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

Abstract

IntroductionGlobal 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 analysisPatients 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 disseminationEthical 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 numberClinicalTrials.gov Registry (NCT03409315).

Personalised Medicine for Tuberculosis and Non-Tuberculous Mycobacterial Pulmonary Disease

“…A recently developed pharmacogenomic assay has been shown to accurately detect NAT2 gene allele patterns in pulmonary TB patients and may be of use in guiding isoniazid dosing [102]. The feasibility and effect on sputum conversion rates of TDM for fluoroquinolones, which are used in the treatment of drug-resistant TB [103], is currently under investigation [104].…”

Development, Validation, and Clinical Application of an Ultra–High-Performance Liquid Chromatography Coupled With Tandem Mass Spectrometry Method for the Determination of 10 Antituberculosis Drugs in Human Serum

“…Therefore, it is necessary to closely monitor the blood drug concentration. 16 In treating drug-resistant TB, multiple drug combinations are often used; however, separately measuring drug concentrations in the serum considerably increases the workload and is very time-consuming. 17 Whether for the prevention of adverse drug reactions or the development of new combination drug regimens, the need for the simultaneous, rapid, and accurate detection of multiple drug concentrations in serum has increased.…”