Comprehensive observational study evaluating the enduring effectiveness of 4CMenB, the meningococcal B vaccine against gonococcal infections in the Northern Territory and South Australia, Australia: study protocol.

INTRODUCTION: The effectiveness of antibiotics for treating gonococcal infections is compromised due to escalating antibiotic resistance; and the development of an effective gonococcal vaccine has been challenging. Emerging evidence suggests that the licensed meningococcal B (MenB) vaccine, 4CMenB is effective against gonococcal infections due to cross-reacting antibodies and 95% genetic homology between the two bacteria, Neisseria meningitidis and Neisseria gonorrhoeae, that cause the diseases. This project aims to undertake epidemiological and genomic surveillance to evaluate the long-term protection of the 4CMenB vaccine against gonococcal infections in the Northern Territory (NT) and South Australia (SA), and to determine the potential benefit of a booster vaccine doses to provide longer-term protection against gonococcal infections. METHODS AND ANALYSES: This observational study will provide long-term evaluation results of the effectiveness of the 4CMenB vaccine against gonococcal infections at 4-7 years post 4CMenB programme implementation. Routine notifiable disease notifications will be the basis for assessing the impact of the vaccine on gonococcal infections. Pathology laboratories will provide data on the number and percentage of N. gonorrhoeae positive tests relative to all tests administered and will coordinate molecular sequencing for isolates. Genome sequencing results will be provided by SA Pathology and Territory Pathology/New South Wales Health Pathology, and linked with notification data by SA Health and NT Health. There are limitations in observational studies including the potential for confounding. Confounders will be analysed separately for each outcome/comparison. ETHICS AND DISSEMINATION: The protocol and all study documents have been reviewed and approved by the SA Department for Health and Well-being Human Research Ethics Committee (HREC/2022/HRE00308), and the evaluation will commence in the NT on receipt of approval from the NT Health and Menzies School of Health Research Human Research Ethics Committee. Results will be published in peer-reviewed journals and presented at scientific meetings and public forums.

Australian Gonococcal Surveillance Programme, 1 January to 31 March 2023.

Abstract: The Australian National Neisseria Network (NNN) comprises reference laboratories in each state and territory that report data on antimicrobial susceptibility testing to an agreed group of antimicrobial agents for the Australian Gonococcal Surveillance Programme (AGSP). The AGSP data are presented quarterly in tabulated form, as well as in the AGSP annual report. This report presents national gonococcal antimicrobial resistance surveillance data from 1 January to 31 March 2023.

Australian Gonococcal Surveillance Programme, 1 April to 30 June 2023.

Abstract: The Australian National Neisseria Network (NNN) comprises reference laboratories in each state and territory that report data on antimicrobial susceptibility testing to an agreed group of antimicrobial agents for the Australian Gonococcal Surveillance Programme (AGSP). The AGSP data are presented quarterly in tabulated form, as well as in the AGSP annual report. This report presents national gonococcal antimicrobial resistance surveillance data from 1 April to 30 June 2023.

Australian Gonococcal Surveillance Programme, 1 July to 30 September 2023.

Abstract: The Australian National Neisseria Network (NNN) comprises reference laboratories in each state and territory that report data on antimicrobial susceptibility testing to an agreed group of antimicrobial agents for the Australian Gonococcal Surveillance Programme (AGSP). The AGSP data are presented quarterly in tabulated form, as well as in the AGSP annual report. This report presents national gonococcal antimicrobial resistance surveillance data from 1 July to 30 September 2023.

Multicentre double-blind randomised placebo-controlled trial evaluating the efficacy of the meningococcal B vaccine, 4CMenB (Bexsero), against Neisseria gonorrhoeae infection in men who have sex with men: the GoGoVax study protocol.

INTRODUCTION: Gonorrhoea, the sexually transmissible infection caused by Neisseria gonorrhoeae, has a substantial impact on sexual and reproductive health globally with an estimated 82 million new infections each year worldwide. N. gonorrhoeae antimicrobial resistance continues to escalate, and disease control is largely reliant on effective therapy as there is no proven effective gonococcal vaccine available. However, there is increasing evidence from observational cohort studies that the serogroup B meningococcal vaccine four-component meningitis B vaccine (4CMenB) (Bexsero), licensed to prevent invasive disease caused by Neisseria meningitidis, may provide cross-protection against the closely related bacterium N. gonorrhoeae. This study will evaluate the efficacy of 4CMenB against N. gonorrhoeae infection in men (cis and trans), transwomen and non-binary people who have sex with men (hereafter referred to as GBM+). METHODS AND ANALYSIS: This is a double-blind, randomised placebo-controlled trial in GBM+, either HIV-negative on pre-exposure prophylaxis against HIV or living with HIV (CD4 count >350 cells/mm3), who have had a diagnosis of gonorrhoea or infectious syphilis in the last 18 months (a key characteristic associated with a high risk of N. gonorrhoeae infection). Participants are randomised 1:1 to receive two doses of 4CMenB or placebo 3 months apart. Participants have 3-monthly visits over 24 months, which include testing for N. gonorrhoeae and other sexually transmissible infections, collection of demographics, sexual behaviour risks and antibiotic use, and collection of research samples for analysis of N. gonorrhoeae-specific systemic and mucosal immune responses. The primary outcome is the incidence of the first episode of N. gonorrhoeae infection, as determined by nucleic acid amplification tests, post month 4. Additional outcomes consider the incidence of symptomatic or asymptomatic N. gonorrhoeae infection at different anatomical sites (ie, urogenital, anorectum or oropharynx), incidence by N. gonorrhoeae genotype and antimicrobial resistance phenotype, and level and functional activity of N. gonorrhoeae-specific antibodies. ETHICS AND DISSEMINATION: Ethical approval was obtained from the St Vincent's Hospital Human Research Ethics Committee, St Vincent's Hospital Sydney, NSW, Australia (ref: 2020/ETH01084). Results will be disseminated in peer-reviewed journals and via presentation at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04415424.

Australian Meningococcal Surveillance Programme Annual Report, 2022.

In Australia, both probable and laboratory-confirmed cases of invasive meningococcal disease (IMD) are reported to the National Notifiable Diseases Surveillance System (NNDSS). Compared to 2021, the number of IMD notifications in 2022 increased by 81% to 127, alongside the easing of COVID-19 containment measures. Laboratory confirmation occurred in 95% of these cases, with 51% (62/121) diagnosed by bacterial culture and 49% (59/121) by nucleic acid amplification testing. The serogroup was determined for 97% of laboratory-confirmed cases (117/121): serogroup B (MenB) accounted for 83% of infections (100/121); MenW for 4% (5/121); MenY for 10% (12/121); no infections were attributed to MenC disease. Fine typing was available on 67% of the cases for which the serogroup was determined (78/117). In MenB isolates, 27 porA types were detected, the most prevalent of which were P1.7-2,4 (18%;11/62), P1.22,14 (15%; 9/62), P1.18-1,34 (10%; 6/62) and P1.7,16-26 (10%; 6/62). All five MenW infections identified as porA type P1.5,2 with different MLST sequence types (ST): 11, 574, 1287, 12351, 13135 all belonging to clonal complex 11, the hypervirulent strain reported in outbreaks in Australia and overseas. In MenY, the predominant porA type was P1.5-1,10-1 (73%; 8/11), ST 1655 and from clonal complex 23. Children less than 5 years of age and people aged 15-19 years were overrepresented with IMD notifications, accounting for 22% (27/121) and 23% (28/121) of laboratory-confirmed cases respectively. Fifteen percent of laboratory-confirmed notifications (18/121) were in persons aged 45-64 years. MenB infections were detected in all age groups but predominated in persons aged 15-19 years (93% of IMD in this age group; 26/28) and comprised 89% (24/27) of infections in children aged less than 5 years. MenW infections were markedly reduced in 2022, accounting for two IMD detections in children 1-4 years (2/16) and sporadic detections in other older age groups. MenY infections were largely detected in adults aged 45-64 years, accounting for 28% of IMD in this age group (5/18). All 62 cultured IMD isolates had antimicrobial susceptibility testing performed. Minimum inhibitory concentration (MIC) values were categorised using Clinical Laboratory Standards Institute (CLSI) interpretative criteria: 5% (3/62) were defined as penicillin resistant (MIC value ≥ 0.5 mg/L); 71% (44/62) had intermediate susceptibility to penicillin (MIC values 0.125 and 0.25 mg/L) and 24% (15/62) were susceptible to penicillin. All isolates were susceptible to ceftriaxone, ciprofloxacin and rifampicin.

Australian Gonococcal Surveillance Programme Annual Report, 2022.

The Australian Gonococcal Surveillance Programme (AGSP) has continuously monitored antimicrobial resistance in Neisseria gonorrhoeae for more than 40 years. In 2022, a total of 8,199 isolates from patients in the public and private sectors, in all jurisdictions, were tested for in vitro antimicrobial susceptibility by standardised methods. The current treatment recommendation for gonorrhoea, for the majority of Australia, continues to be dual therapy with ceftriaxone and azithromycin. In 2022, of N. gonorrhoeae isolates tested, 0.51% (42/8,199) met the WHO criterion for ceftriaxone decreased susceptibility (DS), defined as a minimum inhibitory concentration value ≥ 0.125 mg/L. Resistance to azithromycin was reported in 3.9% of N. gonorrhoeae isolates, proportionally stable since 2019. There were nine isolates with high-level resistance to azithromycin (MIC value ≥ 256 mg/L) reported in Australia: Queensland (4), New South Wales (3), Victoria (1) and non-remote Western Australia (1). This is the highest number detected annually by the AGSP. In 2022, penicillin resistance was found in 38.8% of gonococcal isolates, and ciprofloxacin resistance in 63.3%, however, there was considerable variation by jurisdiction. In some remote settings, penicillin resistance remains low; in these settings, penicillin continues to be recommended as part of an empiric therapy strategy. In 2022, in remote Northern Territory, one penicillin-resistant isolate was reported; in remote Western Australia, 11.8% of gonococcal isolates (9/76) were penicillin resistant. There were three ciprofloxacin-resistant isolates reported from remote Northern Territory; ciprofloxacin resistance rates remain comparatively low in remote Western Australia (6/76; 7.9%).

Disc Test for Detecting Staphylococcus aureus Strains Producing Type A and Type C ß-Lactamases.

Staphylococcus aureus can produce ß-lactamases capable of hydrolyzing penicillins and first-generation cephalosporins. The propensity of type A and type C ß-lactamase-producing S. aureus (TAPSA and TCPSA) to hydrolyze cefazolin at a high inoculum is termed the cefazolin inoculum effect (CIE). Strains with a CIE have a theoretical risk of causing treatment failure and are unable to be detected routinely by most laboratories. We developed a high-performing yet straightforward ß-lactamase disc test that identifies and differentiates both TAPSA and TCPSA and is suitable for routine diagnostic laboratory workflows. Clinical isolates of S. aureus resistant to penicillin were identified, and their blaZ genes were sequenced. MICs were determined at low and high inocula (5 × 105 CFU/mL and 5 × 107 CFU/mL), and isolates demonstrating a CIE were characterized. A semimechanistic model was established to describe differential hydrolysis patterns, and candidate models were iteratively assessed using area-under-the-curve analysis from competitor receiver operating characteristic (ROC) curves. Biomarker thresholds were derived from Youdon index-derived optimal cutoff values. Genetic analysis of 99 isolates identified 26 TAPSA isolates and 45 TCPSA isolates. The model best differentiating TAPSA from non-TAPSA utilized cefazolin-to-cephalothin ratio analysis (sensitivity, 96.2%; specificity, 98.6%). The model best differentiating TCPSA from non-TCPSA incorporated cefazolin, cephalothin, and oxacillin (sensitivity, 88.6%; specificity, 96.6%). TAPSA and TCPSA can be differentiated using three antibiotic discs on a single agar plate. The test has potential value in typing the ß-lactamase type from isolates from patients that are candidates for or have failed cefazolin therapy. IMPORTANCE The key significance of this article is that it details a straightforward method of performing a disc test that can differentiate Staphylococcus aureus isolates that are likely to be associated with a cefazolin inoculum effect and theoretical risk of cefazolin treatment failure from isolates that are less likely to be associated with a cefazolin inoculum effect.

Antimicrobial susceptibility assays for Neisseria gonorrhoeae: a proof-of-principle population-based retrospective analysis.

BACKGROUND: Neisseria gonorrhoeae treatment guided by molecular antimicrobial susceptibility assays could improve treatment options and antimicrobial stewardship; however, few commercial assays are available. We aimed to investigate antimicrobial susceptibility of N gonorrhoeae isolates in New South Wales, Australia, and estimate the potential usefulness of hypothetical combinations of rapid molecular antimicrobial susceptibility assays. METHODS: In this proof-of-principle, population-based, retrospective analysis, we assessed N gonorrhoeae susceptibility data for ceftriaxone, azithromycin, ciprofloxacin, and penicillin. Isolates were previously collected as part of the Australian Gonococcal Surveillance Programme between Jan 1, 2008, and Dec 31, 2019. All cultured N gonorrhoeae isolates with susceptibility data to all four antimicrobials were included. However, only one isolate was included if several isolates originated from the same individual within 13 days of the previous isolate originating from that individual, and there were less than two standard double-dilution minimum inhibitory concentrations between the isolates. We assessed the use of different combinations of hypothetical antimicrobial susceptibility assays and treatment combinations in terms of their ability to minimise overall ceftriaxone use, and use specifically in isolates with decreased susceptibility to ceftriaxone, compared with standard non-assay-guided empirical ceftriaxone treatment. FINDINGS: We included 23 089 N gonorrhoeae isolates. The prevalence of antimicrobial sensitivity fluctuated significantly during the study. Isolates with decreased susceptibility to ceftriaxone were more likely to be resistant to one or more antimicrobials than isolates without decreased susceptibility (782 [98·6%] of 793 vs 10 661 [47·8%] of 22 296), particularly ciprofloxacin (p<0·0001) and penicillin (p<0·0001). Compared with empirical ceftriaxone treatment, we estimated that strategies based on the use of hypothetical antimicrobial susceptibility would reduce ceftriaxone use (p<0·0001). However, because of co-resistance, most assay-directed treatment strategies, including those involving use of assays for two antibiotics, would result in only moderate reductions in ceftriaxone use among isolates with decreased susceptibility to ceftriaxone. INTERPRETATION: Individualised treatment guided by molecular antimicrobial susceptibility diagnostics could help to reduce overall ceftriaxone use in gonorrhoea. However, the use of these assays needs to be informed by the non-random nature of co-resistance among circulating N gonorrhoeae strains. FUNDING: Australian Government and Queensland Government.

Australian Gonococcal Surveillance Programme Annual Report, 2021.

The Australian Gonococcal Surveillance Programme, established in 1981, has continuously monitored antimicrobial resistance in Neisseria gonorrhoeae for more than 40 years. In 2021, a total of 6,254 isolates from patients in the public and private sectors, in all jurisdictions, were tested for in vitro antimicrobial susceptibility by standardised methods. The current treatment recommendation for gonorrhoea, for the majority of Australia, continues to be dual therapy with ceftriaxone and azithromycin. In 2021, of isolates tested, 0.9% were reported nationally with decreased susceptibility (DS) to ceftriaxone (minimum inhibitory concentration [MIC] value ≥ 0.06 mg/L). There was one isolate from non-remote Western Australia that was resistant to ceftriaxone (MIC value ≥ 0.25 mg/L). Resistance to azithromycin (MIC value ≥ 1.0 mg/L) was reported nationally in 4.7% of N. gonorrhoeae isolates. This is increased from that reported in 2020 (3.9%) but similar to the percentage reported in 2019 (4.6%). Isolates with high-level resistance to azithromycin (MIC value ≥ 256 mg/L) are identified sporadically in Australia; none were reported in 2021. In 2021, penicillin resistance was found in 38% of gonococcal isolates nationally, and ciprofloxacin resistance in 53%; however, there is considerable variation by jurisdiction. In some remote settings, penicillin resistance remains low; in these settings, penicillin continues to be recommended as part of an empiric therapy strategy. In 2021, in remote Northern Territory, one penicillin-resistant isolate was reported, and in remote Western Australia 2/83 of gonococcal isolates (2.4 %) were penicillin resistant. There were two ciprofloxacin-resistant isolates reported from remote Northern Territory; ciprofloxacin resistance rates remain comparatively low in remote Western Australia (3/83; 3.6 %).