What clinical evidence is there for the association of gonorrhoea cephalosporin resistance with treatment failure?
28 Mar, 13 | by Leslie Goode, Blogmaster
Earlier blogs have featured the disquieting propensity of neisseria gonorrhoea to evolve resistance to every known line of treatment (http://blogs.bmj.com/sti/category/gonorrhoea/). Surveillance data indicate the prevalence of the infection in core populations, and the importance of focussing treatment on them ( http://sti.bmj.com/content/85/5/317.abstract?sid=c28b9898-65c9-4548-a10e-9f6ebade86f9); at the same time this is precisely the strategy most likely to disseminate resistance (http://sti.bmj.com/content/88/3/200.abstract?sid=c28b9898-65c9-4548-a10e-9f6ebade86f9). The quandary that this represents for public health is all the more serious, now that resistance seems to be emerging in cephalosporins, which are our last line of defence – with no new anti-biotic therapies in the pipeline (http://sti.bmj.com/content/86/6/415.abstract?sid=c28b9898-65c9-4548-a10e-9f6ebade86f9).
This brings an urgency to the question dealt with in a recent paper by Allen and Low (http://www.ncbi.nlm.nih.gov/pubmed/23299608): namely, what the state of the clinical evidence actually is on cephalosporin resistance in gonorrhoea leading to treatment failure. Since the late 90s, pharmacokinetic analyses across the world have identified gonorrhoea isolates showing increasing levels of resistance to cefixime – with minimum inhibitory concentrations (MIC) rising to ≥0.12 μg/mL. There have also been reports from Japan, UK, Norway France and Austria of cefixime treatment failure due to isolates with cefixime MIC at ≥0.12 μg/mL. Currently lacking, however, are studies that demonstrate and evaluate the relationship between cefixime resistance and treatment failure in clinical settings – no doubt on account of the de-normalization of testing for cure and of culture-based methods of detection. Allen & Low seeks to fill this gap for North America by means of a longitudinal cohort study in the context of a Toronto clinic where both testing for cure and culture-based detection remain routine practice.
Of the 133 (out of 291) participants returning for repeat-testing, 13 appeared to have treatment failure, of whom 9 provided explicit denial of sexual re-exposure. Assuming an equivalent level of treatment failure for non-returners as for returners, the study demonstrates clinical treatment failure of 6.77% – which exceeds the 5% threshold established by CDC and WHO for an acceptable treatment. As regards the relationship of cefixime resistance to treatment failure, the study finds a treatment failure rate of 25% for gonorrhoea with a cefixime MIC of ≥0.12 μg/mL, and a failure rate of 1.9% for gonorrhoea with cefixime MIC <0.12 μg/mL. This is worrying when seen against the background of the trend indicated by pharmokinetic data for the years 2000-2010 from the US CDC which shows the proportion of gonorrhoea with cefixime MIC of ≥0.25 μg/mL rising from 0.2% to 1.4%, and data for the same years from Canadian Surveillance Program showing the modal cefixime MICs rising from 0.016 to 0.12 μg/mL. The US CDC now recommends as sole preferred treatment ceftriaxone, 250g, intramuscularly combined with either azithromycin, 1g orally, or doxycyline 100mg, orally twice a day for 7 days as sole preferred treatment regimen. But resistance in ceftriaxone is following the same trend as in cefixime: pharmokinetic data for the years 2000-2010 from US CDC show the proportion of gonorrhoea with ceftriaxone MIC ≥0.12 μg/mL rising from 0.1% to 0.3%, data from the Canadian Surveillance Program show modal ceftriaxone MICs rising from 0.016 to 0.063 μg/mL. The elimination of ceftriaxone would leave the world of bereft of any known effective defence against the onset of gonorrhoea.