Neisseria gonorrhoeae isolates with high-level resistance to azithromycin in Australia

Sir, Antimicrobial resistance in Neisseria gonorrhoeae is a major public health concern globally. Over time, gonococci have developed resistance to most antimicrobial agents used for first-line treatment and declining susceptibility to the extended-spectrum cephalosporins is emerging worldwide.1–3 Consequently, dual antimicrobial therapy consisting of ceftriaxone (250 or 500 mg by intramuscular injection) together with azithromycin (1 or 2 g orally) is now recommended as standard treatment for gonorrhoea in the USA, the UK and Europe and is now gradually being adopted in major clinics throughout Australia.4–7 Monotherapy with 2 g of azithromycin is an alternative treatment in patients who are allergic to cephalosporins.4 These treatment regimens are threatened by the emergence of azithromycin resistance in gonococci, particularly high-level azithromycin resistance. High-level azithromycin resistance in N. gonorrhoeae, defined by an azithromycin MIC >256 mg/L, is associated with mutations in the peptidyltransferase loop in domain V of the 23S rRNA gene, principally A2059G, and a single base pair deletion (A) in the promoter region of the mtrR gene.8,9 Isolates of gonococci displaying high-level azithromycin resistance have been reported from the UK, Italy, Argentina, the USA and Sweden.10–14 Here, we provide the first report of gonococci in Australia with high-level azithromycin resistance. The Australian Gonococcal Surveillance Programme (AGSP) monitors gonococcal antimicrobial resistance to a wide range of antimicrobials, which is achieved through the referral of gonococcal isolates from clinical diagnostic laboratories to nominated state or territory reference laboratories. These reference laboratories together form the National Neisseria Network (NNN) of Australia, through which ∼3500 N. gonorrhoeae isolates are tested for antimicrobial resistance annually. Since 2011, six isolates of gonococci submitted to NNN laboratories were found to exhibit high-level azithromycin resistance: one isolate from the state of New South Wales, two isolates from the state of Victoria and three isolates from the state of Queensland. Details are summarized in Table 1. Characteristics of the first strains of N. gonorrhoeae with high-level resistance to azithromycin from Australia NSW, New South Wales; QLD, Queensland; VIC, Victoria; PPNG, penicillinase-producing N. gonorrhoeae; TRNG, tetracycline-resistant N. gonorrhoeae; S, susceptible; R, resistant. Characteristics of the first strains of N. gonorrhoeae with high-level resistance to azithromycin from Australia NSW, New South Wales; QLD, Queensland; VIC, Victoria; PPNG, penicillinase-producing N. gonorrhoeae; TRNG, tetracycline-resistant N. gonorrhoeae; S, susceptible; R, resistant. Briefly, identification was confirmed as N. gonorrhoeae on the basis of Gram stain, oxidase, superoxol and carbohydrate utilization tests or MALDI Biotyper® (Bruker Daltonik, Bremen, Germany). Breakpoint MICs were initially determined by agar plate dilution using the method of the AGSP.15 Azithromycin MICs were confirmed by Etests (bioMérieux, Marcy-l'Étoile, France). In addition, the 23S rRNA and mtrR genes of each isolate were characterized8,9 and N. gonorrhoeae multiantigen sequence typing (NG-MAST) genotyping performed.16 All six isolates displayed azithromycin MICs >256 mg/L and contained the A2059G mutation in all four 23S RNA alleles. A single base pair deletion (A) in the mtrR promoter was present in isolates 1, 2, 3 and 6, but absent in isolates 4 and 5. The isolates comprised five different NG-MAST types (Table 1), suggesting independent generation of high-level azithromycin resistance. Limited epidemiological information was available, but isolates 1, 3, 4 and 6 were most likely acquired outside Australia (China and Hong Kong) or from contact with persons who had travelled to one of these countries. Isolate 2 was locally acquired. No details for isolate 5 were available, but it is of note that this isolate was the same NG-MAST type as isolate 4 (ST649). In summary, Australia is now included in the list of countries reporting gonococci with high-level resistance to azithromycin. While our national surveillance programme has detected just 6 isolates displaying high-level azithromycin resistance since 2011, further dissemination of such strains would threaten the long-term efficacy of the current recommended treatments for gonorrhoea. The Microbiological Diagnostic Unit, Public Health Laboratory receives funding from the Department of Health Victoria. The National Neisseria Network is funded by the Australian Government Department of Health. None to declare. We wish to thank all Australian laboratories who submit isolates of N. gonorrhoeae for antimicrobial surveillance purposes.