The Pediatric Infectious Disease Journal • Volume 33, Number 9, September 2014 Letters © 2014 Lippincott Williams & Wilkins www.pidj.com | 993 In Reply: Short Intensified Treatment in Children With Drug-Susceptible Tuberculous Meningitis child effectively on isoniazid monotherapy for most of their treatment. This can be a problem in areas with high prevalence of iso- niazid resistance. In addition, the poor CSF penetration of ethambutol 2 renders its inclu- sion in the regimen questionable. The short intensified treatment regi- men used in the Western Cape for nearly 2 decades with higher isoniazid and rifampin dosages, longer administration of pyrazina- mide and substitution of ethambutol with ethionamide provides higher CSF concentra- tions of anti-tuberculosis drugs for the entire duration of treatment. 2 It may also overcome isoniazid-monoresistance 3 and children appear to tolerate combination treatment with pyrazinamide better than adults. Twelve years before the most recent WHO recommendations in 2010, this group published their experience with the same treat- ment regimen, showing that it was effective and associated with one of the lowest mortal- ity rates reported. 4 It is disappointing that this regimen has not been evaluated further in other centers and that most authorities still rec- ommend only 2 months of intensive treatment. Despite demonstrating good out- comes and a shorter duration of treatment, the study by van Toorn is observational without a randomized control group for comparison; it thus may provide insufficient evidence to change international policy. In addition, the regimen employs a drug usu- ally reserved for second-line treatment, which could have implications for accept- ability by tuberculosis programs. Further, recent WHO dosing recommendations may make it difficult to use the higher dosages described in the study, given the shortage of single drug formulations in many settings. 5 However, these operational obstacles should not impede the identification of the best possible treatment regimen. An appro- priately powered randomized controlled trial to address this question is long overdue. One- hundred eighty-four children with TBM were enrolled in this study from a single center in 4 years; patient numbers, although limited, should not be an impediment to conducting a multicenter trial. Such a trial should compare the standard WHO-recommended regimen with a shortened regimen using drugs with good CSF penetration for the full duration. Consideration should be given to using a fluo- roquinolone (levofloxacin or moxifloxacin) instead of ethionamide, as many pediatricians are hesitant to use ethionamide because of its side-effect profile as well as cross-resistance with isoniazid. Particular attention should be paid to using standardized assessments of neurologic outcome and toxicity and the issue of blinding. Until better evidence is provided, children with TBM will continue to be treated with what is likely to be a suboptimal regimen. Aslınur Ozkaya-Parlakay, MD Ankara Hematology and Oncology Research Hospital Hasan Tezer, MD Gazi University Pediatric Infectious Disease Department Ankara, Turkey REFERENCES 1. Enweronu-Laryea CC, Sagoe KW, Mwenda JM, et al. Severe acute rotavirus gastroenteritis in chil- dren less than 5 years in southern Ghana: 2006– 2011. Pediatr Infect Dis J. 2014;33(suppl 1): S9–S13. 2. World population prospects: the 2004 revision. New York: United Nations Population Division, Department of Economic and Social Affairs, 2005. Available at: http://www.un.org/esa/popu- lation/ publications/WPP2004/2004Highlights_ finalrevised.pdf. 3. Parashar UD, Bresee JS, Glass RI. The global burden of diarrhoeal disease in children. Bull World Health Organ. 2003;81:236. 4. Gurbuz F, Tezer H, Revide-Sayli T. Etiologic fac- tors and clinical findings of patients hospitalized children for acute gastroenteritis: epidemiologic study. Turkish J Pediatr Dis. 2010;4:211–218. 5. Ceyhan M, Alhan E, Salman N, et al. Multicenter prospective study on the burden of rotavirus gastroenteritis in Turkey, 2005–2006: a hospital- based study. J Infect Dis. 2009;200(suppl 1): S234–S238. Short Intensified Treatment in Children with Drug-susceptible Tuberculous Meningitis The authors have no funding or conflicts of interest to disclose. Copyright © 2014 by Lippincott Williams & Wilkins. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the origi- nal work is properly cited. ISSN: 0891-3668/14/3309-0993 DOI: 10.1097/INF.0000000000000371 To the Editors: W e read with interest the results of the study by van Toorn et al. describing short intensified treatment for children with drug-susceptible tuberculous meningitis (TBM). 1 The paper raises important questions regarding the most appropriate antimicrobial treatment regimen for children with TBM. The World Health Organization (WHO) recommends giving 2 months of iso- niazid, rifampin, pyrazinamide and ethambu- tol followed by 10 months of isoniazid and rifampin. After meningeal inflammation has subsided, rifampin has poor penetration into the cerebrospinal fluid (CSF) 2 leaving the Anna Turkova, MRCPCH Imperial College Healthcare NHS Trust London James A. Seddon, PhD Department of Academic Paediatrics Imperial College London Andrew J. Nunn, MSc Diana M. Gibb, MD Patrick P.J. Phillips, PhD MRC Clinical Trials Unit at UCL Institute of Clinical Trials and Methodology London, United Kingdom On behalf of the North London TB Journal Club REFERENCES 1. van Toorn R, Schaaf HS, Laubscher JA, et al. Short intensified treatment in children with drug-susceptible tuberculous meningitis. Pediatr Infect Dis J. 2014;33:248–252. 2. Donald PR. Cerebrospinal fluid concentrations of antituberculosis agents in adults and children. Tuberculosis (Edinb). 2010;90:279–292. 3. Seddon JA, Visser DH, Bartens M, et al. Impact of drug resistance on clinical outcome in chil- dren with tuberculous meningitis. Pediatr Infect Dis J. 2012;31:711–716. 4. Donald PR, Schoeman JF, Van Zyl LE, et al. Intensive short course chemotherapy in the man- agement of tuberculous meningitis. Int J Tuberc Lung Dis. 1998;2:704–711. 5. Detjen A, Macé C, Perrin C, et al. Adoption of revised dosage recommendations for childhood tuberculosis in countries with different child- hood tuberculosis burdens. Public Health Action 2012;2:126–132. The authors have no funding or conflicts of interest to disclose. Reply: W e agree with the North London TB journal club about the impor- tance of trials that would determine the most appropriate antimicrobial regimen for children with tuberculous meningitis (TBM). The study design advocated by the authors is a randomized controlled trial (RCT) of short intensified versus standard treatment (as advised by the World Health Organization). Although a RCT would be the pre- ferred study method, a large sample size Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3309-0993 DOI: 10.1097/INF.0000000000000409