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Editorials

social, and psychological burden that severe Extremely obese children respond better than extremely obese
adolescents to lifestyle interventions. Pediatr Obes 2015;10:7-14.
obesity causes in a growing number of American 4. Skinner AC, Perrin EM, Moss LA, Skelton JA. Cardiometa-
youth. However, even longer-term (>10-year) fol- bolic risks and severity of obesity in children and young adults.
low-up will be necessary to track the persistence N Engl J Med 2015;373:1307-17.
5. Sumithran P, Prendergast LA, Delbridge E, et al. Long-term
of the associated micronutrient deficiencies, as persistence of hormonal adaptations to weight loss. N Engl J Med
well as the emergence of other deficiencies and 2011;365:1597-604.
other unanticipated long-term complications. 6. Apovian CM, Aronne LJ, Bessesen DH, et al.. Pharmacologi-
cal management of obesity: an Endocrine Society clinical prac-
Only then will providers be fully informed for tice guideline. J Clin Endocrinol Metab 2015;100:342-62.
the counseling of adolescents and their families 7. Kelly AS, Barlow SE, Rao G, et al. Severe obesity in children
with regard to the benefits, risks, and timing of and adolescents: identification, associated health risks, and
treatment approaches: a scientific statement from the American
bariatric surgery. Heart Association. Circulation 2013;128:1689-712.
Disclosure forms provided by the author are available with the 8. Gortmaker SL, Wang YC, Long MW, et al. Three interven-
full text of this article at NEJM.org. tions that reduce childhood obesity are projected to save more
than they cost to implement. Health Aff (Millwood) 2015;34:
From the Boston University School of Medicine and Boston 1932-9.
Medical Center both in Boston. 9. Ionut V, Burch M, Youdim A, Bergman RN. Gastrointestinal
hormones and bariatric surgery-induced weight loss. Obesity
1. Skinner AC, Skelton JA. Prevalence and trends in obesity and (Silver Spring) 2013;21:1093-103.
severe obesity among children in the United States, 1999-2012. 10. Inge TH, Courcoulas AP, Jenkins TM, et al. Weight loss and
JAMA Pediatr 2014;168:561-6. health status 3 years after bariatric surgery in adolescents. N Engl
2. Skelton JA, Cook SR, Auinger P, Klein JD, Barlow SE. Preva- J Med 2016;374:113-23.
lence and trends of severe obesity among US children and ado-
lescents. Acad Pediatr 2009;9:322-9. DOI: 10.1056/NEJMe1514957
3. Knop C, Singer V, Uysal Y, Schaefer A, Wolters B, Reinehr T. Copyright 2016 Massachusetts Medical Society.

Chemotherapy for Tuberculous Meningitis


PeterR. Donald, M.D.

Tuberculous meningitis, the most destructive with the standard therapy of isoniazid, para-
form of tuberculosis, continues to be associated aminosalicylic acid, and streptomycin that was
with considerable mortality and morbidity; used in treatment from 1952 to 1970.2 Another
among children, it is the major cause of death recent trial, conducted in Indonesia and involv-
resulting from tuberculosis. The consequences ing a much smaller number of patients with tu-
of tuberculous meningitis are yet again clearly berculous meningitis, assessed treatment with
shown in the article by Heemskerk et al. in this another fluoroquinolone moxifloxacin at a
issue of the Journal.1 This randomized, controlled standard dose of 400 mg and at a higher dose of
study of tuberculous meningitis in Vietnamese 800 mg, as well as treatment with a higher ri-
adults, probably the largest ever undertaken, was fampin dose (13 mg per kilogram) administered
carefully planned and executed and evaluated an intravenously. The 6-month mortality associated
intensified regimen that included both a higher with the lower and higher doses of moxifloxacin
dose of oral rifampin than the standard dose (42% and 63%, respectively) did not differ sig-
(15 mg per kilogram of body weight vs. 10 mg nificantly from that associated with the regimen
per kilogram) and the addition of levofloxacin to without moxifloxacin (45%); however, mortality
the standard regimen that has been used for was lower among patients who received the
almost 40 years. It is disappointing that there higher rifampin dose administered intravenously
was no advantage associated with the use of this than among those who received the standard
intensified treatment regimen, with regard to oral rifampin dose of 10 mg per kilogram (34%
overall mortality (28%) and most measures of vs. 65%)3. Further exploration of higher doses of
illness; indeed, the mortality associated with rifampin may yet lead to improvements in the
both the standard regimen and the intensified outcome of tuberculous meningitis.
regimen, when clinical disease staging was taken Coupled with the recent findings of the fail-
into account, was no better than that associated ure of fluoroquinolone treatment to contribute

n engl j med 374;2nejm.org January 14, 2016 179


The New England Journal of Medicine
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Copyright 2016 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e

to the sterilization of lesions and to shorten the etration into the CSF, the concentrations reached
duration of treatment for pulmonary tuberculo- after administration of the usually recommend-
sis, these results are disappointing, and they ed doses are lower than the concentrations in
suggest that although fluoroquinolones may re- the blood, in both adults and children,7 and this
place isoniazid because of their good bactericidal is particularly likely to be the case with faster
activity and may assist in treating drug-resistant N-acetyltransferase 2 isoniazid acetylators. It is
tuberculosis, they are not going to revolutionize also infrequently realized that isoniazid at con-
the treatment of pulmonary tuberculosis or tuber- centrations approaching 5 g per milliliter has
culous meningitis. The usefulness of fluoroqui- an appreciable mutant-inhibition capacity, prob-
nolones is also threatened by a rising prevalence ably directed mainly at inhA mutants.8 Ethion-
of fluoroquinolone resistance among Mycobacte- amide not only has good CSF penetration7 but
rium tuberculosis isolates in many countries.4 New probably will retain activity in the presence of
antituberculosis drugs are at last becoming avail- katG mutants that confer isoniazid resistance.
able, and they may in due course contribute to These facts are important in a world with an
our management of tuberculous meningitis; how- increasing prevalence of isoniazid resistance.
ever, it is unfortunate that the three drugs that Pyrazinamide also has good penetration into the
are closest to wider clinical use bedaquiline CSF, and in the presence of isoniazid resistance
(TMC207), delamanid (OPC-67683), and preto- it can have a substantial effect on relapse rates
manid (PA-824) are highly protein-bound and if administration is continued throughout the
unlikely to have free penetration into cerebrospi- 6months of treatment, reducing the rate of re-
nal fluid (CSF), and the threat of adverse events lapses in pulmonary tuberculosis to 1%, as com-
will probably limit any increase in their dose.5 pared with 7% if it is given for only 2 months.9
The results described above stand in stark It has been cogently stated that the central
contrast to those of our group in treating chil- nervous system is a unique therapeutic com-
dren with tuberculous meningitis in the Western partment that requires special consideration in
Cape Province of South Africa. For close to 30 the treatment of tuberculous meningitis.10 The
years, we have used a pragmatic regimen that time has come to remember this when making
takes into account the ability of the relevant drugs recommendations regarding the drugs and dos-
to penetrate into the CSF at more efficacious con- es to be used in chemotherapy for a disease as
centrations and the doses of the drugs needed to deadly as tuberculous meningitis.
achieve these concentrations without undue toxic Disclosure forms provided by the author are available with the
effects. With a combination of isoniazid (15 to full text of this article at NEJM.org.

20 mg per kilogram), rifampin (20 mg per kilo-


From the Desmond Tutu TB Center, Department of Paediatrics
gram), pyrazinamide (40 mg per kilogram), and and Child Health, Stellenbosch University, Tygerberg, South
ethionamide (20 mg per kilogram), all given Africa.
throughout 6 months of treatment, the most
recent overall mortality among 184 children, 1. Heemskerk AD, Bang ND, Mai NTH, et al. Intensified anti-
tuberculosis therapy in adults with tuberculous meningitis. N
with more than 80% of the children having Engl J Med 2016;374:124-34.
stage 2 or 3 tuberculous meningitis (British 2. Donald PR. The chemotherapy of tuberculous meningitis in
Medical Council Research Council classification), children and adults. Tuberculosis (Edinb) 2010;90:375-92.
3. Ruslami R, Ganiem AR, Dian S, et al. Intensified regimen
was 3.8% and the mortality was concentrated containing rifampicin and moxifloxacin for tuberculous menin-
among children with stage 3 meningitis.6 We gitis: an open-label, randomised controlled phase 2 trial. Lancet
also pay close attention to monitoring the pres- Infect Dis 2013;13:27-35.
4. Chiang CY. State of the Art series on drug-resistant tubercu-
ence of hydrocephalus and, depending on the losis: its time to protect fluoroquinolones. Int J Tuberc Lung Dis
type of hydrocephalus and degree of the associ- 2009;13:1319.
ated raised intracranial pressure, manage this 5. Global Alliance for TB Drug Development. Handbook of anti-
tuberculosis agents: introduction. Tuberculosis (Edinb) 2008;88:
with a combination of furosemide and acetazol- 85-6.
amide, with ventriculoperitoneal shunting in 6. van Toorn R, Schaaf HS, Laubscher JA, van Elsland SL, Don-
selected cases; all children also receive predni- ald PR, Schoeman JF. Short intensified treatment in children
with drug-susceptible tuberculous meningitis. Pediatr Infect
sone for the first month of treatment. Dis J 2014;33:248-52.
With regard to isoniazid, despite its good pen- 7. Donald PR. Cerebrospinal fluid concentrations of antituber-

180 n engl j med 374;2nejm.org January 14, 2016

The New England Journal of Medicine


Downloaded from nejm.org on January 17, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
Editorials

culosis agents in adults and children. Tuberculosis (Edinb) 2010; assessment of a combined preparation of isoniazid, rifampin
90:279-92. and pyrazinamide. Am Rev Respir Dis 1991;143:700-6.
8. Mitchison DA. Plasma concentrations of isoniazid in the 10. Berning SE, Cherry TA, Iseman MD. Novel treatment of
treatment of tuberculosis. In:Davies DA, Prichard BNC, eds. meningitis caused by multidrug-resistant Mycobacterium tuber-
Biological effects of drugs in relation to their plasma concentra- culosis with intrathecal levofloxacin and amikacin: case report.
tion. London:MacMillan, 1973:169. Clin Infect Dis 2001;32:643-6.
9. Hong Kong Chest Service/British Medical Research Council.
Controlled trial of 2, 4, and 6 months, three-times-weekly regi- DOI: 10.1056/NEJMe1511990
mens for smear-positive pulmonary tuberculosis including an Copyright 2016 Massachusetts Medical Society.

n engl j med 374;2nejm.org January 14, 2016 181


The New England Journal of Medicine
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Copyright 2016 Massachusetts Medical Society. All rights reserved.

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