Isoniazid Resistance and Tuberculous Meningitis

Summary and Comment |
September 15, 2010

Isoniazid Resistance and Tuberculous Meningitis

  1. Stephen G. Baum, MD

Among patients with tuberculous meningitis and positive cerebrospinal fluid cultures, initial isoniazid resistance significantly raised the risk for death.

  1. Stephen G. Baum, MD

Tuberculous meningitis, a devastating manifestation of tuberculosis (TB), has become more common since the convergence of the TB and HIV epidemics. Isoniazid (INH) is the only bactericidal component of modern antituberculous therapy that easily crosses the blood–brain barrier, and it is the first-line drug with the strongest early bactericidal activity. When INH has been used in combination with other active antituberculous drugs, initial INH resistance has not been associated with poorer outcomes in patients with pulmonary TB. But what about patients with tuberculous meningitis?

Using records from the CDC's National Tuberculosis Surveillance System, researchers examined data on cases of tuberculous meningitis reported from 1993 (when drug-susceptibility information was first collected) through 2005. The completeness of this reporting system was previously shown to be >99%. Approximately 97% of culture-positive cases have accompanying drug-susceptibility data.

Among the patients with TB reported during this period, 3114 had a clinical diagnosis of tuberculous meningitis, were alive at diagnosis, and were started on antituberculous therapy. Those who had cultures (from any site) positive for Mycobacterium tuberculosis, had INH susceptibility information, and did not have multidrug-resistant disease were selected for analysis (n=1896).

During treatment, 541 patients died: 43 of the 123 with INH-resistant bacteria, compared to 498 of 1773 without such resistance (35% vs. 28%; odds ratio, 1.38; 95% confidence interval, 0.94–2.02). Among the 1614 patients with positive cerebrospinal fluid (CSF) cultures, initial INH resistance was associated with subsequent death (OR, 1.61; 95% CI, 1.08–2.40). This association was independent of patients' HIV status.


Given the difficulty of achieving therapeutic and bactericidal drug levels in CSF, it is not surprising that INH resistance confers increased mortality in patients with tuberculous meningitis. The authors excluded patients with multidrug-resistant disease; with the marked increase in such infections during the last decade, one can only assume that the situation has worsened. As the authors point out, second-line drugs such as cycloserine and the fluoroquinolones may not even be available in the areas where they are most needed.


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