Peculiarities of penetration of anti-tuberculosis drugs into the foci of infection in patients with tuberculosis of the central nervous system and the choice of pharmacotherapy

Abstract

Background. Tuberculosis (TB) of the central nervous system (CNS) is the most severe and life-threatening form of TB. Diagnosis of TB of CNS is difficult, and treatment is suboptimal. At present, the treatment of tuberculous meningitis (TBM) involves the same drugs and doses as for pulmonary TB, however, the problem is that not all the drugs cross the blood-brain barrier.
 Objective. To describe the penetration of anti-TB drugs (ATBD) into the foci of infection in patients with TB of CNS and the choice of pharmacotherapy.
 Materials and methods. Analysis of literature sources on this issue.
 Results and discussion. Options for optimizing the TBM treatment include a non-pharmacological approach, treatment prolongation, and increasing the residence time of ATBD at the infection site. A meta-analysis of 17 observational studies found no significant benefits of 9-month treatment over 6-month regimens. To increase the residence time of the drug in CNS, you can increase the dose of drugs that poorly penetrate the CNS, add drugs with better brain penetration characteristics, modify drug delivery systems and physical and chemical properties of drugs. The optimal dose provides the maximum effectiveness of the active substance on the background of the minimum number of side effects, so increase of the dose without taking into account the risks of side effects is not advisable. One of the main ATBD rifampicin is characterized by poor penetration into the cerebrospinal fluid. The killer activity of rifampicin depends on its concentration. In our own study, it was found that the administration of a high dose of rifampicin (600 mg) intravenously for 14 days was characterized by lower mortality in patients with TBM than treatment with oral rifampicin (standardized risk ratio was 0.42). Intravenous high-dose treatment was safe and well tolerated by patients. The disadvantages of this treatment include its high cost, invasiveness and poor availability. A meta-analysis of Indonesian patient data confirmed that high doses of rifampicin were associated with lower mortality (Svensson E. et al., 2019). Other drugs that need research in TBM include a new drug bedaquiline, fluoroquinolones (levofloxacin), linezolid. Isoniazid, pyrazinamide, cycloserine, ethionamide, prothionamide are also characterized by the good permeability to cerebrospinal fluid. Therefore, in a strategy to optimize the TBM treatment high-dose rifampicin, high-dose isoniazid and pyrazinamide (?) are the first line, and cycloserine, ethionamide, linezolid, delamanide, pretomanide – the second line.
 Conclusions. 1. Diagnosis of TB of CNS is difficult, and treatment is suboptimal. 2. Not all the drugs cross the blood-brain barrier. 3. Options for optimization of the TBM treatment include a non-pharmacological approach, prolongation of therapy and increasing the residence time of ATBD in the infection focus. 4. Administration of high-dose rifampicin (600 mg) intravenously for 14 days was characterized by lower mortality in patients with TBM than treatment with oral rifampicin. 5. High-dose rifampicin, high-dose isoniazid and pyrazinamide (?) are the first line of TBM treatment.