Simultaneous analysis of 11 medications for drug resistant TB in small hair samples to quantify adherence and exposure using a validated LC-MS/MS panel

Gerona, Roy; Wen, Anita; Aguilar, David; Shum, Jamie; Reckers, Andrew; Bacchetti, Peter; Gandhi, Monica; Metcalfe, John

doi:10.1016/j.jchromb.2019.121729

Cited by 12 publications

(17 citation statements)

References 32 publications

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“…20 We found a high sensitivity of our hair assay for all the DR-TB drugs except for ETH (most likely due to the poor incorporation of ETH in hair, as previously noted). 14 Participant Enrollment and Testing…”

Section: Discussionmentioning

confidence: 99%

“…We analyzed the samples using our validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantitation of eleven MDR-TB drugs in small hair samples. 14 Briefly, hair strands (~20-30 cut to 3 cm and weighed to 2 mg) were pulverized and extracted with methanol. The hair extract was reconstituted to water with 1% formic acid before injection into the Agilent LC 1260 (Agilent Technologies, Sta.…”

Section: Investigational Lc-ms/ms Assaymentioning

confidence: 99%

“…Diagnostic specificity was also monitored during method validation using hair samples from laboratory members who have not taken any of the drugs in the panel. 14…”

Section: Investigational Lc-ms/ms Assaymentioning

confidence: 99%

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Evaluation of a Liquid Chromatography-Tandem Mass Spectrometry Assay for Second-line Tuberculosis Drug Concentrations in Small Hair Samples

Metcalfe¹,

Bacchetti²,

Esmail³

et al. 2019

Preprint

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Background Treatment monitoring of multidrug-resistant (MDR) and extensively drug-resistant tuberculosis (XDR-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. Methods Small hair samples were collected from participants at various timepoints during directly-observed MDR/XDR-TB treatment at an inpatient tertiary referral facility in South Africa (DR-TB cohort). We assessed an LC-MS/MS index panel assay including isoniazid, ethambutol, pyrazinamide, levofloxacin, moxifloxacin, ethionamide, prothionamide, linezolid, clofazimine, pretomanid, and bedaquiline 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. Results 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. Conclusions We developed an 11-drug panel assay to quantitatively ascertain drug exposure within second- and third-line DR-TB treatment regimens. Because hair concentrations reflect long-term exposure, 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 are not known.

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Section: Discussionmentioning

confidence: 99%

Section: Investigational Lc-ms/ms Assaymentioning

confidence: 99%

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Evaluation of a Liquid Chromatography-Tandem Mass Spectrometry Assay for Second-line Tuberculosis Drug Concentrations in Small Hair Samples

Metcalfe¹,

Bacchetti²,

Esmail³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Diagnostic speci city was also monitored during method validation using hair samples from laboratory members who have not taken any of the drugs in the panel. 9…”

Section: Investigational Lc-ms/ms Assaymentioning

confidence: 99%

“…Recently, we developed and validated a multi-drug assay panel for measuring eleven anti-tuberculosis drug concentrations in small hair samples. 8,9 Here, we report a clinical diagnostic accuracy study of qualitative results for individual drugs (as determined by detection above the assay's limit of detection (LOD)) as measured against a gold standard of inpatient treatment administration records in a routine care setting in South Africa. In a post-hoc assessment, we validated assay speci city within an external cohort of patients receiving isoniazid alone for latent TB infection (LTBI) where ingestion of drugs used to treat RR-TB would be highly improbable.…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Accuracy of a Liquid Chromatography-Tandem Mass Spectrometry Assay for Rifampin-resistant Tuberculosis Drug Concentrations in a Routine Care Setting

Metcalfe

Bacchetti

Esmail

et al. 2020

Preprint

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BackgroundTreatment 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.MethodsSmall 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.ResultsAmong 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.ConclusionsHair 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.

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Alternative Methods for Therapeutic Drug Monitoring and Dose Adjustment of Tuberculosis Treatment in Clinical Settings: A Systematic Review

et al. 2023

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Background and Objective Quantifying exposure to drugs for personalized dose adjustment is of critical importance in patients with tuberculosis who may be at risk of treatment failure or toxicity due to individual variability in pharmacokinetics. Traditionally, serum or plasma samples have been used for drug monitoring, which only poses collection and logistical challenges in high-tuberculosis burden/low-resourced areas. Less invasive and lower cost tests using alternative biomatrices other than serum or plasma may improve the feasibility of therapeutic drug monitoring. Methods A systematic review was conducted to include studies reporting anti-tuberculosis drug concentration measurements in dried blood spots, urine, saliva, and hair. Reports were screened to include study design, population, analytical methods, relevant pharmacokinetic parameters, and risk of bias. Results A total of 75 reports encompassing all four biomatrices were included. Dried blood spots reduced the sample volume requirement and cut shipping costs whereas simpler laboratory methods to test the presence of drug in urine can allow point-of-care testing in high-burden settings. Minimal pre-processing requirements with saliva samples may further increase acceptability for laboratory staff. Multi-analyte panels have been tested in hair with the capacity to test a wide range of drugs and some of their metabolites. Conclusions Reported data were mostly from small-scale studies and alternative biomatrices need to be qualified in large and diverse populations for the demonstration of feasibility in operational settings. High-quality interventional studies will improve the uptake of alternative biomatrices in guidelines and accelerate implementation in programmatic tuberculosis treatment.

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Simultaneous analysis of 11 medications for drug resistant TB in small hair samples to quantify adherence and exposure using a validated LC-MS/MS panel

Cited by 12 publications

References 32 publications

Evaluation of a Liquid Chromatography-Tandem Mass Spectrometry Assay for Second-line Tuberculosis Drug Concentrations in Small Hair Samples

Evaluation of a Liquid Chromatography-Tandem Mass Spectrometry Assay for Second-line Tuberculosis Drug Concentrations in Small Hair Samples

Diagnostic Accuracy of a Liquid Chromatography-Tandem Mass Spectrometry Assay for Rifampin-resistant Tuberculosis Drug Concentrations in a Routine Care Setting

Alternative Methods for Therapeutic Drug Monitoring and Dose Adjustment of Tuberculosis Treatment in Clinical Settings: A Systematic Review

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