CERCENADOE,GARCÍA-GARROTE F,BOUZA E.In vitro activity of linezolid against multiply resistant Gram-positive clinical isolates[J].J Antimicrob Chemother,2001,47(1):77-81.
The in vitro activity of the oxazolidinone linezolid was compared with the activities of vancomycin and teicoplanin against 450 Gram-positive clinical isolates, including a variety of multiply resistant strains. Linezolid inhibited all microorganisms tested at < or = 4 mg/L, including methicillin- and teicoplanin-resistant staphylococci, glycopeptide-resistant enterococci, penicillin- and multiply resistant pneumococci and viridans streptococci, and erythromycin-resistant beta-haemolytic streptococci. The MIC(90) of linezolid for all isolates was 2 mg/L.
MATSUMOTOK,TAKESHITAA,IKAWAK,et al.Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renaldysfunction[J].Int J Antimicrob Agents,2010,36(2):179-181.
The major adverse event associated with linezolid treatment is reversible myelosuppression, mostly thrombocytopenia. 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 of this toxicity are still unknown. The present study thus aimed to investigate the relationship between renal function and linezolid exposure as well as the effects of drug exposure on thrombocytopenia. A statistically significant (P<0.01) strong correlation (r=0.933) was observed between linezolid clearance and creatinine clearance. A negative correlation (r=-0.567) was also shown between linezolid clearance and blood urea nitrogen, although the correlation was not statistically significant. In thrombocytopenic patients, the trough concentration was 14.4-35.6 mg/L and the area under the plasma linezolid concentration-time curve for 24h (AUC(24h)) was 513.1-994.6 mg h/L; in non-thrombocytopenic patients, drug exposure was relatively low (6.9 mg/L and 7.2mg/L for trough concentration and 294.3 mg h/L and 323.6 mg h/L for AUC(24h)). These results provide a pharmacokinetic explanation for the mechanism of the adverse event that renal dysfunction increased linezolid trough concentration and AUC and that higher drug exposure induced thrombocytopenia.
COSSU AP,MUSUM,MURAP,et al.Linezolid-induced thrombocytopenia in impaired renal function:is it time for a dose adjustment? A case report and review of literature[J].Eur J Clin Pharmacol,2014,70(1):23-38.
MAUROLS,PELOQUIN CA,SCHMUDEK,et al.Clearance of linezolid via continuous venovenous hemodiafiltration[J].Am J Kidney Dis,2006 ,47(6):83-86.
Abstract BACKGROUND: Linezolid is being used increasingly for life-threatening vancomycin-resistant infections in critically ill patients. Limited data suggest that linezolid is cleared by intermittent hemodialysis. However, information on clearance of linezolid by continuous renal replacement therapy is limited. A patient undergoing continuous venovenous hemodiafiltration (CVVHDF) was evaluated to determine linezolid clearance through CVVHDF. METHODS: A 33-year-old man with necrotizing fasciitis and acute-on-chronic renal failure requiring CVVHDF was treated with linezolid, 600 mg every 12 hours, for a vancomycin-resistant urinary tract infection. The study was performed on day 4 of therapy after a 1-hour infusion of linezolid. A series of blood samples and all urine and diafiltrate were collected during a 12-hour period. Linezolid concentrations were determined by using high-performance liquid chromatography assay. Linezolid clearance through CVVHDF was determined by using 2 methods. Method 1 evaluated the amount of drug recovered in diafiltrate. Method 2 evaluated plasma drug concentrations in prefilter and postfilter (PAN-10 Hemofilter; Asahi Medical Co, Tokyo, Japan) samples. RESULTS: Clearance of linezolid through CVVHDF was 15.6 mL/min by method 1 and 21.6 mL/min by method 2. Total-body clearance was 189 mL/min. The amount of linezolid recovered in diafiltrate was 50 mg (8.3% of the dose). CONCLUSION: Clearance of linezolid through CVVHDF in this patient was marginal. It does not appear that supplemental dosing of linezolid is necessary in patients undergoing CVVHDF.
KRAFT MD,PASKO DA,DEPESTEL DD,et al.Linezolid clearance during continuous venovenous hemodiafiltration:a case report[J].Pharmacotherapy,2003,23(8):1071-1075.
Objective. To determine the linezolid clearance and serum concentrations in a critically ill man receiving continuous venovenous hemodiafiltration (CVVHDF).Methods. Intravenous linezolid 600 mg every 12 hours was administered to a critically ill, 85-year-old man with anuria who was receiving CVVHDF at a dialysate flow rate of 2000 ml/hour and a mean ultrafiltrate production rate of 775 ml/hour. Samples of blood and spent dialysate and ultrafiltrate were obtained at the time of linezolid peaks and troughs, and linezolid concentrations were determined.Results. The CVVHDF yielded a mean linezolid clearance of 36.5 ml/minute and an elimination half-life of 7.5 hours. The linezolid saturation coefficient ranged from 0.77鈥0.81. Administration of intravenous linezolid 600 mg every 12 hours yielded suitable serum trough concentrations.Conclusion. Administration of intravenous linezolid 600 mg every 12 hours maintained therapeutic serum trough concentrations in this critically ill patient receiving CVVHDF.
HIRAKIY,TSUJIY,MISUMMIN,et al.Pharmacokinetics and elimination efficiency of linezolid during dialysis[J].Ren Fail,2013,35(3):418-420.
Linezolid (LZD) is an option for treating infections caused by multi-resistant Gram-positive bacteria. The protein-binding rate of LZD markedly influences its elimination by dialysis, with limited data suggesting that LZD is cleared by intermittent hemodialysis. Here, we investigated the protein-binding rate and elimination efficiency of LZD in a sepsis patient receiving dialysis. The oral administration of LZD at 600 mg/day resulted in protein-binding and free rates of the drug of 20.4% and 79.6%, respectively, 24 h after administration. By comparing the LZD concentration before and after dialysis, the elimination efficiency of free LZD as a result of dialysis was found to be 40.6%. Our sepsis patient showed higher plasma concentrations of LZD at trough after hemodialysis than the reported concentrations in normal renal function patients. However, it is not clear from our present findings if a relationship exists between myelosuppression and plasma LZD concentration.
ROAERC,MULLERL,WALLIS SC,et al.Population pharmacokinetics of linezolid in critically ill patients on renal replacement therapy:comparison of equal doses in continuous venovenous haemofiltration and continuous venovenous haemodiafiltration[J].J Antimicrob Chemother,2016,71(2):464-470.
ABES,COWORKERK,CIRINCIONEB,et al.Population pharmacokinetic analysis of linezolid in patients with infectious disease:application to lower body weight and elderly patients[J].J Clin Pharmacol,2009,49(9):1071-1078.
Linezolid (Zyvox), belonging to oxazolidinone antibiotics, is commonly used for the treatment of patients infected with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Although linezolid has been approved worldwide, the Japanese pharmacokinetic (PK) profile has not been characterized in detail. The objective of this study is to develop a population PK model for linezolid that can be applied to a Japanese population. This population PK model was established based on the 1 Japanese phase III and 4 Caucasian phase II/III studies. A total of 2539 linezolid plasma concentration measurements from 455 patients, aged 18 to 98 years and body weight 30 to 190.5 kg, were used for the analysis. The data were analyzed using nonlinear mixed effects modeling. Body weight (BW), age, ethnicity, and gender were investigated as covariates. The final model was validated by the bootstrap technique. The PK profiles of linezolid were described with a 1-compartment PK model with first-order absorption and first-order elimination. In the final population PK model, BW and age were influential covariates on clearance, and the distribution volume was affected by BW. The present population PK model of linezolid described well the PK profiles in Japanese patients who have lower BW and are relatively older compared with those in the United States/European Union.
TSUJIY,YUKAWAE,HIRAKIY,et al.Population phar-macokinetic analysis of linezolid in low body weight patients with renal dysfunction[J].J Clin Pharmacol,2013,53(9):967-973.
Linezolid has antibacterial activity against aerobic Gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA). Adjustment of the dose of linezolid has been proposed to be unnecessary in patients with reduced renal function. However, platelet counts and hemoglobin levels were shown to be significantly lower in such patients than in patients with normal renal function. The population pharmacokinetic (PPK) of linezolid was investigated in MRSA infected patients with renal dysfunction. Linezolid concentrations in serum were measured by high-performance liquid chromatography. PPK analysis was performed in the nonlinear mixed effects model (NONMEM) computer program. In the final PPK model, total body weight (TBW), estimated glomerular filtration rate (eGFR), hemoglobin (HB), and alanine amino transferase (ALT) were influential covariates on total body clearance (CL), and the volume of distribution (Vd) was affected by TBW, which was expressed as CL (L/h)090009=0900090.003270900090103090009TBW0900090103090009eGFR0.4280900090103090009HB0.50209000901030900090.283 (ALT090009090906090009100090009IU/L) and CL (L/h)090009=0900090.003270900090103090009TBW0900090103090009eGFR0.4280900090103090009HB0.502 (ALT090009<090009100090009IU/L), Vd (L)090009=0900091.3100900090103090009TBW. The PPK parameters of linezolid obtained here are useful for the optimal use of linezolid with similar patient population characteristics.
MATSUMOTOK,SHIGEMIA,TAKESHITAA,et al.Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid:a dosage strategy according to the trough concentration target and renal function in adult patients[J].Int J Antimicrob Agents,2014 ,44(3):242-247.
The pharmacokinetic/pharmacodynamic (PK/PD) index for the efficacy of linezolid is a 24-h area under the plasma drug concentration–time curve (AUC 24 )/minimum inhibitory concentration (MIC) ratio of ≥100. The main adverse event associated with administration of linezolid is thrombocytopenia. Therefore, the aims of the present study were to define PD thresholds that would minimise linezolid-induced thrombocytopenia and to perform a population PK analysis to identify factors influencing the pharmacokinetics of linezolid. Population PK analysis revealed that creatinine clearance (CL Cr ) significantly affected linezolid pharmacokinetics: the mean parameter estimate of drug clearance (CL; in L/h)02=020.025802×02CL Cr 02+022.03. A strong correlation ( r 02=020.970) was found between AUC 24 and trough plasma concentrations ( C min ) [AUC 24 02=0218.202×02 C min 02+02134.4]. The C min value for AUC 24 02=02200 (in the case of MIC02=02202μg/mL) was estimated to be 3.602μg/mL. Regarding safety, C min was a significant predictor of thrombocytopenia during treatment, and its threshold to minimise linezolid-induced thrombocytopenia was 8.202μg/mL. A Kaplan–Meier plot revealed that the median time from initiation of therapy to the development of thrombocytopenia was 15 days. Therefore, the target C min range was 3.6–8.202μg/mL. The following formula to achieve a target C min in patients with different degrees of renal function was proposed based on these results: initial daily dose (mg/day)02=02CL02×02AUC 24 02=02(0.025802×02CL Cr 02+022.03)02×02(18.202×02 C min 02+02134.4). This recommended initial dosage and subsequent dosage adjustment for the target concentration range should avoid adverse events, thereby enabling effective linezolid-based therapies to be continued.
CHOIG,GOMERSALLCD,TIANQ,et al.Principles of antibacterial dosing in continuous renal replacement therapy[J].Blood Purif,2010,30(3):195-212.
Background: Appropriate antibacterial therapy is important to maximize patient survival in sepsis. Acute renal failure complicates optimal antibiotic administration. Methods: MEDLINE search from 1986 to 2010 using the terms ‘acute renal failure’, ‘pharmacokinetics’, ‘clearance’, ‘dosage’, ‘h(a)emofiltration’, ‘h(a)emodialysis’, ‘h(a)emodiafiltration’, ‘continuous renal replacement therapy’, ‘antibiotics’, ‘intensive care’ and ‘critically ill’. Results: Maximal bacterial killing and minimization of side effects depend on achieving pharmacokinetic targets appropriate to the selected antibacterial agent. Volume of distribution and clearance may be altered by critical illness and/or acute kidney injury. Clearance is determined by nonrenal clearance, residual renal clearance and continuous renal replacement therapy dose. Sieving and saturation coefficients are membrane specific, but may be altered by changes in protein binding induced by critical illness. A significant proportion of studies failed to report the essential dataset required for adequate antibacterial dosage calculation. Conclusions: Individualized dosing based on first principles may be the most appropriate method of dosing, particularly when enhanced by therapeutic drug monitoring.
ATTASSIK,HERSHBERGERE,ALAMR,et al.Thrombocytopenia associated with linezolid therapy[J].Clin Infect Dis,2002,34(5):695-698.
We evaluated the incidence and clinical characteristics of linezolid-induced thrombocytopenia in 19 patients who were treated with linezolid. Overall, thrombocytopenia (platelet count, <100,000 platelets/mm(3)) was observed in 32% of patients who received linezolid for >10 days; gastrointestinal bleeding was observed in 1 patient and 4 patients required platelet transfusions. These data suggest that even patients who are not considered to be at risk for development of thrombocytopenia should be monitored closely if linezolid therapy is continued for >10 days.
Population pharmacokinetics of linezolid in critically ill patients on renal replacement therapy:comparison of equal doses in continuous venovenous haemofiltration and continuous venovenous haemodiafiltration
Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid:a dosage strategy according to the trough concentration target and renal function in adult patients
, 张蓓霞, 杨玲英
