Related Experiment Videos
Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis
G A Ellard1, M J Humphries, B W Allen
1National Institute for Medical Research, London, United Kingdom.
Abstract:
Tuberculous meningitis is a very serious form of tuberculosis. In the absence of randomized controlled trials of alternative treatment regimens, its management depends on employing potent drugs that penetrate well into the cerebrospinal fluid (CSF). The penetration of isoniazid, rifampin, and streptomycin into the CSF of 27 Chinese patients was studied using fluorimetric and microbiologic procedures. Isoniazid rapidly diffused into the CSF, peak concentrations in excess of 3 mg/L, or over 30 times its minimal inhibitory concentration (MIC) against Mycobacterium tuberculosis being attained within 4 hr. In contrast, rifampin and streptomycin penetrated very slowly across the meninges, and CSF levels only slightly in excess of their MICs against M. tuberculosis were achieved. The penetration of the drugs into the CSF correlated poorly with differences in their partitioning between octanol/water and cyclohexane/water but could be predicted using a simple model based on their renal clearance rates and plasma protein binding. It is recommended that patients with tuberculous meningitis should be treated for at least 9 months with a combination of isoniazid, rifampin, and pyrazinamide, which may be supplemented in the first 2 mo with streptomycin.
Insights
Tuberculous meningitis treatment requires drugs that reach cerebrospinal fluid (CSF). Isoniazid effectively penetrates CSF, while rifampin and streptomycin penetration is poor, impacting treatment efficacy for this serious tuberculosis form.
Area of Science:
- Infectious Diseases
- Neurology
- Pharmacology
Background:
- Tuberculous meningitis (TBM) is a severe form of tuberculosis with high morbidity and mortality.
- Effective TBM management relies on antimicrobial agents with adequate cerebrospinal fluid (CSF) penetration.
- Limited clinical trial data necessitates understanding drug pharmacokinetics in TBM.
Purpose of the Study:
- To evaluate the CSF penetration of key anti-tuberculosis drugs: isoniazid, rifampin, and streptomycin.
- To correlate drug penetration with physicochemical properties and patient factors.
- To inform optimal treatment strategies for tuberculous meningitis.
Main Methods:
- Studied CSF drug concentrations in 27 Chinese patients with TBM using fluorimetric and microbiologic assays.
- Measured peak and trough levels of isoniazid, rifampin, and streptomycin in CSF and plasma.
- Correlated CSF penetration with octanol/water and cyclohexane/water partitioning, renal clearance, and plasma protein binding.
Main Results:
- Isoniazid demonstrated rapid and high CSF penetration, exceeding 30 times its MIC within 4 hours.
- Rifampin and streptomycin showed slow penetration, achieving CSF levels only slightly above their MICs.
- Drug penetration correlated poorly with lipid solubility but was predictable by a model incorporating renal clearance and protein binding.
Conclusions:
- Isoniazid is a key component for TBM treatment due to excellent CSF penetration.
- Rifampin and streptomycin penetration is limited, suggesting potential need for alternative or adjunctive therapies.
- Recommended treatment duration for TBM is at least 9 months with isoniazid, rifampin, and pyrazinamide, possibly supplemented with streptomycin initially.