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J Antimicrob Chemother 2013; 68: 2128 – 2133 doi:10.1093/jac/dkt133 Advance Access publication 26 April 2013 High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia Yoko Nukui1, Shuji Hatakeyama2*, Koh Okamoto2, Takehito Yamamoto3, Akihiro Hisaka4, Hiroshi Suzuki3, Nahoko Yata5, Hiroshi Yotsuyanagi2 and Kyoji Moriya1 1 Department of Infection Control and Prevention, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Infectious Diseases, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; 3Department of Pharmacy, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; 4Pharmacology and Pharmacokinetics, 22nd Century Medical and Research Center, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; 5Department of Clinical Research, Tokyo Metropolitan Children’s Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo 183-8561, Japan 2 *Corresponding author. Tel: +81-3-3815-5411; Fax: +81-3-5800-8805; E-mail: [email protected] Received 23 January 2013; returned 15 February 2013; revised 17 March 2013; accepted 18 March 2013 Objectives: Thrombocytopenia is sometimes observed during linezolid therapy. Here, we aimed to investigate the factors affecting linezolid-induced thrombocytopenia. Methods: A prospective observational study was performed between October 2009 and February 2011; 30 patients were included. Plasma linezolid trough concentrations were measured on days 3, 7 and 14 after initial drug administration. Platelet counts and haemoglobin levels were also monitored. Results: Thrombocytopenia occurred in 17 patients (56.7%). Median linezolid trough concentrations on day 3 were significantly higher in patients with renal impairment (creatinine clearance ,60 mL/min) than in patients without renal impairment (14.7 versus 4.8 mg/L; P,0.0001). Median linezolid trough concentrations on day 3 in patients who developed thrombocytopenia were also significantly higher than those in patients who did not (13.4 versus 4.3 mg/L, P,0.0001). Development of thrombocytopenia occurred significantly more frequently in patients with linezolid trough concentration .7.5 mg/L (OR, 90.0; P,0.0001) and renal impairment (OR, 39.0; P ¼ 0.0002). The Kaplan –Meier plot showed that the median time from the initiation of therapy to development of thrombocytopenia was 11 days. Conclusions: Patients with renal impairment are more likely to have a high plasma linezolid concentration. In addition, a high plasma linezolid concentration and renal impairment significantly affected the development of linezolid-induced thrombocytopenia. Further studies are required to evaluate whether therapeutic drug monitoring-guided dosage adjustment of linezolid decreases the adverse effects while maintaining treatment efficacy in patients with renal dysfunction. Keywords: anti-MRSA agents, adverse effects, haematological toxicity, renal dysfunction, therapeutic drug monitoring Introduction Linezolid is an oxazolidinone antibiotic with a broad spectrum of activity against Gram-positive bacteria, including methicillinresistant Staphylococcus aureus and vancomycin-resistant enterococci.1 EUCAST and CLSI have defined the susceptibility breakpoint for linezolid as an MIC of ≤4 mg/L for Staphylococcus spp. The availability of intravenous and oral formulations, with the latter having nearly 100% bioavailability,2 is expected to facilitate the treatment of infections caused by these organisms. In addition, linezolid has very favourable rates of penetration into tissues.3 This suggests a potential pharmacokinetic advantage of linezolid over glycopeptides in the treatment of deep-seated infections such as pneumonia4 and CNS infections.5 Prolonged use of linezolid can lead to haematological side effects, particularly thrombocytopenia.6 Indeed, several studies have reported that the incidence of thrombocytopenia associated with linezolid therapy is much higher (7.5%–64.7%)6 – 11 than the incidence reported in an early clinical study (2.4%) conducted by the manufacturer.12 The risk factors reported for the development of thrombocytopenia during linezolid therapy are renal insufficiency,10,13 – 15 chronic liver disease,14 – 16 malignancy17 and previous vancomycin use.18 Reversible myelosuppression with red-cell hypoplasia after linezolid therapy has # The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected] 2128 JAC High linezolid concentration affects thrombocytopenia also been reported during Phase 3 clinical trials of linezolid and in another recent study.19 Consequently, weekly monitoring of haematological parameters is recommended for patients on linezolid therapy. Considering the findings of case reports that patients with thrombocytopenia retain adequate numbers of megakaryocytes in their bone marrow, it is thought that linezolid-induced thrombocytopenia is not attributable to bone marrow suppression.20,21 Bernstein et al.20 speculated that linezolid-induced thrombocytopenia is caused by immune-mediated platelet destruction, based on a decreased rate of decline in platelet counts following immunoglobulin therapy. However, the mechanisms underlying linezolid-related haematological toxicity remain to be clarified. Currently, therapy with linezolid does not include therapeutic drug monitoring (TDM) and dose adjustment based on the results of early studies, which suggested that linezolid clearance was not altered in patients with renal dysfuncion22 and that the oxidative metabolism of linezolid was non-enzymatic and did not involve the CYP450 hepatic microsomal oxidative system.23 However, recent observations that thrombocytopenia may be more likely to occur during linezolid therapy in patients with renal insufficiency or liver cirrhosis than in patients without these conditions10,13 – 16 have prompted us to investigate the influences of plasma linezolid concentrations on haematological toxicity. Patients and methods Patients This study was conducted between October 2009 and February 2011 at the University of Tokyo Hospital, Japan, and involved patients who were treated with linezolid. Patients younger than 20 years were excluded from this study. Written informed consent was obtained from each patient, and the Ethics Committee of the University of Tokyo reviewed and approved this study. Measurement of plasma linezolid concentrations The patients were treated with 1200 mg of linezolid daily (600 mg twice daily) by either the parenteral or the oral route. On days 3, 7 and 14 after initial administration, venous blood samples were collected just before subsequent administration of the drug to assess the trough plasma concentration. Linezolid concentrations in plasma were analysed by validated liquid chromatography –tandem mass spectrometry, according to a previous study by Phillips et al.24 with minor modifications. Precision and accuracy were assessed by performing replicate analyses of quality control samples against calibration standards, and the intra- and interassay coefficients of variation were found to be always ,10%. The lower limit of detection was 0.2 mg/L. Evaluation of haematological parameters and creatinine clearance (CLCR) Changes in the haematological parameters were assessed every 2–4 days during linezolid therapy. Thrombocytopenia was defined as a decrease in platelet count to ,75% of the baseline levels and anaemia as a ≥2 g/dL decrease in haemoglobin concentration from the baseline.7,25 No well-known potential thrombocytopenia-inducing agents (e.g. quinidine, quinine, rifampicin and trimethoprim/sulfamethoxazole) were administered to any of the patients. CLCR was estimated by means of the Cockcroft and Gault formula.26 Statistical analysis Categorical variables were compared using Fisher’s exact test. The Mann–Whitney U-test was used for continuous variables. A P value of ,0.05 was required to achieve statistical significance. The cut-off value of plasma linezolid concentration that had the best combination of sensitivity and specificity for distinguishing between patients who developed thrombocytopenia and patients who did not was determined by receiver operating characteristic (ROC) curve analysis. The time from initiation of linezolid therapy to development of thrombocytopenia was estimated using the Kaplan– Meier method. All statistical analyses were performed using JMP Pro version 9 (SAS Institute, NC, USA). Results Of the 31 Japanese patients who participated in this study, we excluded 1 patient who had a haematological malignancy and had received frequent red blood and platelet transfusions during the study period. Consequently, 30 patients were included in the primary analysis. The patients’ characteristics and the conditions for which the patients were treated with linezolid are listed in Table 1. The main indications for linezolid therapy were intravascular device-related bloodstream infections (50.0%) and surgical site infections (33.3%). No patient was diagnosed with disseminated intravascular coagulation. We recorded 69 trough plasma concentrations of linezolid in the 30 patients, of whom 18 were treated intravenously with the fixed dosing regimen of 600 mg of linezolid twice daily, and 12 were treated orally with the same regimen. Median linezolid trough concentrations on day 3 did not differ significantly between patients who received linezolid orally and those who received it intravenously (7.0 versus 8.1 mg/L, P ¼ 0.78). Linezolid was administered for a median of 12.0 days (IQR, 7.0–17.3 days). Median CLCR was 78.5 mL/min (IQR, 39.6– 110.3 mL/min), 90.0 mL/min (IQR, 41.0– 117.0 mL/min), 84.0 mL/min (IQR, 45.0 –121.0) and 95.5 mL/min (IQR, 49.5–121.8 mL/min) before linezolid administration and at days 3, 7 and 14, respectively. Fourteen patients (46.7%) had renal impairment (CLCR ,60 mL/min) at baseline (before linezolid administration). Thrombocytopenia developed in 17 of the 30 patients (56.7%) during linezolid therapy. Of the 17 patients who developed thrombocytopenia, 10 developed concurrent anaemia. Platelet decrease was more commonly observed in patients with high linezolid trough concentrations in their blood and with baseline CLCR levels of ,60 mL/min. Median linezolid trough concentrations were significantly higher in patients with renal impairment (CLCR ,60 mL/min) than in patients without renal impairment (P,0.0001): 14.7 mg/L (IQR, 10.9–24.8 mg/L) versus 4.8 mg/L (IQR, 3.1 –6.9 mg/L) on day 3, 16.3 mg/L (IQR, 12.4– 28.9 mg/L) versus 4.9 mg/L (IQR, 3.5–9.0 mg/L) on day 7 and 13.6 mg/L (IQR, 7.2 –25.2 mg/L) versus 7.3 mg/L (IQR, 3.0–13.7 mg/L) on day 14 (Figure 1). Median linezolid trough concentrations in patients who developed thrombocytopenia were also found to be significantly higher than those in patients who did not (P,0.0001): 13.4 mg/L (IQR, 8.4 –23.1 mg/L) versus 4.3 mg/L (IQR, 2.1 –6.0 mg/L) on day 3, 15.3 mg/L (IQR, 10.9– 27.3 mg/L) versus 3.8 mg/L (IQR, 3.1–6.1 mg/L) on day 7 and 15.2 mg/L 2129 Nukui et al. Table 1. Characteristics and underlying medical conditions of patients who received linezolid therapy Baselinea characteristics of patients no. of patients age (years)b gender (male/female) body weight (kg)b CLCR (mL/min)b Dosage of linezolid (mg/kg/12 h)b Duration of linezolid treatment (days)b 30 46 (34 –69) 21/9 55.0 (46.5–64.0) 78.5 (39.6–110.3) 10.9 (9.4– 12.9) 12.0 (7.0– 17.3) Platelet count (× 104 cells/mm3)b baselinea (n¼30) day 3 (n¼30) day 7 (n¼25) day 14 (n ¼14) 21.7 (16.8–29.0) 18.8 (15.4–26.2) 19.4 (14.9–26.0) 18.7 (16.1–21.3) Haemoglobin level (mg/dL)b baselinea (n¼29) day 3 (n¼29) day 7 (n¼24) day 14 (n ¼13) 10.3 (9.3– 11.7) 9.8 (9.1– 11.7) 9.6 (8.6– 11.5) 9.6 (7.7– 11.4) Reason for linezolid treatment, n (%) intravascular device-related bloodstream infections surgical site infections hospital-acquired pneumonia osteomyelitis CNS infection CLCR <60 mL/min CLCR ≥60 mL/min 60 P<0.0001 40 20 0 (n = 14) (n = 16) (n = 12) (n = 13) (n = 6) Day 3 Day 7 (n = 8) Day 14 Figure 1. Box (median and 25th to 75th percentiles) and whisker (5th and 95th percentiles) plots of linezolid trough concentrations on days 3, 7 and 14 after starting therapy in patients with CLCR ,60 or ≥60 mL/min. Open circles indicate outliers. 15 (50.0) 10 (33.3) 2 (6.7) 2 (6.7) 1 (3.3) CLCR, estimated creatinine clearance by the Cockcroft– Gault formula. a Before linezolid administration. b Median (IQR). (IQR, 8.0 –21.4 mg/L) versus 5.0 mg/L (IQR, 1.3 –6.7 mg/L) on day 14 (Figure 2). The ROC curves showed that the best cut-off value of linezolid trough concentration, which could be used to distinguish between thrombocytopenic patients and non-thrombocytopenic patients, was 7.6 mg/L. Development of thrombocytopenia during linezolid therapy was significantly more frequent in patients with linezolid trough concentrations .7.5 mg/L in plasma on day 3 (OR, 90.0; 95% CI, 7.3– 1115.9; P,0.0001), and if CLCR was ,60 mL/min (OR, 39.0; 95% CI, 3.8 –399.8; P ¼0.0002) (Table 2). The Kaplan – Meier plot revealed that the overall median time from the initiation of therapy to development of thrombocytopenia was 11 days (Figure 3). Among the patients who developed thrombocytopenia, the median relative platelet levels expressed as a percentage of the baseline level decreased to 87.9% on day 3, 74.0% on day 7 and 61.0% on day 14. Linezolid therapy had to be discontinued in 10 patients because of severe thrombocytopenia. During anaemia analysis, we excluded a patient who experienced haemorrhage after surgical debridement and received a red blood cell transfusion. Consequently, 29 patients were included in the anaemia analysis. Twelve of the 29 patients 2130 Linezolid concentration (mg/L) Value 80 Linezolid concentration (mg/L) Characteristics and underlying medical conditions 80 Thrombocytopenia (+) Thrombocytopenia (−) P<0.0001 60 40 20 0 (n = 17) (n = 13) (n = 15) (n = 10) (n = 9) Day 3 Day 7 (n = 5) Day 14 Figure 2. Box (median and 25th to 75th percentiles) and whisker (5th and 95th percentiles) plots of linezolid trough concentrations on days 3, 7 and 14 after starting therapy in patients with or without thrombocytopenia. Open circles indicate outliers. (41.4%) developed anaemia during treatment with linezolid. Among the patients who developed anaemia, the median relative haemoglobin levels expressed as a percentage of the baseline level were 87.9% on day 3, 92.4% on day 7 and 75.2% on day 14. However, no significant relationship was observed between development of anaemia and CLCR levels, linezolid trough concentrations or any other factors listed in Table 2 JAC High linezolid concentration affects thrombocytopenia (data not shown). Linezolid therapy had to be discontinued in two patients because of severe anaemia. Discussion In this study, high plasma trough concentrations of linezolid and renal impairment were identified as risk factors for the development of thrombocytopenia in patients receiving linezolid therapy. In addition, renal impairment was found to be associated with a significant increase in plasma trough levels of linezolid. Recent studies have reported that the incidence of linezolid-induced thrombocytopenia was higher in patients with renal failure than in patients with normal renal function, although the underlying mechanisms explaining this toxicity remain unknown.10,13,14,27,28 Takahashi et al.14 recently identified renal dysfunction as one of the four variables associated with thrombocytopenia (defined as a ≥10×104 cells/mm3 decrease from the baseline or a ≥30% reduction) in patients treated with linezolid: duration of linezolid therapy ≥14 days (OR, 3.0; P,0.001); CLCR ,50 mL/min (OR, 2.3; P,0.001); chronic liver disorders (OR, 1.6; P¼0.09); and respiratory tract infections (OR, 1.8; P¼0.03). Lin et al.10 reported that the development of severe thrombocytopenia (,10×104 cells/mm3) was significantly more common in patients who had renal insufficiency and were treated with linezolid (64.7% versus 35.6%, Table 2. Factors affecting the development of thrombocytopenia during linezolid therapy Factor OR (95% CI) P value Age ≥65 years 4.9 (0.8– 29.1) 0.12 Gender male 0.3 (0.04–1.6) 0.23 Weight ,50 kg 2.3 (0.5– 11.7) 0.44 CLCR ,60 mL/min 39.0 (3.8– 399.8) 0.0002 Duration of linezolid treatment ≥14 days 1.8 (0.4– 7.8) 0.48 Linezolid trough concentrationa .7.5 mg/L 90.0 (7.3– 1115.9) ,0.0001 Intravenous administration of linezolid 0.5 (0.1– 2.3) 0.47 Previous vancomycin use 0.5 (0.1– 2.3) 0.47 CLCR, estimated creatinine clearance by the Cockcroft– Gault formula. a Linezolid trough concentration in plasma on day 3 after initiation of drug administration. P¼0.039). Although these studies were not aimed at investigating plasma linezolid concentrations, their data regarding the possible association between thrombocytopenia and renal insufficiency were in agreement with our study results. Brier et al.22 demonstrated that renal function had little effect on the overall clearance of the drug. Pea et al.29 also demonstrated that neither the estimated CLCR nor body weight were useful predictors of linezolid exposure. However, since renal dysfunction may be associated with linezolid-induced thrombocytopenia, we have discussed the effects of high concentrations of the drug and its metabolites. Pharmacokinetic studies of linezolid have indicated that 30% of linezolid is eliminated unchanged via the kidneys,23,30 – 34 while the majority is metabolized by the oxidation of its morpholino ring (mediated by ubiquitous reactive oxygen species) to create two metabolites, an aminoethoxyacetic acid metabolite (PNU-142586) and a hydroxyethyl glycine metabolite (PNU-142300).35 It has been reported that the total exposure to both metabolites (area under the plasma concentration versus time curve) is approximately more than 7- to 8-fold greater in patients with severe renal insufficiency (CLCR ,30 –40 mL/min) than in subjects with normal renal function.22,35 Although the clinical significance of the accumulation of these metabolites remains undetermined, further studies are required to assess the effect of the metabolites on haematological toxicities. To date, few studies have assessed the effects of plasma linezolid concentrations on haematological toxicity. Moreover, it is not clear whether high linezolid concentration or renal insufficiency is a more important predictor of linezolid-associated thrombocytopenia. Several recent Japanese studies have discussed the relationship between linezolid concentration and thrombocytopenia. Matsumoto et al. 36 reported that the trough linezolid concentration of thrombocytopenic patients (n¼ 4) was higher than that of non-thrombocytopenic patients (n¼ 2) (14.4 –35.6 versus 6.9– 7.2 mg/L), although the number of patients was too small for statistical analysis. Hiraki et al.37 showed that low total body clearance of linezolid (L/h), determined by the Bayesian estimation method, was weakly correlated with low platelet counts (r 2 ¼ 0.31) and moderately correlated with low haemoglobin levels (r 2 ¼0.54) in 16 patients treated with linezolid. A subsequent subanalysis, in which they evaluated data from eight pneumonia patients in their study, showed that the high linezolid trough concentrations in patients with renal dysfunction correlated with platelet counts in a logit Probability of developing thrombocytopenia 1 0.5 0 0 10 20 Days after initiation of linezolid therapy 30 Figure 3. Kaplan– Meier plot showing the time from initiation of linezolid therapy to development of thrombocytopenia. 2131 Nukui et al. analysis model, and a significant decrease in platelet count was observed in patients with trough linezolid concentrations .22.1 mg/L.38 Similarly, Tsuji et al.27 reported that platelet and haemoglobin levels decreased with an increase in the linezolid AUC from 0 to 24 h (AUC0 – 24) in three patients with renal insufficiency. Despite the small sample sizes, these results are in agreement with those of our study, suggesting that the high blood linezolid levels possibly influence the haematological toxicity. Further studies, particularly those focusing on differences between races, may be required. Several studies have indicated that linezolid-induced thrombocytopenia typically occurs gradually if the therapy continues for .14 days. In a prospective study of 20 adult patients with Grampositive bacterial infections treated with linezolid, the development of thrombocytopenia (,15×104 cells/mm3) was observed 40 days after starting linezolid therapy, on average.18 Another study showed that long-term therapy with linezolid (.14 days) increased the risk of thrombocytopenia from 2.9% to 4.1%, although this increase was not significant.39 In the current study, however, the decrease in platelet count occurred rapidly after the initiation of linezolid therapy; among patients who developed thrombocytopenia, about one-half were estimated to experience thrombocytopenia within 11 days of starting linezolid. Therefore, attention should be paid to this adverse effect even early in the course of linezolid therapy. A drop in haemoglobin levels was observed in 40% of treated patients, although there was no significant association between the trough linezolid concentrations and haemoglobin levels. Linezolid-related anaemia has been thought to be induced by inhibition of mitochondrial protein synthesis and respiration,20,40 and this condition rarely occurs before day 14 of linezolid therapy.19 Monson et al.41 reported a case of reversible pure red cell aplasia in a patient who had been on linezolid therapy for 8 weeks, and Green et al.42 reported reversible linezolid-associated hypoproliferative anaemia in three patients who were receiving 600 mg of linezolid twice daily for 6 –12 weeks. Clinicians should also pay attention to monitoring this adverse effect, and further research is required to assess the precise mechanism underlying linezolid-related anaemia. The current study showed that impaired renal function was associated with high plasma linezolid concentrations on day 3 after the start of therapy, and that a linezolid trough concentration of .7.5 mg/L on day 3 was a possible predictor of the development of thrombocytopenia. Monitoring of linezolid trough concentrations on day 3 may therefore be useful in predicting haematological adverse events, particularly in patients with renal insufficiency. In a recent pharmacokinetic –pharmacodynamic simulation study consisting of 50 Japanese individuals, patients who had renal insufficiency (CLCR ,30 mL/min) and received a standard dose of linezolid (1200 mg/day) had a remarkably increased risk of thrombocytopenia, while patients with normal renal function (CLCR .50 mL/min) and without liver cirrhosis did not.15 The estimated probability of thrombocytopenia at 14 days after the start of linezolid treatment in patients with insufficient renal function (CLCR 30–10 mL/min) was 32.6%–51.0%, which is comparable to the incidence reported in the current study. For these high-risk patients, the current standard dose of 1200 mg/day was considered too high with respect to safety, and a reduced regimen of 600 mg/day was thought to be appropriate on the basis of the AUC/MIC ratio. Furthermore, in 2132 patients with severe renal insufficiency (CLCR ,10 mL/min) or severe liver cirrhosis, a high incidence of thrombocytopenia was estimated even at 600 mg/day, probably because of the elevated exposure levels.15 A recent small retrospective study showed that TDM-guided dosage adjustment (reduction) to maintain linezolid trough concentrations between 2 and 7 mg/L and/or AUC0 – 24 between 160 and 300 mg.h/L allowed recovery from thrombocytopenia and enabled the achievement of favourable outcomes for therapy.43 Taken together, our results indicate that further large prospective studies are required to evaluate whether TDM-guided dose adjustment of linezolid leads to decreased adverse effects while maintaining treatment efficacy. One of the main limitations of most previous studies, including ours, on linezolid-associated haematological toxicities is the heterogeneous definition of thrombocytopenia and anaemia. In addition, the mechanisms of linezolid-induced thrombocytopenia and anaemia remain unclear. Nevertheless, several studies have suggested that attention must be paid to thrombocytopenia during linezolid therapy, particularly in patients with renal dysfunction. In summary, a high plasma linezolid trough concentration (.7.5 mg/L) and renal dysfunction (CLCR ,60 mL/min) significantly affected the development of thrombocytopenia during linezolid therapy. Furthermore, plasma linezolid trough concentrations were significantly higher in Japanese patients with renal dysfunction than in those without renal dysfunction. Funding This work was a self-funded project of the Department of Infectious Diseases, University of Tokyo. Transparency declarations None to declare. References 1 Vinh DC, Rubinstein E. Linezolid: a review of safety and tolerability. J Infect 2009; 59 Suppl 1: S59–74. 2 Stevens DL, Dotter B, Madaras-Kelly K. A review of linezolid: the first oxazolidinone antibiotic. 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