A retrospective study of the risk factors for linezolid-induced thrombocytopenia and anemia

Hanai, Yuki; Matsuo, Kazuhiro; Ogawa, Miki; Higashi, Ayaka; Kimura, Itsuki; Hirayama, S.; Kosugi, Tadayoshi; Nishizawa, Kenji; Yoshino, Takashi

doi:10.1016/j.jiac.2016.05.003

Cited by 89 publications

(130 citation statements)

References 28 publications

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“…Renal impairment and end-stage renal disease have been associated with 2-and 3to 6-fold increases in the odds of developing thrombocytopenia, respectively, in patients receiving linezolid (10,12,13,18,19). In the present analysis, we demonstrate a 2-fold increase in the risk of thrombocytopenia with an eGFR of Ͻ60 ml/min/1.73 m 2 .…”

Section: Discussionsupporting

confidence: 51%

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Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety

Crass

Cojutti

Pai

et al. 2019

Antimicrob Agents Chemother

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Linezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy. In study 1, data from adult patients receiving linezolid for Ն10 days were retrospectively reviewed to determine the frequency of thrombocytopenia in patients with and without renal impairment. Time-to-event analyses were performed using Cox proportional-hazards models. In study 2, population pharmacokinetic modeling was employed to build covariatestructured models using an independent data set of linezolid concentrations obtained during routine therapeutic drug monitoring (TDM). Monte Carlo simulations were performed to identify linezolid dosing regimens that maximized attainment of therapeutic trough concentrations (2 to 8 mg/liter) across various renal-function groups. Toxicity analysis (study 1) included 341 patients, 133 (39.0%) with renal impairment. Thrombocytopenia occurred more frequently among patients with renal impairment (42.9% versus 16.8%; P Ͻ 0.001), and renal impairment was independently associated with this toxicity in multivariable analysis (adjusted hazard ratio [aHR], 2.37; 95% confidence interval [CI], 1.52 to 3.68). Pharmacokinetic analyses (study 2) included 1,309 linezolid concentrations from 603 adult patients. Age, body surface area, and estimated glomerular filtration rate (eGFR) were identified as covariates of linezolid clearance. Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with eGFR values of Ͻ60 ml/min. Thrombocytopenia occurs more frequently in patients with renal impairment receiving standard linezolid doses. Linezolid dose reduction and trough-based TDM are predicted to mitigate this treatment-limiting toxicity.

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Section: Discussionsupporting

confidence: 51%

“…Indeed, reports soon emerged of increased thrombocytopenia in this population with multiple-dose administration (10,11). This finding has since been replicated in multiple observational studies, most of which have been conducted in Asian populations (12)(13)(14)(15)(16)(17)(18)(19).…”

mentioning

confidence: 87%

Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety

Crass

Cojutti

Pai

et al. 2019

Antimicrob Agents Chemother

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“…Duration of therapy ≥15 days was selected as the second splitting variable. To our knowledge, there are no reports of long‐term administration of GCV as a predictor of neutropaenia, possibly because of its associated side effects with oral valganciclovir and other drugs . Occurrence of HSCTs was selected as the third splitting variable.…”

Section: Discussionmentioning

confidence: 99%

“…The first splitting variable, baseline ANC <3854 cells/mm 3 , was almost consistent with a previous report.Duration of therapy ≥15 days was selected as the second splitting variable. To our knowledge, there are no reports of long-term administration of GCV as a predictor of neutropaenia, possibly because of its associated side effects with oral valganciclovir and other drugs 16,22,23. Occurrence of HSCTs was selected as the third splitting TA B L E 2 Univariate and multivariable analyses of risk factors for neutropaenia…”

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confidence: 99%

Construction of a flow chart–like risk prediction model of ganciclovir‐induced neutropaenia including severity grade: A data mining approach using decision tree

et al. 2019

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What is known and objective Haematological toxicities such as neutropaenia are a common side effect of ganciclovir (GCV); however, risk factors for GCV‐induced neutropaenia have not been well established. Decision tree (DT) analysis is a typical technique of data mining consisting of a flow chart–like framework that shows various outcomes from a series of decisions. By following the flow chart, users can estimate combinations of risk factors that may increase the probability of certain events. In our previous study, we demonstrated the usefulness of this approach in the evaluation of adverse drug reactions. Therefore, we aimed to construct a risk prediction model of GCV‐induced neutropaenia including severity grade. Methods We performed a retrospective study at the Hokkaido University Hospital and enrolled patients who received GCV between April 2008 and March 2018. Neutropaenia was defined as an absolute neutrophil count (ANC) <1500 cells/mm3 and a decrease to <75% relative to baseline. We classified the patients who developed neutropaenia in three groups (Grades 2‐4) based on the National Cancer Institute‐Common Terminology Criteria for Adverse Events. Data collection was achieved through the retrieval of medical records. We employed a chi‐squared automatic interaction detection algorithm to construct the DT model and compared the accuracies to the logistic regression model (a conventional statistical method) to evaluate the established model. Results and discussion In total, 396 adult patients were included in the study; 61 (15.4%) developed neutropaenia. Three predictive factors (hematopoietic stem cell transplantation, baseline ANC <3854 cells/mm3 and duration of therapy ≥15 days) were extracted using the DT analysis to produce five subgroups, the incidence of neutropaenia ranged between 1.7% and 52.8%. In each subgroup, patients who developed neutropaenia were categorized based on the severity. The accuracies of each model were the same (84.6%), which indicated precision. What is new and conclusion We successfully built a risk prediction model of GCV‐induced neutropaenia including severity grade. This model is expected to assist decision‐making in the clinical setting.

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“…Antibiotic-induced thrombocytopenia has been discussed in the literature. Hanai et al [12] found that 48.4% of patients on linezolid developed thrombocytopenia [12]. Meropenem has also been linked with the platelet abnormality [13].…”

Section: Discussionmentioning

confidence: 99%