Articles
Decreased susceptibility to cephalosporins among gonococci: data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales, 2007–2011

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Summary

Background

Effective treatment of gonorrhoea is fundamental to public health control; however, the ability of Neisseria gonorrhoeae to successively develop resistance to different treatments has hampered control efforts. The extended-spectrum cephalosporins—cefixime and ceftriaxone—have been recommended in the UK for treatment of gonorrhoea since 2005. We looked at surveillance data from England and Wales to ascertain the current usefulness of these drugs and to inform changes to national treatment guidelines.

Methods

We obtained data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) for patients attending 26 genitourinary medicine clinics in England and Wales between 2007 and 2011. We did analyses with univariate and multivariable logistic regression methods to identify trends in susceptibility to cephalosporins and risk factors associated with infection with isolates with decreased susceptibility to cefixime, and we assessed changes in prescribing practices. We did molecular typing to investigate genetic relatedness of non-susceptible isolates.

Findings

The prevalence of decreased susceptibility to both cefixime and ceftriaxone rose between 2007 and 2010 but was more noticeable for cefixime (an increase from 1·5% in 2007 to 17·1% in 2010), with a bimodal distribution of minimum inhibitory concentration recorded between 2009 and 2010. By multivariable analysis, isolates with decreased susceptibility to cefixime were associated with infection in men who have sex with men (odds ratio 5·47, 95% CI 3·99–7·48; p<0·0001) and year of isolation (in 2010, 13·08, 7·49–22·8; p<0·0001). Such isolates had a largely clonal population, with most belonging to genogroup G1407 and harbouring the penA mosaic gene. Data from 2011 showed a significant decline in prevalence of isolates with decreased cefixime susceptibility, falling from 17·1% in 2010 to 10·8% in 2011 (p<0·0001), concomitant with the change in prescribing practice in 2010 from cefixime to ceftriaxone plus azithromycin.

Interpretation

Guidance for treatment of gonorrhoea in England and Wales was changed in 2010 to prolong the use of cephalosporins. The decline in prevalence of isolates with decreased cefixime susceptibility cannot be attributed unequivocally to this change in prescribing practice; however, the association is striking.

Funding

Department of Health (England), Public Health England.

Introduction

Gonorrhoea is a sexually transmitted infection of major public health concern, with 106 million cases reported by WHO in 2008.1 In 2011, 39 176 cases were reported in the EU and European Economic Area2 and 21 183 in the UK.3 Antimicrobial treatment is essential to control gonorrhoea and to prevent serious sequelae, which have inherent health-care costs. However, the emergence of resistance to successive recommended treatments for gonorrhoea over several decades has compromised infection control, with treatment failures ensuing.4 Treatment is usually given empirically, before the results of any laboratory susceptibility tests are known, with choice of first-line treatment informed by national and international guidelines. Surveillance programmes monitor patterns of resistance to ensure that antimicrobial drugs continue to achieve greater than 95% therapeutic success.5 Once a 5% resistance threshold has been reached, guidelines are changed to recommend an alternative treatment to which resistance has not proliferated.

In the UK, national guidelines are developed by the British Association of Sexual Health and HIV (BASHH) and are informed by surveillance data produced by the national programme for England and Wales—the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP).6 In 2004, after resistance to ciprofloxacin grew, recommended treatments for gonorrhoea in the UK changed to the extended-spectrum cephalosporins cefixime (given orally) and ceftriaxone (given intramuscularly).7 Cefixime has been used most widely6 because of its ease of administration. When these drugs were introduced they were highly effective, with only one report of treatment failure from Japan.8 However, failures have been reported increasingly since 2010 and are associated with decreased susceptibility, or occasionally with high-level resistance, to cefixime. Ceftriaxone resistance is rare but has also been recorded.9 Cephalosporin resistance is associated, at least in part, with novel penA mosaic genes,9 which have probably evolved via uptake and incorporation of fragments of penicillin-binding protein 2 (PBP2) genes released by commensal Neisseria species. In England, treatment failure to cefixime associated with decreased susceptibility was reported in 2011.10, 11

Between the 1940s and 1970s, Neisseria gonorrhoeae progressively accrued stepwise reductions in susceptibility to penicillin antibiotics.12 Fears now exist that current cephalosporins will also become ineffective. Disturbingly, no obvious reserve treatments are available for gonorrhoea after the cephalosporins, no new agents have been licensed, and no alternative drugs exist to which resistance has not been noted.13 These setbacks raise the real possibility that gonorrhoea could become difficult to treat or untreatable.

GRASP produces a unique enhanced dataset for England and Wales, combining epidemiological, behavioural, and microbiological information on gonococcal resistance. Here, we aim to describe changes in treatment for gonorrhoea and review subsequent, possibly contingent, changes in resistance trend.

Section snippets

Patients

GRASP is a sentinel national surveillance programme for antimicrobial resistance in N gonorrhoeae run by the UK Health Protection Agency (now Public Health England). It includes a network of 26 genitourinary medicine clinics and 24 laboratories chosen to give regional representation across England and Wales and collects and tests isolates from 7–10% of patients with gonorrhoea reported in each year.14 Isolates obtained from consecutive patients attending GRASP participating clinics over a 3

Results

7378 N gonorrhoeae isolates were collected between 2007 and 2011, and an antimicrobial susceptibility result was available for 6176 (83·7%) isolates. Table 1 presents susceptibility data for cefixime and ceftriaxone. 547 (8·9%) isolates showed decreased susceptibility to cefixime (MIC ≥0·125 mg/L), with a progressive increase from 1·5% in 2007 to 17·1% in 2010 (p<0·0001), followed by a subsequent fall to 10·8% in 2011 (p<0·0001). The geometric mean MIC of cefixime rose between 2007 and 2010,

Discussion

Data produced by GRASP and presented here show an increasing drift towards decreased susceptibility to cefixime in gonococci from 2007 to 2010 and the emergence of a bimodal MIC distribution by 2009. Isolates showing decreased cefixime susceptibility, predominantly belonging to ST1407 or related lineages, were also resistant to ciprofloxacin. The decreased susceptibility to cefixime in ST1407 and related types is associated with the penA mosaic gene, leading to expression of modified

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