Kenyon Chris, Gestels Zina, Vanbaelen Thibaut, Abdellati Said, Van Den Bossche Dorien, De Baetselier Irith, Xavier Basil Britto, Manoharan-Basil Sheeba Santhini
STI Unit, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
Division of Infectious Diseases and HIV Medicine, University of Cape Town, Cape Town, South Africa.
Front Microbiol. 2023 Aug 30;14:1208014. doi: 10.3389/fmicb.2023.1208014. eCollection 2023.
Four randomized controlled trials have now established that doxycycline post exposure (sex) prophylaxis (PEP) can reduce the incidence of chlamydia and syphilis in men who have sex with men. These studies have concluded that the risk of selecting for antimicrobial resistance is low. We evaluated this risk and using a infection model.
We evaluated how long it took for doxycycline resistance to emerge during passage on doxycycline containing agar plates in 4 species - , , and . We then assessed if could acquire resistance to doxycycline (and cross resistance to other antimicrobials) during intermittent exposure to doxycycline in a model of doxycycline PEP.
In our passage experiments, we found that resistance first emerged in . By day 7 the MIC had increased from 2 mg/L to a median of 96 mg/L (IQR 64-96). Under various simulations of doxycycline PEP in the G. mellonella model, the doxycycline MIC of increased from 2 mg/L to 48 mg/L (IQR 48-84). Ceftriaxone and ciprofloxacin MICs increased over ten-fold. Whole genome sequencing revealed acquired mutations in ramR which regulates the expression of the AcrAB-TolC efflux pump.
Doxycycline PEP can select for doxycycline, ceftriaxone and ciprofloxacin resistance in in a G. mellonella model. The emergent ramR mutations were similar to those seen in circulating strains of . These findings suggest that we need to assess the effect of doxycycline PEP on resistance induction on a broader range of bacterial species than has hitherto been the case.
四项随机对照试验现已证实，多西环素暴露后（性行为）预防（PEP）可降低男男性行为者中衣原体和梅毒的发病率。这些研究得出结论，选择产生抗菌药物耐药性的风险较低。我们使用感染模型评估了这一风险。
我们评估了在含有多西环素的琼脂平板上传代过程中，四种菌株（具体菌株未给出）对多西环素耐药性出现所需的时间。然后，我们评估了在多西环素PEP的黄粉虫模型中间歇暴露于多西环素期间，该菌株是否会获得对多西环素的耐药性（以及对其他抗菌药物的交叉耐药性）。
在我们的传代实验中，我们发现耐药性首先在（具体菌株未给出）中出现。到第7天，该菌株的最低抑菌浓度（MIC）从2mg/L增加到中位数96mg/L（四分位间距64 - 96）。在黄粉虫模型中多西环素PEP的各种模拟情况下，该菌株的多西环素MIC从2mg/L增加到48mg/L（四分位间距48 - 84）。头孢曲松和环丙沙星的MIC增加了十倍以上。全基因组测序显示，调节AcrAB - TolC外排泵表达的ramR基因发生了获得性突变。
在黄粉虫模型中，多西环素PEP可导致该菌株对多西环素、头孢曲松和环丙沙星产生耐药性。出现的ramR突变与在该菌株流行株中观察到的突变相似。这些发现表明，我们需要在比以往更广泛的细菌物种范围内评估多西环素PEP对耐药性诱导的影响。
