Intensified antituberculosis therapy doesn’t appear to improve survival in adults with tuberculous meningitis, compared with standard treatment, according to a report published online Jan. 14 in the New England Journal of Medicine.
This result, from a 3-year randomized double-blind placebo controlled clinical trial involving 817 adults in Vietnam, contradicts findings from previous small studies which suggested that increasing the rifampin dose and adding a fluoroquinolone to the standard regimen might improve outcomes, said Dr. A. Dorothee Heemskerk of the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam, and her associates.
©Komolafe, M., Sunmonu, T., Esan, O./Wikimedia Commons/CC-BY-2.0
Current guidelines recommend at least 2 months of therapy with four antituberculosis agents, followed by treatment with rifampin (10 mg/kg) and isoniazid for an additional 7-10 months. “However, these recommendations are based on data from pulmonary tuberculosis and do not take into account the differential ability of antituberculosis drugs to penetrate the brain,” the investigators noted.
The concentration of rifampin in cerebrospinal fluid reaches only 30% of that in the plasma, so it has been proposed that higher-dose rifampin (15 mg/kg) might be more effective for tuberculous meningitis. Fluoroquinolones such as levofloxacin were proposed because they are active against tuberculosis and achieve good penetration of the blood-brain barrier.
Dr. Heemskerk and her associates tested this hypothesis at two tertiary referral centers for severe cases of tuberculosis or infectious diseases in Vietnam. All the study participants received standard daily isoniazid (5 mg/kg), rifampin (10 mg/kg), pyrazinamide (25 mg/kg), and ethambutol (20 mg/kg) for 3 months, followed by the same doses of rifampin and isoniazid for an additional 6 months. Approximately half (408 patients in the intensive-therapy group) received additional rifampin (5 mg/kg) and levofloxacin (20 mg/kg), while the other half (409 patients in the control group) received matching placebos.
The median patient age was 35 years. Approximately 43% of patients were coinfected with HIV.
The primary outcome measure – death at 9-month follow-up – occurred in 113 of the intensive-therapy group and 114 of the control group, a nonsignificant difference (HR, 0.94). The intensified treatment was no better than was standard treatment in any subgroup of patients or in any secondary outcomes, including neurologic disability and time to a new neurologic event or death, the investigators said (N Engl J Med. 2016 Jan 14. doi:10.1056/NEJMoa1507062).
However, intensive therapy was associated with a higher frequency of seizures (23 vs. 11 patients), visual impairment (14 vs. 4 patients), allergic reactions (30 patients vs. 17 patients), jaundice (19 vs. 7 patients), grade 3 or 4 hyponatremia (112 patients vs. 81 patients), and adverse events leading to treatment interruptions (95 patients vs. 64 patients).
It is possible that raising the dose of rifampin by only 5 mg/kg may not have increased intracerebral drug concentrations “sufficiently to enhance bacterial killing. Recent data suggest that much higher doses (up to 35 mg/kg per day) may have an acceptable side-effect profile and may be necessary to significantly increase the killing of M. tuberculosis in pulmonary tuberculosis,” Dr. Heemskerk and her associates noted.
“Although the results of our study do not support a change in the currently recommended treatment regimens for tuberculous meningitis, enhanced antituberculosis treatment with higher doses of first-line drugs, including intravenous rifampin, or the newer antituberculosis drugs bedaquiline and delamanid, still require investigation,” they added.
Wellcome Trust and the Li Ka Shing Foundation supported the study. Dr. Heemskerk and her associates reported having no relevant financial disclosures.