a Department of Internal Medicine I, Division of Infectious Diseases, b Department of Internal Medicine IV, Intensive Care Unit, c Department of Laboratory Medicine and d Department of Virology, University of Vienna, Waehringer Guertel 1820, A-1090 Vienna, Austria
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Abstract |
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Introduction |
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The time for which drug levels exceed the MIC is a major pharmacokinetic parameter correlating with therapeutic efficacy of ß-lactam antibiotics.1 Optimal activity with maximal bacterial cell killing occurs at four to five times the breakpoint MIC for the target pathogens,2,3 and data related to ceftazidime indicate that the concentration should exceed the MIC for the pathogen by at least one-fold and perhaps by four- to five-fold.4 In neutropenic patients it is recommended that the concentration of ß-lactams be maintained above the MIC for the entire dosage interval.5,6
In patients with normal glomerular function, 90% of ceftazidime is excreted unchanged in the urine within 24 h. Its protein binding is approximately 17%, and the free fraction in stable end-stage renal disease (ESRD) patients is reported to be between 0.75 and 0.90.7,8 The elimination half-life (tH) is approximately 1.52.0 h and is prolonged up to 25 h in patients with renal impairment.7 In critically ill patients the tH is 1.74.8 h.912 Depending on the characteristics of the renal replacement technique and the membrane used, tH values during intermittent haemodialysis are 2.83.3 h, and in patients with continuous renal replacement therapy 2.814.7 h.7,1315 Drug elimination by continuous venovenous haemofiltration (CVVH) is influenced mainly by the ultrafiltration rate, the protein binding of the drug and the sieving coefficient of the membrane.16 Thus, dosage recommendations found in the literature are quite varied.
Sepsis and multi-organ failure in critically ill patients often requires extracorporeal renal replacement therapy such as CVVH, which is characterized by a high clearance rate. Although use of ceftazidime is well established in nosocomial infections, no multiple-dose studies with new synthetic, highly efficient membranes are available. Thus, the aim of this study was, in consideration of the various published dosage recommendations, to analyse the pharmacokinetics of ceftazidime during CVVH in anuric critically ill patients and to derive a dosage recommendation based on the clearance data obtained.
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Materials and methods |
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The study was performed in accordance with the guidelines of the local ethics committee. Twelve intensive care patients (Table 1) with acute renal failure and suspected or proven Gram-positive or Gram-negative infection were included. The mean (± s.d.) age and body weight were 55.6 ± 17.7 years and 104.0 ± 62.1 kg, respectively. All patients were anuric. Concomitant drug therapy comprised iv catecholamines, anticoagulation with heparin and morphine derivatives. None of the patients received albumin substitution. All patients received parenteral nutrition and required mechanical ventilation. None of the patients had a known hypersensitivity to ceftazidime or other ß-lactams.
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Drug administration and sampling
All patients received ceftazidime (Glaxo Wellcome, Vienna, Austria) 2 g q8h after initiation of CVVH. Ceftazidime was dissolved in 100 mL of physiological saline solution and infused over 30 min into a central venous catheter different from the venous catheter used for CVVH. Blood samples were collected from the arterial (input) and venous (output) line of the extracorporeal circuit immediately before (trough) and at 45, 90, 240, 420 and 510 min after starting the first infusion as well as immediately before and 30 min after the start of the infusion of consecutive doses. Ultrafiltration samples were collected from the outlet of the ultrafiltrate compartment of the haemofilter at corresponding times. All samples were separated immediately and serum was stored at -70°C until analysis.
Drug assay
Concentrations of ceftazidime in serum and ultrafiltrate were determined by high-performance liquid chromatography.18 The assay was calibrated with standards between 1 and 200 mg/L. The lowest detection limit in serum was 0.45 mg/L. Intra- and interassay coefficients of variation were <6%.
Pharmacokinetic analysis
The methods used for pharmacokinetic analysis have been described recently.19 In brief, an open one-compartment model was applied. The tH was calculated as ln 2/kel. The area under the serum concentrationtime curve (AUC) was determined by the trapezoidal rule and by extrapolation of the terminal slope to infinity. The total clearance (CLtot) was estimated as CLtot = iv dose/AUC, the volume of distribution (Vd) as Vd = CL/kel. The clearance of haemofiltration (CLHF) was determined according to the formula CLHF = [UFR x CUF]/CA where UFR refers to the ultrafiltration rate and CUF and CA to ultrafiltrate and arterial serum ceftazidime concentrations, respectively. The sieving coefficient (Sc) was calculated as Sc = CUF/CA. Total removal (Re) of the drug during haemofiltration was calculated as Re = (Cmax - Cmin)/Cmax x 100, where Cmax and Cmin are arterial serum drug concentrations at the peak (45 min after the start of the drug infusion) and at the trough of the first dosing interval, respectively.
Time above the MIC (T > MIC) was calculated according to the equation %T > MIC = ln [Dose/(Vd x MIC)] x (tH/ln2) x (100/DI) where DI is the dosing interval (h), using mean values for tH and Vd.5 Based on T > MIC the total daily dose of ceftazidime was calculated to achieve an average steady-state concentration of four times the typical MICs of 4, 8 or 16 mg/L for important Enterobacteriaceae collected from intensive care units throughout Austria using the equation: Dose = Exp {100[(ln2/tH)] x (DI/100) x (Vd x MIC x 4)}.20 Data are presented as mean ± s.d.
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Results |
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The individual pharmacokinetic parameters are listed in Table 2. Mean tH was 4.3 ± 0.6 h. The mean AUC was 344.0 ± 51.6 mgh/L, CLtot and ceftazidime CLHF were 98.7 ± 13.2 and 32.1 ± 7.9 mL/min, respectively. Sc was 0.69 ± 0.18. The average total removal during haemofiltration was 74.5 ± 6.5% and the mean difference in ceftazidime concentration between the arterial and venous ports was 21.5 ± 4.2%.
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Discussion |
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Pharmacokinetic aspects
All patients tolerated the iv infusion of ceftazidime 2 g (22.7 ± 7.4 mg/kg of body weight) without apparent side effects. Owing to the administration during CVVH and elevated volume of distribution the peak concentration achieved was significantly lower than the peak of 185 mg/L found in healthy volunteers after a 2 g bolus.21 Trough levels 8 h later were 14.0 ± 3.2 mg/L compared with 4.7 mg/L in healthy volunteers.21 Pharmacokinetic parameters and resulting dosage recommendations vary with renal replacement therapy methods and are hardly comparable. Reported trough levels were 4.0 ± 1.5 mg/L during intermittent venovenous haemofiltration (IVVHF) after ceftazidime 1 g, 14.7 ± 5.8 mg/L at the end of a 12 h continuous venovenous haemodiafiltration (CVVHDF) after ceftazidime 1 g and 12.324.1 mg/L during a 12 h continuous arteriovenous haemodialysis (CAVHD) after ceftazidime 500 mg.14,15,22
The tH of ceftazidime was 4.3 ± 0.6 h compared with about 1.8 h in healthy volunteers and with 4.8 ± 1.9 h in critically ill patients with normal renal function.7,9 In patients with renal replacement therapy, the tH ranged between 2.8 and 15.1 h as shown in Table 3. These various tH values clearly demonstrate the dependence of drug elimination on numerous renal replacement associated factors. In our study the 8 h haemofiltration process removed 74.5% compared with 81% by a 12 h CVVHDF, 60% by IVVHF, 55% by a 4 h haemodialysis and 21.9% by CAVHD, respectively.13,15,22,23 The dependence of ceftazidime CVVH clearance on ultrafiltration rate and protein binding as described recently is confirmed by this study in critically ill patients.8
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The goal of ß-lactam dosing is to maintain concentrations above the MIC at the site of infection throughout the dosing interval. Additionally, an average steady-state concentration of 4 x MIC for the target organism is necessary to achieve maximal killing.5 In our study ceftazidime 2 g q8h during CVVH ensures a sufficient T > MIC to cover strains with an MIC of 4 mg/L. However, this higher dosage is not in agreement with recently published guidelines. Matzke et al.8 recommended a lower maintenance dose of ceftazidime 500 mg q12h. These diverse recommendations are probably caused by different kinds of patients (ESRD patients without an infection versus critically ill patients).
In neutropenic patients drug levels should exceed the MIC for the entire dosing interval (T > MIC = 100%).5,6 We believe that critically ill patients should receive maximal treatment (T > MIC close to 100%) to avoid treatment failures often with fatal consequences. A ceftazidime 2 g q8h guideline facilitates a T > MIC of 100% for all strains up to an MIC of 3.8 mg/L. However, to achieve maximal killing of pathogens with an MIC of 8 mg/L a dosage recommendation of 4255 ± 748 mg q8h is necessary. The data presented indicate that in the treatment of intermediately susceptible Enterobacteriaceae mean serum concentrations after ceftazidime 2 g are below the target concentration for 58% of the first dosing interval (Table 4).
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Notes |
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References |
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Received 15 February 2001; returned 30 May 2001; revised 20 August 2001; accepted 4 September 2001