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BRIEF REPORTS |
From the Laboratory of Biopharmaceutics and Pharmacokinetics, Department of Pharmaceutical Technology, School of Pharmacy, University of Athens, Greece (Ms Syka, Dr Markantonis) and Intensive Care Unit, Konstantinopoulio Hospital, Athens, Greece (Dr Mathas, Dr Maggina).
Address for reprints: Sophia L. Markantonis, PhD, Laboratory of Biopharmaceutics and Pharmacokinetics, Department of Pharmaceutical Technology, School of Pharmacy, University of Athens Panepistimiopolis, Zographou 15771, Athens, Greece.
Key Words: Netilmicin • pharmacokinetics • continuous venovenous hemodiafiltration (CVVHD)
Netilmicin, a semisynthetic aminoglycoside, is administered to patients in the intensive care unit (ICU), usually in combination with ß-lactam antibiotics to treat severe infections caused by gram-negative bacteria.1 It is considered to be the least oto- and nephrotoxic aminoglycoside, and it is for this reason that it is widely used in this clinical setting.2 Acute renal failure is a serious and common complication in critically ill patients.3 Continuous venovenous hemodiafiltration (CVVHD) has been introduced in intensive care units for patients in whom intermittent hemodialysis fails to control hypervolemia or uremia and for those who do not tolerate intermittent hemodialysis and in whom peritoneal dialysis is not possible. To date, the pharmacokinetics of aminoglycosides such as isepamicin,4 gentamicin,5 and amikacin6 during CVVHD have been studied. Netilmicin pharmacokinetics during CVVHD have not yet been characterized.
The purpose of this pilot study was to describe the pharmacokinetics of netilmicin during CVVHD, following the administration of the standard dosage regimen used in the ICU of the Konstantinopoulio Hospital, Greece.
MATERIALS AND METHODS
Study
This was a single-dose pharmacokinetic study. The Medical Ethics Research Committee of the Konstantinopoulio Hospital, "Agio Olga", Neas Ionias, approved the study protocol and waived the need for informed consent.
Patients
Six critically ill patients (3 women and 3 men) in the ICU of the hospital, with acute oliguric renal failure and severe infections, participated in the study (age range, 20-80 years). All patients were considered to have severe infections based on their Acute Physiology and Chronic Health Evaluation (APACHE II) and Sepsis-Related Organ Failure Assessment (SOFA) scores, high temperatures (above 39°C), and the development of multiple organ failure. Each patient required CVVHD and antimicrobial therapy, which included netilmicin. All patients were on mechanical ventilation. The clinical characteristics of the patients are shown in Table I.
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Target Netilmicin Concentrations for Effective Prophylaxis in ICU Patients
According to the microbiology laboratory at the hospital, netilmicin minimum inhibiton concentrations (MICs) at which 90% of the isolates in ICU are inhibited (mainly gram-negatives [Pseudomonas aeruginosa], Enterobacteriaceae [Escherichia coli, Klebsiella spp., Enterobacter spp.], and gram-positives [Staphylococcus aureus]) are in the range of 1 to 4 µg/mL; based on an acceptable maximum concentration (Cmax)/MIC ratio 
8:1,7,8 serum netilmicin concentrations for effective prophylaxis should be in the range of 8 to 32 µg/mL.
CVVHD Procedure
The CVVHD was performed in a standard fashion. Access to the circulation was established through the subclavian or femoral or internal jugular vein. A 0.6-m2 polyacrilonitrile cylinder hemofilter (Prisma M100 Preset AN69HF; Hospal, Lyon, France) was connected after heparinized saline priming. An initial dose of 200 U heparin bolus, followed by a low-dose heparin infusion (1.2 mL/h), was delivered into the heparin infusion port before the hemofilter for anticoagulation of the circuit. Blood was pumped through the membrane hemofilter at a rate of 130 mL/min. The dialysate fluid (HF-11; Fresenius, Bad Homburg, Germany) passed once across the membrane into the dialysate compartment of the filter, in a direction countercurrent to the blood flow at a rate of between 500 and 1800 mL/h (mean 875 mL/h). The ultrafiltration rate was between 100 and 400 mL/h (mean 150 mL/h). Replacement fluid was infused into the venous line at a rate appropriate to the patients' fluid requirements. Each filter was used for 2 (patients 2 and 5) or 3 (patients 1, 3, 4, and 6) x 24 hours continuously and then replaced.
Administration of Netilmicin
According to standard practice at the ICU of our hospital, netilmicin was given at a dose of 150 mg/12 h and infused intravenously over a period of 30 minutes. After at least a 36-hour administration of this dosage regimen, blood samples were collected from the intravenous (IV) line at the end of the infusion of the fourth dose of netilmicin (30 minutes) and at 1, 2, 3, 4, 6, 8, 10, and 11.75 hours. The duration of CVVHD before the administration of the first dose of netilmicin was at least 12 hours. This dosage interval was chosen so as to ensure stabilization (steady state) of drug concentrations. Serum was separated by centrifugation and stored at -20°C until analyzed.
Analytical Procedures
Concentrations of netilmicin in serum were measured on a TDx analyzer (Abbott Laboratories Ltd, Abbot Park, Ill) using a fluorescence polarization immunoassay (FPIA).9 The method was linear for concentrations from 1 to 10 µg/mL, the mean extraction coefficient was 98%, and the limit of quantification was less than 1 µg/mL (ie, 0.09 µg/mL). Between-day coefficients of variation (CV) calculated for netilmicin concentrations of 1.0, 4.0, and 8.0 µg/mL were 2.76%, 2.35%, and 3.14%, respectively, whereas within-day coefficients of variation for the same netilmicin concentrations were 1.86%, 1.96%, and 2.03%.
Pharmacokinetic Analysis
Estimations of the parameters Cmax, Vss (volume of distribution at steady state), AUC (area under the concentration-time curve), Kel (elimination rate constant), t1/2 (terminal half-life associated with rate constant), and CL (total body clearance, CL = Dose/AUC), for each IV infusion of netilmicin (ie, for each patient), were made using the WinNonlin Nonlinear Estimation Program. The best estimations were achieved with the pharmacokinetic model defined as
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for a constant-rate (duration, 0.5 hours) IV infusion (first-order elimination).
RESULTS
Creatinine clearance estimations as a measure of the glomerular filtration rate, and thus the renal function prior to CVVHD, were between 14 and 26 mL/min for female patients (normal range, 27-110) and between 18.7 and 32 mL/min for male patients (normal range, 50-98) (Table II).
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For patient 5, it was not feasible to adhere to the predetermined time schedule for concentration monitoring. For this particular patient, drug concentrations were measured following the administration of the third dose (ie, after 24 hours of netilmicin therapy and after only 9 hours of dialysis). Maximum median netilmicin concentrations, achieved 0.5 hours after infusion, were 5.96 µg/mL (25th and 75th interquartiles, 5.35 and 6.93 µg/mL, respectively), and concentrations gradually decreased to a minimum median concentration of 1.84 µg/mL (25th and 75th interquartiles, 1.11 and 2.24 µg/mL, respectively) at 11.75 hours. Thus, concentrations decreased an average of 70% after 11 hours of dialysis. The netilmicin concentration-time plots depicted a first-order elimination of the antibiotic. Parameter estimations for each of the above plots are given in Table II. Netilmicin clearance and half-life of elimination were estimated to range from 1.68 to 3.63 L/h and 5.02 to 9.37 hours, respectively, whereas the estimated mean volume of distribution was 24.92 ± 5.96 L.
DISCUSSION
The major findings of this study were that in patients with acute oliguric renal failure undergoing CVVHD (ultrafiltration rate, 150 mL/h; blood flow rate, 130 mL/min), estimated Cmax values achieved following IV administration of 150-mg/12-h netilmicin were between 4.02 and 7.69 µg/mL—that is, not within the recommended range for effective prophylaxis, based on an acceptable Cmax/MIC ratio 8:1 in our ICU patients. Also, in 2 of the 6 patients, trough concentrations were >2 µg/mL, and it is recommended that trough concentrations remain below 2µg/mL to minimize potential toxicities.
Physicochemical properties of a drug that determine its clearance by CVVHD include molecular size, plasma protein binding, and volume of distribution. Based on its molecular weight (1442 kD), large un-bound concentration in plasma (plasma protein binding not clinically significant), and small apparent volume of distribution, clearance during CVVHD was anticipated. It is possible that residual renal function and nonrenal clearance in our patients contributed to the diafiltration rate generated by CVVHD, achieving effective netilmicin clearance.
Although the physicochemical properties of the drug determine the dialysis capacity of molecules, the pharmacokinetic parameters depend on the type of dialyzer used and the technical conditions under which dialysis is carried out. The limiting factor for drug removal in CVVHD is the dialysate flow rate. In the present study, the variability in the flow rate of the dialyzing fluid (ie, 500-1800 mL/h) introduced a minor source of error in exact calculations of pharmacokinetic parameters. Also, parameter estimations for patient 5 were expected to differ slightly from those of the other patients because of the difference in the sampling period for netilmicin blood concentrations in this individual.
During continuous arteriovenous hemofiltration (CAVH) of gentamicin,10 CAVH of gentamicin and tobramycin,11 continuous arteriovenous hemodiafiltration (CAVHD) of gentamicin,5 continuous venovenous hemofiltration (CVVH) of tobramycin,12 and CVVH of amikacin,13 the authors reported a variable contribution of continuous hemofiltration techniques to total body clearance of these aminoglycosides, and this, together with interpatient variability in the total clearance of these drugs, precludes the prediction of dose requirements of these antibiotics based on estimates of clearance during hemofiltration. These findings, coupled with reports from previous studies of considerable variation due to different filters used, the use of pre- or postdilution, variable ultrafiltration rate, and patient groups, contributed to the authors' decision not to include measurement of clearance by hemofiltration in the study protocol.
Despite the trend toward adopting once-daily aminoglycoside dosing schedules, in the ICU of the Konstantinopoulio Hospital, the standard practice is twice-a-day dosing, and specifically for those patients selected for CVVHD, a fixed dose of netilmicin is administered. Under the technical conditions for CVVHD used in this study, the 150-mg/12-h (
2 mg/kg) netilmicin dosage regimen did not achieve estimated target maximum therapeutic concentrations in the critically ill patients with acute oliguric renal failure. Minimum concentrations in 2 of the study patients exceeded 2 µg/mL and in another 2 were above 1.7 µg/mL. These results suggest that when patients receive CVVHD, a higher netilmicin dose should be given at a longer dosage interval. Nevertheless, appropriate adjustment of both dose and dosing interval should be determined by monitoring netilmicin concentrations in blood.
CONCLUSIONS
It appears that a twice-a-day infusion of netilmicin (150 mg) in critically ill patients with acute renal failure who undergo CVVHD (ultrafiltration rate, 150 mL/h) does not provide effective peak drug levels of the aminoglycoside based on what is considered to be the acceptable Cmax/MIC ratio (8:1) for severe infections. Peak serum concentrations in several-fold excess of the MIC are required to achieve optimal concentration-dependent bacterial activity. Therefore, adjustment of this dosage regimen is required for effective bactericidal activity against susceptible strains of the gram-negative pathogens commonly encountered within the ICU setting. Multiple serum aminoglycoside concentrations are required to assess dosage requirements accurately. Irrespective of the dose administered, circulating antibiotic levels should always be closely monitored to confirm the presence of suitable blood levels of the antibiotic in patients with rapidly changing renal function.
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