Division of Pulmonary and Critical Care Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California, San Francisco, 1001 Potrero Avenue, Rm 5K1, San Francisco, CA, 94110-0111, USA.
Department of Epidemiology and Biostatistics, UCSF, San Francisco, CA, USA.
BMC Infect Dis. 2021 Jan 22;21(1):99. doi: 10.1186/s12879-020-05738-5.
Treatment monitoring of drug-resistant tuberculosis (DR-TB) in resource-limited settings is challenging. We developed a multi-analyte assay for eleven anti-TB drugs in small hair samples as an objective metric of drug exposure.
Small hair samples were collected from participants at various timepoints during directly observed RR-TB treatment at an inpatient tertiary referral facility in South Africa (DR-TB cohort). We assessed qualitative determination (i.e., detection above limit of detection) of bedaquiline, linezolid, clofazimine, pretomanid, levofloxacin, moxifloxacin, pyrazinamide, isoniazid, ethambutol, ethionamide, and prothionamide in an LC-MS/MS index panel assay against a reference standard of inpatient treatment records. Because treatment regimens prior to hospitalization were not available, we also analyzed specificity (for all drugs except isoniazid) using an external cohort of HIV-positive patients treated for latent TB infection with daily isoniazid (HIV/LTBI cohort) in Uganda.
Among the 57 DR-TB patients (58% with pre-XDR/XDR-TB; 70% HIV-positive) contributing analyzable hair samples, the sensitivity of the investigational assay was 94% or higher for all drugs except ethionamide (58.5, 95% confidence interval [CI], 40.7-99.9). Assay specificity was low across all tested analytes within the DR-TB cohort; conversely, assay specificity was 100% for all drugs in the HIV/LTBI cohort.
Hair drug concentrations reflect long-term exposure, and multiple successive regimens commonly employed in DR-TB treatment may result in apparent false-positive qualitative and falsely elevated quantitative hair drug levels when prior treatment histories within the hair growth window are not known.
在资源有限的环境中，耐药结核病（DR-TB）的治疗监测具有挑战性。我们开发了一种小型毛发样本中的 11 种抗结核药物的多分析物测定法，作为药物暴露的客观指标。
在南非的一家三级转诊医院，对接受直接观察 RR-TB 治疗的参与者在治疗过程中的各个时间点采集小型毛发样本（DR-TB 队列）。我们评估了 LC-MS/MS 索引面板测定法中-bedaquiline、linezolid、clofazimine、pretomanid、levofloxacin、moxifloxacin、pyrazinamide、isoniazid、ethambutol、ethionamide 和 prothionamide-定性测定（即检测超过检测限）的情况，同时还使用乌干达 HIV 阳性患者潜伏性结核病感染的每日异烟肼治疗（HIV/LTBI 队列）的住院治疗记录参考标准来评估了除异烟肼以外所有药物的特异性。由于无法获得住院前的治疗方案，我们还分析了除异烟肼以外所有药物的特异性（HIV/LTBI 队列）。
在 57 名 DR-TB 患者（58%为预 XDR/XDR-TB；70%为 HIV 阳性）中，该研究测定法对除 ethionamide（58.5，95%置信区间 [CI]，40.7-99.9）以外的所有药物的敏感性均为 94%或更高。在 DR-TB 队列中，所有检测分析物的测定法特异性均较低；相反，在 HIV/LTBI 队列中，所有药物的测定法特异性均为 100%。
毛发中的药物浓度反映了长期暴露情况，在未知毛发生长窗内的既往治疗史的情况下，DR-TB 治疗中通常采用的多种连续方案可能导致明显的假阳性定性和假性升高的毛发药物水平。
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