Short versus Long Infusion of Meropenem in Very-Low-Birth-Weight
Neonates
Helgi Padari,a Tuuli Metsvaht,a Lenne-Triin Kõrgvee,a Eva Germovsek,b Mari-Liis Ilmoja,c Karin Kipper,d Koit Herodes,d
Joseph F. Standing,b Kersti Oselin,a and Irja Lutsare
Tartu University Hospital, Tartu, Estoniaa; Centre for Paediatric Pharmacy Research, London School of Pharmacy, London, United Kingdomb; Tallinn Children’s Hospital,
Tallinn, Estoniac; Institute of Chemistry University of Tartu, Tartu, Estoniad; and Institute of Microbiology, University of Tartu, Tartu, Estoniae
Prolonged infusion of meropenem has been suggested in studies with population pharmacokinetic modeling but has not been
tested in neonates. We compared the steady-state pharmacokinetics (PK) of meropenem given as a short (30-min) or prolonged
(4-h) infusion to very-low-birth-weight (gestational age, <32 weeks; birth weight, <1,200 g) neonates to define the appropriate
dosing regimen for a phase 3 efficacy study. Short (n ⴝ 9) or prolonged (n ⴝ 10) infusions of meropenem were given at a dose of
20 mg/kg every 12 h. Immediately before and 0.5, 1.5, 4, 8, and 12 h after the 4th to 7th doses of meropenem, blood samples were
collected. Meropenem concentrations were measured by ultrahigh-performance liquid chromatography. PK analysis was performed with WinNonlin software, and modeling was performed with NONMEM software. A short infusion resulted in a higher
mean drug concentration in serum (Cmax) than a prolonged infusion (89 versus 54 mg/liter). In all but two patients in the prolonged-infusion group, the free serum drug concentration was above the MIC (2 mg/liter) 100% of the time. Meropenem clearance (CL) was not influenced by postnatal or postmenstrual age. In population PK analysis, a one-compartment model provided
the best fit and the steady-state distribution volume (Vss) was scaled with body weight and CL with a published renal maturation
function. The covariates serum creatinine and postnatal and gestational ages did not improve the model fit. The final parameter
estimates were a Vss of 0.301 liter/kg and a CL of 0.061 liter/h/kg. Meropenem infusions of 30 min are acceptable as they balance a
reasonably high Cmax with convenience of dosing. In very-low-birth-weight neonates, no dosing adjustment is needed over the
first month of life.
atients in the neonatal intensive care unit (NICU), especially
premature newborns with immature organ systems, frequently suffer nosocomial infections caused by microorganisms
resistant to narrow-spectrum antibiotics like ampicillin and gentamicin and thus require the introduction of agents with a wider
spectrum of activity (7, 14, 29). Meropenem is active against a
wide variety of Gram-negative and Gram-positive microorganisms and offers good penetration of body fluids and tissues (1, 9).
It has been shown to be well tolerated by children and neonates
(6), including preterm babies (10, 18), with the advantage of allowing monotherapy instead of combined therapy (37).
The pharmacokinetic (PK) characteristics of meropenem for
children ⬍3 months old have been described in four studies (6, 28,
35, 36) indicating that for babies with a gestational age (GA) of
⬍32 weeks, 20 mg/kg every 12 h during the first 14 days of life and
every 8 h thereafter ensures an adequate serum drug concentration profile.
Meropenem is given mostly via a 30-min infusion, as some
data indicate rapid degradation after reconstitution (4, 24). Dose
recommendations from two pediatric studies using Monte Carlo
simulation have emphasized that a 4-h infusion may be needed for
microorganisms with increased MICs, more specifically, for Pseudomonas aeruginosa (6, 35). A prolonged-infusion strategy, however, has not been tested in neonates, although some data suggest
that, apart from patient-associated variability, extremely small infusion volumes may significantly affect the drug amount actually
delivered (27).
We aimed to compare the steady-state PK and safety of
meropenem given via short or prolonged infusion to neonates
with a GA of ⬍32 weeks to define the most appropriate dosing
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regimen for a phase 3 efficacy study of neonatal late-onset sepsis (LOS) (20).
MATERIALS AND METHODS
Study design. A prospective open-label study was carried out from 7 April
2010 to 1 February 2011 in the NICUs of Tartu University Hospital, Tartu,
Estonia, and Tallinn Children’s Hospital, Tallinn, Estonia. Neonates requiring meropenem treatment for sepsis, pneumonia, or necrotizing enterocolitis due to a pathogen with proven or highly suspected resistance or
for clinical deterioration on empirical antibiotics were eligible for this
study if they had (i) a GA of ⱕ32 weeks and a birth weight (BW) of ⬍1,500
g, (ii) a postnatal age (PNA) of ⱕ56 days, (iii) written consent signed by a
parent or guardian, and (iv) an arterial or central venous cannula settled
on clinical indications. Infants with major uncorrected congenital malformations or expected to die within 24 h were excluded.
Study drug administration. Meropenem (AstraZeneca Limited,
Macclesfield, United Kingdom) was reconstituted in normal saline to a
final concentration of 10 mg/ml immediately prior to administration.
Each dose of 20 mg/kg was given intravenously every 12 h to the first 9
neonates over 30 min (short infusion, group 1) and to the next 10 neonates as a 4-h infusion (prolonged infusion, group 2). In the latter group,
the first dose was given over 30 min and after informed consent (IC) was
obtained, at least two prolonged infusions were administered prior to the
Received 28 March 2012 Returned for modification 6 May 2012
Accepted 17 June 2012
Published ahead of print 25 June 2012
Address correspondence to Helgi Padari, helgi.padari@kliinikum.ee.
Copyright © 2012, American Society for Microbiology. All Rights Reserved.
doi:10.1128/AAC.00655-12
p. 4760 – 4764
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P
Meropenem Pharmacokinetics in Neonates
September 2012 Volume 56 Number 9
TABLE 1 Demographic data of the study patients in the short- and
prolonged-infusion groupsa
Parameter
BW (g)
Current body wt (g)
GA (wk)
PNA at PK sampling (days)
Male sex (no. of subjects)
First-min Apgar score
AVLb/CPAPc (no. of subjects)
Vasoactive support (no. of
subjects)
Serum creatinine at
enrollment (mol/liter)
Urine creatinine during PK
sampling (mol/liter)
Positive blood culture (no. of
subjects)
Duration of meropenem
therapy (days)
Concomitant vancomycin,
ibuprofen (no. of subjects)
Group 1
(n ⫽ 9)
Group 2
(n ⫽ 10)
P
value
895.6 (239.4)
984.6 (291.6)
26.9 (1.4)
15.6 (8.6)
6
2.9 (2.2)
5/3
5
842.4(102.2)
969.5 (102.9)
25.8 (25.8)
20.5 (6.6)
6
5.2 (1.9)
8/2
3
0.624
0.967
0.112
0.191
51.4 (21.2)
44.8 (24.0)
0.278
816.7 (338.8)
670.8 (272.5)
0.258
4
7
11 (1.9)
9.2 (3.5)
4
3
0.041
0.067
a
Groups: 1, short infusion; 2, long infusion. Data are presented as means (SD) if not
stated otherwise.
b
AVL, artificial ventilation of lungs.
c
CPAP, continuous positive airway pressure.
Pharsight Corporation) by applying a noncompartmental model that assumed the use of a 30-min or 4-h intravenous infusion, as appropriate.
Creatinine clearance (CLCR) was calculated directly from the urine and
serum creatinine concentrations at 12 h postdose.
A population PK model was developed by using the serum drug concentration data. One- and two-compartment models were considered, and volume parameters were scaled with linear body weight. An investigation to
derive a maturation and weight function from the data as recommended by
Tod et al. (34) was performed, compared with scaling of clearance with the
size and maturation function proposed by Rhodin et al. (25). The influence of
serum creatinine on clearance scaled by expected serum creatinine as described by Ceriotti et al. (8) was also investigated. Nonlinear mixed-effect
modeling was performed in NONMEM version 7.1 (3).
The protocol was approved by the Ethics Committee of the University
of Tartu. This study was registered at the EU Clinical Trials Register under
number 2009-017823-24.
RESULTS
Study population and clinical observations. Altogether, 21 families were approached and IC was obtained from the parents of 20
patients. One infant was withdrawn for lack of an arterial or central venous cannula, leaving 19 patients to constitute the study
population. As presented in Table 1, the baseline demographics
and concomitant use of potentially nephrotoxic drugs were similar in both groups, except for a lower median first-minute Apgar
score in group 2 than in group 1. Meropenem was given to 16
patients for sepsis and to 3 patients for pneumonia with no differences in the distribution of diagnoses between groups. Eleven patients (58%) had altogether 13 positive blood cultures (coagulasenegative staphylococci, n ⫽ 5; Enterobacteriaceae, n ⫽ 4;
Enterococcus faecalis, n ⫽ 2; Staphylococcus aureus, n ⫽ 1; Pseudomonas aeruginosa, n ⫽ 1). Most of the patients were severely ill,
with 95% requiring respiratory support and 42% requiring vasoactive treatment (Table 1). One neonate in each group died, each
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study dose to ensure a steady state. After PK sampling, meropenem administration was changed back to a 30-min infusion.
Sampling and sample handling. Immediately before and 0.5, 1.5, 4, 8,
and 12 h after the 4th to 7th doses of meropenem (study dose), 200 to 300
l of blood was drawn from an arterial cannula into dry vials. Blood was
centrifuged immediately, and serum was stored at ⫺20°C for a maximum
of 24 h and then transferred to ⫺70°C until analyzed within 7 months.
Five infusion lines collected at the end of the 4-h infusion were stored for
meropenem concentration measurement as described for other samples.
Urine samples were collected at 4-h intervals within 12 h after administration of the meropenem study dose. The quantity of urine collected
was measured, and possible losses were estimated by weighing the diapers.
The samples were stored as described above for serum samples.
Meropenem assay. Samples were melted at room temperature, and
50-l serum were transferred into 250-l PCR tubes. For serum sample
extraction, 50 l of methanol (containing ertapenem at a concentration of
10 g/ml as an internal standard [IS]) was added. After vigorous shaking
with a Vortex mixer for 1 min, the sample was centrifuged at 8,000 rpm
(3,500 ⫻ g) for 10 min and the supernatant (approximately 75 l) was
separated, filtered through 0.22-m Millex-GV polyvinylidene difluoride
filters, and transferred into a high-performance liquid chromatography
autosampler vial.
Urine samples were melted at room temperature and diluted with
ultrapure water (1/9 or more). A 3-l volume of the prepared sample was
injected into the Agilent 1290 Infinity UHPLC system. Gradient elution
with methanol and 0.1% formic acid (pH 2.6) at a flow rate of 0.3 ml/min
was used for chromatographic separation. Samples were chromatographed using a Waters Acquity UPLC ethylene bridged hybrid (BEH)
C18 column (2.1 by 100 mm, 1.7 m) equipped with a Waters VanGuard
Acquity UPLC BEH C18 guard column (2.1 by 5 mm, 1.7 m). Samples
were analyzed with a diode array detector at 306 nm, and an electrospray
interface Varian 320-MS triple-quadrupole liquid chromatography-mass
spectrometry apparatus was used to analyze samples in the single-reaction
monitoring mode. Transitions of the parent ion with m/z 384 [M ⫹ 1] to
daughter ions with m/z 254, 298, and 340 were used for meropenem quantification and qualification.
The calibration curves were linear from 0.1 to 200 g/ml in serum and
from 1 to 250 g/ml in urine. The limit of detection (LOD) and limit of
quantification (LOQ as 10 times the standard deviation) were estimated
from five replicate analyses of spiked blank serum samples. The LOQ for
serum samples was 0.1 g/ml, and the LOD was 0.01 g/ml. The LOQ for
urine samples, as the lowest concentration of calibration samples, was 1
g/ml with accuracy and precision of 100% ⫾ 3% and a coefficient of
variation (CV) of ⬍2%.
Method within-day accuracy ranged from 100% ⫾ 2% to 100% ⫾ 8%
for the serum calibration curve and from 100% ⫾ 4% to 100% ⫾ 6% (as
relative standard deviation) for the urine calibration curve. The betweenday precision was ⬍5% for serum samples and ⬍4% for urine samples.
Sample preparation recovery was 84% ⫾ 7% (CV, 8%) over the calibration curve in duplicate, which is the same as previously described (17).
Patient monitoring. All infants were monitored for adverse events.
Laboratory and vital parameters and positive microbiological cultures
were monitored for at least 7 days after the end of meropenem treatment.
Serum creatinine was measured by a Jaffe kinetic method. Electroencephalography (EEG) of all but four patients was performed at least once
during meropenem therapy. Doppler echocardiography was performed
when clinically indicated. Concomitant medications were recorded from
7 days before to 12 h after study dose infusion.
Statistical and PK analyses. Statistical analysis was performed with
the R version 2.12.0 software. The means of the groups were compared by
Mann-Whitney test. Spearman rank correlation was used to test the relationships between variables. In calculations of the fraction of time in the
dose interval when the plasma drug level exceeds the MIC (fT⬎MIC), the
EUCAST susceptibility breakpoint (ⱕ2 mg/liter) was used (13).
PK analysis was performed with WinNonlin software (version 6.1;
Padari et al.
Parameterb
Group 1
Group 2
P
value
Actual meropenem
dose (mg/kg)
t1/2 (h)
Cmax (mg/liter)
Tmax (h)
Cmin (mg/liter)
CLssM (ml/h/kg)
Vss (ml/kg)
AUClastc (h · g/ml)
fT⬎MIC (%)d (95% CI)
18.9 (5)
18.3 (2.4)
0,650
3.4 (0.9)
89.3 (32.7)
0.7 (0.4)
6.5 (3.7)
52.4 (15.5)
270.6 (83.3)
369.2 (66.1)
100 (100–100)
3.3 (1.7)
54.5 (19.0)
4.0 (1.9)
7.2 (6.1)
62.7 (31.6)
342.9 (174.3)
338.6 (121.6)
99.9 (99.6–100)
0.436
0.005
0.002
0.780
0.842
0.447
0.497
0.193
a
Groups: 1, short infusion; 2, prolonged infusion. Data are presented as means (SD) if
not stated otherwise.
b
t½, half-life.
c
AUClast, area under the concentration-time curve from time zero to the last point of
the curve.
d
Calculated for the EUCAST MIC susceptibility breakpoint of 2 mg/liter for P.
aeruginosa and Enterobacteriaceae.
more than 7 days after the completion of meropenem therapy, for
reasons not related to the study drug. No side effects, EEG
changes, or drug-related laboratory abnormalities were registered.
The mean meropenem concentration in the infusion lines at the
end of the 4-h infusion was 11.68 ⫾ 0.5 mg/ml.
Noncompartmental PK analysis. Except for a higher Cmax in
the short-infusion group and a higher time to drug Cmax in serum
(Tmax) in the prolonged-infusion group, all of the PK parameters of
the two groups were similar (Table 2). Large interpatient variability
was seen, especially in Cmax. The mean concentration-time curves by
study group are presented in Fig. 1. All of the PK parameters of subjects with a PNA of ⬍15 days (n ⫽ 6) and a PNA of ⱖ15 days (n ⫽ 13)
were similar in both groups (data not shown). All of the patients in
the short-infusion group and 8/10 in the long-infusion group
achieved an fT⬎MIC of 100% for an MIC of 2 mg/liter. The fT ⬎6.2⫻
MIC (value required to prevent resistance development in P. aeruginosa [32]) was 80.2% (95% CI, 70.8 to 89.6) in the short-infusion
group and 81.9% (95% CI, 69.6 to 94.4) in the prolonged-infusion
group. No significant correlation between meropenem clearance
(CLssM) and postmenstrual age or PNA was observed.
The mean (standard deviation [SD]) CLCR values in the 30-min
and 4-h infusion groups were 18.7 (7.8) and 21.4 (9.2) ml/min/1.73
m2, respectively. The mean (SD) renal recovery of the meropenem
dose was 86.4 (32.8)% for the four patients in the short-infusion
group and 57.8% (19.3) for the five patients in the prolonged-infusion group, 100% of whose excreted urine was collected.
Population modeling. There was no significant difference in the
NONMEM objective function value between one- and two-compartment models, so a one-compartment model was used. Maturation function parameters could not be estimated, and thus, the fixed
Rhodin model (25) was used, and serum creatinine corrected for
PNA did not significantly improve the fit. Goodness-of-fit plots and a
visual predictive check of the final model are shown in Fig. 2 and 3.
DISCUSSION
To the best of our knowledge, this is the first study comparing the
steady-state PK of meropenem given via short or prolonged infusion to seriously ill premature neonates. Despite some differences,
in general, the PK parameters were similar; no difference in the
FIG 1 Meropenem concentration-time curves of groups 1 (A) and 2 (B). Each line represents an individual patient. Dots indicate PK sampling times.
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TABLE 2 Results of noncompartmental analysis of PK parameters in
the short- and prolonged-infusion groupsa
Meropenem Pharmacokinetics in Neonates
FIG 2 Basic goodness-of-fit plots from the final population model. VD, dependent variable; PRED, population prediction; IPRED, individual prediction; CWRES, conditional weighted residuals.
FIG 3 Prediction-corrected visual predictive check of the final population
September 2012 Volume 56 Number 9
model. The solid line shows the median prediction-corrected (Pred Corr) data,
and the gray-shaded area represents the 95% simulated prediction interval
from 1,000 simulations. The broken line represents the median of the original
data.
30 min to 6 h revealed only a minor decrease in the number of the
few outliers not achieving an fT⬎MIC of at least 80%, with the vast
majority having an fT⬎MIC between 95 and 100% (30).
Recently the Cmin/MIC ratio has been suggested to play a role
in resistance suppression (32). However, by how much the drug
concentration should exceed the MIC (Cmin/MIC) has not been
studied in neonates. Tam et al. have demonstrated in vitro that to
avoid non-plasmid-mediated resistance in P. aeruginosa, a Cmin/
MIC ratio of at least 6.2 is needed (32). Unfortunately, even for in
vitro conditions, these relationships are not straightforward, with
inoculum size (i.e., the likelihood of the presence of resistant
strains in a population) and resistance mechanisms but also the
duration of the experiment likely affecting conclusions (12, 32)
and making the uniform achievement of these values under clinical circumstances questionable.
The concentration at which a maximal bactericidal effect is
achieved is an important determinant of efficacy (21, 31). Prolonged infusion results in a much lower Cmax and longer Tmax than
administration over 30 min, potentially compromising the attainment of the 4⫻ MIC necessary for the optimum killing properties
of beta-lactams in the critically ill (21, 31). Potential drawbacks are
associated with the degradation of meropenem after reconstitution (2), probably dependent on the formulation used. A recent
study indicated that at a concentration of 4% at room temperature
(ⱕ25°C), the degradation will be ⬍10% over 12 h (4). The same
was observed by us in a limited number of infusion lines at the end
of infusion.
Some limitations of this study should be noted. First, full covariate analysis was not possible because of the relatively small
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fT⬎MIC or in the minimum drug concentration in serum (Cmin)
was found with different infusion durations. Furthermore, the PK
parameters of meropenem among those studied with a PNA of less
than or more than 2 weeks were similar and no correlation between PNA and meropenem CLssM over the first month of life was
seen. Thus, in contrast to the findings of Bradley et al. (6), our
findings do not support the routine change of dosing frequency at
the age of 2 weeks in severely ill neonates with a GA of ⱕ32 weeks.
Still, given the small number of patients and the narrow range of
GAs in our study, this approach should not be extended to more
mature infants.
Our finding that prolongation of meropenem infusion does
not necessarily result in an advantageous PK/pharmacodynamic
(PD) profile when antibiotic-sensitive strains are encountered, is
consistent with the results reported previously for neonates (6,
35). The lower clearance of meropenem by preterm neonates than
by adults and even term neonates results in a 2 to 3 times longer
half-life, and accordingly, even after a short infusion of 20 mg/kg,
a greater fT⬎MIC and Cmin will be achieved (5, 11, 15, 28, 33).
Furthermore, in all age groups, the short and long infusions of
meropenem have not been different in terms of effect against Escherichia coli and Klebsiella spp., organisms that cause a significant
proportion of the Gram-negative infections in neonates (16). For
intermediate or resistant microorganisms (with meropenem
MICs of ⬎2 mg/liter) like Acinetobacter spp. and Pseudomonas
aeruginosa, previous PK/PD simulation studies involving neonates (35) and pediatric patients (23) have suggested better PK/PD
target attainment with 4-h infusions. Of note, both of the abovementioned microorganisms are still very rare in the neonatal setting (22). However, treatment options for infections with these
organisms are limited and carbapenems might be the only option.
Based on our results at a MIC cutoff of 8 mg/liter with a short
infusion, no neonate is expected to have an fT⬎MIC of ⬍40%, with
typical values of ⬎95%. Modeling of various infusion times from
number of patients with a narrow GA range, allowing conclusions
to be drawn for this specific patient group only (26). Second,
meropenem PK may further be affected by unpredictable covariates like the severity of disease and therapeutic interventions (vasoactive treatment, volume replacement, etc.) (19). Still, we believe that these limitations have not prevented us from coming to
appropriate conclusions.
Conclusions. In VLBW neonates, meropenem infusions of 30
min are optimal, as they balance a reasonably high Cmax and
fT⬎MIC for susceptible organisms with convenience of dosing with
no dosing adjustment over the first month of life. On the basis of
the results reported here, we have recommended that a dose of 20
mg/kg given as a 30-min infusion be used in a larger study of
efficacy in patients with LOS (20).
ACKNOWLEDGMENTS
We thank all of the patients and their parents for their kind cooperation;
our study nurses, Irina Bljudz, Marianna Mihhailova, Birgit Kiilaspää, and
Pille Org, for their diligent work; and Merck & Co., Inc., for providing
ertapenem for use as an analytical method IS.
This study was funded by the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 242146. J.
Standing is supported by Methodology Fellowship G1002305 from the
UK Medical Research Council. I. Lutsar and T. Metsvaht are partly supported by grants from the Estonian Science Foundation (8799) and Estonian Target Financing (SF0180004s12) and from the European Union
through the European Regional Development Fund and the Archimedes
Foundation.
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