Precision Dosing of To-Marrow: Linezolid Therapeutic Drug Monitoring

Linezolid (LZD) is a fully synthetic oxazolidinone with reliable activity against most Gram-positive aerobic and anaerobic organisms including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium.¹ LZD is characterized by its nearly 100% oral bioavailability, excellent tissue penetration, and overall tolerability. Despite being approved as fixed dose regimen of 600 mg twice daily, interindividual variability of up to 20-fold difference in LZD exposure with traditional dosing has been reported.

This has led to theoretical concerns for subtherapeutic concentrations and therapeutic failure particularly in patients with augmented renal clearance and obesity.^{3, 5-9} However supratherapeutic concentrations and associated side effects, namely hematological toxicities have been more consistently reported.^3-4 Significant, up to 20-fold, interindividual variability in LZD exposure with traditional dosing has been reported,² leading to increased risks for LZD-associated side effects, namely hematological toxicities.^3-4 As with other antimicrobials, there is growing discussion around LZD dosing in patients with augmented renal clearance and obesity but reports of subtherapeutic concentrations of LZD in these scenarios have been inconsistent.^3,5-9 This emerging literature suggests a potential role for therapeutic drug monitoring (TDM) of LZD to minimize the risk for LZD-associated toxicities while maintaining efficacy in select populations.^3,10

Practical Considerations for Linezolid TDM

1. Candidate Selection

While a variety of risk factors have been identified for LZD-induced thrombocytopenia (Table 1), as well as both subtherapeutic (Table 2) and supratherapeutic (Table 3) LZD exposure, the association between prolonged (>14 days) LZD exposure in renal insufficiency and supratherapeutic concentrations appears to be the most consistent. Furthermore, evidence also suggest the consideration of LZD TDM with certain concomitant medications (e.g. rifampin) that could lead to out-of-range LZD concentrations. While TDM of LZD is not yet routinely recommended, it could be considered for indications requiring exceptionally long LZD courses (e.g. multidrug-resistant tuberculosis) in patients with renal dysfunction.

2. Sampling Strategy and Therapeutic Target

The ratio of the area under the curve (AUC) to minimum inhibitory concentration (MIC) is the optimal pharmacokinetic-pharmacodynamic target for LZD.¹¹ From a practical standpoint, however, a LZD serum trough concentration of at least 2 mg/L can be utilized as a surrogate for bacterial killing.^12-13 Additionally, several studies have also established an upper limit toxicity threshold of 7-8 mg/L as associated with at least 50% probability of LZD-induced thrombocytopenia. ^4,13-14 A reasonable PK sampling strategy for linezolid TDM is obtaining a serum trough concentration at steady state, after at least 2-3 days of treatment, with a proposed therapeutic window of 2-8 mg/L. Samples taken prior to the first dose of the day may be more optimal in the outpatient setting.

The following laboratories offer LZD assay monitoring though associated costs and turnaround times vary:

• Infectious Disease Pharmacokinetics Laboratory
• Atlantic Diagnostics Laboratories
• National Jewish Health PK Laboratory

3. Dose Adjustment Considerations

Elimination of LZD is mostly linear¹ with potential saturation at high concentrations.¹⁵ Utilization of a linear dose adjustment strategy to target the therapeutic window of 2-8 mg/L is supported by current evidence.^5-6 Oral LZD is only available in unscored 600-mg tablets, making it challenging to dose reduce, or a 100 mg/5 mL suspension which is cost prohibitive for many patients. Intravenous (IV) LZD is available in various concentrations (200 mg/100 mL, 400 mg/200 mL, and 600 mg/300 mL) allowing for easier dose adjustment but outpatient IV access and home health expenses must be navigated. Furthermore, it is unclear if changing between formulations results in consistent measurement of LZD serum trough concentrations and repeat TDM may be warranted.

References

1. Linezolid (ZYVOX®) [package insert]. NY: Pfizer 2000.
2. Cattaneo D, Gervasoni C, Cozzi V, Castoldi S, Baldelli S, Clementi E. Therapeutic drug management of linezolid: a missed opportunity for clinicians? Int J Antimicrob Agents. 2016 Dec;48(6):728-731. doi: 10.1016/j.ijantimicag.2016.08.023.
3. Cojutti PG, Merelli M, Bassetti M, Pea F. Proactive therapeutic drug monitoring (TDM) may be helpful in managing long-term treatment with linezolid safely: findings from a monocentric, prospective, open-label, interventional study. J Antimicrob Chemother. 2019 Dec 1;74(12):3588-3595. doi: 10.1093/jac/dkz374.
4. Dong HY, Xie J, Chen LH, Wang TT, Zhao YR, Dong YL. Therapeutic drug monitoring and receiver operating characteristic curve prediction may reduce the development of linezolid-associated thrombocytopenia in critically ill patients. Eur J Clin Microbiol Infect Dis. 2014 Jun;33(6):1029-35. doi: 10.1007/s10096-013-2041-3.
5. Blackman AL, Jarugula P, Nicolau DP, Chui SH, Joshi M, Heil EL, Gopalakrishnan M. Evaluation of Linezolid Pharmacokinetics in Critically Ill Obese Patients with Severe Skin and Soft Tissue Infections. Antimicrob Agents Chemother. 2021 Jan 20;65(2):e01619-20. doi: 10.1128/AAC.01619-20.
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8. Silva CM, Baptista JP, Santos I, Martins P. Recommended Antibiotic Dosage Regimens in Critically Ill Patients with Augmented Renal Clearance: A Systematic Review. Int J Antimicrob Agents. 2022 May;59(5):106569. doi: 10.1016/j.ijantimicag.2022.106569.
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10. Kawasuji H, Tsuji Y, Ogami C, Kimoto K, Ueno A, Miyajima Y, Kawago K, Sakamaki I, Yamamoto Y. Proposal of initial and maintenance dosing regimens with linezolid for renal impairment patients. BMC Pharmacol Toxicol. 2021 Mar 4;22(1):13. doi: 10.1186/s40360-021-00479-w..
11. Andes D, van Ogtrop ML, Peng J, Craig WA. In vivo pharmacodynamics of a new oxazolidinone (linezolid). ^{Antimicrob Agents Chemother}. 2002 Nov;46(11):3484-9. doi: 10.1128/AAC.46.11.3484-3489.2002.
12. Srinivas NR, Syed M. Applicability of a Single Time Point Strategy for the Prediction of Area Under the Concentration Curve of Linezolid in Patients: Superiority of Ctrough- over Cmax-Derived Linear Regression Models. Drugs R D. 2016 Mar;16(1):69-79. doi: 10.1007/s40268-015-0117-5.
13. Pea F, Furlanut M, Cojutti P, Cristini F, Zamparini E, Franceschi L, Viale P. Therapeutic drug monitoring of linezolid: a retrospective monocentric analysis. Antimicrob Agents Chemother. 2010 Nov;54(11):4605-10. doi: 10.1128/AAC.00177-10.
14. Fang J, Chen C, Wu Y, Zhang M, Zhang Y, Shi G, Yao Y, Chen H, Bian X. Does the conventional dosage of linezolid necessitate therapeutic drug monitoring?-Experience from a prospective observational study. Ann Transl Med. 2020 Apr;8(7):493. doi: 10.21037/atm.2020.03.207.
15. Cheng CN, Wu CC, Kuo CH, Wang CC, Wang JT, Lin YT, Jhang RS, Lin SW. Impact of high plasma concentrations of linezolid in Taiwanese adult patients- therapeutic drug monitoring in improving adverse drug reactions. J Formos Med Assoc. 2021 Jan;120(1 Pt 2):466-475. doi: 10.1016/j.jfma.2020.06.011.