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
Daan J Touw,
Geoffrey Eather,
Tjip S van der Werf,
Giovanni Sotgiu,
Simone HJ van den Elsen,
Marieke GG Sturkenboom,
Onno Akkerman,
Linda Barkane,
Judith Bruchfeld,
Scott K Heysell,
Henadz Hurevich,
Liga Kuksa,
Johanna Kuhlin,
Katerina Manika,
Charalampos Moschos,
Stellah G Mpagama,
Marcela Muñoz Torrico,
Alena Skrahina,
Marina Tadolini,
Francesca Volpato,
Malcolm R Wilson,
Joaquin Zúñiga,
Giovanni B Migliori,
Jan-Willem Alffenaar
Affiliations
Daan J Touw
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Geoffrey Eather
Department of Respiratory and Sleep Medicine, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
Tjip S van der Werf
Department of Pulmonary Diseases and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Giovanni Sotgiu
Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Sardinia Region, Italy
Simone HJ van den Elsen
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Marieke GG Sturkenboom
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Onno Akkerman
Department of Pulmonary Diseases and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Linda Barkane
Department of Multidrug Resistant Tuberculosis, Riga East University Hospital TB and Lung Disease Clinic, Riga, Latvia
Judith Bruchfeld
Division of Infectious Diseases, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
Scott K Heysell
Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA
Henadz Hurevich
The Republican Scientific and Practical Center for Pulmonology and Tuberculosis, Minsk, Belarus
Liga Kuksa
Department of Multidrug Resistant Tuberculosis, Riga East University Hospital TB and Lung Disease Clinic, Riga, Latvia
Johanna Kuhlin
Division of Infectious Diseases, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
Katerina Manika
Pulmonary Department, Respiratory Infections Unit, G. Papanikolaou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
Charalampos Moschos
Drug-Resistant Tuberculosis Unit, 'Sotiria' Hospital for Chest Diseases, Athens, Greece
Stellah G Mpagama
Kibong'oto Infectious Diseases Hospital, Kilimanjaro, United Republic of Tanzania
Marcela Muñoz Torrico
Clínica de Tuberculosis, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
Alena Skrahina
The Republican Scientific and Practical Center for Pulmonology and Tuberculosis, Minsk, Belarus
Marina Tadolini
Department of Medical and Surgical Sciences, Unit of Infectious Diseases, Alma Mater Studiorum University of Bologna, Bologna, Italy
Francesca Volpato
Department of Medical and Surgical Sciences, Unit of Infectious Diseases, Alma Mater Studiorum University of Bologna, Bologna, Italy
Malcolm R Wilson
Department of Respiratory Medicine and Metro South Clinical Tuberculosis Service, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
Joaquin Zúñiga
Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
Giovanni B Migliori
Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri IRCCS, Tradate, Italy
Jan-Willem Alffenaar
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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).
