1 Department of Internal Medicine I, Division of Infectious Diseases, Medical University of Vienna, Waehringer Guertel 1820, A-1090, Vienna ; 2 Department of Internal Medicine II, Intensive Care Unit, Medical University of Vienna, Vienna; 3 Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, Vienna; 4 Department of Internal Medicine I, Intensive Care Unit, Medical University of Vienna, Vienna; 5 Institute of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
Received 17 November 2004; returned 12 January 2005; revised 15 March 2005; accepted 23 March 2005
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Abstract |
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Patients and methods: Twenty anuric ICU patients undergoing CVVH (mean age and body weight 60.7 ± 10.9 years and 86.0 ± 18.0 kg) were included. All patients received linezolid 600 mg intravenously every 12 h. CVVH was performed using highly permeable polysulphone membranes (PSHF 1200, Baxter, Germany and AV 400, Fresenius, Germany). Mean blood flow rate and ultrafiltration rate were 186 ± 15 and 40 ± 8 mL/min, respectively. Post-dilution was performed.
Results: The pharmacokinetics of linezolid in critically ill patients with acute renal failure undergoing CVVH were comparable to healthy subjects and patients without renal impairment. The elimination half-life, total clearance and haemofiltration clearance were 4.3 ± 1.7 h, 9.3 ± 3.5 L/h and 1.9 ± 0.8 L/h, respectively.
Conclusions: Our results showed that linezolid was highly removable by CVVH. These data suggest that a schedule of 600 mg linezolid at least twice daily may also be an appropriate dosing for patients with severe Gram-positive infections undergoing CVVH with both types of membranes.
Keywords: intensive care units , staphylococci , sepsis , acute renal failure
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Introduction |
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In healthy subjects, intravenous (iv) administration of a single dose of 625 mg linezolid resulted in peak serum concentrations of 13.4 mg/L linezolid.10
The elimination half-life was 4.4 h, the area under the serum concentration versus time curve (AUC) was 83.6 mg h/L and the volume of distribution (V) 46 L.10
The total clearance was 7.5 L/h. The main metabolic route involves non-enzymic reactions and non-renal excretion. The major metabolites show no anti-infective activity. Approximately 33% of the linezolid dose was eliminated through the renal route.10
Linezolid shows low protein-binding (31%).11
Linezolid is a dialysable drug; a significant amount of the drug is removed during 4 h of haemodialysis.12,13 No adjustment of the linezolid dosage is needed in patients with various degrees of renal dysfunction or mild-to-moderate liver failure.12,13
Although linezolid has been used to treat severe infections, including sepsis and multiple organ failure, no data are available about linezolid pharmacokinetics in patients under continuous venovenous haemofiltration (CVVH).1417 This is an important and frequently used extracorporeal replacement therapy in critically ill patients suffering from sepsis and systemic inflammatory response syndrome. CVVH is characterized by a high filtration rate of up to 2550 mL/min; CVVH is able to subtract a significant amount of any given drug.
Bearing in mind the profile of linezolid (relatively low protein binding, relatively high non-renal clearance), the characteristics of CVVH (high filtration rate) and of the dialyser (polysulphone filter, surface area) a first theoretical approximation can be made according to previously published guidelines.18,19 However, pharmacokinetics in critically ill patients are known to be significantly altered due to different volumes of distribution, altered haemodynamic status, organ dysfunction and complex drugdrug interactions.20,21 To assure effective antimicrobial therapy, knowledge of the pharmacokinetic profile of linezolid in critically ill patients undergoing CVVH is essential.
The aim of this study was to propose a rational dosage adjustment for linezolid treatment in patients undergoing CVVH.
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Patients and methods |
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This was a prospective, single-centre, open-label, two-arm study performed at the intensive care unit (ICU of the Department of Cardiology) of the Vienna General Hospital. The study was conducted in accordance with the guidelines of the ethics committee of this institution and complied with the Declaration of Helsinki, the Austrian Drug Law, and the Good Clinical Practice guidelines of the European Commission. Written informed consent was obtained from all patients as soon as possible, i.e. when sedation was stopped and the patients were conscious and responsive. Patients were only entered into the study after written informed consent was obtained.
Inclusion/exclusion criteria
Anuric intensive care patients, aged 1980 years, with suspected or proven Gram-positive infection requiring parenteral antibiotic therapy and mechanical ventilation were included in the study. Patients undergoing extracorporeal therapy other than CVVH were excluded from the study. Patients with an expected survival of <3 days and patients with bleeding disorders were excluded from the study.
Permissable concomitant drug therapy included iv catecholamines, anticoagulation with heparin, morphine derivates and sucralfate. Additional antimicrobial therapy with ciprofloxacin to cover Gram-negative pathogens and antimycotic therapy were permitted.
Continuous venovenous haemofiltration
CVVH was accomplished with a roller pump (Brady BM 11, Brady, Vienna, Austria) in conjunction with an automatic balancing system (Equaline, Amicon, Ireland). Patients were treated with two different dialysers depending on filter availability; highly permeable polysulphone capillary haemofilters with a surface area of 1.2 m2 (PSHF 1200, Baxter, Germany) or 0.9 m2 (Fresenius AV 400, Fresenius, Germany) were used. Dialysers and lines were steam sterilized. The standard blood flow rate was 180 mL/min; rates were adjusted according to clinical need. Bicarbonate was infused as substitution fluid into the venous line (post-dilution) at a rate that depended on balanced fluid therapy.
Drug administration
All patients received a dose of 600 mg linezolid (ZYVOXTM; Pfizer Inc, New York, NY, USA) every 12 h. Linezolid was infused over a period of 30 min into a central venous line separate from that used for the CVVH. Treatment duration was at least 72 h.
Blood and filtrate sampling
Blood and ultrafiltrate samples were drawn into K3-EDTA Vacutainers (Becton, Dickinson and Co., Franklin Lakes, NJ, USA). Serial blood samples were collected from the arterial and the venous line of the extracorporeal circuit at 0, 0.25, 0.5, 1, 1.5, 3, 6, 8, 12 and 12.5 h after the start of the infusion. Ultrafiltrate samples collected from the outlet of the CVVH were taken at corresponding times. Additional blood samples from the venous line of the extracorporeal circuit were taken before and after every drug administration during the multiple-dose study period of 72 h. Actual sampling times were recorded and used in the pharmacokinetic calculations. All samples were centrifuged immediately and stored at 70°C until assayed.
Drug assay
The method of drug assay has been described previously.22 In short, linezolid and metabolite (PNU-142300 and PNU-142586) concentrations in serum and ultrafiltrate were assayed using sensitive and selective high-performance liquid chromatography (reverse-phase column: Zorbax RX-8, MAC-MOD Analytical, Chadds Ford, PA, USA; mobile-phase: trifluoroacetic acid/tetrahydrofuran/methanol/water). Plasma and ultrafiltrate samples were prepared with solid-phase excretion and eluted with methanol. Upon evaporation of the organic material, the residual material was reconstituted in acetonitrile/water and samples were put onto the chromatography columns. Ultraviolet detection was at 251 nm.10,23 Plasma and ultrafiltrate samples were analysed at AvTech Laboratories, Inc., Kalamazoo, MI, USA.
Pharmacokinetic analysis
The multiple-dose serum pharmacokinetics of linezolid and its main metabolites, PNU-142300 and PNU-142586, were assessed at 12.5 and at 72.5 h, i.e. immediately after completion of infusion of the 12 and 72 h doses.
The pharmacokinetic analysis methods used have been described previously.24
In brief, an open two-compartment model was applied. The elimination half-life was calculated by where kel is the elimination rate constant. The AUC was determined by the trapezoidal rule and by extrapolation of the terminal slope to infinity. The total clearance (CLtot) was estimated after the first dose as
the V as
The clearance of haemofiltration (CLHF) was determined according to the haemofiltration formula:
where UFR refers to the ultrafiltration rate and CUF and CA to ultrafiltrate and arterial (dialyser inlet) serum linezolid concentrations, respectively, and in addition, according to the haemodialysis formula:
where QB refers to the dialyser blood flow and CV to the venous concentration (dialyser outlet).25
The sieving coefficient (Sc) was calculated as
where CUF is the drug concentration in the ultrafiltrate and CA is the concentration in the arterial blood line of the extracorporeal system. Calculations for CLHF and Sc were conducted on each pair of samples, followed by the recording of arithmetic averages. Total removal (Re) of the drug during haemofiltration was calculated as
where Cmax and Cmin are arterial serum drug concentrations at the peak and at the trough of the first dosing interval, respectively. Results were calculated for each patient. Mean values ± standard deviation (SD) were calculated.
Times above the minimal inhibitory concentration (MIC) (t > MIC) were calculated according to the equation % where ln is the natural logarithm and DI the dosing interval (h).26
t > MIC was estimated using the standard dose (600 mg), twice-daily dosing (DI 12 h) and an MIC of 4 mg/L for the least susceptible staphylococcal isolates considered susceptible to linezolid.
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Results |
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Twenty ICU patients (18 men, two women) with acute renal failure and suspected or proven Gram-positive infection were included using haemofilters with a surface area of 1.2 m2 [PSHF 1200, seven patients (group 1)] or 0.9 m2 [AV 400, 13 patients (group 2); Table 1]. The mean age and body weight were 60.7 ± 10.9 years and 86.0 ± 18.0 kg. The mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 30 ± 5 in group 1 and 26 ± 8 in group 2. All patients were anuric and required mechanical ventilation. Concomitant drug therapy consisted of iv catecholamines and anticoagulation with heparin and sedoanalgesia with morphine derivatives. The mean blood flow rate was 186 ± 15 mL/min (189 ± 15 mL/min in group 1 and 185 ± 15 mL/min in group 2). The mean ultrafiltration rate was 40 ± 8 mL/min (42 ± 10 mL/min in group 1 and 39 ± 7 mL/min in group 2).
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Pharmacokinetics of linezolid
The mean Cmax, which was reached 30 min after the start of the first infusion, was 15.3 ± 4.0 mg/L. The mean Cmin of linezolid 12 h after starting the first infusion was 1.9 ± 1.7 mg/L. At the venous port, linezolid concentrations at 30 min and 12 h after the start of infusion were 13.2 ± 3.5 and 1.9 ± 1.7 mg/L, respectively. The maximum and minimum concentrations of linezolid detected in the ultrafiltrate were 12.0 ± 3.9 and 1.3 ± 0.9 mg/L 30 min and 12 h after starting the infusion, respectively.
The serum concentrations of linezolid following the first infusion are depicted in Figure 1. The peak and trough levels of linezolid during the multiple-dose administration are depicted in Figure 2.
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The individual pharmacokinetic parameters are shown in Table 2.
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Maximum concentrations of the metabolite PNU-142300 were detected 8 h after the first administration of linezolid with a concentration of 0.97 ± 0.56 and 0.83 ± 0.46 mg/L at the arterial and the venous ports, respectively. The concentration of PNU-142300 in the ultrafiltrate was 0.81 ± 0.38 mg/L at 8 h. The minimum serum concentrations of the metabolite 12 h after the first infusion were 0.89 ± 0.59 and 0.72 ± 0.49 mg/L at the arterial and venous ports, respectively. The ultrafiltrate concentration 12 h after the infusion was 0.74 ± 0.37 mg/L.
The maximum serum concentrations of the second metabolite PNU-142586 were 3.58 ± 1.65 and 2.94 ± 1.62 mg/L at the arterial and the venous ports respectively. The concentration of PNU-142586 in the ultrafiltrate was 2.76 ± 1.19 mg/L at the corresponding time.
The individual pharmacokinetic parameters are shown in Table 3.
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Discussion |
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Peak linezolid serum levels were comparable with those observed in healthy subjects and in patients undergoing haemodialysis. Trough levels were lower in our patients compared with healthy volunteers and haemodialysis patients.
So far, linezolid dosage in patients undergoing CVVH has been derived from general concepts of dose adaptation during continuous renal replacement therapy. Theoretical concepts were based on the pharmacokinetic profile of the drug and on the characteristics of the extracorporeal technique used. Bearing in mind the high unbound fraction of linezolid (70%, approximation that Sc = unbound), its high non-renal clearance (5 L/h for 67% of a CL normal of 7.5 L/h) and high-filtration rate of CVVH (e.g. 40 mL/min, therefore Quf = 2.4 L) one would expect a
18
that is, 90% of the clearance in normal individuals. Thus, as a first approximation, patients under CVVH should receive 90% of the standard daily dose, if similar trough levels are to be reached. Practically, considering the inter-individual variability in linezolid pharmacokinetic, a 10% dose adjustment makes no sense, so the rational recommendation would be to apply no adaptation for CVVH.
The clearance in our study was higher than predicted: we calculated a total clearance of 9.31 ± 3.48 L/h. We calculated haemofiltration clearance twice in our study: according to the haemofiltration formula and according to the haemodialysis formula.25 Results were similar: clearance was slightly lower according to the haemodialysis formula taking into account the venous concentration instead of the ultrafiltrate concentration. A higher haemodialysis clearance would implicate the presence of drug-filter interaction: a recovery of linezolid through the filter, thus showing creation of the drug inside the filter possibly due to catalytic action of the CVVH filter. However, due to the relatively small haemodialysis clearance in our study, no major drug-filter interaction is proven.25
Other mechanisms possibly contributing to the lower linezolid concentrations observed in our study include different volumes of distribution, and altered metabolism as by forced oxygenation and non-enzymic degradations observed in critical illness. However, data are scarce and further investigation is warranted (Table 4).
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In this study, we demonstrated that the linezolid PNU-100766 is significantly eliminated by CVVH. Both main metabolitesPNU-142300 and PNU-142586show significant accumulation. To date, however, no major clinical effects of PNU-142300 and PNU-142586 are known and they have no significant potential to inhibit various cytochrome P450 enzymes or monoamine oxidase.27 Accumulation of PNU-142300 and PNU-142586 suggests the need for further investigation.
Linezolid is a bacteriostatic agent and has significant post-therapeutic antibacterial effects against most target pathogens.28 The probabilities of eradication and clinical cure are suggested to be associated with the ratio of AUC to MIC (AUC/MIC) as well as the percentage of time that tissue and serum concentrations exceed the MIC (% t > MIC).29
In our study, the total clearance was 25% higher and the trough concentration 50% lower than in normal conditions. Calculating the t > MIC, in our CVVH patients, a standard dosage regimen of 600 mg linezolid twice daily resulted in a % t > MIC of 93% for pathogens with an MIC of 2 mg/L. Thus, the current linezolid regimen of 600 mg twice daily is effective in most of our patients for treating pathogens with MICs as high as 2 mg/L. However, considering the least susceptible pathogens with an MIC up to 4 mg/L, t > MIC was considerably shorter (57 ± 32%). Thus, with regard to the least-susceptible pathogens and the inter-individual variability in some ICU patients t > MIC might be slightly less favourable compared with t > MIC in normal subjects and patients outside the ICU. Therefore, dose escalation might be warranted in certain cases to achieve maximal antibacterial activity and to assure optimal clinical response.
In conclusion, linezolid is significantly eliminated during CVVH. The amount of linezolid removed is slightly higher than in healthy subjects. The present data support a dosage of 600 mg linezolid at least twice daily for critically ill patients undergoing CVVH.
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Acknowledgements |
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