a Departments of Surgical Intensive Care and b Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre, Rotterdam; c Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
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Abstract |
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Introduction |
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IAIs are almost always polymicrobial and comprise Gram-negative enteric bacteria, as well as obligate anaerobes. Antimicrobial chemotherapy should cover these microorganisms.2 Antimicrobial selection pressure may change the spectrum of isolates to less susceptible Enterobacteriaceae and Pseudomonas aeruginosa,3 against which ceftazidime is often the drug of choice.
The bactericidal activity of ceftazidime depends on the length of time that the concentration is above the MIC for the causative pathogen4,5 and maximal killing is achieved at concentrations of 4 x or 5 x MIC.6 Furthermore, ceftazidime does not exhibit a post-antibiotic effect against Gram-negative bacilli.5 From a pharmacodynamic point of view therefore, continuous infusion (CI) may be preferable to intermittent dosing. CI eliminates the unnecessarily high peak and sub-MIC trough concentrations found with intermittent dosing.7,8 From a pharmacokinetic point of view the advantages are less clear. A faster total body clearance after CI of piperacillin at high doses has been described.9 Furthermore, drug concentration profiles in the peritoneal cavity after either method of administration have never been compared.
Cardiovascular and metabolic changes as well as renal and liver dysfunction can markedly alter the pharmacokinetics of ceftazidime during critical illness.1012 To our knowledge, the pharmacokinetics of ceftazidime in serum of critically ill patients with severe IAI has not been documented, nor have concentrations in peritoneal exudate been measured.
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Materials and methods |
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Patient population
Patients who were admitted to the surgical intensive care unit (ICU) between January 1997 and May 1998 and who met the following criteria were eligible for enrolment in the study: over 18 years of age; severe IAI, defined as an IAI accompanied by a systemic inflammatory response, necessitating repeated laparotomies, open abdominal treatment or percutaneous drainage and intensive care support; suspected or proven Gram-negative infection.
Exclusion criteria were: known allergy to ceftazidime; creatinine clearance <30 mL/min and/or urinary output <10 mL/h over the preceding 12 h and/or haemofiltration or dialysis; severe granulocytopenia defined as <500 PMN/µL; APACHE II score 30; use of selective decontamination of the digestive tract; causative pathogens resistant to ceftazidime.
All patients were classified according to the APACHE II score.13 Use of concomitant drugs was documented and MICs of ceftazidime for the causative pathogens were determined by Etest (AB Biodisk, Solna, Sweden).
The following parameters were assessed: demography data including age, gender, weight and cause of the IAI; the number of surgical interventions and the amount of rinse fluid used in case of post-operative continuous lavage (i.e. maximum of 2 L 0.9% NaCl/24 h). Serum creatinine, alanine aminotransferase, aspartate aminotransferase, bilirubin, albumin, platelets and neutrophils were assessed daily. Creatinine clearance was estimated from the serum creatinine concentration using the CockroftGault equation.14 All adverse events were documented during the treatment period.
Study design
The study had two parts: the first was a prospective, non-randomized, non-comparative pilot study in which six patients received ceftazidime 1 g iv loading dose followed by a 4.5 g iv CI. This regimen was based on an assumed volume of distribution (Vd) of 300 mL/kg and a target concentration in serum of at least 40 mg/L. The second part was a prospective, randomized, comparative study in which 12 patients were randomized to receive either ceftazidime 1 g iv followed by a 4.5 g iv CI as above or ceftazidime 1.5 g iv bolus tds. Treatment was continued for up to 10 days.
Ceftazidime administration and dosage modulation
In patients with normal renal function, ceftazidime (GlaxoWellcome, Zeist, The Netherlands) was diluted in 250 mL 0.9% NaCl and continuously infused using an electronic pump (Ivac Medical System, Basingstoke, UK). The loading and intermittent bolus doses were prepared according to the manufacturerapos; guidelines and infused over 20 min. If creatinine clearance was between 49 and 30 mL/min, the total daily dosage was reduced to 2 g. If creatinine clearance dropped below 29 mL/min during the study period, the total daily dosage was reduced to 1 g.
Pharmacokinetics
Blood, peritoneal exudate and urine samples for the determination of ceftazidime concentrations were drawn on days 2 and 4. Peritoneal exudate cultures were taken before the start of therapy and repeated as considered necessary by the clinician.
Blood samples were taken from the non-infusion arm; during CI samples were drawn twice daily at intervals ranging from 8 to 12 h; during intermittent therapy, samples were drawn pre-dose (t = 0) and at 20 min, and 1, 2, 4 and 8 h after the start of the 20 min infusion. Blood was allowed to clot on ice for 20 min and centrifuged at 1500g for 10 min. The serum was stored at -70°C until analysis.
Peritoneal exudate was drawn from drainage catheters. During CI, samples were drawn at the same time as blood samples; after intermittent therapy, samples were taken 1 and 8 h after the start of the infusion. The total amount of peritoneal fluid drained was collected and a sample was taken for ceftazidime assay. Exudate was stored at -70°C until analysis.
Urine was collected over 24 h. The volume was measured and a sample was stored at -70°C for ceftazidime assay. Ceftazidime concentrations were determined using high-performance liquid chromatography.15 The lower limit of quantification was 0.4 mg/L in both serum and exudate and the method was linear up to 250 mg/L.
The primary descriptive parameters were area under the concentration curve (AUC024), the serum elimination half-life (tHß), the volume of distribution at steady state (Vdss), the total body clearance (CL) and concentrations reached in serum and exudate.
In the CI group, the AUC024 in serum and exudate was calculated as the mean concentration x 24 and the CL was calculated by dividing the infusion rate by the mean concentration over 24 h. In the intermittent therapy group, the AUC024, tHß and Vdss in serum were estimated with the MWpharm program (Mediware, Groningen, The Netherlands) using a two-compartment model. AUC024 was calculated using the trapezoidal rule. CL was calculated using a non-compartmental equation [CL = dose/AUC (L/h)]. The AUC024 in exudate was estimated by multiplying the mean concentration over 8 h by 24.
The AUCexudate/AUCserum ratio was calculated in those patients with both sample ports available. Time above the MIC (T > MIC) was estimated from the individual curves. The peritoneal clearance of ceftazidime was calculated by dividing the concentration of ceftazidime measured in the collected drain fluid by the total amount of ceftazidime infused in the same time period.
Statistical analysis
The MannWhitney test and Fisherapos; exact test were used as appropriate to determine differences between the groups; a P < 0.05 (two-tailed) was considered statistically significant. Correlation of ceftazidime clearance with creatinine clearance was determined using the Spearman correlation statistic. Patients were eligible for analysis if they had completed day 2 of the treatment period.
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Results |
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Demographics
The demographic characteristics of the study patients are summarized in Table 1. The groups were comparable as regards age, APACHE score and creatinine clearance. Severity of illness was reflected in a mean APACHE II score of 15 (= predicted mortality 24%) and an overall mortality on the ICU of 28%. The mean duration of treatment was 5 days.
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Serum ceftazidime concentrations were measured in 12 patients after CI and in six patients after intermittent therapy. The fitted curves for mean concentrations in serum versus time of both regimens are shown in Figure 1. The pharmacokinetic data on days 2 and 4 are shown in Table 2
; only the randomized patients were compared statistically. The total body clearance, and subsequently the AUC024, did not differ between groups. The mean steady state concentration in serum after CI was >40 mg/L. The lowest serum concentration during CI was 21.1 mg/L and the lowest trough concentration was 5.6 mg/L during intermittent therapy. The serum tH ranged widely. The Vdss approached the extracellular volume. Correlation between creatinine clearance and total body clearance of ceftazidime was 0.8 (R2 = 0.64).
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Concentrations reached in peritoneal exudate were measured in nine patients after CI and in four patients after intermittent therapy. In three patients repeat laparotomy was cancelled; in two patients the intra-abdominal drains were removed before sample day 2. The fitted curves for mean concentrations in peritoneal exudate versus time of both regimens are shown in Figure 2.
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Pathogens
Table 3 shows the pathogens cultured and the MICs of ceftazidime. Twenty-six ceftazidime-susceptible Gram-negative pathogens were isolated from 18 patients. In one patient an intermediately susceptible (MIC
16 mg/L) Enterobacter cloacae was cultured for which the antibiotic regimen was adjusted. Ceftazidime-resistant pathogens including anaerobes, coagulase-negative staphylococci, enterococci and Candida spp. were concomitantly treated with specific antimicrobial drugs.
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Discussion |
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As critically ill patients show highly variable drug pharmacokinetics, the length of time that the serum concentrations remained above the target concentration of 32 mg/L for individual patients is important. In our study population, concentrations 32 mg/L were reached only for approximately 70% of the dosing interval for both regimens. When the concentration falls below the threshold concentration regrowth of pathogens and development of resistance can occur. Therefore, a higher ceftazidime dosage is indicated in cases of Pseudomonas infection for which the MIC is 8 mg/L.
Other studies investigating CI of ceftazidime in critically ill patients found variable serum concentrations depending on the total body clearance. In critically ill medical patients, a mean steady state serum ceftazidime concentration of 30 mg/L was reached with an infusion of 3 g/24 h, while the total body clearance was approximately 4 L/h.10 In patients with nosocomial pneumonia using the same regimen (3 g/24 h), the total body clearance was twice as high (± 8 L/h), and therefore a mean steady state concentration of only 17 mg/L was reached.17 Lipman et al.12 showed that ceftazidime CI 6 g/24 h was needed in (unspecified) critically ill patients with a total body clearance of approximately 6 L/h to maintain a serum concentration of 40 mg/L.
Antimicrobial drugs must act at the site of infection. Thus, in the case of severe IAIs, the concentrations reached in the peritoneal exudate are relevant. In this study, CI resulted in a mean steady state concentration at the site of infection > 24 mg/L, while intermittent dosing resulted in much lower mean maximum and trough concentrations measured in the peritoneal exudate. This resulted in the T > MIC at the site of infection during CI being more favourable. However, both dosing regimens failed to achieve 32 mg/L, suggesting that a higher dosage might improve bacteriological efficacy.
AUCs in the peritoneal exudate were approximately 60% of the concomitant serum AUCs after CI. Since the binding of ceftazidime to plasma protein is only 17%,18 this can only partly explain this discrepancy. Another explanation would be incomplete passage through the blood peritoneum barrier. Corbett et al.19 found that the ceftazidime concentration in normal peritoneal fluid of patients undergoing elective abdominal surgery was only 62% of the concomitant serum level. In our patients, rapid clearance through the drains may have prevented equilibration. Alternatively, the peritoneal fluid may have been diluted by continuous lavage. The AUCexudate/AUCserum ratio after intermittent therapy was lower (30%) than after CI, but this did not reach statistical significance. The difference between continuous and intermittent administration could be explained by the method of sampling. If the time to reach the peak concentration in the peritoneal exudate is longer than 1 h, we measured a submaximal concentration and therefore underestimated the AUC. However, Mouton et al.20 measured concentrations reached in blister fluid after CI and intermittent infusion in healthy volunteers and found equal peak concentrations at 1 h with both regimens.
Compared with data from healthy volunteers (Vd = 180 mL/kg; tH = 1.6 h; CL = 8.5 L/h),20,21 the serum pharmacokinetic parameters in this study revealed an increased volume of distribution and a decreased total body clearance resulting in an increased tH. In addition, the data showed considerable variance. Comparable variability of the pharmacokinetic profile has been observed in critically ill patients with pneumonia.1012,17 Since ceftazidime is not metabolized, has low protein binding and is almost entirely eliminated by glomerular filtration, the variability in clearance depends mainly on renal function22 and this varies widely among the critically ill. Approximately 30% of all patients with severe sepsis develop renal failure.23 In addition, critical illness can be associated with a significant increase in the volume of distribution.11
Variable pharmacokinetics result in variable concentration profiles with unpredictable low trough concentrations after intermittent dosing of ceftazidime.24 Using CI it is easier to sustain a target concentration. Based on these data, a population model for patients with complicated IAIs can be made. Routinely available clinical variables such as bodyweight, age, gender and serum creatinine can be used to predict ceftazidime clearance.25 Using information about the individual pharmacokinetic profile and the MIC for the causative pathogen, the optimal dose of ceftazidime can be determined. This goal-oriented dosing of ceftazidime might result in higher bacteriological cure rates. Extrapolating the data available to our situation (Vd = 260 mL/kg, CL 4 L/h and 60% penetration), the dose of ceftazidime must be between 1.5 and 4.5 g/24 h after a loading dose of = 1 g to achieve an optimal concentration in peritoneal exudate for pathogens for which the MIC is 26 mg/L. In the case of peritonitis caused by Pseudomonas for which the MIC is 8 mg/L, the dosage of ceftazidime must be at least 6 g/24 h after a loading dose of 1 g. In critically ill patients with a total body clearance >4 L/h,17,24 the dosage must be even higher. Although ceftazidime is a drug with low toxicity, mild hypersensitivity being the most common side effect,26 dosage regimens of >80 mg/kg/24 h have not been tested in humans.
We conclude that from a pharmacokinetic and pharmacodynamic point of view, CI of ceftazidime results in more favourable concentrations in serum and peritoneal exudate compared with intermittent administration to critically ill surgical patients with complicated IAIs. In addition, with CI, serum concentrations can be predicted, allowing a more accurate dosage adjustment. Since the AUCexudate/ AUCserum ratio after CI was approximately 60%, higher dosage may be necessary when treating patients with those pathogens for which MICs are higher (e.g. Pseudomonas).
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Acknowledgements |
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Notes |
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References |
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Received 4 May 2001; returned 8 July 2001; revised 30 August 2001; accepted 10 September 2001