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Antimicrobial resistance

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.



Fresh WHO guidelines on gonorrhoea management + latest US surveillance data on gonorrhoea resistance

13 Oct, 16 | by Leslie Goode, Blogmaster

The emergence in various locations of resistant strains of Neisseria gonorrhoeae (Ng) is narrowing the therapeutic options. The recent (July 2016) WHO Guidelines, revised from 2003, reflect the concern both to treat effectively and steward our remaining defences against the infection in a globally coordinated manner.  They recommend either dual therapy with either single dose 250g intra-muscular ceftriaxone or 400g oral cefixime combined with 1g oral azithromycin (preferred options), or else single therapy with either ceftriaxone, cefixime or 2g spectinomycin).  The choice between these options will depend on local considerations, including Ng susceptibility data.   In the event of treatment failure following WHO-recommended dual therapy, they recommend any of: 500mg ceftraxone, 800mg cefixime, 240mg gentamicin, or 2g spectinomycin, each of them in combination with 2g azithromycin.

Reported surveillance data for a given location will be crucially important, then, for determining at local level the best options for treatment.  Given the global dimension of the threat, however, this data may also be potential evidence for global trends.  Hence the wider interest of the latest (2014) US surveillance data from the Gonococcal Isolate Surveillance Project (GISP)).  Hitherto, the US picture (as in the UK) has been one of steady progression (2006-2011) in prevalence of Ng isolates exhibiting reduced susceptibility (cefixime: MIC ≥0.25 μg/mL; ceftriaxone: MIC ≥0.125 μg/mL), interrupted by a decline in 2013; this is the pattern both for cefixime (0.1%-1.4%-0.4%) and ceftriaxone (0.1%-0.4%-0.1%) (see also Kirkcaldy & Bolan (STIs)).

So where do the latest (2014) data point? As regards cefixime, to a return to the pre-2013 upward trend, it seems, with prevalence rising once again from 0.4% to 0.8%; with ceftriaxone, to the maintenance of the 2013 prevalence level (0.1%).  Presumably, it is the prevalence levels of ceftriaxone that, in the US, constitute the primary focus of concern – since, as in the UK, that is the drug currently recommended, along with azithromycin, for dual therapy.  (See  Town & Hughes (STI) for  an equivalent report of ceftriaxone resistance in the UK).  But the greatest surprise of the 2016 GISP report is the sudden rise of decreased susceptibility to azithromycin: from 0.6% prevalence of reduced resistance strains (MIC ≥2.0 μg/mL) in 2013 to 2.5% in 2014.  The report comments that the recommended dual therapy with azithromycin is unlikely to be a contributor to this trend – though it is possible, they argue, that the small increase in the azithromycin monotherapy by US STD clinics over the last decade could have had some influence on the prevalence of azithromycin resistant strains.  There is evidence of high or rising levels of azithromycin resistance in other locations (Dillon & Thakur (STIs); Bala & Ramesh (STIs)), including, recently, the UK (Chisholm & Fifer/STIs).

Is increasing gonorrhoea resistance in MSM is a result of more treatment, rather than greater sexual activity?

20 Jul, 16 | by Leslie Goode, Blogmaster

Emerging antibiotic resistance to the last-ditch treatment of Neisseria gonorrhoeae compels health policy-makers to balance opposing concerns.  On the one hand, successfully combating spread of the infection requires targeted treatment of core-group individuals.  On the other, a focus on the core-group causes a rebound in core-group incidence, with maximal dissemination of resistance (Chan & McCabe/STIs (C&M); Chan & Fisman/STIs).

Recent public health orthodoxy has tended to favour the more intensive screening of core-group individuals (Ison & Unemo (STI); Giguere & Alary/STIs; Lewis/STIs).  However Fingerhut & Althaus (F&A), in a recent modelling study, seek to shift the balance in the opposite direction.  They claim their model demonstrates that the wide disparity in the spread of resistance spread as between populations of MSM and of HMW (heterosexual men and women) reflects differing levels of treatment rather than differences in sexual behaviour (‘more sexual partners’).

So far as concerns the first part of the claim (‘gonorrhoea spreads faster with more treatment’), F&A’s findings corroborate those of C&M.  However, in coupling this with the claim that gonorrhoea spread is not the result of sexual behaviour (‘gonorrhoea (does not) spread faster with more sexual partners’) they place the balance of responsibility for spread with the prevailing policy of treatment.  This is presumably intended to push policy makers in the direction of a more conservative attitude to targeting testing and screening.

But can F&A really justify this  change of emphasis by differentiating the respective contributions of ‘more treatment’ as against ‘greater sexual activity’ to the difference in resistance between MSM and MSW popultions ?  We are wrong, the authors argue, to assume that ‘more partners’ amongst the MSM population necessarily entails more transmissions (p. 11) – and their model apparently demonstrates this.   A common sense response, however, would be to object that ‘more partners’ presumably implies ‘more sex acts with more partners’ – and that, even if ‘more partners’ does not in itself entail more transmissions, ‘more sex acts with more partners’ might certainly be expected to do so.

Interestingly, Althaus in another paper (see Althaus & Alizon) – admittedly, in connection with heterosexual groups – corroborates our common sense expectation by showing that the number of partners displays, if not a proportional, then at least a linear, relation  to number of sex acts. So can it really be the case that there is not a greater number of transmissions amongst the MSM population, given the greater number of partners? The authors evidently believe not.

Nevertheless, it would be interesting – as well as pertinent, I suspect, to the goals of the study – to have a more satisfying explanation of why, here, as elsewhere, common sense turns out to be wrong.




Gonorrhoea antimicrobial resistance: is UK antibiotic stewarding policy shows “some success”

14 May, 14 | by Leslie Goode, Blogmaster

A widely circulated press release from the Society of General Microbiology’s (SGM) Annual Conference 2014 (April 14th – 17th) reports that Health for England’s Gonorrhoea Resistance Action Plan, according to representative, Dr Catherine Ison, “has shown some success in delaying the onset of treatment failure to the oral antibiotic cefixime”.  At issue here is the policy of switching to intra-muscular ceftriaxone with azithromycin as the first line treatment for gonorrhoea in the face of alarming evidence of an increase in gonococcal resistance to oral cefixime – a policy that aims to delay the emergence of cefixime resistance, and so “steward” our last remaining antibiotic defences against the infection (STI/blogs/Ison & Lowndes).

So the reprieve continues, we are to assume – in the absence from the press-release of even a head-line figure in support of Ison’s bare claim to “some success”.  If we turn to the Gonococcal Resistance to Antimicrobials Surveillance Programme’s last report (GRASP 2012: published October 2013) we find that the prevalence of GUM isolates exhibiting decreased susceptibility to cefixime (MIC ≥0.125 mg/L) declined significantly in MSM from 17% in 2011 to 7% in 2012, and in females from 3% in 2011 to 1.6% in 2012 (though isolates from heterosexual men show little change in cefixime MICs), following alarming increases in resistance from 2007-2010. In June 2013, Ison & Lowndes (I&L) (STI/blogs/Ison & Lowndes) noted a “striking association” between this decline in resistance and the change in UK prescribing practice referred to above, though “causality cannot be attributed to this observation” (Ison: Doctor’s Channel).  (Any argument for causality would, as a minimum, require precise information regarding the timing of the policy change – which is conspicuously absent from the I&L paper).  The SGM press-release appears to indicate a continuation of the same downward trend, and presumably offers further endorsement for the policy adopted at some point in 2011.

The SGM devoted a Report to sexually transmitted infections in 2013 (SGM – 2013). Anti-microbial resistance (most urgently, at present, in gonorrhoea) heads the list of three research challenges.  Recommendations include investment in research to track the impact of new interventions (e.g. optimizing the use of existing antibiotics), and extending lessons learned on gonorrhoea to understand treatment failure in chlamydia and mycoplasma genitalium – as well, of course, as initiating a drug development strategy that addresses the current problems of market failure.  Interestingly, however, the second challenge, that of rapid diagnosis of bacterial STIs, is also highly relevant to the problem of stewarding antibiotic defences.  The future development of enhanced diagnostic point-of-care tests based on genomic rapid sequencing techniques could enable a more “tailored” response to infection, based on profiling antibiotic susceptibility in the individual case, which would facilitate switching back to “abandoned” antibiotics where the their resistance profile disappears from the local population.

Needless to say, the development of new antibiotics (potentially Cempra’s solithromycin or AstraZeneca’s AZD0914), and of rapid sequencing-based diagnostic techniques, are in the future.  Meantime, the reprieve achieved through stewarding of cephalosporins may, says Ison, be short-lived.




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