawil from the Microbiological Diagnostic Unit Public Health Laboratory (MDUPHL), University of Melbourne, for their assistance with laboratory testing and Athena Limnios from the WHO Collaborating Centre for Sexually Transmitted Diseases, Sydney, for her comments on the manuscript prior to submission.