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Linezolid induced thrombocytopenia in critically ill patients: Risk factors and development of a machine learning-based prediction model

      Abstract

      Introduction

      Linezolid is an antimicrobial with broad activity against Gram-positive bacteria. Thrombocytopenia is one of its most common side effects often leading to severe complications.
      The aim of this study is to identify factors related with development of this condition in critically ill patients and to develop and evaluate a predictive machine learning-based model considering easy-to-obtain clinical variables.

      Methods

      Data was obtained from the Medical Information Mart for Intensive Care III. Patients who received linezolid for over three days were considered, excluding those under 18 years and/or lacking laboratory data. Thrombocytopenia was considered as a platelet decrease of at least 50% from baseline.

      Results

      Three hundred and twenty patients met inclusion criteria of which 63 developed thrombocytopenia and presented significant greater duration of treatment, aspartate-aminotransferase, bilirubin and international normalized ratio; and lower renal clearance and platelet count at baseline. Thrombocytopenia development was associated with a worse outcome (30 days mortality [OR: 2.77; CI95%: 1.87–5.89; P < .001], 60 days mortality [OR: 3.56; CI95%: 2.18–7.26; P < .001]). Thrombocytopenia was also correlated with higher length of hospital stays (35.56 [20.40–52.99] vs 22.69 [10.05–38.61]; P < .001). Median time until this anomaly was of 23 days (CI95%:19.0-NE).
      Two multivariate models were performed. Accuracy, sensitivity, specificity and AUROC obtained in the best of them were of 0.75, 0.78, 0.62 and 0.80, respectively.

      Conclusion

      Linezolid associated thrombocytopenia entails greater mortality rates and hospital stays. Although the proposed predictive model has to be subsequently validated in a real clinical setting, its application could identify patients at risk and establish screening and surveillance strategies.

      Keywords

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      References

        • Kaya Kılıç E.
        • Bulut C.
        • Sönmezer M.
        • Ozel Ö.
        • Ataman Hatipoğlu Ç.
        • Tuncer Ertem G.
        • et al.
        Risk factors for linezolid-associated thrombocytopenia and negative effect of carbapenem combination.
        J Infect Dev Ctries. 2019; 13: 886-891https://doi.org/10.3855/jidc.10859
        • Cazavet J.
        • Bounes F.
        • Ruiz S.
        • Seguin T.
        • Crognier L.
        • Rouget A.
        • et al.
        Risk factor analysis for linezolid-associated thrombocytopenia in critically ill patients.
        Eur J Clin Microbiol Infect Dis. 2019; 39: 527-538https://doi.org/10.1007/s10096-019-03754-1
        • Stein G.E.
        • Wells E.M.
        The importance of tissue penetration in achieving successful antimicrobial treatment of nosocomial pneumonia and complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus: vancomycin and linezolid.
        Curr Med Res Opin. 2010; 26: 571-588https://doi.org/10.1185/03007990903512057
        • Conte J.
        • Golden J.
        • Kipps J.
        • Zurlinden E.
        Intrapulmonary pharmacokinetics of linezolid.
        Antimicrob Agents Chemother. 2002; 46: 1475-1480https://doi.org/10.1128/AAC.46.5.1475-1480.2002
        • Tajima M.
        • Kato Y.
        • Matsumoto J.
        • Hirosawa I.
        • Suzuki M.
        • Takashio Y.
        • et al.
        Linezolid-induced thrombocytopenia is caused by suppression of platelet production via phosphorylation of myosin light chain 2.
        Biol Pharm Bull. 2016; 39: 1846-1851https://doi.org/10.1248/bpb.b16-00427
        • Choi G.
        • Lee J.
        • Chang M.
        • Kim Y.
        • Cho Y.
        • Yu Y.
        • et al.
        Risk factors for linezolid-induced thrombocytopenia in patients without haemato-oncologic diseases.
        Basic Clin Pharmacol Toxicol. 2018; 124: 228-234https://doi.org/10.1111/bcpt.13123
        • Vandijck D.M.
        • Blot S.I.
        • De Waele J.J.
        • Hoste E.A.
        • Vandewoude K.H.
        • Decruyenaere J.M.
        Thrombocytopenia and outcome in critically ill patients with bloodstream infection.
        Heart Lung. 2010; 39: 21-26https://doi.org/10.1016/j.hrtlng.2009.07.005
        • Rabon A.D.
        • Fisher J.P.
        • MacVane S.H.
        Incidence and risk factors for development of thrombocytopenia in patients treated with linezolid for 7 days or greater.
        Ann Pharmacother. 2018; 52: 1162-1164https://doi.org/10.1177/1060028018783498
        • Hanai Y.
        • Matsuo K.
        • Ogawa M.
        • Higashi A.
        • Kimura I.
        • Hirayama S.
        • et al.
        A retrospective study of the risk factors for linezolid-induced thrombocytopenia and anemia.
        J Infect Chemother. 2016; 22: 536-542https://doi.org/10.1016/j.jiac.2016.05.003
        • Dong H.
        • Xie J.
        • Chen L.
        • Wang T.
        • Zhao Y.
        • Dong Y.
        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; 33: 1029-1035https://doi.org/10.1007/s10096-013-2041-3
        • Birmingham M.
        • Rayner C.
        • Meagher A.
        • Flavin S.
        • Batts D.
        • Schentag J.
        Linezolid for the treatment of multidrug‐resistant, gram‐positive infections: experience from a compassionate‐use program.
        Clin Infect Dis. 2003; 36: 159-168https://doi.org/10.1086/345744
        • Lin Y.
        • Wu V.
        • Tsai I.
        • Ho Y.
        • Hwang J.
        • Tsau Y.
        • et al.
        High frequency of linezolid-associated thrombocytopenia among patients with renal insufficiency.
        Int J Antimicrob Agents. 2006; 28: 345-351https://doi.org/10.1016/j.ijantimicag.2006.04.017
        • Aster R.H.
        • Curtis B.R.
        • McFarland J.G.
        • Bougie D.W.
        Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management.
        J Thromb Haemostasis. 2009; 7: 911-918https://doi.org/10.1182/asheducation-2009.1.153
        • Tsuji Y.
        • Mizoguchi A.
        • Sadoh S.
        • Hiraki Y.
        • Matsumoto K.
        • Morita K.
        • et al.
        Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction.
        J Infect Chemother. 2011; 17: 70-75https://doi.org/10.1007/s10156-010-0080-6
        • Zhou D.
        • Li Z.
        • Wu L.
        • Shi G.
        • Zhou J.
        Thrombocytopenia and platelet course on hospital mortality in neurological intensive care unit: a retrospective observational study from large database.
        BMC Neurol. 2020; 20: 220https://doi.org/10.1186/s12883-020-01794
        • Senneville E.
        • Legout L.
        • Valette M.
        • Yazdanpanah Y.
        • Giraud F.
        • Beltrand E.
        • et al.
        Risk factors for anaemia in patients on prolonged linezolid therapy for chronic osteomyelitis: a case–control study.
        J Antimicrob Chemother. 2004; 54: 798-802https://doi.org/10.1093/jac/dkh409
        • Pea F.
        • Viale P.
        • Cojutti P.
        • Del Pin B.
        • Zamparini E.
        • Furlanut M.
        Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients.
        J Antimicrob Chemother. 2012; 67: 2034-2042https://doi.org/10.1093/jac/dks153
        • Wu V.C.
        • Wang Y.T.
        • Wang C.Y.
        • Tsai I.J.
        • Wu K.D.
        • Hwang J.J.
        • et al.
        High frequency of linezolid-associated thrombocytopenia among patients with renal insufficiency.
        Int J Antimicrob Agents. 2006; 28: 345-351https://doi.org/10.1086/498509
        • Hirano R.
        • Sakamo to Y.
        • Tachibana N.
        • Ohnishi M.
        Retrospective analysis of the risk factors for linezolid-induced thrombocytopenia in adult Japanese patients.
        Int J Clin Pharm. 2014; 36: 795-799https://doi.org/10.1007/s11096-014-9961-6
        • Ichie T.
        • Suzuki D.
        • Yasui K.
        • Takahashi H.
        • Matsuda M.
        • Hayashi H.
        • et al.
        The association between risk factors and time of onset for thrombocytopenia in Japanese patients receiving linezolid therapy: a retrospective analysis.
        J Clin Pharm Therapeut. 2015; 40: 279-284https://doi.org/10.1111/jcpt.12260
        • Grau S.
        • Morales-Molina J.A.
        • Mateu-de Antonio J.
        • Marín-Casino M.
        • Alvarez-Lerma F.
        Linezolid: low pre-treatment platelet values could increase the risk of thrombocytopenia.
        J Antimicrob Chemother. 2005; 56: 440-441https://doi.org/10.1093/jac/dki202
        • Attassi K.
        • Hershberger E.
        • Alam R.
        • Zervos M.J.
        Thrombocytopenia associated with linezolid therapy.
        Clin Infect Dis. 2002; 34: 695-698https://doi.org/10.1086/338403
        • Johnson A.E.
        • Pollard T.J.
        • Shen L.
        • Lehman L.W.
        • Feng M.
        • Ghassemi M.
        • et al.
        MIMIC-III, a freely accessible critical care database.
        Sci Data. 2016; 3160035https://doi.org/10.1038/sdata.2016.35
        • Pfizer. Zyvox (linezolid)
        ([package insert])
        • Kim H.S.
        • Lee E.
        • Cho Y.J.
        • Lee Y.J.
        • Rhie S.J.
        Linezolid-induced thrombocytopenia increases mortality risk in intensive care unit patients, a 10 year retrospective study.
        J Clin Pharm Therapeut. 2019; 44: 84-90https://doi.org/10.1111/jcpt.12762
        • González-Del J.
        • Candel F.J.
        • Manzano-Lorenzo R.
        • Arias L.
        • García-Lamberechts E.J.
        • Martín-Sánchez F.J.
        • et al.
        Predictive score of haematological toxicity in patients treated with linezolid.
        Eur J Clin Microbiol Infect Dis. 2017; 36: 1511-1517https://doi.org/10.1007/s10096-017-2960-5
        • Wicha S.
        • Frey O.
        • Roehr A.
        • Pratschke J.
        • Stockmann M.
        • Alraish R.
        • et al.
        Linezolid in liver failure: exploring the value of the maximal liver function capacity (LiMAx) test in a pharmacokinetic pilot study.
        Int J Antimicrob Agents. 2017; 50: 557-563https://doi.org/10.1016/j.ijantimicag.2017.06.023
        • Oiwa K.
        • Fujita K.
        • Lee S.
        • Morishita T.
        • Tsukasaki H.
        • Negoro E.
        • et al.
        Utility of the geriatric 8 for the prediction of therapy‐related toxicity in older adults with diffuse large B‐cell lymphoma.
        Oncol. 2020; 26: 215-223https://doi.org/10.1002/onco.13641
        • Chen H.
        • Gong S.
        • Yu R.
        Association between normalized lactate load and mortality in patients with septic shock: an analysis of the MIMIC-III database.
        BMC Anesthesiol. 2021; 21https://doi.org/10.1186/s12871-021-01239-3
        • Wu W.
        • Zhou Z.
        A comprehensive way to access hospital death prediction model for Acute mesenteric ischemia: a combination of traditional statistics and machine learning.
        Int J Gen Med. 2021; 14: 591-602https://doi.org/10.2147/IJGM.S300492