Perioperative pharmacokinetics of cefotaxime in serum and bile during continuous and intermittent infusion in liver transplant patients

S. E. Buijk1,*, I. C. Gyssens2,3, J. W. Mouton2,6, H. J. Metselaar4, T. H. Groenland5, H. A. Verbrugh2 and H. A. Bruining1

1 Department of Surgery, 2 Department of Medical Microbiology and Infectious Diseases, 3 Department of Internal Medicine, Division of Infectious Diseases, 4 Department of Hepatology and Gastroenterology, 5 Department of Anaesthesiology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, 6 Department of Medical Microbiology & Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands

Received 7 December 2003; returned 22 January 2004; revised 17 March 2004; accepted 6 April 2004


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background: Drug pharmacokinetics may be altered during liver transplantation. Cefotaxime (CTX), used as perioperative prophylaxis, demonstrates time-dependent killing and therefore continuous infusion might have pharmacodynamic advantages.

Objectives: To determine the pharmacokinetics of CTX and desacetylcefotaxime (DCTX) in serum, bile and urine during continuous and intermittent infusion when performing liver transplantation.

Methods: Fifteen patients undergoing liver transplantation were studied after continuous infusion (CI) (4000 mg iv per 24 h following a loading dose of 1000 mg) and intermittent bolus infusion (BI) (1000 mg iv four times daily). Samples were collected during the first 48 h after liver transplantation. Concentrations of CTX and DCTX were determined by HPLC.

Results: During surgery, the mean concentration in serum after CI was 18 mg/L. The lowest serum concentration was 5 mg/L in the CI group and levels were undetectable in the BI group. Target serum concentrations of ≥4 mg/L were reached for 100% of the dosing interval during CI and ~60% during BI. Post-operatively, the mean concentration in serum after CI was 26 mg/L. The lowest serum concentration was 8 mg/L in the CI group and levels were undetectable after BI. The peroperative pharmacokinetics of CTX in this patient group were deranged and variable, mainly caused by an increased volume of distribution and decreased hepatic clearance. Metabolism was hampered, but DCTX area under the curve (AUC)/CTX AUC ratios varying between 0.7–0.9 were reached peroperatively. Post-operatively, DCTX AUC/CTX AUC ratios were higher (1.1–1.4). Unchanged CTX in bile was ~0.1% of the administered dose, leading to concentrations >4 mg/L throughout the dosing interval for both regimens.

Conclusion: Although an intermittent bolus infusion of CTX 1000 mg produces t > target concentration for 60% of the dosing interval during liver transplantation, serum concentrations may be insufficient during the reperfusion phase. Continuous infusion overcomes this. Post-operatively, CTX clearance is impaired by decreased metabolic clearance and there is substantial accumulation of DCTX. In bile, sufficient concentrations of CTX and its active metabolite are reached with both regimens.

Keywords: antibiotics , critical care , surgery , pharmacodynamics , desacetylcefotaxime


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Orthotopic liver transplantation (OLT) is frequently complicated by bacterial infections of the abdomen, the lower respiratory tract and the bloodstream. Up to 83% of the patients become infected at some stage1 and overall, 79% of all infections in the ICU are caused by bacteria.2 Perioperative translocation of Gram-negative bacteria is believed to be an important factor in the pathophysiology of infectious complications after OLT, especially during the anhepatic phase of liver transplantation when the hepatic clearance of endotoxin by Kupffer cells is absent.3 Therefore, perioperative broad-spectrum antibiotics are used to treat bacteraemia and to prevent surgical site infection.

Cefotaxime (CTX), a third-generation broad-spectrum cephalosporin is commonly used as perioperative antimicrobial prophylaxis in OLT. CTX is partly metabolized in the liver to three metabolites, of which one, desacetylcefotaxime (DCTX), has an activity eight-fold lower than that of CTX against the common Enterobacteriaceae.4 Although controversial, antimicrobial prophylaxis is often continued post-operatively for 48 h to cover the perioperative vulnerable period adequately in OLT. Administration of systemic antibiotics during major surgery may require adjustment because of extensive peroperative blood loss and fluid replacement, which may change distribution volumes and clearance of these drugs and reduce their prophylactic efficacy.5 Impaired clearance of CTX after OLT has been reported,6,7 but to our knowledge no data are available on biliary concentrations during the first 48 h post-operatively.

Both from a pharmacodynamic and pharmacokinetic point of view, it seems more appropriate to administer CTX by continuous infusion. Studies in vitro and in laboratory animals show that killing of microorganisms by cephalosporins is time- rather than concentration-dependent and that time above the MIC is the most important pharmacodynamic index.8,9 Furthermore, CTX does not show a post-antibiotic effect against Gram-negative bacilli. Intermittent administration produces high peak and low trough concentrations in serum, which may fall below the MIC for the organisms during the dosing interval. Continuous infusion of CTX produces a relatively constant concentration that can be maintained above the MIC, thereby optimizing the drug's pharmacodynamic properties.10

We conducted a study to investigate whether continuous infusion of CTX would produce more favourable concentration versus time profiles in patients—in relation to a target MIC in serum and bile compared with intermittent infusion—during the first 48 h of liver transplantation surgery.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The study protocol met the standards of the hospital's medical ethics committee. Written informed consent was obtained from the patients.

Patient population

Patients >16 years of age who underwent an elective OLT during January 1997–October 1998 were asked to participate in the study. Exclusion criteria were: (i) known allergy to CTX; (ii) pre-operative severe renal impairment, defined as a calculated creatinine clearance <10 mL/min and/or urinary output <10 mL/h over the preceding 12 h and/or haemofiltration or dialysis.

The following parameters were assessed perioperatively: demographic data including age, sex, weight and cause of liver disease. Peroperative blood loss, fluid replacement and duration of surgery were documented.

Serum creatinine, alanine aminotransferase, aspartate aminotransferase, bilirubin and albumin were assessed daily. Creatinine clearance was estimated from the serum creatinine concentration by using the Cockroft–Gault equation.11

Operation

The technique of OLT consists of three phases: (i) the hepatectomy phase during which the diseased liver is resected. Blood loss can be substantial due to the presence of portal hypertension and severe coagulopathy. Large amounts of fluid, packed red blood cells, fresh frozen plasma and donor platelets are needed to compensate the loss; (ii) the anhepatic phase during which the graft is anastomosed takes ~30–60 min, a period in which no liver metabolism takes place; and (iii) the reperfusion phase during which the transplant is connected to the circulatory system again and the bilio-digestive anastomosis is made. Profound haemodynamic disturbances and clotting disorders occur due to bacterial translocation, circulating cytokines and enhanced fibrinolysis.12,13

Study design

This observational study had a non-randomized block design. The indications for liver transplantation and operative procedure did not change during the study period. The daily dose was 4000 mg per 24 h. In the first block, eight elective patients received CTX 1000 mg iv by bolus infusion (BI) intermittently every 6 h. In the second block, seven elective patients received a CTX 1000 mg iv loading dose directly before the start of a 4000 mg iv continuous infusion (CI) over 24 h. The maximum duration of prophylaxis and thus the maximum study period was 48 h. The first dose was given 30 min prior to incision.

CTX administration
For continuous infusion, 4000 mg of CTX (Claforan, Hoechst Marion Roussel, Hoevelaken, The Netherlands) was dissolved in 50 mL 0.9% NaCl prior to administration and infused with an electronic pump (Ivac Medical System, Hampshire, UK). The loading dose and the intermittent bolus infusions were prepared according to the manufacturer's guidelines and infused over 20 min using an electronic pump.

Only in cases of severe renal impairment is there a significant change in elimination rate of CTX. When the calculated creatinine clearance dropped to ≤10 mL/min the total daily dose was halved.14,15

Pharmacokinetics

Peroperative and post-operative serum sampling
To determine CTX and DCTX concentrations in serum, 2 mL blood samples were taken from an indwelling arterial catheter in the contralateral arm prior to infusion (t=0) and at 20, 30 and 60 min and then once hourly throughout surgery for both CI and BI. Post-operatively, four samples were taken within 48 h, with a sample interval of at least 6 h during continuous infusion. During intermittent infusion, blood samples were taken just prior to the fifth or sixth dose (i.e. at steady state) and at 20 and 30 min, and 1, 2, 4 and 6 h following the start of infusion.

Post-operative bile sampling
In patients with a T-tube, a minimum of 500 µL of bile was sampled at intervals at the same time as the serum samples, to determine the CTX and DCTX concentrations. During continuous infusion, four samples were taken within 48 h with a sample interval of at least 6 h. During intermittent infusion, bile samples were taken just prior to (–30–0 min) the fifth or sixth dose (i.e. at steady state) and at 0–30 min, 30 min–1 h, 1–1.5 h, 1.5–2 h, 3.5–4 h, and 5.5–6 h following the start of infusion.16,17

Post-operative urine sampling
Urine was collected over the same 6 h period during which the serum and bile were sampled. The volume was measured and a sample taken for analysis of CTX and DCTX concentrations.

Pharmacokinetic analysis
After sampling, blood was allowed to clot on ice for 20 min and centrifuged. Serum, bile and urine samples were stored at –70°C until analysis. CTX and DCTX concentrations were determined using HPLC.18 Laboratory material was obtained from the manufacturer (Hoechst-Marrion-Roussel, Hoevelaken, The Netherlands). Briefly, an ODS column (Chromopack, Middelburg, The Netherlands) was used with a 0.05 M ammonium diphosphate solution containing acetonitrile as mobile phase. A perchloric acid solution, containing 50 mg/L cefoxitin (for CTX) or cefaclor (for DCTX) as an internal standard, was added to an equal volume of sample. After centrifugation, the supernatant was filtered through a membrane filter (Millipore Corp. Type HV, 0–45 µm). The lower limit of detection was 0.1 mg/L in serum and bile and 0.5 mg/L in urine, and the method was linear up to 100 mg/L. The interday coefficient of variation was <10%.

The primary descriptive parameters after BI were area under the concentration curve (AUC0–6), the serum elimination half-life (t1/2ß), the volume of distribution (V), the total body clearance (CLtotal) and concentrations in serum and bile reached perioperatively. Time above a target concentration (t>C) was estimated from the individual curves. Perioperatively, a target CTX concentration of the susceptibility breakpoint in The Netherlands of 4 mg/L was chosen.

In the CI group, the AUC0–6 in serum and bile was calculated by multiplying the mean concentration in serum and bile over 24 h by six. The CLtotal was calculated by dividing the infusion rate through the mean concentration over 24 h. In the intermittent therapy group, the AUC0–6, t1/2ß and V in serum were estimated with the MWpharm program (Mediware, Groningen, The Netherlands) using a two-compartment open model. The AUC was calculated using the trapezoidal rule (AUC0–24). The CLtotal was calculated using a non-compartmental equation [clearance = dose/AUC (mL/min)]. The AUC0–6 in bile was estimated by multiplying the mean concentration over 6 h by six. The AUCbile/AUCserum ratio was calculated in patients with both sample ports available.

The renal clearance of CTX or DCTX (CLR) was defined as fe x CL, where fe is the percentage CTX or DCTX eliminated in urine in 6 h. The biliary clearance (CLbile) was calculated by CLbile = Q0–6/AUC0–6, where Q0–6 is the total amount of CTX or DCTX recovered in bile during 6 h. The total metabolic clearance (CLtm) was estimated as follows: CLtm = CLtotal (CLR + CLbile); this metabolic clearance represents the biotransformation of CTX in all metabolites. The partial metabolic clearance (CLpm), which is the clearance by biotransformation of CTX into DCTX, was calculated as follows: CLpm=(fe x CL) + (CLbile of DCTX), where fe is the percentage DCTX eliminated in urine in 6 h.

Statistical analysis

For a description of serum concentration profiles (i.e. plots, tables) after administration of CTX and DCTX, means and standard deviations were used. Mann–Whitney tests were used to determine differences between groups; a P value < 0.05 (two-tailed) was considered statistically significant. Correlation of CTX clearance with peroperative blood loss was determined by using the Spearman correlation statistic. Patients were eligible for analysis if they had completed the peroperative phase.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Fifteen patients were enrolled, of whom seven received continuous and eight intermittent CTX as perioperative antibiotic prophylaxis. Post-operatively, all patients were concomitantly given a selective decontamination regimen consisting of tobramycin, colistin and amphotericin B orally.19 All patients received the standard regimen; dose adjustments due to impaired renal function were not necessary. One patient in the intermittent group died after 1 day due to hepatic artery thrombosis; one patient in the CI group died at the end of surgery due to a myocardial infarction.

Demographics

The demographic characteristics of the study patients are summarized in Table 1. The groups were comparable as regards to age, body mass index, transaminases, bilirubin and creatinine clearance. The duration of operation varied between 4.3 and 9 h. The peroperative blood loss varied between 4 and 36 L and peroperative infused volume varied between 11 and 41 L.


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Table 1. Demographics (n=15)

 
Pharmacokinetics in serum

Peroperatively, serum concentrations were measured in seven patients after CI and in eight patients after BI. Post-operatively, serum concentrations were measured in six patients after CI and in seven patients after BI. Table 2 illustrates the peroperative pharmacokinetic parameters in serum of both dosing regimens.


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Table 2. Peroperative pharmacokinetic parameters of cefotaxime and DCTX in serum in liver transplant patients

 
CTX

The curves for mean (S.D.) serum concentrations of CTX versus time of both regimens are shown in Figure 1. The total body clearance did not significantly differ between the two dosing regimens. The mean concentration in serum after CI was 18 mg/L (concentrations from the loading dose were not included). The lowest serum concentration was 5 mg/L in the CI group and undetectable in the intermittent group. Serum concentrations of ≥4 mg/L were reached for 100% of the dosing interval during CI and ~60% during intermittent administration. Seven out of eight patients in the intermittent group had trough concentrations <4 mg/L; two patients had undetectable concentrations. There was no correlation between the amount of blood loss and the rate of total body clearance (R=0.32).



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Figure 1. Serum concentrations of cefotaxime in liver transplantation patients after intermittent (n=8) and continuous (n=7) infusion.

 
Post-operatively, the mean AUC0–6 in serum were comparable for both regimens. The mean concentration in serum after CI was 26 mg/L (intra-individual variance = 12%). The lowest serum concentration was 8 mg/L in the CI group. One patient in the intermittent group had trough concentrations <0.1 mg/L, two of seven patients had trough concentrations <4 mg/L. Overall, the mean (S.D.) amount of unchanged CTX found in urine was 51 (23)% of the administered dose, corresponding with a mean (S.D.) renal clearance of 91 (69) mL/min. The overall total metabolic clearance was 54 (43) mL/min and the partial metabolic clearance was 32 (31) mL/min.

DCTX

The curves for mean (S.D.) serum concentrations of DCTX versus time of both regimens are shown in Figure 2. Metabolism was hampered, but still AUCdctx/AUCctx ratios varying between 0.7–0.9 were reached peroperatively. The mean concentration in serum after CI was 15 mg/L. The lowest serum concentration was 7 mg/L in the CI group and undetectable in the intermittent group.



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Figure 2. Serum concentrations of desacetylcefotaxime in liver transplantation patients after intermittent (n=8) and continuous (n=7) infusion.

 
Post-operatively, AUCdctx/AUCctx ratios were higher than peroperatively (1.1–1.4). The mean concentration in serum after CI was 29.3 mg/L. The lowest serum concentration was 6 mg/L in the CI group; the lowest trough concentration in the BI group was 2 mg/L. Overall, the mean (S.D.) amount of DCTX found in urine was 24 (13)% of the administered dose.

Pharmacokinetics in bile

CTX and DCTX concentrations reached in bile were measured in six patients after CI and in six patients after BI. In one patient in the BI group no T-tube was present.

CTX

Table 3 illustrates that the mean AUC0–6 in bile after intermittent administration did not significantly differ from the AUC0–6 during CI. In bile, an AUC of ~80%–90% of the concomitant serum AUC was attained. The mean concentration in bile after CI was 23 mg/L (intra-individual variance = 19%). The lowest concentration in bile was 5 mg/L in the CI group and 4 mg/L in the BI group. With both regimens, concentrations exceeded 4 mg/L throughout the dosing interval. The total amount of unchanged CTX found in bile was ~0.1% of the administered dose, which corresponds with a clearance of CTX in bile of ~0.1 mL/min.


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Table 3. Post-operative pharmacokinetic parameters of CTX and DCTX in serum and bile in liver transplant patients after intermittent and continuous administration

 
DCTX

The total amount of DCTX found in bile was ~0.1% of the administered dose. Noteworthy is the observation that the AUCbile/AUCserum ratio was significantly higher after CI.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
CTX demonstrates time-dependent activity, therefore the time above the MIC determines the microbiological outcome. In general, efficacy of cephalosporins is considered optimal when concentrations in serum are maintained above the MIC for at least 60% of the dosing interval.9,20 In this study, both regimens reached a target concentration of 4 mg/L for a least 60% of the dosing interval. However, in the case of surgical prophylaxis during OLT, the exact time of the contamination is unknown. Sufficient concentrations have to be present in the tissues during the entire procedure as exogenous contamination may occur at any time until the wound is closed. Furthermore, endogenous contamination can occur late in the course of the procedure. In a prolonged operation such as OLT, the standard BI can produce insufficient concentrations at the end of the dosing interval. We postulate that it might be important to maintain a target concentration throughout the dosing interval, especially during the reperfusion phase (5–6 h after start of surgery) when translocated pathogens recirculate. In this study, the continuous regimen resulted in a mean steady state concentration in serum of 4 x MIC for 100% of the dosing interval during surgery. The intermittent bolus regimen resulted in trough concentrations in serum below the intended concentration of 4 mg/L in seven out of eight patients. Twenty-five percent of the patients in the intermittent group had undetectable trough concentrations in serum during surgery. During the anhepatic phase (2–3 h after start of surgery) serum concentrations were sufficient for both regimens. However, from a pharmacokinetic point of view, intermittent administration resulted in insufficient concentrations during the reperfusion phase. Whether this has clinical relevance needs to be investigated in a randomized clinical trial.

Patients undergoing an OLT are exposed to several assaults on their physiology, which can influence their pharmacokinetic profile.12,13 Compared with healthy volunteers21,22 (t1/2=1.2 h; CL = 200 mL/min and V=0.24 L/kg), the mean serum half-life of the OLT patients was increased, the mean total body clearance was comparable and the mean volume of distribution was increased approaching total body water. In addition, the extent of blood loss and the total body clearance did not correlate.21,22 Most likely, there was an increased clearance, but the impaired hepatic clearance during the anhepatic phase compensated for antibiotic loss caused by bleeding, resulting in a normal total body clearance. The suboptimal concentrations in serum after intermittent administration during surgery, however, can be explained by the large increase in volume of distribution. Blood loss exerts an influence on serum concentrations of drugs, which are mainly distributed intravascularly. CTX is distributed extracellularly. Therefore, the increase in the volume of distribution during surgery, caused by large amounts of fluid replacement, is important. From this increased extravascular pool, CTX steadily reenters the circulation causing lower, and sometimes suboptimal concentrations in serum during intermittent administration. Arnow et al.23 found normal serum concentrations of intermittently administered CTX in 15 OLT patients, with a high dosing schedule (e.g. 8 g/24 h). However, intra-operative blood loss was much lower (3.3 L) than in our population.23 They reported an increase in volume of distribution (300 mL/kg), but not as large as in our population. Furthermore, total body clearance was lowered by impaired hepatic and renal function in their population.

Despite compromised hepatic function (due to pre-existent liver failure and during the anhepatic phase), the DCTX AUC was ~70%–90% of the CTX AUC in serum. Apparently, the remaining hepatic function was sufficient, reflected in the mean transaminases of 36–72 U/L. The DCTX concentrations were high compared with data derived from healthy volunteers15,24 and patients with chronic hepatic disease.14 There are several hypotheses that might explain these results. There could be a difference in volume of distribution between CTX and DCTX in this specific population. The molecular structure and physicochemical properties of DCTX are different from CTX and the volume of distribution in these patients is much larger than in healthy volunteers. It may be possible that CTX was distributed throughout a ‘third space’, whereas the distribution of DCTX was more restricted. In addition, a difference in protein binding during surgery could play a role.

Post-operatively, the pharmacokinetic profile of the patient can be influenced by decreased graft function, haemodynamic instability (rejection, sepsis, bleeding), an enlarged V (peroperative positive fluid balance) and renal dysfunction (reperfusion damage). We found post-operatively that the CI regimen provided serum CTX concentrations of ≥4 mg/L for 100% of the dosing interval, whereas during intermittent administration two of seven patients dropped below this target concentration. The volume of distribution was much higher than in healthy volunteers, most likely caused by the positive fluid balance. The total body clearance was impaired beyond predictions based on renal function. Whereas the renal clearance was comparable to values found in healthy volunteers (105 mL/min), the metabolic clearance (normal values: 93–103 mL/min) was decreased.16,22 Hepatic function in transplanted livers is suboptimal early after the operation, and consequently, the clearance of CTX by metabolizing it is lower. Both the increased volume of distribution and the decreased clearance resulted in a two-fold increase in elimination half-life. Burckart et al.7 reported an impaired clearance of CTX after OLT as well.

The DCTX AUC was ~110%–150% of the CTX AUC in serum. Besides being cleared by glomerular filtration, CTX is also eliminated by tubular secretion and is therefore relatively insensitive to renal impairment. Only in cases of creatinine clearance <10 mL/min, is there accumulation of CTX.14,15 DCTX starts to accumulate in mild renal insufficiency (CLCR 30–89 mL/min).25 In the post-operative phase, there was a drop in creatinine clearance in both groups that may explain the accumulation of DCTX.

The biliary tract anastomosis is the site at risk after OLT surgery when bile flow is minimal. Biliary anastomotic leakage and cholangitis due to biliary obstruction are frequently encountered complications after OLT.1,26 Therefore, adequate biliary concentrations are desirable to suppress bacterial proliferation in the (relatively) stagnant bile. In this study, the CTX AUCs in bile were ~90% of the concomitant serum AUCs for both regimens. This resulted in the time above the target concentration of 4 mg/L in bile of 100% of the dosing interval for both regimens. By using an indwelling T-drain, an unknown part of produced bile flows into the duodenum, therefore we underestimated the biliary clearance of CTX. Jehl et al.16 measured biliary clearance of CTX in cholecystectomized patients with a T-drain, in which the distal end of the intracholedochal branch of the T-drain was locked by an inflated balloon of a Fogarty catheter. They found a mean bile production of 108 mL in 8 h and a biliary clearance approximately twice as high as our estimated biliary clearance.16 Strikingly, the DCTX concentration and subsequently the AUC in bile were significantly higher after continuous infusion. The biliary transport of drugs is, similar to active secretion in the kidney, confined to a maximum rate of transport.27 A possible explanation for the difference is, therefore, that during intermittent infusion the transport rate is maximal with DCTX serum peak concentrations and less than maximal during trough concentrations (Michaelis–Menten kinetics). During CI, the transport rate is maximal throughout the dosing interval, causing higher concentrations of DCTX in bile.

In conclusion, although an intermittent bolus infusion of CTX of 1000 mg produces T > target concentration for 60% of the dosing interval during surgery in patients undergoing liver transplantation, insufficient serum concentrations for prophylaxis can occur during the reperfusion phase. This can be avoided with continuous infusion. Whether this has any clinical relevance needs to be investigated in a randomized clinical trial. Post-operatively, the clearance of CTX is impaired by decreased metabolic clearance and there is substantial accumulation of DCTX. In bile, sufficient concentrations of CTX and its active metabolite are reached with both regimens.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Part of these results was presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy 1999, San Francisco, USA.

This study was supported in part with an unrestricted grant by Hoechst Marrion Roussel, Hoevelaken, The Netherlands.


    Footnotes
 
* Corresponding author. Tel: +31-104-639-222; Fax: +31-104-366-978; Email: stevenbuijk{at}hotmail.com


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
1 . Kusne, S., Dummer, J. S., Singh, N. et al. (1988). Infections after liver transplantation. An analysis of 101 consecutive cases. Medicine (Baltimore) 67, 132–43.[ISI][Medline]

2 . Singh, N. (2000). The current management of infectious diseases in the liver transplant recipient. Clinics in Liver Disease 4, 657–73.[Medline]

3 . Miyata, T., Yokoyama, I., Todo, S. et al. (1989). Endotoxaemia, pulmonary complications, and thrombocytopenia in liver transplantation. Lancet ii, 189–91.[CrossRef]

4 . Wise, R., Wills, P. J., Andrews, J. M. et al. (1980). Activity of the cefotaxime (HR756) desacetyl metabolite compared with those of cefotaxime and other cephalosporins. Antimicrobial Agents and Chemotherapy 17, 84–6.[ISI][Medline]

5 . Levy, M., Egersegi, P., Strong, A. et al. (1990). Pharmacokinetic analysis of cloxacillin loss in children undergoing major surgery with massive bleeding. Antimicrobial Agents and Chemotherapy 34, 1150–3.[ISI][Medline]

6 . Kuse, E., Vogt, P. & Rosenkranz, B. (1990). Pharmacokinetics of cefotaxime in patients after liver transplantation. Infection 18, 268–72.[ISI][Medline]

7 . Burckart, G. J., Ptachcinski, R. J., Jones, D. H. et al. (1987). Impaired clearance of ceftizoxime and cefotaxime after orthotopic liver transplantation. Antimicrobial Agents and Chemotherapy 31, 323–4.[ISI][Medline]

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

9 . Mouton, J. W. & Vinks, A. A. (1996). Is continuous infusion of beta-lactam antibiotics worthwhile?—efficacy and pharmacokinetic considerations. Journal of Antimicrobial Chemotherapy 38, 5–15.[Abstract]

10 . Benko, A. S., Cappelletty, D. M., Kruse, J. A. et al. (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 . Cockroft, D. W. & Gault, M. H. (1976). Prediction of creatinine clearance from serum creatinine. Nephron 16, 31–41.[ISI][Medline]

12 . Pappas, G., Palmer, W. M., Martineau, G. L. et al. (1971). Hemodynamic alterations caused during orthotopic liver transplantation in humans. Surgery 70, 872–5.[ISI][Medline]

13 . Starzl, T. E., Iwatsuki, S. & Shaw, B. W. (1988). Techniques of liver transplantation. In Surgery of the Liver and Biliary Tract (Blumgart, l. H., Ed.), pp. 1537–1552. Churchill Livingstone, New York, USA.

14 . Wise, R., Wright, N. & Wills, P. J. (1981). Pharmacology of cefotaxime and its desacetyl metabolite in renal and hepatic disease. Antimicrobial Agents and Chemotherapy 19, 526–31.[ISI][Medline]

15 . Ings, R. M., Fillastre, J. P., Godin, M. et al. (1982). The pharmacokinetics of cefotaxime and its metabolites in subjects with normal and impaired renal function. Reviews of Infectious Diseases 4, Suppl, S379–91.[ISI][Medline]

16 . Jehl, F., Peter, J. D., Picard, A. et al. (1987). Investigation of the biliary clearances of cefotaxime and desacetylcefotaxime by an original procedure in cholecystectomised patients. Infection 15, 450–4.[ISI][Medline]

17 . Westphal, J. F., Jehl, F., Schloegel, M. et al. (1993). Biliary excretion of cefixime: assessment in patients provided with T-tube drainage. Antimicrobial Agents and Chemotherapy 37, 1488–91.[Abstract]

18 . Lecaillon, J. B., Rouan, M. C., Souppart, C. et al. (1982). Determination of cefsulodin, cefotiam, cephalexin, cefotaxime, desacetyl-cefotaxime, cefuroxime and cefroxadin in plasma and urine by high-performance liquid chromatography. Journal of Chromatography 228, 257–67.[Medline]

19 . Zwaveling, J. H., Maring, J. K., Klompmaker, I. J. et al. (2002). Selective decontamination of the digestive tract to prevent postoperative infection: a randomized placebo-controlled trial in liver transplant patients. Critical Care Medicine 30, 1204–9.[ISI][Medline]

20 . Craig, W. A. (1998). Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clinical Infectious Diseases 26, 1–10; quiz 11-12.[ISI][Medline]

21 . Kemmerich, B., Lode, H., Belmega, G. et al. (1983). Comparative pharmacokinetics of cefoperazone, cefotaxime, and moxalactam. Antimicrobial Agents and Chemotherapy 23, 429–34.[ISI][Medline]

22 . Wise, R., Baker, S. & Livingston, R. (1980). Comparison of cefotaxime and moxalactam pharmacokinetics and tissue levels. Antimicrobial Agents and Chemotherapy 18, 369–71.[ISI][Medline]

23 . Arnow, P. M., Furmaga, K., Flaherty, J. P. et al. (1992). Microbiological efficacy and pharmacokinetics of prophylactic antibiotics in liver transplant patients. Antimicrobial Agents and Chemotherapy 36, 2125–30.[Abstract]

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