Abstract
Reducing linezolid dose in the treatment of MDR-/XDR-TB to a 300 mg OD could reduce severe side-effects and cost http://ow.ly/AtU7F
To the Editor:
We are following the debate about the administration and the preferred dosage of linezolid in the treatment of multidrug-resistant (MDR) tuberculosis (TB) and extensively drug-resistant (XDR) TB with great interest. Linezolid is a high potent drug against M. tuberculosis, but its widespread use is limited due to severe side-effects in long-term treatment, which often occurs after the usage of 600 mg twice a day in bacterial disease for >28 days and mainly includes severe haematotoxic effects (i.e. myelosuppression, anaemia, thrombocytopaenia) or polyneuropathy [1]. However, the current standards in MDR- and XDR-TB require several months of treatment. In addition, the administration of 1200 mg linezolid per day leads to high treatment costs, which limits the usage, especially in low-income countries [1, 2]. Lowering the dosage of linezolid could, therefore, be an effective step towards reducing costs and severe side-effects.
In a letter from Sotgiu et al. [3], published in the European Respiratory Journal, the authors analysed a subgroup of patients enrolled in their previous meta-analysis about the safety, efficacy and tolerability of linezolid in the treatment of MDR-TB [1]. They found, in a crude statistical comparison of their results to the findings by Lee et al. [4] who had provided prospective experimental data for the safety of linezolid in the treatment of XDR-TB, that the best risk-benefit profile was a daily dose of ≤600 mg [3]. This suggestion was supported by three other studies, which showed some evidence that lower, but yet effective, dosage of linezolid may reduce both toxicity and cost [2, 5, 6]. In this context, drug susceptibility testing is necessary to determine efficacy of linezolid against a wide range of M. tuberculosis strains and could provide a further rationale for the application of a lower dosage.
For this purpose we retrospectively evaluated the in vitro susceptibility test results of linezolid from clinical routine assessment via minimal inhibitory concentrations (MICs) against 148 M. tuberculosis strains including 18 MDR-TB strains isolated from patients treated in our centre from 2002 to 2012. Testing for MIC was performed on solid Middlebrook-7H10 agar plates as described elsewhere [7]. MICs were defined as the lowest drug concentration, after a two-fold serially diluted concentration of linezolid, that inhibited the growth of >99% of a bacterial proportion of the tested M. tuberculosis strain on solid Middlebrook-7H10 agar plates within 14–21 days of incubation at 37°C [7]. We found the MICs for 18 MDR-TB-strains in the range of 0.125–0.5 μg·mL−1 and 130 non-MDR-TB strains between 0.125–0.5 μg·mL−1 (n=4 with MIC=0.125 μg·mL−1, n=121 with MIC=0.25 μg·mL−1 and n=5 with MIC=0.5 μg·mL−1) (table 1). These results show a similar MIC distribution (0.125–0.5 μg·mL−1) compared to the study by Schön et al. [8] but in a higher number of tested M. tuberculosis strains.
In long-term treatment the use of linezolid is limited by severe neurotoxic and haematopoetic side-effects, but it seems that their occurrence and severity is dose dependent [1, 2, 3]. Koh et al. [6] investigated the administration of 300 mg linezolid once daily in 24 patients with MDR-TB or XDR-TB and found a reduction in the occurrence of severe side-effects as compared to patients treated with 600 mg or 1200 mg once daily. Furthermore, in a prospective study of linezolid in patients with XDR-TB Lee et al. [4] showed a reduction of adverse events in the group, which received a daily dose of 300 mg compared to the group that was administered 600 mg once daily (69% versus 82%, respectively). Recently two meta-analyses studies suggested that there was no significant difference in the treatment success comparing a daily linezolid doses of ≤600 mg versus >600 mg [1, 2].
Importantly, the concept of a lower linezolid administration was supported by earlier pharmacokinetics/pharmacodynamics (PK/PD) studies, which indicated a sufficient tissue penetration occurred despite a reduced drug dose being administrated. The main PK/PD precondition for efficacy of an antibacterial drug is a high concentration in the tissue and a very low MIC. Honeybourne et al. [9] measured the concentration of linezolid in bronchial mucosa, pulmonary macrophages, and epithelial lining fluid in 10 adult patients and compared them with simultaneous blood levels and found a mean concentration of 13.4 mg·L−1 in serum, 8.1 mg·L−1 in alveolar macrophages and 25.1 mg·L−1 in epithelial lining fluid, suggesting a good penetration of linezolid into the pulmonary tissues. Although this study administered a higher dose (600 mg twice a day), in another study a single daily administration of 375 mg linezolid led to a similar maximum concentrations (Cmax) in serum (10.8 mg·L−1), which is exceeding the predicted MICs in our study twenty-fold [10]. Koh et al. [5] could even show that a mean Cmax of 11.6 mg·L−1 (range 1.5–15 mg·L−1) could be achieved by a daily use of 300 mg [5].
In conclusion, our study found very low MICs in a wide range of M. tuberculosis strains. This adds to the evidence for lowering the daily dosage of linezolid in M. tuberculosis treatment, because it will probably not jeopardise the efficacy, but will, most likely, reduce the side-effects. Clinical efficacy and safety with daily doses of 300 mg should, therefore, be evaluated in prospective studies.
Footnotes
Support statement: Timo Weiss was supported by an unrestricted grant from the Oskar-Helene-Heim foundation.
Conflict of interest: None declared.
- Received May 7, 2014.
- Accepted July 14, 2014.
- Copyright ©ERS 2015