Int J Clin Pharm DOI 10.1007/s11096-015-0101-8
RESEARCH ARTICLE
Targeting cefuroxime plasma concentrations during coronary artery bypass graft surgery with cardiopulmonary bypass Marieke Aalbers1 • Peter G. J. ter Horst2 • Wobbe Hospes2 • Michel L. Hijmering3 Alexander J. Spanjersberg3
•
Received: 11 September 2014 / Accepted: 10 March 2015 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2015
Abstract Backgound Patients are at risk for severe postoperative infections after coronary artery bypass graft (CABG) surgery. Clinical laboratory data showed that unbound plasma concentrations of cefuroxime were not always adequate, therefore we developed a new dosing regimen. Objective The aim of this prospective study is to evaluate the new dosing strategy by monitoring patients for unbound cefuroxime plasma concentrations during CABG surgery with cardiopulmonary bypass (CPB). Setting A Dutch teaching hospital. Methods In this prospective trial, patients scheduled for CABG surgery with CPB were included. A starting dose of 1500 mg cefuroxime was given with anesthesia induction, followed by 750 mg cefuroxime every hour until wound closure. In case of renal failure the dosing regimen was adapted. Serial blood samples were collected before, during and after the CPB process. Pharmacokinetic modelling was performed by using an ‘iterative two-stage Bayesian population procedure’. Main outcome measure Unbound plasma concentrations of cefuroxime. Results 22 patients were included, data could be evaluated of 21 patients. In 24 % of the patients the
Electronic supplementary material The online version of this article (doi:10.1007/s11096-015-0101-8) contains supplementary material, which is available to authorized users. & Marieke Aalbers [email protected] 1
Department of Clinical Pharmacy, Hospital Pharmacy Emmen, Boermarkeweg 60, 7824 AA Emmen, The Netherlands
2
Department of Clinical Pharmacy, Isala Clinics, Zwolle, The Netherlands
3
Department of Thoracic Anaesthesia and Intensive Care, Isala Clinics, Zwolle, The Netherlands
unbound cefuroxime plasma concentration was below the target range during surgery before CPB started. Patients with a bodyweight above 100 kg or age \60 years were more likely to have unbound plasma concentrations below the target range (P = 0.030 and P = 0.008). During CPB, the half-life of unbound cefuroxime increased by 17 % and the clearance decreased by 11 % compared to before CPB (P = 0.033 and P = 0.014). The mean pharmacokinetic parameters before, during and after CPB were as follows: elimination half-life 72, 84 and 76 min; clearance of unbound cefuroxime (Clu) 14.2, 12.7, 13.8 l/h and volume of distribution (Vu) 0.280, 0.284 and 0.290 l/kg respectively. Variations in unbound fractions before, during and after CPB were below 2 %, implicating the unbound fraction of cefuroxime is not influenced by CPB. Conclusion Our results show that CPB during CABG surgery does not lead to inadequate unbound cefuroxime concentrations. Age, renal function and possibly also weight are more important factors that can result in unbound plasma cefuroxime concentrations below the target value. Keywords Antibiotic prophylaxis Cardiopulmonary bypass Cefuroxime Coronary artery bypass graft surgery Pharmacokinetics
Impacts on practices • • •
The unbound fraction of cefuroxime is not influenced by cardiopulmonary bypass. Cardiopulmonary bypass is not a risk factor for inadequate concentrations of cefuroxime. Age, renal function and possibly also weight are more important parameters that can result in unbound plasma cefuroxime concentrations below the target value.
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Introduction Coronary artery bypass graft (CABG) surgery is a major therapeutic approach in the treatment of coronary artery disease. While performing this procedure, the function of the heart and lungs can temporarily be taken over using cardiopulmonary bypass (CPB) by extracorporeal circulation. Patients who have had CABG surgery are at risk for severe postoperative infections. The incidence of sternal surgical site infections ranges from 0.9 to 20 % [1]. The incidence of deep sternal infections, such as mediastinitis, ranges from 1 to 2 % [1]. In the Netherlands, the incidence of sternal infections is about 2.4 % and the incidence of deep sternal infections, for example mediastinitis, is about 1.5 % [2]. The mortality rate for patients with deep sternal infections is about 10–15 % [3]. The most common pathogens responsible for postoperative infections are Staphylococcus aureus (44 %) and coagulase-negative staphylococci (15 %) [1, 2]. Second generation cephalosporins like cefuroxime, have a favorable spectrum, low toxicity and good tissue penetration, which makes them first choice as antibiotic prophylaxis in cardiac surgery [4, 5]. Cephalosporins, like cefuroxime, show time-dependent killing. The parameter which best describes killing for cephalosporins is time above minimum inhibitory concentration (MIC) (T [ MIC). The MIC for the most suspected bacteria is B8 mg/l [6, 7]. Because of the life-threatening consequences of deep sternal infections, maximal killing is pursued. Maximal killing rates are achieved with unbound cefuroxime concentrations above four times MIC, i.e. C32 mg/l [8]. From other studies we know that the use of CPB, however, may have a substantial effect on the pharmacokinetics of administered drugs, including the cephalosporins [9, 10]. CPB can alter the time course of cefuroxime plasma concentrations by hemodilution, hypotension, hypothermia and alterations of the binding capacity of proteins, which could lead to sub-optimal antibiotic prophylaxis [11]. Pharmacokinetics of cefuroxime during CABG surgery including CPB were studied before, however, in the studies of Mandak, Pojar, Nascimento and Knoderer detailed information about the operation procedures and CPB device used was lacking and the target concentrations seemed not to be adequate referring to CLSI and Eucast values [2, 4, 9, 11, 12]. In most studies, the trough target values were less aggressive ranging from [2 mg/l [13] to [16 mg/l. These considerations and the use of different cefuroxime dosing regimens made us to decide to set up a pilot study in our setting. In the pilot study, 10 patients with normal renal function were included [14]. Of those, eight patients had calculated unbound plasma cefuroxime concentrations
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below 32 mg/l at some point during surgery, suggesting insufficient antibiotic prophylaxis. Therefore, an adapted dosage schedule was developed, based on the data from our pilot experiment. The aim of this prospective study is to evaluate the new dosing strategy by monitoring patients for unbound cefuroxime plasma concentrations during CABG surgery with CPB.
Methods Study design This study was performed at the Isala Clinics in Zwolle, The Netherlands, a 1000 bed teaching hospital. Approximately 500 CABG surgeries with CPB are performed every year, next to about 1000 other open heart surgeries with CPB. We got a waiver from the local ethics committee, because samples were obtained from existing catheters and the dosing of cefuroxime was in accordance with the SPC of Cefuroxim Fresenius Kabi (max 6000 mg per day) [15]. Inclusion criteria were patients with coronary artery disease scheduled for CABG surgery with CPB who gave their written informed consent. Excluded were patients with age below 18 years or with a prescription of cefuroxime before surgery or actual use of mirtazapine, because of interference in our analytical assay. Surgical and anesthetic procedures The surgical and anesthetic procedures are described in the pilot study [14]. Dosing and sampling The first dose, 1500 mg of cefuroxime i.v., was given with anesthesia induction. The second dose, 750 mg i.v., was given 1 h after the first dose (t = 1 h). The dosing regimen was continued with cefuroxime 750 mg every hour until wound closure (t = 2; t = 3; t = 4; t = 5). In case of moderate or severe renal failure (e.g. eGFR \60 ml/min/ 1.73 m2 calculated by the ‘Modification of Diet in Renal Disease’ (MDRD) formula [16] the dosing regimen after the second dose was continued with cefuroxime 750 mg every 2 h until wound closure (t = 3 and t = 5). Blood samples were collected from the radial artery catheter or directly arterial from the CPB system. Prior to the CABG procedure 1 blank sample was drawn from the radial artery catheter. During surgery, peak and trough samples of blood were collected. Trough samples were taken just before the next dose; peak samples were taken 30 min after the dose. Moreover, samples were also drawn
Int J Clin Pharm
at time of skin incision, at start of CPB, every 30 min of CPB, at the end of CPB and at wound closure. The actual sampling times varied depending on the clinical situation. Samples were collected in EDTA bloodcollection tubes, stored on ice, mixed and centrifuged at 3000 rpm for 5 min directly after the procedure. Analytical procedure The high pressure liquid chromatographic procedure, described in the article of Bertholee et al. was used [14]. Selectivity of the method was tested before actual validation. All compounds reasonably used in the target population with a retention time near cefuroxime were investigated on possible interference with the cefuroxime assay and no interferences were found. Moreover, during the actual analysis of patient material, peak purity was investigated and selective analysis of cefuroxime was confirmed. In addition to Bertholee et al., the unbound concentrations were determined. For preparation of the unbound cefuroxime samples, 1 ml of plasma was converted to the Centrifree ultrafiltration device (Millipore) and centrifuged at 2000 rpm for 30 min. The limit of quantification for cefuroxime was experimentally determined to be 2.5 mg/L (n = 6). The assay was linear in the range 5–160 mg/L (n = 4). The within-day (n = 5) and between-day (n = 5) coefficients of variation for spiked controls (15, 30, and 50 mg/L) were B3.1 and B3.3 %, respectively.
Pharmacokinetic analysis Pharmacokinetic modelling was performed by using an ‘iterative two-stage Bayesian population procedure’ (ITSB) using MW Pharm version 3.80 (Mediware, Zuidhorn, the Netherlands). For pharmacokinetic modeling, the unbound cefuroxime concentrations were used. Based on the Akaike information criterion (AIC) a one-compartment pharmacokinetic model was used to describe cefuroxime pharmacokinetics [17, 18]. In the present study, pharmacokinetic parameters, including fr (Eq. 2), half-life, plasma clearance rate (Clu) and volume of distribution (Vu) were determined before, during and after CPB, with u representing the unbound fraction of cefuroxime. For the pharmacokinetic parameters, a log-normal distribution was assumed. The model-equations and abbreviations are given below: Ct ¼ C0 ekt
Statistical analysis Demographic and peri-operative parameters were compared by using analysis of variance and descriptive methods, i.e. mean ± SD. Data estimated or parameters obtained after PK-modeling were statistically analyzed for normality based on kurtosis (range -1 to ?1), skewness (range -1 to ?1) and the Shapiro–Wilk test (P \ 0.05). The nonparametric Wilcoxon signed-rank test for paired data or, when a normal distribution was found, the paired t test was used for the comparison of cefuroxime pharmacokinetics before, during and after CPB. Statistical analysis was performed using SPSS software (version 18.0) and Excel Microsoft. A P value of \0.05 was considered statistically significant.
Results In February and March 2012, 22 patients were included. In Table 1, the demographics of the 22 included patients are shown. Unbound concentrations Unfortunately, due to technical errors, the unbound concentrations of patient 18 could not be analyzed, therefore we excluded patient 18 from this study. The unbound cefuroxime concentrations of the remaining 21 patients are presented in Fig. 1. In 5 patients the unbound cefuroxime plasma concentration was below the target range during surgery before CPB started. Of those 5 patients, 3 patients had also unbound cefuroxime plasma concentrations below the target range during CPB. Patients with a weight above 100 kg are more likely to have unbound plasma concentrations below the target range during surgery before start of CPB. (P = 0.030, Pearson Chi-Square test). Moreover, age below 60 years was also found to be predictive of unbound plasma concentrations below the target range during surgery before start of CPB (P = 0.008). Other factors including CPB time, gender and type of cardioplegia (data not shown) were not found to be predictive of unbound concentrations below the target range.
ð1Þ
Unbound fractions
ð2Þ
For 21 patients, the unbound fractions of cefuroxime (fu) were calculated by dividing the unbound plasma
Standard equation for first order kinetics Clu ¼ fr Clcr
Clu = clearance of unbound cefuroxime, Clcr = clearance of plasma creatinine, fr = fraction
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Int J Clin Pharm Table 1 Demographics of included patients Serum creatinine (lmol/l)
Height (cm)
Weight (kg)
eGFR (ml/min/1.73 m2)a
CPB volume (ml)
Operation time (min)
1850
161
CPB time (min)
Subject
Age (years)
1 (m)
71
87
174
77
2 (f)
62
78
173
100
69
1800
262
131
3 (m)
60
56
182
89
137
1500
224
102
4 (m)
48
86
179
80
88
1000
199
47
5 (m)
63
86
188
104
83
1850
228
109
6 (f)
74
63
161
54
85
1850
207
101
7 (m) 8 (m)
71 68
112 79
172 176
63 98
56 90
1850 1850
147 181
58 72
80
60
9 (m)
76
93
175
77
73
1850
153
71
10 (m)
75
101
183
99
66
1250
167
74
11 (f)
67
61
162
66
90
1850
301
103
12 (f)
66
78
157
60
68
1250
184
85
13 (m)
77
99
173
80
68
1350
213
96
14 (m)
75
96
177
86
70
1850
231
75
15 (m)
77
68
183
77
104
1850
227
105
16 (m)
84
81
176
96
84
1850
170
60
17 (f)
61
54
156
64
106
1250
175
47
18 (m)
72
76
180
85
93
1850
210
66
19 (m)
59
73
189
105
101
1850
287
125
20 (m)
62
59
179
122
128
1850
204
97
21 (m)
57
83
180
84
88
1450
221
92
22 (m) Mean
49 67.0
71 79
183 175
101 85
109 88
1850 1679
293 211
143 87
SD
9.3
15
9
17
20
283
44
27
a
eGFR MDRD measured 1 day before start of surgery
concentrations by the total plasma concentrations. The total mean unbound fraction of cefuroxime is 72.5 ± 5.0 %. Variations in unbound fractions before, during and after CPB were below 2 %, implicating the unbound fraction of cefuroxime is not influenced by CPB. Pharmacokinetic parameters Unbound plasma concentrations of cefuroxime were determined in 21 patients, with a total of 147 samples. Pharmacokinetic parameters before, during and after CPB are shown in Table 2. The interindividual variability (coefficient of variation) of the parameter fr varied between 14.8 and 23.9 %. Because cefuroxime is both filtered and secreted, the parameter fr is[1. The coefficient of variation of volume of distribution of the unbound cefuroxime (Vu) varied between 12.2 and 26.3 %. The residual standard error (rse, standard error of the mean) for the parameter fr varied between 3 and 5 % and residual standard error of Vu varied between 3 and 6 %. During CPB, the clearance decreased with on average 11 % compared to the clearance before CPB as shown in
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Table 2 (P = 0.014 resp, SPSS Wilcoxon signed-rank test).
Discussion In 24 % of the patients the unbound cefuroxime plasma concentration was below the target concentration of 32 mg/ l at some point during surgery. We expected to find at maximum 10 % of the patients below the target concentration. This result is explained by renal function, because in our study for the patients with good renal function or mild renal disease (e.g. eGFR [60 ml/min), renal function was better than in the pilot study [14] (90 ± 19 vs. 75 ± 10 ml/min) [14]. Compared to the pilot study [14], in which 80 % of the patients with good renal function or mild renal disease had plasma cefuroxime concentrations below the target, the new dosing schedule improved antibiotic prophylaxis. For cefuroxime, concentration-dependent toxicity is limited, and it can be argued that using an even more aggressive dosing strategy would result in all patients
Int J Clin Pharm 100
90
80
Unbound cefuroxime (mg/L)
70
60
50
40
30
20
10
0 0
1
2
3
4
5
6
7
8
9
10
Sampling intervals
Fig. 1 Unbound plasma concentrations of cefuroxime at different sampling intervals. 1 = at skin incision, 2–8 = trough and peak samples. Trough samples were taken just before the next dose; peak samples were taken 30 min after the dose. 9 = wound closure
Table 2 Population pharmacokinetic parameter values by ITSB analysis mean ± SD (range) Parameter fr
Before CPB
During CPB
After CPB
3.26 ± 0.38 (2.36–4.26)
3.00 ± 0.62 (1.56–4.24)
3.23 ± 0.59 (1.84–4.20)
Vu (l/kg)
0.280 ± 0.068 (0.189–0.521)
0.284 ± 0.015 (0.255–0.310)
0.290 ± 0.043 (0.200–0.380)
Clu (l/h)
14.17 ± 4.41 (9.15–25.02)
12.66 ± 3.25 (7.43–18.61)
13.77 ± 3.19 (9.25–20.38)
72 ± 20 (40–106)
84 ± 25 (50–151)
76 ± 18 (52–107)
Half-life (min)
reaching the target, however we were limited by a maximum of 6 g per day [15]. Instead, to improve the dosing regimen, continuous infusion could be applied. Zeisler et al. [19] demonstrated similar efficacy between intermittent and continuous infusion of cefuroxime in infected patients with the continuous infusion group requiring 55 % less drug over the course of therapy. In a paper of Pass et al. [20] serum concentrations of cefuroxime after continuous infusion in coronary bypass graft patients were described, however, with their dosing strategy, only a few patients would have maintained concentrations above our target limit of 32 mg/l. In addition to optimization of the dosing strategy, another advantage of continuous infusion is that instead of six syringes for every hour, only two syringes have to be prepared and the dosing schedule is simplified. To further optimize the dosing strategy, a continuous infusion regimen could be used to reduce the fluctuations in plasma levels and to maximize the time the unbound cefuroxime plasma concentration remains above 32 mg/l [20].
In finding an optimal dosing strategy, demographic characteristics and peri-operative characteristics could possibly influence cefuroxime concentrations. In our study, patients with a weight above 100 kg were found to be more likely to have unbound plasma concentrations below the target range during surgery before start of CPB. (P = 0.030, Pearson Chi Square test), although the number of patients above 100 kg in our study was very limited. Moreover, age below 60 years was also found to be predictive of unbound plasma concentrations below the target range during surgery before start of CPB (P = 0.008). In a study of Broekhuysen et al. [21] age was found to be related to cefuroxime clearance, suggesting higher cefuroxime dosing in patients below 60 years. In our study, other factors including CPB time, gender and type of cardioplegia were not found to be predictive of unbound concentrations below the target range. In this study, the total mean unbound fraction of cefuroxime was 72.5 %, which is similar to the unbound fraction of 73 % Mandak and Pojar found in their study
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before the start of CPB [2, 11]. However, throughout the course of CPB, Mandak and Pojar found lower protein binding for cefuroxime with unbound fractions [83 %. In our study, however, variations in unbound fractions before, during and after CPB were below 2 %. The primer solution Mandak and Pojar used in their study did not contain albumin which could explain altered protein binding. In the present study, the kinetic disposition of cefuroxime was investigated based on plasma curve decay applying a 1-compartment open model. Nascimento et al. [12] used an open 1-compartment model before to describe the pharmacokinetics of cefuroxime. Significant differences between the present study and Nascimento et al. were observed in the kinetic parameters half-life and plasma clearance as shown in Table 3. The volume of distribution Nascimento found, however, is similar to the results in the present study. During CPB, the clearance decreased with on average 11 % compared to the clearance before CPB (P = 0.014). The volume of distribution remained unchanged and no hemodilution-effect was found. The change in clearance is probably related to the CPB procedure which involves reduction of blood perfusion of highly vascularized tissues, including organs that eliminate the agent [9]. In this study, CPB had a ‘protective’ effect on the plasma concentration of unbound cefuroxime resulting in higher cefuroxime plasma concentration by the use of CPB than would be expected without CPB. This conclusion is confirmed by Nascimento et al. [9]. Nascimento found higher systemic cefuroxime exposure for CPB patients compared with patients without CPB. Therefore CPB alone does not require adaptation of the dose in an intermittent dosing regimen, but other factors like age, renal function and possibly also weight are more important factors that can result in unbound plasma cefuroxime concentrations below the target value. The strength of our study is that we actually measured the free cefuroxime concentrations. As a result, we were able to determine the unbound cefuroxime fractions related to our operation procedures and CPB device used. Moreover, we determined the pharmacokinetic parameters before, during and after CPB, which made it possible to research the influence of CPB on the pharmacokinetic parameters. Our study is limited by the small number of patients with a weight above 100 kg. To study the effects Table 3 Population parameters by Nascimento et al. [12] (n = 17, based on unbound concentrations) Parameter
Median (95 % CI)
Vu (l/kg)
0.27 (0.21–0.37)
Clu (l/h)
8.54 (6.71–9.77)
Half-life (min)
108 (102–120)
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of this parameter on the plasma cefuroxime concentration, a larger number of patients should be further studied. Another limitation is the choice of the target of free cefuroxime concentration. In our study we chose C32 mg/l as a target, however, this cut-off has not been clinically validated. Therefore the choice of C16 mg/l as a target probably would have been more appropriate.
Conclusion Our results show that in 24 % of the patients the unbound cefuroxime plasma concentration was below the target concentration of 32 mg/l at some point during surgery. We found that CPB during CABG surgery is not a risk factor for inadequate unbound cefuroxime concentrations. Risk factors for insufficient cefuroxime concentrations during CABG procedures with CPB were renal function, age and weight, however this should be further studied. Acknowledgments The authors would like to thank the surgical and anaesthetic team at the Isala Klinieken for their support during the study. Funding The research was funded by the Isala Klinieken, Zwolle, The Netherlands. Conflicts of interest
None.
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RESEARCH ARTICLE
Targeting cefuroxime plasma concentrations during coronary artery bypass graft surgery with cardiopulmonary bypass Marieke Aalbers1 • Peter G. J. ter Horst2 • Wobbe Hospes2 • Michel L. Hijmering3 Alexander J. Spanjersberg3
•
Received: 11 September 2014 / Accepted: 10 March 2015 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2015
Abstract Backgound Patients are at risk for severe postoperative infections after coronary artery bypass graft (CABG) surgery. Clinical laboratory data showed that unbound plasma concentrations of cefuroxime were not always adequate, therefore we developed a new dosing regimen. Objective The aim of this prospective study is to evaluate the new dosing strategy by monitoring patients for unbound cefuroxime plasma concentrations during CABG surgery with cardiopulmonary bypass (CPB). Setting A Dutch teaching hospital. Methods In this prospective trial, patients scheduled for CABG surgery with CPB were included. A starting dose of 1500 mg cefuroxime was given with anesthesia induction, followed by 750 mg cefuroxime every hour until wound closure. In case of renal failure the dosing regimen was adapted. Serial blood samples were collected before, during and after the CPB process. Pharmacokinetic modelling was performed by using an ‘iterative two-stage Bayesian population procedure’. Main outcome measure Unbound plasma concentrations of cefuroxime. Results 22 patients were included, data could be evaluated of 21 patients. In 24 % of the patients the
Electronic supplementary material The online version of this article (doi:10.1007/s11096-015-0101-8) contains supplementary material, which is available to authorized users. & Marieke Aalbers [email protected] 1
Department of Clinical Pharmacy, Hospital Pharmacy Emmen, Boermarkeweg 60, 7824 AA Emmen, The Netherlands
2
Department of Clinical Pharmacy, Isala Clinics, Zwolle, The Netherlands
3
Department of Thoracic Anaesthesia and Intensive Care, Isala Clinics, Zwolle, The Netherlands
unbound cefuroxime plasma concentration was below the target range during surgery before CPB started. Patients with a bodyweight above 100 kg or age \60 years were more likely to have unbound plasma concentrations below the target range (P = 0.030 and P = 0.008). During CPB, the half-life of unbound cefuroxime increased by 17 % and the clearance decreased by 11 % compared to before CPB (P = 0.033 and P = 0.014). The mean pharmacokinetic parameters before, during and after CPB were as follows: elimination half-life 72, 84 and 76 min; clearance of unbound cefuroxime (Clu) 14.2, 12.7, 13.8 l/h and volume of distribution (Vu) 0.280, 0.284 and 0.290 l/kg respectively. Variations in unbound fractions before, during and after CPB were below 2 %, implicating the unbound fraction of cefuroxime is not influenced by CPB. Conclusion Our results show that CPB during CABG surgery does not lead to inadequate unbound cefuroxime concentrations. Age, renal function and possibly also weight are more important factors that can result in unbound plasma cefuroxime concentrations below the target value. Keywords Antibiotic prophylaxis Cardiopulmonary bypass Cefuroxime Coronary artery bypass graft surgery Pharmacokinetics
Impacts on practices • • •
The unbound fraction of cefuroxime is not influenced by cardiopulmonary bypass. Cardiopulmonary bypass is not a risk factor for inadequate concentrations of cefuroxime. Age, renal function and possibly also weight are more important parameters that can result in unbound plasma cefuroxime concentrations below the target value.
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Introduction Coronary artery bypass graft (CABG) surgery is a major therapeutic approach in the treatment of coronary artery disease. While performing this procedure, the function of the heart and lungs can temporarily be taken over using cardiopulmonary bypass (CPB) by extracorporeal circulation. Patients who have had CABG surgery are at risk for severe postoperative infections. The incidence of sternal surgical site infections ranges from 0.9 to 20 % [1]. The incidence of deep sternal infections, such as mediastinitis, ranges from 1 to 2 % [1]. In the Netherlands, the incidence of sternal infections is about 2.4 % and the incidence of deep sternal infections, for example mediastinitis, is about 1.5 % [2]. The mortality rate for patients with deep sternal infections is about 10–15 % [3]. The most common pathogens responsible for postoperative infections are Staphylococcus aureus (44 %) and coagulase-negative staphylococci (15 %) [1, 2]. Second generation cephalosporins like cefuroxime, have a favorable spectrum, low toxicity and good tissue penetration, which makes them first choice as antibiotic prophylaxis in cardiac surgery [4, 5]. Cephalosporins, like cefuroxime, show time-dependent killing. The parameter which best describes killing for cephalosporins is time above minimum inhibitory concentration (MIC) (T [ MIC). The MIC for the most suspected bacteria is B8 mg/l [6, 7]. Because of the life-threatening consequences of deep sternal infections, maximal killing is pursued. Maximal killing rates are achieved with unbound cefuroxime concentrations above four times MIC, i.e. C32 mg/l [8]. From other studies we know that the use of CPB, however, may have a substantial effect on the pharmacokinetics of administered drugs, including the cephalosporins [9, 10]. CPB can alter the time course of cefuroxime plasma concentrations by hemodilution, hypotension, hypothermia and alterations of the binding capacity of proteins, which could lead to sub-optimal antibiotic prophylaxis [11]. Pharmacokinetics of cefuroxime during CABG surgery including CPB were studied before, however, in the studies of Mandak, Pojar, Nascimento and Knoderer detailed information about the operation procedures and CPB device used was lacking and the target concentrations seemed not to be adequate referring to CLSI and Eucast values [2, 4, 9, 11, 12]. In most studies, the trough target values were less aggressive ranging from [2 mg/l [13] to [16 mg/l. These considerations and the use of different cefuroxime dosing regimens made us to decide to set up a pilot study in our setting. In the pilot study, 10 patients with normal renal function were included [14]. Of those, eight patients had calculated unbound plasma cefuroxime concentrations
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below 32 mg/l at some point during surgery, suggesting insufficient antibiotic prophylaxis. Therefore, an adapted dosage schedule was developed, based on the data from our pilot experiment. The aim of this prospective study is to evaluate the new dosing strategy by monitoring patients for unbound cefuroxime plasma concentrations during CABG surgery with CPB.
Methods Study design This study was performed at the Isala Clinics in Zwolle, The Netherlands, a 1000 bed teaching hospital. Approximately 500 CABG surgeries with CPB are performed every year, next to about 1000 other open heart surgeries with CPB. We got a waiver from the local ethics committee, because samples were obtained from existing catheters and the dosing of cefuroxime was in accordance with the SPC of Cefuroxim Fresenius Kabi (max 6000 mg per day) [15]. Inclusion criteria were patients with coronary artery disease scheduled for CABG surgery with CPB who gave their written informed consent. Excluded were patients with age below 18 years or with a prescription of cefuroxime before surgery or actual use of mirtazapine, because of interference in our analytical assay. Surgical and anesthetic procedures The surgical and anesthetic procedures are described in the pilot study [14]. Dosing and sampling The first dose, 1500 mg of cefuroxime i.v., was given with anesthesia induction. The second dose, 750 mg i.v., was given 1 h after the first dose (t = 1 h). The dosing regimen was continued with cefuroxime 750 mg every hour until wound closure (t = 2; t = 3; t = 4; t = 5). In case of moderate or severe renal failure (e.g. eGFR \60 ml/min/ 1.73 m2 calculated by the ‘Modification of Diet in Renal Disease’ (MDRD) formula [16] the dosing regimen after the second dose was continued with cefuroxime 750 mg every 2 h until wound closure (t = 3 and t = 5). Blood samples were collected from the radial artery catheter or directly arterial from the CPB system. Prior to the CABG procedure 1 blank sample was drawn from the radial artery catheter. During surgery, peak and trough samples of blood were collected. Trough samples were taken just before the next dose; peak samples were taken 30 min after the dose. Moreover, samples were also drawn
Int J Clin Pharm
at time of skin incision, at start of CPB, every 30 min of CPB, at the end of CPB and at wound closure. The actual sampling times varied depending on the clinical situation. Samples were collected in EDTA bloodcollection tubes, stored on ice, mixed and centrifuged at 3000 rpm for 5 min directly after the procedure. Analytical procedure The high pressure liquid chromatographic procedure, described in the article of Bertholee et al. was used [14]. Selectivity of the method was tested before actual validation. All compounds reasonably used in the target population with a retention time near cefuroxime were investigated on possible interference with the cefuroxime assay and no interferences were found. Moreover, during the actual analysis of patient material, peak purity was investigated and selective analysis of cefuroxime was confirmed. In addition to Bertholee et al., the unbound concentrations were determined. For preparation of the unbound cefuroxime samples, 1 ml of plasma was converted to the Centrifree ultrafiltration device (Millipore) and centrifuged at 2000 rpm for 30 min. The limit of quantification for cefuroxime was experimentally determined to be 2.5 mg/L (n = 6). The assay was linear in the range 5–160 mg/L (n = 4). The within-day (n = 5) and between-day (n = 5) coefficients of variation for spiked controls (15, 30, and 50 mg/L) were B3.1 and B3.3 %, respectively.
Pharmacokinetic analysis Pharmacokinetic modelling was performed by using an ‘iterative two-stage Bayesian population procedure’ (ITSB) using MW Pharm version 3.80 (Mediware, Zuidhorn, the Netherlands). For pharmacokinetic modeling, the unbound cefuroxime concentrations were used. Based on the Akaike information criterion (AIC) a one-compartment pharmacokinetic model was used to describe cefuroxime pharmacokinetics [17, 18]. In the present study, pharmacokinetic parameters, including fr (Eq. 2), half-life, plasma clearance rate (Clu) and volume of distribution (Vu) were determined before, during and after CPB, with u representing the unbound fraction of cefuroxime. For the pharmacokinetic parameters, a log-normal distribution was assumed. The model-equations and abbreviations are given below: Ct ¼ C0 ekt
Statistical analysis Demographic and peri-operative parameters were compared by using analysis of variance and descriptive methods, i.e. mean ± SD. Data estimated or parameters obtained after PK-modeling were statistically analyzed for normality based on kurtosis (range -1 to ?1), skewness (range -1 to ?1) and the Shapiro–Wilk test (P \ 0.05). The nonparametric Wilcoxon signed-rank test for paired data or, when a normal distribution was found, the paired t test was used for the comparison of cefuroxime pharmacokinetics before, during and after CPB. Statistical analysis was performed using SPSS software (version 18.0) and Excel Microsoft. A P value of \0.05 was considered statistically significant.
Results In February and March 2012, 22 patients were included. In Table 1, the demographics of the 22 included patients are shown. Unbound concentrations Unfortunately, due to technical errors, the unbound concentrations of patient 18 could not be analyzed, therefore we excluded patient 18 from this study. The unbound cefuroxime concentrations of the remaining 21 patients are presented in Fig. 1. In 5 patients the unbound cefuroxime plasma concentration was below the target range during surgery before CPB started. Of those 5 patients, 3 patients had also unbound cefuroxime plasma concentrations below the target range during CPB. Patients with a weight above 100 kg are more likely to have unbound plasma concentrations below the target range during surgery before start of CPB. (P = 0.030, Pearson Chi-Square test). Moreover, age below 60 years was also found to be predictive of unbound plasma concentrations below the target range during surgery before start of CPB (P = 0.008). Other factors including CPB time, gender and type of cardioplegia (data not shown) were not found to be predictive of unbound concentrations below the target range.
ð1Þ
Unbound fractions
ð2Þ
For 21 patients, the unbound fractions of cefuroxime (fu) were calculated by dividing the unbound plasma
Standard equation for first order kinetics Clu ¼ fr Clcr
Clu = clearance of unbound cefuroxime, Clcr = clearance of plasma creatinine, fr = fraction
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Int J Clin Pharm Table 1 Demographics of included patients Serum creatinine (lmol/l)
Height (cm)
Weight (kg)
eGFR (ml/min/1.73 m2)a
CPB volume (ml)
Operation time (min)
1850
161
CPB time (min)
Subject
Age (years)
1 (m)
71
87
174
77
2 (f)
62
78
173
100
69
1800
262
131
3 (m)
60
56
182
89
137
1500
224
102
4 (m)
48
86
179
80
88
1000
199
47
5 (m)
63
86
188
104
83
1850
228
109
6 (f)
74
63
161
54
85
1850
207
101
7 (m) 8 (m)
71 68
112 79
172 176
63 98
56 90
1850 1850
147 181
58 72
80
60
9 (m)
76
93
175
77
73
1850
153
71
10 (m)
75
101
183
99
66
1250
167
74
11 (f)
67
61
162
66
90
1850
301
103
12 (f)
66
78
157
60
68
1250
184
85
13 (m)
77
99
173
80
68
1350
213
96
14 (m)
75
96
177
86
70
1850
231
75
15 (m)
77
68
183
77
104
1850
227
105
16 (m)
84
81
176
96
84
1850
170
60
17 (f)
61
54
156
64
106
1250
175
47
18 (m)
72
76
180
85
93
1850
210
66
19 (m)
59
73
189
105
101
1850
287
125
20 (m)
62
59
179
122
128
1850
204
97
21 (m)
57
83
180
84
88
1450
221
92
22 (m) Mean
49 67.0
71 79
183 175
101 85
109 88
1850 1679
293 211
143 87
SD
9.3
15
9
17
20
283
44
27
a
eGFR MDRD measured 1 day before start of surgery
concentrations by the total plasma concentrations. The total mean unbound fraction of cefuroxime is 72.5 ± 5.0 %. Variations in unbound fractions before, during and after CPB were below 2 %, implicating the unbound fraction of cefuroxime is not influenced by CPB. Pharmacokinetic parameters Unbound plasma concentrations of cefuroxime were determined in 21 patients, with a total of 147 samples. Pharmacokinetic parameters before, during and after CPB are shown in Table 2. The interindividual variability (coefficient of variation) of the parameter fr varied between 14.8 and 23.9 %. Because cefuroxime is both filtered and secreted, the parameter fr is[1. The coefficient of variation of volume of distribution of the unbound cefuroxime (Vu) varied between 12.2 and 26.3 %. The residual standard error (rse, standard error of the mean) for the parameter fr varied between 3 and 5 % and residual standard error of Vu varied between 3 and 6 %. During CPB, the clearance decreased with on average 11 % compared to the clearance before CPB as shown in
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Table 2 (P = 0.014 resp, SPSS Wilcoxon signed-rank test).
Discussion In 24 % of the patients the unbound cefuroxime plasma concentration was below the target concentration of 32 mg/ l at some point during surgery. We expected to find at maximum 10 % of the patients below the target concentration. This result is explained by renal function, because in our study for the patients with good renal function or mild renal disease (e.g. eGFR [60 ml/min), renal function was better than in the pilot study [14] (90 ± 19 vs. 75 ± 10 ml/min) [14]. Compared to the pilot study [14], in which 80 % of the patients with good renal function or mild renal disease had plasma cefuroxime concentrations below the target, the new dosing schedule improved antibiotic prophylaxis. For cefuroxime, concentration-dependent toxicity is limited, and it can be argued that using an even more aggressive dosing strategy would result in all patients
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90
80
Unbound cefuroxime (mg/L)
70
60
50
40
30
20
10
0 0
1
2
3
4
5
6
7
8
9
10
Sampling intervals
Fig. 1 Unbound plasma concentrations of cefuroxime at different sampling intervals. 1 = at skin incision, 2–8 = trough and peak samples. Trough samples were taken just before the next dose; peak samples were taken 30 min after the dose. 9 = wound closure
Table 2 Population pharmacokinetic parameter values by ITSB analysis mean ± SD (range) Parameter fr
Before CPB
During CPB
After CPB
3.26 ± 0.38 (2.36–4.26)
3.00 ± 0.62 (1.56–4.24)
3.23 ± 0.59 (1.84–4.20)
Vu (l/kg)
0.280 ± 0.068 (0.189–0.521)
0.284 ± 0.015 (0.255–0.310)
0.290 ± 0.043 (0.200–0.380)
Clu (l/h)
14.17 ± 4.41 (9.15–25.02)
12.66 ± 3.25 (7.43–18.61)
13.77 ± 3.19 (9.25–20.38)
72 ± 20 (40–106)
84 ± 25 (50–151)
76 ± 18 (52–107)
Half-life (min)
reaching the target, however we were limited by a maximum of 6 g per day [15]. Instead, to improve the dosing regimen, continuous infusion could be applied. Zeisler et al. [19] demonstrated similar efficacy between intermittent and continuous infusion of cefuroxime in infected patients with the continuous infusion group requiring 55 % less drug over the course of therapy. In a paper of Pass et al. [20] serum concentrations of cefuroxime after continuous infusion in coronary bypass graft patients were described, however, with their dosing strategy, only a few patients would have maintained concentrations above our target limit of 32 mg/l. In addition to optimization of the dosing strategy, another advantage of continuous infusion is that instead of six syringes for every hour, only two syringes have to be prepared and the dosing schedule is simplified. To further optimize the dosing strategy, a continuous infusion regimen could be used to reduce the fluctuations in plasma levels and to maximize the time the unbound cefuroxime plasma concentration remains above 32 mg/l [20].
In finding an optimal dosing strategy, demographic characteristics and peri-operative characteristics could possibly influence cefuroxime concentrations. In our study, patients with a weight above 100 kg were found to be more likely to have unbound plasma concentrations below the target range during surgery before start of CPB. (P = 0.030, Pearson Chi Square test), although the number of patients above 100 kg in our study was very limited. Moreover, age below 60 years was also found to be predictive of unbound plasma concentrations below the target range during surgery before start of CPB (P = 0.008). In a study of Broekhuysen et al. [21] age was found to be related to cefuroxime clearance, suggesting higher cefuroxime dosing in patients below 60 years. In our study, other factors including CPB time, gender and type of cardioplegia were not found to be predictive of unbound concentrations below the target range. In this study, the total mean unbound fraction of cefuroxime was 72.5 %, which is similar to the unbound fraction of 73 % Mandak and Pojar found in their study
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before the start of CPB [2, 11]. However, throughout the course of CPB, Mandak and Pojar found lower protein binding for cefuroxime with unbound fractions [83 %. In our study, however, variations in unbound fractions before, during and after CPB were below 2 %. The primer solution Mandak and Pojar used in their study did not contain albumin which could explain altered protein binding. In the present study, the kinetic disposition of cefuroxime was investigated based on plasma curve decay applying a 1-compartment open model. Nascimento et al. [12] used an open 1-compartment model before to describe the pharmacokinetics of cefuroxime. Significant differences between the present study and Nascimento et al. were observed in the kinetic parameters half-life and plasma clearance as shown in Table 3. The volume of distribution Nascimento found, however, is similar to the results in the present study. During CPB, the clearance decreased with on average 11 % compared to the clearance before CPB (P = 0.014). The volume of distribution remained unchanged and no hemodilution-effect was found. The change in clearance is probably related to the CPB procedure which involves reduction of blood perfusion of highly vascularized tissues, including organs that eliminate the agent [9]. In this study, CPB had a ‘protective’ effect on the plasma concentration of unbound cefuroxime resulting in higher cefuroxime plasma concentration by the use of CPB than would be expected without CPB. This conclusion is confirmed by Nascimento et al. [9]. Nascimento found higher systemic cefuroxime exposure for CPB patients compared with patients without CPB. Therefore CPB alone does not require adaptation of the dose in an intermittent dosing regimen, but other factors like age, renal function and possibly also weight are more important factors that can result in unbound plasma cefuroxime concentrations below the target value. The strength of our study is that we actually measured the free cefuroxime concentrations. As a result, we were able to determine the unbound cefuroxime fractions related to our operation procedures and CPB device used. Moreover, we determined the pharmacokinetic parameters before, during and after CPB, which made it possible to research the influence of CPB on the pharmacokinetic parameters. Our study is limited by the small number of patients with a weight above 100 kg. To study the effects Table 3 Population parameters by Nascimento et al. [12] (n = 17, based on unbound concentrations) Parameter
Median (95 % CI)
Vu (l/kg)
0.27 (0.21–0.37)
Clu (l/h)
8.54 (6.71–9.77)
Half-life (min)
108 (102–120)
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of this parameter on the plasma cefuroxime concentration, a larger number of patients should be further studied. Another limitation is the choice of the target of free cefuroxime concentration. In our study we chose C32 mg/l as a target, however, this cut-off has not been clinically validated. Therefore the choice of C16 mg/l as a target probably would have been more appropriate.
Conclusion Our results show that in 24 % of the patients the unbound cefuroxime plasma concentration was below the target concentration of 32 mg/l at some point during surgery. We found that CPB during CABG surgery is not a risk factor for inadequate unbound cefuroxime concentrations. Risk factors for insufficient cefuroxime concentrations during CABG procedures with CPB were renal function, age and weight, however this should be further studied. Acknowledgments The authors would like to thank the surgical and anaesthetic team at the Isala Klinieken for their support during the study. Funding The research was funded by the Isala Klinieken, Zwolle, The Netherlands. Conflicts of interest
None.
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