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Linezolid for Children With Tuberculous Meningitis: More Evidence Required

Basu Roy, Robindra MRCPCH; Seddon, James A. PhD

The Pediatric Infectious Disease Journal: April 2017 - Volume 36 - Issue 4 - p 439
doi: 10.1097/INF.0000000000001464
Letters to the Editors

Department of Academic Paediatrics, Imperial College London, London, United Kingdom

R. Basu Roy is a Clinical Research Training Fellow jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement, and this funding is also part of the EDCTP2 programme supported by the European Union (MR/K023446/1). J. A. Seddon is an Academic Clinical Lecturer funded by the National Institute of Health Research and also the recipient of a Starter Grant from the Academy of Medical Sciences (AMS-SGCL11-Seddon).

The authors have no conflicts of interest to disclose.

Address for correspondence: R. Basu Roy, MRCPCH; E-mail

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To the Editors:

Tuberculous meningitis (TBM) is a devastating disease. With the currently available treatment regimens, 1 in 5 children die, and only a third of surviving children escape neurologic sequelae.1 We were interested to read the study by Li et al regarding the use of linezolid in children with TBM in Beijing.2

Linezolid is an attractive therapeutic option given its good bioavailability, excellent cerebrospinal fluid penetration and proven efficacy against Mycobacterium tuberculosis. However, 3 major obstacles currently limit the use of linezolid in the treatment of pediatric TBM: efficacy, safety and current high cost. Until this report, the only described use of linezolid in pediatric TBM had been in the successful treatment of a South African case of extensively drug-resistant TBM.3

Caution is warranted in interpreting the efficacy of linezolid in the treatment of pediatric TBM from this report. The retrospective design, unrandomized nature of group allocations and unblinded ascertainment of outcomes limit how much can be inferred. In terms of patient selection, children were given linezolid if they remained febrile after 2 weeks of receiving conventional treatment and had no neurologic improvement in that time. It is, therefore, unclear why greater than 50% of children in the control group had a fever clearance time of greater than 4 weeks. It would be useful for the authors to further clarify on the criteria for using linezolid and from what common reference point during therapy, fever clearance time comparisons were made. Persistent fever after initiation of antituberculous therapy with confirmed drug-susceptible strains of M. tuberculosis is a recognized, although unusual, clinical phenomenon.4

It would also be important to know if the improved outcomes were because of linezolid, improving the treatment of TBM generally, or if the advantage was the result of improved treatment in cases with drug resistance. It would be interesting to know if there are any molecular or phenotypic drug resistance results available from either the 14 microbiologically confirmed TB cases or from the TB source cases identified in 50 of the children.

Regarding safety, the authors report no significant difference in adverse events between the 36 children treated with linezolid and those who received standard treatment. However, it is unclear from the report how the children were evaluated for adverse events and whether they may have experienced any other side effects (such as lactic acidosis, optic neuropathy, impaired renal function, raised amylase or hypoglycemia5).

We commend the authors on reporting these cases and providing some much-needed data. We look forward to learning from their experiences in even more depth. In our opinion, however, there is currently still insufficient evidence to warrant use of linezolid in pediatric TBM without information strongly suggestive of drug resistance.

Robindra Basu Roy, MRCPCH

James A. Seddon, PhD

Department of Academic Paediatrics

Imperial College London

London, United Kingdom

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1. Chiang SS, Khan FA, Milstein MB, et al. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis. 2014;14:947–957.
2. Li H, Lu J, Liu J, et al. Linezolid is associated with improved early outcomes of childhood tuberculous meningitis. Pediatr Infect Dis J. 2016;35:607–610.
3. Alsleben N, Garcia-Prats AJ, Hesseling AC, et al. Successful treatment of a child with extensively drug-resistant tuberculous meningitis. J Pediatric Infect Dis Soc. 2015;4:e41–e44.
4. Coulter JB, Baretto RL, Mallucci CL, et al. Tuberculous meningitis: protracted course and clinical response to interferon-gamma. Lancet Infect Dis. 2007;7:225–232.
5. Viswanathan P, Iarikov D, Wassel R, et al. Hypoglycemia in patients treated with linezolid. Clin Infect Dis. 2014;59:e93–e95.
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