Pharmacokinetics of repeated dosing of linezolid in a hemodialysis patient with chronic renal failure

Tsuji, Yasuhiro; Hiraki, Yoichi; Mizoguchi, Akiko; Hayashi, Waka; Kamohara, Ryotaro; Kamimura, Hidetoshi; Karube, Yoshiharu

doi:10.1007/s10156-008-0587-2

Cited by 35 publications

(18 citation statements)

References 16 publications

(17 reference statements)

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“…We previously reported that the measured blood LZD concentration was about four times higher in hemodialysis patients who developed thrombocytopenia compared to the concentration predicted using the PPK method [10]. The measured blood LZD concentration was also about 2-8 times higher than the predicted concentration in this study (Table 3), and the difference was significant (p \ 0.01).…”

Section: Discussionsupporting

confidence: 46%

“…However, thrombocytopenia and anemia are adverse effects of LZD [6,7], and have also been reported after LZD administration in patients with renal dysfunction compared to those in patients with normal renal function [8,9]. We also observed the development of pancytopenia in the presence of a high blood LZD concentration in patients undergoing hemodialysis treatment for MRSA infection [10].…”

Section: Introductionmentioning

confidence: 54%

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Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction

Tsuji

Hiraki

Matsumoto

et al. 2011

Journal of Infection and Chemotherapy

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Section: Discussionsupporting

confidence: 46%

Section: Introductionmentioning

confidence: 54%

Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction

Tsuji

Hiraki

Matsumoto

et al. 2011

Journal of Infection and Chemotherapy

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“…A few reports investigated the contribution of renal function to the pharmacokinetics of LZD; however, their results are controversial (7,24,27,37). Brier et al evaluated the pharmacokinetics of LZD after a single oral administration and showed that the total apparent CL of LZD did not change in patients with impaired renal function (7).…”

Section: Discussionmentioning

confidence: 99%

“…In short, after a single dose, the LZD levels are not high enough to saturate the nonrenal pathway, while with repeated doses, especially in patients with insufficient renal function, accumulated LZD causes the saturation of nonrenal CL, and thus the contribution of the renal pathway is relatively great. Actually, the nonlinearity of LZD CL was reported (4,27,29), and elevated levels in patients with renal sufficiency were seen elsewhere, though the sample sizes were quite small (24,37,38). Plock et al investigated the mechanism of the nonlinearity of LZD CL by a population PK modeling approach and suggested that this nonlinearity comes from the inhibition of its metabolism by LZD itself (29).…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic and Pharmacodynamic Analysis of Linezolid and a Hematologic Side Effect, Thrombocytopenia, in Japanese Patients

Sasaki

Takane

Ogawa

et al. 2011

Antimicrob Agents Chemother

112

136

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Linezolid is an antimicrobial agent to treat infections by Gram-positive pathogens, including methicillinresistant Staphylococcus aureus (MRSA). While effective, linezolid treatment frequently is associated with hematological side effects, especially thrombocytopenia. However, little is known about the mechanism of this side effect and the exposure-response relationship. The present population pharmacokinetic/pharmacodynamic (PPK/PD) study was undertaken to elucidate the factors that determine linezolid levels, the relationship between exposure to linezolid and a decrease in platelet counts, and appropriate dosage adjustments based on exposure levels. In total, 50 patients (135 plasma samples) were used for the PPK analysis. The PPK analysis revealed that renal function and severe liver cirrhosis (Child Pugh grade C) significantly affect the pharmacokinetics of linezolid according to the equation clearance (liter/h) ‫؍‬ 2.85 ؋ (creatinine clearance/60.9) 0.618 ؋ 0.472 CIR (CIR indicates cirrhosis status; 0 for noncirrhosis, 1 for cirrhosis patients). Using 603 platelet counts from 45 patients, a PPK/PD analysis with a semimechanistic pharmacodynamic model described the relationship between linezolid exposure and platelet counts quantitatively, and the newly constructed model was validated using external data (776 platelet counts from 60 patients). Simulation indicated considerable risks in patients with insufficient renal function (creatinine clearance, <30 ml/min) or severe liver cirrhosis. For these patients, a reduced dosage (600 mg/day) would be recommended for sufficient efficacy (area under the concentration-time curve over 24 h in the steady state divided by the MIC, >100) and safety.

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“…Although the level of renal clearance of linezolid is less than 30%, the early phase of sepsis is often a hypermetabolic condition leading to increased renal blood flow, glomerular filtration rate (GFR), renal creatinine clearance, and clearance of renally eliminated drugs (11) and it could explain the progressive decrease in C min by increasing the values of eGF presented in Table 3. In addition, recent data have shown higher levels of linezolid (12,13) and a higher toxicity (14,15) in patients with renal failure, suggesting that renal function impacts linezolid clearance. The risk of thrombocytopenia within the first 10 days of linezolid therapy is Ͻ10% (16).…”

Section: Discussionmentioning

confidence: 99%

Risk Factors for a Low Linezolid Trough Plasma Concentration in Acute Infections

Morata

Cuesta

Rojas

et al. 2013

Antimicrob Agents Chemother

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Linezolid is an antibiotic with time-dependent activity, and both the percentage of time that plasma concentrations exceed the MIC and the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC 24 /MIC ratio) are associated with clinical response. The aim of this study was to analyze the linezolid trough plasma concentration (C min ) and to determine factors associated with a C min < 2 mg/liter and other clinically relevant thresholds. Characteristics of 78 patients receiving 600 mg/12 h of linezolid with a C min determination at the steady state and within the first 10 days of treatment were retrospectively reviewed. Concentrations were measured using high-pressure liquid chromatography. Univariate and multivariate analysis were performed to identify risk factors of low C min . A total of 29.5% of patients had a C min < 2 mg/liter. The percentage was significantly higher in patients with an estimated glomerular filtration (eGF) > 80 ml/min, in intensive care unit (ICU) patients, and in patients with an infection due to Staphylococcus aureus. The independent predictors of C min < 2 mg/liter were an eGF > 80 ml/min (odds ratio [OR], 10; 95% confidence interval [CI], 2.732 to 37.037; P ‫؍‬ 0.001) and infection due to S. aureus (OR, 5.906; 95% CI, 1.651 to 21.126; P ‫؍‬ 0.006). A linezolid C min of <2 mg/liter was found in 29.5% of cases, and the risk was significantly higher among those with an eGF > 80 ml/min and in infections due to S. aureus. In patients with severe sepsis, a loading dose or continuous infusion and drug monitoring could improve the pharmacodynamic parameters associated with linezolid efficacy.L inezolid belongs to a family of antimicrobials (oxazolidinones) that inhibit bacterial protein synthesis by preventing the fusion of 30S and 50S ribosomal subunits (1). During the last 10 years, linezolid has been widely used with good clinical results for the treatment of skin and soft tissue infections or nosocomial and health care-related pneumonia (2, 3). Linezolid has time-dependent activity, and the best predictors of its efficacy are the percentage of time that plasma concentrations exceed the MIC and the area under the concentrationtime curve over 24 h in the steady state divided by the MIC (AUC 24 /MIC ratio) (4). In a retrospective study of linezolid in a compassionate use program, a higher success rate was observed when concentrations remained above the MIC for the entire dosing interval and when AUC 24 /MIC values were 80 to 120 (5). Some recent data suggest that the linezolid trough plasma concentration (C min ), in some patients, is below the MIC 90 of linezolid for staphylococci (6).The aim of our study was to analyze the linezolid trough plasma concentration in a consecutive series of patients with an acute infection and to determine how often trough concentrations were Ͻ2 mg/liter (MIC 90 of linezolid for Staphylococcus aureus) and other clinically relevant thresholds (0.5, 1, and 4 mg/liter). MATERIALS AND METHODSThe linezolid trough plasma concent...

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Pharmacokinetics of repeated dosing of linezolid in a hemodialysis patient with chronic renal failure

Cited by 35 publications

References 16 publications

Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction

Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction

Population Pharmacokinetic and Pharmacodynamic Analysis of Linezolid and a Hematologic Side Effect, Thrombocytopenia, in Japanese Patients

Risk Factors for a Low Linezolid Trough Plasma Concentration in Acute Infections

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