Abstract
Could therapeutic drug monitoring for fluoroquinolones have a role in the programmatic management of MDR-TB? http://ow.ly/wGdP309R7Z4
From the authors:
Later-generation fluoroquinolones (moxifloxacin, gatifloxacin) are crucial to all treatment regimens in current use for multidrug-resistant (MDR) tuberculosis (TB) (i.e. joint resistance to at least rifampicin and isoniazid) [1]. Resistance to them is known to occur in different geographical settings [2]. L. Davies Forsman and co-workers advocate for therapeutic drug monitoring (TDM) as a means to help keep blood levels of fluoroquinolones within the ranges considered effective during MDR-TB treatment. They refer to reports of substantial variability in fluoroquinolone pharmacokinetics between patients, which makes it difficult to predict when sub-therapeutic levels occur, and could thus predispose to treatment failure and to the emergence of resistant strains. The authors maintain that TDM employing a dried blood spot technique and newer microbroth dilution plate-based methods to test for minimum inhibitory concentration (MICs) now make it possible for clinicians in low-resource settings to ensure that therapeutic levels of fluoroquinolones can be achieved during treatment.
While this reasoning is mainstream and logical and has already been expressed in other articles featured in this journal [3], a number of uncertainties stand in the way of wide recommendations for their use. The correlation between tissue concentration of fluoroquinolones and clinical outcomes is still based on small numbers of observations of patients on treatment. The rapid tests for MIC to multiple antimicrobials cited by the authors still require validation. The feasibility of implementing these tests and TDM under routine programmatic practice still needs to be shown, especially in high TB burden and resource-constrained contexts.
Regardless of this, no effort should be spared to forestall the development of resistance to fluoroquinolones during treatment, a known correlate with poorer patient outcomes [4]. Only about one half of MDR-TB patients worldwide are known to complete their treatment successfully [5]. While about 580 000 new patients requiring MDR-TB treatment are estimated to emerge each year, only about 125 000 patients were reported to have been started on second-line TB treatment in 2015. Since 2016, the World Health Organization (WHO) recommends a shorter MDR-TB regimen with a composition and dosing schedule identical to that used in a randomised controlled trial, including high-dose moxifloxacin [1, 6–8]. This shorter regimen is expected to facilitate the expansion of treatment to more patients and to improve outcomes in those who are eligible. Prior exposure or confirmed resistance to fluoroquinolones, which could favour the acquisition of additional drug-resistance, is among the contraindications to this regimen. Clinical monitoring for response to treatment and for potential harms related to medication (e.g. electrocardiography, serum potassium) is recommended in patients on any novel regimen [9]. Well conducted operational research using observational cohorts could be valuable if blinded randomised controlled trials do not materialise in future. Considerations on whether or when to add TDM to tests generally advised in MDR-TB patients will be discussed at a technical consultation being convened by WHO in April 2017, which will look at critical concentrations and pharmacokinetics/pharmacodynamics of TB medicines.
Acknowledgements
Authors are staff members of the World Health Organization (WHO). They alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions or policies of WHO. The designations used and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area, or of its authorities, nor concerning the delimitation of its frontiers or boundaries.
Footnotes
Conflict of interest: None declared.
- Received February 14, 2017.
- Accepted March 8, 2017.
- Copyright ©ERS 2017