Recent reports emanating from the WHO Western Pacific Region (WPR), already notorious for the emergence of antibiotic resistance, emphasise treatment failures in gonorrhoeae with oral, but not injectable, third-generation cephalosporins1 2 and the spread of “cephalosporin-resistant” gonococcal subtypes within the WPR.3 4 The full range of mechanisms responsible for this cephalosporin “resistance” remains unclear, but importantly these result in different in-vivo (clinical outcomes) and in-vitro (minimal inhibitory concentration; MIC) effects on oral cefixime and injectable ceftriaxone.5 Alterations in penA and the effects of a mosaic penicillin-binding protein type 2 on cephalosporin MIC have attracted particular interest, but additional changes in mtrR and porB are required to increase MIC to clinically relevant levels.5 6

Calls were recently made for improved disease control and surveillance for antimicrobial-resistant Neisseria gonorrhoeae and particularly for cephalosporin-resistant gonococci.7^–9 However, elucidation of the current recommendations for cephalosporin use, choice and dosage in the WPR is also required to help clarify the extent of any possible clinical impact of emerging “cephalosporin-resistant” N gonorrhoeae. Furthermore, enhancement of in-vitro resistance surveillance is hampered by non-uniform provisional criteria used to define “cephalosporin resistance” in vitro, and the incomplete knowledge of underlying resistance mechanisms. Tests to determine susceptibility to ceftriaxone can no longer be used to guide treatment outcomes reliably with oral cephalosporins.2 At present, incomplete data relating MIC determinations to clinical outcomes prevent a group testing approach for all oral third-generation cephalosporins. Any oral cephalosporins used must thus be individually examined in susceptibility tests. Oral cephalosporins potentially available to treat gonorrhoea in the WPR include cefixime, ceftibuten, cefpodoxime, cefdinir and cefoperazone.

The recommended regimens for cephalosporin treatments in the WPR were therefore ascertained to establish their present usage for the treatment of gonorrhoea and to help clarify laboratory testing requirements for cephalosporin “resistance”.

METHODS

Eighteen participants in the WHO WPR Gonococcal Antimicrobial Surveillance Programme and/or their clinical counterparts were asked, in the latter part of 2008, to provide the type, dose and source (for possible efficacy issues) of third-generation cephalosporins recommended for the treatment of gonorrhoea in their jurisdiction.

RESULTS

Fifteen WPR centres provided data (table 1). Ceftriaxone is recommended in 11 jurisdictions, as first-line treatment in nine of these and exclusively in seven centres. Four jurisdictions recommend both oral cephalosporins and ceftriaxone, but oral cefixime is rarely used in Singapore. Cambodia uses oral cefixime only. Three Pacific Island states do not use any cephalosporins.

Single oral doses of cefixime (400 mg) were uniformly recommended. Single intramuscular doses of 250 mg of ceftriaxone were recommended in nine centres and 125 mg in one. Ceftriaxone administration in Japan is 1 g by the intravenous route. Recommendations in China include a 1 g dose option. Both generic and proprietary preparations were widely available for both drugs. Ceftibuten in a dose of 400 mg was the only other oral agent recommended in standard treatment regimens (Hong Kong) and Japan recommends 1 g intravenous cefodizime as an alternative to ceftriaxone.

DISCUSSION

These data indicate that oral and injectable third-generation cephalosporins are widely recommended primary treatments for gonorrhoea in the relevant parts of the WPR, with more extensive use of injectable ceftriaxone in preference to oral cefixime. This may reflect varying drug availability in the WPR, but also recent experience with ceftriaxone efficacy.9 10 Notable also is the almost universal recommendation for higher 250 mg and 1 g ceftriaxone doses (in China and Japan). Current, albeit incomplete, knowledge suggests that the trend towards ceftriaxone treatment in higher doses may help decrease the clinical impact of the increasing circulation of “cephalosporin-resistant” gonococci in the WPR.9 10 The exception was the 125 mg dose in the Philippines that conforms to US recommendations.

It is unclear, however, to what extent these public sector recommendations are adhered to in private clinical practice. There is also an unfortunate history surrounding the emergence and spread of many forms of gonococcal resistance in and from the WPR,7 so that in the wider context of general antibiotic use and misuse in the WPR it is doubtful if these public sector recommendations for the treatment of gonorrhoea will have any lasting effect on the containment of cephalosporin resistance in N gonorrhoeae. This impact of wider clinical cephalosporin use on emerging gonococcal resistance reinforces recommendations for better disease control and resistance surveillance.7^–9

These data also mean that the laboratory focus for cephalosporin “resistance” determination and surveillance in the WHO WPR gonococcal surveillance programmes should be on ceftriaxone and cefixime. This will allow the concentration of resources until additional information, eg, from additional treatment failures,2 is available to help determine the optimal in-vitro strategies for testing the susceptibility of N gonorrhoeae to all third-generation cephalosporins.