Low minimal inhibitory concentrations of linezolid against multidrug-resistant tuberculosis strains

From the authors:

We thank T. Weiss and colleagues who wrote an interesting correspondence citing our research letter published in a previous issue of the European Respiratory Journal [1]. We compared the findings of an individual data meta-analytic observational cohort of extensively drug-resistant (XDR) tuberculosis (TB) patients [2] with those of the first experimental study on linezolid in XDR-TB subjects [3]. The results of both studies on the safety of this anti-TB drug underlined the advantage of prescribing a daily dosage of linezolid at a concentration ≤600 mg, when compared with a dosage >600 mg, once daily, in terms of a reduced proportion of adverse events [2, 3]. Interestingly, the positive tolerability response with ≤600 mg once daily of linezolid identified in both XDR-TB cohorts, had previously been confirmed in the larger, observational cohort of patients with a TB disease caused by Mycobacterium tuberculosis strains that were at least resistant to both isoniazid and rifampicin (multidrug-resistant (MDR) TB) [2].

T. Weiss and his colleagues discussed the importance of a low linezolid dosage (i.e. ≤600 mg once daily) in patients with MDR-TB, providing the most significant in vitro evidence of the above mentioned clinical, observational and experimental, data; in particular, they described the minimal inhibitory concentrations (MICs) of linezolid in a collection of MDR (n=18) and non-MDR (n=130) M. tuberculosis strains, evaluated retrospectively in a German reference centre. The MIC for the MDR group ranged from 0.12 μg·mL⁻¹ to 0.5 μg·mL⁻¹, similarly to previous findings published by Schön et al. [4]. The MIC pattern was almost equal to that obtained in the non-MDR group. On this basis, the authors suggested a reduction of the current recommended linezolid dosage to 300 mg once daily, to decrease the probability of occurrence of linezolid-related adverse events, as well as their severity.

The current clinical trials should carefully keep into account the safety and tolerability profile of the new anti-TB drugs or of the new anti-TB regimens, not only for ethical issues (“Primum non nocere” or “first, do no harm”, as stated by the French clinician Auguste Francois Chomel [5]), but also for the strict association between the occurrence of adverse events (particularly the severe ones), and the low adherence to anti-TB medications [6]. Patients can interrupt their prescribed treatment with relevant clinical and public-health consequences: clinical conditions can worsen and contagiousness can persist with potential transmission of M. tuberculosis strains (new infections) within the community. Additionally, the partial or permanent discontinuation of an antibiotic can favour the emergence of further resistances to other anti-tuberculosis drugs (i.e. reduction of the combined antibiotic pressure, which favours the emergence of resistant sub-populations). Those issues are amplified in individuals infected by M. tuberculosis strains with complex resistance patterns (i.e. resistance to first-, second-, and third-line drugs). When the therapeutic options are scant, such as when XDR-TB is diagnosed, it is crucial not to “lose” any single drug that can allow for the design of an efficacious anti-TB regimen.

We looked for the available evidence on the subject, carrying out a non-systematic PubMed-based review of the most important manuscripts published in the time period from 2007 to 2014. The keywords selected were linezolid and MDR-TB, and the recruited manuscripts included a significant proportion of MDR-TB patients exposed to linezolid 300 mg once daily. The aim of the study did not represent a selection criterion.

Only a few manuscripts explored the efficacy and safety of a daily linezolid dosage of 300 mg (table 1) [3, 7–9]. The four studies demonstrated (with different epidemiological designs and end-points) a similar efficacy of linezolid at the daily dosage of 300 mg or 600 mg, and a better safety profile with the lower dose of the drug.

Well-designed, prospective, studies are needed to assess the pharmacokinetic/pharmacodynamic profile of linezolid and its ex/in vivo efficacy at the proposed new dosage (300 mg once daily).

A more extensive understanding of linezolid pharmacokinetic parameters, accompanied by quality in vitro data, will shed further light on the best strategies to reduce drug exposure to sensitive target anatomical sites (e.g. bone marrow and peripheral nerves) in order to maintain efficacy and lower adverse events.

A recently introduced technology, known as therapeutic drug monitoring (TDM) can guide the clinician to tailor the dosage in individuals with a fast linezolid metabolism or in any clinical conditions where the daily 300 mg dosage is not sufficient. The future clinical frontier will rely on by-passing standard dosages and favouring a more individualised, metabolism-focused treatment approach [10, 11].

It is straightforward that the classical clinical trials are necessary to assess the general efficacy, safety, and tolerability of a new drug; however, to maximise the risk/benefit ratio, i.e. safety/efficacy, it is key to provide experimental data assessing the individual variability.