Investigating the cause of increased tetracycline-resistant Neisseria gonorrhoeae in England, 2016-20.

BACKGROUND: Antimicrobial resistance in Neisseria gonorrhoeae is a global public health concern. Tetracycline resistance (TetR) increased from 39.4% to 75.2% between 2016 and 2021 in N. gonorrhoeae isolates collected through national surveillance in England, despite the absence of use of tetracyclines for the treatment of gonorrhoea. OBJECTIVES: We investigated whether there was correlation between bacterial sexually transmitted infection (STI) tests performed and treatment with antimicrobials, with increased TetR in N. gonorrhoeae. METHODS: We examined correlations between bacterial STI tests, antimicrobial treatment and TetR in N. gonorrhoeae, using national surveillance data from three large sexual health services (SHS) in London during 2016-20. Doxycycline prescribing data and antibiograms of a non-STI pathogen from distinct patient groups (sexual health, obstetric and paediatric), at a large London hospital, were analysed to identify if doxycycline use in SHS was associated with resistance in a non-STI organism. RESULTS: A substantial increase in TetR was observed, particularly in isolates from gay, bisexual and other MSM (GBMSM). Strong positive correlations were observed exclusively in GBMSM between N. gonorrhoeae TetR and both bacterial STI tests (r = 0.97, P = 0.01) and antimicrobial treatment (r = 0.87, P = 0.05). Doxycycline prescribing increased dramatically during the study period in SHS. Prevalence of TetR in Staphylococcus aureus was higher in isolates sourced from SHS attendees than those from other settings. CONCLUSIONS: Frequent screening of GBMSM at higher risk of STIs, such as those on pre-exposure prophylaxis (PrEP) leading to/and increased use of doxycycline for the treatment of diagnosed infections, may account for the increase in TetR in N. gonorrhoeae.

Detection of 10 cases of ceftriaxone-resistant Neisseria gonorrhoeae in the United Kingdom, December 2021 to June 2022.

Between December 2021 and June 2022, 10 cases of ceftriaxone-resistant Neisseria gonorrhoeae (ST8123; n = 8) were detected in the United Kingdom, compared with nine cases during the previous 6 years. Most of these cases were associated with travel from the Asia-Pacific region; all were heterosexual people, with most in their 20s. Although all cases were successfully treated, not all partners of cases could be traced, and there is a risk of further transmission of ceftriaxone-resistant gonococcal infection within the UK.

Antimicrobial-resistant gonorrhoea: the national public health response, England, 2013 to 2020.

Neisseria gonorrhoeae has developed resistance to all antimicrobials used to treat gonorrhoea, and the emergence of ceftriaxone-resistant strains threatens the last-line option for empirical treatment. The 2013 Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) Action Plan recommended measures to delay the spread of antimicrobial resistance (AMR) in N. gonorrhoeae in England. We reviewed trends in gonococcal AMR since then and the experience of implementing the Action Plan's recommendations to respond to incidents of resistant N. gonorrhoeae. Between 2013 and 2019, diagnoses of gonorrhoea in England rose by 128% to 70,922, the largest annual number ever reported. Over this period, N. gonorrhoeae isolates have become less susceptible to azithromycin (minimum inhibitory concentration > 0.5 mg/L), increasing from 4.7% in 2016 to 8.7% in 2020; this led to a change in first-line treatment for gonorrhoea in the United Kingdom (UK) from dual therapy (ceftriaxone/azithromycin) to ceftriaxone monotherapy in 2019. We also detected the first global treatment failure for pharyngeal gonorrhoea with a dual-therapy regimen (ceftriaxone/azithromycin), followed by an additional six ceftriaxone-resistant strains. Continued engagement of sexual health clinicians and laboratories with the UK Health Security Agency (UKHSA) is essential for the timely detection of N. gonorrhoeae strains with ceftriaxone resistance and to rapidly contain transmission of these strains within England.

Podocyte-derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36.

Tubulointerstitial fibrosis is a hallmark of advanced diabetic kidney disease that is linked to a decline in renal function, however the pathogenic mechanisms are poorly understood. Microparticles (MPs) are 100-1000 nm vesicles shed from injured cells that are implicated in intercellular signalling. Our lab recently observed the formation of MPs from podocytes and their release into urine of animal models of type 1 and 2 diabetes and in humans with type 1 diabetes. The purpose of the present study was to examine the role of podocyte MPs in tubular epithelial cell fibrotic responses. MPs were isolated from the media of differentiated, untreated human podocytes (hPODs) and administered to cultured human proximal tubule epithelial cells (PTECs). Treatment with podocyte MPs increased p38 and Smad3 phosphorylation and expression of the extracellular matrix (ECM) proteins fibronectin and collagen type IV. MP-induced responses were attenuated by co-treatment with the p38 inhibitor SB202190. A transforming growth factor beta (TGF-ß) receptor inhibitor (LY2109761) blocked MP-induced Smad3 phosphorylation and ECM protein expression but not p38 phosphorylation suggesting that these responses occurred downstream of p38. Finally, blockade of the class B scavenger receptor CD36 completely abrogated MP-mediated p38 phosphorylation, downstream Smad3 activation and fibronectin/collagen type IV induction. Taken together our results suggest that podocyte MPs interact with proximal tubule cells and induce pro-fibrotic responses. Such interactions may contribute to the development of tubular fibrosis in glomerular disease.

Microparticle Formation in Peritoneal Dialysis: A Proof of Concept Study.

BACKGROUND: Injury to the mesothelial layer of the peritoneal membrane during peritoneal dialysis (PD) is implicated in loss of ultrafiltration capacity, but there are no validated biomarkers for mesothelial cell injury. Microparticles (MPs) are 0.1 to 1.0 µm membrane vesicles shed from the cell surface following injury and are sensitive markers of tissue damage. Formation of MPs in the peritoneal cavity during PD has not been reported to date. METHODS: We designed a single-center, proof of concept study to assess whether peritoneal solution exposure induces formation of mesothelial MPs suggestive of PD membrane injury. We examined MP levels in PD effluents by electron microscopy, nanoparticle tracking analysis (NTA), flow cytometry, procoagulant activity, and Western blot. RESULTS: NTA identified particles in the size range of 30 to 900 nm, with a mean of 240 (SE: 10 nm). MP levels increased in a progressive manner during a 4-hour PD dwell. Electron microscopy confirmed size and morphology of vesicles consistent with characteristics of MPs as well as the presence of mesothelin on the surface. Western blot analysis of the MP fraction also identified the presence of mesothelin after 4 hours, suggesting that MPs found in PD effluents may arise from mesothelial cells. CONCLUSIONS: Our results suggest that MPs are formed and accumulate in the peritoneal cavity during PD, possibly as a stress response. Assessing levels of MPs in PD effluents may be useful as a biomarker for peritoneal membrane damage.

CONTEXTE: Les lésions causées à la couche mésothéliale de la membrane péritonéale au cours d'une dialyse péritonéale (DP) sont impliquées dans la perte de capacité d'ultrafiltration. Toutefois, il n'existe aucun biomarqueur validé permettant la détection de ces lésions. Les microparticules (MP) sont des vésicules membranaires de 0,1 à 1,0 µm qui se détachent de la surface des cellules à la suite des lésions. Les microparticules sont sensibles aux marqueurs de dommages tissulaires. À ce jour, la formation de microparticules dans la cavité péritonéale au cours de la DP n'a pas été observée. MÉTHODOLOGIE: Nous avons conçu une étude de preuve de concept que nous avons menée dans un seul centre. Nous voulions déterminer si l'exposition à la solution de dialyse péritonéale induisait la formation de microparticules mésothéliales, ce qui pourrait indiquer la présence de dommages membranaires provoqués par la DP. Nous avons mesuré les taux de microparticules dans les effluents de la DP par microscopie électronique, par analyse du suivi individuel de particules (Nanoparticle Tracking Analysis­NTA), en cytométrie de flux, par la mesure de l'activité pro-coagulante et par Western Blot. RÉSULTATS: L'analyse par NTA a identifié des particules allant de 30 à 900 nanomètres, dont le diamètre moyen était de 240 ±10 nanomètres. Les taux de MP ont augmenté d'une façon progressive au cours des quatre heures que durait la DP. La microscopie électronique a confirmé la taille et la morphologie de vésicules conformes aux caractéristiques des MP, de même que la présence de mésothéline en surface. L'analyse par Western Blot de fragments de MP a également indiqué la présence de mésothéline après 4 heures, ce qui suggère que les microparticules recueillies dans les effluents de dialyse pourraient provenir de cellules mésothéliales. CONCLUSIONS: Nos résultats suggèrent que des microparticules sont formées au cours de la DP et qu'elles s'accumulent dans la cavité péritonéale, possiblement en réponse au stress. Par conséquent, la mesure des taux de microparticules dans les effluents de DP pourrait s'avérer un bon biomarqueur pour indiquer la présence de lésions dans la membrane péritonéale.