JAC Advance Access originally published online on December 21, 2006
Journal of Antimicrobial Chemotherapy 2007 59(2):277-284; doi:10.1093/jac/dkl485
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Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration
1 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, USA 2 Department of Pulmonary Medicine, Medical School Hannover, Hannover, Germany 3 Department of Pulmonary and Critical Care Medicine, University Otto-von-Guericke, Magdeburg, Germany 4 Department of Clinical Pharmacology, University Rostock, Rostock, Germany
* Corresponding author. Tel: +49-511-532-3661; Fax: +49-511-532-3353; E-mail: burkhardt.olaf{at}mh-hannover.de
Received 1 July 2006; returned 31 August 2006; revised 5 September 2006; accepted 3 November 2006
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Abstract |
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OBJECTIVES: Most information about pharmacokinetics of antimicrobial agents is obtained from studies in healthy volunteers. However, antibiotics are therapeutically used in infected patients with very different pharmacokinetic properties compared with healthy individuals.
PATIENTS AND METHODS: In a single-centre, prospective, open-label study, 17 adult critically ill patients with early-onset ventilator-associated pneumonia (VAP) were treated with 1 g of ertapenem infusion once a day. Blood and urine samples were collected before and at different time-points up to 24 h after medication on day 1. Concentrations of ertapenem in plasma were determined with a validated HPLC method. Free-drug concentrations were estimated using a two-class binding site equation.
RESULTS: The overall clinical success rate of the assessable cases was 66.7% (12/16). Pharmacokinetic parameters of ertapenem in our critically ill patients were clearly different when compared to those reported in the literature for healthy volunteers. The enhanced Vz (17 vs. 8 L) and CLTOT (43 vs. 20 mL/min) with resulting lower Cmax (90 vs. 253 mg/L) and AUC0–
(418 vs. 817 mg · h/L) values were mainly related to hypoalbuminaemia (range 9.2–25.6 g/L) in our patient population. A population pharmacokinetic analysis using the NONMEM program indicated creatinine clearance as a significant covariate for explaining the between-subject variability of ertapenem in the patient population. Estimated free plasma concentrations of ertapenem exceeded a MIC90 of 2 mg/L only for 6 h (25%) after infusion.
CONCLUSIONS: For an adequate dose adjustment of highly protein-bound drugs like ertapenem, knowledge of actual albumin concentrations is necessary. A shortening of the dosage interval or continuous infusion of ertapenem should be considered to ensure optimal free concentrations in critically ill patients with severe hypoalbuminaemia and normal renal function.
Keywords: protein binding , ICU patients , VAP
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Introduction |
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Ventilator-associated pneumonia (VAP) refers to pneumonia that arises more than 48–72 h after endotracheal intubation and is an important cause of morbidity and mortality of critically ill patients admitted to the intensive care unit (ICU).1 VAP occurs in 9–27% of all intubated patients.1–3 Suitable antibiotic treatment is important for the prognosis of these patients, either for timing or appropriate spectrum of antibacterial activity.4,5 It has been clearly documented that two types of VAP with specific and different microbial patterns occur according to time of onset.6 Early-onset VAP, defined as occurring within the first 4 days of hospitalization, usually has a better prognosis, and is more likely to be caused by antibiotic-susceptible bacteria (Haemophilus influenzae, Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus). However, late-onset VAP (5 days or more) is more likely to be caused by multidrug-resistant pathogens (Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia), and is associated with increased patient mortality and morbidity. According to the American Thoracic Society and Infectious Diseases Society of America, different strategies in the initial empirical antibiotic treatment of VAP should be recommended.7 Early-onset VAP without risk factors for multidrug-resistant bacteria may be treated with ceftriaxone, ampicillin/sulbactam, fluoroquinolones (levofloxacin, moxifloxacin, ciprofloxacin) or ertapenem, whereas any onset VAP with risk factors should be treated with a combination regimen involving a fluoroquinolone or an aminoglycoside plus an antibacterial agent providing antipseudomonal activity, such as third- or fourth-generation cephalosporins, antipseudomonal penicillins or carbapenems. Ertapenem, a parenteral broad-spectrum 1-ß-methyl-carbapenem, has good in vitro activity against Gram-positive bacteria such as Streptococcus pneumoniae and methicillin-susceptible staphylococci, Gram-negative bacteria e.g. Escherichia coli and Klebsiella pneumoniae including isolates carrying plasmid- or chromosomally-mediated ß-lactamases, and most anaerobic bacterial pathogens.8–10 Therefore, ertapenem may be considered a valid option in the treatment of early-onset VAP without risk factors for multidrug-resistant bacteria. The single and multiple dose pharmacokinetics of ertapenem in healthy young and older volunteers has been described.11–13 However, in another study with patients undergoing lung surgery, the mean Cmax and AUC0–last of ertapenem in plasma revealed much lower values than those published for healthy young volunteers.14 Pharmacokinetic differences found in healthy volunteers and these surgically treated patients are likely to be more pronounced in the critically ill, in whom drug distribution, third space and membrane permeability are frequently different.15,16 In addition, the effect of concentration-dependent protein binding of ertapenem (84–96%) is not taken into consideration, because only the free fraction of the drug exerts pharmacological action.17 All these aspects may have implications for the clinical efficacy and correct dosage of antibacterial agents. Therefore, the main aim of this study was to investigate the pharmacokinetics of ertapenem in ICU patients with VAP and to perform mixed effect modelling to identify the covariates, which can explain the inter-individual variability for pharmacokinetic parameters in this special patient population.
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Patients and methods |
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Study design and subjects
This single-centre, prospective, open-label study was performed on a cohort of 17 critically ill patients (11 males and 6 females) admitted to the Department of Pulmonary and Critical Care Medicine, University Otto-von-Guericke, Magdeburg, Germany. All patients were treated with 1 g of intravenous ertapenem (Invanz®, MSD Sharp & Dohme, Haar, Germany) over 30 min once daily for early-onset VAP (
4 days of mechanical ventilation), irrespective of their body weight, age and sex. VAP diagnosis was based on a new and persistent infiltrate on the chest radiograph, and two of the following three criteria: fever >38.3°C, WBC count >12 000 cells/mm3, and/or purulent tracheobronchial secretions. Non-inclusion criteria were: child-bearing potential, pregnancy, lactation, a severely immunocompromised status, use of any antibacterial agent 4 weeks before study entry, a concomitant disease that may interfere with the course of the study, severe hepatic and renal impairment (CLCREA < 30 mL/min), drug or alcohol abuse in medical history, and allergy to ß-lactam antibiotics. Creatinine clearance was calculated according to the Cockcroft and Gault's formula. Patients' relatives gave written informed consent. The protocol of the study was approved by the local institutional review board. The study was performed in accordance with the Declaration of Helsinki and the Good Clinical Practice Guideline of the European Commission.
In this study with a limited number of patients, both clinical and microbiological outcomes were assessed. The clinical efficacy of antimicrobial therapy was defined as follows. Clinical success was defined as complete or partial resolution of VAP signs and symptoms at the end of therapy. Therapy failure was defined as the need for a change in therapy during treatment because of persistence or worsening of clinical VAP symptoms. Microbiological outcome was assessed by repeating cultures of tracheobronchial aspirates at the end of antimicrobial therapy and was classified as bacterial eradication, microbiological persistence and superinfection.
Ertapenem sampling and analysis
Blood samples (5 mL) were collected in lithium heparin-coated tubes, via an arterial catheter, before ertapenem infusion and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 18 and 24 h after the start of infusion. Samples were centrifuged at 1300 g for 10 min at 4°C. Plasma was separated and stored at –80°C until analysis.
In eight patients, urine samples were collected pre-dose and over the following intervals: 0–3, 3–6, 6–12, and 12–24 h after administration. The urine volumes were measured after each collection interval and two 5 mL aliquots were saved. The samples were stored in closed sterile tubes at –80°C.
Concentrations of ertapenem in plasma and urine were determined by a new, validated high-performance liquid chromatographic (HPLC) method.18 All calibration functions were linear within the relevant assay ranges. The lower limits of quantification were 0.04 mg/L for plasma and urine. Variability in intra- and inter-day precision (CV) and accuracies (RE) were less than 20%. Recoveries ranged from 87 to 93%.
Non-compartmental pharmacokinetic analysis of the data was performed using the WinNonlin software program (WinNonlin version 3.1, Pharsight Corporation, Mountain View, CA, USA). The maximum concentration in plasma (Cmax) and time to reach Cmax (Tmax) after drug administration were obtained directly by visual examination of concentration–time data. The area under the plasma concentration–time curve from time 0 to infinity (AUC0–) was calculated by log-linear trapezoidal rule until the time of last quantifiable plasma concentration and then extrapolated to infinity by using the quotient of the last measurable concentration (Clast) to the terminal-phase rate constant (ß). The terminal elimination rate constant (ß) was estimated from the slope of terminal exponential phase of the logarithmic plasma concentration–time profile using at least three data points. The elimination half-life (t1/2ß) was determined as 0.693/ß. The mean residence time (MRT) was calculated as AUMC0–/AUC0–, where AUMC0– is the area under the first moment of concentration–time curve. Total body clearance (CLTOT) was determined as dose/AUC0–. The apparent volume of distribution during the terminal phase (Vz) was calculated as dose/ (AUC0–ß). The steady-state volume of distribution (Vss) was calculated as a product of MRT and CLTOT. The urine drug concentration and urine volume data were used to calculate urinary excretion, where fu describes the fraction of the dose cumulatively excreted into urine. Renal clearance (CLR) was determined as the ratio of the amount of drug cumulatively excreted in urine up to the time that the concentration was last quantifiable in urine and the respective plasma AUC up to that time point. For all variables, arithmetic mean values, standard deviations (SD), median, minimum and maximum values were calculated, with the exception of Tmax, for which median and minimum–maximum ranges are given.
Population pharmacokinetic analysis was performed for all 17 patients using NONMEM (NONMEM version 5, Globomax, Ellicott City, MD, USA). Based on an initial examination of the concentration–time curves, potential pharmacokinetic models considered were one- and two-compartment models. Akaike's information criterion (AIC) and Schwartz criteria (SC) were used for deciding the structural pharmacokinetic model. Preliminary data analysis with WinNonlin was used to obtain initial parameter estimates. A two-compartment model (Advan 3 Trans 4 subroutine), with parameterization for clearance (CL), the apparent volumes of distribution of the central compartment (V1), peripheral compartment (V2), and the intercompartmental clearance (Q) was used. Inter-individual variability in parameters (e.g. CL) was modelled using an exponential error model as follows:
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jCL represents the deviation of the jth individual's CL-value and that predicted by the regression model. The jCL is assumed to be an independent, identically distributed (i.i.d.), normal random variable with a zero mean and variance 
2. For residual error or within subject variability (WSV), constant coefficient of variation (CCV) error model was used. The individual estimated model parameters obtained from base model were plotted against each covariate to look for any significant trends. Univariate analysis was performed using likelihood ratio test on covariates showing a trend. Additions [P < 0.05, 
objective function value (OBJF) drop = 3.84] determined the full model. Stepwise backward deletion of the covariates from the full model was performed and deletion (P < 0.001; OBJF increase = 10.83) determined the final model. This conservative approach ensured that only the most meaningful covariates entered the model.19 Estimation of free drug concentration
The free concentrations of ertapenem (Cf) were estimated using a two-class binding site model, which assumes one specific and one non-specific binding site. This model has been reported to explain well the relation between free and total concentrations of ertapenem in preclinical situations.20
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Results |
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Patient characteristics
Within a study period of 6 months, 17 patients with VAP were included in the study (6 women, mean age 63 ± 17 years; and 11 men, mean age 59 ± 12 years). Baseline characteristics including demographic data of all patients are summarized in Table 1. The following diagnoses were reasons for admission to the ICU: cerebrovascular accident (n = 9), cardiac failure (n = 5), respiratory failure (n = 2), and gastrointestinal bleeding (n = 1). Of these 17 patients with early-onset VAP, 10 had a microbiologically confirmed bacterial aetiology (Table 1). Infection was monomicrobial in seven cases, and two microorganisms were recovered in three cases. Methicillin-susceptible Staphylococcus aureus was the most frequent isolate, accounting for 70% of organisms.
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Therapeutic outcome
Median length of ertapenem monotherapy was 7 days. Tolerability of the treatment was good. No serious adverse events were observed. At the end of ertapenem therapy, 1/17 patients was unassessable for clinical efficacy having died on day 2, caused by underlying disease unrelated to the infection. The overall clinical success rate of the assessable cases was 66.7% (12/16), whereas the failure rate was 33.3% (4/16). Bacterial eradication of the primary aetiological agent was obtained in all assessable cases (10/10). On the other hand, superinfection caused by a microorganism resistant in vitro to ertapenem, namely Pseudomonas aeruginosa in two cases, occurred in 20% of cases (2/10).
Pharmacokinetic investigations were completed for all 17 critically ill patients. The concentration–time (mean ± SD, n = 17) profile of total ertapenem is shown in Figure 1. The pharmacokinetic parameters as determined using non-compartment analysis are listed in Table 2. For comparison, single and multiple dose parameters of ertapenem reported earlier by Pletz et al.13 in healthy volunteers are also given. It was observed that critically ill patients with VAP yielded lower Cmax and AUC0– plasma values than young healthy volunteers. However, volumes of distribution (Vz, Vss) and clearance (CLTOT, CLR) determined in our patients were higher compared with values of healthy subjects. There were no visible differences in terminal elimination half-life (4.15 vs 4.5 and 4.3 h). In all patients the given mean fluid volume (4.1 ± 1.8 L/day) was always higher than the mean diuresis (2.8 ± 1.7 L/day). Mean cumulative urinary excretion of ertapenem during the 24 h dosage interval, determined in eight patients, showed that approximately 55% of the administered dose was recovered in urine as unmodified parent drug.
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Mixed effect modelling
A two-compartment model was found to best describe the concentration time data of ertapenem in the present population as indicated by a lower AIC and SC criteria during the preliminary analysis. The initial mean parameter estimates obtained from WinNonlin were 2.59 L/h for CL, 12.32 L/h for inter-compartment CL (Q), 9.15 L and 5.63 L for volume of distribution in central (V1) and peripheral compartment (V2), respectively. These initial estimates were used during NONMEM analysis in the two-compartment base model. In the next step, covariates were tested for their significance by univariate analysis. This analysis indicated age, serum creatinine and creatinine clearance as potential covariates on CL, while no significant covariate was observed for V1. Total protein content was a significant covariate on Q and V2. All selected covariates after univariate analysis were used to create a full model. The final population model was obtained after stepwise backward deletion from the full model. In the final model, only creatinine clearance was found to be a significant covariate on CL, as indicated by decrease in objective function value by 82.49 points (Table 3). The diagnostic plots for the final model are shown in Figure 2. The final population pharmacokinetic parameters were as follows (given as estimate with percentage inter-individual variability in parentheses): CL 2.63 L/h (31.4%), V1 10.6 L (23.7%) and V2 4.24 L (50.6%).
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Estimation of free drug concentrations
Available literature data were used to estimate parameters for the protein binding model.20 Fitting of the observed data was in good agreement with the equation used as shown in Figure 3. For each patient, individual observed concentrations of albumin and remaining protein were used for estimating unbound concentration of ertapenem by the two-class binding site equation. Estimated individual free ertapenem concentrations for a 24 h period in relation to MICs of most frequent VAP pathogens are shown in Figure 4.
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Discussion |
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Like other antimicrobial agents, most information about the pharmacokinetics of ertapenem has been obtained from studies in healthy volunteers.11–13 In our population of critically ill patients with VAP, ertapenem showed a different pharmacokinetic profile in terms of much lower Cmax and AUC0–
, than observed by Pletz et al.13 in young, healthy volunteers, as well as for other main PK parameters such as higher volumes of distribution (Vz, Vss), total body (CLTOT) and renal clearance (CLR). One important reason for the different pharmacokinetic data is that critically ill patients often present with several peculiar pathophysiological or iatrogenic conditions, which may substantially affect distribution and/or elimination of antimicrobial drugs.15,16 This may involve an increased volume of distribution (V), e.g. as a result of oedema, pleural effusion, ascites, or indwelling post-surgical drainage, or an enhanced CLR, e.g. as a result of burns, hyperdynamic conditions in septic shock or use of haemodynamically active drugs.15,16 In our patients without third-space characteristics, we suppose the enhanced V and CLR with resulting low Cmax and AUC0– values were mainly related to the decreased serum albumin concentrations (range 9.2–25.6 g/L), as a consequence of the fluid therapy with a positive daily fluid balance (mean ± SD, 1.8 ± 1.0 L/day). The same results with reference to hypoalbuminaemia-related V and CLR enhancements in critically ill patients were previously reported by Joynt et al.21 for treatment with ceftriaxone and by Pea et al.22 for teicoplanin therapy in a renal transplant patient with septic shock. Additionally, mixed effect modelling indicated that renal function, given as creatinine clearance, is a further important factor contributing to inter-individual variabilities in total systemic clearance of ertapenem. In this study, the range of creatinine clearance varied from 32.7 to 209.9 mL/min (Table 1), which can also explain in part the pharmacokinetic variability observed in our patient population (Figure 4). Another goal of this study was to identify the effect of altered protein concentrations on free plasma concentrations of ertapenem in critically ill patients. Besides the fact that only the free fraction of antimicrobial agents exerts antimicrobial activity, only this fraction has the ability to be distributed to the target site of infection.17,23 Therefore, the determination of the free part of highly bound substances in plasma or target tissue is much more important than the measurement of total (protein-bound and unbound) drug, as performed in most published ertapenem pharmacokinetic studies.13,14 As described above, hypoalbuminaemia observed in our patients resulted in a higher protein-unbound ertapenem fraction with consequences for drug distribution and elimination.
The question arises: are the protein-unbound ertapenem concentrations in plasma high enough to eliminate the bacteria effectively? Like other ß-lactam antibiotics, carbapenems exert their killing effect in a time-dependent manner.24 The main PK/PD parameter for this drug class is the proportion of the dose interval during which the drug concentration exceeds the MIC (t > MIC). For carbapenems, a t > MIC of 30–40% of the dose interval has been previously suggested to be effective due to their rapid bactericidal activity.25 In vitro studies demonstrated that ertapenem inhibited 90% (MIC90) of methicillin-susceptible S. aureus strains and extended-spectrum ß-lactamase (ESBL)-producing Klebsiella pneumoniae strains at 0.5 mg/L.8–10 MIC90 values for penicillin-susceptible, penicillin-intermediate susceptible, and penicillin-resistant Streptococcus pneumoniae strains were 0.03, 0.5, and 2.0 mg/L.8–10 Against most anaerobes, ertapenem had an MIC of 1.0 mg/L and against most Enterobacteriaceae without plasmid- or chromosomally-mediated ß-lactamases MIC90 values ranged from 0.03 to 0.06 mg/L.8–10 In our study, estimated protein-unbound ertapenem plasma concentrations at 12 h after a single intravenous administration of 1 g were 0.87 ± 0.76 mg/L, and 0.24 ± 0.43 mg/L at 24 h after infusion. Therefore, a dose of 1 g once a day, administered in critically ill patients, results in plasma free-drug levels higher than MIC90s of most above-mentioned early-onset VAP pathogens (MIC90 0.5 mg/L) for at least 50% of the entire dosing interval (Figure 4). On the other hand, free ertapenem concentrations exceeded MIC90 values of penicillin-resistant pneumococci as frequently observed respiratory tract pathogens only for 6 h (approximately 25% of the dosing interval) after start of infusion. In addition, lung concentrations of ertapenem might be lower since plasma concentrations frequently overestimate tissue concentrations.23
In conclusion, for an adequate dose adjustment of highly protein-bound antimicrobial agents like ertapenem, knowledge of actual albumin concentrations is necessary. Based on findings of our single-dose pharmacokinetic study, a shortening of the dosage interval or continuous infusion of ertapenem should be considered to ensure optimal free concentrations in critically ill patients with severe hypoalbuminaemia and normal renal function. In general, more pharmacokinetic studies in critically ill patients are needed to optimize the dosing regimen for maximum clinical outcome with minimum resistance development.
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None to declare.
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Acknowledgements |
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The technical assistance of Ilona Skupin, Edda Lautenbach and Antje Schümann is gratefully acknowledged. This study was an investigator-initiated trial and was supported in part by a grant from MSD Sharp & Dohme, Haar, Germany.
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