Pharmacokinetics of Antituberculosis Drugs in Plasma and Cerebrospinal Fluid in a Patient with Pre-Extensive Drug Resistant Tuberculosis Meningitis

Abstract

Drug-resistant tuberculous meningitis (TBM) is the most devastating and critical form of extrapulmonary tuberculosis. Here, we present a case of a 45-year-old male with pre-extensive drug-resistant tuberculosis meningitis (pre-XDR-TBM). He underwent emergency surgery for the long-tunneled external ventricular drainage (LTEVD). Molecular test and phenotypic drug sensitivity test (DST) of Mycobacterium tuberculosis in cerebrospinal fluid (CSF) showed that the isolate was resistant to both rifampin and fluoroquinolones. An anti-tuberculous regimen of isoniazid, pyrazinamide, cycloserine, moxifloxacin, clofazimine, and linezolid was tailored accordingly. We monitored the drug concentration in his plasma and CSF before (at 0-hour) and after anti-TB drugs administration (at 1-hour, 2-hour, 6-hour, and 12-hour) on 10 th day after treatment initiation. We hope to provide reference values of drug exposures in plasma and CSF for patients with pre-XDR-TBM.

Comprehensive Therapeutic Approaches to Tuberculous Meningitis: Pharmacokinetics, Combined Dosing, and Advanced Intrathecal Therapies

“…Utilizing a high dose (800 mg/d), peak CSF concentration (11.57 μg/mL) was observed after 6 h, indicating nearly 100% brain penetration and effective bactericidal activity [ 61 ]. Long-term use of INH may lead to peripheral neuropathy at the sixth month, with reported neuritis [ 92 ]. The MIC of RIF for pre-XDR-TBM found in a case study > 16 µg/mL and for INH is 0.06 µg/mL while the reference value is <1 and <0.25, respectively [ 92 ].…”

“…Long-term use of INH may lead to peripheral neuropathy at the sixth month, with reported neuritis [ 92 ]. The MIC of RIF for pre-XDR-TBM found in a case study > 16 µg/mL and for INH is 0.06 µg/mL while the reference value is <1 and <0.25, respectively [ 92 ].…”

“…Human efflux transporters could further impede brain and CSF access. Findings suggest limited benefits of clofazimine in treating MDR- or pre-XDR-TBM [ 92 ]. The drug’s high plasma protein binding rate and potential interaction with human efflux transporters may impede its CNS access, highlighting the challenges of achieving therapeutic CSF concentrations with certain anti-TB drugs.…”

“…TDM might be considered in specific cases, like when there is persistent positivity in CSF cultures and evidence of therapeutic failure [ 40 , 140 ]. The proposal to use positron emission tomography for tracking drug distribution in TBM patients indicates a potential shift for future research [ 92 , 141 ].…”