a Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Sha Tin, Hong Kong, China; b Intensive Care Facility, Royal Brisbane Hospital and Division of Anaesthesiology and Intensive Care, University of Queensland, Australia
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Abstract |
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Introduction |
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Although ceftriaxone is commonly used in intensive care units, there are few data on the pharmacokinetics of ceftriaxone in critically ill patients. The severity of critical illness was not documented in either of the two studies that have reported data on the disposition of ceftriaxone in critically ill patients.10,11 Neither were individual patient data and trough antibiotic levels. Adequate data on the pharmacokinetics of od administration of ceftriaxone in critically ill patients are therefore lacking and it is unclear whether the current daily dosing recommendation, based on pharmacokinetic data from non-critically ill patients, is appropriate in the critically ill.
We measured plasma concentrations of ceftriaxone in critically ill patients with severe sepsis to determine the pharmacokinetic profile of the normal recommended dose of ceftriaxone for severe infections and to determine whether the current daily dosing recommendation maintains adequate plasma concentrations for antibacterial efficacy.
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Materials and methods |
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Twelve adult patients in the ICU with severe sepsis and who received ceftriaxone according to usual clinical practice were entered into the study. Patients with suspected allergy or renal impairment (plasma creatinine >120 µmol/L at enrolment) were excluded. Clinical indications for ceftriaxone included nosocomial pneumonia, intra-abdominal sepsis, urinary sepsis and empirical therapy for clinical sepsis without proven source. In accordance with usual clinical practice, all patients had an indwelling arterial cannula. All patients met recognized criteria for severe sepsis: clinical evidence of acute infection, temperature >38.3°C or <35.6°C, heart rate >90 beats per minute and tachypnoea >20 breaths per minute, as well as evidence of organ dysfunction or inadequate organ perfusion.12 Evidence of organ hypoperfusion included shock (defined as a systolic blood pressure of <90 mmHg or a decrease in baseline blood pressure of >40 mmHg after adequate fluid resuscitation),12 systemic acidosis, high blood lactate concentrations, oliguria and acute alteration of mental status.12 Blood pressure was measured continuously using an indwelling arterial catheter and recorded hourly for the duration of the study. The presence of shock and the need for inotropes during the study period were recorded.
The patients were prescribed an od dose of ceftriaxone (2 g) administered as an infusion over 30 min. Samples of arterial blood were collected at 0, 5, 10, 20 and 30 min during the first infusion and then, after completion of the infusion, at 1, 2, 5, 10, 20, 30, 60, 120, 210, 450, 690, 930, 1170 and 1410 min. Single specimens of blood for trough concentrations were taken on day 3. Specimens were centrifuged and plasma stored at 70°C for later analysis. Patient demographic data, clinical details and APACHE II scores13 at the time of entry into the study were recorded. Serum biochemistry, serum creatinine, liver function tests, 24 h urine volume and urine creatinine concentration were measured. Creatinine clearance was calculated from these measurements.
Plasma ceftriaxone concentrations were measured by high performance liquid chromatography as described previously.14 The calibration curve for the assay was linear over the range 5500 mg/L (r2 = 0.990). The within-day coefficient of variation at 250 and 40 mg/L was 2.31 and 2.3%, respectively. The mean ceftriaxone recovery relative to the internal standard was 96%.
The non-protein-bound fraction of ceftriaxone was determined by equilibrium dialysis as described previously.15 The free fraction was determined after equilibrium dialysis at pH 7.4 for 3.5 h at 37°C.
Ceftriaxone data were fitted to a two-compartment model using Kinetica (Simed SA, Creteil, France). Ninety-five per cent confidence intervals (95% CIs) were calculated for elimination half-life (tß), volume of distribution at steady state (Vss) and total body clearance (CL), to enable comparison with published data. The association between pharmacokinetic variables and serum bilirubin, albumin and creatinine clearance was determined by linear regression analysis. P values of <0.05 were considered significant.
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Results |
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Because of inadequate sample volume in one patient, protein binding data were available for only 10 patients. The mean non-protein-bound or free fraction of ceftriaxone was 27% (range 159%). Protein binding was concentration dependent (Figure 2). In patients with normal renal function (n = 8), the mean free fraction was 23% (range 150%), and in those with abnormal renal function (n = 2), it was 40% (range 159%). The free (unbound) ceftriaxone concentrationtime curves for individual patients are shown in Figure 3
. The limits of the ceftriaxone assay used were such that ceftriaxone concentrations <0.5 mg/L were not detectable. Reported concentrations <5 mg/L may be less accurate and should be interpreted with caution.
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Discussion |
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Few data on ceftriaxone pharmacokinetics and plasma concentrations in critically ill patients have been published previously. Comparison of pharmacokinetic data obtained in different studies is complicated by the fact that ceftriaxone CL is dose dependent as a result of concentration-dependent plasma protein binding of ceftriaxone.18 In comparison with the results of the three intensive care patients reported by van Dalen & Vree,10 our eight patients had a 130% higher CL, a 50% increase in Vss and a shorter tß (Table III
). The higher ceftriaxone dose (van Dalen & Vree used 1.5 g daily)10 and possible differences in albumin levels and illness severity may explain the differences seen (disease severity was not reported in van Dalen & Vree's study). The ß-lactam antibiotic ceftriaxone is unique because it is >90% protein-bound at clinically relevant doses in non-critically ill patients. In patients with severe sepsis, plasma albumin often falls rapidly.19 This hypo-albuminaemia is marked in our patient group (mean albumin level, 22 ± 6.1) and would be expected to increase the free fraction of ceftriaxone; this is confirmed by our data (Figure 2
). In comparison with normal patients,18 protein binding was decreased by 2030%. Elimination of ceftriaxone by the kidneys is by glomerular filtration,20 and it is well known that plasma protein binding will reduce the rate of drug elimination by glomerular filtration.21 The higher free fraction of ceftriaxone would therefore result in increased ceftriaxone CL in the presence of normal or increased creatinine clearance (Tables I and II
), thereby contributing to the observed low trough concentrations.
Our results are also different from those published by Heinemeyer et al.11 Our patients had an increased CL, increased Vss and a 50% shorter tß (Table III
). The differences in the patient populations investigated in these two studies are the most likely cause of discrepancies between the findings. Our patients have clearly defined severe disease as confirmed by APACHE II scores and presence of severe sepsis, whereas the patients in the Heinemeyer study were described only as post-operative surgical patients with bacterial bronchial tract infectionthe severity of disease was not reported. The reported mean albumin concentration from their series (mean 38 ± 6.6 g/L) is close to normal values. Low albumin has been associated with severity of illness and decreased survival in critically ill patients,22,23 and the lower albumin levels in our patients (mean 22 ± 6.1 g/L compared with 38 ± 6.6 g/L) suggest that our patients were more severely ill. For the reasons discussed previously the low albumin levels would contribute to the higher Vss and ceftriaxone CL seen in our patients.
The occurrence of low ceftriaxone concentrations for a substantial part of the dosing interval has potential clinical implications. The bactericidal activity of ß-lactam antibiotics on Gram-negative bacilli is related to the time that concentrations in tissue and plasma exceed a certain threshold. The effect is maximal at a relatively low antibiotic concentration, approximately four to five times the MIC, and there is no added benefit at higher concentrations.24,25 If antibiotic concentration in vitro falls below the threshold level, breakthrough bacterial growth will occur.26,27 In addition, there is no significant post-antibiotic effect, as seen with the aminoglycosides, and re-growth occurs as soon as concentrations fall below the MIC.28 It has also recently been demonstrated that resistance to ß-lactam antibiotics is associated with antibiotic concentrations that fall below the MIC for more than half the dosing interval.29 Thus, it seems to be necessary for the efficacy of ß-lactams that clinical dosing regimens maintain adequate plasma levels for a substantial part of the course of therapy. Common Gram-negative organisms found in ICU patients include Escherichia coli, Enterobacter spp., Klebsiella spp., Proteus spp., Morganella morganii, Citrobacter spp. and Pseudomonas aeruginosa.30 With the exception of P. aeruginosa, the average MIC90 of ceftriaxone for these organisms is in the region of 2 mg/L (range of averages, <18 mg/L).3134 The National Committee for Clinical Laboratory Standards (NCCLS) recommended MIC breakpoint for ceftriaxone susceptibility is 8 mg/L.35 We therefore conservatively determined the appropriate desired minimum threshold concentration for ceftriaxone to be 8 mg/Lfour times the MIC of most susceptible organisms and at least greater than the NCCLS MIC breakpoint. Four of eight patients with normal renal function failed to maintain total (bound and unbound) ceftriaxone concentrations above the desired threshold for the entire dosing interval and three for a substantial part of the dosing interval (Figure 1). Total trough ceftriaxone concentrations on day 3 continued to be low in all four of these patients (Table II
). Despite the higher percentage of free to total plasma ceftriaxone in our patients, actual free concentrations fall rapidly. Free ceftriaxone concentrations were below the desired MIC in five of eight patients with normal renal function by 4 h, and were undetectable in all patients with normal renal function by 8 h (Figure 3
).
The clinical importance of this observation is not yet clear; however, in intensive care patients, optimal efficacy of antibiotics is particularly important. Patients frequently have underlying disease, are shocked and have severe infections. These categories of patients have altered immune responses and there is evidence that they require markedly increased doses of cephalosporins to ensure efficacy.3638 Therefore, although not clinically proven, it would seem prudent to choose a dose and dosing interval that would maintain optimal antibiotic concentrations in these patients. It may not be possible to estimate tissue antibiotic concentrations and subsequent clinical efficacy directly from blood concentrations; however, it is likely that altered antibiotic disposition and blood concentrations will have effects on tissue concentrations. This is particularly relevant at low concentrations towards the end of the dosing interval. If it is assumed that it is the free fraction of ceftriaxone that is phamacodynamically active, and that plasma concentrations are in approximate equilibrium with extracellular concentrations, then free concentrations fall below the desired MIC (in plasma and tissue) in the majority of patients with normal renal function within 4 h. In a simulated model based on normal subjects and a dose of 2 g iv, the time taken for free ceftriaxone levels to fall below the threshold concentration was approximately double (8 h), and total ceftriaxone levels remained above the threshold level for the entire dosing interval.39
As can be seen from our data, total and free plasma ceftriaxone concentrations are frequently lower than threshold, and lower than those measured in non-critically ill patients. It is therefore likely that tissue concentrations will be low for a substantial part of the dosing interval. In the absence of data describing tissue levels of ceftriaxone in critically ill patients, it would seem appropriate to aim first for adequate total ceftriaxone concentrations in blood, which equate with efficacy in non-critically ill patients.33,34
Our observations suggest that the same daily dose, given at either a shorter dosing interval or with administration by infusion, would be required to ensure adequate ceftriaxone concentrations over the full dosing interval in patients with severe sepsis and normal renal function. To ensure adequate total ceftriaxone concentrations for the entire dosing interval in most patients with normal renal function, we utilized the mean + 2 S.D. of our pharmacokinetic data to calculate the loading and infusion dosage required.40 A loading dose of 300 mg followed by a continuous infusion at 1000 mg over 24 h should ensure antibiotic concentrations >10 mg/L for the entire dosing interval in at least 95% of patients. The potential extra cost of infusion is expected to be small because infusion pumps, a high nursing staff density and pharmacy personnel are already present in ICUs. As the total antibiotic dose required is less than the current recommended dose, cost savings could even be expected if continuous infusion is used.
The consequences of moderate or severe renal failure are an approximately three-fold increase in tß, a 50% increase in Vss, and halved CL, in comparison with baseline values in intensive care patients. The magnitude of these changes is similar to that reported in two previous studies of critically ill patients,10,11 with the exception of the lower Vss reported in the paper by Heinemeyer et al.11 The markedly prolonged t
ß in critically ill patients with renal failure differs from that reported in other acute renal failure patients, in whom the t
ß is only mildly prolonged.41 In non-critically ill patients, the increased proportion of free ceftriaxone that accompanies renal failure results in an increase in hepatic clearance and a consistent or only slightly increased t
ß. It has been demonstrated previously that although the free fraction of ceftriaxone does increase, there is a decrease in hepatic clearance in critically ill patients, the cause of which has not been clearly delineated.11 The results in our critically ill patients confirm this important previous finding that ceftriaxone CL in critically ill patients is primarily dependent on renal CL,11 and the increased Vss and decreased CL result in a markedly prolonged t
ß. This finding is clinically important as renal dysfunction may result in unsuspected accumulation in critically ill patients. The determination of creatinine clearance, preferably by direct measurement, and not simply observation of blood creatinine concentrations is needed. A dose reduction of one-third in patients with
50% reduction in creatinine CL, and a reduction of two-thirds in patients who are anuric has been suggested.11
In conclusion, the pharmacokinetic parameters of ceftriaxone (2 g iv daily) in critically ill patients with severe sepsis are different from those described in normal patients. In critically ill patients with normal renal function, there is an increase in CL and the Vss, which results in a similar tß. Resulting ceftriaxone concentrations, however, are frequently below the desired threshold concentration as a result of the larger volume of distribution. In critically ill patients, it is even more important to optimize factors that could reduce treatment failure and emergence of antibiotic resistance. While not yet supporting a change in clinical practice, we recommend that a decrease in dosing interval or continuous infusion be evaluated further in critically ill patients with normal renal function.
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Acknowledgments |
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Notes |
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References |
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2 . Marshall, J. C., Cook, D. J., Christou, N. V., Bernard, G. R., Sprung, C. L. & Sibbald, W. J. (1995). Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Critical Care Medicine 23, 163852.[ISI][Medline]
3 . Byatt, C. M., Lewis, L. D., Dawling, S. & Cochrane, G. M. (1984). Accumulation of midazolam after repeated dosage in patients receiving mechanical ventilation in an intensive care unit. British Medical Journal 289, 799800.[ISI][Medline]
4 . Lindow, J. & Wijdicks, E. F. (1994). Phenytoin toxicity associated with hypoalbuminemia in critically ill patients. Chest 105, 6024.[Abstract]
5 . Marik, P. E. (1993). Aminoglycoside volume of distribution and illness severity in critically ill septic patients. Anaesthesia and Intensive Care 21, 1723.[ISI][Medline]
6 . Marik, P. E., Havlik, I., Monteagudo, F. S. & Lipman, J. (1991). The pharmacokinetics of amikacin in critically ill adult and paediatric patients: comparison of once- versus twice-daily dosing regimens. Journal of Antimicrobial Chemotherapy 27, Suppl. C, 819.[Abstract]
7 . Gous, A. G., Dance, M. D., Lipman, J., Luyt, D. K., Mathivha, R. & Scribante, J. (1995). Changes in vancomycin pharmacokinetics in critically ill infants. Anaesthesia and Intensive Care 23, 67882.[ISI][Medline]
8 . Cornwell, E. E., 3rd, Belzberg, H., Berne, T. V., Gill, M. A., Theodorou, D., Kern, J. W. et al. (1997). Pharmacokinetics of aztreonam in critically ill surgical patients. American Journal of Health-System Pharmacy 54, 53740.
9 . McKindley, D. S., Boucher, B. A., Hess, M. M., Croce, M. A. & Fabian, T. C. (1996). Pharmacokinetics of aztreonam and imipenem in critically ill patients with pneumonia. Pharmacotherapy 16, 92431.[ISI][Medline]
10 . van Dalen, R. & Vree, T. B. (1990). Pharmacokinetics of antibiotics in critically ill patients. Intensive Care Medicine 16, Suppl. 3, S2358.[ISI][Medline]
11 . Heinemeyer, G., Link, J., Weber, W., Meschede, V. & Roots, I. (1990). Clearance of ceftriaxone in critical care patients with acute renal failure. Intensive Care Medicine 16, 44853.[ISI][Medline]
12 . Anonymous. (1992). American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Critical Care Medicine 20, 86474.[ISI][Medline]
13 . Knaus, W. A., Draper, E. A., Wagner, D. P. & Zimmerman, J. E. (1985). APACHE II: a severity of disease classification. Critical Care Medicine 13, 81829.[ISI][Medline]
14 . Granich, G. G. & Krogstad, D. J. (1987). Ion-pair high performance liquid chromatographic assay for ceftriaxone. Antimicrobial Agents and Chemotherapy 31, 3858.[ISI][Medline]
15 . Popick, A. C., Crouthamel, W. G. & Bekersky, I. (1987). Plasma protein binding of ceftriaxone. Xenobiotica 17, 113945.[ISI][Medline]
16 . Pollock, A. A., Tee, P. E., Patel, I. H., Spicehandler, J., Simberkoff, M. S. & Rahal, J. J., Jr (1982). Pharmacokinetic characteristics of intravenous ceftriaxone in normal adults. Antimicrobial Agents and Chemotherapy 22, 81623.[ISI][Medline]
17 . Patel, I. H., Chen, S., Parsonnet, M., Hackman, M. R., Brooks, M. A., Konikiff, J. et al. (1981). Pharmacokinetics of ceftriaxone in humans. Antimicrobial Agents and Chemotherapy 20, 63441.[ISI][Medline]
18 . Stoeckel, K., McNamara, P. J., Brandt, R., Plozza-Nottebrock, H. & Ziegler, W. H. (1981). Effects of concentration-dependent plasma protein binding on ceftriaxone kinetics. Clinical Pharmacology and Therapeutics 29, 6507.[ISI][Medline]
19 . Kushner, I. (1982). The phenomenon of the acute phase response. Annals of the New York Academy of Sciences 389, 3948.[ISI][Medline]
20 . Stoeckel, K. (1981). Pharmacokinetics of Rocephin, a highly active new cephalosporin with an exceptionally long biological half-life. Chemotherapy 27, Suppl. 1, 426.[ISI][Medline]
21 . Goldstein, A. (1949). The interaction of drugs and plasma proteins. Pharmacological Reviews 1, 10265.[ISI]
22 . McCluskey, A., Thomas, A. N., Bowles, B. J. & Kishen, R. (1996). The prognostic value of serial measurements of serum albumin concentration in patients admitted to an intensive care unit. Anaesthesia 51, 7247.[ISI][Medline]
23 . Knaus, W. A., Wagner, D. P., Draper, E. A., Zimmerman, J. E., Bergner, M., Bastas, P. G. et al. (1991). The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalised adults. Chest 100, 161936.[Abstract]
24 . Vogelman, B., Gudmundsson, S., Leggett, J., Turnidge, J., Ebert, S. & Craig, W. A. (1988). Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. Journal of Infectious Diseases 158, 83147.[ISI][Medline]
25 . Craig, W. A. (1998). Pharmacokinetic/pharmacodynamic parameters: rationale for antimicrobial dosing of mice and men. Clinical Infectious Diseases 26, 112.[ISI][Medline]
26 . 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, 9316.[Abstract]
27 . Manduru, M., Mihm, L. B., White, R. L., Friedrich, L. V., Flume, P. A. & Bosso, J. A. (1997). Comparative bactericidal activity of ceftazidime against isolates of Pseudomonas aeruginosa as assessed in an in vitro pharmacodynamic model versus the traditional timekill method. Antimicrobial Agents and Chemotherapy 41, 252732.[Abstract]
28 . Vogelman, B. S. & Craig, W. A. (1985). Postantibiotic effects. Journal of Antimicrobial Chemotherapy 15, Suppl. A, 3746.[ISI][Medline]
29 . Fantin, B., Farinotti, R., Thabaut, A. & Carbon, C. (1994). Conditions for the emergence of resistance to cefpirome and ceftazidime in experimental endocarditis due to Pseudomonas aeruginosa. Journal of Antimicrobial Chemotherapy 33, 5639.[Abstract]
30
.
Hanberger, H., Garcia-Rodriguez, J. A., Gobernado, M., Goossens, H., Nilsson, L. E. & Struelens, M. J. (1999). Antibiotic susceptibility among aerobic Gram-negative bacilli in intensive care units in 5 European countries. French and Portuguese ICU Study Groups. Journal of the American Medical Association 281, 6771.
31 . Hart, C. A. & Percival, A. (1982). Resistance to cephalosporins among gentamicin-resistant klebsiellae. Journal of Antimicrobial Chemotherapy 9, 27586.[ISI][Medline]
32 . Bremner, D. A. (1983). Ceftriaxonea new broad-spectrum semisynthetic cephalosporin. In vitro activity against Gram-negative bacilli sensitive and resistant to gentamicin. Chemotherapy 29, 2838.[ISI][Medline]
33 . Richards, D. M., Heel, R. C., Brogden, R. N., Speight, T. M. & Avery, G. S. (1984). Ceftriaxone. A review of its antibacterial activity, pharmacological properties and therapeutic use. Drugs 27, 469527.[ISI][Medline]
34 . Brogden, R. N. & Ward, A. (1988). Ceftriaxone. A reappraisal of its antibacterial activity and pharmacokinetic properties, and an update on its therapeutic use with particular reference to once-daily administration. Drugs 35, 60445.[ISI][Medline]
35 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow AerobicallyFifth Edition: Approved Standard M7-A5. NCCLS, Villanova, PA.
36 . Mouton, J. W. & Vinks, A. A. (1996). Is continuous infusion of ß-lactam antibiotics worthwhile? Efficacy and pharmacokinetic considerations. Journal of Antimicrobial Chemotherapy 38, 515.[Abstract]
37 . Livingston, D. H. & Wang, M. T. (1993). Continuous infusion of cefazolin is superior to intermittent dosing in decreasing infection after hemorrhagic shock. American Journal of Surgery 165, 2036.[ISI][Medline]
38 . Livingston, D. H. & Malangoni, M. A. (1993). Increasing antibiotic dose decreases polymicrobial infection after hemorrhagic shock. Surgery, Gynecology and Obstetrics 176, 41822.
39 . Stoeckel, K. & Koup, J. R. (1984). Pharmacokinetics of ceftriaxone in patients with renal and liver insufficiency and correlations with a physiologic nonlinear protein binding model. American Journal of Medicine 77, 2632.
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.
Lipman, J., Gomersall, C. D., Gin, T., Joynt, G. M. & Young R. J. (1999). Continuous infusion ceftazidime in intensive care patients: a randomized controlled trial. Journal of Antimicrobial Chemotherapy 43, 30911.
41 . Stoeckel, K., McNamara, P. J., Hoppe-Seyler, G., Blumberg, A. & Keller, E. (1983). Single-dose ceftriaxone kinetics in functionally anephric patients. Clinical Pharmacology and Therapeutics 33, 63341.[ISI][Medline]
Received 31 May 2000; returned 25 September 2000; revised 6 November 2000; accepted 5 December 2000