Linezolid-associated optic neuropathy in drug-resistant tuberculosis patients in Sulianti Saroso Infectious Disease Hospital

Introduction

Linezolid is a synthetic antibiotic from the oxazolidinone class, widely used to treat infections caused by Gram-positive bacteria. These include infections from vancomycin-resistant Enterococcus, MRSA,^1–3 hospital-acquired pneumonia caused by Staphylococcus aureus,^4,5 and community-acquired pneumonia due to Streptococcus pneumoniae.^6–8 Additionally, it is recommended as a first-line component in standard treatment regimens for patients with multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR-TB), as well as those with fluoroquinolone-resistant strains (pre-XDR-TB).⁹

From 2019 to 2022, the treatment guidelines for MDR/RR-TB recommended by the World Health Organization (WHO) were based on programmatic data, suggesting the use of a minimum of five drugs.^10,11 The three most effective group A drugs are bedaquiline, linezolid, and fluoroquinolone, depending on their tolerability and susceptibility.^12–14 The recommendations specified treatment lengths that varied from a 6-month short course for certain patients to a longer 18-month regimen. Nonetheless, typical side effects linked to these treatments included liver toxicity, along with hematological and neurological complications from extended therapy.¹⁵ The safety of BPaL-containing regimens, which may also include an additional fourth antimicrobial agent, is a critical focus. Linezolid, classified as an oxazolidinone antibiotic, is repurposed for TB treatment but has been associated with peripheral neuropathy,^16,17 optic neuropathy,^18,19 and bone marrow toxicity,¹⁷ especially at high doses.

Although linezolid is highly effective, its prolonged use in patients with multidrug-resistant tuberculosis (MDR TB) is limited by its adverse effects. Approximately 30% of patients experience myelosuppression, particularly those receiving higher doses (over 600 mg per day). Additionally, about 30% develop neurotoxicity, resulting in peripheral neuropathy after 2 to 4 months of treatment with lower doses (less than 600 mg per day). Furthermore, linezolid-associated optic neuropathy occurs in roughly 30% of patients after 5 to 10 months of treatment.²⁰

Linezolid binds to a specific site on the bacterial 23S ribosomal RNA within the 50S subunit, effectively blocking the formation of a functional 70S initiation complex. This mechanism inhibits protein synthesis and disrupts bacterial reproduction. Linezolid exhibits bactericidal activity against most streptococcal strains while demonstrating bacteriostatic effects against staphylococci and enterococci. Consequently, it may not be the best choice for immunosuppressed patients.^3,21,22 The modification of mitochondrial oxidative metabolism within the optic nerve is hypothesized to underlie the pathogenesis of optic neuropathy associated with linezolid.

In clinical studies, the most frequently reported adverse reactions in patients treated with linezolid include diarrhea, vomiting, headache, nausea, and anemia. Additionally, cases of myelosuppression, optic neuropathy, and peripheral neuropathy have been documented. Notably, spontaneous reports of optic and peripheral neuropathies in patients receiving linezolid have primarily occurred when treatment extended beyond the approved maximum duration of 28 days.^23–25 Some visual recovery is reported following treatment discontinuation.¹⁶

The literature on the duration of linezolid treatment in drug-resistant TB patients experiencing optic neuropathy is still limited. This study aims to investigate the effects of the duration of linezolid treatment, both short-term and long-term regimens, on drug-resistant TB patients and the incidence of optic neuropathy as a side effect.

Methods

Population

We conducted a retrospective study of all patients with confirmed drug-resistant tuberculosis (DR-TB) who received linezolid between January 2022 and December 2024 and had been followed up after the end of treatment. All patients were admitted to Sulianti Saroso Infectious Disease Hospital. The tuberculosis treatment regimen was customized for each patient according to their drug susceptibility testing results and in collaboration with the TB RO team, following the recommendations of the World Health Organization (WHO).¹⁴ A total of 103 patients diagnosed with drug-resistant tuberculosis (DR-TB) who were undergoing a regimen that included linezolid (Lzd) participated as subjects in this study. Patient undergoing treatment with ethambutol were excluded. Details regarding the sample selected and the recruitment process for the study subjects are illustrated ( Figure 1). This approach utilized the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10).

Figure 1. Recruitment flow of subject.

Result

Table 1 shows that the majority of patients are in the productive age group (≤60 years). Males (67.7%) had a higher proportion of ON cases compared to females (32.3%). However, the difference may not be very large. Patients drug-resistant tuberculosis (DR-TB) patients receiving linezolid (Lzd)-containing regimen and compares those with and without optic neuropathy (ON). Patients on treatment for >6 months had a higher likelihood of developing ON (87.1% vs. 55.6% in those without ON). Those treated for ≤6 months had a lower ON occurrence (12.9% vs. 44.4%). Longer treatment duration appears associated with a higher risk of ON. Smoking appears to be a major risk factor for developing ON. Linezolid dose (≥600 mg vs. ≤600 mg) does not show a major difference in ON risk.

Table 2 presents the results of a survival analysis, likely using Cox proportional hazards regression. The information presented includes both crude hazard ratios (cHR) and adjusted hazard ratios (aHR), along with their 95% confidence intervals (CI) and p-values for different variables. Some variables, such as Diabetes Mellitus, Age, Sex, Alcohol use, HIV/AIDS, and some BMI measures, do not have an aHR reported, meaning they may not have been included in the final adjusted model. Smoking and treatment duration are significant risk factors affecting optic neuropathy. Treatment duration (>6 months) is significantly an increased hazard (risk) three times more ON than the patient gets treatment duration ≤6 months (p=0.039; adjHR: 3.06; 95%CI: 1.06-8.85). Active smoking patients are at 2.9 times the risk of developing ON compared to non-smokers. Other factors like diabetes, age, and sex do not show significant associations in this model ( Table 2).

Discussion

In the population of DR-TB patients undergoing Linezolid treatment. There was a predominance of males. Accounting for 60.2%. This finding is supported by studies conducted by Safaev et al. and Jaspard et al.^20,30 One possible explanation for this trend could be the increased susceptibility to infections resulting from factors more prevalent in men. Such as smoking. Which can lead to toxic lung injury and diminished immune cell function. These behavioral factors. More commonly exhibited by men, it is likely to contribute to the male dominance observed in this study.³¹

The most prevalent age group identified in this study was individuals under 60 years old. Accounting for 94.2% of the cases. A similar finding was reported in studies conducted in Myanmar and Korea.^32,33 The predominance of the <60 age group in tuberculosis cases may be attributed to several factors: reduced immunity. A higher prevalence of comorbidities. And increased mobility. This demographic is typically more active and productive compared to those over 60, which may enhance the transmission of the disease.³⁴

Optic neuropathy is a common toxic effect associated with the long-term use of linezolid in the treatment of drug-resistant tuberculosis.³⁵ Optic Neuropathy may originate from various factors, including exposure to toxic substances and deficiencies in essential nutrients.^26,36 Existing literature indicates that prescribed daily doses of linezolid range from 300 mg to 1.200 mg, all of which have proven effective when closely monitored to accommodate the specific conditions of patients. However, adverse events have been reported, and their occurrence appears to be linearly correlated with the duration of treatment.³⁷

Diagnosing optic neuropathy is complex and necessitates an optical examination by a qualified professional. To monitor the adverse effects of treatment. Ophthalmologists conduct thorough ophthalmologic examinations for both hospitalized patients and outpatients. Reported ophthalmologic adverse effects include visual acuity loss, visual color abnormalities, and fundus abnormalities. If a patient indicates visual impairment suggestive of optic neuropathy. An ophthalmologist performs a detailed clinical examination, which includes measuring Snellen’s best-corrected visual acuity, conducting slit lamp examinations, performing funduscopic examinations, and assessing color vision using Ishihara tests. Therapeutic drug monitoring for linezolid is initiated for all patients at the beginning of treatment.

Optic neuropathy is an adverse effect associated with prolonged linezolid use.³⁸ In our study. 31 patients developed optic neuropathy, and we found that long-term treatment with linezolid (beyond 6 months) is significantly associated with an increased risk of optic neuropathy in patients with drug-resistant tuberculosis. This highlights the necessity for careful monitoring and consideration of treatment duration in these individuals. Especially. a treatment duration exceeding 6 months is associated with a threefold increase in the hazard of developing optic neuropathy compared to those treated for 6 months or less (p=0.039; adjHR: 3.06; 95% CI: 1.06-8.85). Our findings align with previous studies that reported a link between linezolid treatment and optic neuropathy. A study by Mehta et al. also found a higher incidence of optic neuropathy in patients treated with linezolid for more than 6 months.³⁹ A study by Tang S et al. shows that patients treated with linezolid for more than 6 months had a higher incidence of Optic Neuropathy.⁴⁰

Active smoking patients are at 2.9 times the risk of developing ON compared to non-smokers. This observation is concerning. as smoking is already a well-established risk factor for various forms of optic neuropathy in the general population. A study by Siddharth et al. shows that causes of toxic optic neuropathy include tobacco.⁴¹ The cyanide found in tobacco might be linked to the loss of myelin in the optic nerves. The presence of cyanide and free radicals could disrupt the mitochondrial respiratory process and harm mitochondrial DNA.³⁶

Interestingly. Linezolid dose (within the range of ≤600 mg vs ≥600 mg) did not show a statistically significant association with ON risk in our analysis. This suggests that overall exposure time is crucial. Simply adjusting the dose within this common clinical range may not be sufficient to mitigate the risk of ON. Moreover, the potential role of individualized pharmacokinetics and pharmacodynamics of linezolid in ON risk requires further exploration.

Our findings revealed that demographic characteristics and comorbidities, with the exception of duration of treatment and smoking, did not appear to be linked to the development of optic neuropathy. However, optic neuropathy is a known complication of diabetes. None of the 42 diabetic patients in our study experienced this condition. This suggests that linezolid does not elevate the risk of optic neuropathy in individuals with diabetes.

Clinical Implications: These findings have significant clinical implications. Firstly, vigilant monitoring for signs and symptoms of optic neuropathy is paramount for all patients receiving linezolid. Particularly those undergoing prolonged treatment (>6 months) and those with a history of active smoking. Baseline and regular ophthalmological assessments should be considered, especially in high-risk individuals. Secondly, smoking cessation interventions should be aggressively promoted and integrated into the care of DR-TB patients receiving linezolid. Reducing or eliminating smoking may be a modifiable risk factor to lessen the hazard of ON potentially. Finally, in cases where clinically feasible and guided by infectious disease expertise, careful consideration should be given to optimizing linezolid treatment duration. Weighing the need for effective DR-TB treatment against the increasing risk of ON with prolonged exposure. Further research is warranted to explore strategies for minimizing linezolid-associated ON including potential protective agents, refined dosing strategies based on pharmacokinetics, and a deeper understanding of the underlying mechanisms. Our study has limitations. Examination data were insufficient, so the patient’s visual field and retinal layers could not be evaluated due to limited OCT and perimetry equipment.

Conclusion

In summary, we have outlined the characteristics of optic neuropathy in patients receiving long-term linezolid therapy. Patients undergoing linezolid treatment for more than six months are at a higher risk of developing optic neuropathy. In instances where optic neuropathy is suspected, it is advisable to consider dose adjustments or discontinuation of linezolid to maintain a balance between therapeutic efficacy and safety.

Future studies could investigate the potential benefits of shorter linezolid treatment durations or alternative treatment regimens in patients with drug-resistant tuberculosis. Additionally. research on the genetic factors that may influence linezolid-induced optic neuropathy could help identify individuals at higher risk. Further research is needed to optimize treatment strategies and minimize the risk of optic neuropathy in these patients.

Institutional review board statement

The research study was conducted in accordance with the guidelines established by the Declaration of Helsinki and received formal approval from the Institutional Ethics Committee of Sulianti Saroso Infectious Disease Hospital (No: PP.07.01/D.XXXIX.14/12/2025, dated 4 February 2025).

Informed consent statement

This study used secondary data (Data Source National Registration of Tuberculosis) and Electronic Medical Records. It’s a retrospective study so consent could’ve been waived.