Clin. Pharmacoklnet.

28 (4) 275-286, 1995

DRUG DISPOSITION 0312-5963/95/0004-0275/S06.oo/0

© Adls International Limited . All rights reserved.

Meropenem Clinical Pharmacokinetics

Johan W Mouton 1 and John N. van den Anker2
1 Department of Clinical Microbiology, Erasmus University and University Hospital
Rotterdam/ Sophia Children's Hospital, Rotterdam, The Netherlands
2 Department of Paediatrics, Erasmus University and University Hospital Rotterdam/ Sophia
Children's Hospital, Rotterdam, The Netherlands

Contents
Summary . .. . . . .. . .. . . 275
1. Chemistry and Pharmacology 276
2. Analytical Methods .. . . . . 276
3. Pharmacokinetic Properties . 277
3.1 Plasma Pharmacokinetics 277
3.2 Tissue Penetration . . . . . 278
3.3 Metabolism and Excretion . 278
3.4 Pharmacokinetic Profile of Meropenem Compared with that of Imipenem 279
4. Pharmacokinetics in Patients with Renal Dysfunction 279
5. Pharmacokinetics in Children. . . . . . . . 280
6. Pharmacokinetics in the Elderly . . . . . . . . .. . . 282
7. Pharmacokinetics in Postsurgical Patients .. .. . . 282
8. Pharmacokinetic/Pharmacodynamic Relationships 283
9. Therapeutic Use and Dosage Recommendations. 284
10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . 284

Summary Meropenem is a recently developed carbapenem antibiotic, similar to im-

ipenem, with a wide spectrum of activity against Gram-positive and Gram-
negative bacteria. In comparison with imipenem, meropenem is relatively stable
to hydrolysis by the enzyme dehydropeptidase I (DHP-I), thus precluding the
need for coadministration with an inhibitor of DHP-I, such as cilastatin. Further-
more, meropenem may be less nephrotoxic and neurotoxic than imipenem.
Plasma meropenem concentrations reach a peak (Cmax) of approximately 30
mg/L after administration of a standard dose of Ig intravenously. The elimination
half-life (VI2 ) is approximately 1 hour, and the area under the plasma concentra-
tion-time curve increases linearly in a dose-related manner.
The volume of distribution is 21L, indicating predominantly extracellular dis-
tribution. Meropenem distributes partly into cerebrospinal fluid. The drug is elim-
inated both by metabolism and excretion. In normal volunteers, up to 70% is
recovered in urine, and the remainder is accounted for by a ~-lactam ring-opened
form of the compound, ICI 213689.
The VI2 of meropenem .is prolonged in patients with renal insufficiency and
correlates well with creatinine clearance. Dosage adjustments in people with
decreased creatinine clearance can, thus, be made on the basis of creatinine
clearance.
276 Mouton & van den Anker

Meropenem is a newly developed carbapenem

antibiotic with a wide spectrum of in vitro activity
against Gram-positive and Gram-negative patho-
gens, including Pseudomonas aeruginosa and an-
aerobes. Compared with imipenem, it has the ad-
vantage of being stable to hydrolysis by the
proximal brush border enzyme dehydropeptidase I Fig. 1. Structural formula of meropenem.
(DHP-I). Thus, it can be administered without an
inhibitor of DHP-I, such as cilastatin. This review
focuses on the pharmacokinetic profile of mer- binds to PBP-2.[IO] In Staphylococcus aureus, all
openem, and the relationship between pharmaco- PBP's show a high affinity for meropenem, except
kinetic and pharmacodynamic parameters of the for PBP-3,l1l]
drug. Although stable against most ~-lactamases,
such as the Richmond and Sykes chromosomal
1. Chemistry and Pharmacology Class I ~-lactamases and the plasmid mediated
TEM and SHY ~-lactamases,[6,7] ~-lactamase me-
Meropenem (ICI 194660, SM-7338) is a new diated resistance to meropenem has been described
carbapenem agent (fig. 1). Compared with im- in P. aeruginosa.[l2] The enzyme belongs to the
ipenem, it has a methyl group at C 1, which confers class B of clavulanate-resistant metalloenzymes
the enhanced stability to human DHP-I,lI,2] The and, thus, to the same class of enzymes that has
second major difference between meropenem and been isolated from Bacteroides fragilis and Aero-
imipenem is a dimethykarbamoylpyrrolidinethio monas hydrophila, and recently from Serratia
chain attached at C2. It is probably this latter group marcescens.[l3] Although not yet widespread, in-
that accounts for increased activity against Gram- creasing use of the carbapenems could facilitate
negative bacteria.[3] The molecular weight is distribution of this enzyme and, hence, of resis-
383.46D for the anhydrous form of the drug, and tance. Alternatively, several different types of
437.51D for the trihydrate form. The latter is used ~-lactamases, including metallo- and serine ~­
in the formulated product. Meropenem is sparingly lactamases have been isolated from Stenotropho-
soluble in water, but readily soluble in 5% aqueous monas (Xanthomonas) maltophilia,l14]
sodium carbonate. The clinical formulation con- Development of resistance to imipenem by P.
tains anhydrous sodium carbonate. aeruginosa has also been described as a result of
Meropenem, like other ~-lactams, exerts its anti- decreased penetration associated with a loss of an
bacterial action by entering the bacterial cell and outer membrane protein with a molecular weight
interacting with the target proteins in the cyto- of 45 to 48kD. However, meropenem remained
plasmic membrane. Meropenem is stable against 4-fold more active than imipenem against these re-
most ~-lactamases produced by Gram-negative as sistant strains,l15]
well as by Gram-positive bacteria, resulting in a
wide spectrum of activity,l4-6] It is a relatively poor 2. Analytical Methods
inducer of type I ~-lactamases.[6,7]
It has been demonstrated that the drug pene- Both high-performance liquid chromatography
trates into enterobacteriaceae and P. aeruginosa. [8,9] (HPLC) as well as microbiological assay systems
Several binding studies have been performed, have been described. The microbiological method
showing penicillin-binding protein (PBP)-2 to be of Wise et aU16] uses Iso-Sensitest agar with E. coli
the primary target in Escherichia coli, but both NIHJ as the indicator organism. The lower limit of
PBP-2 and PBP-3 are targets in P. aeruginosa,l8,1O] detection with this assay was 0.1 mg/L. Chimata et
The latter is in contrast to imipenem, which only aU 17] described a thin-layer paper disc method, and

© Adls International Limited. All rights reserved. Clin. Pharmacokinet. 28 (4) 1995
Meropenem Pharmacokinetics 277

used E. coli NIH} grown in nutrient agar as their has also been determined by HPLC.[21] The lower
test organism. The lower limit of this assay was limit of the assay procedure was 5 to 10 mg/L.
0.06 mg/L. An HPLC method has been described
by Bax et al.,[18] based on solid phase extraction 3. Pharmacokinetic Properties
and reverse phase chromatography with detection
by ultraviolet absorbance at 296nm. The lower 3.1 Plasma Pharmacokinetics
limit of the assay procedure was 0.06 mg/L. Acom-
parison of a microbiological method and an HPLC Pharmacokinetic data for meropenem after ad-
ministration of single and multiple doses in healthy
method was made by Leroy et al.[l9] They used E.
male volunteers are summarised in table I. The
coli NIH} as a test strain on nutrient agar, and ob-
elimination half-life (t l/ 2) in most studies is around
tained a good linear correlation between concen-
1 hour after either single or multiple doses, al-
trations of 0.08 and 5.0 mg/L. The HPLC method though there is some variation around this value.
was performed by ICI Pharmaceuticals and is es- In most studies a 2-compartment model was used
sentially the same as that described by Bax et aP18] to estimate pharmacokinetic parameters of me-
They found a linear correlation of r = 0.92 (n = 352) ropenem. The volume of distribution at steady-
between the 2 methods. state (Vss) is around 21L, indicating that merop-
The existence of the metabolite of meropenem, enem is primarily distributed extracellularly, as is
ICI 213689, was determined by radioimmunoas- the case for most other ~-lactam agents, including
say. [20] The sensitivity of this assay was 0.075 imipenem.l25 ,26] The area under the plasma con-
mg/L. The concentration of ICI 213689 in urine centration-time curve (AUC) is linearly related

Table I. Mean pharmacokinetic parameters of meropenem in healthy male volunteers. Values in brackets are standard deviations
Dose No. of tv, Vss AUG GL Urinary Reference
(g) volunteers (h) (L) (mg/Le h) (ml/min)a recovery
(%)
1 (8) 6 1.1 [0.2] 20.6 [5.9] 66.9 [13.7] 253 [51.5] 65.4 [8.8]b 16
10 mg/kg (M) 8 1.05 [0.19] 20.7 [2.8] 43.5 [7.1] 292 [36.8] 61.6[8.7]c 22
0.25(8) 6 1.01 [0.10] 20.7 [2.2] 14.4 [1 .2] 300 [23] 76 [3]c 18
0.5(8) 5 0.97 [0.07] 19.1 [1 .6] 30.1 [2.1] 283 [20] 83 [4]C
1.0(8) 6 0.95 [0.05] 17.8 [0.7] 66.9[4.6] 254 [16] 79 [2]C
0.5(8) 6 0.83 [0.02] 20.4 [0.7] 27.2 [2.2] 277 [10] 71 .8 [2.6]C 20
0.5(8) 6 1.24 [0.18] 26.1 [0.7] 28 [15] 328 [95]d 69.3 [10.4]b 19
0.5(8) 3 1.57 [0.14] 21.2 [6.5]e 29.9 [4.0] 256 [35] 63.0 [2 .7]' 23
0.25 (8) 6 0.98 [0.20] 22.5 [5.4]e 16.3 [4.5] 271 [66] 59.5 [8.3]b 24
0.5(8) 6 1.03[0.13] 22.0 [3.0]e 33.9 [3.4] 248 [26] 64.2 [7.0]b
1.0(8) 6 1.02 [0.12] 25.6 [3.5]e 60.0 [6.5] 291 [36] 60.1 [2.4]b
0.5(8) 6 0.82 [0.13] 20.6 [3.1]e 29.5 [9.0] 301 [76] 54.3 [4.7]C 24
0.5(M) 6 0.88 [0.19] 23.9 [3.5]e 26.7 [5.7] 323 [65] 58.0 [6.6]"
1.0(8) 6 0.90 [0.09] 20.9 [4.6]e 56.7 [3.9] 272 [68] 57.5 [3.2]C
1.0(M) 6 0.90 [0.09] 22.4 [2.1]" 58.5 [7.0] 288 [32] 63.2 [1.4]C
a To convert to Uh multiply by 0.06.
b Urinary recovery over 24 hours.
c Urinary recovery over 12 hours.
d ml/min/1.73 m2 .
e Volume of distribution during elimination phase.
Urinary recovery over 8 hours.
= = =
Abbreviations: AUG area under the plasma concentration-time curve; GL total body clearance; M multiple dose regimen administered
at least until steady-state was achieved; 8 = single dose; "'" = elimination half-life; Vss = apparent volume of distribution at steady-state.

© Adis International Limited . All rights reserved . Clin. Pharmacokinet. 28 (4) 1995
278 Mouton & van den Anker

to the dose over the dosage range studied, 0.25 to tient receiving a dose of 2g 3 times daily, Donnelly
Ig.[18,24] et aU 38] observed mean trough (C min ) and peak
(C max) concentrations in the CSF (± 95% confi-
3.2 Tissue Penetration dence interval; CI) of 0.5 (± 0.14) mg/L (n = 10
measurements) and 1.6 (± 0.96) mg/L (n = 6), re-
Data on penetration of the drug in blister fluid spectively. Although concentrations in plasma
are summarised in table II. Generally, blister fluid were not given, and these data are from a single
penetration is good, as shown in studies with can- patient only, they suggest good penetration. CSF
tharide-induced[l6] and suction blisters.[22] penetration has been studied more extensively in
Penetration in other body fluids and tissues has children (see section 5).
been studied by several groups of investigators.
However, the value of these penetration studies in 3.3 Metabolism and Excretion
different tissues can be questioned. Because the
distribution of meropenem is mostly extracellular, Elimination of meropenem occurs by both me-
total concentrations, e.g. in tissue homogenates, tabolism and excretion. In healthy volunteers, up
may be misleading, as one is never quite sure to 83% of the dose was recovered in urine (table I).
whether the measurement reflects extracellular or The remainder of the dose is accounted for by a
intracellular drug.[26,27] Also, single measurements ~-lactam ring-opened form of the compound (ICI
do not take the kinetics of tissue distribution into 213689), which is also excreted in urine. Opening
account. These data should, therefore, be viewed of the ~-lactam ring can occur spontaneously and
with some caution. Data available are summarised yields the same product that would be formed by
in table III. enzyme hydrolysis in vivo by renal DHP-1. This is
Penetration into body fluids may be more inform- in common with the metabolism of other carba-
ative, especially penetration into closed compart- penems.[39] Although this occurs at physiological
ments such as the aqueous humor, cerebrospinal pH and temperature, minimal conversion occurs at
fluid (CSF) and bile. Of particular interest is the room temperature: concentrations of meropenem
penetration of meropenem into the CSF. In 1 pa- in infusion bags did not differ significantly over 3
hours under typical hospital conditions.[22]
Table II. Penetration of meropenem into skin blister fluid in healthy Several studies have been performed to study
male volunteers. Values are means with standard deviations in the disposition of the metabolite of meropenem,
brackets
ICI 213689)2°,40] Burman et aU20] compared the
Dose No. of AUCs AUC: C max tmax
rate of metabolism of imipenem with that of me-
volunteers (mg/L' h) AUCs (mg/L) (h)
ratio ropenem (see also section 3.4) and found a corre-
(%) lation between the rate of metabolism for these 2
Cantharide blister!161 drugs. On the basis of their findings they concluded
1.0g (8) 6 73.4 111 28.3 0.75 that there is some renal metabolism of meropenem.
(16.1) (15.6) (5.0) (0.3)
This was further substantiated by the excretion of
Suction blisterl221 20% of the open-ringed metabolite into urine, even
10 mg/kg (M) 8 36.3 84.7
though the AVC of the metabolite in plasma was
(3.0) (11.4)
1.66 mg/kg • h 8 32.4 87.1 6.3
only 10% of that of parent meropenem.l20]
(C) (4.2) (8.5) (0.7)a In several studies, it was observed that the renal
a Mean serum concentration during continuous infusion in clearance of meropenem exceeded creatinine clear-
steady-state. ance considerably.[l8,22,41 ,42] This indicates, that re-
Abbreviations: AUC = area under the plasma concentration-time
curve; AUCs = area under the blister fluid concentration-time curve;
nal clearance of meropenem is by both tubular se-
C = continuous infusion; ; Cmax = peak concentration in blister fluid; cretion and glomerular filtration. Furthermore, it
M = multiple dose; 8 = single dose; tmax = time to Cm•x. suggests that probenecid may have some effect on

© Adis International limited. All rights rese rved. Clin. Pharmacokinet. 28 (4) 1995
Meropenem Pharmacokinetics 279

Table III. Penetration of meropenem in various tissues

Body fluid/tissue Dose No. of study Infusion Sampling CtorCI Cp Ct/C p or CI/C p ('Yo) Reference
(g) participants time time (min)" (mg/g or (mg/L) [range]
(gender) (min) mg/L)
Skin 0.5 3 (?) 30 0 3.97 42.6 9.6 [3.4-21 .3] 28
60 3.4 11.9 33.5 [15.6-47.3]
Bumed skin 1.0 2 (?) 30 0 5.5 64.3 8.8 [6.8-10.7]
60 9.2 14.8 61.6 [59.4-63.7]
Tonsil 0.5 6 (3F) 30 45-150 [0-5.0] 29
Tonsil 0.5 10 (8F) 30 0-60 var var 7.1 [4.4-12.6] 30
Maxillary sinus 0.5 12(M) 30 15-100 var var 13.3 [9.6-20.8]
Ethmoid 0.5 7 (4F) 30 0-98 var var 8 [1.9-14.5]
Tonsil 0.5 2 (?) NR 65-95 0.6 14.3 5.3 [2.1-8.5] 31
Middle ear mucosa 0.5 3 (?) NR 90-130 8.6 13.8 [6.4-25]
Maxillary sinus 0.5 10 (?) NR 65-160 var var var [7.6-40.4]
mucosa
Sinus secretion 0.5 7 (?) NR 65-148 var var var [12.1-57.7]
Aqueous humor 0.5 9 (6F) 30 5-35 0.52 18.6 2.9 [0.8-5.3] 32
Prostate 0.5 8(M) 30 30 2.3 13.3 15.6 [3.5-39] 33
Sputum 0.5 2(1F) 30 90 2.2 25.1 8.5 [2.0-15.0] 34
Bile 0.5 7 (?) 30 25-140 var var var [0.2-16.1] 35
Bile 0.5 13 (6F) 30 0-95 0.66-33.6
Bile without obstruction 1.0 11 (?) 15-20 74-203 14.6 14.8 140 [40-300] 36
Bile with obstruction 1.0 13 (?) 61-200 20 8.1 60 [3-320]
Bronchial secretions 1.0(S) 8 (?) 30 60 0.46 18.4 0.03 37
8 (?) 30 120 0.24 8.8 0.03
8 (?) 30 180 0.53 2.7 20.0
a Measured from the end of infusion.
= = =
Abbreviations and symbol: Cf concentrations in fluid ; C p concentrations in plasma; Ct concentrations in tissue at the indicated
= = = = = =
time; F female; M male; NR not reported; S single dose; var variable; ? gender not provided in study.

renal clearance. An effect of probenecid on the and Saito.[44] Generally, the pharmacokinetic pa-
clearance of meropenem was observed in 2 inter- rameters of the 2 agents were comparable. Al-
action studies,l18,42] indicating the existence of re- though the Vss of meropenem was slightly, and sig-
nal tubular secretion (table IV). The urinary recov- nificantly, less than that of imipenem (table V) in
ery of parent meropenem was not affected by the the study of Nilsson-Ehle et al.,[40] Saito[44] found
coadministration of probenecid. Partly because the that the volume of distribution (V d) of meropenem
non-urinary clearance of meropenem is consider- was larger than that of imipenem. The findings
able, the effect of concomitant probenecid was not so far thus offer no basis for the suggestion that
dramatic. However, the effect could be of impor- there is a difference in Vd between imipenem and
tance in patients needing high doses of meropenem meropenem.
for an extended period of time, such as patients
with cystic fibrosis .
4. Pharmacokinetics in Patients
with Renal Dysfunction
3.4 Pharmacokinetic Profile of Meropenem
Compared with that of Imipenem Since meropenem is eliminated primarily un-
changed in urine, meropenem accumulates in pa-
The pharmacokinetics of meropenem were tients with reduced renal function. In studies
compared with imipenem by Nilsson-Ehle et al.[40] undertaken in patients with impaired renal func-

© Adis International Limited. All rights reserved. C lin. Pharmacokinet. 28 (4) 1995
280 Mouton & van den Anker

Table IV. Effect of probenecid on meropenem pharmacokinetics in healthy male volunteers. Values are means with standard deviations in
brackets
Group Dose No. of tl;" Vss AUC CL CLR CLNR Reference
(g) volunteers (h) (L) (mg/L· h) (mllmin)' (mllmin)' (mllmin)'
Meropenem alone 1.0 5 0.98 [0.04] 18.5 [1.2] 61 .5 [5.5] 280 [24] 201 [12] 79[13] 18
Meropenem with 1.0 6 1.30 [0.06] 17.2 [0.4] 95.4 [5.8] 178[11] 129 [9] 49 [6]
probenecid
Meropenem alone 0.5 6b 1.18[0.12] 20.2 [3.2] 28.1 [3.6] 300 [36] 171 [23] 129 [40] 43
Meropenem with 0.5 1.33[0.14] 19.5 [1 .5] 40.2 [3.8] 209 [19] 105 [12] 104[13]
probenecid
a To convert to Uh multiply by 0.06.
b Cross-over study.
Abbreviations: AUC =area under the plasma concentration-time curve; CL =total body clearance; CLR =renal clearance; CLNR =non-renal
clearance; tl;" = elimination half-life; Vss = apparent volume of distribution at steady-state.

tion, a significant correlation was found between patients with impaired renal function. In one study,
creatinine clearance and the total and renal clear- Christensson et aU41J found a t'l2of nearly 24 hours
ance of meropenem (table VI).[17,19,41,45,46] The re- in patients with a creatinine clearance of 10 to 20
sults of these studies are summarised in figure 2. mllmin (0.6 to 1.2 Lib). The compound was readily
As illustrated, the total clearance of meropenem is dialysable. The importance of the prolonged t';2 of
linearly correlated with creatinine clearance. In pa- ICI 213689 in these patients is not known. Al-
tients undergoing regular haemodialysis, a distinc- though Christens son et aU41J found high concen-
tion is made between sessions on and off haemo- trations of ICI 213689 persisted between dialysis
dialysis. Meropenem appears to be well cleared by sessions, no untoward effects in the patients were
haemodialysis; clearance was found to be 79 observed.
mUrnin (4.74 LIb)[4IJ and 81 mllmin (4.86 Llh)JI9J
Since the clearance of meropenem in anuric pa- 5. Pharmacokinetics in Children
tients is around 20 ml/rnin (1.2 Lib), haemodialysis
contributes significantly to the total clearance of Meropenem has t';2 values in children that are
the drug, and dosage adjustments are then neces- quite similar to, or somewhat lower than, those ob-
sary (see section 9). served in adults (table VII). Furthermore, a clear
The major metabolite of meropenem, ICI dose-response was observed for Cmax . However, in
213689, also has a significantly prolonged t,/z in children less than 6 months of age the data are lim-

Table V. Mean plasma derived pharmacokinetic parameters for meropenem and imipenem in healthy male volunteers after intravenous
infusion
Drug and dose No. of tl;., Vss AUC CL Urinary Reference
volunteers (h) (L) (mg/L· h) (mllmin)' recovery
(%)
Meropenem 19 8 0.98 12.5 [1.5] 90.8 [15.2]b 188 [31] 75[9] 40
Imipenem 19 8 1.11 14.4 [1 .2] 92.5 [13.0]b 183 [25] 74[10]
Meropenem 0.5g 6 0.88 [0.08] 19.2 [3.4]C 33.6 [5.1] 252 [33] 64.5 [3.9]d 44
Imipenem 0.5g 6 0.90 [0.08] 15.9 [2.3]C 41 .7(6.3] 203 [30] 64.8 [7.6]d
a To convert to Uh multiply by 0.06.
b Dose-corrected AUC.
c Volume of distribution during elimination phase.
d Urinary recovery over 6 hours.
Abbreviations: AUC = area under the plasma concentration-time curve; CL =total body clearance; It;., = elimination half-life; Vss = apparent
volume of distribution at steady-state.

© Adis International Limited. All rights reserved. Clln. Phormacoklnet. 28 (4) 1995
Meropenem Pharmacokinetics 281

Table VI. Pharmacokinetic parameters of meropenem in patients 1.5 and 2.0 hours, respectively, while concentra-
with various degree of renal function. Values are means with
standard deviations
tions in plasma were 16.6 and 11.1 mg/L, respec-
tively.[55] In another child with purulent meningi-
No. of CLcR CL CLR t"
patients (ml/min)' (ml/min)' (ml/min)' (h) tis, CSF concentrations of meropenem reached
(gender) between 0.66 and 4.01 mg/L over a period of 8 days
Leroy et alP 91 after the administration of 40 mg/kg meropenem
6 (?) 123 (14)b 328 (0.95) 252 (74) 1.24 (0.18) every 6 hours.l471 These concentrations represent
6 (?) 17.1 (4.3)b 77(48) 29 (19) 6.28 (1.13)
1.6 to 12.2% of those reported in plasma.
4 (?) 6.1 (1.7)b 42(8) 12(5) 8.08 (1.68)
In a pharmacokinetic study by Dagan et al.[56]
6 (?) AP 22(3) AP 13.72 (6.17)
in 21 patients, CSF concentrations of meropenem
Christensson et al.l411
6 (M) 99 (22.6)b 186 (28) 142 (26) 0.93
of 0.2 mg/L were reached within 1 hour of admin-
5 (M) 37 (5.1)b 74(16) 41 (16) 2.34 istration of a single intravenous dose of 20 mg/kg,
5 (2F) 22 (6.8)b 53 (16) 23 (12) 3.82 and reached a C max value of up to 6.5 mg/L 2 to 3
2 (3F) AP 19 (2) AP 6.81 hours after a 40 mg/kg dose. The penetration ratio
Chimata et alP 71 was around 20%, but showed large interindividual
4(F) 61(6) 244 (76) 127 (92) 1.54 (0.70) variations. These could be explained by a direct
4 (IF) 34 (2) 128 (58) 46 (32) 3.36 (1.02) relation between CSF concentration and the degree
5 (3F) 12.1 (6.9) 50 (19) 15.4 (11.3) 5.00 (1.05)
of meningeal inflammation. If only patients with
a To convert to Uh multiply by 0.06.
b ml/min/l.73 m2 .
proven bacterial meningitis (other than shunt in-
Abbreviations and symbol: AP = anuric patients; CL = total body fection) were considered, the range of meropenem
clearance; CLcR = clearance of creatinine; CLR = renal clearance; concentrations in patients receiving the 40 mg/kg
F= female; M = male; t" = elimination half-life; ? = gender not given
dosage was 0.9 to 6.5 mg/L, and the investigators
in study details.
concluded that this dosage would achieve plasma
and CSF concentrations in excess of the reported
MIC against 90% of the strains (MIC 90s) for most
ited. Since meropenem is eliminated primarily in
of the pathogens[51 associated with the disease. No
urine, important changes in the pharmacokinetics
central nervous system sequelae, such as seizures,
of meropenem are to be expected due to the im-
were reported.
mature renal function of the newborn. This is con-
firmed by a preliminary report of de Groot et a]J 541
Data on tissue penetration of meropenem in 400
children is available only for penetration of c
'E
meropenem into CSF. Most investigators show i 320

penetration of meropenem into the CSF provides ~

~ 240 o
drug concentrations in excess of the minimum in-
hibitory concentrations (MICs) of pathogens com-
co
CD
U 160
E
o
CD
monly causing meningitis.[47,53,55,56] Fujii et aU 531 c
y = 2.3x + 24 .0
~ 80 r = 0.94
found concentrations of meropenem in the CSF (;;
::;;
of patients with proven bacterial meningitis to be
40 80 120 160 200
0.13 mg/L at a dose of 6 mg/kg every 6 hours and
Creallnlne clearance (mVmin)
between 0.64 and 4.22 mg/L at a dose of 29 to 44
mg/kg every 6 hours. In a child with purulent Fig. 2. Relationship between creatinine clearance and me-
meningitis, administration of meropenem 40 ropenem clearance.l 17.19.4 11The size of the circles indicates the
size of the group. The equation was obtained by linear regres-
mg/kg by a 30-minute drip infusion yielded con- sion, where each group was weighted according to the number
centrations in the CSF of 4.22 and 1.77 mg/L after of patients.

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 28 (4) 1995
282 M outon & van den Anker

Table VII. Pharmacokinetic parameters of meropenem in children . Values are means with standard deviations
Dose No. of Age range Cmax tV2 Urinary recovery Reference
(mg/kg) children (years/months) (mglL) (h) (%)
10 3 1010-11/0 28.4 (6.5) 0.70 (0.08) 51.8 (11 .2) 47
20 4 6/0-13/5 43.6 (10.1) 0.74 (0.21) 45.7 (12.1)
20 4 5/8-914 29 .3 (8.9) 0.66 (0.10) 48
10 3 8/8-10/1 36.6 (2.6) 0.81 (0.19) 67.3 (2.0) 49
20 3 9/10-11 /5 73.5 (14.8) 0.90 (0.03) 65.6 (7.5)
40 3 7/8-8/8 144.6 (12.4) 0.85 (0.03) 68.4 (8.5)
10 5 5/0-9/0 18.8 (4.2) 0.96 (0.22) 70.4 (12.9) 50
10 3 5/0-1117 27.7 (6.1) 0.78 (0.28) 40.9 (2.5) 51
20 4 5/8-910 48.8 (6.3) 0.93 (0.36) 44.8 (7.9)
20 5 017-8/0 58.1 (21.5) 0.84 (0.08) 52
10 20 NA 28.5 (9.3) 0.80 (0.26) 58.9(16) 53
20 27 NA 47.2 (15) 0.93 (0.37) 54.4 (17.8)
40 3 NA 130 (25.2) 0.94 (0.19) 68.1 (10.5)
Abbreviations: Gmax =peak plasma concentration; NA =age data not available; t,;., =elimination half-life.

In conclusion, meropenem seems to penetrate be considered for elderly patients, and may be
reasonably well in CSF and the patients treated so based on an estimation of creatinine clearance.
far have shown a favourable response to treatment.
Further clinical studies are required to determine 7. Pharmacokinetics in
the role of meropenem in the treatment of menin- Postsurgical Patients
gitis in children.
The disposition of meropenem in patients with
abdominal infections (lg every 8 hours) was stud-
6. Pharmacokinetics in the Elderly
ied by Bedikian et aI.l42) (table IX). Sampling was
Meropenem has a prolonged tY2 in the elderly performed postsurgery to reflect pathophysiologi-
(table VIII). This is mainly due to a lower renal cal changes in these patients.[59] Compared with
clearance, and corresponds to the age-associated healthy volunteers, the most important difference
physiological decline in renal function.[57] The noted was the increased Vd, and thus lower AUC,
ring-opened metabolite also has reduced renal probably reflecting changes of third spacing as a
clearance. Dose-reduction of meropenem should result of surgery.[42,59] The tY2 was unchanged.
Based on these finding s, the investigators con-
cluded that administration of Ig 3 times daily in
Table VIII. Pharmacokinetic parameters of meropenem in young and
elderly healthy men. Values are means with standard deviations[57)
these patients should be adequate.
No. of Age Dose t"" Vss AUG GL Urinary
In patients under anaesthesia, Matsumoto et
volunteers (years) (g) (h) (L) (mglLeh) (ml/min)a recovery aU 58] found a prolonged t y2 , with a mean value of
(%)
1.45 (± 0.62) hours. However, there was large inter-
8 73 0.5 1.27 13.8 58.3 145 67.3
(4.6) (1.5) (10.0) (20.9) (4.7)b individual variation, and the patients with a pro-
8 28 0.5 0.81 12.7 39.6 220 68.2 longed tY2 were older than other patients included
(5.2) (1.3) (6.8) (30.8) (7.9) in the study. If patients older than 70 years are ex-
a To convert to Uh multiply by 0.06.
cluded, the mean tY2 reduces to 1.29 hours. Since
b Urinary recovery over 8h.
Abbreviations: AUG = area under the plasma concentration-time curve;
Ljungberg and Nilsson-Ehle l57] found the clear-
= =
GL total body clearance; t,;., elimination half-life; Vss =apparent ance of meropenem to be age dependent, the pro-
volume of distribution at steady-state. longed tY2 of the patients in Matsumoto's study[58]

© Adis International Limited. All rights reseN ed. Clin. Pharmacokinet. 28 (4) 1995
Meropenem Pharmacokinetics 283

Table IX. Mean plasma derived pharmacokinetic parameters for meropenem in various states of disease. Values are means with standard
deviations
No. of patients Dose hI! Vss AUG GL GLR Renal function
(gender) (g) (h) (L) (mg/L· h) (ml/min)a (ml/min)a (ml/min)

Abdominal infections l42!

12 (IF) 1.0 1.04 (0.19) 26.7 (6.9) 57.5 (20.1) 315(72) 137(89) 106 (24)

Anaesthesia l58!
13 (6F) 0.5 1.34 (0.62) 23.2 (7.0)b 47.6 (21 .7) 202 (64)
a To convert to Uh multiply by 0.06.
b Volume of distribution during elimination phase.
Abbreviations: AUG = area under the plasma concentration-time curve; GL = total body clearance; GLR = renal clearance over the first 4
hours; F =female; t'f.1 =elimination half-life; Vss =apparent volume of distribution at steady-state.

can be largely, although not completely, explained larly meropenem. First, avoidance of unnecessar-
by age alone. ily high Croax values would result in lower daily
doses, thus reducing costs while retaining efficacy.
8. Pharmacokinetic/Pharmacodynamic Secondly, emergence of d2-porin-deficient mu-
Relationships tants of P. aeruginosa resistant to imipenem has
Evidence is accumulating that ~-lactam anti- been reported in studies involving intermittent ad-
biotics should be administered continuously in- ministration of meropenem in humansJ66] This is
stead of using conventional intermittent dosage possibly facilitated by low concentrations of drug
regimens.[60] This view is supported by in vitro as at the end of each dosage interval.l67] Finally, one
well as animal studies. The underlying thesis is, of the reasons that imipenem-cilastatin has not
that killing by ~-lactams is time dependent and is been used as a continuous infusion is its instability
maximal at relatively low concentrations.[6!] Other in aqueous solutions at room temperature. The
studies have shown time above the MIC as the most greater stability of meropenem[22] makes continu-
important pharmacodynamic parameter.[62] More- ous infusion of meropenem feasible.
over, most ~-lactam antibiotics lack a significant In summary, although meropenem is usually
postantibiotic effect (PAE) on Gram-negative bac- given as an intermittent infusion, continuous in-
teria. The aim for dosage regimens of ~-lactam fusion could be cost-effective and/or clinically
antibiotics is therefore to maximise the time ofbac-
terial exposure to concentrations exceeding the
MIC, e.g. by continuous infusion. However, the Table X. Dosage recommendations in patients with and without
carbapenems differ from most other ~-lactam anti- renal impairment

biotics in 2 ways: carbapenems do exert a PAE on GLCR Dose Dosage interval

(ml/min)a (mg) (h)
Gram-positive as well as Gram-negative bac-
>50 500-1000b 6-8
teria;[63] and the MICs for many bacterial species 25-50 500-1000 12
are very low, thus providing a supra-MIC concen- 10-25 500 12
tration for most of the dosage interval even when <10 500 24
the drug is given intermittently.[64] Indeed, it was 0, haemodialysis 500 48-72 and after
shown in an animal model, that the duration of haemodialysis
0, GAVHD 500 24
supra-MIC concentrations needed to produce a net
a To convert to Uh multiply by 0.06.
bacteriostatic effect was less for carbapenems than
b 2g 3 times daily for the treatment of meningitis due to Pseudo-
for penicillins or cephalosporins)65] monas aeruginosa has been successful. 138!
There are several arguments in favour of con- =
Abbreviations: GLCR creatinine clearance; GAVHD =continuous
tinuous administration of carbapenems, particu- arteriovenous haemodiafiltration.

© Adis International Limited. All rights reserved. elin. Pharmacokinet. 28 (4) 1995
284 Mouton & van den Anker

beneficial in many situations, and clinical studies Acknowledgements

using this regimen should be undertaken.
We thank H.A. Verbrugh for critically reading the manu-
script.
9. Therapeutic Use and Dosage
Recommendations
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