Clearance of ceftazidime during continuous venovenous haemofiltration in critically ill patients

Friederike Traunmüllera, Peter Schenkb, Christoph Mittermeyerb, Renate Thalhammer-Scherrerc, Klaus Ratheiserb and Florian Thalhammera,d,*

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 18–20, A-1090 Vienna, Austria


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Published recommendations for the optimal dosing regimen of ceftazidime in critically ill patients with continuous venovenous haemofiltration (CVVH) differ. The aim of this prospective study was to analyse the pharmacokinetic and pharmacodynamic parameters of ceftazidime during CVVH with a high-flux polysulphone membrane, and derive a dosage recommendation. Twelve critically ill patients (five female, seven male) with acute renal failure undergoing CVVH using a 0.7 m2 polysulphone high-flux membrane were investigated. All patients received ceftazidime 2 g iv q8h. Peak ceftazidime concentrations were 58.2 ± 11.6 mg/L, with trough concentrations 14.0 ± 3.2 mg/L at the arterial port. The elimination half-life, haemofiltration clearance, volume of distribution and total removal were 4.3 ± 0.6 h, 32.1 ± 7.9 mL/min, 36.4 ± 6.4 L and 74.5 ± 6.5%, respectively. Based on these pharmacokinetic parameters and that maximal killing is at 4 x MIC we recommend at least ceftazidime 2 g iv q8h.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Ceftazidime remains an important option for the empirical therapy of febrile episodes in neutropenic patients, and is frequently employed in critically ill patients with severe Gram-negative nosocomial infections caused by Enterobacteriaceae, including Pseudomonas aeruginosa.

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 1.5–2.0 h and is prolonged up to 25 h in patients with renal impairment.7 In critically ill patients the tH is 1.7–4.8 h.9–12 Depending on the characteristics of the renal replacement technique and the membrane used, tH values during intermittent haemodialysis are 2.8–3.3 h, and in patients with continuous renal replacement therapy 2.8–14.7 h.7,13–15 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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients and CVVH

The study was performed in accordance with the guidelines of the local ethics committee. Twelve intensive care patients (Table 1Go) 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.


View this table:
[in this window]
[in a new window]
 
Table 1. Patient characteristics
 
CVVH was performed as described previously using a high-flux polysulphone capillary haemofilter with a membrane surface of 0.7 m2 (Diafilter-30; Amicon, Limerick, Ireland).17 CVVH was accomplished with a roller pump (Brady BM 11; Brady, Vienna, Austria) in connection with an automatic balancing system (Equaline; Amicon). Mean blood flow rate was 143 ± 13 mL/min and ultrafiltration post-dilution rate was 47 ± 7 mL/min. Bicarbonate-based crystalloid solution was infused as substitution fluid aimed at a balanced fluid therapy. During the first dosing interval CVVH was continuous in all patients included. Six patients had to be excluded from further investigations during the following 16 h because of clotted CVVH or examinations outside the intensive care unit.

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 concentration–time 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.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In the 12 patients, the mean peak ceftazidime concentration 45 min after starting the infusion was 58.2 ± 11.6 mg/L at the arterial port and 45.0 ± 12.2 mg/L at the venous port. The mean trough concentrations 8 h after starting the infusion were 14.0 ± 3.2 and 11.2 ± 2.9 mg/L, respectively. Peak concentrations after the second, third and fourth infusions were 65.6 ± 3.2, 63.6 ± 9.2 and 68.4 mg/L, respectively, at the arterial port. The corresponding arterial trough levels of the second (n = 7) and third infusions (n = 6) were 13.1 ± 1.7 and 20.2 mg/L, respectively (Figure). Since haemofilters usually require changing after 24–36 h due to clotting inside the filter capillary, only one patient received a fourth dose within an uninterrupted haemofiltration period.

The individual pharmacokinetic parameters are listed in Table 2Go. Mean tH was 4.3 ± 0.6 h. The mean AUC was 344.0 ± 51.6 mg•h/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%.


View this table:
[in this window]
[in a new window]
 
Table 2. Individual pharmacokinetic data for 12 study patients
 
The percentage of T > MIC for MICs of 4, 8 and 16 mg/L and 8 hour dosing intervals is 202, 149 and 95%, respectively.20 Since maximal killing of multiresistant strains by ß-lactams has been reported to be highest at about 4 x MIC for the target pathogen, the ceftazidime clearance data obtained from our study were used to calculate the minimal daily dosage that would achieve these levels. Eight-hourly ceftazidime doses of 2128 ± 374, 4255 ± 748 and 8510 ± 1496 mg, respectively, would be required to maintain blood levels at four times these MIC values for the entire dosing interval.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
CVVH is an important supportive treatment in intensive care units and is usually performed because of its good haemodynamic tolerance. Knowledge of the impact of CVVH on the elimination of drugs is essential, but studies with modern polysulphone membranes are scarce. In addition, drug pharmacokinetics in critically ill patients can be altered by an increased volume of distribution and extended tH.9 The present study focused on the pharmacokinetic and pharmacodynamic aspects of ceftazidime treatment during CVVH with modern polysulphone membranes in critically ill patients.

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 12.3–24.1 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 3Go. 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


View this table:
[in this window]
[in a new window]
 
Table 3. Elimination of ceftazidime during renal replacement therapy (summary of published data)
 
Pharmacodynamic aspects

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 4Go).


View this table:
[in this window]
[in a new window]
 
Table 4. Times above the MIC (T > MIC)a for ceftazidime during CVVH
 
In summary, our results indicate that a regimen of ceftazidime 2 g q8h is appropriate for the treatment of susceptible (MIC < 4 mg/L) Gram-negative infections in intensive care patients during CVVH. For infections with intermediately resistant Enterobacteriaceae (MIC 8 mg/L), an increased dosage of at least ceftazidime 3 g q8h is recommended. Further studies are appropriate to determine the value of continuous infusion or more frequent dosing during CVVH.



View larger version (15K):
[in this window]
[in a new window]
 
Figure. Mean arterial serum ceftazidime concentrations after the first dose of ceftazidime 2 g ({diamond}) and peak (•) and trough ({circ}) levels every 8 h in critically ill patients during CVVH (n = 12).

 

    Notes
 
* Corresponding author. Tel: +43-1-40-400-4440; Fax: +49-89-2443-18-696; E-mail: florian.thalhammer{at}akh-wien.ac.at Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Craig, W. A. & Ebert, S. C. (1992). Continuous infusion of beta-lactam antibiotics. Antimicrobial Agents and Chemotherapy 36, 2577–83. [ISI][Medline]

2 . Mouton, J. W. & den Hollander, J. G. (1994). Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model. Antimicrobial Agents and Chemotherapy 38, 931–6. [Abstract]

3 . Mouton, J. W., Vinks, A. A. & Punt, N. C. (1997). Pharmacokinetic–pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion. Antimicrobial Agents and Chemotherapy 41, 733–8. [Abstract]

4 . MacGowan, A. P. & Bowker, K. E. (1998). Continuous infusion of ß-lactam antibiotics. Clinical Pharmacokinetics 35, 391–402. [ISI][Medline]

5 . Turnidge, J. D. (1998). The pharmacodynamics of ß-lactams. Clinical Infectious Diseases 27, 10–22. [ISI][Medline]

6 . Drusano, G. L. (1988). Role of pharmacokinetics in the outcome of infections. Antimicrobial Agents and Chemotherapy 32, 289–97. [ISI][Medline]

7 . Leroy, A., Leguy, F., Borsa, F., Spencer G. R., Fillastre, J. P. & Humbert, G. (1984). Pharmacokinetics of ceftazidime in normal and uremic subjects. Antimicrobial Agents and Chemotherapy 25, 638–42. [ISI][Medline]

8 . Matzke, G. R., Frye, R. F., Joy, M. S. & Palevsky P. M. (2000). Determinants of ceftazidime by continuous venovenous hemofiltration and continuous venovenous hemodialysis. Antimicrobial Agents and Chemotherapy 44, 1639–44. [Abstract/Free Full Text]

9 . Gomez, C. M., Cordingly, J. J. & Palazzo, M. G. (1999). Altered pharmacokinetics of ceftazidime in critically ill patients. Antimicrobial Agents and Chemotherapy 43, 1798–802. [Abstract/Free Full Text]

10 . Benko, A. S., Cappelletty, D. M., Kruse, J. A. & Rybak, M. J. (1996). Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected Gram-negative infections. Antimicrobial Agents and Chemotherapy 40, 691–5. [Abstract]

11 . Hanes, S. D., Wood, G. C., Herring, V., Croce, M. A., Fabian, T. C., Pritchard, E. et al. (2000). Intermittent and continuous ceftazidime infusion for critically ill trauma patients. American Journal of Surgery 179, 436–40. [ISI][Medline]

12 . Young, R. J., Lipman, J., Gin, T., Gomersall, C. D., Joynt, G. M. & Oh, T. E. (1997). Intermittent bolus dosing of ceftazidime in critically ill patients. Journal of Antimicrobial Chemotherapy 40, 269–73. [Abstract]

13 . Nikolaidis, P. & Tourkantonis, A. (1985). Effect of hemodialysis on ceftazidime pharmacokinetics. Clinical Nephrology 24, 142–6. [ISI][Medline]

14 . Davies, S. P., Lacey, L. F., Kox, W. J. & Brown, E. A. (1991). Pharmacokinetics of cefuroxime and ceftazidime in patients with acute renal failure treated by continuous arteriovenous haemodialysis. Nephrology, Dialysis, Transplantation 6, 971–6. [Abstract]

15 . Kinowski, J. M., de la Coussaye, J. E., Bressolle, F., Fabre, D., Saissi, G., Bouvet, O. et al. (1993). Multiple-dose pharmacokinetics of amikacin and ceftazidime in critically ill patients with septic multiple-organ failure during intermittent hemofiltration. Antimicrobial Agents and Chemotherapy 37, 464–73. [Abstract]

16 . Bressolle, F., Kinowski, J. M., de la Coussaye, J. E., Wynn, N., Eledjam, J. J. & Galtier, M. (1994). Clinical pharmacokinetics during continuous haemofiltration. Clinical Pharmacokinetics 26, 457–71. [ISI][Medline]

17 . Traunmüller, F., Thalhammer-Scherrer, R., Locker, G. J., Losert, H., Schmid, R., Staudinger, T. et al. (2001). Single-dose pharmacokinetics of levofloxacin during continuous venovenous hemofiltration in critically ill patients. Journal of Antimicrobial Chemotherapy 47, 229–31. [Abstract/Free Full Text]

18 . Ayrton, J. (1981). Assay of ceftazidime in biological fluids using high pressure liquid chromatography. Journal of Antimicrobial Chemotherapy 8, Suppl. B, 227–31. [ISI]

19 . Thalhammer, F., Schenk, P., Burgmann, H., El Menyawi, I., Hollenstein, U. M., Rosenkranz, A. R. et al. (1998). Single-dose pharmacokinetics of meropenem during continuous venovenous hemofiltration. Antimicrobial Agents and Chemotherapy 42, 2417–20. [Abstract/Free Full Text]

20 . Krause, R., Mittermayer, H., Feierl, G., Allerberger, F., Wendelin, I., Hirschl, A. et al. (1999). In vitro activity of newer broad spectrum beta-lactam antibiotics against Enterobacteriaceae and non-fermenters. A report from Austrian intensive care units. Wiener Klinische Wochenschrift 111, 549–54. [ISI][Medline]

21 . Gentry, L. O. (1985). Antimicrobial activity, pharmacokinetics, therapeutic indications and adverse reactions of ceftazidime. Pharmacotherapy 5, 254–67. [ISI][Medline]

22 . Sato, T., Okamoto, K., Kitaura, M., Kukita, I., Kikuta, K. & Hamaguchi, M. (1999). The pharmacokinetics of ceftazidime during hemodiafiltration in critically ill patients. Artificial Organs 23, 143–5. [ISI][Medline]

23 . Lau, A. H., Pyle, K., Kronfol, N. O. & Libertin, C. R. (1989). Removal of cephalosporins by continuous arteriovenous ultrafiltration (CAVU) and hemofiltration (CAVH). International Journal of Artificial Organs 12, 379–83. [ISI][Medline]

24 . Ohkawa, M., Nakashima, T., Shoda, R., Ikeda, A., Orito, M., Sawaki, M. et al. (1985). Pharmacokinetics of ceftazidime in patients with renal insufficiency and in those undergoing hemodialysis. Chemotherapy 31, 410–6. [ISI][Medline]

Received 15 February 2001; returned 30 May 2001; revised 20 August 2001; accepted 4 September 2001