Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis

Selection of the studies

The scientific literature search identified 88 citations. 12 clinical studies were selected, as summarised in the PRISMA flowchart (fig. 1). The characteristics of the studies and the number of cases analysed in the systematic review and meta-analysis are summarised in table 1. The senior and/or correspondence author of 10 (83.3%) out of 12 studies [8, 30–35, 44–47] responded to the electronic invitation to provide demographic, epidemiological and clinical information missing in the full texts of the retrieved manuscripts.

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Figure 1–

PRISMA flowchart of enrolled studies for systematic review. MDR: multidrug-resistant; XDR-TB: entensively drug-resistant tuberculosis.

Characteristics of the selected studies

Six (50%) out of the 12 studies [8, 22, 33, 35, 44, 47] were conducted in Europe, four (33.3%) out of the 12 in Asia [31, 32, 45, 46], and two (16.7%) out of the 12 in the USA [30, 34] (table 2). Eight (66.7%) out of 12 were retrospective observational studies [8, 22, 30, 34–35, 44–46] while four (33.3%) out of 12 were prospective [31–33, 47]. The majority (66.7%, eight out of 12) of the studies were performed in single, university or tertiary, in/outpatient settings [22, 31–32, 35, 44–47].

Linezolid treatment was administered in an unblinded and nonrandomised manner; all study designs were planned without a control group (table 3) except the multicentre study by Migliori et al. [8]; one (8.3%) out of 12. All but two TB patients who were enrolled in the prospective or retrospective studies were aged ≥15 yrs [8, 22, 30–32, 35, 44–47] and all were given individualised anti-TB therapy based on the results of the DST [8, 22, 30–35, 44–47]. Linezolid dosages ranged from 300 mg b.i.d. [22, 46, 47] to 400 mg q.d. or b.i.d. [34], and 450 mg q.d. [30] to 600 mg q.d. [8, 30–33, 34, 35, 45, 46], b.i.d. [8, 22, 31, 33–35, 44, 47] or three times a week [30].

Characteristics of the international cohort

Individual data from 121 patients treated with linezolid in clinical settings located all over the world (i.e. Europe, North America, and Asia) [8, 22, 30–35, 44–47] were collected (tables 1] and 4]). More than half were males (53.7%) and were born in Asian countries (69.3%), with a median (IQR) age at treatment onset of 32 (25–41) yrs. Known risk factors favouring the development of TB and MDR-/XDR-TB were detected in several patients: 35.4% were migrants from high TB-burden countries; 8.7% were HIV positive; and 76.9% were previously treated with anti-TB therapy >30 days (median (IQR) for the number of times exposed to anti-TB drugs was 1 (0–4)). Almost all individuals with pulmonary TB were sputum smear-positive (102 (92.7%) out of 110) and showed cavitary lesions at the baseline chest-radiograph examination (79 (74.5%). out of 106). XDR-TB was diagnosed in 32.5% of the individuals (I²=67.0%; fig. 2). One fourth of the cases underwent surgery because of the lack of sufficient active drugs or as adjunct intervention. Of the 51 patients with data on hospital stay, discharge occurred after a median (IQR) duration of hospital stay of 39 (15–82) days.

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Figure 2–

Forest plot showing the proportions of extensively drug-resistant tuberculosis (XDR-TB) patients in the enrolled studies. Data are presented as n (95% CI); I²: inconsistency statistics; df: degrees of freedom.

No statistically significant demographic, epidemiological and clinical characteristics were detected between those treated with a daily dosage of linezolid ≤600 mg (72 (59.5%) out of 121), and those treated with a daily dosage >600 mg (49 (40.5%) out of 121) except for the covariates “migration”, “HIV positivity” and “surgery”, which were significantly more frequent in the group of patients exposed to a daily dose >600 mg.

Efficacy of regimes containing linezolid

The majority of individuals converted to sputum smear (86 (92.5%) out of 93; I²=22.9%) and culture (100 (93.5%) out of 107; I²=18.2%) negativity after the exposure to individualised linezolid-containing regimens (table 5 and fig. 3); median (IQR) time to sputum smear and culture conversion was 43.5 (21–90) and 61 (29–119) days, respectively.

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Figure 3–

Forest plots showing the proportion of a) sputum smear converters and b) culture converters in the enrolled studies. Data are presented as n (95% CI); I²: inconsistency statistics; df: degrees of freedom.

More than 80% were successfully treated (99 (81.8%) out of 121; I²=44.8%), while death and treatment failure were observed in 14.1% and 4.1% of the enrolled subjects, respectively (fig. 4) [41].

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Figure 4–

Forest plot showing the proportion of patients who were successfully treated in the enrolled studies. Data are presented as n (95% CI); I²: inconsistency statistics; df: degrees of freedom.

No statistically significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage ≤600 mg versus >600 mg); proportion of cure was ∼80% in both groups and the rate of death and treatment failure occurred in less than one-fourth in both groups, respectively.

Safety and tolerability of linezolid

Approximately one out of every two patients (63 (58.9%) out of 107; I²=82.2%) experienced adverse events attributed to linezolid including 54 (68.4%) out of 79 patients (I²=73.1%) with major adverse events, i.e. they required linezolid treatment interruption or dosage reduction (table 6 and fig. 5). The main adverse events were anaemia (38.1%; I²=69.7%) and peripheral neuropathy (47.1%; I²=44.0%) (fig. 6); other haematological and non-haematological adverse events occurred in a lower proportion of cases, i.e. gastro–intestinal disorders (16.7%), optic neuritis (13.2%) and thrombocytopenia (11.8%).

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Figure 5–

Forest plots showing a) the proportion of patients affected by adverse events and b) the proportion of patients who interrupted their treatment owing to adverse events in the enrolled studies, respectively. Data are presented as n (95% CI); I²: inconsistency statistics; df: degrees of freedom.

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Figure 6–

Forest plots showing a) the proportion of individuals affected by anaemia and b) the proportion of individuals affected by peripheral neuropathy in the enrolled studies. Data are presented as n (95% CI); I²: inconsistency statistics; df: degrees of freedom.

A statistically significant higher risk of adverse events attributed to linezolid treatment was detected in the cohort treated with a linezolid daily dosage >600 mg (74.5% versus 46.7%). In particular, a statistically significant higher probability of anaemia (60% versus 2.5%; p=0.0005), leukopoenia (17.1% versus 2.0%; p=0.012) and gastrointestinal symptoms (29.4% versus 8.0%; p=0.01) was found despite a lower statistically significant exposure duration to linezolid (median (IQR) time of exposure: 252 (120–540) days versus 589.5 (154.5–750) days).

Dosage and duration

10 of the 12 clinical studies evaluated in the present analysis used linezolid at 600 mg·day⁻¹. This meta-analysis of data collected in different settings found no statistical difference in terms of treatment success, proportions of sputum smear or of culture converters between those treated with ≤600 mg q.d. versus those treated with >600 mg b.i.d.

Building on the evidence that a 600 mg daily dose may decrease the occurrence of adverse events, while not compromising efficacy, a study by Alffenaar et al. [47], provided a rationale for sub-dividing the total daily dose of 600 mg, in order to prevent the blood peaks probably responsible for the haematological and non-haematological related adverse events.

Alffenaar et al. [47] demonstrated that the serum concentrations of linezolid obtained following each 300 mg administration b.i.d. are well above the minimum inhibitory concentration ((MIC), i.e. 0.125–0.5 mg·L⁻¹ against M. tuberculosis) and that the serum concentration–time curve over 24 h/MIC ratios were sufficiently high (>100) to predict efficacy in seven out of the eight patients studied. This study provides evidence that a 300 mg b.i.d. dosage may be used to prolong treatment with linezolid, with sustained efficacy and limitation of adverse events.

While properly designed randomised pharmacokinetic studies on larger samples (including comparison of outcomes) will give a final answer on the ideal dose of linezolid, it seems rational to perform kinetics on all cases exposed to the drug [35].

Although very expensive, linezolid is used off-label, with extremely prolonged duration of exposure, beyond its licensed prescription length of 28 days [47]. In this international cohort the median duration of linezolid treatment was 300 days (589.5 days versus 252 days in the group treated with linezolid ≤600 mg q.d. and >600 mg b.i.d., respectively). In two studies linezolid was prescribed for the entire treatment duration, e.g. from 18.6 months to 20.6 months [30, 32]. The optimum duration of linezolid use is still unknown. Administration of linezolid for a shorter duration of time is likely to reduce the occurrence of adverse events, but may compromise efficacy and/or increase likelihood of acquired resistance. More information on this topic is needed and cannot be drawn from the observational studies carried out to date.

Efficacy, safety and tolerability

Linezolid proved to be successful when added to a DST-tailored, individualised treatment regimen composed of several drugs. The pooled estimates of anti-TB treatment success and culture conversion were 82% and 93%, respectively. Median time to sputum smear and culture conversion were 43.5 days and 61 days, respectively.

In spite of some variability, all studies included high percentages of severe MDR-TB cases and XDR-TB patients; the pooled proportion of XDR-TB cases was 32.5% with an inconsistency of 67.0%, reflecting the different prescription habits of the settings where the studies were performed. Success was comparable between patients receiving a daily linezolid dose ≤600 mg and those having a higher dose, notwithstanding the finding that patients with definitional XDR-TB, and who would be expected to have a lower likelihood of success than other MDR-TB patients, were similarly distributed between the two treatment groups.

On the other side, the study results confirm that administration of linezolid is hampered by several toxic effects, although a large variation in major adverse events has been observed. As discussed previously, toxicity was dose–dependent, being lower when a dose ≤600 mg q.d. was used [47]. In eight out of the 12 studies analysed ≥25% of the cases reported major adverse events, making interruption of the drug (or re-adjustment of its dosage) necessary. The meta-analysis showed that the pooled proportion of any adverse event was 59%, of which 69% were major adverse events.

Strengths and weaknesses

The systematic review was based on a sample size of 207 cases taken from three continents and 11 countries (Belarus, Germany, India, Italy, South Korea, the Netherlands, Norway, Portugal, Spain Switzerland and USA).

The meta-analysis on individual data included a large sample size (n=121 cases), representing all the cases having a definite outcome (with the single exception of the Germany cases, which belonged to the largest data-set [8]). Although no specific cohort from Africa and Latin America is available, a proportion of cases born in these continents were included in our study (8% and 6.7%, respectively).

The individual data-set allowed the analysis of all the variables planned, so that the final conclusions were sufficiently robust and, although not necessarily representative, they could be cautiously generalised. Furthermore, subgroup analyses were performed in two comparable cohorts, apart from a few statistically significant differences of some demographic, epidemiological and clinical variables. The meta-analysis is based non-controlled, nonrandomised, unblinded observational data; consequently, a selection bias cannot be excluded in the original studies, as well as publication bias.

Furthermore, owing to the retrospective nature of the majority of the enrolled studies, the efficacy of linezolid was not weighted for the anti-TB drug-combinations and for other clinical and epidemiological confounding variables. The proportion of favourable outcomes is likely to be under-represented if linezolid has been used as a salvage drug, than if it has been prescribed in less compromised patients who could better tolerate adverse events.

In addition the wide time span in which the reviewed studies occurred is unlikely to have biased the results. Consequently this global study adds new information, which was not available in either the largest single study to date [8] or in the other selected smaller studies [30–35, 44–47].

Conclusions

The results of our study suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid for treatment of MDR-TB. Although effective in treating MDR-TB and XDR-TB cases, its administration should be limited to severe cases when an additional active anti-TB drug is needed. Its role in the future generation of shorter regimens needs to be further assessed, although the drug characteristics do not support an easy outpatient-based use in combination with the new drugs, which are expected to be launched onto the market in the near future. A dosage of ≤600 mg per day (either as a single dose or divided into two doses) seems the best recommendation, as it minimises the occurrence of adverse events while not compromising efficacy. The high proportion of cases experiencing adverse events and requiring drug interruption or dosage reduction suggests that the use of linezolid should be limited to specialised MDR-TB reference centres, where both inpatients and outpatients can be carefully monitored for any occurrence of serious adverse events and where facilities are well equipped to manage any serious problem (including the possible need for blood transfusion).