Neisseria gonorrhoeae antimicrobial resistance (AMR) monthly UPDATES - May, 2019

Neisseria gonorrhoeae antimicrobial resistance (AMR) monthly UPDATES

May, 2019

Reviews and Commentary

Addressing the rising rates of gonorrhea and drug-resistant gonorrhea: There is no time like the present.

Bodie M, Gale-Rowe M, Alexandre S, Auguste U, Tomas K, Martin I. (Full Text)

Can Commun Dis Rep. 2019 Feb 7;45(2-3):54-62. doi: 10.14745/ccdr.v45i23a02. eCollection 2019 Feb 7.

Abstract

Increasing rates of gonococcal (GC) infection and antimicrobial resistant (AMR) GC, are a serious public health concern for Canada and around the world. Previously recommended treatments are ineffective against many of the gonorrhea strains circulating today. The current recommendation for combination therapy is now being threatened by globally emerging and increasingly resistant strains. It is important that coordinated efforts be made now to ensure these new global strains do not become established in Canada. Otherwise, we will be faced with the possibility of persistent GC infection which can lead to pelvic inflammatory disease, infertility and chronic pelvic pain in women; and epididymitis in men. The presence of GC can also increase the risk of HIV acquisition and transmission. There are a number of reasons why we are facing this public health threat. GC infection is often asymptomatic and it is highly transmissible. People may hesitate to seek testing (or to offer testing). Treatment is complex: recommendations vary by site of infection and risk of resistance. Sexual contact during travel is an important source of imported emerging resistant global strains. The new screening and diagnostic Nucleic Acid Amplification Test (NAAT) is excellent but has decreased the number of cultures being done and therefore our capacity to track AMR-GC. There are four key actions that clinicians and front-line public health professionals can take to stem the increase in rates of GC and drug resistant GC. First, normalize and increase GC screening based on risk factors and emphasize the need for safer sex practices. NAAT is useful for screening, but culture is still needed for extra-genital sites. Second, conduct pretravel counselling and include a travel history as part of the risk assessment. Third, use culture along with NAAT to establish the diagnosis and follow up for test-of-cure. Finally, refer to the most current Canadian Guidelines on Sexually Transmitted Infections or provincial/territorial recommendations on combination therapies for patients and their contacts as recommendations may have changed in response to evolving AMR-GC trends.

 

Rationale for a Neisseria gonorrhoeae Susceptible Only Interpretive Breakpoint for Azithromycin.

Kersh EN, Allen V, Ransom E, Schmerer M, St Cyr S, Workowski K, Weinstock H, Patel J, Ferraro MJ. (Full Text)

Clin Infect Dis. 2019 Apr 9. pii: ciz292. doi: 10.1093/cid/ciz292. [Epub ahead of print]

 

Abstract

BACKGROUND:

Azithromycin (AZI) is recommended with Ceftriaxone (CRO) for treatment of uncomplicated gonococcal urethritis and cervicitis in the United States (US) and an AZI susceptibility breakpoint is needed. Neither the FDA (Food and Drug Administration) nor the CLSI (Clinical and Laboratory Standards Institute) has set interpretive breakpoints for AZI susceptibility. As a result, AZI antimicrobial susceptibility testing (AST) cannot be interpreted using recognized standards. This has contributed to increasingly unavailable clinical laboratory AST, although gonorrhea is on the rise with over 550,000 US gonorrhea cases reported to the CDC in 2017, the highest number of cases since 1991.



METHODS:

This document summarizes the rationale data reviewed by the CLSI in June 2018.



RESULTS:

CLSI decided to set a susceptible only interpretive breakpoint at the MIC (Minimum Inhibitory Concentration) of and below 1 µg/ml. This is also the epidemiological cut-off value (ECV), i.e., the end of the wild-type susceptibility distribution. This breakpoint presumes that AZI (1 gm single dose) is used in an approved regimen that includes an additional antimicrobial agent (i.e. CRO 250 mg, intramuscular [IM] single dose).



CONCLUSION:

Having a breakpoint can improve patient care and surveillance, and allow future development and FDA regulatory approval of modernized AST to guide treatment. The breakpoint coincides with a EUCAST (European Committee on AST) decision to remove previously established, differing AZI breakpoints and use the ECV as guidance for testing. The CLSI breakpoint is now the recognized standard that defines AZI susceptibility for gonococcal infections.

 

Epidemiology and Surveillance

Decreased Cephalosporin Susceptibility of Oropharyngeal Neisseria Species in Antibiotic-Using Men-who-have-sex-with-men of Hanoi, Vietnam.

Dong HV, Pham LQ, Nguyen H, Nguyen MXB, Nguyen TV, May F, Le GM, Klausner JD. (Full Text)

Clin Infect Dis. 2019 May 3. pii: ciz365. doi: 10.1093/cid/ciz365. [Epub ahead of print]

Abstract

BACKGROUND:

Neisseria gonorrhoeae (NG) infections are a global health burden. Increasing reports of NG resistance to cephalosporins are an imminent threat to public health. Many hypothesize that commensal Neisseria species are an important reservoir for genetic material conferring antimicrobial resistance in NG, however clinical data are lacking.



METHODS:

Men-who-have-sex-with-men (MSM) of Hanoi, Vietnam completed a questionnaire regarding antibiotic use. We collected pharyngeal specimens, cultured Neisseria species, and measured minimum inhibitory concentrations (MIC) to ciprofloxacin, cefixime, ceftriaxone, and cefpodoxime. Using MIC criteria for antimicrobial susceptibility in NG, we categorized the Neisseria species and compared mean MIC levels between different antibiotic user groups.



RESULTS:

Of 207 participants, 38% used at least one antibiotic in the past 6 months; 52% without a prescription. A median of one Neisseria species was cultured from each participant (range 1-4) with 10 different Neisseria species identified overall. The proportion of Neisseria with reduced susceptibility to ciprofloxacin was 93%, cefpodoxime 84%, cefixime, 31% and ceftriaxone, 28%. Antibiotic use within the past month was strongly associated with Neisseria species having increased MICs to cefixime, ceftriaxone, and cefpodoxime; with mean MIC ratios of 6.27, 4.11, and 7.70, respectively, when compared to those who used antibiotics between 1 and 6 months prior (p< 0.05, all comparisons).



CONCLUSIONS:

MSM in our study often used antibiotics without a prescription. At least one commensal Neisseria species colonized all men. Recent use of any antibiotics may select for oropharyngeal Neisseria species with antimicrobial resistance. The normal flora of the oropharynx may be an important source of antimicrobial resistance in Neisseria gonorrhoeae.

Low gonorrhoea antimicrobial resistance and culture positivity rates in general practice: a pilot study.

Visser M, van Westreenen M, van Bergen J, van Benthem BHB. (Full Text)

Sex Transm Infect. 2019 Apr 30. pii: sextrans-2019-054006. doi: 10.1136/sextrans-2019-054006. [Epub ahead of print]

Abstract

OBJECTIVE:

In the Netherlands, the Gonococcal Resistance to Antimicrobials Surveillance (GRAS) programme is carried out at Centres for Sexual Health (CSH), which provide care for sexual high-risk populations. However, half of gonorrhoea infections are diagnosed in general practice (GP). We performed a pilot study to explore expanding GRAS to GPs using laboratory-based surveillance. Additionally, antimicrobial resistance patterns of GP and CSH patients were compared.



METHODS:

Three laboratories from different regions were included, which all perform gonorrhoea diagnostics for GPs and used ESwab for patient sampling. Additional culturing for all GP patients with gonorrhoea took place from February to July 2018. After positive PCR-nucleic acid amplification test, residual ESwab material was used for culture. In positive cultures, susceptibility testing was performed for azithromycin, ciprofloxacin, cefotaxime and ceftriaxone using Etest.



RESULTS:

During the study period, 484 samples were put in culture. 16.5% of cultures were positive (n=80). Antimicrobial resistance levels were low, with 2.6% resistance to azithromycin, 21.5% to ciprofloxacin and 0.0% to cefotaxime and ceftriaxone. Resistance levels in CSH GRAS data (first half of 2018) were 19.2% for azithromycin, 31.5% for ciprofloxacin, 1.9% for cefotaxime and 0.0% for ceftriaxone.



CONCLUSIONS:

Culture positivity rates for GP patients were low, probably due to long transportation times and awaiting PCR test results before attempting culture. Positivity rates might be improved by making changes in sampling and/or transportation methods, but that would require involvement of GPs and patients instead of keeping the surveillance lab based. Resistance levels appeared to be lower at GPs than at the CSH, indicating that resistance might emerge first in more high-risk populations. It is important to consider all potentially relevant patient populations when establishing a gonococcal antimicrobial resistance surveillance programme. However, based on the findings from this study the current GRAS programme will not be extended to GPs.

Just Google it! Impact of media coverage of an outbreak of high-level azithromycin-resistant Neisseria gonorrhoeae on online searches, and attendances, testing and diagnoses at sexual health clinics in England between 2015 and 2016: an interrupted time series analysis using surveillance data.

Smolarchuk C, Mohammed H, Furegato M, Town K, Fifer H, Wilson J, Nardone A, Lee A, Hughes G. (Full Text)

Sex Transm Infect. 2019 Apr 30. pii: sextrans-2019-053986. doi: 10.1136/sextrans-2019-053986. [Epub ahead of print]

Abstract

OBJECTIVES:

To determine if media coverage of an outbreak of high-level azithromycin-resistant Neisseria gonorrhoeae (HL-AziR) impacted online search interest or was temporally associated with health-seeking behaviours in several English cities.



METHODS:

A descriptive analysis of outbreak-related online media articles and relative search interest (RSI) using Google and an interrupted time series analysis using routine surveillance data from sexual health clinics (SHCs) in England (GUMCAD STI surveillance system). The main outcomes were adjusted incidence rate ratios (IRRs) of weekly attendances, gonorrhoea tests and diagnoses of gonorrhoea or 'any STI' in selected cities after media coverage of the outbreak in 2015 and 2016.



RESULTS:

RSI for outbreak-related terms peaked during media coverage in September 2015 with smaller peaks coinciding with subsequent coverage. The greatest increase in RSI was in Leeds, which coincided with a 63% rise (n=1932; IRR 1.26, 95% CI 1.12 to 1.43) in SHC attendances by women. There was only a 7% (n=1358; IRR 1.01, 95% CI 0.91 to 1.11) increase in attendances by men. Modest increases in outcomes occurred in four other cities with a high RSI. There was no evidence of increases in outcomes in cities, other than Leeds, after subsequent media coverage of the outbreak.



CONCLUSIONS:

National and local media coverage of the HL-AziR outbreak coincided with peak RSI for related terms, and a transient increase in attendances, gonorrhoea tests and diagnoses of gonorrhoea or 'any STI' in some cities with a high RSI. Our analysis demonstrates the potential for media coverage to influence health-seeking behaviours during high-profile STI outbreaks.

Phenotypic and Genotypic Characterization of Neisseria gonorrhoeae Isolates from New Zealand with Reduced Susceptibility to Ceftriaxone.

Jamaludin N, Gedye K, Collins-Emerson J, Benschop J, Nulsen M. (Full Text)

Microb Drug Resist. 2019 Apr 25. doi: 10.1089/mdr.2018.0111. [Epub ahead of print]

Abstract

Aim: To characterize mutations in penA, mtrR, ponA, and porBIB, considered target genes for antimicrobial resistance, in Neisseria gonorrhoeae isolates with elevated minimum inhibitory concentrations (MICs) of ceftriaxone cultured from patients in New Zealand. Results: Out of 28 isolates supplied by the Institute of Environmental Science and Research Limited (ESR), Porirua, New Zealand, 14 were found to show reduced susceptibility to ceftriaxone (MIC of 0.06 mg/L) according to criteria used by the ESR and the Australian Gonococcal Surveillance Programme (AGSP) when tested in our laboratory. Rates of resistance to ciprofloxacin, azithromycin, penicillin, and tetracycline were 100% (28/28), 7% (2/28), 36% (10/28), and 25% (7/28), respectively. Ten different penA (Penicillin binding protein 2 [PBP2]) sequences were observed. The most common mosaic penA M-1 resembled mosaic penA XXXIV, which has been associated with ceftriaxone treatment failures in other countries. Four semimosaic PBP2 sequences were observed and may be novel PBP sequences, while four out of five nonmosaic PBP2 sequences were similar to PBP2 sequences reported in Australia. Twenty-one isolates harbored mutations in all 4 genes (penA, mtrR, porBIB, and ponA), and 13 of these exhibited reduced susceptibility to ceftriaxone. Conclusion: Mutations in penA, mtrR, porBIB, and ponA observed in this study may have contributed to reduced susceptibility to ceftriaxone among New Zealand gonococcal isolates. Over half (16/22) of mosaic penA sequences from the gonococcal isolates resembled penA XXXIV.

Multidrug-resistant and extensively drug-resistant Neisseria gonorrhoeae in Canada, 2012-2016.

Martin I, Sawatzky P, Allen V, Lefebvre B, Hoang L, Naidu P, Minion J, Van Caeseele P, Haldane D, Gad RR, Zahariadis G, Corriveau A, German G, Tomas K, Mulvey MR. (Full Text)

Can Commun Dis Rep. 2019 Feb 7;45(2-3):45-53. doi: 10.14745/ccdr.v45i23a01. eCollection 2019 Feb 7.

Abstract

BACKGROUND:

Neisseria gonorrhoeae have acquired resistance to many antimicrobials, including third generation cephalosporins and azithromycin, which are the current gonococcal combination therapy recommended by the Canadian Guidelines on Sexually Transmitted Infections.



OBJECTIVE:

To describe antimicrobial susceptibilities for N. gonorrhoeae circulating in Canada between 2012 and 2016.



METHODS:

Antimicrobial resistance profiles were determined using agar dilution of N. gonorrhoeae isolated in Canada 2012-2016 (n=10,167) following Clinical Laboratory Standards Institute guidelines. Data were analyzed by applying multidrug-resistant gonococci (MDR-GC) and extensively drug-resistant gonococci (XDR-GC) definitions.



RESULTS:

Between 2012 and 2016, the proportion of MDR-GC increased from 6.2% to 8.9% and a total of 19 cases of XDR-GC were identified in Canada (0.1%, 19/18,768). The proportion of isolates with decreased susceptibility to cephalosporins declined between 2012 and 2016 from 5.9% to 2.0% while azithromycin resistance increased from 0.8% to 7.2% in the same period.



CONCLUSION:

While XDR-GC are currently rare in Canada, MDR-GC have increased over the last five years. Azithromycin resistance in N. gonorrhoeae is established and spreading in Canada, exceeding the 5% level at which the World Health Organization states an antimicrobial should be reviewed as an appropriate treatment. Continued surveillance of antimicrobial susceptibilities of N. gonorrhoeae is necessary to inform treatment guidelines and mitigate the impact of resistant gonorrhea.

Clonal expansion and spread of the ceftriaxone-resistant Neisseria gonorrhoeae strain FC428, identified in Japan in 2015, and closely related isolates.

Lee K, Nakayama SI, Osawa K, Yoshida H, Arakawa S, Furubayashi KI, Kameoka H, Shimuta K, Kawahata T, Unemo M, Ohnishi M. (Full Text)

J Antimicrob Chemother. 2019 Apr 19. pii: dkz129. doi: 10.1093/jac/dkz129. [Epub ahead of print]

Abstract

OBJECTIVES:

Ceftriaxone resistance in Neisseria gonorrhoeae is a major public health concern globally because a high-dose (1 g) injection of ceftriaxone is the only remaining option for empirical monotherapy of gonorrhoea. The ceftriaxone-resistant gonococcal strain FC428, cultured in Osaka in 2015, is suspected to have spread nationally and internationally. We describe the complete finished genomes of FC428 and two closely related isolates from Osaka in 2015, and examine the genomic epidemiology of these isolates plus three ceftriaxone-resistant gonococcal isolates from Osaka and Hyogo in 2016-17 and four ceftriaxone-resistant gonococcal isolates cultured in 2017 in Australia, Canada and Denmark.



METHODS:

During 2015-17, we identified six ceftriaxone-resistant gonococcal isolates through our surveillance systems in Kyoto, Osaka and Hyogo. Antimicrobial susceptibility testing (six antimicrobials) was performed using Etest. Complete whole-genome sequences of the first three isolates (FC428, FC460 and FC498) from 2015 were obtained using PacBio RS II and Illumina MiSeq sequencing. The three complete genome sequences and draft genome sequences of the three additional Japanese (sequenced with Illumina MiSeq) and four international ceftriaxone-resistant isolates were compared.



RESULTS:

Detailed genomic analysis suggested that the Japanese isolates (FC428, FC460, FC498, KU16054, KM383 and KU17039) and the four international MLST ST1903 isolates from Australia, Canada and Denmark formed four linked subclades.



CONCLUSIONS:

Using detailed genomic analysis, we describe the clonal expansion of the ceftriaxone-resistant N. gonorrhoeae strain FC428, initially identified in 2015 in Japan, and closely related isolates. FC428 and its close relatives show some genomic diversity, suggesting multiple genetic subclades are already spreading internationally.

Typing of Neisseria gonorrhoeae isolates by phenotypic and genotypic techniques in New Delhi, India.

Sood S, Mahajan N, Singh R, Agrawal SK, Shende T, Kapil A, Kar HK, Sharma VK. (Full Text)

J Lab Physicians. 2019 Jan-Mar;11(1):45-50. doi: 10.4103/JLP.JLP_107_18.

Abstract

BACKGROUND:

The objective of this study is to investigate gonococcal isolates using phenotypic and genotypic methods.



METHODOLOGY:

Sixty gonococcal isolates obtained were examined. Strains were divided into 9 resistant phenotypes: Chromosomally mediated penicillin-resistant Neisseria gonorrhoeae (CMRNGP), penicillinase-producing NG (PPNG), chromosomally mediated tetracycline-resistant NG (CMRNGT), TRNG, PPNG and TRNG, CMRNGPT, quinolone resistant NG (QRNG), Azithro R, and decreased susceptibility (DS) to ceftriaxone. These isolates were also subjected to auxotyping and NG-multi-antigen sequence typing (MAST).



RESULTS:

Of 60 isolates, 32 (53.33%) PPNG and only one was CMRNGP; 16 (26.66%) were CMRNGT, while 18 (30%) were TRNG. Both PPNG and TRNG found in 13 (21.66%) and none were CMRNGPT. QRNG was seen in 93.33%, 5% Azithromycin R, and 6.66% were DS to ceftriaxone. Based on auxotyping, 24 (40%) nonrequiring, 16 (26.66%) were proline requiring, 13 (21.66%) arginine requiring while 7 (11.66%) belonged to others. The most common ST was 6058 (32.5%). The discriminatory indices of antibiogram, auxotyping and NG-MAST were 0.77, 0.72, and 0.95, respectively.



CONCLUSIONS:

NG-MAST is the method of choice for epidemiological studies.

Australian Gonococcal Surveillance Programme Annual Report, 2017

Lahra MM, Enriquez R, George CRR. (Full Text)

Commun Dis Intell (2018). 2019 Apr 15;43. doi: 10.33321/cdi.2019.43.13.

Abstract

The Australian Gonococcal Surveillance Programme (AGSP) has continuously monitored antimicrobial resistance in clinical isolates of Neisseria gonorrhoeae from all states and territories since 1981. In 2017, there were 7,835 clinical isolates of gonococci from public and private sector sources tested for in vitro antimicrobial susceptibility by standardized methods. Current treatment recommendations for gonorrhoea for the majority of Australia, is a dual therapeutic strategy of ceftriaxone and azithromycin. Decreased susceptibility to ceftriaxone (Minimum Inhibitory Concentration or MIC value 0.06-0.125 mg/L) was found nationally in 1.06% of isolates, which is lower than that reported in the AGSP Annual Report 2016 (1.7%). The highest proportions were reported from Victoria and Western Australia (urban and rural) (2.1% and 1.4% respectively). Resistance to azithromycin (MIC value ≥1.0 mg/L) was found nationally in 9.3% of isolates, which is approximately double the proportion reported in 2016 (5.0%) and more than three times the proportion reported in 2015 (2.6%). The highest proportions were reported from Victoria (13.5%), South Australia (12.8%) and New South Wales (9.3%). High level resistance to azithromycin (MIC value ≥256 mg/L) was reported in 4 strains nationally in 2017, 2 from Victoria, one from New South Wales, and one from Queensland. The proportion of strains resistant to penicillin in non-remote Australia ranged from 10.3% in non-remote Northern Territory to 44.1% in Tasmania. In remote Northern Territory, penicillin resistance rates remain low (2.5%). In remote Western Australia, penicillin resistance rates continue to increase (6.7%) compared to the previous years, however, there were relatively low numbers of strains available for isolate based testing (n=12). To address this and to monitor resistance and inform treatment guidelines, widespread molecular testing for penicillin resistance in Western Australia is in place, and these data are included in the AGSP. The proportion of strains resistant to ciprofloxacin in non-remote Australia ranged from 17.2% in non-remote Northern Territory to 61% in Tasmania. Ciprofloxacin resistance rates remain comparatively low in remote Northern Territory (1.3%) and remote Western Australia (5.0%).

gyrA and parC mutations in fluoroquinolone-resistant Neisseria gonorrhoeae isolates from Kenya.

Kivata MW, Mbuchi M, Eyase FL, Bulimo WD, Kyanya CK, Oundo V, Muriithi SW, Andagalu B, Mbinda WM, Soge OO, McClelland RS, Sang W, Mancuso JD. (Full Text)

BMC Microbiol. 2019 Apr 8;19(1):76. doi: 10.1186/s12866-019-1439-1.

Abstract

BACKGROUND:

Phenotypic fluoroquinolone resistance was first reported in Western Kenya in 2009 and later in Coastal Kenya and Nairobi. Until recently gonococcal fluoroquinolone resistance mechanisms in Kenya had not been elucidated. The aim of this paper is to analyze mutations in both gyrA and parC responsible for elevated fluoroquinolone Minimum Inhibitory Concentrations (MICs) in Neisseria gonorrhoeae (GC) isolated from heterosexual individuals from different locations in Kenya between 2013 and 2017.



METHODS:

Antimicrobial Susceptibility Tests were done on 84 GC in an ongoing Sexually Transmitted Infections (STI) surveillance program. Of the 84 isolates, 22 resistant to two or more classes of antimicrobials were chosen for analysis. Antimicrobial susceptibility tests were done using E-test (BioMerieux) and the results were interpreted with reference to European Committee on Antimicrobial Susceptibility Testing (EUCAST) standards. The isolates were sub-cultured, and whole genomes were sequenced using Illumina platform. Reads were assembled de novo using Velvet, and mutations in the GC Quinolone Resistant Determining Regions identified using Bioedit sequence alignment editor. Single Nucleotide Polymorphism based phylogeny was inferred using RaxML.



RESULTS:

Double GyrA amino acid substitutions; S91F and D95G/D95A were identified in 20 isolates. Of these 20 isolates, 14 had an additional E91G ParC substitution and significantly higher ciprofloxacin MICs (p = 0.0044*). On the contrary, norfloxacin MICs of isolates expressing both GyrA and ParC QRDR amino acid changes were not significantly high (p = 0.82) compared to MICs of isolates expressing GyrA substitutions alone. No single GyrA substitution was found in the analyzed isolates, and no isolate contained a ParC substitution without the simultaneous presence of double GyrA substitutions. Maximum likelihood tree clustered the 22 isolates into 6 distinct clades.



CONCLUSION:

Simultaneous presence of amino acid substitutions in ParC and GyrA has been reported to increase gonococcal fluoroquinolone resistance from different regions in the world. Our findings indicate that GyrA S91F, D95G/D95A and ParC E91G amino acid substitutions mediate high fluoroquinolone resistance in the analyzed Kenyan GC.

 

Novel antibiotics, mechanisms, vaccine, and other advances

Gentamicin compared with ceftriaxone for the treatment of gonorrhoea (G-ToG): a randomised non-inferiority trial.

Ross JDC, Brittain C, Cole M, Dewsnap C, Harding J, Hepburn T, Jackson L, Keogh M, Lawrence T, Montgomery AA, Roberts TE, Sprange K, Tan W, Thandi S, White J, Wilson J, Duley L; G-ToG trial team. (Full Text)

Lancet. 2019 May 2. pii: S0140-6736(18)32817-4. doi: 10.1016/S0140-6736(18)32817-4. [Epub ahead of print]

Abstract

BACKGROUND:

Gonorrhoea is a common sexually transmitted infection for which ceftriaxone is the current first-line treatment, but antimicrobial resistance is emerging. The objective of this study was to assess the effectiveness of gentamicin as an alternative to ceftriaxone (both combined with azithromycin) for treatment of gonorrhoea.



METHODS:

G-ToG was a multicentre, parallel-group, pragmatic, randomised, non-inferiority trial comparing treatment with gentamicin to treatment with ceftriaxone for patients with gonorrhoea. The patients, treating physician, and assessing physician were masked to treatment but the treating nurse was not. The trial took place at 14 sexual health clinics in England. Adults aged 16-70 years were eligible for participation if they had a diagnosis of uncomplicated genital, pharyngeal, or rectal gonorrhoea. Participants were randomly assigned to receive a single intramuscular dose of either gentamicin 240 mg (gentamicin group) or ceftriaxone 500 mg (ceftriaxone group). All participants also received a single 1 g dose of oral azithromycin. Randomisation (1:1) was stratified by clinic and performed using a secure web-based system. The primary outcome was clearance of Neisseria gonorrhoeae at all initially infected sites, defined as a negative nucleic acid amplification test 2 weeks post treatment. Primary outcome analyses included only participants who had follow-up data, irrespective of the baseline visit N gonorrhoeae test result. The margin used to establish non-inferiority was a lower confidence limit of 5% for the risk difference. This trial is registered with ISRCTN, number ISRCTN51783227.



FINDINGS:

Of 1762 patients assessed, we enrolled 720 participants between Oct 7, 2014, and Nov 14, 2016, and randomly assigned 358 to gentamicin and 362 to ceftriaxone. Primary outcome data were available for 306 (85%) of 362 participants allocated to ceftriaxone and 292 (82%) of 358 participants allocated to gentamicin. At 2 weeks after treatment, infection had cleared for 299 (98%) of 306 participants in the ceftriaxone group compared with 267 (91%) of 292 participants in the gentamicin group (adjusted risk difference -6·4%, 95% CI -10·4% to -2·4%). Of the 328 participants who had a genital infection, 151 (98%) of 154 in the ceftriaxone group and 163 (94%) of 174 in the gentamicin group had clearance at follow-up (adjusted risk difference -4·4%, -8·7 to 0). For participants with a pharyngeal infection, a greater proportion receiving ceftriaxone had clearance at follow-up (108 [96%] in the ceftriaxone group compared with 82 [80%] in the gentamicin group; adjusted risk difference -15·3%, -24·0 to -6·5). Similarly, a greater proportion of participants with rectal infection in the ceftriaxone group had clearance (134 [98%] in the ceftriaxone group compared with 107 [90%] in the gentamicin group; adjusted risk difference -7·8%, -13·6 to -2·0). Thus, we did not find that a single dose of gentamicin 240 mg was non-inferior to a single dose of ceftriaxone 500 mg for the treatment of gonorrhoea, when both drugs were combined with a 1 g dose of oral azithromycin. The side-effect profiles were similar between groups, although severity of pain at the injection site was higher for gentamicin (mean visual analogue pain score 36 of 100 in the gentamicin group vs 21 of 100 in the ceftriaxone group).



INTERPRETATION:

Gentamicin is not appropriate as first-line treatment for gonorrhoea but remains potentially useful for patients with isolated genital infection, or for patients who are allergic or intolerant to ceftriaxone, or harbour a ceftriaxone-resistant isolate. Further research is required to identify and test new alternatives to ceftriaxone for the treatment of gonorrhoea.



FUNDING:

UK National Institute for Health Research.

Exploitation of Neisseria meningitidis Group B OMV Vaccines Against N. gonorrhoeae to Inform the Development and Deployment of Effective Gonorrhea Vaccines.

Petousis-Harris H, Radcliff FJ. (Full Text)

Front Immunol. 2019 Apr 9;10:683. doi: 10.3389/fimmu.2019.00683. eCollection 2019.

Abstract

Have potential clues to an effective gonorrhea vaccine been lurking in international disease surveillance data for decades? While no clinically effective vaccines against gonorrhea have been developed we present direct and indirect evidence that a vaccine is not only possible, but may already exist. Experience from Cuba, New Zealand, and Canada suggest that vaccines containing Group B Neisseria meningitides outer membrane vesicles (OMV) developed to control type-specific meningococcal disease may also prevent a significant proportion of gonorrhea. The mechanisms for this phenomenon have not yet been elucidated but we present some strategies for unraveling potential cross protective antigens and effector immune responses by exploiting stored sera from clinical trials and individuals primed with a meningococcal group B OMV vaccine (MeNZB). Elucidating these will contribute to the ongoing development of high efficacy vaccine options for gonorrhea. While the vaccine used in New Zealand, where the strongest empirical evidence has been gathered, is no longer available, the OMV has been included in the multi component recombinant meningococcal vaccine 4CMenB (Bexsero) which is now licensed and used in numerous countries. Several lines of evidence suggest it has the potential to affect gonorrhea prevalence. A vaccine to control gonorrhea does not need to be perfect and modeling supports that even a moderately efficacious vaccine could make a significant impact in disease prevalence. How might we use an off the shelf vaccine to reduce the burden of gonorrhea? What are some of the potential societal barriers in a world where vaccine hesitancy is growing? We summarize the evidence and consider some of the remaining questions.

Efficacy and Safety of Single-Dose Oral Delafloxacin Compared With Intramuscular Ceftriaxone for Uncomplicated Gonorrhea Treatment: An Open-Label, Noninferiority, Phase 3, Multicenter, Randomized Study.

Hook EW 3rd, Golden MR, Taylor SN, Henry E, Tseng C, Workowski KA, Swerdlow J, Nenninger A, Cammarata S. (Full Text)

Sex Transm Dis. 2019 May;46(5):279-286. doi: 10.1097/OLQ.0000000000000971.

Abstract

BACKGROUND:

We evaluated single oral dose of delafloxacin versus single intramuscular ceftriaxone in participants with uncomplicated urogenital gonorrhea (primary objective). Secondary objectives included the efficacy, safety, and tolerability of delafloxacin versus ceftriaxone for uncomplicated urogenital, rectal, and/or pharyngeal gonorrhea.



METHODS:

In this open-label, multicenter study, 460 participants at 25 study centers were randomized (2:1) to receive a single 900-mg oral dose of delafloxacin or 250-mg intramuscular ceftriaxone. Neisseria gonorrhoeae culture, nucleic acid amplification test, and clinical responses were evaluated. The primary efficacy end point was the urogenital microbiological cure in the urogenital microbiological intention-to-treat population; noninferiority (NI) was assessed using a 10% NI margin.



RESULTS:

In the urogenital microbiological intention-to-treat population, urogenital cure rates for delafloxacin were 85.1% (194/228) versus 91.0% (91/100) for ceftriaxone (95% confidence interval, -13.18% to 1.36%). Because the lower bound of the confidence interval exceeded the prespecified -10% NI margin, delafloxacin did not demonstrate NI to ceftriaxone. Treatment failures were more often associated with N. gonorrhoeae with higher delafloxacin minimum inhibitory concentration (MIC) values. In microbiologically evaluable participants, failure occurred in 1 (0.6%) of 177 urogenital infections caused by isolates with delafloxacin MICs <0.008 μg/mL and 31 (64.6%) of 48 infections caused by isolates with delafloxacin MICs ≥0.008 μg/mL. Gastrointestinal adverse events were common with 900-mg of delafloxacin and typically included mild to moderate diarrhea, flatulence, nausea, and vomiting. The most common adverse event was diarrhea in both treatment groups.



CONCLUSIONS:

A single 900-mg dose of delafloxacin is not a reliable treatment of uncomplicated urogenital gonorrhea. Treatment failures were common in infections caused by N. gonorrhoeae with delafloxacin MICs ≥0.008 μg/mL. Additional testing with alternative dosing regimens could be considered. ClinicalTrials.gov Identifier: NCT02015637.