Clinical efficacy of linezolid in the treatment of tuberculous meningitis: a retrospective analysis and literature review

Highlights

Retrospective study evaluating linezolid in 99 TBM patients.

Linezolid significantly reduced CSF protein levels, especially in critically ill patients.

Similar adverse event rates between groups.

Relevant literature reviews were reviewed.

Abstract

Background

Tuberculous meningitis (TBM) is the most severe form of tuberculosis, with high morbidity and mortality. This retrospective study evaluates the clinical efficacy of linezolid in patients with TBM.

Methods

We analyzed 99 TBM patients treated at the Shanghai Public Health Clinical Center from June 2013 to March 2020. Patients were divided into two groups: those receiving standard therapy (n = 43) and those receiving standard therapy plus linezolid (n = 56). Clinical outcomes, cerebrospinal fluid parameters, and adverse events were assessed.

Results

Of the included patients, 42.4% were female, and the median age was 24.00 (7.00–44.00) years. Baseline characteristics between the two groups were comparable. After six months of treatment, both groups showed improvements in cerebrospinal fluid parameters, with no significant differences in intracranial pressure, white blood cell count, glucose, or chloride levels (all P > 0.05). Adding linezolid significantly reduced cerebrospinal fluid protein levels compared to the standard therapy group (0.873 [0.228–1.591] g/L vs. 0.172 [-0.691–0.559] g/L, P = 0.018), correlating with better 6-month survival (adjusted OR 1.850, 95% CI 1.111–3.081, P = 0.018), with a stronger effect in critically ill patients (1.010 [0.257–2.019] g/L vs. 0.121 [-0.556–0.510] g/L, P = 0.004). Although intracranial lesion resolution rates were higher in the linezolid group, they were not statistically significant (P > 0.05). Adverse event rates were similar between groups (16.1% vs. 18.6%, P = 0.392).

Conclusion

Linezolid appears to offer clinical benefits in managing TBM, particularly in critically ill patients, warranting further prospective studies to optimize treatment protocols.

Introduction

According to the recent World Health Organization Global Tuberculosis Report, approximately 10.8 million people worldwide were infected with tuberculosis (TB) in 2023 [1]. TB continues to pose a significant public health burden, with tuberculous meningitis (TBM) being the most severe form of the disease [1]. Standard treatment regimens, while effective against drug-sensitive strains, exhibit limited efficacy for TBM due to their poor penetration across the blood-brain barrier, often resulting in suboptimal therapeutic concentrations in the cerebrospinal fluid and contributing to high mortality and neurological sequelae in drug-resistant cases [2]. Recent studies have demonstrated that linezolid exhibits potent anti-mycobacterial activity against mycobacterium tuberculosis (MTB), with robust efficacy against drug-resistant strains and high cerebrospinal fluid (CSF) penetration, suggesting its potential advantage in treating TBM [3,4,5,6]. However, data on the impact of linezolid on CSF parameters and intracranial lesion improvement in TBM patients remain limited. This study aims to evaluate the clinical efficacy of linezolid in patients with TBM.

Methods

This retrospective cohort study analyzed the medical records of 99 patients diagnosed with drug-sensitive TBM at the Shanghai Public Health Clinical Center from June 2013 to March 2020. The study aimed to evaluate the clinical efficacy of Linezolid, focusing on CSF parameters, intracranial lesion improvement, and overall treatment outcomes. Data were extracted from the hospital’s electronic medical records, and patients were included based on defined diagnostic criteria for TBM. The retrospective design ensured that no direct patient interventions were conducted during the study period. Patients with human immunodeficiency virus (HIV) infection, incomplete data, poor medication adherence, or other central nervous system infections were excluded from the study. All patients who received Linezolid provided informed consent after being fully briefed about the non-standard nature of the treatment, its potential benefits, and associated risks, including possible adverse effects. This study was conducted in compliance with ethical guidelines, and the protocol was reviewed and approved by the Ethics Committee of the Shanghai Public Health Clinical Center (approval number: 2024-S002-01). For the retrospective analysis of medical records, the Ethics Committee waived the requirement for informed consent, as the study did not involve direct patient intervention. All procedures adhered to ethical standards outlined by the Declaration of Helsinki and local regulations.

TBM was classified into “Definite,” “Probable,” and “Possible” categories based on clinical standards, relevant CSF indicators, brain imaging criteria, and other TB-related evidence [7].

Definite TBM: Diagnosis was confirmed by the presence of Mycobacterium tuberculosis in CSF via methods such as acid-fast bacilli staining, culture, or commercial nucleic acid amplification tests.

Probable TBM: This diagnosis was made if the total score from the diagnostic criteria was ≥ 10 without neuroimaging or ≥ 12 with neuroimaging.

Possible TBM: Diagnosis was considered when the total score was between 6 and 9 without neuroimaging or 6–11 with neuroimaging.

Tbm grading standards

The severity of TBM at admission was assessed using the British Medical Research Council (BMRC) grading system, which is based on Glasgow Coma Scale (GCS) scores and focal neurological deficits: [8]

Grade I: GCS score of 15 with no focal neurological deficits.

Grade II: GCS score of 15 with focal neurological deficits or GCS score of 11–14.

Grade III: GCS score ≤ 10.

All enrolled patients underwent detailed medical history-taking and physical examinations at baseline. Clinical data collected included general information (age, gender, residence, etc.), disease-related symptoms and signs (cough, sputum production, fever, headache, seizures, altered consciousness, extrapulmonary TB, etc.), TBM diagnostic classification, BMRC staging, relevant laboratory tests (blood routine, biochemistry, electrolytes, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), T-cell enzyme-linked immunospot assay (T-spot), lymphocyte subsets, etc.), CSF parameters (white blood cell count, chloride, glucose, protein levels, staining, and culture, etc.), and imaging examinations (chest X-ray/CT and cranial MRI/CT scans). Baseline CSF samples were obtained via lumbar puncture for all patients, and follow-up lumbar punctures were performed during treatment to evaluate therapeutic response and changes in CSF parameters, providing critical data on the progression and management of TBM.

The treatment regimens were as follows:

Non-LZD group (n = 43): standard four-drug anti-TB regimen consisting of rifampin (15 mg/kg, administered intravenously during hospitalization, followed by oral administration after discharge), isoniazid (15 mg/kg, administered intravenously during hospitalization, followed by oral administration after discharge), oral pyrazinamide (30 mg/kg), and oral ethambutol (15 mg/kg). The total duration of the treatment was 12 months.

LZD group (n = 56): The same standard regimen with the addition of 600 mg of linezolid daily (QD). The total treatment duration in this group was 12 weeks for linezolid, while the other anti-TB drugs were continued for the standard 12 months.

All patients received corticosteroid therapy (dexamethasone or prednisolone) based on TBM standard dosages and clinical judgment, along with necessary supportive treatments such as mannitol to reduce intracranial pressure. Patients were followed up monthly for 6 months after discharge, either through phone calls or outpatient visits, to assess clinical symptoms and signs, CSF parameters (protein levels, cell count, Pandy’s test positivity), imaging changes (cerebral infarction, tuberculoma, hydrocephalus, meningeal enhancement, and ventricular enlargement), medication adherence, and drug-related adverse events (visual disturbances, liver function impairment, bone marrow suppression, peripheral numbness, and rash). Treatment outcome was determined based on survival status at the end of the treatment course [9], or at six months if the patient did not complete the course. Outcomes were categorized as survival or death.

Statistical analysis

Statistical analyses were conducted using SPSS 25.0. Continuous variables were expressed as means ± standard deviations (SD) or medians (interquartile range, IQR), while categorical variables were presented as counts and percentages. Group comparisons were performed using the t-test, Mann-Whitney U test, χ2 test, or Fisher’s exact test as appropriate. Linear regression was employed to identify factors associated with changes in CSF parameters, and logistic regression was used for prognostic analysis, with odds ratios (ORs) adjusted for age and sex. Statistical significance was set at p < 0.05.

Results

Based on the exclusion criteria, a total of 99 TBM patients were retrospectively included (Fig. 1). Among them, 42.4% were female, 54.5% had extrapulmonary TB, and the median age was 24.00 (7.00–44.00) years. Fever was the most common symptom (71.7%). BMRC staging classified 55 patients in stage I, 36 in stage II, and 8 in stage III (Table 1). According to Marais criteria, 29 patients were diagnosed with definite TBM (CSF culture positive in 18 cases), 48 with probable TBM, and 22 with possible TBM. Forty-three received the standard four-drug anti-TB therapy (Non-LZD group), while 56 received the standard regimen plus linezolid (LZD group). Both groups were comparable in age, gender distribution, BMI, and symptoms. No significant differences were found in disease severity or blood test parameters (Table 1). We also performed a baseline comparison of demographic characteristics between the 91 patients with incomplete data and the enrolled cohort, as shown in Supplementary Table 1.

Fig. 1

Study flow diagram. LZD, linezolid; HIV, human immunodeficiency virus

Table 1 Demographic and clinical characteristics of study participants

At baseline, CSF protein levels were significantly higher in the LZD group compared to the Non-LZD group (1.352 vs. 0.685 g/L, P = 0.001), along with higher levels of ADA (6.00 vs. 1.96 U/L, P = 0.018) and lactate dehydrogenase (49.00 vs. 27.50 U/L, P = 0.045). No significant differences were observed in other CSF parameters (P > 0.05). After six months of treatment, both groups showed improvements in these parameters (Table 2 and Supplementary Table 2). Specifically, the LZD group demonstrated a significantly greater reduction in CSF protein compared to the Non-LZD group (0.873 vs. 0.172 g/L, P = 0.018, Fig. 2).

Table 2 Comparison of CSF parameters between groups at baseline and 6-Month Follow-Up

Fig. 2

Changes in CSF Parameters After Six Months of Treatment. This figure presents individual pre- and post-treatment changes in cerebrospinal fluid (CSF) parameters for the linezolid (LZD) and non-LZD groups after six months of treatment. Panel A shows the reduction in intracranial pressure, while Panel B depicts the decrease in CSF white blood cell (WBC) count. Panels C and D illustrate changes in CSF glucose and chloride levels, respectively. Panels E and F highlight changes in CSF adenosine deaminase (ADA) and lactate dehydrogenase (LDH) levels. Panel G demonstrates alterations in CSF protein levels for all patients, whereas Panels H and I focus on changes in mild and critically ill cases, respectively. *P < 0.05

When evaluating the proportion of patients with CSF protein levels within the normal range at six months, a greater proportion of patients in the LZD group achieved normal CSF protein levels compared to the Non-LZD group. In critically ill patients, the LZD group showed a significantly greater reduction in CSF protein (1.010 vs. 0.121 g/L, P = 0.004), while no significant difference was observed in mild cases (P = 0.379). This suggests that the reduction in CSF protein in the LZD group may be primarily driven by improvements in critically ill patients (Fig. 2). After adjusting for disease severity, the results still show that LZD was significantly associated with a reduction in CSF protein (P = 0.16).

Resolution of tuberculomas, hydrocephalus, meningeal enhancement, and ventricular enlargement occurred, with no significant differences between groups. Tuberculoma resolution rates were 93.8% vs. 85.7% (P = 0.526), hydrocephalus 66.7% vs. 50.0% (P = 0.604), meningeal enhancement 100.0% vs. 90.9% (P > 0.999), and ventricular enlargement 100.0% vs. 80.0% (P = 0.313). The incidence of drug-related adverse events was similar between the groups (16.1% vs. 18.6%; P = 0.392) (Table 3). No recurrence of TBM was observed in any patient during the follow-up period, as confirmed by a thorough review of each patient’s medical record.

Table 3 Comparison of Drug-Related adverse events between groups

To explore clinical factors associated with the reduction in CSF protein levels, a linear regression analysis was performed. Univariate analysis identified gender, abnormal muscle tone at disease onset, prothrombin time, positive Pandy’s test, positive CSF polymerase chain reaction, baseline CSF protein levels, and inclusion of linezolid in the treatment regimen as potential factors (P < 0.1). Multivariate analysis further confirmed that baseline CSF protein levels (B, 0.726; 95% confidence interval [CI], 0.521–0.931; P<0.001) and the addition of linezolid (B, 0.428; 95% CI, 0.029–0.827; P = 0.036) were independently associated with CSF protein reduction (Table 4). After adjusting for age and gender, a significant difference was observed between the LZD and non-LZD groups in critically ill patients (B = 0.824; 95% CI, 0.169–1.479; P = 0.015). However, no such difference was seen in non-critically ill patients, where the result did not reach statistical significance (B = 0.156; 95% CI, -0.745–1.058; P = 0.728). Additionally, we reanalyzed the data, including the 29 HIV-infected patients, in Supplementary Tables 3–6. The regression analysis showed no significant correlation between HIV infection and changes in CSF parameters or treatment outcomes (all P > 0.05). Furthermore, adjusting for HIV status in the multivariate analysis demonstrated that the addition of LZD remained independently associated with a reduction in CSF protein levels (B = 0.355; 95% CI, 0.012–0.697; P = 0.043).

Table 4 Univariate and multivariate analysis of factors associated with CSF protein reduction

At six months, the survival rate was 85.7% (48/56) in the LZD group and 81.4% (35/43) in the Non-LZD group, but the difference was not statistically significant (P = 0.563). Logistic regression analysis demonstrated that a reduction in CSF protein levels was significantly associated with survival (adjusted OR 1.850, 95% CI: 1.111–3.081, P = 0.018). There was no significant correlation between the diagnostic categories and changes in CSF parameters following treatment (all P > 0.05). Additionally, logistic regression analysis revealed no significant association between diagnostic categories and patient prognosis (P = 0.069).

Literature review

We reviewed papers in PubMed and Google Scholar using the keyword “Linezolid” AND (“Tuberculous meningitis” OR “tuberculosis meningitis”). Only clinical trials and randomized controlled trials published in English were included. Based on the search results, Table 5 summarizes the key clinical findings from these studies.

Table 5 Summary of literature review reporting the efficacy of LZD in patients with TBM

One notable study is a randomized controlled trial by Akhil Sahib et al., which evaluated linezolid as adjunctive therapy during the intensive phase of TBM treatment. The treatment group received 600 mg of oral linezolid twice daily (BD) alongside the standard anti-TB regimen. The results showed significant improvements in clinical outcomes, particularly in GCS and modified Rankin Scale (mRS) scores, with no major safety issues in the linezolid group [4]. Another retrospective study examined linezolid in rifampin-resistant (RR) and multidrug-resistant (MDR) TBM. Mortality was significantly lower in patients receiving a linezolid regimen compared to those who did not (0% vs. 60%, P = 0.045), indicating linezolid’s role in reducing mortality in RR/MDR-TBM cases [3]. In pediatric TBM, Huimin Li et al. found that adding linezolid to first-line therapy improved early symptoms and prognosis, shortened hospital stays, and had minimal adverse effects (P = 0.896) [5]. A retrospective analysis of 33 severe TBM patients (MRC grade II/III) reported significant benefits in the linezolid group. Kaplan-Meier analysis showed better GCS recovery (P = 0.032) and body temperature normalization (P = 0.032) within four weeks. The linezolid group also had higher CSF/blood glucose ratios (P = 0.04) and lower white blood cell counts (P = 0.02), reflecting better inflammation control [6].

Discussion

The present study provides a comprehensive evaluation of the clinical efficacy of linezolid in TBM patients, offering valuable insights into its potential benefits. Our findings indicate that linezolid, when added to the standard treatment regimen, can significantly reduce CSF protein levels, particularly in critically ill patients. This observation aligns with prior research indicating linezolid’s potent anti-mycobacterial activity and its ability to achieve high penetration into the CSF, making it a promising candidate for TBM treatment [3,4,5,6, 10, 11]. The marked reduction in protein levels observed in the critically ill subgroup further emphasizes linezolid’s potential benefits in advanced cases of TBM.

Previous research has shown that cycloserine and linezolid have favorable CSF penetration, with rates ranging from 80 to 100% [10]. Moreover, the LASER-TBM pharmacokinetic sub-study found that high-dose rifampin did not alter linezolid’s pharmacokinetics, further supporting its utility in TBM treatment [11]. A meta-analysis also demonstrated that linezolid reduced the risk of treatment failure (relative risk = 0.42, p = 0.02) and improved body temperature normalization (p < 0.001) [12].

Both groups showed improvements in CSF parameters after six months of treatment. The LZD group had higher, though not statistically significant, resolution rates of tuberculomas, hydrocephalus, meningeal enhancement, and ventricular enlargement, likely due to the small sample size and retrospective design. Patients in the LZD group generally had better outcomes, though the difference was not statistically significant, possibly due to worse baseline conditions in this group. Notably, LZD patients experienced a greater reduction in CSF protein levels, and this reduction was significantly correlated with improved prognosis, suggesting that linezolid may aid in resolving intracranial lesions and enhancing clinical outcomes.

Although the inclusion of linezolid in TB treatment regimens has been associated with significant clinical improvements, particularly in critically ill patients, concerns regarding adverse events such as myelosuppression, peripheral neuropathy, and anemia have prompted exploration into lower dosages and shorter treatment durations [13]. Recent studies suggest that reducing the linezolid dose to 300 mg daily or shortening the duration of therapy can maintain therapeutic efficacy while minimizing toxicity [14, 15]. A meta-analysis has further indicated that linezolid reduces the risk of treatment failure and enhances the resolution of clinical symptoms in TB patients [16]. However, the precise dosing strategies remain to be fully optimized, and further research is needed to balance efficacy and safety [17].

Our findings align with previous reports, demonstrating that linezolid significantly reduces cerebrospinal fluid protein levels, particularly in critically ill patients, suggesting enhanced control of the inflammatory response in TBM. Although no significant difference in the incidence of adverse events was observed between the two groups during treatment and moderate follow-up, it is important to note that long-term use of linezolid may increase the risk of certain side effects, including bone marrow suppression, peripheral neuropathy, and optic neuritis. With appropriate monitoring, linezolid may be safely administered to TBM patients without a significant increase in drug-related adverse events. However, given the potential cumulative toxicity of prolonged use, larger, randomized trials are needed to confirm these findings and refine therapeutic protocols, ensuring optimal outcomes with minimal side effects, particularly in cases requiring extended treatment durations.

The limitations of this study include its retrospective design, potential selection bias, and lack of randomization, all of which may impact the generalizability of the results. The retrospective nature of the study led to imbalances in baseline characteristics between the LZD and non-LZD groups. To address this, we performed multivariate analyses adjusting for key variables. Furthermore, the small sample size may have limited our ability to detect rare adverse events, such as bone marrow suppression and peripheral neuropathy. The relatively short follow-up period also may not have been sufficient to fully assess the long-term side effects of linezolid. Therefore, prospective studies with larger sample sizes and randomized controlled trials are needed to confirm these findings and refine treatment protocols for TBM.

In conclusion, our study demonstrates that linezolid can play a beneficial role in managing TBM, particularly in reducing CSF protein levels in critically ill patients. Prospective randomized trials are warranted to confirm these findings and refine therapeutic protocols.