Summary of the main repurposed antituberculosis drugs with the most relevant studies and related findings
| Drug | Class | Main findings | [Ref.] |
| Linezolid | Oxazolidinone | Systematic review and meta-analysis of efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis of 12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases. Most MDR-TB cases achieved SS (86 (92.5%) out of 93) and C (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (interquartile range) times for SS and C conversions were 43.5 (21–90) and 61 (29–119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage ≤600 versus >600 mg). AEs were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major AEs that included anaemia (38.1%), peripheral neuropathy (47.1%), gastrointestinal disorders (16.7%) optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg. The study results suggest an excellent efficacy but also the necessity for caution in the prescription of linezolid. | [23] |
| Retrospective, nonrandomised, unblinded observational study evaluating safety and tolerability of linezolid (600 mg once or twice daily). In MDR/XDR-TB treatment in four European countries. Out of 195 MDR/XDR-TB patients, 85 were treated with linezolid for a mean of 221 days. Of these, 35 (41.2%) out of 85 experienced major AEs attributed to linezolid (anaemia, thrombocytopenia and/or polyneuropathy), requiring discontinuation in 27 (77%) cases. Most AEs occurred after 60 days of treatment. Twice-daily administration produced more major AEs than once-daily dosing (p=0.0004), with no difference in efficacy found. Outcomes were similar in patients treated with/without linezolid (p=0.8), although linezolid-treated cases had more first-line (p=0.002) and second-line (p=0.02) drug resistance and a higher number of previous treatment regimens (4.5 versus 2.3; p=0.07). Linezolid 600 mg once daily added to an individualised multidrug regimen may improve the chance of bacteriological conversion, providing a better chance of treatment success in only the most complicated MDR/XDR-TB cases. Its safety profile does not warrant use in cases for which there are other, safer, alternatives. | [21] | ||
| 41 patients were enrolled, who had C-positive XDR-TB and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their OBR. The primary end-point was the time to SS/C conversion on solid medium, with data censored 4 months after study entry. By 4 months, 15 (79%) out of 19 patients in the immediate-start group and seven (35%) out of 20 in the delayed-start group had C conversion (p=0.001). 34 (87%) out of 39 patients had a negative C within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant AEs that were possibly or probably related to linezolid, including three patients who discontinued therapy. Patients who received 300 mg per day after the second randomisation had fewer AEs than those who continued taking 600 mg per day. 13 patients completed therapy and did not relapse. Four cases of acquired resistance to linezolid were observed. Linezolid is effective at achieving C conversion among patients with treatment-refractory pulmonary XDR-TB but patients must be monitored carefully for AEs. | [24] | ||
| The authors evaluated treatment with linezolid (800 mg once daily for 1–4 months as guided by SS/C status and tolerance, and then at 1200 mg thrice weekly until ≥1 year after C conversion) in addition to OBD among 10 consecutive patients with XDR-TB or fluoroquinolone-resistant MDR-TB. All achieved stable cure, with anaemia corrected and neuropathy stabilised, ameliorated, or avoided after switching to intermittent dosing. Serum linezolid profiles appeared better optimised. | [28] | ||
| Prospective pharmacokinetic study aimed at quantifying the effect of clarithromycin on the exposure of linezolid. All subjects received 300 mg linezolid twice daily during the entire study, consecutively co-administered with 250 and 500 mg clarithromycin once daily. Linezolid exposure increased by a median (interquartile range) of 44% (23–102%, p=0.043) after co-administration of 500 mg clarithromycin (n=5) compared to baseline, whereas 250 mg clarithromycin had no statistically significant effect. Co-administration was well tolerated by most patients; none experienced severe AEs. One patient reported common toxicity criteria grade 2 gastrointestinal AE. Clarithromycin significantly increased linezolid serum exposure after combining clarithromycin with linezolid in MDR-TB patients. The drug–drug interaction is possibly P-glycoprotein-mediated. Due to large interpatient variability, TDM is advisable to determine individual effect size. | [29] | ||
| Meropenem/clavulanate | Carbapenem/clavulanic acid | The study aimed to evaluate the contribution of meropenem/clavulanate when added to linezolid-containing regimens in terms of efficacy and safety/tolerability in treating MDR/XDR-TB cases after 3 months of second-line treatment. The clinical severity of cases was worse than that of controls (drug susceptibility profile, proportion of SS positive and of re-treatment cases). The group of cases yielded a higher proportion of SS converters (28 (87.5%) out of 32 versus nine (56.3%) out of 16; p=0.02) and C converters (31 (83.8%) out of 37 versus 15 (62.5%) out of 24; p=0.06). Excluding XDR-TB patients (11 (11.2%) out of 98), cases scored a significantly higher proportion of C converters than controls (p=0.03). One case had to withdraw from meropenem/clavulanate due to increased transaminase levels. The results of our study provide: 1) preliminary evidence on effectiveness and safety/tolerability of meropenem-clavulanate; 2) reference to design further trials; and 3) a guide to clinicians for its rationale use within salvage/compassionate regimens. | [30] |
MDR: multidrug-resistant; TB: tuberculosis; SS: sputum smear; C: culture; AE: adverse event; XDR: extensively drug-resistant; OBR: optimised background regimen; SS/C: sputum smear and culture; TDM: therapeutic drug monitoring.