Prospective evaluation of improving fluoroquinolone exposure using centralised therapeutic drug monitoring (TDM) in patients with tuberculosis (PERFECT): a study protocol of a prospective multicentre cohort study

Introduction Global multidrug-resistant tuberculosis (MDR-TB) treatment success rates remain suboptimal. Highly active WHO group A drugs moxifloxacin and levofloxacin show intraindividual and interindividual pharmacokinetic variability which can cause low drug exposure. Therefore, therapeutic drug monitoring (TDM) of fluoroquinolones is recommended to personalise the drug dosage, aiming to prevent the development of drug resistance and optimise treatment. However, TDM is considered laborious and expensive, and the clinical benefit in MDR-TB has not been extensively studied. This observational multicentre study aims to determine the feasibility of centralised TDM and to investigate the impact of fluoroquinolone TDM on sputum conversion rates in patients with MDR-TB compared with historical controls. Methods and analysis Patients aged 18 years or older with sputum smear and culture-positive pulmonary MDR-TB will be eligible for inclusion. Patients receiving TDM using a limited sampling strategy (t=0 and t=5 hours) will be matched to historical controls without TDM in a 1:2 ratio. Sample analysis and dosing advice will be performed in a centralised laboratory. Centralised TDM will be considered feasible if >80% of the dosing recommendations are returned within 7 days after sampling and 100% within 14 days. The number of patients who are sputum smear and culture-negative after 2 months of treatment will be determined in the prospective TDM group and will be compared with the control group without TDM to determine the impact of TDM. Ethics and dissemination Ethical clearance was obtained by the ethical review committees of the 10 participating hospitals according to local procedures or is pending (online supplementary file 1). Patients will be included after obtaining written informed consent. We aim to publish the study results in a peer-reviewed journal. Trial registration number ClinicalTrials.gov Registry (NCT03409315)

Corrigendum to "Mass spectrometry for therapeutic drug monitoring of anti-tuberculosis drugs" [Clin. Mass Spectrom. 14(Part A) (2019) 34-45]

[This corrects the article DOI: 10.1016/j.clinms.2018.10.002.]

Impact of pyrazinamide resistance on multidrug-resistant tuberculosis in Karakalpakstan, Uzbekistan.

SETTING: The World Health Organization (WHO) recommends the inclusion of pyrazinamide (PZA) in treatment regimens for multidrug-resistant tuberculosis (MDR-TB) unless resistance has been confirmed. OBJECTIVE: To investigate the association between PZA susceptibility and MDR-TB treatment outcome among patients treated with a PZA-containing regimen and whether the duration of the intensive phase of the PZA-containing regimen affected treatment outcome. DESIGN: We conducted a retrospective cohort study including all eligible MDR-TB patients starting treatment in 2003-2013 in the TB programme in Karakalpakstan, Uzbekistan. PZA drug susceptibility testing (DST) using liquid culture was performed, and outcomes were classified according to the WHO 2013 definitions. RESULTS: Of 2446 MDR-TB patients included, 832 (34.0%) had an available baseline PZA DST result, 612 (73.6%) of whom were PZA-resistant. We found no association between treatment success and PZA susceptibility (adjusted odds ratio [aOR] 0.86, 95%CI 0.51-1.44, P = 0.6) in patients treated with PZA. Furthermore, among patients with no baseline PZA DST result, no evidence was seen of an association between treatment success and PZA treatment duration (aOR 0.86, 95%CI 0.49-1.51, P = 0.6). CONCLUSION: Treatment of MDR-TB with a standard PZA regimen does not appear to improve treatment outcomes, regardless of PZA susceptibility or duration of treatment

Mass spectrometry for therapeutic drug monitoring of anti-tuberculosis drugs

Therapeutic drug monitoring (TDM) uses drug concentrations, primarily from plasma, to optimize drug dosing. Optimisation of drug dosing may improve treatment outcomes, reduce toxicity and reduce the risk of acquired drug resistance. The aim of this narrative review is to outline and discuss the challenges of developing multi-analyte assays for anti-tuberculosis (TB) drugs using liquid chromatography-tandem mass spectrometry (LC-MS/MS) by reviewing the existing literature in the field. Compared to other analytical methods, LC-MS/MS offers higher sensitivity and selectivity while requiring relatively low sample volumes. Additionally, multi-analyte assays are easier to perform since adequate separation and short run times are possible even when non-selective sample preparation techniques are used. However, challenges still exist, especially when optimizing LC separation techniques for assays that include analytes with differing chemical properties. Here, we have identified seven multi-analyte assays for first-line anti-TB drugs that use various solvents for sample preparation and mobile phase separation. Only two multi-analyte assays for second-line anti-TB drugs were identified (including either nine or 20 analytes), with each using different protein precipitation methods, mobile phases and columns. The 20 analyte assay did not include bedaquiline, delamanid, meropenem or imipenem. For these drugs, other assays with similar methodologies were identified that could be incorporated in the development of a future comprehensive multi-analyte assay. TDM is a powerful methodology for monitoring patient’s individual treatments in TB programmes, but its implementation will require different approaches depending on available resources. Since TB is most-prevalent in low- and middle-income countries where resources are scarce, a patient-centred approach using sampling methods other than large volume blood draws, such as dried blood spots or saliva collection, could facilitate its adoption and use. Regardless of the methodology of collection and analysis, it will be critical that laboratory proficiency programmes are in place to ensure adequate quality control. It is our intent that the information contained in this review will contribute to the process of assembling comprehensive multiplexed assays for the dynamic monitoring of anti-TB drug treatment in affected individuals