Helen Fifer

Failure of Dual Antimicrobial Therapy in Treatment of Gonorrhea

Increasing antibacterial resistance in Neisseria gonorrhoeae is threatening the success of routine treatment. This letter describes the clinical failure of ceftriaxone and azithromycin in a patient with gonorrhea.

An outbreak of high-level azithromycin resistant Neisseria gonorrhoeae in England

Objectives To investigate a potential outbreak of high-level azithromycin resistant (HL-AziR) gonococcal infections diagnosed in eight patients attending a sexual health clinic in Leeds, North England, between November 2014 and March 2015. Methods Eight cases of infection with gonococci exhibiting azithromycin minimum inhibitory concentrations (MICs) ≥256 mg/L were identified from patients in Leeds as part of the routine service provided by the Sexually Transmitted Bacteria Reference Unit. All patient records were reviewed to collate epidemiological and clinical information including evaluation of patient management. Whole-genome sequencing (WGS) was performed on seven gonococcal isolates to determine Neisseria gonorrhoeae multiantigen sequence type (NG-MAST), WGS comparison and mutations in the 23S rRNA genes. Results All patients were heterosexual (five male, three female) from a range of ethnic backgrounds and from the Leeds area. Three patients were linked by partner notification. All patients were infected at genital sites and two women had pharyngeal infection also. Six patients received the recommended first-line therapy for uncomplicated gonorrhoea, one was treated for pelvic inflammatory disease and one received spectinomycin followed later by ciprofloxacin. Test of cure was achieved in seven patients and confirmed successful eradication. All seven isolates sequenced were identical by NG-MAST and WGS comparison, and contained an A2143G mutation in all four 23S rRNA alleles. Conclusions Epidemiological and microbiological investigations confirm that an outbreak of a gonococcal strain showing HL-AziR is ongoing in the North of England. Every effort should be made to identify and curtail dissemination of this strain as it presents a significant threat to the current recommended front-line dual therapy.

Sustained transmission of high-level azithromycin-resistant Neisseria gonorrhoeae in England: an observational study

BACKGROUND Between Nov 3, 2014, and Feb 24, 2017, 70 cases of high-level azithromycin-resistant (HL-AziR; minimum inhibitory concentration [MIC] ≥256 mg/L) Neisseria gonorrhoeae were reported from across England. Whole-genome sequencing was done to investigate this outbreak to determine whether the ongoing outbreak represented clonal spread of an HL-AziR N gonorrhoeae strain identified in Leeds. We also wanted to elucidate the molecular mechanisms of azithromycin resistance in N gonorrhoeae in the UK. METHODS In this observational study, whole-genome sequencing was done on the HL-AziR N gonorrhoeae isolates from England. As comparators, 110 isolates from the UK and Ireland with a range of azithromycin MICs were also sequenced, including eight isolates from Scotland with azithromycin MICs ranging from 0·12 mg/L to 1·00 mg/L that were N gonorrhoeae multi-antigen sequence type 9768 (ST9768), which was the sequence type initially responsible for the outbreak. The presence of mutations or genes associated with azithromycin resistance was also investigated. FINDINGS 37 of the 60 HL-AziR isolates from England belonged to ST9768, and were genetically similar (mean 4·3 single-nucleotide polymorphisms). A 2059A→G mutation was detected in three or all four alleles of the 23S rRNA gene. Five susceptible ST9768 isolates had one mutated 23S rRNA allele and one low-level resistant ST9768 isolate had two mutated alleles. INTERPRETATION Sustained transmission of a successful HL-AziR clone was seen across England. Mutation 2059A→G was found in isolates with lower azithromycin MICs. Azithromycin exposure might have provided the selection pressure for one or two mutated copies of the 23S rRNA gene to recombine with wild-type copies, leading to three or four mutated copies and the HL-AziR phenotype. HL-AziR could emerge in isolates with low azithromycin MICs and eliminate the effectiveness of azithromycin as part of dual therapy for the treatment of gonorrhoea. FUNDING Public Health England.

British Association for Sexual Health and HIV: framework for guideline development and assessment.

Summary The Clinical Effectiveness Group of the British Association for Sexual Health has updated their methodology for the production of national guidelines for the management of sexually transmitted infections and related conditions. The main changes are the adoption of the GRADE system for assessing evidence and making recommendations and the introduction of a specific Conflict of Interests policy for Clinical Effectiveness Group members and guideline authors. This new methodology has been piloted during the production of the 2015 British Association for Sexual Health & HIV guideline on the management of syphilis.

Gonorrhoea treatment position statement

The British Association of Sexual Health and HIV (BASHH) and Public Health England work in partnership to support clinicians with up-to-date guidance on managing sexually transmitted infections. In 2011, the BASHH gonorrhoea treatment guidelines were changed to ceftriaxone 500 mg intramuscular in combination with azithromycin 1 g per oral, as first-line therapy. This dual therapy aims to delay the accumulation of resistance and extend the useful life of ceftriaxone.1 The advice has been widely adopted. Data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) show that the regimen was used in 86% of patients in 2013. Most of the remainder received ceftriaxone plus doxycycline. Of this latter group, 65% were men who have sex with men and 29% were women; 36% had concurrent chlamydia, and 51% had rectal gonorrhoea. We have identified two main clinical scenarios where doxycycline …

Nucleic acid amplification tests for the diagnosis of Neisseria gonorrhoeae in low-prevalence settings: a review of the evidence

Objectives In UK Microbiology laboratories there is widespread use of nucleic acid amplification tests (NAATs) which allow the simultaneous ‘dual’ detection of Neisseria gonorrhoeae and Chlamydia trachomatis, although the prevalence of gonorrhoea in most areas is low and this may lead to high numbers of false positive results. The aim of this study was to examine the evidence base for unselected testing for gonorrhoea in the community. Methods A literature search was performed to review the use of dual testing in low prevalence settings by searching PubMed for appropriate terms linked to gonorrhoea diagnosis up to 1 December 2013 but without restriction of publication date. All publications with a prevalence of <1% were defined as low prevalence and included in this review. Results The publication search found data in low prevalence settings from three sources; genitourinary medicine clinics, laboratories outside the UK and from the National Chlamydia Screening Programme. The evidence base to support widespread screening for gonorrhoea was found to be limited and of variable quality. Conclusions We were unable to find an evidence base to support widespread screening for gonorrhoea in the community. However, the increasing availability of dual NAATs may lead to more testing but this should be tempered by the public health need. Pilot studies and development of robust testing algorithms should be encouraged.

Analysis of the potential for point-of-care test to enable individualised treatment of infections caused by antimicrobial-resistant and susceptible strains of Neisseria gonorrhoeae : a modelling study

Objective To create a mathematical model to investigate the treatment impact and economic implications of introducing an antimicrobial resistance point-of-care test (AMR POCT) for gonorrhoea as a way of extending the life of current last-line treatments. Design Modelling study. Setting England. Population Patients accessing sexual health services. Interventions Incremental impact of introducing a hypothetical AMR POCT that could detect susceptibility to previous first-line antibiotics, for example, ciprofloxacin or penicillin, so that patients are given more tailored treatment, compared with the current situation where all patients are given therapy with ceftriaxone and azithromycin. The hypothetical intervention was assessed using a mathematical model developed in Excel. The model included initial and follow-up attendances, loss to follow-up, use of standard or tailored treatment, time taken to treatment and the costs of testing and treatment. Main outcome measures Number of doses of ceftriaxone saved, mean time to most appropriate treatment, mean number of visits per (infected) patient, number of patients lost to follow-up and total cost of testing. Results In the current situation, an estimated 33 431 ceftriaxone treatments are administered annually and 792 gonococcal infections remain untreated due to loss to follow-up. The use of an AMR POCT for ciprofloxacin could reduce these ceftriaxone treatments by 66%, and for an AMR POCT for penicillin by 79%. The mean time for patients receiving an antibiotic treatment is reduced by 2 days in scenarios including POCT and no positive patients remain untreated through eliminating loss to follow-up. Such POCTs are estimated to add £34 million to testing costs, but this does not take into account reductions in costs of repeat attendances and the reuse of older, cheaper antimicrobials. Conclusions The introduction of AMR POCT could allow clinicians to discern between the majority of gonorrhoea-positive patients with strains that could be treated with older, previously abandoned first-line treatments, and those requiring our current last-line dual therapy. Such tests could extend the useful life of dual ceftriaxone and azithromycin therapy, thus pushing back the time when gonorrhoea may become untreatable.

Prevalence of and factors associated with MDR Neisseria gonorrhoeae in England and Wales between 2004 and 2015: analysis of annual cross-sectional surveillance surveys.

Objectives To describe trends in prevalence, susceptibility profile and risk factors for MDR Neisseria gonorrhoeae (MDR-NG) in England and Wales. Methods Isolates from 16 242 gonorrhoea episodes at sexual health clinics within the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) underwent antimicrobial susceptibility testing. MDR-NG was defined as resistance to ceftriaxone, cefixime or azithromycin, plus at least two of penicillin, ciprofloxacin and spectinomycin. Trends in resistance are presented for 2004-15; prevalence and logistic regression analyses for MDR-NG cover the period of the most recent treatment guideline (ceftriaxone plus azithromycin), 2011-15. Results Between 2004 and 2015, the proportion of N. gonorrhoeae isolates fully susceptible to all antimicrobial classes fell from 80% to 46%, with the proportion resistant to multiple (two or more) classes increasing from 7.3% to 17.5%. In 2011-15, 3.5% of isolates were MDR-NG, most of which were resistant to cefixime (100% in 2011, decreasing to 36.9% in 2015) and/or azithromycin (4.2% in 2011, increasing to 84.3% in 2015). After excluding azithromycin-resistant isolates, modal azithromycin MICs were higher in MDR versus non-MDR isolates (0.5 versus 0.125 mg/L), with similar results for ceftriaxone (modal MICs 0.03 versus ≤0.002 mg/L). After adjustment for confounders, MDR-NG was more common among isolates from heterosexual men, although absolute differences in prevalence were small [4.6% versus 3.3% (MSM) and 2.5% (women)]. Conclusions N. gonorrhoeae is becoming less susceptible to available antimicrobials. Since 2011, a minority of isolates were MDR-NG; however, MICs of azithromycin or ceftriaxone (first-line therapies) for many of these were elevated. These findings highlight the importance of continued antimicrobial stewardship for gonorrhoea.

Persistence of an outbreak of gonorrhoea with high-level resistance to azithromycin in England, November 2014‒May 2018

Between November 2014 and May 2018, 118 laboratory-confirmed cases of high-level azithromycin resistant Neisseria gonorrhoeae were identified in England. Cases emerged among heterosexuals in Leeds but spread across England and into sexual networks of men who have sex with men as the outbreak progressed. The few epidemiological links identified indicate substantial under-diagnosis of cases and this, along with the upturn in cases in 2017, highlights the difficulties in controlling the outbreak.

Poor adherence to gonorrhoea treatment guidelines in general practice in England

Gonorrhoea diagnoses are on the increase in England and a cluster of high-level azithromycin resistance was detected in 2015.1,2 Treatment options are limited and, in response to emerging antimicrobial resistance, treatment guidelines have changed twice since 2004.3,4 Current recommended treatment for gonorrhoea is dual therapy with 500 mg ceftriaxone (intramuscularly) and 1 g azithromycin (orally).3 Following a diagnosis of gonorrhoea in general practice, referral to …