Post-exposure prophylaxis (PEP) efficacy of rifampin, rifapentine, moxifloxacin, minocycline, and clarithromycin in a susceptible-subclinical model of leprosy
Post-exposure prophylaxis (PEP) efficacy of rifampin, rifapentine, moxifloxacin, minocycline, and clarithromycin in a susceptible-subclinical model of leprosy
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DOI：
10.1371/journal.pntd.0008583
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发表时间：
2020-09-01
影响因子：
3.8
通讯作者：
Adams, Linda B.
中科院分区：
文献类型：
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作者：
Lenz, Shannon M.;Collins, Jaymes H.;Adams, Linda B.
虽然多种药物治疗（MDT）已成功地降低了麻风病的全球流行率，但新病例发现率或发病率仍然保持一致。这些情况表明麻风病的传播仍在发生。亚临床无症状麻风感染被认为是持续传播的主要原因。控制这一来源的一种手段是有效的接触后预防（PEP）方案，这将防止个人随后发展为临床麻风病并将疾病传播给他人。因此，在这项研究中，我们使用了一种改良的动力学小鼠足垫筛选试验和敏感的分子细菌计数在一个易感的亚临床小鼠模型，以确定有效的潜在PEP药物治疗麻风病的方案。使用这些方法，我们发现单剂量PEP方案在易感宿主中无效，需要多次间歇剂量的联合治疗。该模型可为PEP方案的制定提供有用的临床前信息。背景麻风分枝杆菌亚临床感染是麻风传播的一个潜在来源，暴露后预防（PEP）方案已被提出来控制这一来源。由于PEP试验需要相当大的投资，我们应用了一个敏感的变化的动力学小鼠足垫（MFP）筛选试验，以帮助选择药物和方案的临床试验。方法学/主要发现无胸腺裸鼠在足垫（FP）中接种6 × 10（3）个活麻风杆菌，并通过胃管饲法给予单剂量利福平（SDR）、利福平+氧氟沙星+米诺环素（SD-ROM）或利福平+米诺环素+莫西沙星（SD-PMM）或拟定PEP++方案的三个每月一次剂量的利福平+莫西沙星（RM），利福平+克拉霉素（RC）、利福喷丁+莫西沙星（PM）或利福喷丁+克拉霉素（PC）。在处理后的不同时间，从FP中纯化DNA，并通过RLEP定量PCR计数麻风分枝杆菌。计算回归分析，以确定预期的RLEP值，如果99.9%的杆菌被杀死后，每一个方案的管理。SDR和SD-ROM在这种高度易感的亚临床感染小鼠模型中诱导很少的生长延迟。相比之下，SD-PMM将接种物上方可测量的麻风杆菌生长延迟了8个月。四种多剂量方案在治疗停止后延迟细菌生长> 9个月。结论/意义治疗后可辨别的麻风杆菌生长延迟是早期（3-4个月）和晚期（8-9个月）药物疗效的良好指标。我们的数据表明，可能需要多剂量PEP来控制亚临床麻风高度易感个体的感染，以预防疾病并减少传播。
Author summary While multi-drug therapy (MDT) has been successful in decreasing the worldwide prevalence of leprosy, the new case detection rate, or incidence, remains consistent. These circumstances indicate that leprosy transmission is still occurring. Subclinical asymptomatic leprosy infections are considered a leading cause of ongoing transmission. One means to control this source is an effective post-exposure prophylaxis (PEP) regimen that would prevent both subsequent progression to clinical leprosy for the individual and transmission of the disease to others. Therefore, in this study, we used a modified kinetic mouse footpad screening assay and sensitive molecular bacterial enumeration in a susceptible-subclinical mouse model to identify effective potential PEP drug regimens for leprosy. Using these methods, we showed that a single dose PEP regimen is not effective in a susceptible host, and multiple intermittent doses of combination therapies are required. This model could provide useful pre-clinical information for the development of PEP regimens for leprosy.Background Subclinical infection withMycobacterium lepraeis one potential source of leprosy transmission, and post-exposure prophylaxis (PEP) regimens have been proposed to control this source. Because PEP trials require considerable investment, we applied a sensitive variation of the kinetic mouse footpad (MFP) screening assay to aid in the choice of drugs and regimens for clinical trials. Methodology/Principal findings Athymic nude mice were inoculated in the footpad (FP) with 6 x 10(3)viableM.lepraeand treated by gastric gavage with a single dose of Rifampin (SDR), Rifampin + Ofloxacin + Minocycline (SD-ROM), or Rifapentine + Minocycline + Moxifloxacin (SD-PMM) or with the proposed PEP++ regimen of three once-monthly doses of Rifampin + Moxifloxacin (RM), Rifampin + Clarithromycin (RC), Rifapentine + Moxifloxacin (PM), or Rifapentine + Clarithromycin (PC). At various times post-treatment, DNA was purified from the FP, andM.lepraewere enumerated by RLEP quantitative PCR. A regression analysis was calculated to determine the expected RLEP value if 99.9% of the bacilli were killed after the administration of each regimen. SDR and SD-ROM induced little growth delay in this highly susceptible murine model of subclinical infection. In contrast, SD-PMM delayed measurableM.lepraegrowth above the inoculum by 8 months. The four multi-dose regimens delayed bacterial growth for >9months post-treatment cessation. Conclusions/Significance The delay in discernableM.lepraegrowth post-treatment was an excellent indicator of drug efficacy for both early (3-4 months) and late (8-9 months) drug efficacy. Our data indicates that multi-dose PEP may be required to control infection in highly susceptible individuals with subclinical leprosy to prevent disease and decrease transmission.