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

Abstract

Tuberculous meningitis (TBM) presents a critical neurologic emergency characterized by high mortality and morbidity rates, necessitating immediate therapeutic intervention, often ahead of definitive microbiological and molecular diagnoses. The primary hurdle in effective TBM treatment is the blood–brain barrier (BBB), which significantly restricts the delivery of anti-tuberculous medications to the central nervous system (CNS), leading to subtherapeutic drug levels and poor treatment outcomes. The standard regimen for initial TBM treatment frequently falls short, followed by adverse side effects, vasculitis, and hydrocephalus, driving the condition toward a refractory state. To overcome this obstacle, intrathecal (IT) sustained release of anti-TB medication emerges as a promising approach. This method enables a steady, uninterrupted, and prolonged release of medication directly into the cerebrospinal fluid (CSF), thus preventing systemic side effects by limiting drug exposure to the rest of the body. Our review diligently investigates the existing literature and treatment methodologies, aiming to highlight their shortcomings. As part of our enhanced strategy for sustained IT anti-TB delivery, we particularly seek to explore the utilization of nanoparticle-infused hydrogels containing isoniazid (INH) and rifampicin (RIF), alongside osmotic pump usage, as innovative treatments for TBM. This comprehensive review delineates an optimized framework for the management of TBM, including an integrated approach that combines pharmacokinetic insights, concomitant drug administration strategies, and the latest advancements in IT and intraventricular (IVT) therapy for CNS infections. By proposing a multifaceted treatment strategy, this analysis aims to enhance the clinical outcomes for TBM patients, highlighting the critical role of targeted drug delivery in overcoming the formidable challenges presented by the blood–brain barrier and the complex pathophysiology of TBM.

Efficacy and safety of intrathecal dexamethasone combined with isoniazid in the treatment of tuberculous meningitis: a meta-analysis

“…The intrathecal injection is the process of injecting a drug directly into the subarachnoid space [ 10 , 44 ]. As such, the drug enters the CSF directly without crossing the blood–brain barrier and reaches its effective concentration rapidly [ 10 , 44 ].…”

“…The intrathecal injection is the process of injecting a drug directly into the subarachnoid space [ 10 , 44 ]. As such, the drug enters the CSF directly without crossing the blood–brain barrier and reaches its effective concentration rapidly [ 10 , 44 ]. Advantages of intrathecal therapy include increased concentrations of anti-TB drugs in the CSF to improve efficacy, and reduced side effects of anti-TB drugs, such as gastrointestinal discomfort and hepatotoxicity [ 10 , 44 , 45 ].…”

“…As such, the drug enters the CSF directly without crossing the blood–brain barrier and reaches its effective concentration rapidly [ 10 , 44 ]. Advantages of intrathecal therapy include increased concentrations of anti-TB drugs in the CSF to improve efficacy, and reduced side effects of anti-TB drugs, such as gastrointestinal discomfort and hepatotoxicity [ 10 , 44 , 45 ]. However, intrathecal therapy still carries risks, such as nosocomial CNS infections even when injections are performed under sterile conditions [ 46 , 47 ].…”

“…However, intrathecal therapy still carries risks, such as nosocomial CNS infections even when injections are performed under sterile conditions [ 46 , 47 ]. Currently, there is no consensus on intrathecal injection frequency and safety, and there are fewer references on intrathecal injections for TBM [ 10 ] (the frequency of intrathecal injections for each of the included studies is found in Table 2 ).…”

“…Currently, TBM is treated primarily using oral or intravenous anti-pulmonary TB regimens, the drug regimen and dosing duration for each stage of TBM are not as clearly defined compared with pulmonary TB [ 9 ], leading to urgent calls for action for new and better defined treatment strategies [ 4 ]. It has been suggested that intrathecal anti-TB medication has become a promising approach for the treatment of TBM [ 10 ], where drugs used for intrathecal injections include streptomycin and hydrocortisone [ 11 ], isoniazid, dexamethasone, and chymotrypsin [ 12 ], and isoniazid and prednisone [ 13 ]. It is also suggested that intrathecal antibiotics should be considered, especially for multi-drug-resistant bacteria, if no response to intravenous antibiotics or CSF drug concentrations is achieved [ 14 ], and there is increasing evidence of their efficacy [ 12 , 13 , 15 ].…”