Linezolid: safety and efficacy monitoring
- Mathieu S. Bolhuis⇓,
- Arianna D. Pranger and
- Jan-Willem C. Alffenaar
- Dept of Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- M.S. Bolhuis, Dept of Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: m.s.bolhuis{at}umcg.nl
To the Editors:
We read with interest the recent European Respiratory Journal article by Singla et al. [1], which described the treatment outcome of 29 (pre-)extensively drug-resistant (XDR) tuberculosis (TB) patients from Delhi, India. All patients received linezolid as part of their anti-TB regimen. The high percentage of favourable treatment outcomes in the study led Singla et al. [1] to conclude that “Linezolid could have played a key role”. However, in our opinion, conclusions on the role of a single agent, such as linezolid, are difficult to draw from a series of cases without controls, in which every patient received linezolid in addition to an injectable antimycobacterial agent and a fluoroquinolone. Indeed, the important role of later-generation fluoroquinolones is addressed, but neither drug sensitivity testing (DST) nor drug concentration monitoring for linezolid was performed. Therefore, linezolid treatment itself could even be subtherapeutic [2].
Singla et al. [1] conclude that “an aggressive, comprehensive management programme using linezolid along with other drugs can favourably treat significant number of patients”. Although we concur with this statement, a closer look at the management programme applied in this study suggests that the programme might not be too aggressive or comprehensive. For instance, no directly observed therapy (DOT) was applied, nor did the patients receive nutritional or good psychosocial support. Compliance was only assessed indirectly by checking empty blister packs. Since noncompliance could lead to treatment failure and increase of resistance against the few drugs that are still effective in (pre-)XDR-TB treatment, we would strongly advise to abandon DOT only in exceptional cases where compliance is highly probable [3]. Therapeutic drug monitoring (TDM) can be recommended to ensure adequate drug exposure during treatment. In rural areas, dried blood spot analysis may enable TDM by offering an affordable tool for drug concentration measurement in a centralised laboratory using stable, easy-to-obtain samples [4].
The very low incidence of major adverse events (AEs) of 10.3% reported by Singla et al. [1] is in contrast with findings in literature, where 41.2% of 85 multidrug-resistant/XDR-TB patients treated with linezolid experienced major AEs [5]. The authors provided no explanation for low AE incidence found in their study. Perhaps the fact that temporary discontinuation of linezolid was scored as a minor adverse event, along with the absence of DOT, resulted in a lower score of AEs in the study by Singla et al. [1]. Unfortunately, the authors provided no information on the manufacturer of the linezolid. Only the low cost of linezolid of less than US$1 per tablet is mentioned, compared with approximately US$80 per tablet in the Netherlands. It is well established that counterfeit drugs pose a great threat and counterfeit drugs sometimes contain little to none of the claimed drug [6]. Although there is no evidence that the administered drugs in this study were counterfeit, it also cannot be excluded based on the information provided by Singla et al. [1]. This, combined with the absence of DOT and TDM, could very well be a reason for the low incidence of major AEs as observed in the study by Singla et al. [1].
In our opinion, only a randomised controlled trial of linezolid versus a placebo, in addition to an adequate background regimen using DST and TDM, will provide comprehensive results on efficacy and safety of linezolid as potential drug for (pre-)XDR-TB treatment regimen.
Footnotes
Statement of Interest
A statement of interest for J-W.C. Alffenaar can be found at www.erj.ersjournals.com/site/misc/statements.xhtml
- ©ERS 2012