Intensive Care Med

DOI 10.1007/s00134-008-1034-7

Julia Langgartner
Antje Vasold
Thomas Glck
Michel Reng
Frieder Kees

Received: 20 September 2007

Accepted: 24 December 2007
Springer-Verlag 2008
The authors wrote this article in cooperation
with the TAHI section of the ESICM.

J. Langgartner (u) A. Vasold

University of Regensburg, Department
of Internal Medicine I,
93042 Regensburg, Germany
e-mail:
julia.langgartner@klinik.uni-regensburg.de
T. Glck
General Hospital Traunstein, Department
of Internal Medicine,
Postfach 1820, 83276 Traunstein, Germany
M. Reng
General Hospital Bogen, Department
of Internal Medicine,
Mussinanstr. 8, 94327 Bogen, Germany
F. Kees
University of Regensburg, Department
of Pharmacology,
93053 Regensburg, Germany

BRIEF REPORT

Pharmacokinetics of meropenem during

intermittent and continuous intravenous
application in patients treated by continuous
renal replacement therapy

Abstract Objective: The clinical

effect of beta-lactam antibiotics
depends on the time of drug concentration above the minimal inhibitory
concentration (MIC) for a susceptible
bacterium. Continuous infusion (CI)
of -lactams such as meropenem
may therefore be a more rational
approach than intermittent bolus
injections (IB). The aim of this
study was to test whether CI of
meropenem achieves effective drug
concentrations comparable to IB
in patients treated by continuous
renal replacement therapy (CRRT).
Design: Prospective, randomised
cross-over study. Setting: Twelvebed medical intensive care unit
(ICU). Patients and interventions:
Six ICU patients were randomised
to receive either meropenem 1 g IB
every 12 h or a 0.5 g i.v. loading dose
followed by 2 g i.v. CI over 24 h.
After 2 days, regimens were crossed
over. Meropenem pharmacokinetics
were determined on days 2 and 4.
Measurements and results: Peak
serum concentration [median (25%

Introduction
Antimicrobial agents such as aminoglycosides and fluoroquinolones exhibit a concentration-dependent activity.
Their antibacterial effect is related to their peak concentrations. By contrast the clinical effect of -lactam
antibiotics depends on the time of drug concentration
above the minimal inhibitory concentration (MIC) for
a susceptible bacterium. -Lactams achieve maximum

and 75% quartiles)] after short

infusion of 1 g meropenem were 62.8
(51.4; 85.0) mg/l, trough levels at
12 h were 8.1 (4.5; 18.7) mg/l, and
serum half-life was 5.3 (5.1; 7.0) h.
Steady-state concentrations during
CI were 18.6 (13.3; 24.5) mg/l. The
AUCs during either treatment were
comparable and determined as 233
(202; 254) mg/l*h (IB) and 227 (182;
283) mg/l*h (CI), respectively. Four
hours after IB, drug concentrations
dropped below CI steady-state
concentrations. Conclusion: Appropriate antibacterial concentrations of
meropenem in patients with CRRT
are easily achievable with CI. CI may
be an effective alternative dosing
regimen to IB. A prospective comparison of the clinical efficacy of the
two dosage regimens is warranted.
Keywords Meropenem Beta-lactam
antibiotics Continuous infusion
Pharmacokinetics CVVHD Renal
replacement therapy Pharmacodynamics

bacterial killing at concentrations 45 times the MIC for

the microorganism and exhibit no or only a minimum
post-antibiotic effect [14]. Further elevation of drug
concentration does not improve antibacterial activity [5].
Intermittent administration of a drug leads to high peak
and low trough serum concentrations; the latter may fall
below the MIC for the microorganism during the dosing
interval. Continuous i.v. infusion (CI) produces a constant
concentration of the antibiotic, thereby optimising the

pharmacodynamic characteristics of the -lactam antibiotics. This has led to reconsideration of CI of -lactam
antibiotics as a potentially valuable approach [2, 6, 7],
provided that doses sufficient to reach concentrations
several times above the MIC are chosen.
Meropenem is a -lactam antibiotic. Because of the
short half-life of meropenem, necessitating frequent dosing in intermittent bolus (IB) regimens, it is considered an
excellent candidate for application by CI.
On pharmacokinetic considerations, especially critically ill patients with continuous renal replacement therapy
(CRRT) would benefit from a continuous administration of
-lactam antibiotics.
Therefore, the aim of this study was to test whether
CI of meropenem achieves effective drug concentrations
comparable to IB in patients with renal failure treated by
CRRT.
Some of the data were presented at the World Conference of Magic Bullets, held in Nuremberg, Germany
in September 2004 in celebration of the 150th anniversary of Paul Ehrlichs birth (abstract book Nr. 241, A-61;
http://www.ehrlich2004.org).

nius Medical Care, Bad Homburg, Germany). Continuous

haemodiafiltration (CVVHD) was performed using a highflux polysulfone capillary haemofilter with a membrane
surface area of 1.4 m2 (Ultraflux AV600S; Fresenius
Medical Care). NaBic substitution fluid was reinfused. The
standard blood flow rate in the dialyser was 150 ml/min.
The ultrafiltrate pump rate was adjusted to 25 ml/kg
BW/h.

Study design
This prospective study was conducted in a randomised,
cross-over design. The patients received meropenem
either as 0.5 g i.v. loading dose followed by 2 g CI per 24 h
divided in two 1 g fractions or as a 1 g IB over 1520 min
administered every 12 h. IB or CI was continued for 2
days, then patients were crossed over to the other treatment for another 2 days. At days 2 and 4 of the study
pharmacokinetic analyses were performed. Thereafter,
therapy was continued by standard intermittent dosing.
The study protocol was approved by the ethics committee of the University of Regensburg.

Material and methods

Patients

Drug administration and sampling

Patients who were admitted to the medical intensive care

unit of the University Hospital of Regensburg, Germany,
were eligible for enrolment into the study if they met
the following criteria: (1) suspected infection warranting
antibiotic therapy; (2) suspected pathogen presumably
susceptible to meropenem, according to standard criteria
for empirical antimicrobial therapy for critically ill patients; (3) age at least 18 years; (4) i.v. antibiotic treatment
of the infection expected to be necessary for more than 4
days; (5) renal failure with indication for CRRT.
Patients were excluded if they had documented
or presumed hypersensitivity to meropenem or penicillins. Switch to an alternative regimen at any time
was left to the discretion of the attending physician in
charge, if microbiological results or other information
indicated that therapy with meropenem was no longer
adequate.
The patients demographic data of the patients were
recorded. Daily data collection included peak body temperature, leucocyte count, serum urea nitrogen, and creatinine.

All patients received meropenem (Meronem ; Astra

Zeneca, Germany), which was reconstituted according to
the manufacturers instructions. The solutions were given
via an infusion pump.
Blood samples (34 ml) were obtained immediately
prior to the start of dosing on days 2 and 4 (time 0), and at
20 min (the end of short infusion) and 1, 2, 3, 4, 6, 8, 10
and 12 h thereafter. All blood samples were drawn from
indwelling arterial catheters. The blood was centrifuged
(2.500 g for 10 min), and serum separated immediately.
Similarly, aliquots of dialysate collected from timed
fractionated collection bags were taken. All samples were
kept at 80 C until assayed.

Analytical methods

Meropenem was determined by means of an adapted

high-performance liquid chromatographic (HPLC)
method [8]. Meropenem eluted after 5.45.8 min (flow
rate of 1.0 ml/min). The lower limit of detection was
300 pg meropenem injected.
To prove the stability of meropenem in the infusion
Renal replacement therapy
solution, 1 g meropenem was dissolved in 100 ml saline,
and an aliquot of 3 ml was incubated at 25.0 C up to 24 h
Vascular access was obtained by insertion of a double- in the autosampler of the HPLC apparatus. Aliquots were
lumen dialysis catheter. Each patient was dialysed, injected automatically onto the column at intervals of
using a Fresenius Multifiltrate dialysis monitor (Frese- 0.51 h and assayed for meropenem.

Pharmacokinetic analysis

Table 1 Demographic data of patients

Pharmacokinetic parameters were determined by noncompartmental analysis. The area under the curve during
one dosing interval (AUCt ) was estimated by the lineartrapezoidal rule. The total clearance (CL) was then derived
as CL = D/AUCt (l/h) where D is the administered dose
of 1.0 g. The apparent terminal elimination rate constant
(z ) was determined by log-linear least squares regression
analysis of the serum concentrations from 2 h post dose
until the end of the dosing interval. The elimination halflife (t1/2 ) and the terminal volume of distribution (Vz ) were
calculated as t1/2 = ln(2)/z (h) and Vz = CL/z (l). The
sieving coefficient Sc was calculated as Sc = CUF /CS , with
CUF being the concentration of meropenem in ultrafiltrate
(CUF ) and Cs the concomitant serum concentration. The
percentage of time with a meropenem concentration above
a MIC (%(T)>MIC) of 4 mg/l and 8 mg/l, respectively,
was extrapolated from serological measurements.

Patient Age
Sex Size Weight
(years)
(cm) (kg)

Main diagnosis

Outcome

50

175

70

Survived

2
3

51
65

F
M

160
180

55
95

4
5
6

56
42
58

M
M
M

170
175
180

90
60
86

Pneumonia and
sepsis
Acute pancreatitis
Pneumonia and
sepsis
Sepsis
Sepsis
Pneumonia

Survived
Survived
Died
Died
Survived

study drug was observed in any patient during the study

period.
Stability of meropenem solution
Seven per cent loss of concentration of meropenem infusion solution (10 mg/ml) at room temperature (25 C) was
observed after 12 h and 10% loss after 17 h.

Statistical analysis
Pharmacokinetic parameters

Values are reported as median and interquartile range.

Results
Patient demographics
11 patients were enrolled into the study. Five of these were
withdrawn for different reasons: one patient died during
the study, in one patient antibiotic therapy was changed,
and in three patients CVVHD was interrupted due to
rapidly improving renal function. Two of the six evaluated
patients (five males, one female) died in the further course
of ICU treatment (Table 1). No adverse event related to the

After 45 h median drug concentrations were higher in the

CI than in the IB regimen (Fig. 1). The median peak concentration of meropenem was 62.8 mg/l at the end of IB
and decreased to 8.2 mg/l at the end of the 12-h dosing interval with a median serum half-life of 5.3 h (Table 2). The
median volume of distribution was 32 l (range 2550 l).
During CI the lowest serum concentration measured at any
time in any patient was 6.5 mg/l and the highest concentration 56.8 mg/l. The %(T)>MIC at 4 mg/l and 8 mg/l was
higher for CI than for IB. The median serum concentration
in the patients over the dosing interval was 19.1 mg/l. Median total clearance was 4.3 l/h (IB) vs 4.4 l/h (CI), and the
sieving coefficient was 0.97 (IB) vs 0.89 (CI).

Table 2 Pharmacokinetic parameters of meropenem in six patients during CVVHD following bolus infusion or continuous infusion of 1.0 g
meropenem q12 h
Patient

1
2
3
4
5
6
Median
25%
75%

Bolus infusion
Cmax
Cmin
mg/l
mg/l

%(T)
%(T)
t1/2
>8 mg/l >4 mg/l h

CL
l/h

Vz
L

Sc

Continuous infusion
Cmax
Cmin
Cmedian %(T)
%(T)
CL
mg/l
mg/l
mg/l
>8 mg/l >4 mg/l l/h

Sc

90.6
92.3
49.4
41.9
57.4
68.3
62.8
51.4
85.0

54.7
49.2
32.1
64.6
42.5
25.0
45.9
34.7
53.3

2.60
3.91
6.68
3.99
4.66
5.05
4.32
3.93
4.96

28.1
31.0
50.1
43.0
33.7
25.0
32.3
28.9
40.7

0.41
1.02
0.92
0.86
1.08
1.06
0.97
0.87
1.05

18.8
26.5
10.2
56.8
20.0
20.0
20.0
19.1
24.8

0.77
1.01
0.72
0.91
0.93
0.87
0.89
0.79
0.93

18.7
8.1
4.5
10.8
8.2
4.0
8.2
5.4
10.1

75.6
72.1
53.8
95.8
63.8
47.5
67.9
56.3
74.7

7.5
5.5
5.2
7.5
5.0
3.4
5.3
5.1
7.0

12.0
22.8
6.5
17.0
14.4
19.0
15.7
12.6
18.5

13.3
25.4
9.8
22.7
18.7
19.6
19.1
14.6
23.6

1.0
1.0
0.83
1.0
1.0
1.0
1.0
1.0
1.0

1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0

5.93
3.34
9.20
2.99
4.53
4.27
4.40
3.58
5.58

Cmax , peak concentration; Cmin , trough concentration; individual Cmedian , median concentration during continuous infusion; %(T), percentage of time with meropenem concentration above MIC; t1/2 , terminal half-life; CL, total clearance from serum; V z , volume of distribution;
Sc, sieving coefficient

Fig. 1 Steady-state serum

concentrations of meropenem in
six patients during CVVHD
following 1 g meropenem b.i.d.
as bolus infusion (a) or as
continuous infusion (b)

Discussion
Meropenem is a carbapenem with a broad spectrum of activity against Gram-positive and Gram-negative bacteria.
It is often used for the treatment of nosocomial infections
and sepsis in critical care units. As -lactam antibiotics exhibit time-dependent bacterial killing, time above MIC is
the parameter that correlates best with clinical efficacy [6].
Therefore, CI appears to be a particularly attractive option
for parenterally administered -lactam antibiotics such as
meropenem.
Meropenem is primarily eliminated renally, so dosage
adjustment is necessary in patients with impaired renal
function. In patients with renal failure and CRRT, correct
dosing of antibiotics is very difficult. Several factors that
are dependent on the particular modality of CRRT have to
be considered. In these patients, underdosing causing ineffective antimicrobial therapy is a more frequent problem
than the risk of toxicity due to overdosed antibiotics. From
pharmacokinetic considerations, patients with CRRT in
particular would benefit from CI of -lactam antibiotics.
A prerequisite for CI is sufficient stability of the drugs
in solution at room temperature. In good agreement with
previous studies [912] we demonstrated that meropenem
is sufficiently stable in the infusion solution at 25 C
for 12 h with a loss of concentration of 7%. Therefore,
the 2 g i.v. CI in 24 h was divided into two 1-g fractions.
The only study reporting different findings on the stability
of antipseudomonal -lactams was published by Viaene
et al. [13]. We could not confirm that meropenem is
too unstable to be recommended for CI dosing in an
air-conditioned ICU setting. For tropical countries without
air conditioning Jaruratanasirikul et al. showed a loss
of concentration of meropenem at room temperature
(3237 C) of 12% after 8 h [9].
In general, few data are available on meropenem and
CRRT. Most of the published studies evaluated pharmacokinetic parameters of meropenem in patients with acute
renal failure on continuous veno-venous haemofiltration
(CVVHF) or continuous veno-venous haemodiafiltration (CVVHD) [1424]. The peak concentrations of

meropenem differ significantly among these studies. Also,

the half-life during CVVHF ranges from 2.46 h in the
study by Thalhammer et al. [19] to 7.5 h in the study by
Valtonen et al. [15]. The reason may be the different ultrafiltration flow rates used in these two studies. Accordingly,
recommendations for dosage adjustments for meropenem
for patients with CRRT range between 0.5 g twice daily
and 1 g every 8 h. No studies have been published on the
pharmacokinetic parameters of meropenem in patients on
CVVHD.
The main objectives of this study were to investigate
the pharmacokinetics of CI compared to IB administration of meropenem in ICU patients on CVVHD, and to
determine the applicability of CI in this special condition.
In order to shorten the time necessary to reach effective
antibacterial serum concentrations and to improve treatment success, we chose a loading dose of 0.5 g meropenem
before initiation of CI. During the whole period of CI,
antibiotic serum concentrations were high enough to provide sufficient antibacterial activity at a MIC of 4 mg/l and
even 8 mg/l of meropenem. In IB, there was a drop below the MIC in most patients. The %(T)>MIC is higher at
CI than at IB. Hence, theoretically, CI should be a more
suitable application mode for meropenem than IB. Median half-life, volume of distribution and total clearance of
meropenem at CI in our patients were in good agreement
with published data [15, 1824].
Pseudomonas aeruginosa is a common, difficult to
treat bacterium that often causes infections in critically ill
patients. To cover intermediately resistant P. aeruginosa
stains with a MIC of 8 mg/l, a mean meropenem concentration of at least 12 mg/l is desired. Our pharmacokinetic
parameters during IB dosing show a median Cmax of
63 mg/l and a Cmin of 8.2 mg/l at the end of the dosing
interval. Accordingly, 1.0 g meropenem every 12 h for
patients during CVVHD can be recommended if the
same CVVHD parameters are used. However, our data
cannot easily be transferred to other CVVHD settings
or even other modes of renal replacement therapy. In
addition, more data on the influence of patient-dependent
parameters (e.g. weight, ethnic background) are desir-

able. Therefore, further investigations are necessary to

evaluate the clinical efficacy of both dosing regimens.
Until then therapeutic drug monitoring may be useful
in this subset of patients to obtain optimal meropenem
concentrations.

bacterial therapy in ICU patients similar to IB, with serum

concentrations well above the MIC for most pathogens. In
CI, a loading dose of 0.5 g of meropenem is recommended
to obtain bactericidal drug concentrations as quickly as
possible. Prospective studies are warranted to compare
the clinical efficacy of CI and IB regimens in patients on
CVVHD.

Conclusions
Thanks to Carl Waldman for his stimulating
CI of meropenem can achieve serum concentrations Acknowledgements.
comments on our work.
sufficient for the treatment of various bacterial infections.
This work was supported by a grant from AstraZeneca for pharOur data suggest that CI allows a safe and effective anti- macokinetic analysis.

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