使用多西環素暴露後預防(doxycycline postexposure prophylaxis)奈瑟菌淋病

對頭孢曲​​松(ceftriaxone)耐藥性之選擇

資料來源：www.thelancet.com/infection Vol 23 August 2023

     越來越多的證據顯示，多西環素暴露後預防(doxy-PEP) 可有效預防高危患者中的性傳播感染，尤其是使用HIV 暴露前預防的患者。然而，必須權衡這一益處與潛在風險，包括抗菌藥物耐藥性的選擇。 Vanbaelen 及其同事使用 2018 年 Euro-GASP 調查中 2,375 個淋病球菌分離株的全基因組測序數據顯示，淋病奈瑟菌四環素耐藥相關突變和基因通常與其他抗菌素耐藥標記共同選擇。此外，作者強調，在不存在多西環素或四環素耐藥性的情況下，doxy-PEP 還可以與其他抗菌藥物耐藥性共同選擇。 耐藥性一旦建立，就會與許多基因組骨幹或基因型上的強烈克隆傳播相關。在這項研究中，基因組基因型包括公認的與頭孢曲松 (ceftriaxone) 敏感性降低有關的 G1407 基因組。頭孢曲松是全球淋病奈瑟菌治療的中流砥柱，有關於攜帶penA60 的頭孢曲松耐藥菌株激增的新報告。我們試圖更好地了解透過多西環素治療在淋病奈瑟菌對頭孢曲​​松耐藥選擇上的潛力。

     首先，我們回顧了迄今為止報導的帶有 penA60 的頭孢曲松耐藥菌株的已發表數據（附錄第 1、2 頁）。 這些數據顯示，當 2015 年在日本首次報導時，這些菌株對四環素敏感。自這起最初的病例以來，已經發表了 32 份 penA60（以及最近出現的密切相關的 penA237）報告。 總共，這需要來自 14 個國家的 96 個分離株或菌株，並且在 96 個報告菌株中的 75 個 (78·1%) 有四環素敏感性數據。在報告的具有四環素耐藥性數據的菌株中，75 株中只有8 株(10·7%) 顯示出對四環素的敏感性，其中8 株(10·7%) 表現出中等敏感性，59 株(78·7%) 對四環素耐藥（使用EUCAST 和四環素的 CLSI 斷點）。其次，我們從PubMLST 檢索了所有分離株(n=4,346) 的數據，報告了完整的多位點序列類型和分類四環素敏感性。在62·9% 的報告分離株中觀察到四環素耐藥性，並且這種耐藥性很廣泛，發生在許多克隆背景中（附錄第 3 頁）。我們還對2015-22年報導的來自澳大利亞新南威爾士州的所有對頭孢曲松耐藥性或敏感性降低的淋病奈瑟菌分離株（MIC值≥0·125 mgL）進行了回顧性四環素最低抑菌濃度（MIC）檢測； 其66 株測試的淋病奈瑟菌分離株中有 64 株 (97%)具有四環素耐藥性。

     總體而言，這些數據增加了 Vanbaelen 及其同事提出的擔憂，並顯示對頭孢曲松敏感性或耐藥性降低的淋病奈瑟菌菌株通常表現出對四環素的雙重耐藥性。 因此，增加 doxy-PEP 的使用可能會選擇雙重耐藥菌株並增加頭孢曲松耐藥性。

     全球淋球菌頭孢曲松耐藥程度尚不清楚。鑑於已知抗菌藥物耐藥性監測在許多情況下是有限的，報告的分離株很可能僅代表淋病奈瑟菌多樣性的一小部分。儘管這些數據可能顯示 doxy-PEP對頭孢曲松耐藥性的選擇，但雙耐藥菌株的選擇發生的速度有多快尚不清楚。 這可能取決於許多因素，包括 doxy-PEP 使用的廣泛程度、使用人群（包括淋病球菌抗菌藥物耐藥性相關的循環概況）以及是否採取其他措施，例如透過增強淋病奈瑟菌抗菌藥物抗藥性監測來補充 doxy-PEP使用。 此外，抗生素選擇之壓力對循環中淋病奈瑟菌克隆產生的淨影響，特別是如果doxy-PEP策略僅針對高危人群，同樣亦尚不清楚（特別是考慮到抗生素的消耗，包括用於治療其他性傳播感染的多西環素，在高風險人群中可能已經高得多），當（無論有意或無意）抗菌藥物使用於doxy-PEP 無法預防的感染，以及這些感染對淋病球菌抗菌藥物耐藥性的貢獻等。

總體而言，需要仔細權衡使用 doxy-PEP 預防和治療性傳播感染的益處與雙重耐藥菌株的選擇和增加淋病奈瑟菌頭孢曲​​松耐藥性的風險。至少，需要考慮使用 doxy-PEP 加強對人群中淋病奈瑟菌耐藥性的監測，包括透過使用分子檢測策略和全基因組測序。

DMW 報告了來自 SpeeDx 的研究資助。 SpeeDx 對阻力引導治療特別感興趣。 SpeeDx 在本手稿的構思或起草中沒有任何作用。 DMW 得到昆士蘭州政府高級昆士蘭臨床研究獎學金的支持。 這項工作得到了澳大利亞研究委員會抗菌素耐藥性研究中心資助（計畫 ID：IH190100021）的支持。 澳大利亞淋球菌監測計畫得到澳大利亞政府衛生和老年照護部的支持。 其他作者聲明沒有競爭利益。

*David M Whiley、Jacob A Tickner、Ratan L Kundu、Tiffany R Hogan、Sebastiaan J van Hal、Monica M Lahra d.whiley@uq.edu.au

澳大利亞昆士蘭州布里斯班昆士蘭大學醫學院臨床研究中心（DMW、JAT）； 病理學昆士蘭中心實驗室，昆士蘭健康中心，澳大利亞昆士蘭州布里斯班 (DMW)； 世界衛生組織性傳播感染和抗菌素耐藥性合作中心、新南威爾斯州健康病理學微生物學、威爾斯親王醫院，澳大利亞新南威爾士州蘭德威克（RLK、TRH、MML）； 新南威爾斯州健康病理學、皇家阿爾弗雷德王子醫院傳染病和微生物學系，雪梨，新南威爾斯州 2050，澳大利亞 (SJvH)； 雪梨大學中央臨床學院，雪梨，新南威爾斯州 2006，澳大利亞 (SJvH)； 新南威爾斯大學醫學院，澳大利亞新南威爾斯州雪梨 (MML)

Selection of Neisseria gonorrhoeae ceftriaxone resistance using doxycycline postexposure prophylaxis

www.thelancet.com/infection Vol 23 August 2023

    There is increasing evidence that doxycycline post-exposure prophylaxis (doxy-PEP) is effective for preventing sexually transmitted infections among high-risk patients, particularly in patients using HIV preexposure prophylaxis. However, this benefit must be weighed against potential risks, including selection of antimicrobial resistance. Using whole genome sequencing data of 2375 gonococcal isolates from the 2018 Euro-GASP survey, Vanbaelen and colleagues showed that N gonorrhoeae tetracycline resistance associated mutations and genes are often co-selected with additional antimicrobial resistance markers. In addition, the authors highlighted that doxy-PEP can also select for other antimicrobial resistance in the absence of doxycycline or tetracycline resistance. Resistance, once established, is associated with strong clonal spread on many genomic backbones or genotypes. In this study, genomic genotypes included the well-recognised G1407 genogroup associated with decreased susceptibility to ceftriaxone. Ceftriaxone is the mainstay for N gonorrhoeae treatment globally and there are new reports concerning a surge of penA60-harboring ceftriaxone-resistant strains. We sought to better understand the potential for selection of N gonorrhoeae ceftriaxone resistance through doxycycline treatment.

    Firstly, we reviewed published data for penA60-harboring ceftriaxoneresistant strains reported to date (appendix pp 1, 2). These data show that these strains were susceptible to tetracycline when first reported in Japan in 2015. Since this initial case, 32 more penA60 (and the more recently emerged and closely related penA237) reports have been published. Combined, this entails 96 isolates or strains from 14 countries, with tetracycline susceptibility data available for 75 (78·1%) of 96 reported strains. Of strains with tetracycline resistance data reported, only eight (10·7%) of 75 showed susceptibility to tetracyclines, with eight (10·7%) showing intermediate susceptibility, and 59 (78·7%) resistant to tetracyclines (using EUCAST and CLSI breakpoints for tetracycline). Secondly, we retrieved data from PubMLST for all isolates (n=4346) reporting both a complete multilocus sequence type and categorical tetracycline susceptibility.8 Tetracycline resistance was observed in 62·9% of reported isolates and was widespread, occurring in many clonal backgrounds (appendix p 3). We also did retrospective tetracycline minimum inhibitory concentration (MIC) testing on all N gonorrhoeae isolates with decreased susceptibility or resistance to ceftriaxone (MIC values ≥0·125 mgL) from NSW, Australia, reported in 2015–22; and 64 (97%) 66 of these N gonorrhoeae isolates tested were tetracycline resistant.

    Overall, these data add weight to the concerns raised by Vanbaelen and colleagues4 and show that N gonorrhoeae strains with decreased susceptibility or resistance to ceftriaxone typically exhibit dual resistance to tetracyclines. Hence, there is a risk that increased use of doxy-PEP will select for dual resistant strains and increased ceftriaxone resistance.

    The extent of N gonorrhoeae ceftriaxone resistance globally is unknown. The isolates reported very probably represent only a fraction of N gonorrhoeae diversity, given that antimicrobial resistance surveillance is known to be limited in many settings. Although these data potentially point to doxy-PEP selecting for ceftriaxone resistance, how quickly selection of dual resistant strains would occur is unknown. It is likely that this will depend on many factors, including how widespread the doxy-PEP use is, the populations in which it is used (including associated circulating gonococcal antimicrobial resistance profiles), and whether additional measures are put in place, such as complementing doxy-PEP with enhanced N gonorrhoeae antimicrobial resistance surveillance. Furthermore, the net effects that antimicrobial selection pressure will have on the circulating N gonorrhoeae clones, especially if doxy-PEP strategies are only focused on high-risk populations, is likewise unclear (particularly given antibiotic consumption, including doxycycline for treatment of other STIs, might already be much higher in populations at high risk), as is the use of antimicrobials (either intentionally or incidentally) on infections that are not prevented by use of doxy-PEP, and the contribution of these infections to gonococcal antimicrobial resistance.

    Overall, the risk of selecting for dual resistant strains and increasing N gonorrhoeae ceftriaxone resistance needs to be carefully balanced against the benefits of using doxy-PEP to prevent and treat sexually transmitted infections. At the very least, consideration needs to be given to enhancing surveillance of N gonorrhoeae antimicrobial resistance in populations using doxy-PEP, including via the use of molecular testing strategies and whole genome sequencing.

DMW reports research funding from SpeeDx. SpeeDx has specific interest related to resistanceguided therapy. SpeeDx did not have any role in the conception or drafting of this manuscript. DMW is supported by an Advancing Queensland Clinical Research Fellowship from the Queensland Government. This work is supported by an Australian Research Council Hub grant for antimicrobial resistance (Project ID: IH190100021). The Australian Gonococcal Surveillance Programme is supported by the Australian Government Department of Health and Aged Care. The other authors declare no competing interests.

*David M Whiley, Jacob A Tickner, Ratan L Kundu, Tiffany R Hogan, Sebastiaan J van Hal, Monica M Lahra d.whiley@uq.edu.au

UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia (DMW, JAT); Pathology Queensland Central Laboratory, Queensland Health, Brisbane, Queensland, Australia (DMW); World Health Organization Collaborating Centre for STI and AMR, New South Wales Health Pathology Microbiology, The Prince of Wales Hospital, Randwick, New South Wales, Australia (RLK, TRH, MML); Department of Infectious Diseases and Microbiology, NSW Health Pathology, Royal Prince Alfred Hospital, Sydney, NSW 205