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Pharmacokinetics of once-daily dosing of ertapenem in critically ill patients with severe sepsis
International Journal of Antimicrobial Agents 33 (2009) 432–436
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Pharmacokinetics of once-daily dosing of ertapenem in critically ill patients with severe sepsis A.J. Brink a,∗ , G.A. Richards b , V. Schillack c , S. Kiem d , J. Schentag d a
Department of Clinical Microbiology, Ampath National Laboratory Services, Milpark Hospital, Johannesburg, South Africa Department of Intensive Care, Johannesburg Hospital and University of the Witwatersrand, Johannesburg, South Africa c Department of Esoteric Sciences, Ampath National Laboratory Services, 614 Pretorius str, Pretoria, South Africa d School of Pharmacy, University at Buffalo, and CPL Associates, LLC, Buffalo, New York, USA b
a r t i c l e
i n f o
Article history: Received 25 September 2008 Accepted 2 October 2008 Keywords: Ertapenem Once daily Pharmacokinetics Severe sepsis Albumin
a b s t r a c t Adequate data on the pharmacokinetics of once-daily administration of ertapenem in critically ill patients are largely lacking. This single-centre, prospective, open-label study was performed on a cohort of eight critically ill patients with severe sepsis with normal renal function treated with 1 g of ertapenem once daily. Samples of venous blood and urine were collected before infusion and at specific time points in the 24-h post-infusion period. Plasma and urine ertapenem levels were determined by reverse-phase highperformance liquid chromatography (HPLC) with ultraviolet detection. The non-protein-bound fraction was determined in the filtrate by HPLC using a Centrifree device. The current study showed a lower maximum plasma concentration (Cmax ) (52.3.0 mg/L vs. 253 mg/L) and area under the concentration–time curve from 0 h to infinity (AUC0–∞ ) (188 mg h/L vs. 817 mg h/L) but higher volume of distribution at steady state (Vss ) (26.8 L vs. 5.7 L) compared with those observed in young healthy volunteers. For unbound ertapenem, geometric means of Cmax and AUC0–∞ were 29.5 mg/L and 103.5 mg h/L, respectively, and correlated negatively with hypoalbuminaemia. Unbound levels failed to exceed a minimum inhibitory concentration of 1 mg/L for more than 7.1 h (30%) of the dosing interval in two patients. The highly variable and unpredictable intersubject pharmacokinetic parameters documented in this study resulted in suboptimal unbound concentrations in some patients. This raises the question as to whether ertapenem is an appropriate agent for initial use in critically ill patients with severe sepsis. © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction Ertapenem is a parenteral broad-spectrum carbapenem with in vitro activity that includes extended-spectrum -lactamase (ESBL)-producing Enterobacteriaceae such as Klebsiella pneumoniae [1]. In this regard, the increased use of carbapenems is driven by accumulation of cephalosporin and fluoroquinolone resistance amongst such Enterobacteriaceae [2]. Ertapenem is deemed a suitable and ‘tailored’ alternative for directed therapy of ESBL infections and is also considered a valid empirical option in the treatment of community-acquired intra-abdominal infections, community-acquired pneumonia (CAP) and early-onset hospitalor ventilator-associated pneumonia (VAP) where risk factors for non-fermentative pathogens such as Pseudomonas aeruginosa are not present [3,4].
∗ Corresponding author. Tel.: +27 11 726 6260; fax: +27 11 482 3361. E-mail address: [email protected] (A.J. Brink).
Ertapenem is a time-dependent antibiotic, requiring the unbound fraction to exceed the minimum inhibitory concentration (MIC) for >20% and >40% of the dosing interval to ensure bacteriostatic and maximal bactericidal effect, respectively [5]. However, the pharmacokinetic (PK) profile of once-daily administration of ertapenem in patients in the critical care setting is largely unavailable. In patients with VAP, the unbound ertapenem serum and epithelial lining fluid concentrations exceed the MIC90 (the MIC for 90% of the organisms) of most pathogens over 50–100% of the dosing interval [6]. In contrast, Burkhardt et al. [7] recently estimated that the unbound plasma concentration of ertapenem in critically ill patients with early-onset VAP exceeds a MIC90 of 2 mg/L for only 6 h (25% of the dosing interval) after infusion and advocated shortening of the dosing interval or continuous infusion to ensure optimal free concentrations in these patients. The same author had previously documented that the mean maximum plasma concentration (Cmax ) and area under the concentration–time curve from 0 h to infinity (AUC0–∞ ) of ertapenem in the plasma of patients undergoing lung surgery was much lower than those values documented for healthy young or elderly volunteers [8–10].
0924-8579/$ – see front matter © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2008.10.005
A.J. Brink et al. / International Journal of Antimicrobial Agents 33 (2009) 432–436
The aim of this study was to investigate the pharmacokinetics of ertapenem in critically ill patients with severe sepsis and to determine whether the current registered daily dosing of 1 g once daily provides adequate unbound plasma concentrations for antibacterial efficacy. 2. Patients and methods 2.1. Study design This single-centre, prospective, open-label study was performed in the Department of Critical Care, Johannesburg Hospital, Johannesburg, South Africa. Subjects consisted of eight critically ill patients with severe sepsis. Written informed consent was obtained either from the patient or, when appropriate, from their closest relative. At the discretion of the physician, all patients received 1 g of intravenous ertapenem (Invanz® ; Merck, Sharp & Dohme, Midrand, South Africa) over 30 min once daily for indications that included directed therapy for Gramnegative intra-abdominal or urinary infections, empirical therapy for community-acquired and early hospital-acquired pneumonia or community-acquired intra-abdominal infection associated with features of severe sepsis. Criteria for the latter included: clinical evidence of acute infection; temperature >38.8 ◦ C or <35.6 ◦ C; heart rate >90 beats/min; tachypnoea >20 breaths/min; evidence of organ dysfunction or inadequate organ perfusion [including hypotension (systolic blood pressure of <90 mmHg or a decrease in baseline blood pressure of >40 mmHg after adequate fluid resuscitation)]; systemic acidosis; blood lactate ≥4 mmol/L; oliguria; or acute alteration of mental status. Patients with suspected -lactam allergy, pregnancy, lactation or co-morbid disease that may interfere with the study and those with hepatic and renal impairment were excluded. Serum creatinine concentrations were determined at the same time as the sampling for ertapenem analysis. Creatinine clearance (CLCr ) was calculated by means of the Cockcroft–Gault formula and patients were considered to have normal renal function if the CLCr was >50 mL/min. The following information was recorded: demographic data including age and weight; clinical details including underlying co-morbid illnesses; microbiology (in cases of directed therapy); duration of ertapenem treatment and outcome; concomitant antibiotics and dosages; Acute Physiology and Chronic Health Evaluation (APACHE) II scores; serum biochemistry; serum creatinine; liver function tests; 24-h urine volume; urine creatinine concentration; and adverse events. 2.2. Sampling and analysis Samples (10 mL) of venous blood were collected before and 0.5, 1, 2, 4, 6, 8, 12, 18 and 24 h after the start of the ertapenem infusion. Samples were centrifuged and plasma was stored at −70 ◦ C for later analysis. Urine specimens were collected pre dose and for the periods 0–2, 2–4, 4–6, 6–8, 8–12, 12–18 and 18–24 h. All urine passed during each period was pooled, mixed thoroughly, measured and stored at 2–8 ◦ C. Subsequently, a 10 mL aliquot was removed and stored at −70 ◦ C after a stabiliser [equal volumes of urine and the buffer 0.1 M 2-ethanesulfonic acid salt (pH 6.5)] had been added at the study site. Plasma and urine ertapenem levels were determined at the Department of Esoteric Sciences, Ampath National Laboratory Services, Pretoria, South Africa, by reverse-phase high-performance liquid chromatography (HPLC) with ultraviolet detection without the column switching option used for high-volume throughput of samples, as described by Musson et al. [11]. The non-protein-bound fraction of ertapenem was
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determined by HPLC after filtration with a Centrifree device [12]. The limit of quantification for bound and unbound ertapenem was determined as 0.5 mg/L, with a linearity range of 0.5–100 mg/L, regression (r2 ) of 0.9983, precision <10% coefficient of variation (n = 5) and accuracy of 50.0 ± 6% based on nominal concentrations of 1.0 mg/L and 50 mg/L. 2.3. Pharmacokinetic analysis PK analysis was done by the School of Pharmacy, University at Buffalo, and CPL Associates, LLC, Buffalo, New York, USA. The AUC0–∞ was calculated by the log-linear trapezoidal rule until the time of last quantifiable plasma concentration and then extrapolated to infinity using the quotient of the last measurable concentration to the rate constant (K). The first-order rate constant (K), estimated from the slope of the exponential phase of the logarithmic plasma concentration–time profile, was used. The rate K was estimated from the slope of the exponential phase of the logarithmic plasma concentration–time profile. The elimination half-life (t1/2 ) was determined as 0.693/K. Total body clearance (CLT ) was determined as dose/AUC0–∞ . The volume of distribution at steady state (Vss ) was calculated as dose·AUMC/(AUC0–∞ ), where AUMC is the area under the first moment curve from time zero to infinity. The urine drug concentration and urine volume data were used to calculate urinary excretion. To calculate total urinary excretion (Xu ), the quotient of the last average measurable excretion rate to the rate K was added to the amount of drug cumulatively excreted in urine up to the time of the last quantitation of urine concentration. The fraction of the dose cumulatively excreted into urine and renal clearance (CLR ) were determined as Xu /dose and Xu /plasma AUC0–∞ , respectively. The Cmax was obtained directly from actual measured data. The time (h) above each of the following plasma concentrations (0.06, 0.5, 1.0, 2.0, 4.0, 8.0 mg/L) for both total and unbound ertapenem was calculated from the equation log C = log C0 −K /2.303 × t. For all variables, arithmetic mean value, standard deviation (S.D.) and geometric mean were calculated, with the exception of time above the MIC (T > MIC), for which median is given. 3. Results 3.1. Patient characteristics Eight patients with severe sepsis were recruited over an 18month period. Their demographic data are shown in Table 1. Reasons for Intensive Care Unit (ICU) admission included severe CAP (n = 3), post-surgical intra-abdominal sepsis (n = 3), Guillain–Barré syndrome with urinary sepsis (n = 1) and a case of malaria with Gram-negative sepsis (n = 1). The microbiological aetiology was established in three patients: Escherichia coli from blood culture and urine and Morganella morganii from a tracheal aspirate. Three patients had low serum protein (range 41–90 g/L), and all except one had hypoalbuminaemia (range 16–46 g/L, mean ± S.D. 26.9 ± 9.0 g/L). No patient had impaired renal function. No serious adverse advents were noted and all patients survived. 3.2. Pharmacokinetic profile Considerable intersubject variability was documented in this study (Table 2). The mean ± S.D. and geometric mean total ertapenem PK data for the eight patients are given in Table 3. The geometric mean total Cmax and AUC0–∞ were 52.3 mg/L and 188 mg h/L, respectively. The Vss , CLT and CLR were all elevated at 26.8 L, 88.6 mL/min and 33.2 mL/min, respectively. The elimination half-life was recorded as a geometric mean of 4.5 h. For unbound
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Table 1 Patient characteristics at enrolment (n = 8; 5 female, 3 male). Patient
Age (years)
Weight (kg)
APACHE II score
Creatinine (mol/L)
CLCr (mL/min)
Protein (g/L)a
Albumin (g/L)b
ICU admission
Pathogen/source
1 2
43 40
55 60
8 9
89 56
63 132
90 75
32 25
Severe CAP Severe CAP
3
43
43
15
64
131
42
23
4
56
80
4
51
158
41
16
5
21
60
4
67
122
79
46
Post-surgical IA sepsis Post-surgical IA sepsis Guillain–Barré
N/A Morganella morganii, tracheal aspirate N/A
6
42
75
7
134
68
46
22
7 8
24 24
60 50
18 6
147 103
50 50
85 73
24 27
Mean ± S.D. Median Range
36.6 ± 12.3 41 21–56
60.4 ± 12.2 60 43–80
8.9 ± 5.1 8 4–18
88.9 ± 36.3 78 51–147
96.8 ± 43.3 95 50–158
66.4 ± 20.1 74 41–90
26.9 ± 9.0 25 16–46
Post-surgical IA sepsis Malaria Severe CAP
N/A Escherichia coli, urine N/A E. coli, blood N/A
APACHE, Acute Physiology and Chronic Health Evaluation; CLCr , creatinine clearance; ICU, intensive care unit; CAP, community-acquired pneumonia; N/A, not available; IA, intra-abdominal. a Normal range 60–83 g/L. b Normal range 35–52 g/L. Table 2 Total ertapenem pharmacokinetic data after a single 1 g infusion in eight critically ill patients with severe sepsis. Parameter
t1/2 (h) Vss (L) CLT (mL/min) CLR (mL/min) fu (% of dose) AUC0–∞ (mg h/L) Cmax (mg/L)
Patient number 1
2
3
4
5
6
7
8
3.3 7.3 28.9 9.5 33.0 577.3 146.9
1.4 11.9 101.6 35.0 34.4 164.0 87.7
6.6 77.4 356.5 272.8 76.5 46.8 10.3
3.5 23.1 70.0 44.3 64.5 238.0 89.9
5.6 11.8 32.5 7.8 24.3 512.8 212.2
4.2 258.0 910.7 176.8 19.4 18.3 5.5
17.2 78.0 82.6 12.3 13.2 201.8 22.6
3.9 7.3 21.3 21.2 97.7 782.4 177.3
t1/2 , elimination half-life; Vss , volume of distribution at steady state; CLT , total body clearance; CLR , renal clearance; fu , urinary recovery; AUC0–∞ , area under the concentration–time curve from 0 h to infinity; Cmax , maximum plasma concentration.
ertapenem, the following geometric mean parameters were noted: t1/2 of 4.8 h, Cmax of 29.5 mg/L and AUC0–∞ of 103.5 mg h/L, respectively (Table 4). 3.3. Pharmacokinetic/pharmacodynamic profile Calculations of the time unbound ertapenem would exceed certain plasma concentrations are shown for each patient individually and also as a median in Table 5. Unbound ertapenem did not exceed the MIC breakpoint of 2 mg/L for Enterobacteriaceae for >40% (9.6 h) of the 24-h dosing interval in four patients. The required
bacteriostatic pharmacokinetic/pharmacodynamic target of >20% (4.8 h) was also not achieved in two patients with post-surgical intra-abdominal infections (Tables 1 and 5; patients 3 and 6). For a MIC of 1 mg/L, levels did not exceed the dosing interval for more than 7.1 h (30%) of the time in both of these patients. 4. Discussion Dosing regimens are based primary on PK profiles from healthy volunteers rather than from critically ill patients where antibiotic disposition is variable and unpredictable due to alterations in
Table 3 Comparison of total ertapenem pharmacokinetic data after a single 1 g infusion obtained in critically ill patients with severe sepsis versus published data for critically ill patients with early-onset ventilator-associated pneumonia [7] and healthy volunteers [9,17]. Parameter
Mean ± S.D. t1/2 (h) Vss (L) CLT (mL/min) CLR (mL/min) fu (% of dose) AUC0–∞ (mg h/L) Cmax (mg/L)
Burkhardt et al. [7] (n = 17)a
This study (n = 8)
5.7 59.4 200.5 72.5 45.1 317.7 94.1
± ± ± ± ± ± ±
4.9 85.7 306.9 98.3 30.3 274.6 79.0
Majumdar et al. [9] (n = 16)a
Pletz et al. [17] (n = 10)b
3.8 8.2 ± 1.5 29.5 ± 3.4 12.9 ± 4.3 44.4 ± 14.8 572.1 ± 68.6 154.9 ± 22.0
4.5 (23) 5.7 (18) 20.4 (18) 9.38 (37) 45.1 (36) 817 (20) 253 (15)
Geometric mean 4.5 26.8 88.6 33.2 36.7 188.0 52.3
4.15 14.8 43.2 31.8 54.8 418.5 90.5
± ± ± ± ± ± ±
1.33 3.78 23.7 23.3 19.09 171.6 26.1
S.D., standard deviation; t1/2 , elimination half-life; Vss , volume of distribution at steady state; CLT , total body clearance; CLR , renal clearance; fu , urinary recovery; AUC0–∞ , area under the concentration–time curve from 0 h to infinity; Cmax , maximum plasma concentration. a Data reported as mean ± S.D. b Data reported as geometric mean [coefficient of variation (%)].
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Table 4 Comparison of unbound ertapenem pharmacokinetic data after a single 1 g infusion obtained in critically ill patients with severe sepsis versus published data for young adults [9] and healthy elderly subjects [10]. Parameter
This study (n = 8) Mean ± S.D.
t1/2 (h) Vss (L) CLT (mL/min) CLR (mL/min) AUC0–∞ (mg h/L) Cmax (mg/L)
10.1 89.9 316.2 147.5 180.6 46.4
± ± ± ± ± ±
Majumdar et al. [9] (n = 16)a
Musson et al. [10] (n = 8)a
– 123.1 513.6 223.3 33.2 12.9
4.7 – – 122.4 ± 28.6 55.40 ± 7.6 –
Geometric mean
18.2 92.3 374.3 219.2 167.4 40.5
4.8 54.3 161.0 63.4 103.5 29.5
± ± ± ± ±
37.2 80.8 67.8 6 5.5 3.2
S.D., standard deviation; t1/2 , elimination half-life; Vss , volume of distribution at steady state; CLT , total body clearance; CLR , renal clearance; AUC0–∞ , area under the concentration–time curve from 0 h to infinity; Cmax , maximum plasma concentration. a Data reported as mean ± S.D.
intravascular volume, composition of plasma proteins, and renal and hepatic function [13]. As a consequence of these variables, variations in PK characteristics have been demonstrated for antibiotics such as ciprofloxacin [14], vancomycin [15] and imipenem [16]. The current study shows lower Cmax and AUC0–∞ and higher Vss , CLT and CLR for total ertapenem compared with those observed in young healthy volunteers [9,17]. This confirms results obtained from a recent study performed in critically ill patients with earlyonset VAP [7]. However, compared with critically ill patients with severe sepsis in this study, the Vss , CLT and CLR were much higher (59.4 L vs. 14.8 L, 200.5 mL/min vs. 43.2 mL/min and 72.5 mL/min vs. 31.8 mL/min, respectively) than for those patients with earlyonset VAP. The Cmax and AUC0–∞ of unbound ertapenem were much higher than those in healthy elderly or young adult volunteers and this could be explained by the low serum albumin concentrations that are indicative of the severity of illness in these patients (range 16–46 g/L, mean ± S.D. 26.9 ± 9.0 g/L). Similar findings for ertapenem were previously reported by Burkhardt et al. [7]. Ertapenem has concentration-dependent protein binding of between 84% and 96% [7]. This implies that as the level of albumin decreases the unbound Cmax and AUC0–∞ increase and that the Vss , CLT and CLR would also change as a consequence. Similar effects of hypoalbuminaemia on PK parameters in critically ill patients have been reported by Joynt et al. [18] with ceftriaxone and by Pea et al. [19], with teicoplanin. Unique to the current study is the extreme variability of the PK parameters between patients with severe sepsis. Factors other than hypoalbuminaemia, such as the altered pathophysiological conditions present in severe sepsis as well as iatrogenic interventions, may also have substantially influenced the distribution and elimination of ertapenem. These may have included the presence of ascites, post-surgical fluid losses, fluid resuscitation and pleural Table 5 Calculated time (h) of unbound plasma ertapenem above certain concentrations in critically ill patients with severe sepsis after 1 g 30-min infusions. Patient
Concentration (mg/L) 0.06
0.5
1
2
4
8
1 2 3 4 5 6 7 8
31.9 14.2 18.1 22.8 48.3 27.6 367.8 41.4
21.5 9.6 9.8 14.1 31.9 8.8 199.4 29.3
18.2 8.1 7.1 11.2 26.5 2.6 144.3 25.3
14.8 6.6 4.4 8.4 21.2 0.0 89.3 21.3
11.4 5.1 1.7 5.5 15.8 0.0 34.2 17.4
8.0 3.6 0.0 2.6 10.4 0.0 0.0 13.4
Median Min. Max.
29.8 14.2 367.8
17.8 8.8 199.4
14.7 2.6 144.3
11.6 0.0 89.3
8.4 0.0 34.2
3.1 0.0 13.4
Min., minimum; Max., maximum.
effusions. Unbound ertapenem failed to exceed a MIC of 1 mg/L for more than 7.1 h (30%) of the dosing interval, specifically in two of the patients with abdominal sepsis who also had the highest Vss , CLT and CLR . The enhanced CLR documented may have been as a result of the use of haemodynamically active drugs or the hyperdynamic conditions associated with severe sepsis. It is also possible that considerable amounts of the antibiotic may be lost in surgical patients as it is strongly bound to protein and up to 2 g of nitrogen (12.5 g of protein) per litre may be lost in any patient with an open abdomen [20]. In addition to the above possibilities, renal function is an important factor contributing to interpatient PK variability as ca. 80% of ertapenem is excreted in the urine (38% unchanged and 37% metabolised in the kidney to an open-ring form). CLCr in this cohort of patients ranged from 50 mL/min to 158 mL/min, which would be sufficient to influence partially the recorded parameters. A population PK analysis had previously indicated CLCr as a significant covariate explaining the intersubject variation of ertapenem in the critical care setting [7]. In a comparative PK and pharmacodynamic target attainment study in normal weight, obese and extremely obese adults, Chen et al. [21] reported that the standard 1 g ertapenem dose may not provide adequate drug exposure for any body mass index for MICs in excess of 0.25–0.5 mg/L. Similarly, the results of this study suggest that 1 g of ertapenem as a single daily infusion would not suffice in all critically ill patients with severe sepsis. This is in accordance with the findings of Burkhardt et al. [7], who recently recommended shortening of the dosage interval or continuous infusion as options to increase T > MIC. The same authors have also previously performed Monte Carlo simulations comparing the probability of pharmacodynamic target attainment in healthy volunteers versus ICU patients with early VAP. In this study they found that at a MIC of 1 g/L, the probability of attaining a bacteriostatic target T > MIC of 20% was <70% in the ICU population [22]. However, whereas higher or more frequent doses might optimise bacterial outcome, they may as an unintended consequence theoretically select for resistance to imipenem, meropenem and doripenem in nosocomial pathogens such as P. aeruginosa that are frequent colonisers in critically ill patients. Although recent ecological studies have refuted concerns that ertapenem may select for carbapenem cross-resistance in this pathogen, these studies were performed in hospital wards [23] or the percentage use of ertapenem in the critical care setting was not stipulated [24]. This concern should also be directed to the treatment of infections due to fermentative pathogens such as ESBL-producing K. pneumoniae in ICU patients with sepsis. It has previously been documented that use of ertapenem in this setting has been associated with a 3- and 8-fold increase in imipenem and meropenem MICs, respectively [2]. Limitations of this study include the fact that a very heterogeneous group was studied and therefore the numbers may be too small to reflect fairly the characteristics of the drug. Also, patients
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with hepatic or renal dysfunction were specifically excluded and as a consequence this detracts from extrapolating these results to all patients with severe sepsis. These factors, similar to other agents studied in this patient population, do not provide sufficient data to allow specific dosing recommendations. However, the important concerns that are raised and the highly variable and unpredictable intersubject pharmacokinetics documented raise the question as to whether ertapenem is an appropriate and suitable agent to use as initial therapy for critically ill patients with severe sepsis, particularly in those with significant loss of protein from the abdomen. Funding: The study was funded by Merck & Co., Rahway, NJ, USA. Competing interests: AJB has received recent research funding from sanofi-aventis, acted on the advisory board of MSD, Wyeth and Pfizer and has served on speaker’s bureaus for Astra-Zeneca, Abbott Laboratories, Bayer, GlaxoSmithKline, Merck, Pfizer, sanofi-aventis and Wyeth pharmaceuticals. GAR has served on advisory boards for MSD, Pfizer, Abbott Laboratories, Fresenius Kabi and Roche, has received research funding from Bristol-Myers Squibb, and served on speaker’s bureaus for Merck, sanofi-aventis, Roche, Astra-Zeneca, Pfizer, Bayer, GlaxoSmithKline, Wyeth, Boehringer and Fresenius Kabi. All other authors have no competing interests to declare. Ethical approval: Ethical approval was obtained from the University of Witwatersrand, Johannesburg, South Africa. References [1] Livermore DM, Sefton AM, Scott GM. Properties and potential of ertapenem. J Antimicrob Chemother 2003;52:331–44. [2] Elliott E, Brink AJ, Van Greune J, Els Z, Woodford N, Turton G, et al. In-vivo development of ertapenem resistance in a patient with pneumonia caused by Klebsiella pneumoniae with extended-spectrum -lactamase. Clin Infect Dis 2006;42:e95–8. [3] Brink AJ, Feldman C, Grolman DC, Muckardt D, Pretorius J, Richards GA, et al. Appropriate use of the carbapenems. S Afr Med J 2004;94:857–61. [4] American Thoracic Society/Infectious Disease Society of America. Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388–416. [5] Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol 2004;2:289–300. [6] Boselli E, Breilh D, Saux M, Gordien J, Allaouchiche B. Pharmacokinetics and lung concentrations of ertapenem in patients with ventilator-associated pneumonia. Intensive Care Med 2006;32:2059–62. [7] Burkhardt O, Kumar V, Katterwe D, Majcher-Peszynska J, Drewelouw B, Derendorf H, et al. Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration. J Antimicrob Chemother 2007;59:277–84.
[8] Burkhardt O, Majcher-Peszynska J, Borner K, Mundkowski R, Drewelouw B, Derendorf H, et al. Penetration of ertapenem into different pulmonary compartments of patients undergoing lung surgery. J Clin Pharmacol 2005;45:659–65. [9] Majumdar AK, Musson DG, Birk KL, Kitchen CJ, Holland S, McCrea J, et al. Pharmacokinetics of ertapenem in healthy young volunteers. Antimicrob Agents Chemother 2002;46:3506–11. [10] Musson DG, Majumdar A, Holland S, Birk K, Xi L, Mistry G, et al. Pharmacokinetics of total and unbound ertapenem in healthy elderly subjects. Antimicrob Agents Chemother 2004;48:521–4. [11] Musson DG, Birk KL, Cairns AM, Majumdar AK, Rogers JD. High-performance liquid chromatographic methods for the determination of a new carbapenem antibiotic, L-749,345, in human plasma and urine. J Chromatogr B Biomed Sci Appl 1998;720:99–106. [12] Musson DG, Birk KL, Kitchen CJ, Zhang J, Hsieh JY, Majumdar AK, et al. Assay methodology for the quantitation of unbound ertapenem, a new carbapenem antibiotic, in human plasma. J Chromatogr B Biomed Analyt Technol Biomed Life Sci 2003;783:1–9. [13] Pea F, Viale P, Furlanut M. Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet 2005;44:1009–34. [14] Lipman J, Scribante J, Gous AGS, Hon H, Tshukutsoane S. Pharmacokinetic profiles of high-dose intravenous ciprofloxacin in severe sepsis. The Baragwanath Ciprofloxacin Study Group. Antimicrob Agents Chemother 1998;42:2235–9. [15] Gous AGS, Dance MD, Lipman J, Luyt DK, Mathivha R, Scribante J. Changes in vancomycin pharmacokinetics in critically ill infants. Anaesth Intensive Care 1995;23:678–82. [16] McKindley DS, Boucher BA, Hess MM, Croce MA, Fabian TC. Pharmacokinetics of aztreonam and imipenem in critically ill patients with pneumonia. Pharmacotherapy 1996;16:924–31. [17] Pletz MWR, Rau M, Bulitta J, De Roux A, Burkhardt O, Kruse G, et al. Ertapenem pharmacokinetics and impact on intestinal microflora, in comparison to those of ceftriaxone, after multiple dosing in male and female volunteers. Antimicrob Agents Chemother 2004;48:3765–72. [18] Joynt GM, Lipman J, Gomersall CD, Young RJ, Wong ELY, Gin T. The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients. J Antimicrob Chemother 2001;47:421–9. [19] Pea F, Brollo L, Viale P, Pavan P, Furlanut M. Teicoplanin therapeutic drug monitoring in critically ill patients: a retrospective study emphasizing the importance of a loading dose. J Antimicrob Chemother 2003;51:971–5. [20] Cheatham ML, Safcsak K, Brzezinski SJ, Lube MW. Nitrogen balance, protein loss, and the open abdomen. Crit Care Med 2007;35:127–31. [21] Chen M, Nafziger AN, Drusano GL, Ma L, Bertino JS. Comparative pharmacokinetics and pharmacodynamic target attainment of ertapenem in normal-weight, obese and extremely obese adults. Antimicrob Agents Chemother 2006;50:1222–7. [22] Burkhardt O, Derendorf H, Welte T. Ertapenem: the new carbapenem 5 years after first FDA licensing for clinical practice. Expert Opin Pharmacother 2007;8:237–56. [23] Carmeli Y, Lidji S, Shabtai E, Navon-Venezia S, Schwaber MJ. The effects of group 1 vs. group 2 carbapenems on imipenem resistant (IMP-R) P. aeruginosa (PA): ecological study. In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Washington, DC: ASM Press; 2007. Abstract K396. [24] Goff DA, Mangino JE. Ertapenem: no effect on aerobic Gram-negative susceptibilities to imipenem. J Infect 2008;57:123–7.
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International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Pharmacokinetics of once-daily dosing of ertapenem in critically ill patients with severe sepsis A.J. Brink a,∗ , G.A. Richards b , V. Schillack c , S. Kiem d , J. Schentag d a
Department of Clinical Microbiology, Ampath National Laboratory Services, Milpark Hospital, Johannesburg, South Africa Department of Intensive Care, Johannesburg Hospital and University of the Witwatersrand, Johannesburg, South Africa c Department of Esoteric Sciences, Ampath National Laboratory Services, 614 Pretorius str, Pretoria, South Africa d School of Pharmacy, University at Buffalo, and CPL Associates, LLC, Buffalo, New York, USA b
a r t i c l e
i n f o
Article history: Received 25 September 2008 Accepted 2 October 2008 Keywords: Ertapenem Once daily Pharmacokinetics Severe sepsis Albumin
a b s t r a c t Adequate data on the pharmacokinetics of once-daily administration of ertapenem in critically ill patients are largely lacking. This single-centre, prospective, open-label study was performed on a cohort of eight critically ill patients with severe sepsis with normal renal function treated with 1 g of ertapenem once daily. Samples of venous blood and urine were collected before infusion and at specific time points in the 24-h post-infusion period. Plasma and urine ertapenem levels were determined by reverse-phase highperformance liquid chromatography (HPLC) with ultraviolet detection. The non-protein-bound fraction was determined in the filtrate by HPLC using a Centrifree device. The current study showed a lower maximum plasma concentration (Cmax ) (52.3.0 mg/L vs. 253 mg/L) and area under the concentration–time curve from 0 h to infinity (AUC0–∞ ) (188 mg h/L vs. 817 mg h/L) but higher volume of distribution at steady state (Vss ) (26.8 L vs. 5.7 L) compared with those observed in young healthy volunteers. For unbound ertapenem, geometric means of Cmax and AUC0–∞ were 29.5 mg/L and 103.5 mg h/L, respectively, and correlated negatively with hypoalbuminaemia. Unbound levels failed to exceed a minimum inhibitory concentration of 1 mg/L for more than 7.1 h (30%) of the dosing interval in two patients. The highly variable and unpredictable intersubject pharmacokinetic parameters documented in this study resulted in suboptimal unbound concentrations in some patients. This raises the question as to whether ertapenem is an appropriate agent for initial use in critically ill patients with severe sepsis. © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction Ertapenem is a parenteral broad-spectrum carbapenem with in vitro activity that includes extended-spectrum -lactamase (ESBL)-producing Enterobacteriaceae such as Klebsiella pneumoniae [1]. In this regard, the increased use of carbapenems is driven by accumulation of cephalosporin and fluoroquinolone resistance amongst such Enterobacteriaceae [2]. Ertapenem is deemed a suitable and ‘tailored’ alternative for directed therapy of ESBL infections and is also considered a valid empirical option in the treatment of community-acquired intra-abdominal infections, community-acquired pneumonia (CAP) and early-onset hospitalor ventilator-associated pneumonia (VAP) where risk factors for non-fermentative pathogens such as Pseudomonas aeruginosa are not present [3,4].
∗ Corresponding author. Tel.: +27 11 726 6260; fax: +27 11 482 3361. E-mail address: [email protected] (A.J. Brink).
Ertapenem is a time-dependent antibiotic, requiring the unbound fraction to exceed the minimum inhibitory concentration (MIC) for >20% and >40% of the dosing interval to ensure bacteriostatic and maximal bactericidal effect, respectively [5]. However, the pharmacokinetic (PK) profile of once-daily administration of ertapenem in patients in the critical care setting is largely unavailable. In patients with VAP, the unbound ertapenem serum and epithelial lining fluid concentrations exceed the MIC90 (the MIC for 90% of the organisms) of most pathogens over 50–100% of the dosing interval [6]. In contrast, Burkhardt et al. [7] recently estimated that the unbound plasma concentration of ertapenem in critically ill patients with early-onset VAP exceeds a MIC90 of 2 mg/L for only 6 h (25% of the dosing interval) after infusion and advocated shortening of the dosing interval or continuous infusion to ensure optimal free concentrations in these patients. The same author had previously documented that the mean maximum plasma concentration (Cmax ) and area under the concentration–time curve from 0 h to infinity (AUC0–∞ ) of ertapenem in the plasma of patients undergoing lung surgery was much lower than those values documented for healthy young or elderly volunteers [8–10].
0924-8579/$ – see front matter © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2008.10.005
A.J. Brink et al. / International Journal of Antimicrobial Agents 33 (2009) 432–436
The aim of this study was to investigate the pharmacokinetics of ertapenem in critically ill patients with severe sepsis and to determine whether the current registered daily dosing of 1 g once daily provides adequate unbound plasma concentrations for antibacterial efficacy. 2. Patients and methods 2.1. Study design This single-centre, prospective, open-label study was performed in the Department of Critical Care, Johannesburg Hospital, Johannesburg, South Africa. Subjects consisted of eight critically ill patients with severe sepsis. Written informed consent was obtained either from the patient or, when appropriate, from their closest relative. At the discretion of the physician, all patients received 1 g of intravenous ertapenem (Invanz® ; Merck, Sharp & Dohme, Midrand, South Africa) over 30 min once daily for indications that included directed therapy for Gramnegative intra-abdominal or urinary infections, empirical therapy for community-acquired and early hospital-acquired pneumonia or community-acquired intra-abdominal infection associated with features of severe sepsis. Criteria for the latter included: clinical evidence of acute infection; temperature >38.8 ◦ C or <35.6 ◦ C; heart rate >90 beats/min; tachypnoea >20 breaths/min; evidence of organ dysfunction or inadequate organ perfusion [including hypotension (systolic blood pressure of <90 mmHg or a decrease in baseline blood pressure of >40 mmHg after adequate fluid resuscitation)]; systemic acidosis; blood lactate ≥4 mmol/L; oliguria; or acute alteration of mental status. Patients with suspected -lactam allergy, pregnancy, lactation or co-morbid disease that may interfere with the study and those with hepatic and renal impairment were excluded. Serum creatinine concentrations were determined at the same time as the sampling for ertapenem analysis. Creatinine clearance (CLCr ) was calculated by means of the Cockcroft–Gault formula and patients were considered to have normal renal function if the CLCr was >50 mL/min. The following information was recorded: demographic data including age and weight; clinical details including underlying co-morbid illnesses; microbiology (in cases of directed therapy); duration of ertapenem treatment and outcome; concomitant antibiotics and dosages; Acute Physiology and Chronic Health Evaluation (APACHE) II scores; serum biochemistry; serum creatinine; liver function tests; 24-h urine volume; urine creatinine concentration; and adverse events. 2.2. Sampling and analysis Samples (10 mL) of venous blood were collected before and 0.5, 1, 2, 4, 6, 8, 12, 18 and 24 h after the start of the ertapenem infusion. Samples were centrifuged and plasma was stored at −70 ◦ C for later analysis. Urine specimens were collected pre dose and for the periods 0–2, 2–4, 4–6, 6–8, 8–12, 12–18 and 18–24 h. All urine passed during each period was pooled, mixed thoroughly, measured and stored at 2–8 ◦ C. Subsequently, a 10 mL aliquot was removed and stored at −70 ◦ C after a stabiliser [equal volumes of urine and the buffer 0.1 M 2-ethanesulfonic acid salt (pH 6.5)] had been added at the study site. Plasma and urine ertapenem levels were determined at the Department of Esoteric Sciences, Ampath National Laboratory Services, Pretoria, South Africa, by reverse-phase high-performance liquid chromatography (HPLC) with ultraviolet detection without the column switching option used for high-volume throughput of samples, as described by Musson et al. [11]. The non-protein-bound fraction of ertapenem was
433
determined by HPLC after filtration with a Centrifree device [12]. The limit of quantification for bound and unbound ertapenem was determined as 0.5 mg/L, with a linearity range of 0.5–100 mg/L, regression (r2 ) of 0.9983, precision <10% coefficient of variation (n = 5) and accuracy of 50.0 ± 6% based on nominal concentrations of 1.0 mg/L and 50 mg/L. 2.3. Pharmacokinetic analysis PK analysis was done by the School of Pharmacy, University at Buffalo, and CPL Associates, LLC, Buffalo, New York, USA. The AUC0–∞ was calculated by the log-linear trapezoidal rule until the time of last quantifiable plasma concentration and then extrapolated to infinity using the quotient of the last measurable concentration to the rate constant (K). The first-order rate constant (K), estimated from the slope of the exponential phase of the logarithmic plasma concentration–time profile, was used. The rate K was estimated from the slope of the exponential phase of the logarithmic plasma concentration–time profile. The elimination half-life (t1/2 ) was determined as 0.693/K. Total body clearance (CLT ) was determined as dose/AUC0–∞ . The volume of distribution at steady state (Vss ) was calculated as dose·AUMC/(AUC0–∞ ), where AUMC is the area under the first moment curve from time zero to infinity. The urine drug concentration and urine volume data were used to calculate urinary excretion. To calculate total urinary excretion (Xu ), the quotient of the last average measurable excretion rate to the rate K was added to the amount of drug cumulatively excreted in urine up to the time of the last quantitation of urine concentration. The fraction of the dose cumulatively excreted into urine and renal clearance (CLR ) were determined as Xu /dose and Xu /plasma AUC0–∞ , respectively. The Cmax was obtained directly from actual measured data. The time (h) above each of the following plasma concentrations (0.06, 0.5, 1.0, 2.0, 4.0, 8.0 mg/L) for both total and unbound ertapenem was calculated from the equation log C = log C0 −K /2.303 × t. For all variables, arithmetic mean value, standard deviation (S.D.) and geometric mean were calculated, with the exception of time above the MIC (T > MIC), for which median is given. 3. Results 3.1. Patient characteristics Eight patients with severe sepsis were recruited over an 18month period. Their demographic data are shown in Table 1. Reasons for Intensive Care Unit (ICU) admission included severe CAP (n = 3), post-surgical intra-abdominal sepsis (n = 3), Guillain–Barré syndrome with urinary sepsis (n = 1) and a case of malaria with Gram-negative sepsis (n = 1). The microbiological aetiology was established in three patients: Escherichia coli from blood culture and urine and Morganella morganii from a tracheal aspirate. Three patients had low serum protein (range 41–90 g/L), and all except one had hypoalbuminaemia (range 16–46 g/L, mean ± S.D. 26.9 ± 9.0 g/L). No patient had impaired renal function. No serious adverse advents were noted and all patients survived. 3.2. Pharmacokinetic profile Considerable intersubject variability was documented in this study (Table 2). The mean ± S.D. and geometric mean total ertapenem PK data for the eight patients are given in Table 3. The geometric mean total Cmax and AUC0–∞ were 52.3 mg/L and 188 mg h/L, respectively. The Vss , CLT and CLR were all elevated at 26.8 L, 88.6 mL/min and 33.2 mL/min, respectively. The elimination half-life was recorded as a geometric mean of 4.5 h. For unbound
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Table 1 Patient characteristics at enrolment (n = 8; 5 female, 3 male). Patient
Age (years)
Weight (kg)
APACHE II score
Creatinine (mol/L)
CLCr (mL/min)
Protein (g/L)a
Albumin (g/L)b
ICU admission
Pathogen/source
1 2
43 40
55 60
8 9
89 56
63 132
90 75
32 25
Severe CAP Severe CAP
3
43
43
15
64
131
42
23
4
56
80
4
51
158
41
16
5
21
60
4
67
122
79
46
Post-surgical IA sepsis Post-surgical IA sepsis Guillain–Barré
N/A Morganella morganii, tracheal aspirate N/A
6
42
75
7
134
68
46
22
7 8
24 24
60 50
18 6
147 103
50 50
85 73
24 27
Mean ± S.D. Median Range
36.6 ± 12.3 41 21–56
60.4 ± 12.2 60 43–80
8.9 ± 5.1 8 4–18
88.9 ± 36.3 78 51–147
96.8 ± 43.3 95 50–158
66.4 ± 20.1 74 41–90
26.9 ± 9.0 25 16–46
Post-surgical IA sepsis Malaria Severe CAP
N/A Escherichia coli, urine N/A E. coli, blood N/A
APACHE, Acute Physiology and Chronic Health Evaluation; CLCr , creatinine clearance; ICU, intensive care unit; CAP, community-acquired pneumonia; N/A, not available; IA, intra-abdominal. a Normal range 60–83 g/L. b Normal range 35–52 g/L. Table 2 Total ertapenem pharmacokinetic data after a single 1 g infusion in eight critically ill patients with severe sepsis. Parameter
t1/2 (h) Vss (L) CLT (mL/min) CLR (mL/min) fu (% of dose) AUC0–∞ (mg h/L) Cmax (mg/L)
Patient number 1
2
3
4
5
6
7
8
3.3 7.3 28.9 9.5 33.0 577.3 146.9
1.4 11.9 101.6 35.0 34.4 164.0 87.7
6.6 77.4 356.5 272.8 76.5 46.8 10.3
3.5 23.1 70.0 44.3 64.5 238.0 89.9
5.6 11.8 32.5 7.8 24.3 512.8 212.2
4.2 258.0 910.7 176.8 19.4 18.3 5.5
17.2 78.0 82.6 12.3 13.2 201.8 22.6
3.9 7.3 21.3 21.2 97.7 782.4 177.3
t1/2 , elimination half-life; Vss , volume of distribution at steady state; CLT , total body clearance; CLR , renal clearance; fu , urinary recovery; AUC0–∞ , area under the concentration–time curve from 0 h to infinity; Cmax , maximum plasma concentration.
ertapenem, the following geometric mean parameters were noted: t1/2 of 4.8 h, Cmax of 29.5 mg/L and AUC0–∞ of 103.5 mg h/L, respectively (Table 4). 3.3. Pharmacokinetic/pharmacodynamic profile Calculations of the time unbound ertapenem would exceed certain plasma concentrations are shown for each patient individually and also as a median in Table 5. Unbound ertapenem did not exceed the MIC breakpoint of 2 mg/L for Enterobacteriaceae for >40% (9.6 h) of the 24-h dosing interval in four patients. The required
bacteriostatic pharmacokinetic/pharmacodynamic target of >20% (4.8 h) was also not achieved in two patients with post-surgical intra-abdominal infections (Tables 1 and 5; patients 3 and 6). For a MIC of 1 mg/L, levels did not exceed the dosing interval for more than 7.1 h (30%) of the time in both of these patients. 4. Discussion Dosing regimens are based primary on PK profiles from healthy volunteers rather than from critically ill patients where antibiotic disposition is variable and unpredictable due to alterations in
Table 3 Comparison of total ertapenem pharmacokinetic data after a single 1 g infusion obtained in critically ill patients with severe sepsis versus published data for critically ill patients with early-onset ventilator-associated pneumonia [7] and healthy volunteers [9,17]. Parameter
Mean ± S.D. t1/2 (h) Vss (L) CLT (mL/min) CLR (mL/min) fu (% of dose) AUC0–∞ (mg h/L) Cmax (mg/L)
Burkhardt et al. [7] (n = 17)a
This study (n = 8)
5.7 59.4 200.5 72.5 45.1 317.7 94.1
± ± ± ± ± ± ±
4.9 85.7 306.9 98.3 30.3 274.6 79.0
Majumdar et al. [9] (n = 16)a
Pletz et al. [17] (n = 10)b
3.8 8.2 ± 1.5 29.5 ± 3.4 12.9 ± 4.3 44.4 ± 14.8 572.1 ± 68.6 154.9 ± 22.0
4.5 (23) 5.7 (18) 20.4 (18) 9.38 (37) 45.1 (36) 817 (20) 253 (15)
Geometric mean 4.5 26.8 88.6 33.2 36.7 188.0 52.3
4.15 14.8 43.2 31.8 54.8 418.5 90.5
± ± ± ± ± ± ±
1.33 3.78 23.7 23.3 19.09 171.6 26.1
S.D., standard deviation; t1/2 , elimination half-life; Vss , volume of distribution at steady state; CLT , total body clearance; CLR , renal clearance; fu , urinary recovery; AUC0–∞ , area under the concentration–time curve from 0 h to infinity; Cmax , maximum plasma concentration. a Data reported as mean ± S.D. b Data reported as geometric mean [coefficient of variation (%)].
A.J. Brink et al. / International Journal of Antimicrobial Agents 33 (2009) 432–436
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Table 4 Comparison of unbound ertapenem pharmacokinetic data after a single 1 g infusion obtained in critically ill patients with severe sepsis versus published data for young adults [9] and healthy elderly subjects [10]. Parameter
This study (n = 8) Mean ± S.D.
t1/2 (h) Vss (L) CLT (mL/min) CLR (mL/min) AUC0–∞ (mg h/L) Cmax (mg/L)
10.1 89.9 316.2 147.5 180.6 46.4
± ± ± ± ± ±
Majumdar et al. [9] (n = 16)a
Musson et al. [10] (n = 8)a
– 123.1 513.6 223.3 33.2 12.9
4.7 – – 122.4 ± 28.6 55.40 ± 7.6 –
Geometric mean
18.2 92.3 374.3 219.2 167.4 40.5
4.8 54.3 161.0 63.4 103.5 29.5
± ± ± ± ±
37.2 80.8 67.8 6 5.5 3.2
S.D., standard deviation; t1/2 , elimination half-life; Vss , volume of distribution at steady state; CLT , total body clearance; CLR , renal clearance; AUC0–∞ , area under the concentration–time curve from 0 h to infinity; Cmax , maximum plasma concentration. a Data reported as mean ± S.D.
intravascular volume, composition of plasma proteins, and renal and hepatic function [13]. As a consequence of these variables, variations in PK characteristics have been demonstrated for antibiotics such as ciprofloxacin [14], vancomycin [15] and imipenem [16]. The current study shows lower Cmax and AUC0–∞ and higher Vss , CLT and CLR for total ertapenem compared with those observed in young healthy volunteers [9,17]. This confirms results obtained from a recent study performed in critically ill patients with earlyonset VAP [7]. However, compared with critically ill patients with severe sepsis in this study, the Vss , CLT and CLR were much higher (59.4 L vs. 14.8 L, 200.5 mL/min vs. 43.2 mL/min and 72.5 mL/min vs. 31.8 mL/min, respectively) than for those patients with earlyonset VAP. The Cmax and AUC0–∞ of unbound ertapenem were much higher than those in healthy elderly or young adult volunteers and this could be explained by the low serum albumin concentrations that are indicative of the severity of illness in these patients (range 16–46 g/L, mean ± S.D. 26.9 ± 9.0 g/L). Similar findings for ertapenem were previously reported by Burkhardt et al. [7]. Ertapenem has concentration-dependent protein binding of between 84% and 96% [7]. This implies that as the level of albumin decreases the unbound Cmax and AUC0–∞ increase and that the Vss , CLT and CLR would also change as a consequence. Similar effects of hypoalbuminaemia on PK parameters in critically ill patients have been reported by Joynt et al. [18] with ceftriaxone and by Pea et al. [19], with teicoplanin. Unique to the current study is the extreme variability of the PK parameters between patients with severe sepsis. Factors other than hypoalbuminaemia, such as the altered pathophysiological conditions present in severe sepsis as well as iatrogenic interventions, may also have substantially influenced the distribution and elimination of ertapenem. These may have included the presence of ascites, post-surgical fluid losses, fluid resuscitation and pleural Table 5 Calculated time (h) of unbound plasma ertapenem above certain concentrations in critically ill patients with severe sepsis after 1 g 30-min infusions. Patient
Concentration (mg/L) 0.06
0.5
1
2
4
8
1 2 3 4 5 6 7 8
31.9 14.2 18.1 22.8 48.3 27.6 367.8 41.4
21.5 9.6 9.8 14.1 31.9 8.8 199.4 29.3
18.2 8.1 7.1 11.2 26.5 2.6 144.3 25.3
14.8 6.6 4.4 8.4 21.2 0.0 89.3 21.3
11.4 5.1 1.7 5.5 15.8 0.0 34.2 17.4
8.0 3.6 0.0 2.6 10.4 0.0 0.0 13.4
Median Min. Max.
29.8 14.2 367.8
17.8 8.8 199.4
14.7 2.6 144.3
11.6 0.0 89.3
8.4 0.0 34.2
3.1 0.0 13.4
Min., minimum; Max., maximum.
effusions. Unbound ertapenem failed to exceed a MIC of 1 mg/L for more than 7.1 h (30%) of the dosing interval, specifically in two of the patients with abdominal sepsis who also had the highest Vss , CLT and CLR . The enhanced CLR documented may have been as a result of the use of haemodynamically active drugs or the hyperdynamic conditions associated with severe sepsis. It is also possible that considerable amounts of the antibiotic may be lost in surgical patients as it is strongly bound to protein and up to 2 g of nitrogen (12.5 g of protein) per litre may be lost in any patient with an open abdomen [20]. In addition to the above possibilities, renal function is an important factor contributing to interpatient PK variability as ca. 80% of ertapenem is excreted in the urine (38% unchanged and 37% metabolised in the kidney to an open-ring form). CLCr in this cohort of patients ranged from 50 mL/min to 158 mL/min, which would be sufficient to influence partially the recorded parameters. A population PK analysis had previously indicated CLCr as a significant covariate explaining the intersubject variation of ertapenem in the critical care setting [7]. In a comparative PK and pharmacodynamic target attainment study in normal weight, obese and extremely obese adults, Chen et al. [21] reported that the standard 1 g ertapenem dose may not provide adequate drug exposure for any body mass index for MICs in excess of 0.25–0.5 mg/L. Similarly, the results of this study suggest that 1 g of ertapenem as a single daily infusion would not suffice in all critically ill patients with severe sepsis. This is in accordance with the findings of Burkhardt et al. [7], who recently recommended shortening of the dosage interval or continuous infusion as options to increase T > MIC. The same authors have also previously performed Monte Carlo simulations comparing the probability of pharmacodynamic target attainment in healthy volunteers versus ICU patients with early VAP. In this study they found that at a MIC of 1 g/L, the probability of attaining a bacteriostatic target T > MIC of 20% was <70% in the ICU population [22]. However, whereas higher or more frequent doses might optimise bacterial outcome, they may as an unintended consequence theoretically select for resistance to imipenem, meropenem and doripenem in nosocomial pathogens such as P. aeruginosa that are frequent colonisers in critically ill patients. Although recent ecological studies have refuted concerns that ertapenem may select for carbapenem cross-resistance in this pathogen, these studies were performed in hospital wards [23] or the percentage use of ertapenem in the critical care setting was not stipulated [24]. This concern should also be directed to the treatment of infections due to fermentative pathogens such as ESBL-producing K. pneumoniae in ICU patients with sepsis. It has previously been documented that use of ertapenem in this setting has been associated with a 3- and 8-fold increase in imipenem and meropenem MICs, respectively [2]. Limitations of this study include the fact that a very heterogeneous group was studied and therefore the numbers may be too small to reflect fairly the characteristics of the drug. Also, patients
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with hepatic or renal dysfunction were specifically excluded and as a consequence this detracts from extrapolating these results to all patients with severe sepsis. These factors, similar to other agents studied in this patient population, do not provide sufficient data to allow specific dosing recommendations. However, the important concerns that are raised and the highly variable and unpredictable intersubject pharmacokinetics documented raise the question as to whether ertapenem is an appropriate and suitable agent to use as initial therapy for critically ill patients with severe sepsis, particularly in those with significant loss of protein from the abdomen. Funding: The study was funded by Merck & Co., Rahway, NJ, USA. Competing interests: AJB has received recent research funding from sanofi-aventis, acted on the advisory board of MSD, Wyeth and Pfizer and has served on speaker’s bureaus for Astra-Zeneca, Abbott Laboratories, Bayer, GlaxoSmithKline, Merck, Pfizer, sanofi-aventis and Wyeth pharmaceuticals. GAR has served on advisory boards for MSD, Pfizer, Abbott Laboratories, Fresenius Kabi and Roche, has received research funding from Bristol-Myers Squibb, and served on speaker’s bureaus for Merck, sanofi-aventis, Roche, Astra-Zeneca, Pfizer, Bayer, GlaxoSmithKline, Wyeth, Boehringer and Fresenius Kabi. All other authors have no competing interests to declare. Ethical approval: Ethical approval was obtained from the University of Witwatersrand, Johannesburg, South Africa. References [1] Livermore DM, Sefton AM, Scott GM. Properties and potential of ertapenem. J Antimicrob Chemother 2003;52:331–44. [2] Elliott E, Brink AJ, Van Greune J, Els Z, Woodford N, Turton G, et al. In-vivo development of ertapenem resistance in a patient with pneumonia caused by Klebsiella pneumoniae with extended-spectrum -lactamase. Clin Infect Dis 2006;42:e95–8. [3] Brink AJ, Feldman C, Grolman DC, Muckardt D, Pretorius J, Richards GA, et al. Appropriate use of the carbapenems. S Afr Med J 2004;94:857–61. [4] American Thoracic Society/Infectious Disease Society of America. Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388–416. [5] Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol 2004;2:289–300. [6] Boselli E, Breilh D, Saux M, Gordien J, Allaouchiche B. Pharmacokinetics and lung concentrations of ertapenem in patients with ventilator-associated pneumonia. Intensive Care Med 2006;32:2059–62. [7] Burkhardt O, Kumar V, Katterwe D, Majcher-Peszynska J, Drewelouw B, Derendorf H, et al. Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration. J Antimicrob Chemother 2007;59:277–84.
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