推動使用抗生素預防性傳播感染引起關注

該策略已被證明可以減少性傳播感染，但可能會增加抗生素耐藥性。

資料來源：Dyani Lewis / 新聞 / 2022 年 11 月 23 日 / 自然 / 財團法人台灣紅絲帶基金會編譯

 

 

淋病細菌（如圖）對某些抗生素具有耐藥性。圖片：SPL

 

美國的一個衛生部門率先建議性傳播感染 (STI) 高危人群在無保護性行為後服用預防劑量的抗生素。臨床試驗表明，該策略可以減少衣原體、梅毒和淋病等感染。但一些研究人員擔心它會導致抗生素耐藥性。

上個月，舊金山公共衛生部建議高感染風險人群在無保護性行為後服用一劑抗生素多喜黴素(doxycycline)，以預防細菌性性傳播感染。

在過去十年中，細菌性 STI 的發病率一直在穩步攀升，尤其是在男男性行為者 (MSM) 中。「我們沒有任何工具可以降低 [細菌] 性傳播感染的發生率，除了要求人們使用保險套」，包括口交時，巴黎大學的傳染病醫師 Jean-Michel Molina 說。

莫利納 (Molina) 領導了多喜黴素暴露後預防的首次試驗——一種稱為 doxyPEP 的預防性治療策略——於 2018 年報告了結果。在該試驗中，於九個多月後使用多喜黴素的人中有 22% 感染了 STI，而沒有使用多喜黴素的人中有 44% 感染了 STI。抗生素的使用使參與者的衣原體感染減少了 70%，梅毒感染減少了 73%。淋病感染並沒有顯著減少。

DoxyPEP 類似於在無保護性行為前服用抗病毒藥物以預防 HIV 感染的非常成功的策略——稱為 HIV-PrEP。服用 HIV-PrEP 可將透過性行為感染 HIV 的風險降低約 99%。

試驗成功

在另一項名為 DoxyPEP 的試驗的中期結果於 7 月下旬在蒙特婁舉行的國際愛滋病大會上公佈後，舊金山採用了該政策。該試驗涉及感染 HIV 或服用 HIV-PrEP 的 MSM 和跨性別女性，該試驗被提前終止，因為在無保護性行為後服用多喜環素對減少性傳播感染非常有效。由加利福尼亞大學舊金山分校的傳染病醫生 Annie Luetkemeyer 領導的試驗中的每個人都接受了 doxyPEP。在服用 doxyPEP 的患者中，每三個月的衣原體和梅毒感染率降低了 70% 以上，淋病感染率降低了 55%。在沒有服用 doxyPrep 的人群中，每個季度約有 30% 的人感染了一種或多種 STI。

如果不及時治療，男性梅毒會導致嚴重的健康問題，例如失明和神經損傷。男性的衣原體和淋病感染很少會很嚴重，但在女性中，它們會導致不孕。梅毒可以傳染給未出生的孩子，導致出生時患有這種疾病的嬰兒流產、死產或大腦和器官受損。

但研究人員對僅有 MSM 的有效性證據是否足以做出正式推出 doxyPEP 的決定仍存在分歧。倫敦大學學院的性健康醫師兼研究員 Manik Kohli 表示，需要來自多項試驗的更多數據來證明 doxyPEP 是否會導致抗生素耐藥性。

與舊金山公共衛生局相比，其他司法管轄區採取了更為謹慎的態度，後者沒有回應《自然》雜誌的置評請求。英國衛生安全局和英國性健康與愛滋病協會表示，他們不認可用於預防梅毒或衣原體的 doxyPEP 策略，部分原因是缺乏抗生素耐藥性的數據。

面對阻力

當暴露於抗生素時，具有耐藥性並存活下來的細菌會傳播。比利時安特衛普熱帶醫學研究所的微生物學家 Chris Kenyon 說，使用多喜黴素預防感染會大大增加一個人接觸抗生素的機會，這可能會產生耐藥性。在 DoxyPEP 試驗中，一些參與者每月服用 20 多劑多喜黴素，Kenyon 將其描述為「天文數字」。

多喜黴素是一種「極其重要」的抗生素，可用於治療其他疾病，包括由金黃色葡萄球菌引起的皮膚感染和細菌性肺炎，Kenyon 說。他說，DoxyPEP 可能會導致導致這些感染的細菌出現抗生素耐藥性，並限制治療選擇。

他說，醫護人員在開抗生素處方作為預防性治療時應採取預防措施，尤其是在 MSM 中。如果抗生素使用率高，他們是出現抗生素耐藥性的關鍵人群，因為人們往往有多個性伴侶和性網絡，這增加了耐藥細菌傳播的機會。性工作者是過去出現過抗生素耐藥性的另一個群體。

對四環素類抗生素（包括多喜黴素）的耐藥性在淋病中已經很常見。在美國，大約 25% 的淋病病例是由四環素耐藥細菌引起的。在其他地方，耐藥率更高，據研究報告，歐洲的耐藥率接近 60% 或 70%。

Molina 預計 doxyPEP 對淋病的有效性將取決於當地社區的耐藥率，並且隨著耐藥水平的升高可能會隨著時間的推移而下降其有效性。

但 Luetkemeyer 說，法國第二項名為 DOXYVAC 的試驗的早期結果顯示，多喜黴素可以減少淋病感染——儘管耐藥性水平很高。結果顯示，該藥物仍然可以防止感染發生，即使它不能有效治療已確定的感染。「預防疾病所需的藥物通常比治癒疾病所需的藥物少得多」，她說。

其他感染

衣原體或梅毒尚未出現多喜黴素耐藥性。 Molina 說，弄清楚 doxyPEP 是否會導致這些感染產生耐藥性可能需要數年時間。

Luetkemeyer 和她的同事收集了拭子和糞便樣本，以了解使用多喜黴素作為預防工具的人是否會改變生活在腸道中的微生物群落或增加抗生素耐藥性。這些結果將在 2023 年 2 月的一次會議上公佈。Luetkemeyer 還指出，社區中還有其他多喜黴素來源可能會導致耐藥性。

一種希望是，在 MSM 中使用 doxyPEP 可以降低更廣泛社區（包括受衣原體和淋病感染影響最大的女性）的細菌性性傳播感染率，就像 HIV-PrEP 在高收入國家對 HIV 所做的那樣。

但 Kenyon 懷疑 doxyPEP 是否會降低 STI 發生率，即使在大規模介入後，STI 發生率仍可能居高不下。在 1990 年代後期，為消除溫哥華爆發的梅毒爆發而使用抗生素阿奇黴素 (azithromycin，紅黴素的一種) 進行的大規模治療運動最初降低了感染率，但很快就反彈了。

仿單外使用

他說，自從 Molina 和他的同事在 2018 年發表了第一項 doxyPEP 研究的結果以來，人們一直在仿單外使用多喜黴素作為預防工具。 Kenyon 擔心 doxyPEP 可能會使人們接觸抗生素數年甚至數十年。

Kohli 說，對於已經在使用 doxyPEP 的人來說，公共衛生建議不太可能說服他們停止使用。在 Luetkemeyer 於 7 月在國際多愛滋病大會上發表演講後，美國疾病控制與預防中心發布了指導 doxyPEP 使用的信息。一位發言人告訴《自然》雜誌，該機構將在最終數據發布和審查後發布後續指引。

在明尼蘇達州明尼阿波利斯的 Hennepin Healthcare的性健康醫師珍妮爾·斯圖爾特 (Jenell Stewart) ，斯圖爾特正在肯亞領導一項針對服用 HIV-PrEP 的女性的多喜黴素預防試驗。

儘管存在未知數，但斯圖爾特表示，收益大於風險。「如果對他們及他們的生活方式有意義，人們應該要有途徑去使用這個工具」，她說。

 

doi: https://doi.org/10.1038/d41586-022-03801-6

參考文獻：

1. Molina, J.-M. et al. 《刺胳針感染症》。18, 308–317 (2018)。

2. Rekart, M. L. et al. 《刺胳針》。 361, 313–314 (2003)。

3. Merrick, R. et al. 《歐盟監測》。 27, 2200057 (2022).

4. Stewart, J. et al. 《試驗》23、495（2022 年）。

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Push to use antibiotics to prevent sexually transmitted infections raises concerns

The strategy has been shown to reduce STIs, but could increase antimicrobial resistance.

Dyani Lewis / NEWS / 23 November 2022 / Nature

 

 

 

Gonorrhoea bacteria (pictured) has development resistance to some antibiotics. Credit: SPL

A health department in the United States has become one of the first to recommend that people who are at high risk of getting a sexually transmitted infection (STI) take a preventive dose of antibiotics after unprotected sex. Clinical trials have shown the strategy can reduce infections such as chlamydia, syphilis and gonorrhoea. But some researchers worry it will contribute to antibiotic resistance.

Last month, the San Francisco Department of Public Health recommended that people at high risk of infection take a dose of the antibiotic doxycycline after unprotected sex to prevent bacterial STIs.

Rates of bacterial STIs have been climbing steadily over the past decade, particularly in men who have sex with other men (MSM). “We don’t have any tool to reduce the rate of [bacterial] STIs, except asking people to use condoms,” including for oral sex, says infectious-diseases physician Jean-Michel Molina at the University of Paris.

Molina led the first trial of doxycycline post-exposure prophylaxis ― a preventive-treatment strategy known as doxyPEP ― which reported results in 2018. In that trial, 22% of those using doxyPEP, and 44% who were not, were infected with an STI over nine months. Antibiotic use led to a 70% reduction in chlamydia infections and a 73% reduction in syphilis infections in participants. Gonorrhoea infections weren’t substantially reduced.

DoxyPEP is similar to the hugely successful strategy of taking antivirals before unprotected sex to prevent infection from HIV ― known as HIV-PrEP. Taking HIV-PrEP reduces the risk of getting HIV from sex by about 99%.

Trial success

San Francisco adopted the policy after interim results from another trial ― called DoxyPEP ― were presented at the International AIDS Conference in Montreal in late July. That trial, involving MSM and transgender women either living with HIV or taking HIV-PrEP, was stopped early because taking doxycycline after unprotected sex was so effective at reducing STIs. Everyone enrolled in the trial, led by infectious-diseases physician Annie Luetkemeyer at the University of California, San Francisco, was then offered doxyPEP. Chlamydia and syphilis infections were more than 70% lower, and gonorrhoea infections were 55% lower in each three-month period in those who took doxyPEP. In people who didn’t take doxyPrep, around 30% were infected with one or more STI each quarter.

Syphilis in men can cause serious health problems, such as blindness and nerve damage if left untreated. Chlamydia and gonorrhoea infections in men are rarely serious, but in women, they can lead to infertility. And syphilis can pass to unborn children and cause miscarriage, still birth, or brain and organ damage in babies born with the disease.

But researchers are divided about whether the evidence of effectiveness in MSM alone is enough to make the decision to officially roll-out doxyPEP. Manik Kohli, a sexual-health physician and researcher at University College London, says more data from multiple trials are required to show whether doxyPEP drives antibiotic resistance.

Other jurisdictions are taking a more cautious approach than the San Francisco Department of Public Health, who did not respond to Nature’s request for comment. The UK Health Security Agency and the British Association for Sexual Health and HIV state they do not endorse the doxyPEP strategy for prevention of syphilis or chlamydia, in part because of a lack of data on antimicrobial resistance.

Facing resistance

When exposed to antibiotics, bacteria that harbour resistance and survive can spread. Chris Kenyon, a microbiologist at the Institute of Tropical Medicine in Antwerp, Belgium, says that using doxycycline to prevent infections drastically increases a person’s exposure to the antibiotic, which could drive resistance. In the DoxyPEP trial, some participants took more than 20 doses of doxycycline each month, an amount that Kenyon describes as “astronomical”.

Doxycycline is a “critically important” antibiotic for treating other conditions, including skin infections caused by Staphylococcus aureus and bacterial pneumonia, says Kenyon. DoxyPEP could lead to the emergence of antibiotic resistance in the bacteria that cause these infections and limit treatment options, he says.

He says that health-care workers should take a precautionary approach when prescribing antibiotics as a preventive treatment, particularly among MSM. They are a key population for the emergence of antibiotic resistance if antibiotic use is high, because people tend to have multiple sex partners and networks that increase the chance of resistant bacteria spreading. Sex workers are another group in which antimicrobial resistance has emerged in the past.

Resistance to tetracycline-class antibiotics, which includes doxycycline, is already common for gonorrhoea. In the United States, around 25% of gonorrhoea cases are caused by tetracycline-resistant bacteria. Elsewhere, rates of resistance are higher, with studies reporting rates closer to 60% or 70% in Europe.

Molina expects that the effectiveness of doxyPEP against gonorrhoea will depend on the rates of resistance in the local community and will probably decline over time as resistance levels rise.

But Luetkemeyer says that early results from a second French trial, called DOXYVAC, show doxycycline reduces gonorrhoea infections ― in spite of high resistance levels. The results suggest that the drug still prevents an infection from taking hold, even if it is ineffective at treating an established infection. “It often takes a lot less of a drug to prevent a disease than it does to cure a disease,” she says.

Other infections

Doxycycline resistance has not emerged in chlamydia or syphilis. Working out whether doxyPEP leads to resistance in these infections could take years, says Molina.

Luetkemeyer and her colleagues have collected swab and stool samples to see if people using doxycycline as a preventive tool alters the community of microorganisms that live in the gut or increases antibiotic resistance. Those results will be presented at a conference in February 2023. Luetkemeyer also notes that there are other sources of doxycycline in the community that could contribute to resistance.

One hope is that doxyPEP use in MSM could lower rates of bacteria STIs in the broader community ― including in women, who bear the greatest effects of chlamydia and gonorrhoea infections ― just as HIV-PrEP has done for HIV in high-income countries.

But Kenyon is sceptical that doxyPEP will lower STI rates, which can remain stubbornly high even after large-scale interventions. In the late 1990s, a mass treatment campaign with the antibiotic azithromycin to eliminate an outbreak of syphilis in Vancouver lowered rates initially, but they soon rebounded.

Off-label use

Since Molina and his colleagues published results of the first doxyPEP study in 2018, people have been using doxycycline off-label as a preventive tool, he says. Kenyon fears that doxyPEP could expose people to the antibiotic for years or even decades.

For people already using doxyPEP, public-health recommendations are unlikely to convince them to stop, says Kohli. Following Luetkemeyer’s presentation at the International AIDS Conference in July, the US Centers for Disease Control and Prevention published information to guide the use of doxyPEP. The agency will publish subsequent guidance when the final data is published and reviewed, a spokesperson told Nature.

Guidelines about use are important for informing people about the safety of a strategy they might already be using, and making preventive treatment available to people who might not be in a position to advocate for doxyPEP on their own, says sexual-health physician Jenell Stewart at Hennepin Healthcare in Minneapolis, Minnesota. Stewart is leading a trial of doxycycline prophylaxis in Kenya for women taking HIV-PrEP.

Despite the unknowns, Stewart says that the benefits outweigh the risks. “People should have access to this tool, if it makes sense for them and their lifestyle,” she says.

doi: https://doi.org/10.1038/d41586-022-03801-6

References

1.Molina, J.-M. et al. Lancet Infect. Dis. 18, 308–317 (2018).

2.Rekart, M. L. et al. Lancet 361, 313–314 (2003).

3.Merrick, R. et al. Euro Surveill. 27, 2200057 (2022).

4.Stewart, J. et al. Trials 23, 495 (2022).