Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis

Joseph Phan, Mercer University College of Pharmacy

According to the World Health Organization, in 2014, 9.6 million people fell ill with tuberculosis (TB) and 1.5 million died from the disease. Tuberculosis is considered to be a leading killer of HIV (Human Immunodeficiency Virus)-positive people. In 2015, it is stated that one in three HIV deaths were due to TB. [1]

It has been suggested that an increase in rifampin dose and an addition of a fluroquinolone to a standard regimen may improve the outcome in patients with tuberculous meningitis. [2,3]

Title: Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis
Design Randomized, double-blind, placebo-controlled trial; N= 817
Objective To test the hypothesis that intensified antituberculosis treatment with higher-dose rifampin and added levofloxacin for the first eight weeks of treatment would reduce death and disability from tuberculosis meningitis
Study Groups Standard treatment; n= 409
Intensive antituberculosis treatment; n= 408
Methods Adults age ≥ 18 years with a clinical diagnosis of tuberculosis meningitis were classified as having definite, probable, or possible tuberculosis meningitis. Patients were then randomized into standard treatment or intensive treatment. Standard treatment consisted of isoniazid (5 mg/kg/day; maximum 300 mg/day), rifampin (10 mg/kg/day), pyrazinamide (25 mg/kg/day; maximum 2 g/day); and ethambutol (20 mg/kg/day; maximum 1.2 g/day) for three months, followed by rifampin and isoniazid at the same dose for an additional six months.

Patients who previously received treatment for tuberculosis also received streptomycin (20 mg/kg/day; maximum 1 g/day) for the first three months. All patients received adjunctive treatment with dexamethasone for the first six to eight weeks of treatment. Intensified treatment consisted of the same 9-month regimen with the addition for the first eight weeks of treatment of 15 mg/kg/day and levofloxacin (20 mg/kg/day). Patients were assessed at two, six, and nine months after randomization.

Duration April 18, 2011 through June 18 2014
Primary Outcome Measure Death by 9 months after randomization
Baseline Characteristics Of all patients, 68.5% were male, average 35 years of age, 42.7% were HIV positive, 49.8% were diagnosed with definite tuberculosis meningitis, 26.2% with probable, 21.3% with possible, 1% with unlikely, and 1.7% with a confirmed other condition.
Results During 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard treatment group died (hazard ratio 0.94; 95% CI 0.73- 1.22; p= 0.66).

There was no evidence of a differential effect of intensified treatment in the overall population or in any of the pre-specified subgroups, although there was a suggestion of benefits of intensified treatment for patients with isoniazid-resistant infections (p= 0.06).

Adverse Events Common Adverse Events (Standard treatment/Intensified treatment): deterioration of consciousness (21.8%/22.1%; p= 0.93), headache (7.3%/8.8%; p= 0.44), hemiplegia (5.1%/7.6%; p= 0.16)
Serious Adverse Events: seizures (2.7%/5.6%; p= 0.04), hepatotoxicity (6.8%/4.2%; p= 0.12)
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions Although the results of the study do not support a change in the currently recommended treatment regimens for tuberculosis meningitis, enhanced antituberculosis treatment with higher doses of first-line antituberculosis drugs, including intravenous rifampin, or the newer antituberculosis drugs bedaquiline and delamanid, still require investigation.

The results of this randomized, double-blind trial shows no difference in effect or cure rates of tuberculous meningitis. [4] Although previous studies have resulted in improvement in cure rates, the results of this study contradict those results which highlights that the need for further study and development of newer drugs for this disease is necessary. [2,3]

References

  1. World Health Organization. (2015). Tuberculosis [Fact sheet].
    Retrieved from: http://www.who.int/mediacentre/factsheets/fs104/en/
  1. Ruslami R, Ganiem AR, Dian S, et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis 2013;13:27-35
  1. Thwaites GE, Bhavnani SM, Chau TT, et al. Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis. Antimicrob Agents Chemother 2011;55:3244-3253
  1. Heemskerk AD, Bang ND, Mai NT, et al. Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis. N Engl J Med. 2016;374(2):124-34.
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