Single-Center Pharmacokinetic Study and Simulation of a Low Meropenem Concentration in Brain-Dead Organ Donors

Meropenem is an ultrabroad-spectrum antibiotic of the carbapenem family. In brain-dead organ donors, administration of standard meropenem dosages does not reach therapeutic levels.

ABSTRACT

Meropenem is an ultrabroad-spectrum antibiotic of the carbapenem family. In brain-dead organ donors, administration of standard meropenem dosages does not reach therapeutic levels. Our objectives were to determine the plasma concentration of meropenem after the administration of standard meropenem dose and to estimate an improved dosage regimen for these patients. One gram of meropenem was administered as a 1-h infusion every 8 h for 1 to 3 days, and blood samples were collected. The plasma concentration of meropenem was measured and subjected to pharmacokinetic analysis. Simcyp simulation was performed to predict the optimum plasma levels and dosage based on the patients' individual pharmacokinetic parameters. The maximum plasma concentration of meropenem was 3.29 μg/ml, which was lower than four times the MIC of 8 μg/ml. Although the mean creatinine clearance of patients was moderately low (67.5 ml/min), the apparent volume of distribution at steady state (V_ss) and time-averaged total body clearance (CL) of meropenem were markedly elevated (4.97 liters/kg and 2.06 liters/h/kg, respectively), owing to massive fluid loading to decrease the high sodium levels and to treat shock or dehydration. The simulation revealed that dose and infusion time of meropenem should be increased based on patients' V_ss and CL, and a loading dose is recommended to reach rapidly the target concentration. In conclusion, a standard meropenem regimen is insufficient to achieve optimal drug levels in brain-dead patients, and an increase in dose and extended or continuous infusion with intravenous bolus administration of a loading dose are recommended for these patients.

INTRODUCTION

Meropenem is an ultrabroad-spectrum injectable antibiotic belonging to the carbapenem family (1). The antimicrobial activity of meropenem is predominantly time dependent; the antibiotic concentrations in the serum and tissue should be above the MIC for the pathogen to achieve adequate antimicrobial activity (2, 3). For critically ill patients with hemodynamic instability, severe edema and an imbalance in body fluid composition affect the distribution of numerous drugs. Altered pharmacokinetics, especially time-averaged total body clearance (CL) and the apparent volume of distribution (V_d), can result in insufficient serum meropenem concentrations when standard dosages are administered (4, 5). Although meropenem is used widely, therapeutic drug monitoring (TDM) of this antibiotic is not as common as it is for vancomycin or aminoglycosides (6). It is recommended that 1 to 2 g of meropenem via prolonged infusion is sufficient to achieve optimal exposure in critically ill patients; however, there are still some reports that showed insufficient drug level and clinical outcome with the use of this standard regimen (2–6).

In brain-dead organ donors, central diabetes insipidus is very common, and serum sodium levels can be high (7). To declare a patient brain dead while maintaining organ quality, serum sodium levels should be below 155 mmEq/liter (8, 9). Moreover, brain-dead organ donors are usually critically ill patients in hemodynamic shock (10). Sometimes, massive hydration (200 to 1,000 ml/h) is needed to stabilize donors (9).

Meropenem is an empirical antibiotic commonly used in brain-dead organ donors. Large volumes of fluid administered to donors during the management period make it highly improbable to achieve the optimal therapeutic range of meropenem in patients who are administered the standard meropenem dosage of 3 g/day.

In this study, we measured the plasma concentration of meropenem in brain-dead organ donors during the donor management period and investigated whether standard meropenem therapy afforded optimal therapeutic levels in the plasma. If the meropenem level was insufficient to achieve antibacterial activity, we attempted to identify improved dose regimens and infusion times based on the pharmacokinetic parameters of the brain-dead organ donors.

RESULTS

The demographic characteristics and management data of 12 brain-dead organ donors are listed in Tables 1 and 2, respectively. The average white blood cell count was 10.8 ± 3.9 g/liter (normal range, 4 to 10 g/liter), and the average C-reactive protein level was 60.3 ± 7.2 mg/dl (data not shown). Furthermore, no infection was observed. All brain-dead organ donors were also administered fluid at volumes ranging from 1.51 to 11.4 liters/day based on their serum sodium concentrations to maintain their electrolyte balance and reduce the serum sodium contents for organ transplantation (Table 2). A positive fluid balance was maintained in all brain-dead organ donors except in patient 11. Packed red blood cells (PRBC) were also transfused at 400 to 1,600 ml (Table 2).

TABLE 1.

Demographics of the 12 enrolled brain-dead organ donors

Patient	Age (yr)	Sexa	Ht (cm)	BW (kg)b	Cause of brain death	APACHE II scorec
1	49	M	157	55	Subarachnoid hemorrhage	27
2	48	M	175	62	Subarachnoid hemorrhage	27
3	52	F	160	57	Suicidal hanging	24
4	55	M	170	70	Traumatic brain hemorrhage	24
5	55	M	170	62	Intracranial hemorrhage	24
6	44	F	157	53	Traumatic brain hemorrhage	33
7	54	M	172	71	Suicidal hanging	28
8	46	M	170	58	Intracranial hemorrhage	27
9	76	F	150	60	Anoxia from choking	34
10	79	F	160	66	Traumatic brain hemorrhage	28
11	36	M	160	69	Suicidal hanging	16
12	42	F	168	51	Subarachnoid hemorrhage	24

^aF, female; M, male.

^bBW, body weight.

^cAPACHE, acute physiology and chronic health evaluation.

TABLE 2.

Management of the 12 enrolled brain-dead organ donors

Patients	Length of management (days)	Input/output (ml)a				PRBC transfusion (ml)b
		1st day	2nd day	3rd day	Net
1	2	5,446/4,755	3,304/1,090		8,750/5,845 (2,905)	1,200
2	3	6,569/905	5,952/3,180	2,723/2,018	1,5244/6,103 (9,141)	800
3	3	8,595/4,245	9,453/5,010	1,510/580	19,558/9,835 (9,723)	900
4	2	9,475/4,540	4,638/2,345		14,113/6,885 (7,228)	1,600
5	2	5,720/1,470	5,728/2,000		11,448/3,470 (7,978)	800
6	3	8,325/2,740	8,325/2,740	1,713/1,150	18,363/6,630 (11,733)	800
7	5	5,519/4,570	6,615/2,413	5,652/3,780	17,786/10,763 (7,023)	640
8	3	6,263/3,490	11,420/4,580	5,385/5,530	23,068/13,600 (9,468)	800
9	2	6,696/285	3,098/228		9,794/513 (8,866)	800
10	3	3,774/1,640	6,369/3,970	2,561/80	12,704/5,690 (7,014)	800
11	3	4,163/4,155	4,777/4,850	3,558/3,420	12,498/12,425 (73)	400
12	10	4,083/5,090	8,374/5,850	9,005/3,565	21,462/14,505 (6,957)	720

^aValues in parentheses are the net fluid balance.

^bAll transfusion fluids were administered on the last day of donor management. PRBC, packed red blood cell.

The pharmacokinetic parameters of meropenem after a 1-h intravenous infusion of the first dose of meropenem (1 g) during the management are listed in Table 3, and plasma concentration-time profiles for each patient are shown in Fig. 1. After a 1-h intravenous infusion of meropenem, the plasma concentration of meropenem was low; the maximum plasma concentration (C_max) values of all patients were less than 4× the MIC (8 μg/ml), and the mean C_max of meropenem was approximately 3.29 μg/ml (range, 2.03 to 5.16 μg/ml). The mean terminal half-life of meropenem in brain-dead organ donors was 3.33 h, which was longer than the 1.24 h reported in normal healthy volunteers (11).

TABLE 3.

Pharmacokinetic parameters of meropenem after 1-h intravenous infusion of 1 g meropenem in 12 brain-dead organ donors

Parametera	Data by patientb												Mean	SD
	1	2	3	4	5	6	7	8	9	10	11	12
Sex	M	M	F	M	M	F	M	M	F	F	M	F
Age (yr)	49	48	52	55	55	44	54	46	76	79	36	42	53.0	12.8
Body wt (kg)	55	62	57	70	62	53	71	58	60	66	69	51	61.2	6.73
Half-life (h)	3.98	0.511	4.56	1.72	1.26	11.2	4.59	1.61	7.00	2.02	1.13	0.358	3.33	3.19
AUC (μg · h/ml)	28.1	4.98	13.0	6.36	12.8	19.4	23.4	3.22	27.7	5.60	6.10	5.90	13.1	9.29
Cmax (μg/ml)	4.65	3.66	2.84	2.68	2.98	2.35	5.16	2.03	2.13	3.21	4.04	3.78	3.29	0.990
Tmax (h)	0.5	1	0.5	1	4	1	1.1	0.91	2.83	1	0.9	1.16	1.33	1.03
CL (liters/h/kg)	0.647	3.24	1.35	2.25	1.26	0.973	0.602	5.35	0.601	2.71	2.38	3.32	2.06	1.44
Vss (liters/kg)	3.48	2.73	7.77	4.21	4.07	14.1	3.52	6.83	4.69	4.91	1.98	1.37	4.97	3.40
SCr (mg/dl)	3.19	1.93	1.83	1.85	0.73	0.78	2.79	1.01	4.82	0.68	0.90	0.39	1.74	1.31
CLCr (ml/min)	21. 8	41.1	32.4	44.7	100	77	30.4	75	9.4	69.9	111	151.3	67.5	41.6

^aS_Cr was measured on the second day of meropenem therapy. CL_Cr was estimated from S_Cr on the second day using the Cockcroft-Gault equation. AUC, area under the plasma concentration-time curve from time zero to infinity; C_max, maximum plasma concentration; T_max, time to reach C_max; CL, time-averaged total body clearance; V_ss, apparent volume of distribution at steady state; S_Cr, serum creatinine concentration; CL_Cr, creatinine clearance.

^bF, female; M, male.

FIG 1.

Plasma concentration-time profiles of meropenem after 1-h intravenous infusion of meropenem (1 g every 8 h for 48 h) in 12 brain-dead organ donors. The dotted line represents a concentration of 4× the MIC (8 μg/ml).

The mean V_d at steady state (V_ss) of meropenem after a 1-h intravenous infusion of meropenem was approximately 4.97 liters/kg (range, 1.37 to 14.1 liters/kg) in brain-dead organ donors. The V_ss was significantly greater than the 0.39 liters/kg reported in normal healthy subjects (11–14). The mean CL was 2.06 liters/h/kg, which is approximately six times that reported in normal healthy subjects (328 ml/min/1.73 m²) (11). As a result, the plasma concentration of meropenem was low, and thus, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of meropenem in brain-dead organ donors was lower than that reported in healthy normal volunteers (13.1 and 28.0 μg · h/ml, respectively) (11). This was due to the faster CL and greater V_ss of meropenem in brain-dead organ donors (14, 15), which suggest that the plasma concentration of meropenem may not be sufficient to produce antibacterial activity in brain-dead organ donors.

The renal function of brain-dead organ donors was moderately impaired based on their mean creatinine clearance (CL_Cr) of 67.5 ml/min (Table 3). To evaluate the changes of renal function in the patients during the management period, CL_Cr was measured on the first and last days, and the changes in CL_Cr were estimated between the first and last days. As shown in Table 4, the CL_Cr on the last day of the therapy increased by 38.2% compared to that on the first day of therapy.

TABLE 4.

Changes of CL_Cr during the management of 1 g meropenem in 12 brain-dead organ donors

Parametera	Data by patient												Mean	SD
	1	2	3	4	5	6	7	8	9	10	11	12
First day
SCr (mg/dl)	4.11	2.54	1.73	1.85	0.73	1.17	3.91	1.08	5.95	0.76	1.02	0.49	2.10	1.70
CLCr (ml/min)	16.9	32.3	34.2	44.7	100	51.3	21.7	70.1	7.62	62.5	97.7	120	53.6	37.5
Last day
SCr (mg/dl)b	4.24	1.66	1.29	1.02	0.57	0.92	3.19	0.54	5.59	0.47	0.85	0.37	1.73	1.70
CLCr (ml/min)	16.4	47.7	45.9	81.0	128	65.3	26.6	140	8.11	101	117	159	78.1	51.0
Change in CLCr (%)	−3.08	47.6	34.1	81.3	28.4	27.2	22.5	100	6.43	61.7	20.0	32.4	38.2	30.0

^aCreatinine clearance (CL_Cr) was estimated from serum creatinine concentration (S_Cr) using the Cockcroft-Gault equation. S_Cr was measured on the second day during meropenem therapy in patients 1, 5, and 9 due to death, and the rest was measured on the third day of meropenem therapy. Change in CL_Cr was estimated between the first and last days.

The percentages of the time (T) for which the plasma level was maintained at four times the target MIC (T > 4× the MIC) and T > MIC over the treatment period are shown in Table 5. The standard therapy did not meet 40% T > 4× the MIC or 100% T > MIC over the whole therapy period. Therefore, simulations of plasma concentrations were performed based on patients' pharmacokinetic parameters. The simulated plasma concentration-time profiles and the percentages of T > 4× the MIC for each patient are shown in Fig. 2 to 5 and Table 5, respectively. The doses for all patients had to be increased to 2 to 4 g meropenem regardless of the infusion time. In simulation I, the infusion time for five patients had to be increased to up to 2 h for an optimal therapeutic concentration. The C_max of patients 3 and 6 did not reach 4× the MIC (8 μg/ml) during the first meropenem infusion, and these patients reached the effective level at the third meropenem infusion and met the effective duration (40% of 72-h meropenem therapy period at the level of 4× the MIC) (Fig. 2). Other patients reached the effective concentration or higher from the first infusion of meropenem and met the effective duration. A greater fluctuation between the peak and trough concentrations was observed in patients 2, 11, and 12 (Fig. 2 and 3), and this could be due to the short half-life (approximately ≤1 h) compared to the mean value, 3.33 h (Table 3). In simulation II (Fig. 3), the plasma concentration-time profiles were similar to those in simulation I, but the difference is that C_max values after the first infusion of meropenem were low compared to those in simulation I. During the continuous infusion of meropenem in simulation III, the effective duration was prolonged, but the time to reach 4× the MIC tended to be delayed compared to that observed during the intermittent infusion in simulations I and II. The time to reach 4× the MIC was not attained during the first infusion of meropenem (8 h) in 9 of 12 patients (Fig. 4). To quickly reach the target concentration (4× the MIC), simulation of continuous infusion (simulation III) with intravenous bolus administration of a loading dose was performed (simulation IV). As shown in Fig. 5, all patients attained the target concentration from the beginning of the therapy except patient 6. The percentages of T > 4× the MIC were 100% in all brain-dead organ donors except patients 3 and 6, but patient 3 maintained near the target concentration throughout the therapy (Fig. 5).

TABLE 5.

Duration above target concentration of meropenem during the treatment in brain-dead organ donors

Subgroup concn	Data by patient												Mean	SD
	1	2	3	4	5	6	7	8	9	10	11	12
Observed plasma concn of meropenem after 1-h intravenous infusion of 1 g meropenema
T > MIC (%)	88.1	22.9	1.1	5.6	14.2	16.5	50.8	1.3	11.7	3.0	9.1	14.0	19.9	25.4
T > 4× the MIC (%)	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Concn (%) of meropenem after 2 h, 4 h, and continuous infusion of meropenem by simulationb
I	43	40.5	40	41.5	40	60.5	47	51	40.5	51	41	35	44.3	6.96
II	44.5	45	42	42	56.5	66	51.5	57.5	43.5	41	41	46.5	48.1	8.05
III	63	90.5	52.5	83.5	84	41.5	74.5	78	58	81.5	92	93.5	74.4	16.9
IV	100	100	82.5	100	100	56.0	100	100	100	100	100	100	94.9	13.2

^aT, duration of target level over entire meropenem therapy (%). See Fig. 1 for plasma concentration-time profiles for each patient.

^bSimulation I, T > 4× the MIC with infusion time of up to 2 h; simulation II, T > 4× the MIC with infusion time of up to 4 h; simulation III, T > 4× the MIC with continuous infusion of meropenem; simulation IV, T > 4× the MIC with continuous infusion with intravenous administration of loading dose.

FIG 2.

Simulated plasma concentration-time profiles of meropenem in 12 brain-dead organ donors after dose and infusion time adjustments based on each patient's pharmacokinetic parameters (CL and V_ss). Simulation was performed with an infusion time of up to 2 h (simulation I). Clinical trials in 100 virtually healthy subjects (10 trials × 10 subjects) were simulated using Simcyp by increasing the dose and infusion time over 72 h. Each patient's meropenem plasma concentration-time profile was selected at the best condition with the lowest dose and the longest effective duration. The dotted line represents a concentration of 4× the MIC (8 μg/ml). CL, time-averaged total body clearance; V_ss, apparent volume of distribution at steady state.

FIG 3.

Simulated plasma concentration-time profile of meropenem in 12 brain-dead organ donors after dose and infusion time adjustments based on each patient's pharmacokinetic parameters (CL and V_ss). Simulation was performed with infusion time of up to 4 h (simulation II). Clinical trials in 100 virtually healthy subjects (10 trials × 10 subjects) were simulated using Simcyp by increasing the dose and infusion time over 72 h. Each patient's meropenem plasma concentration-time profile was selected at the best condition with the lowest dose and the longest effective duration. The dotted line represents a concentration of 4× the MIC (8 μg/ml).

FIG 4.

Simulated plasma concentration-time profile of meropenem in 12 brain-dead organ donors after continuous infusion of meropenem (simulation III) with dose adjustments based on each patient's pharmacokinetic parameters (CL and V_ss). Clinical trials in 100 virtually healthy subjects (10 trials × 10 subjects) were simulated using Simcyp by increasing the dose over 72 h. Each patient's meropenem plasma concentration-time profile was selected at the best condition with the lowest dose and the longest effective duration. The dotted line represents a concentration of 4× the MIC (8 μg/ml).

FIG 5.

Simulated plasma concentration-time profile of meropenem in 12 brain-dead organ donors after continuous infusion of meropenem (simulation III) with intravenous bolus administration of a loading dose simultaneously (simulation IV) with dose adjustments based on each patients' pharmacokinetic parameters (CL and V_ss). Clinical trials in 100 virtually healthy subjects (10 trials × 10 subjects) were simulated using Simcyp over 72 h. The dotted line represents a concentration of 4× the MIC (8 μg/ml). LD, loading dose.

Meropenem is a time-dependent antibiotic. Based on our simulations, an extended or a continuous infusion of meropenem as well as increased dosage is recommended for critically ill patients to maintain the target level for a prolonged period and could prevent the infection of Pseudomonas aeruginosa or eliminate this microorganism. To rapidly reach the target level, continuous infusion with an intravenous bolus administration of a loading dose is preferable.

DISCUSSION

Our study showed that the optimal therapeutic level of meropenem with the standard dosage regimen could not be attained in brain-dead organ donors. For successful brain death determination and the management of brain-dead organ donors, large volumes of fluid are administered. This was necessary to maintain a positive fluid level but might cause augmented renal clearance (ARC) (5, 15, 16), which enhanced the excretion rate of drug; thus, the plasma concentration of the renally excreted drug decreased to suboptimal levels (15, 16). We presumed that the basal physiological conditions, such as cardiac output, vascular tone, organ blood flow, and fluid status, as well as the primary pathophysiological conditions, such as central type diabetes insipidus, could also contribute to the ARC in brain-dead organ donors (5, 15, 16). As a result, a greater V_ss and faster CL were observed under positive fluid balance and ARC conditions than under normal conditions, especially for drugs with low plasma protein binding (<2% for meropenem). However, despite low concentrations of meropenem, none of the subjects had developed infection.

Generally, a higher CL value indicates fast metabolism and/or increased excretory ability, and CL is a summation of renal clearance (CL_R) and metabolic CL (17). More than 70% of meropenem is renally excreted, and less than 30% is metabolized by renal dehydropeptidase. Therefore, the elimination of meropenem is dependent on the renal function. A higher CL does not reflect the fast metabolism of meropenem because the renal function of our patients was not normal, as indicated by the CL_Cr values. The best index of renal function is the glomerular filtration rate (GFR), but CL_Cr is widely accepted in clinical settings for the estimation of GFR because of the ease of measurement (18). The mean CL_Cr was 67.5 ml/min, based on the serum creatinine concentration (S_Cr) on the 2nd day during meropenem therapy (Table 3), which did not reflect the presence of ARC. Only one patient was considered to have ARC (CL_Cr over 130 ml/min) (19, 20), as estimated from S_Cr using Cockcroft-Gault formula (21). However, considering that most of our patients showed impaired kidney function and CL_Cr measured on the last day of therapy that increased by 38.2% compared to that on the first day of therapy (Table 4), we presumed that our patients had ARC. CL_Cr and S_Cr were inversely correlated in our patients (data not shown), which could be due to the fact that Cockcroft-Gault's equation is not accurate to estimate CL_Cr, especially at low S_Cr (22). Furthermore, there was no relationship between CL_Cr and CL (r² = 0.193), which suggests that CL_Cr based on S_Cr did not reflect the accurate kidney function in our patients. No correlation between CL_Cr and CL was identified in critically ill patients with trauma, but septic patients had some correlation (19). Therefore, the low plasma concentration of meropenem could be due to the greater V_ss and faster CL induced by fluid resuscitation, as represented by the V_ss and CL values that were 12.3 and 6.28 times higher, respectively, than those reported in normal healthy subjects (11, 23). Although we did not measure the urinary excretion of meropenem, the CL of meropenem was faster in our brain-dead organ donors than in other healthy volunteers, which indicates that ARC was independent of CL_Cr, S_Cr, or both in our patients. In contrast, vancomycin efficacy shows a clear correlation between CL_Cr and CL (22), and therefore, elevated CL_Cr values are associated with subtherapeutic drug levels if CL_Cr is measured from the urine and plasma instead of estimation from S_Cr using Cockcroft-Gault's equation.

The recommendations of most drug dosages are derived from information about patients with normal renal function or with chronic kidney disease, while information about dosing in critically ill patients is rare. Changes in cardiac output, vascular tone, organ blood flow, and fluid status can affect the V_ss and CL of numerous commonly prescribed drugs (5). Our data show that the mean plasma concentrations of meropenem in critically ill patients were lower and appeared to vary more than those in other patients or normal populations. This result suggests that TDM should be performed with meropenem treatment just as it currently is with vancomycin treatment. The case for TDM is even stronger for meropenem, which is renally excreted (65 to 80%), than it is for vancomycin, which is excreted by glomerular filtration (80 to 90%) as the unchanged drug (24). Our data show that brain-dead patients require the benefit of TDM to prevent significant underexposure to meropenem. Based on the mean CL_Cr value in our patients, a dose reduction of meropenem would have been appropriate. However, patients subjected to fluid resuscitation strategies maintained a positive fluid balance and showed increased urine output and CL, indicating that the kidneys were functioning at an increased level and that an increased dose of meropenem was needed. Similarly, another study showed that a more positive fluid balance early in resuscitation and cumulatively over 4 days was associated with an increased risk of mortality from septic shock due to the suboptimal therapeutic ranges of antibiotics in the serum of critically ill patients (25).

Known patient risk factors for ARC are younger age and disease-related factors, such as sepsis, trauma, surgery (including neurosurgery), febrile neutropenia due to hematological malignancy, burn injury, and cystic fibrosis (24). For our patients, age was not a risk factor (average age, 53.0 years). Disease-related risk factors, such as neurosurgery, were only observed in two patients, but this could not have been the major factor influencing the ARC of the patients. We therefore presume that fluid resuscitation to reduce the sodium level for organ transplantation caused a positive fluid balance and thus ARC, which resulted in suboptimal therapeutic levels of meropenem. Unfortunately, we did not measure the renal clearance (CL_R) of meropenem but did observe that the CL increased significantly, which reflects the increased CL_R of meropenem in the patients.

Based on the increased CL and V_ss in brain-dead patients, we performed the Simcyp simulation to estimate each patient's optimal dose and infusion time. Continuous infusion markedly increased the effective duration compared to that with the intermittent infusion. Interestingly, the time to reach C_max (T_max) was shorter in patients with a short half-life (about 1 h or less) when infused continuously, but these patients exhibited a greater fluctuation in peak and trough concentrations when meropenem was administered via intermittent infusion, which was independent of CL and V_ss. Therefore, the patients' CL and V_ss determined the plasma concentration of meropenem, while the terminal half-life affected the fluctuation of the drug concentration in the plasma during the intermittent infusion of meropenem and T_max during the continuous infusion. Therefore, it is recommended that a patient's pharmacokinetic characteristics (CL and V_ss) for meropenem be assessed and applied when designing the therapeutic regimen for critically ill patients.

Since critically ill patients show rapid variations in kidney function, volume state, and metabolic activity, it is challenging to individualize patient therapies. Therefore, determination of the plasma drug concentrations is recommended to protect critically ill patients from excessive overexposure or underexposure to renally eliminated drugs (26, 27). The use of extended infusions and daily determination of CL_Cr calculated from the urine and plasma should also be considered to obtain better pharmacokinetic profiles, which should allow drug levels to be maintained in the optimal therapeutic range.

Generally, the terminal half-life and T > 4× the MIC of β-lactam antibiotics have been reported to be unpredictable and heterogeneous in critically ill patients; CL and V_ss showed more than 2-fold variation on average (23). As a result, the antibacterial effects are not guaranteed. However, extended or even continuous infusion of carbapenem antibiotics with a loading dose usually produces superior antimicrobial activity in critically ill patients. Our results showed that a shorter infusion of meropenem resulted in a faster achievement of 4× the MIC, whereas a longer infusion resulted in a longer duration over 4× the MIC of meropenem. Considering the role of brain-dead organ donors, continuous infusion with intravenous bolus administration of a loading dose of meropenem is recommended for organ transplantation to quickly reach the target level and maintain activity during therapy. Nonetheless, continuous and intermittent infusions of meropenem are pharmacodynamically equivalent (3), and no differences were observed in mortality, infection recurrence, clinical outcome, superinfection, and safety analyses (28).

In conclusion, the pharmacokinetics of carbapenem antibiotics is heterogeneous and largely unpredictable in critically ill patients. Therefore, TDM may be an invaluable approach to optimize meropenem exposure in intensive care unit (ICU) patients with ARC. Meropenem dosing should be supported by pharmacokinetic concepts, including data derived from pharmacokinetic studies of critically ill patients and TDM.

MATERIALS AND METHODS

Materials.

Meropenem was provided by JW Pharmaceutical Corporation (Seoul, Republic of Korea), and a human plasma mixture, consisting of an equal volume of plasma from six healthy volunteers, was purchased from BioChemed Services (Winchester, VA, USA). Other chemicals were of analytical grade and were used without further purification.

Subjects.

We performed a prospective study of brain-dead organ donors in the surgical ICU and emergency ICU of Ajou University Hospital (Suwon, Republic of Korea). The protocol and consent forms were approved by the institutional review board of the Ajou University School of Medicine (AJIRB-MED-CT4-15-424). Twelve (7 male and 5 female) patients were enrolled, and written consent was provided by the family members of the brain-dead patients. The exclusion criteria were patients younger than 18 years and those who were administered meropenem injections before enrollment in this study. The patient demographics are described in Table 1. All the patients were suitable for organ donation, and the mean number of organs donated was four.

Fluid transfusion management.

The mean period of brain-dead organ donor management was 2.5 days (range, 2 to 3 days), which started at the time the patient was referred or transferred to the brain-dead organ donor management team and ended when the patient entered the operating room for organ procurement. During this period, the selection and volume of transfusion fluid were determined based on the electrolyte levels, especially serum sodium levels, of the patients (Table 2). When the serum sodium concentration was below or above 150 mEq/liter, Ringer's lactate solution or a combination of 5% dextrose and half saline was administered, respectively. The volume of fluid administered was as per the following parameters: patients with serum sodium levels of 150 to 160, 161 to 170, and >170 mEq/liter were administered the fluid at 200, 300, and >400 ml/h, respectively (9). Patients were transfused with PRBC if their serum hemoglobin level and platelet concentration were below 10 g/dl and 5 × 10⁴/μl, respectively. All transfused blood products were administered on the last day of the donor management period.

Antibiotic management and blood sampling.

In Ajou University Hospital, all brain-dead organ donors are administered a combination antibiotic regimen of teicoplanin and meropenem during the management period to prevent infection by methicillin-resistant Staphylococcus aureus and broad-spectrum bacteria, including Pseudomonas aeruginosa. The standard meropenem dosage is 1 g every 8 h without a loading dose, regardless of the patients' body weight. Each dose of meropenem was mixed with 100 ml 5% dextrose and infused to the patients over 1 h. To measure the plasma concentration of meropenem, 10 ml of arterial blood was collected from the radial arterial line at each sampling time point and stored in heparinized tubes. Blood sampling was performed at 0 (just before the first meropenem infusion), 0.5, 1 (immediately after the first meropenem infusion), 2, 3, and 5 h for the first infusion, and then just before and immediately after the next eight infusions to estimate pharmacokinetic parameters, especially elimination rate constant and half-life in the terminal phase, with these minimum sampling time points (3, 11, 12). The plasma obtained was mixed with the same volume of 1 M 3-morpholinopropanesulfonic acid (MOPS) buffer as a stabilizer and stored at −70°C until it was subjected to high-performance liquid chromatographic (HPLC) analysis to determine the concentration of meropenem (29).

Pharmacokinetic endpoints.

The adequacy of carbapenem therapy was assessed by calculating T > 4× the MIC. The optimal T > 4× the MIC of meropenem was considered to be >40% of the dosing interval for Gram-negative bacterial infections (30). MICs were determined for problematic pathogens, such as Pseudomonas aeruginosa, which are commonly isolated from patients in the ICU, and designated the empirical target thresholds (31). According to the European Committee on Antimicrobial Susceptibility Testing, the threshold of meropenem sensitivity based on the MIC for this pathogen is 2 μg/ml or less (4, 32).

HPLC analysis of meropenem.

A Shimadzu Prominence LC-20A HPLC system (Kyoto, Japan) equipped with an UV detector (SPD-20A/20AD) (33) was used for HPLC analysis. All components of the HPLC system were controlled using a CBM-20A system controller. The HPLC conditions used for meropenem detection were based on a previously reported method (29), with slight modifications. Briefly, the mobile phase was a mixture of 15 mM phosphate buffer (pH 5) and acetonitrile (88.5:11.5 [vol/vol]) at a flow rate of 0.8 ml/min. Chromatograms were monitored using a UV detector set at 280 nm. The retention time of meropenem was approximately 7.0 min. Plasma samples with MOPS buffer were transferred to a Nanosep 10K centrifugal filter device (Pall Corporation, Ann Arbor, MI, USA) and centrifuged at 12,000 × g for 10 min at 4°C (29). The filtrate (50 μl) was then injected into the HPLC system for the analysis of meropenem.

The lower limit of quantification for meropenem in human plasma was 0.05 μg/ml. Intraday and interday variations were calculated based on the response factors (RF) for each standard concentration. The mean intraday coefficients of variation (CVs) of meropenem in human plasma were low, with an average value of 10.1%. Based on the intraday CVs, the linearity of this method was good between 0.05 and 100 μg/ml (r² = 0.997). The interday CV of the same samples across three consecutive days was 11.4% in human plasma. The accuracy was between 97.7% and 106.3% over 0.05 μg/ml.

Pharmacokinetic analysis.

Standard methods (17) were used to calculate the following pharmacokinetic parameters using a noncompartmental analysis (WinNonlin version 2.1; Pharsight, Sunnyvale, CA, USA) after an intravenous infusion: terminal half-life, AUC (34), CL, and V_ss (35, 36). The C_max and T_max were determined from the plasma concentration-versus-time curves, while CL_Cr was estimated using Cockcroft-Gault equation (21).

Simulations.

Simcyp (version 15 release 1; Certara, Sheffield, UK) was used to simulate and predict the dose and infusion time of meropenem required to reach the optimal therapeutic level. The meropenem model was developed based on the physicochemical properties and in vitro pharmacokinetic parameters of meropenem (37). The meropenem plasma concentration-time profiles were simulated using a minimal physiologically based pharmacokinetic model. A clinical trial simulation of meropenem was performed in 10 trials using virtual healthy population with 10 subjects in each trial. When simulating individual clinical trials, the age, sex, body weight, V_ss, and CL values of each patient were used. Clinical trials were simulated by increasing the dose and infusion time every 8 h for 3 days. Simulation I used infusion times of up to 2 h, while simulation II used infusion times of up to 4 h. Simulation III used 8-h continuous infusion, and simulation IV used 8-h continuous infusion (simulation III) with intravenous bolus administration of a loading dose. Each patient's meropenem plasma concentration was selected at the point of best condition, which indicates the lowest dose and the longest effective duration found in simulations I and II.