European Respiratory Society

To the Editors:

To further comment on the safety, tolerability and efficacy profile of linezolid in treating “difficult” tuberculosis (TB) cases, following the recent study by Villar et al. [1], we here report on the experience of the E. Morelli Hospital in Sondalo, Italy, a reference centre for difficult-to-treat TB cases, e.g. those affected by multidrug-resistant (MDR)- and extensively drug-resistant (XDR)-TB, located in northern Italy [23].

As reported elsewhere [3], linezolid has been prescribed “off label” in Sondalo, Italy since 2005 to treat patients for whom at least four active drugs cannot be ensured, according to World Health Organization recommendations [4].

Administration of linezolid, within regimens designed to balance efficacy and tolerability, needs to be guided by clear scientific evidence focused on the ideal dosage (per kg body weight per day) and duration [1, 59].

The aim of this letter is to describe our recent experience of linezolid tolerability and efficacy between 2009 and 2010.

Methods and definitions are consistent with those used in previous studies by our group [1, 6].

MDR- and XDR-TB have been defined, respectively, as in vitro resistance to at least isoniazid and rifampicin (the two most potent first-line drugs for TB treatment) and resistance to isoniazid and rifampicin plus any fluoroquinolone and at least one of the injectable drugs amikacin, capreomycin or kanamycin.

The main results of this study are summarised in tables 13.

View this table:
Table 1– Epidemiological characteristics of 12 patients with multidrug-resistant/extremely drug-resistant (XDR) tuberculosis (TB) treated with linezolid in Sondalo, Italy
View this table:
Table 2– Clinical characteristics of 12 patients with multidrug-resistant/extremely drug-resistant tuberculosis (TB) treated with linezolid in Sondalo, Italy
View this table:
Table 3– Comparison of 12 patients with multidrug-resistant/extremely drug-resistant tuberculosis treated with linezolid in Sondalo with two other recently published cohorts

The features of the Sondalo cohort cases (table 1) are substantially similar to those illustrated by Villar et al. [1], the prevalence of resistance to first-line anti-TB drugs being similar, the prevalence of resistance to XDR-TB-defining drugs slightly lower and the proportion of previous exposure to anti-TB drugs (as well as the number of previous anti-TB treatment exposures >30 days) slightly higher.

The majority of the cases (11 (91.7%) out of 12) were migrants from high MDR-TB burden countries (six from Romania, two from Ukraine, one from Moldova, one from Pakistan and one from India) versus almost one-third (five (31.3%) out of 16; p=0.0014) reported in Portugal [1].

In our cohort, linezolid was administered for a median (interquartile range (IQR)) time of 63.5 (37–100) days with a dosage of 600 mg twice a day for the majority (10 (83.3%) out of 12) of the cases, while two patients were prescribed 600 mg once daily and 450 mg twice a day, respectively.

All patients were males, with a mean±sd age of 40±9.2 yrs. Two cases were HIV infected and were treated with antiretroviral drugs, while two patients underwent surgery in addition to chemotherapy.

As in other reference centres, the E. Morelli Hospital needs to transfer out all admitted cases to the hospitals referring them for specialised treatment, when culture conversion and clinical stability have been achieved. Patients were transferred out after a median (IQR) hospital stay of 75.5 (51.5–127.5) days; 12 (100%) out of 12 and nine (75%) out of 12 achieved sputum-smear and culture conversion, after a median (IQR) time of 40.5 (24–64) and 70 (44–95) days, respectively. As of June 2011, one patient was cured, two had died and nine were still under treatment.

Four (33.3%) cases reported adverse events, two being major (16.7%; neuropathy and low platelet count, needing temporary interruption of linezolid) and two minor (neuropathy and mild anaemia). All adverse events were reversible.

In conclusion, despite the intrinsic difficulty of evaluating the safety and tolerability of linezolid (administered within different regimens including multiple anti-TB drugs guided by drug susceptibility testing), the study results are consistent with the findings described by Villar et al. [1] and Schecter et al. [10]. Based on the results of the study, the dose of linezolid has been reduced in Sondalo from a minimum of 450 to a maximum of 600 mg·day−1 (determined by kinetics performed on all cases).

At present, a systematic review including information from the patients treated with linezolid globally is probably the easiest option to better define the efficacy, safety and tolerability of the drug in the treatment of MDR-/XDR-TB.


  • Support Statement

    This study was supported by the current research funds of the participating institutions. For this publication, the research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement FP7- 223681.

  • Statement of Interest

    None declared.