Abstract

Background: Tuberculous meningitis (TBM) is the most common central nervous system infection of Mycobacterium tuberculosis (M.tb). The infection will cause focal neurological deficits and can be fatal, so that it will increase the morbidity and mortality rates. Adequate treatment is needed so that the drug can reach the center of infection. Not all anti-tuberculosis (TB) drugs can effectively cross the blood–brain and blood-cerebrospinal fluid barriers. The use of higher doses is expected to be able to work on the center of infection effectively. However, the use of higher doses will also increase the risk of drug-induced liver injury, which requires temporary discontinuation of the suspected drug.

Methods: This scientific work aims to determine the penetration rate of first-line anti-TB drugs that are often used in patients infected with M.tb, especially TBM. Journal searches were performed on PubMed/PMC and BioMed Central/BMC search engines with the appropriate keywords. Critical appraisal analysis was carried out in selected journals. CSF sampling can be done to establish the diagnosis of TBM. CSF characteristics in TBM include lymphocyte pleocytosis, increased protein levels, and decreased glucose levels.

Results: The results of CSF analysis depend on the volume of CSF used, the delivery of the sample, and the technical expertise of the clinician. If clinically, a patient is suspected of having TBM even though the results of CSF analysis show negative results for M.tb bacteria, a drug regimen can be given immediately to prevent worsening of the patient’s condition. Bacterial cultures may be performed as treatment progresses. Based on the penetration rate of anti-TB drugs in the CSF, isoniazid (INH), pyrazinamide, and fluoroquinolones, especially levofloxacin, are drugs with fairly good CSF penetration.

Conclusion: The use of INH is beneficial because it has high bactericidal activity. Gatifloxacin and ciprofloxacin, which are included in the fluoroquinolone class of drugs, are safe to use even though their CSF penetration is not as good as levofloxacin.

Keywords: Anti-tuberculosis drug penetration, Cerebrospinal fluid, Tuberculous meningitis

INTRODUCTION

Tuberculous meningitis (TBM) is the most serious disease of the central nervous system caused by the spread of Mycobacterium tuberculosis (M.tb) in the meninges or lining of the brain, which can even extend to the brain parenchyma.[ 1 , 2 ] Early diagnosis and appropriate therapy are needed to be able to determine the patient’s condition in the future, improve or die. Various ways of establishing the diagnosis of tuberculosis (TB) can be done, one of which is by analyzing cerebrospinal fluid (CFS) samples to see levels of glucose, protein, lymphocytes, and others.[ 3 ] Not only for diagnosis but CFS can also be used for monitoring therapy to determine the patient’s prognosis.[ 4 ]

MATERIALS AND METHODS

A search for related journal articles was performed on the PubMed/PMC and BioMed Central/BMC search engine. Search for journal articles using the advanced search feature with keywords such as “cerebrospinal fluid analysis” OR “CSF” AND “tuberculosis” OR “tuberculosis meningitis.” The journals used are original English journals for the period 2013–2023, which contain information about the design, objectives, population, results, and limitations of the study. Critical appraisals are carried out on selected journals to facilitate understanding of the contents of the journal.

RESULTS

Seven journals match the criteria. Out of the seven journals obtained, three of them had experimental research designs, and the rest were retrospective and prospective studies with two journals, respectively. There are many articles with appropriate topics, and the discussion is quite interesting and easy to understand. Unfortunately, they are not original articles and do not contain the required information, as shown in Table 1 .

Table 1:

The main sections of the articles reviewed in regard to cerebrospinal fluid analysis in TBM.

DISCUSSION

TBM diagnosis based on CSF analysis

Sampling and analysis of CSF are very important to aid in diagnostic tests, description of groups, and determining prognosis.[ 3 , 11 ] The diagnosis of TBM can be difficult and may be based solely on clinical findings and initial CSF examination [ Table 2 ] without definitive microbiological confirmation. Certain clinical characteristics such as long duration of symptoms (>6 days), moderate CSF pleocytosis, and the presence of focal neurological deficits raise the possibility of TBM.[ 3 ] Characteristic CSF findings from TBM include:

Lymphocytic predominant pleocytosis. The total white blood cell count usually ranges between 100 and 500 cells/µL. In the early development of the disease, the neutrophil count may be lower.

Table 2:

Clinical and CSF findings in pediatric and adult patients with TBM.[ 1]

A single CSF acid-resistant smear sample has low sensitivity, around 20–40%. Several large-volume lumbar punctures (10–15 mL) daily are often necessary to establish the microbiological diagnosis; sensitivity increases to >85% when four lumbar puncture samples have been obtained.[ 5 ] Although culture can take several weeks and also has low sensitivity (∼40–80%), culture should still be performed to determine drug susceptibility. Isoniazid (INH)-resistant strains of M.tb have been associated with a two-fold increase in mortality.[ 3 ]

Given the relatively low sensitivity of acid–fast smears and the time-consuming process of culturing, new diagnostic methods for TBM have been developed recently.[ 6 ] Although enzyme-linked immunosorbent assay tests have been developed to detect specific antibodies to M.tb antigen in CSF with varying sensitivity, their limited availability precludes their use in resource-poor countries. A recent study in children aged 6–24 months showed that adenosine deaminase levels ≥10 U/L in CSF had >90% sensitivity and specificity for diagnosing TBM. However, other studies have demonstrated poor adenosine deaminase specificity for diagnosing TBM in certain populations, particularly in adults who are also infected with human immunodeficiency virus (HIV) or have cerebral lymphoma.[ 3 ]

CSF sampling

Microbiological results are affected by CSF volume, delivery of samples, processing techniques, and technical expertise of laboratory personnel. The volume of CSF sample used for each mycobacterial diagnostic test should be reported. In addition, adequate quality assurance from all research laboratories is essential to ensure the reliability of the test.[ 3 , 11 ]

Pharmacokinetic activity of anti-TB drugs on CSF penetration

Prompt and appropriate treatment can produce satisfactory results in TBM patients. Thus, empiric treatment is necessary when clinical features and CSF findings suggest TBM even before microbiological confirmation. The recommended treatment regimen for suspected drug-susceptible TBM consists of 2 months of daily INH, rifampicin (RIF), pyrazinamide (PZA), and either streptomycin (SM) or ethambutol (EMB), followed by INH and RIF for 7–10 months. Months [ Table 3 ]. INH is considered the most critical of the first-line agents because of its excellent CSF penetration and high bactericidal activity [ Table 4 ]. Apart from being caused by the low penetration of RIF into CSF, the high mortality of TBM is also caused by the presence of a type or strain of bacteria that is resistant to RIF. PZA has excellent penetration into the CSF and is a key drug in reducing the total treatment time for drug-susceptible TB. Therefore, if PZA is not tolerated, treatment for TBM should be extended for a total of 18 months. Inflammation disrupts the BBB and thus would allow these two drugs to enter the brain cells. It should be emphasized that not only the choice of antimicrobials but also the doses used and the duration of treatment are empiric in TBM and are largely based on the treatment of pulmonary TB.[ 3 ]

Table 3:

Anti-TB drug recommendations for TBM cases.[ 3]

Table 4:

Pharmacokinetic activity and CSF penetration of antituberculosis drugs.[ 3]

Given that the new generation fluoroquinolones (FQNs), e.g., levofloxacin and moxifloxacin, have strong activity against most strains of M.tb and have excellent CSF penetration and safety profiles, FQNs appear to have great potential as part of first-line therapy for TBM. In a randomized controlled study for the treatment of TB, the addition of an FQN to a standard regimen improved anti-TB performance as measured by various clinical parameters. Although there was no significant difference in mortality, this study does not appear to have sufficient power to demonstrate this effect. It is important to note that serum FQN concentrations are lowered with concomitant RIF use; furthermore, the ratio of optimal area-under-curve to minimum inhibitory concentration for FQNs as anti-TB agents has not been well elucidated. Another randomized controlled study is currently underway to evaluate TBM treatment with high-dose RIF and levofloxacin compared with standard treatment; if the result is positive, the standard treatment recommended may change in the future. No controlled trials have been published to date for the treatment of multidrug-resistant TBM, which is defined as resistance to at least INH and RIF. In addition, very few studies have been published on the CSF penetration of many second-line and newer anti-TB agents.[ 3 ]

Two recent studies have investigated the role of intensive therapy for TBM. The first is a parallel three-arm randomized controlled trial comparing the effect of adding a fluoroquinolone (ciprofloxacin, levofloxacin, or gatifloxacin) to standard therapy in 61 Vietnamese adults with TBM. Levofloxacin has greater CSF penetration than gatifloxacin or ciprofloxacin. Surprisingly, worse outcomes were noted in patients with lower and higher fluoroquinolone exposure compared with intermediate exposure. Those with high exposure are older and tend to have more severe diseases, which may result in greater damage to the blood–brain barrier. A second study conducted in Indonesia investigated the use of high-dose (600 mg) or standard (450 mg) rifampicin and high-dose (800 mg) or standard (400 mg) moxifloxacin in 60 Indonesian adults with TBM. High-dose rifampin results in increased plasma and CSF levels and is associated with reduced mortality (65 vs. 35%). A large randomized controlled trial of high-dose rifampicin and levofloxacin versus standard therapy is underway in Vietnam and is expected to be reported soon.[ 1 ]

Among the new anti-TB agents, bedaquiline (TMC207, a diarylquinoline) and delamanid (OPC-67683, a nitro-dihydroimidazo-oxazole) appear most promising. Both drugs are still in phase III clinical trials. Three additional new agents, sudoterb (LL3858, a pyrrole derivative), PA-824 (nitroimidazole-oxazine), and SQ109 (an EMB analog), are currently in phase II trials. Their ability to penetrate the CSF has not been studied sufficiently [ Table 4 ].[ 3 ]

Pharmacokinetic analysis should ideally include plasma and CSF measurements, although CSF concentrations may not reflect brain tissue concentrations of highly lipophilic drugs. CSF sampling after weeks of treatment may yield different results, as penetration of CSF drugs may decrease as meningeal inflammation decreases. The standard method for assessing CSF penetration is the ratio of CSF to plasma to total drug exposure (area under the concentration–time curve) over the dosing interval, which requires multiple plasma and CSF samples.[ 11 ]

Suppose a detectable high plasma level of the protein-bound drug has excellent CSF penetration. In that case, the CSF-to-plasma ratio based on the nonprotein-bound drug concentration will be close to one. Conversely, a ratio based on total concentration (bound + unbound) would incorrectly indicate poor penetration, as is the case with rifampicin. Therefore, correction of protein binding to plasma concentrations should always be performed. Of note, drug concentrations in CSF cannot be measured using plasma assays without careful validation.[ 11 ]

CONCLUSION

Drugs that can act on the central nervous system are needed to treat TBM. In other words, the drugs used should be drugs that can penetrate the blood–brain barrier and blood-CSF barrier. It was stated in the journal that the concentration of some TB drugs in CSF is lower than plasma concentrations, so it requires higher doses of drugs to reach the brain. Meanwhile, high doses of drugs are believed to cause side effects such as drug-induced liver injury, which requires temporary discontinuation of the drug suspected of causing this condition. Therefore, further research is needed regarding the types of drugs that can effectively penetrate the blood barrier so that they can reach the center of infection in treating TBM.

Ethical approval:

Institutional Review Board approval is not required.

Declaration of patient consent:

Patient’s consent is not required as there are no patients in this study.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

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