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Gonorrhoea

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.

 

 

 

Warding off the scourge of untreatable gonorrhoea?

4 Feb, 16 | by Leslie Goode, Blogmaster

 

A recent analysis (Kircaldy & Papp (K&P) of 2006-2014 US CDC (Centre for Disease Control and Prevention) data on Neisseria gonorrhea (NG) susceptibility to cefixime and ceftriaxone in isolates suggests a halt in the drift to resistance over the period 2011-13 followed by a return in 2014 to the upward trend. Among isolates from MSM the proportion with resistance rose from 0.2% in 2008 to 4% in 2010, then fell incrementally to 0.8% in 2013, before rising once again to 1.3%. It is tempting to see a correlation between these resistance trends and recent treatment guideline changes. After all, 2010 – the year before the beginning of this fall in NG resistance – saw the establishment in the US of a therapeutic regime involving combination therapy with cefixime or ceftriaxone plus a second antimicrobial; whereas 2012 – the year before the trend reached its lowest point – saw the further attempt to safeguard cefixime susceptibility through a regime of ceftriaxone-based combination therapy as the single recommended therapy. However, K&P caution against assuming a causal relation between resistance trends and these measures, since various factors might have contributed to the improvement. But, even if we do assume a causal relation, the 2014 data suggest that, as K&P put it, ‘the improvement in susceptibility may be short-lived’.

Nevertheless, experts seem broadly in favour of antimicrobial stewardship – and, more specifically, the currently recommended regime – as a last-ditch attempt to postpone the progress of multi-resistant NG. Yet, the chances of combination therapy achieving more than a temporary reprieve are slender – at least according to a recent comprehensive examination of the question (Rice (STIs). So what is to be done? Much is made in the literature of the role of ‘core’ populations – chiefly MSM and female sex workers – in sustaining epidemics, and of the importance of developing interventions directed specifically to these groups (Lewis/2013 (STIs); Guiguere & Alary (STIs). (For example, the alarmingly increased proportion of resistant isolates registered by K&P has hitherto affected, almost exclusively, MSM in the West of the US.) The problem with this, however, is that, while NG control is achievable only when core groups are treated, the treatment of those groups maximizes dissemination of antimicrobial-resistant strains (Chan & Fisman (STIs). One possible way out of this epidemiological ‘catch-22’ is indicated in another recent paper (Lewis/2015 (STIs). Lewis draws attention to the importance of the oropharyngeal niche in enabling the dissemination of NG resistant-strains, and proposes widespread screening of core populations, using state-of-the-art resistance-detecting NAATs and treatment with those antimicrobials known to be of greater efficacity for the oropharyngeal site – such as ciprofloxacin. Even where such interventions were affordable, however, there remains, given the largely asymptomatic character of oropharyngeal NG, the not inconsiderable problem of defining and accessing the core group (Guiguere & Alary (STIs)) – and time may be short.

Incidental gonorrhoea screening in the general population via dual NAAT is no benefit

12 Jun, 15 | by Leslie Goode, Blogmaster

Fifer & Ison (STIs) express concern over the use of the “dual” nucleic acid amplification tests (NAATs) for the detection of chlamydia and gonorrhoea in the context of chlamydia screening in the UK.  Additional testing for gonorrhoea, when the real target is chlamydia, does not necessarily confer an additional net benefit.   This is because even a high specificity test such as Cobas 4800 (Perry & Corden (STIs); Rockett & Limnios (STIs)) will generate a high proportion of false positives when the infection tested for has extremely low prevalence, as in the  case of gonorrhoea in the general population.  And the potential disbenefit of the additional test in terms of the psychological impact, and the impact on relationships, of false positive diagnoses could easily outweigh the medical benefit represented by the diagnoses which are accurate (Dixon-Woods & Shukla (STIs); McCaffery & Wardle (STIs)).

The potential impact of the adoption of the dual NAAT as a stand-alone test – if not confirmed by further testing using either a second NAAT or else culture – is illustrated by a recent Australian study published in the Medical Journal of Australia (MJA).  Chow & Fairley perform a retrospective analysis of insurance and notification data from Melbourne over the years 2008-2013.  They seek to demonstrate that the apparent rise in identified gonorrhoea cases amongst the general female – non-indigenous – population (from 98 to 343) is at least partly an “artefact” of the growing employment by laboratories of the dual NAAT.  They do this by eliminating the alternative possibility of a genuine increase in gonorrhoea in the general population.  To this purpose they use their data to investigate changes in the proportion of positive dual NAAT gonorrhoea diagnoses to the number of dual NAAT test ordered, over the period during which dual NAATs were being introduced.  They also investigate rates of positive gonorrhoea diagnoses over this period at a “sentinel” clinic in Victoria where culture alone was used as a means ofgGonorrhea diagnosis.  They find that the proportion of positive dual NAAT diagnoses in Victoria remained relatively constant over time (around 0.2-0.3%), as did the proportion of positive culture diagnoses at the Melbourne clinic (around 0.4-0.6%).  Of 25 untreated women who had a positive NAAT result for gonorrhoea and were referred to the Melbourne clinic, only 10/25 were confirmed by culture.  The authors comment that this is in line with what might be expected in the light of the published specificity of the various NAAT tests employed.

C&F recommend that laboratories suppress gonorrhoea diagnoses from the dual NAATs.  An MJA editorial in the same issue questions the feasibility of this.  Instead, the editors propose that the NAAT should, in the case of Gonorrhoea, be used as either a triage, with positive diagnoses confirmed by culture, or as an add-on where high prevalence populations are first tested by culture.  They also consider the possibility of confirming the initial NAAT with a NAAT using a different target.  However, they come down in favour of retaining culture in the diagnostic pathway on account of its value as a means of assessing resistance.  They also question whether even the double NAAT would guarantee adequate predictive value in very low prevalence populations.

Evidently, further studies are required.

Trialling innovative approaches to STI partner services: Partner-Delivered vv. Accelerated Partner Therapy

26 Feb, 15 | by Leslie Goode, Blogmaster

It is vital to treat partners of patients with curable STIs as quickly as possible.  But the effectiveness of interventions to achieve this proves hard to measure – and the case for increasing resources correspondingly difficult to make.  The inadequacy of the resources available to existing partner services has led some investigators in the US and UK to seek out innovative approaches to ensuring the treatment of partners which are less expensive.  One option – Patient-Delivered Partner Therapy (PDPT) – is to provide treatment for partners via the patient and without prior medical assessment of the partner.  The problems with this are: first, that PDPT may not conform to legal (Cramer & Leichliter (STI)) or professional guidelines; second, that concomitant infections (e.g. HIV) in the partner may go undiagnosed and untreated. An alternative solution – Accelerated Partner Therapy (APT) – is to treat the partner via the patient, but only after a medical assessment conducted by telephone or with a pharmacist (Golden & Estcourt (STI); Dombrowski & Golden (STI)).

The option of PDPT has been trialled in various US clinics (Mickievicz & Rietmeijer (STI); Sanchez & Schillinger (STI); but its impact is difficult to evaluate on a local level. Now, for the first time, Golden & Holmes have attempted a population-level randomized control trial of uptake and impact across 23 out of the 25 counties of Washington State.  This impressively large-scale operation had two elements.  The first was the provision of free PDPT, and involved: 1. informing all clinicians about the programme; 2. making stocks of free PDPT available to clinicians who had reported ≥ one case of Chlamydia or Gonorrhoea, and to certain large pharmaceutical chains; 3. visiting clinicians reporting frequent cases for the purpose of educating staff about the programme.  The second element was the possibility offered to diagnosing practitioners via routine report forms of having the provision of partner services handled by the state public health department. This intervention was rolled out in four successive waves to different counties in turn, thus enabling the impact of the intervention to be controlled against the default situation in the counties of each wave.

As regards uptake, percentage of persons receiving PDPT from clinicians rose in intervention periods from 18% to 34%, and percentage receiving partner services from 25% to 45%.  This is broadly comparable with what has been achieved by more local interventions in the US.  Unfortunately, it is one thing for a pack to be accepted by the index patient, another for a partner to be successfully treated.  Hence the interest of G&S’s attempt to evaluate population-level impact – through testing in sentinel clinics in the case of Chlamydia, and through incidence of reported infection in the case of Gonorrhoea. It was undoubtedly ambitious of G&S to seek an indicator of population level impact for a comparatively brief intervention.  It is no surprise that the results are less than overwhelming. Chlamydia test positivity and gonorrhoea incidence in women declined respectively from 8.2% to 6.5% and from 59.6 to 26.4 per 100,000. The latter more impressive reduction is unfortunately hard to distinguish from a strong secular trend in the same direction in various states.

There are more general problems, however – such as knowing whether the handing over of PDPT packs is resulting in the successful treatment of disease, or whether it may even be contributing to an ongoing failure to diagnose concomitant partner infections.  These might weigh in favour of the alternative approach recently developed in UK clinics: APT.  Estcourt & Johnson (STI) report uptakes of 66% and 59% for versions of APT as against 36% for conventional PS.  Sending a treatment pack following a telephone interview would seem to offer a better guarantee of partner treatment, than offering a pack on the basis of nothing more than a stated willingness of the index patient to deliver it.  At the same time, interviewing the partner averts the risk of doing harm by pre-empting consultations at which a fuller diagnosis of the partner’s condition would have been possible.  A population-level trial of the impact of APT has yet to be undertaken.

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.

 

 

 

“Stewarding” may be the best policy for prolonging the efficacy of anti-Gonorrhoea drugs

9 Aug, 13 | by Leslie Goode, Blogmaster

With reports of the growing resistance of Neisseria gonorrhoeae to cephalosporins, currently the last weapon in the antibiotic armoury,  control seems rapidly to be running out of options. Given the 21,183 reported cases in the UK (2011) – over half the EU total for the same year – this is a matter of grave public health concern. Contributions to STI journal have traced the history of gonococcal resistance (sti-Lewis), and assessed the narrowing possibilities for future management (sti-Ross & Lewis).

A recent study (Ison & Lowndes) draws attention – and lends support – to a change in prescribing policy for gonorrhoea in the UK (Guidelines 2011).  In the past, policy has tended to adhere to the dogma that one microbial agent should only be replaced by an alternative when treatment failures due to resistance cross a 5% threshold. Given the availability of two cephalosporin treatment options, oral cefixime and intra-muscular Ceftriaxone, and the far lower levels of non-susceptibility encountered with intra-muscular ceftriaxone, this would have led to continuing use of Cefixime until the 5% threshold of resistance had been reached, and its subsequent replacement with Ceftriaxone.  Yet the 2011 UK guidelines based on data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) adopted the new strategy of “stewarding the first line of antibiotic defence” by shifting pre-emptively to intra-muscular Ceftriaxone and combining with azithromycin or doxicycline in order to “steward” the efficacity of Cefixime as the antibiotic first line of defence.

The study itself analysed GRASP surveillance data from 26 UK clinics respecting prescribing policy and levels of cephalosporin resistance encountered in gonococcal isolates over the period 2007-2011; it also performed molecular typing to investigate the genetic relatedness of resistant isolates.  The findings are particularly interesting because they cover the years following the policy shift.  Prescribing policy seems to have followed the guidelines with the use of cefixime as part of the treatment falling over the years 2010-2011 from 50% to 5% and use of ceftriaxone as part of the treatment rising from 41% to 93%.  Over the same period the proportion of isolates showing decreased susceptibility to Cefixime (defined as a minimum inhibitory concentration of ≥ 0.125 mg/l) fell from 17.1% to 10.8%, suggesting a direct impact of the change of prescribing policy on cefixime resistance.  Molecular typing of non-susceptible isolates suggested a largely clonal population, with most belonging to genogroup G1407 and all but eight harbouring the penA mosaic gene.  Over 86% of these isolates were from MSM (men who have sex with men); on multivariate analysis the association of resistant isolates with MSM infection showed an odds ratio of 5.47. Cefixime resistance, the authors conclude, is at present limited largely if not entirely to the MSM population – though there seems every likelihood of it bridging the gap into the non-MSM population, as has occurred in the past with other antibiotics.  In the meantime the more tactical approach of “stewarding” may offer the best hope of extending the usefulness of cephalosporins pending, hopefully, the development of new treatments in the future (see: sti-Ross & Lewis).

 

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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