Re: “Linezolid for Children With Tuberculous Meningitis

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We thank Dr R. Basu Roy and his co-workers for their interests in our article.1,2 Despite the advent of newer antitubercular agents, tuberculous meningitis (TBM) still causes high mortality rates and severe neurologic sequelae. The poor treatment outcomes in childhood TBM have not substantially improved during the past 5 decades.3 Therefore, there is an urgent need to explore new treatment regimens to improve the prognosis of this severe disease. Our retrospective study showed that the regimen containing linezolid could improve the early outcome of childhood TBM. A study of TMB in adults also revealed that a linezolid supplementation regimen had a remarkable therapeutic benefit on cerebrospinal fluid (CSF) improvement, consciousness recovery and temperature recovery in the first 4 weeks of treatment.4
We agree on the importance of randomized controlled trials and high-quality prospective cohort studies to evaluate the efficacy and safety of a drug. The major challenges to organize a randomized clinical trial containing linezolid in childhood TBM are the uncertainty of its efficacy and safety and its high cost. Many families cannot afford the long-term treatment with linezolid. Such research may have ethical concerns.
Fever and neurologic symptoms are the main clinical manifestations of childhood TBM, and they are closely related to TBM severity.3,4 Despite the current conventional antituberculous and corticosteroid therapy, we observed that fever still persisted for more than 2–4 weeks in most children with TBM treated at the Beijing Children’s Hospital, the causes of which might be (1) their diseases were not completely controlled, (2) their condition was serious or (3) they had drug-resistant TB. Fever clearance in children with TBM can be considered an important manifestation of improvement. So some patients were selected to use linezolid in our study, whose fever and neurologic symptoms had no improvement after conventional treatment for more than 2 weeks.
Although linezolid is currently recommended as an important component for the treatment of drug-resistant TB, particularly extensively drug-resistant TB, linezolid could have good bacteriostatic activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis strains.5 We do not think the improved outcomes in our study were only because of improved treatment in cases with drug resistance. Because of the paucibacillary feature of TBM, mycobacterial culture of CSF is often negative in children with TBM; only 16% of our patients had positive cultures. Because of the limitation of the laboratory environment, our hospital cannot perform drug susceptibility testing (DST) for TB. Thus, we did not have the DST results for 14 microbiologically confirmed TB cases. We also could not identify the suspected source cases’ DST results for all the children from their case records. The Xpert MTB/RIF assay using CSF specimen has been available in our hospital since this year.
The adverse events were monitored and evaluated in the linezolid group. In addition to close observation of possible clinical symptoms, we followed the full blood counts, serum liver and renal function every 1 or 2 weeks and performed ophthalmologic examinations monthly in these patients. The incidence of linezolid-related adverse events in our study was low. Only 1 patient presented with thrombocytopenia, and linezolid was discontinued. Other side effects such as lactic acidosis, optic neuropathy, impaired renal function, pancreatitis or hypoglycemia were not seen during the study. The low incidence of linezolid-related adverse events could have been associated with the short duration (1–4 months) of linezolid administration. Garcia-Prats et al5 reviewed the adverse events in 8 studies using linezolid for drug-resistant tuberculosis. Nine of 18 children presented with different adverse events, which occurred after 4 months of linezolid administration.

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