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 Pier Giorgio Cojutti 1,2 , Maria Merelli 3 , Matteo Bassetti 1,3 and Federico Pea 1,2 * 1 Department of Medicine, University of Udine, Udine, Italy; 2 Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital of Udine, ASUIUD, Udine, Italy; 3 Clinic of Infectious Diseases, Santa Maria della Misericordia University Hospital of Udine, ASUIUD, Udine, Italy *Corresponding author. E-mail: federico.pea@uniud.it Received 28 May 2019; returned 6 July 2019; revised 25 July 2019; accepted 30 July 2019 Background: Thrombocytopenia may be a dose-dependent adverse effect of linezolid therapy. Objectives: To assess whether proactive therapeutic drug monitoring (TDM) could be helpful in preventing and/ or in recovering from the occurrence of linezolid-induced thrombocytopenia during long-term treatment. Methods: This was a monocentric, prospective, open-label, interventional study conducted between June 2015 and December 2017 among adult patients receiving >10 days of linezolid therapy and undergoing proactive TDM (desired trough level 2–8 mg/L) and platelet count assessment at day 3–5 and then once weekly up to the end of treatment. Results: Sixty-one patients were included. Twenty-eight (45.9%) always had desired trough level (group A) and 33 (54.1%) experienced linezolid overexposure (group B) [29/33 transiently (subgroup B1) and 4/33 persistently (subgroup B2)]. No patient experienced linezolid underexposure. Median duration of treatment for the different groups ranged between 19 and 54days. Thrombocytopenia occurred overall in 14.8% of cases (9/61). The inci- dence rate of thrombocytopenia was significantly lower (P =0.012) in both group A (10.7%; 3/28) and subgroup B1 (10.3%; 3/29) than in subgroup B2 (75.0%; 3/4). Thrombocytopenic patients belonging to both group A and group B1 recovered from thrombocytopenia without the need for discontinuing therapy. Multivariate linear re- gression analysis revealed that thrombocytopenia was independently associated with baseline platelet count and with median linezolid trough concentrations. Conclusions: Proactive TDM of linezolid may be beneficial either in preventing or in recovering from dose- dependent thrombocytopenia, even when treatment lasts for more than 28 days. Larger prospective studies are warranted to confirm our findings. Introduction Drug-dosing personalization of antimicrobials may be essential for treatment success. Therapeutic drug monitoring (TDM) has proved to be a fundamental tool for dose personalization of several antimi- crobials in many patient populations. 1,2 Consequently, the applica- tion of TDM has been gradually widened from only aminoglycosides and glycopeptides to several other antimicrobials, including b- lactam antibiotics, antitubercular drugs and antifungal azoles. 3 Recent evidence has suggested that TDM may also be useful for optimizing therapy with linezolid. 4–6 Linezolid is an oxazolidinone antibiotic originally licensed for the treatment of MDR Gram- positive-related pneumonia and skin and soft-tissue infections. 7 Owing to the high penetration rate into deep-seated sites, linezolid use has been progressively extended to other indica- tions in clinical practice, for example bone and joint infections 8,9 and MDR TB. 10,11 According to the manufacturer’s fact sheet, it’s recommended that duration of treatment should be limited to a maximum of 28 days in order to prevent linezolid-related adverse effects. Thrombocytopenia is an adverse event that may occur rather fre- quently during linezolid treatment. 6,12 It was recently shown that this drug-related adverse event may even increase the risk of mor- tality among critically ill patients 13 and that it is dose-dependent. 14 Various authors suggested that patients having linezolid trough levels (C min ) above a threshold of 8mg/L may be at higher risk of experiencing thrombocytopenia. 6,15 V C The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. 3588 J Antimicrob Chemother 2019; 74: 3588–3595 doi:10.1093/jac/dkz374 Advance Access publication 31 August 2019 Downloaded from https://academic.oup.com/jac/article/74/12/3588/5557817 by guest on 20 June 2022