Challenging the management of drug-resistant tuberculosis

Kim, Hannah Yejin; Heysell, Scott K; Mpagama, Stella; Marais, Ben J.; Alffenaar, Jan-Willem

doi:10.1016/s0140-6736(20)30049-0

Cited by 12 publications

(9 citation statements)

References 3 publications

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“…While levofloxacin peak ( C max ) and estimated total exposure (AUC 0–24 ) were consistently lower in saliva than serum, a positive linear correlation in values was observed, such that saliva exposure can predict serum exposure below clinically relevant thresholds that would either prompt dose adjustment pending optimization of specificity or serve as a screening test to identify those in need of further confirmatory testing with serum assays. 29 , 30 Given that the spectrophotometer did not require the laboratory infrastructure of chromatography or MS instruments, and saliva collection obviated the need for venipuncture, centrifugation and cold transport, this form of personalized care may be suited for decentralized MDR-TB management.…”

Section: Discussionmentioning

confidence: 99%

Levofloxacin pharmacokinetics in saliva as measured by a mobile microvolume UV spectrophotometer among people treated for rifampicin-resistant TB in Tanzania

Mohamed

Mvungi²,

Sariko

et al. 2021

Journal of Antimicrobial Chemotherapy

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Background Early detection and correction of low fluoroquinolone exposure may improve treatment of MDR-TB. Objectives To explore a recently developed portable, battery-powered, UV spectrophotometer for measuring levofloxacin in saliva of people treated for MDR-TB. Methods Patients treated with levofloxacin as part of a regimen for MDR-TB in Northern Tanzania had serum and saliva collected concurrently at 1 and 4 h after 2 weeks of observed levofloxacin administration. Saliva levofloxacin concentrations were quantified in the field via spectrophotometry, while serum was analysed at a regional laboratory using HPLC. A Bayesian population pharmacokinetics model was used to estimate the area under the concentration–time curve (AUC0–24). Subtarget exposures of levofloxacin were defined by serum AUC0–24 <80 mg·h/L. The study was registered at Clinicaltrials.gov with clinical trial identifier NCT04124055. Results Among 45 patients, 11 (25.6%) were women and 16 (37.2%) were living with HIV. Median AUC0–24 in serum was 140 (IQR = 102.4–179.09) mg·h/L and median AUC0–24 in saliva was 97.10 (IQR = 74.80–121.10) mg·h/L. A positive linear correlation was observed with serum and saliva AUC0–24, and a receiver operating characteristic curve constructed to detect serum AUC0–24 below 80 mg·h/L demonstrated excellent prediction [AUC 0.80 (95% CI = 0.62–0.94)]. Utilizing a saliva AUC0–24 cut-off of 91.6 mg·h/L, the assay was 88.9% sensitive and 69.4% specific in detecting subtarget serum AUC0–24 values, including identifying eight of nine patients below target. Conclusions Portable UV spectrophotometry as a point-of-care screen for subtarget levofloxacin exposure was feasible. Use for triage to other investigation or personalized dosing strategy should be tested in a randomized study.

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Section: Discussionmentioning

confidence: 99%

Levofloxacin pharmacokinetics in saliva as measured by a mobile microvolume UV spectrophotometer among people treated for rifampicin-resistant TB in Tanzania

Mohamed

Mvungi²,

Sariko

et al. 2021

Journal of Antimicrobial Chemotherapy

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“…The availability of screening assays using non-invasive saliva samples should increase the accessibility and feasibility of programmatic implementation of TDM, in settings where advanced quantitative assays, such as LC-MS/MS, are not available. 15,34 Implementation studies are required to demonstrate its clinical feasibility and value to guide optimal linezolid dosing of MDR-TB patients. Saliva assay for linezolid monitoring JAC…”

Section: Discussionmentioning

confidence: 99%

Saliva-based linezolid monitoring on a mobile UV spectrophotometer

Kim

Ruiter

Jongedijk

et al. 2021

Journal of Antimicrobial Chemotherapy

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Background In TB, therapeutic drug monitoring (TDM) is recommended for linezolid; however, implementation is challenging in endemic settings. Non-invasive saliva sampling using a mobile assay would increase the feasibility of TDM. Objectives To validate a linezolid saliva assay using a mobile UV spectrophotometer. Methods The saliva assay was developed using NanoPhotometer NP80® and linezolid concentrations were quantified using second-order derivative spectroscopy. Sample preparation involved liquid–liquid extraction of saliva, using saturated sodium chloride and ethyl acetate at 1:1:3 (v/v/v). The assay was validated for accuracy, precision, selectivity, specificity, carry-over, matrix effect, stability and filters. Acceptance criteria were bias and coefficient of variation (CV) <15% for quality control (QC) samples and <20% for the lower limit of quantification (LLOQ). Results Linezolid concentrations correlated with the amplitude between 250 and 270 nm on the second-order derivative spectra. The linezolid calibration curve was linear over the range of 3.0 to 25 mg/L (R2 = 0.99) and the LLOQ was 3.0 mg/L. Accuracy and precision were demonstrated with bias of −7.5% to 2.7% and CV ≤5.6%. The assay met the criteria for selectivity, matrix effect, carry-over, stability (tested up to 3 days) and use of filters (0.22 μM Millex®-GV and Millex®-GP). Specificity was tested with potential co-medications. Interferences from pyrazinamide, levofloxacin, moxifloxacin, rifampicin, abacavir, acetaminophen and trimethoprim were noted; however, with minimal clinical implications on linezolid dosing. Conclusions We validated a UV spectrophotometric assay using non-invasive saliva sampling for linezolid. The next step is to demonstrate clinical feasibility and value to facilitate programmatic implementation of TDM.

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“…Ideally cheap and fast point-of-care test should be available to truly implement TDM in every setting to benefit all patients. Semi-quantitative test could be a solution to preselect patients that actually would require TDM [192]. There is a good example based on DBS how to introduce TDM into practice.…”

Section: Expert Opinionmentioning

confidence: 99%

Therapeutic drug monitoring in patients with tuberculosis and concurrent medical problems

Märtson

Burch

Ghimire

et al. 2020

Expert Opinion on Drug Metabolism & Toxicology

139

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Introduction: Therapeutic drug monitoring (TDM) has been recommended for treatment optimization in tuberculosis (TB) but is only is used in certain countries e.g. USA, Germany, the Netherlands, Sweden and Tanzania. Recently, new drugs have emerged and PK studies in TB are continuing, which contributes further evidence for TDM in TB. The aim of this review is to provide an update on drugs used in TB, treatment strategies for these drugs, and TDM to support broader implementation.Areas covered: This review describes the different drug classes used for TB, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), along with their pharmacokinetics, dosing strategies, TDM and sampling strategies. Moreover, the review discusses TDM for patient TB and renal or liver impairment, patients co-infected with HIV or hepatitis, and special patient populations -children and pregnant women. Expert opinion: TB treatment has a long history of using 'one size fits all.' This has contributed to treatment failures, treatment relapses, and the selection of drug-resistant isolates. While challenging in resource-limited circumstances, TDM offers the clinician the opportunity to individualize and optimize treatment early in treatment. This approach may help to refine treatment and thereby reduce adverse effects and poor treatment outcomes. Funding, training, and randomized controlled trials are needed to advance the use of TDM for patients with TB.

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Challenging the management of drug-resistant tuberculosis

Cited by 12 publications

References 3 publications

Levofloxacin pharmacokinetics in saliva as measured by a mobile microvolume UV spectrophotometer among people treated for rifampicin-resistant TB in Tanzania

Levofloxacin pharmacokinetics in saliva as measured by a mobile microvolume UV spectrophotometer among people treated for rifampicin-resistant TB in Tanzania

Saliva-based linezolid monitoring on a mobile UV spectrophotometer

Therapeutic drug monitoring in patients with tuberculosis and concurrent medical problems

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