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antimicrobials

Can laboratory-guided treatment of gonorrhoea with ciprofloxacin help to stem the emergence of resistance to ceftiaxone?

28 Jun, 17 | by Leslie Goode, Blogmaster

With antimicrobial-resistant gonorrhoea now an urgent health threat, requiring improved antibiotic stewardship, one option frequently proposed is laboratory-guided recycling of older antibiotics (Lewis (STI); Ison & Unemo (STI); A new kind of treatment for gonorrhoea? (STI/blogs)).  Lewis (STI) alludes to the potential use of floroquinolone therapy – specifically in respect to the oropharyngx, which is the site at which treatment failure is most likely to occur.  Epidemiological typing to detect markers associated with antibiotic resistance makes this kind of intervention a real possibility (Graham & Jennison (STI).

Lao-tzu & Klausner (L&K) have recently reported a trial that claims to demonstrate the feasibility of just the kind of therapy envisaged by Lewis.  The researchers at University of California Los Angeles (UCLA) Health Clinical Microbiology Laboratory developed and implemented a molecular assay for the prediction of gonorrhoea (Ng) ciprofloxacin susceptibility.  Over the period from November 2015 to July 2016 all Ng positive specimens were subjected to the assay, and treatment recommendations issued on that basis.  In the final two months (June-July 2016) electronic reminder notifications were introduced – and it was only at that point that the intervention had any substantial impact on the treatment of patients.

Of the 176 infections detected, 121 (69%) were successfully genotyped.  Of the latter, 72 (60%) showed wild-type gyrA (the gene associated with antimicrobial resistance, 49 (40%) were mutant.  In the final successful two-month phase of assay implementation, this enabled 9 out of 11 (82%) of Ng infections to be treated with ciprofloxacin. The authors claim this shows the potential for laboratory-guided treatment of floroquinolones to limit recourse to ceftriaxone – and thereby slow the emergence of antibiotic resistant Ng.  Clearly, the trial needs to be run again, but this time using electronic reminder notifications from the start.

When it comes to the more specific issue of antimicrobial resistance to Ng at the oropharyngeal site, the results of the study are less promising. The proportion of gyrA mutant Ng infections did not vary significantly by site (pharyngeal 33%; rectal 45.7%; vaginal/cervical 57%; urine 39%); but of the 62 pharyngeal infections, most (40) could not be genotyped.  So laboratory-guided ciprofloxacin treatment would be of limited usefulness in key populations – such as MSM.

 

 

 

A new kind of treatment for multi-resistant gonorrhoea?

31 Jan, 17 | by Leslie Goode, Blogmaster

Recent research at York University (Ward & Lynam (W&L)), UK, suggests the possible efficacity of carbon monoxide-releasing molecules as an antimicrobial against gonorrhoea.  The work is at an early stage – but the urgency of our current situation lends it a heightened interest.

Growing  resistance of Neisseria gonorrhoeae (Ng) to the last-defence antibiotic treatments (Lewis/STIs) – cephixime and ceftriaxone – has placed sexual health policy in a dilemma: to have an impact on the epidemic requires them to  focus treatment on core-groups; yet the treatment of these individuals has to be shown to heighten antibiotic resistance (Chan & Fisman/STIs).   Ison & Unemo/STIs survey the narrowing options, including heightened surveillance (see also Unemo & Khotenashvili/STIs) and the careful stewarding of our remaining antibiotic resources.  Others suggest recourse to less obvious measures, such as the comprehensive treatment of pharyngeal Ng in MSM (Lewis/STIs), or the use of topical antiseptics (Miari & Ison/STIs).  Ultimately, however, the answer will lie in the developments of new antibiotics.

So how about the York researchers’ carbon monoxide-releasing molecules (CORMs)?  Though – to repeat – it is early days, this avenue looks promising.  The agent, tryptophan manganese carbonyl (Trypto-CORM), has been shown by earlier studies to be toxic to Escherichia coli and Staphylococcus aureus through the effect of CO molecules released by Trypto-CORM when irradiated.  W&L report that in the case of Ng, the bacterium appeared to be destroyed even by the very small amounts of CO released before irradiation.  The idea that Ng might be ‘exquisitely sensitive’ to CO would, of course, be good news.  It suggests the levels of CO necessary for efficacity against Ng might be sufficiently low to eliminate undesired toxic effects.  However, the results of W&L  also raise the suspicion that in the case of Ng, the cytotoxic effect might arise from some mechanism other than release of CO.  Fortunately, another innovation of the study appears to eliminate that possibility.  This is the use of extremely high CO affinity leg-haemoglobin (as opposed to the less high affinity deoxy-myoglobin) to ‘rescue’ the Ng culture by ‘scavenging’ the CO.  So it really does seem that the sensitivity of Ng to CO, not some other mechanism, is producing the cytotoxic effect.

A final potentially medically significant element of the study is the effect of culture age.  Cultures that had been stored for are longer time were more sensitive to Trypto-CORM – a finding that turns out not to be attributable to the number of viable cells in the inoculums.  The authors suggest the effect is due to the depletion in the number of active haem-copper oxidase complexes in near dormant cells.  This too could be good news.  Persistent bacteria in an infection that are recalcitrant to treatment are frequently slow-growing or dormant, and could be particularly susceptible to Trypto-CORM.

 

 

Could Chlamydia treatment failure be the result of genital contamination from persistent gut infection

6 Mar, 14 | by Leslie Goode, Blogmaster

The persistence of Chlamydia trachomatis  (Ct) infection in treated patients is generally attributed either to re-infection or poor treatment adherence.  To some, however, the evidence has suggested the operation of an additional factor – such as treatment failure (STIs/ Goetz & Bruisten; STIs/ Pitt & Ison; STIs/ Horner).

A recent study (Rank & Yeruva (R&Y)) develops an interesting hypothesis, based on evidence of Ct. infection in the gastro-intestinal (GI) tract of mice.  This supports the possibility that Ct. persistence in humans might be a result of ongoing Ct. infection of the gut, and re-infection of the genital via the lower GI tract (Yeruva & Rank).  According to R&Y’s research on animals, Ct. of the GI tract does not elicit an inflammatory response, and never resolves.  It provokes an immune response – but not at a level that would cure the GI infection.  The orthodoxy states that Ct. found in the human GI tract is “non-replicating”.  R&Y claim this not based on evidence.  So they see nothing to exclude the possibility that, in humans, as in mice, treatment failure may be due to auto-innoculation from the lower GI tract.

This hypothesis is highly relevant to discussion of Ct. persistence in this journal, which has arisen around such questions as: whether persistence is due to some factor other than re-infection or poor adherence, such as anti-microbial resistance (STIs/ Goetz & Bruisten; STIs/ Pitt & Ison); how important that factor is, and what it means for Chlamydia screening programs (STIs/ Regan & Hocking).  If R&Y’s hypothesis proves valid for humans as for mice, then that other factor – or, at least, some element of it – is explained, and would certainly need to be taken account of when modelling the effectiveness of screening programs.

The idea that persistence of Ct. in humans results from contamination from persistent GI tract infection seems to be a new one in the STI literature (though apparently cases have been documented by the veterinary literature in numerous animals as early as the 1950s).  It is certainly worthy of further investigation, given the implications that it would have, if proven, for diagnosis and management of human Ct. infection.  In that event, it would be necessary to consider, for example, what importance to attach to the clearing Ct. from the GI tract – and, supposing this to be necessary, how this would affect the nature and duration of treatment given for genital Ct..  In treating rectal Ct., for example, treatment with Azithromycin (≤13%) has been claimed to be inadequate (STIs/ Drummond & Donovan), while Hathorn & Goold find treatment with doxycycline to be a more effective alternative (STIs/ Hathorn & Goold).

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.

 

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