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.

On 6^th June the World Health Organization (WHO) put out an alert regarding drug-resistant gonorrhoea (http://www.who.int/mediacentre/news/notes/2012/gonorrhoea_20120606/en/ ) simultaneously with the publication of a Global Action Plan (http://whqlibdoc.who.int/publications/2012/9789241503501_eng.pdf).  The last year or so has seen the emergence of strains of the infection that are resistant to cephalosporins, the antibiotics of last resort.  The plan includes: increased awareness of correct use of antibiotics; systematic monitoring and reporting of treatment failure; improved surveillance; research into new treatment regimens.  But the brute fact remains that with no new drugs even on the horizon, we face a future in which there will increasingly be no effective treatment for Neisseria gonorrhoea.

This may raise in some minds the questions of how we ever coped in the days before antibiotics.

If you have ever wondered what the venereological world was like before the 1940s, the STI journal archive contains a wealth of material.  Contrasted assessments of the various treatment regimes for gonorrhoea current in the 1920s and their drawbacks can be found in papers by Prof.  Jadassohn, 1926 (http://sti.bmj.com/content/2/6/152.full.pdf+html?sid=cb748843-f7a4-40c9-99aa-b50a4d6faeea) and F.W.F. Purcell, 1931 (http://sti.bmj.com/content/7/3/187.full.pdf+html?sid=cb748843-f7a4-40c9-99aa-b50a4d6faeea).  I would particularly recommend a paper by L.W. Harrison in commemoration of venereologist Albert Neisser (http://sti.bmj.com/content/31/2/65.full.pdf+html?sid=8635f797-ed0e-4f71-a264-72f060bf8461).  Harrison profits from the occasion to reminisce at length on his own venereological career going back to experiences in charge of a clinic during World War I; he offers frank opinions of the treatments used at different periods by himself and others, and what he felt these owed to Neisser.

Use of injections of silver nitrate via urinary meatus go back to the nineteenth century and continue until the 1940s. The late C19th also saw the employment of an eye-watering range of injected “astringents” from potassium permanganate to hot water and sulphurous acid (Harrison).  These treatment regimens partly give way in the early C20th to the use of silver nitrate and a range of organic silver compounds (protargol, ichthargan, albargin etc.) – a change that Harrison attributes to the influence of Neisser.  A wide range of treatments, however, continue to be described in the literature (see above).  Occasional doubts are voiced as to the effectiveness of organic silver compounds, as compared with silver nitrate (http://sti.bmj.com/content/1/4/245.full.pdf+html?sid=cb748843-f7a4-40c9-99aa-b50a4d6faeea).

Two issues discussed at the recent ISSTDR (International Society Sexually Transmitted Diseases Research) for Conference (11th-14th July) in Montreal, Canada, have made the headlines.

First, the emergence in Japan of a new drug resistant “superbug” – an apparently untreatable strain of Gonorrhea (H041). Dr Magnus Unemo of the Swedish Reference Laboratory for Pathogenic Neisseria reported on his work with Japanese colleagues to characterize the new strain which has proved resistant to all the current frontline drugs, including cephalosporins. This development is “alarming”, since cephalosporins are the last line of defence; but also “predictable”, given that gonorrhoea has progressively developed resistance to all the drugs used against it – first, to penicillin and tetracycline, and subsequently, since the early 80s, to fluoroquinolines. At present CDC (the US Centers for Disease Control and Prevention) recommends treatment with a cephalosporin and either azithromycin or doxycycline. Dr Unemo’s statement follows just three days after a recent report emanating from the CDC that US gonorrhea was proving increasingly less susceptible to frontline drugs, including cephalosporins.

Traditionally, southeast Asia has developed resistant isolates, which have subsequently spread across the Pacific to the US. The new strain seems to be capable of passing its resistance quickly when grown in culture with other strains, increasing their resistance 500-fold. The upshot is that we can expect gonorrhoea to become progressively harder to treat over the next five years, unless new drugs are developed. Prevention will increasingly remain the only strategy.

ISSTDR abstracts to be found in:

Sexually Transmitted Infections, July 2011, vol. 87, suppl. 1: 19th Biennial Conference of the International Society for Sexually Transmitted Diseases Research

http://sti.bmj.com/content/87/Suppl_1.toc

Laura Blue, Time, Scientists Discover Drug-Resistant Gonorrhea “Superbug”, 11 July, 2011

http://healthland.time.com/2011/07/11/scientists-discover-drug-resistant-gonorrhea-superbug/

Neisseria gonorrhoeae is a nimble bacterium, and past master at adapting itself to resist the challenge of our antibiotics.  So maybe we shouldn’t be surprised at this latest accolade: to have been the first proven case of horizontal gene transfer (HGT) between organisms as disparate as the bacterium and a human being!  A recent study claims to demonstrate that Neisseria gonorrhoeae has integrated human genetic material into its own genome, and that this development is of recent evolutionary origin. Horizontal (inter-species) transfer of genetic material is, of course, the means by which these organisms evolve – along with vertical (inter-generation) transfer.  But transfer from mammal to bacterium has not, it seems, been recorded – until now.

There is actually a good reason why it should be  Neisseria gonorrhoeae of all bacteria that gains this place in history. Its exclusive relationship to its human host seems to have been a characteristic that has facilitated the identification of the transferred genetic material.  As for whether it derives any advantage from this particular adaptation, or whether it offers a clue to the gonococcus’s nimble ability to continually adapt and survive in its human host, we really don’t know yet. But this discovery may turn out to have important implications for our future understanding of its success.

Mark T.Anderson and H. Steven Seifert, “Opportunity and Means: Horizontal Gene Transfer from the Human Host to a Bacterial Pathogen”, mBio 2011

http://www.asm.org/