ADIS DRUG EVALUATION Drugs 2000 Mar; 59 (3): 653-680

0012-6667/00/0003-0653/$25.00/0

© Adis International Limited. All rights reserved.

Meropenem
A Review of its Use in Patients in Intensive Care
Miriam Hurst and Harriet M. Lamb
Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:

J.L. Blumer, Division of Paediatric Pharmacology and Critical care, Rainbow Babies and Children’s hospital,
University Hospitals of Cleveland, Cleveland, Ohio, USA; F. Colardyn, Department of Intensive Care,
University Hospital Ghent, Ghent, Belgium; B.A. Cunha, Infectious Disease Division, Winthrop-University
Hospital, Mineola, New York, USA; J. Garau, Department of Medicine, Hospital de Mutua de Terrassa,
Barcelona, Spain; I.M. Hoepelmann, University Hospital Utrecht, Division of Infectious Diseases and AIDS,
Utrecht, The Netherlands; T. Horii, Department of Bacteriology, Nagoya University School of Medicine,
Nagoya, Japan; C.E. Nord, Karolinska Instituet, Department of Immunology, Microbiology, Pathology and
Infectious Diseases, Huddinge University Hospital, Huddinge, Sweden; S.R. Norrby, Department of
Infectious Diseases and Medical Microbiology, University of Lund, Lund, Sweden; M.A. Pfaller, Medical
Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa,
USA; J.P. Quinn, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA; E.C.
Reisinger, Department of Internal Medicine, Infectious Diseases and Tropical Medicine, University of
Rostock, Rostock, Germany; F. Thalhammer, Department of Internal Medicine, Division of Infectious
Diseases, University of Vienna, Vienna, Austria; C. Verwaest, Department of Intensive Care Medicine,
Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium.

Data Selection
Sources: Medical literature published in any language since 1966 on Meropenem, identified using AdisBase (a proprietary database of Adis
International, Auckland, New Zealand) and Medline. Additional references were identified from the reference lists of published articles.
Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: AdisBase search terms were ‘Meropenem’ or ‘ICI-194660’ or ‘ICI-213689’ or ‘SM-7338’ and ‘Bacterial-Infections’. Medline
search terms were ‘Meropenem’ or ‘ICI 194660’ or ‘ICI 213689’ or ‘SM 7338’ and ‘Bacterial-Infections’. Searches were last updated 6 March
2000.
Selection: Studies in patients with serious infections in intensive care units who received meropenem. Inclusion of studies was based mainly
on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred.
Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: meropenem, bacterial infections, intensive care, serious infections, pharmacodynamics, pharmacokinetics, therapeutic use.

Contents

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654
1. Infections in the Intensive Care Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658
2.1 Antibacterial Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658
2.1.1 Gram-Negative Aerobic Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658
2.1.2 Gram-Positive Aerobic Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660
2.1.3 Anaerobic Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
2.2 Mechanisms of Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
2.2.1 Production of β-Lactamases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
2.2.2 Alterations in Permeability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
2.2.3 Alterations in Penicillin-Binding Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
2.3 Other Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
654 Hurst & Lamb

2.3.1 Effect on Endotoxin Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662

2.3.2 Postantibiotic Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
2.3.3 Additive/Synergistic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
3. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
3.1 Special Patient Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
3.1.1 Patients with Serious Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
3.1.2 Renal and Hepatic Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
3.1.3 Children and the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
4. Clinical Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
4.1 Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
4.1.1 Compared with Imipenem/Cilastatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
4.1.2 Compared with Cephalosporin-Based Regimens . . . . . . . . . . . . . . . . . . . . . 667
4.2 Special Patient Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
4.2.1 Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
4.2.2 Neonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668
4.2.3 Elderly Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
5.1 CNS Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
5.2 Special Patient Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
7. Place of Meropenem in the Management of Patients in Intensive Care . . . . . . . . . . . . . . . 673

Summary
Abstract Meropenem is a carbapenem antibacterial agent that has antimicrobial activity
against Gram-negative, Gram-positive and anaerobic micro-organisms. In vitro
studies involving isolates from patients in intensive care units (ICUs) indicate
that meropenem is more active against most Gram-negative pathogens than other
comparators (including imipenem), although, compared with imipenem,
meropenem is less active against most Gram-positive organisms. Resistance to
meropenem is uncommon in most bacteria.
Treatment with meropenem as initial empirical monotherapy was effective in
a range of serious infections in adult and paediatric ICU patients. Meropenem
monotherapy was as effective as imipenem/cilastatin in 4 comparative trials in
terms of satisfactory clinical and bacteriological responses.
Meropenem monotherapy was significantly more effective than ceftazidime-
based combination treatments in 2 trials in patients with nosocomial lower respi-
ratory tract infections (LRTIs) in terms of both clinical and bacteriological
responses. Meropenem was also more active than ceftazidime-based treatments
against both Gram-positive and Gram-negative organisms. However, 2 studies in
patients with a range of serious infections found no significant differences be-
tween meropenem and cephalosporin-based treatments in terms of clinical or
bacteriological response. Meropenem was also as effective as cephalosporin-
based treatments in comparative trials in children with serious infections.
Meropenem is well tolerated as either a bolus or an infusion, and clinical trials
have shown similar incidences of adverse events to those observed with cepha-
losporin-based treatments. It is well tolerated by the CNS, with seizures reported
infrequently, and can therefore be used at high doses and in patients with menin-
gitis. The incidence of drug-related nausea and vomiting is low and, in contrast
to imipenem/cilastatin, does not increase with dose or speed of administration.

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Meropenem: A Review 655

Conclusions: Meropenem is a well tolerated broad spectrum antibacterial

agent that, when used as initial empirical monotherapy, is as effective as im-
ipenem/cilastatin in the treatment of a range of serious infections (including nos-
ocomial) in adults and children in ICUs. Compared with cephalosporin-based
combination treatments, meropenem monotherapy may be more effective in the
treatment of nosocomial LRTIs and can be used as monotherapy. Meropenem has
an important role in the empirical treatment of serious infections in adults and
children in ICUs.
Pharmacodynamic Meropenem has a broad spectrum of activity against most common intensive care
Properties unit (ICU) pathogens in in vitro studies, and, in particular, was more active than
most other agents (including imipenem) against Enterobacteriaceae. A survey of
14 857 isolates (not all from ICUs) found that values for the minimum drug
concentration required to inhibit the growth of 90% of bacterial strains (MIC90)
with meropenem were 4- to 16-fold lower than those with imipenem (≤0.06 to
0.5 mg/L and 0.25 to 8 mg/L, respectively). All Enterobacteriaceae isolated from
13 ICUs were highly susceptible to meropenem, with MIC90 values ranging from
0.13 to 1 mg/L; values for imipenem ranged from 1 to 4 mg/L.
Haemophilus influenzae and Neisseria meningitidis were also highly suscep-
tible to meropenem (MIC90 ≤1 mg/L); data from North American centres indi-
cated that meropenem was more active than imipenem against H. influenzae (99.4
and 85.3% of isolates were susceptible, respectively). Isolates of Pseudomonas
aeruginosa from ICU patients were of intermediate susceptibility to meropenem
and resistant to all other agents tested, including imipenem. Stenotrophomonas
maltophilia was resistant to both carbapenems.
Gram-positive bacteria susceptible (MIC90 ≤4 mg/L) to meropenem include
methicillin-sensitive Staphylococcus aureus and S. epidermidis, and Streptococ-
cus pneumoniae. Meropenem is less active than imipenem against Enterococcus
faecalis. Methicillin-resistant staphylococci and E. faecium are resistant to
meropenem. Meropenem is highly active against most anaerobic bacteria, with 1
review finding that 99.1% of 2257 isolates were susceptible.
Meropenem, like imipenem, is highly resistant to hydrolysis by most of the
serine-based β-lactamases produced by Gram-negative bacteria; however, both
drugs are susceptible to the metallo-β-lactamases and clavulanic acid-inhibited
carbapenemases produced by S. maltophilia and some Flavobacterium spp.
Hyperproduction of β-lactamases by some bacteria is also associated with de-
creased susceptibility when expressed in conjunction with certain porin deficien-
cies. Alterations in penicillin-binding proteins account for the inherent resistance
of E. faecium and methicillin-resistant S. aureus.
Meropenem has demonstrated additive or synergistic activity when used in
combination with a range of antibacterial agents in in vitro studies. Like im-
ipenem, meropenem has a postantibiotic effect on Gram-negative bacilli.
Meropenem may cause less release of endotoxin from Gram-negative bacteria
than other agents such as the cephalosporins, although results are inconsistent.
Pharmacokinetic Profile Meropenem has linear pharmacokinetics and distributes into a wide range of body
fluids and tissues. Mean values for peak plasma concentrations (Cmax) in healthy
volunteers were 54.8 to 61.6 mg/L after single dose meropenem 1g; these values
were similar 1 hour after either bolus or infusion administration. Mean values for
elimination half-life (t1⁄2) were 1.0 to 1.4 hours, and volume of distribution was
12.5 to 23L. Meropenem is largely excreted renally, with 54 to 79% of a 1g dosage

© Adis International Limited. All rights reserved. Drugs 2000 Mar; 59 (3)
656 Hurst & Lamb

excreted unchanged in the urine and 19 to 27% excreted as an inactive metabolite.

Unlike imipenem, meropenem is stable to human renal dehydropeptidase-1.
Data relating to the effects of serious infections on the pharmacokinetics of
meropenem are limited, but the changes seen in studies in small numbers of
patients appear to result from factors other than infection (such as recent surgery).
However, dosage adjustments are necessary in patients with renal impairment.
Meropenem is primarily excreted through the kidneys; because of this, total body
and renal clearance of meropenem decrease, and t1⁄2 increases, as creatinine clear-
ance decreases. Patients with renal failure requiring continuous veno-venous
haemofiltration may require higher dosages of meropenem than those recom-
mended for their level of renal impairment in order to maintain adequate serum
concentrations. Hepatic impairment had no significant effect on the pharmacoki-
netics of meropenem.
Clinical Efficacy Meropenem is effective in the treatment of serious infections, including those
acquired in hospital or the ICU. The most common diagnosis in these studies was
pneumonia or another lower respiratory tract infection (LRTI); intra-abdominal
infections were also diagnosed frequently.
In 4 randomised nonblind comparative trials, intravenous meropenem and
imipenem/cilastatin (both 1g every 8 hours) demonstrated similar efficacy, with
satisfactory clinical responses observed in 76 to 88% of meropenem recipients
compared with 68 to 85% of imipenem/cilastatin recipients; 67 to 94% and 60 to
88% of patients, respectively, experienced satisfactory bacteriological responses.
Eradication of Gram-negative organisms was observed in 70 to 100% of
meropenem recipients and 64 to 84% of imipenem/cilastatin recipients; eradica-
tion rates for Gram-positive organisms were 69 to 83% and 87 to 96%, respec-
tively, and there were no statistical comparisons.
Significantly more evaluable patients experienced satisfactory clinical and/or
bacteriological responses with meropenem than with ceftazidime-based treat-
ments in 2 randomised nonblind multicentre trials in patients with nosocomial
LRTIs; rates of satisfactory clinical response were 83 and 89% with meropenem,
compared with 66 and 72% with ceftazidime-based treatments (p ≤ 0.04). Bac-
teriological success was observed in 74 and 89% of meropenem recipients, com-
pared with 54 and 67% of ceftazidime-based treatment recipients (p ≤ 0.042).
Meropenem was more active than ceftazidime-based treatments in terms of erad-
ication of both Gram-negative (83 and 93% vs 72 and 79%, respectively) and
Gram-positive (89 and 80% vs 62 and 65%, respectively) organisms. However,
2 other studies in patients with serious bacterial infections (including those aged
≥65 years) found no significant differences between meropenem and cephalospo-
rin-based treatments in terms of clinical or bacterial response, including effects
on Gram-negative and Gram-positive organisms.
Although there are no comparative studies focusing solely on paediatric ICU
patients, 3 multicentre trials in children (aged 1 month to 15 years) with serious
bacterial infections (not including meningitis) found that meropenem 10 to 20
mg/kg every 8 hours was as effective as either ceftazidime alone (10 to 30 mg/kg
every 8 hours) or cefotaxime-based therapies (100 to 160 mg/kg daily in 2 to 4
divided doses). Satisfactory clinical responses ranged from 97 to 98% with
meropenem, compared with 93 to 96% with cephalosporin-based treatments; 88
to 97% of bacterial responses were satisfactory with meropenem, compared with
89 to 93% with comparative treatments. The use of meropenem in children aged

© Adis International Limited. All rights reserved. Drugs 2000 Mar; 59 (3)
Meropenem: A Review 657

< 3 months is ‘off label’; however, 4 small noncomparative studies have found
meropenem to be effective in the treatment of invasive infections in neonates,
including those who failed to respond to previous antibacterial therapy.
Tolerability In a safety analysis of 9514 patients with serious bacterial infections, the inci-
dences of adverse events and drug-related adverse events with meropenem were
similar to those seen with imipenem/cilastatin or cephalosporin-based treatments.
The most frequently reported drug-related adverse events for meropenem were
diarrhoea (2.3% of treatment exposures), rash (1.4%), nausea and vomiting
(1.4%) and inflammation at the injection site (1.1%), with all other drug-related
adverse events occurring in <1% of patient exposures. Drug-related elevations in
hepatic enzymes (AST, ALT and alkaline phosphatase) and thrombocytosis were
observed in 1.5 to 4.3% of patient exposures to meropenem; all other laboratory
abnormalities considered to be associated with meropenem occurred in <1% of
patients. Adverse events did not appear to be dosage-related and bolus adminis-
tration of meropenem was well tolerated. ICU patients had similar incidences of
adverse events to those in general wards.
Clinical and animal data indicate that meropenem is well tolerated by the CNS
and seizures during treatment are uncommon, even in patients with predisposing
conditions such as meningitis. Renal failure had little effect on the frequency of
meropenem-related adverse events, although vomiting during meropenem ther-
apy was slightly more common in renally impaired patients (1.4 vs 0.2%).
Meropenem was also well tolerated in children (whether administered as an in-
travenous bolus or as an infusion) and in the elderly.
Dosage and In patients with serious infections, meropenem 1g intravenously every 8 hours is
Administration recommended; if necessary, this can be increased to a maximum of 2g every 8
hours. Either bolus or infusion methods of administration can be used. Patients
with renal impairment should receive reduced dosages.
For children (3 months to 12 years), meropenem 10 to 20 mg/kg every 8 hours
is recommended (40 mg/kg in children with meningitis). No dosage adjustments
are necessary in elderly patients with normal renal function or patients with he-
patic impairment.

1. Infections in the Intensive Care Unit
Infections in the intensive care unit (ICU) in-
clude those acquired there as well as those severe
enough to require treatment in intensive care. They
are a common problem: a survey of 10 038 patients
in 1417 European ICUs found that 4501 (44.8%)
had 1 or more infections on the day of the study,
and almost half of them (2064) had become in-
fected in the ICU (an overall prevalence of
20.6%).[1] The risk of ICU-acquired infection in-
creases with the length of stay[1-3] (a stay of 3 to 4
days was associated with a 3-fold increase in infec-
tion risk compared with a shorter stay[1]) and the
performance of invasive procedures.[1-3] In a US
study of ICU-acquired infections, 87% of 2694
bloodstream infections occurred in patients who
had central lines inserted, and 86% of 3828 cases
of nosocomial pneumonia were in patients receiv-
ing mechanical ventilation.[2] Significant increases
in the risk of infection (p < 0.05) were also associ-
ated with the presence of trauma on admission and
the use of stress ulcer prophylaxis.[1]
The most common adult ICU-acquired infec-
tions reported in both European and American sur-
veys are pneumonia, urinary tract and bloodstream
infections.[1,2] Other infections reported include
lower respiratory tract (not pneumonia), gastroin-
testinal, wound, and skin and soft tissue infections.

© Adis International Limited. All rights reserved. Drugs 2000 Mar; 59 (3)
658
CH3
OH
H H
CH3
CON
CH3
CH3
H S
N NH
O
COOH
Fig. 1. Chemical structure of meropenem.
The causative micro-organisms most commonly
isolated from patients with ICU-acquired infec-
tions in a European study were Enterobacteriaceae
(34.4%), Staphylococcus aureus (30.1%), Pseudo-
monas aeruginosa (28.7%), coagulase-negative
staphylococci (19.1%) and fungi (17.1%), although
some infections were polymicrobial.[1] Data from
a survey of 61 paediatric ICUs indicate similar
trends in nosocomial infection type and pathogen
frequency, although bloodstream infections were
more common than pneumonia (38 vs 21%).[4]
The presence of infection is associated with in-
creased duration of stay, cost of illness and, in some
studies, increased mortality rates.[1,5-7] Aggressive
antibacterial treatment is required. Standard prac-
tice is to begin treatment empirically with a broad
spectrum antibacterial regimen and then, if possible,
use a more specific agent once the micro-organism
and its susceptibilities are known.[8]
This review focuses on meropenem, a car-
bapenem antibacterial agent (fig. 1), and its use in
ICU patients with serious infections, whether hos-
pital or community acquired. The general use of
meropenem for serious infections has previously
been reviewed in Drugs.[9] The current review does
not consider patients with febrile neutropenia, who
are usually treated in specialist haematology units
(see the recent review by Lamb & Goa[10]).
2. Pharmacodynamic Properties
2.1 Antibacterial Activity
The in vitro activity of meropenem against a
range of pathogens is presented in table I. These
data are from a review by Pfaller and Jones of 121
European and North American studies, including
© Adis International Limited. All rights reserved.
Hurst & Lamb
over 30 000 clinical isolates; however, the number
of isolates obtained from ICU patients was not
stated.[11] The percentage susceptibilities were cal-
culated using breakpoints from the National Commit-
tee for Clinical Laboratory Standards (NCCLS).
The results of Pfaller and Jones[11] have been
confirmed by a number of smaller reviews of bac-
terial susceptibility to meropenem which have in-
cluded isolates taken from ICUs.[12-18] Preliminary
comparative data from the Meropenem Yearly Sus-
ceptibility Test Information Collection (MYSTIC),
a large (33 centres) ongoing 3-year study that in-
cludes data from ICUs, is provided in table II.[19]
2.1.1 Gram-Negative Aerobic Bacteria
Enterobacteriaceae
Preliminary data from 13 ICUs participating in
MYSTIC indicate that all Enterobacteriaceae were
highly susceptible to meropenem, with values for
the minimum drug concentration required to in-
hibit the growth of 90% of bacterial strains (MIC90)
ranging from 0.13 to 1 mg/L (table II).[19] Mode
MIC90 values ranged from 0.03 to 0.06 mg/L. Ad-
ditional smaller reviews where all isolates were ob-
tained from patients in adult[14,16,17] or paediatric
ICUs,[20] or from patients with serious infections,[18]
found that 92 to 100% of Enterobacteriaceae were
susceptible to meropenem.[14,16-18,20]
The review by Pfaller and Jones found that
meropenem was more active against 14 857 iso-
lates of enteric Gram-negative bacilli than any
other comparator tested;[11] 98.8 to 100% of iso-
lates were susceptible, compared with 85.4 to
100% for imipenem, 86.5 to 100% for cipro-
floxacin, 74.8 to 100% for piperacillin/tazobactam,
68.4 to 99.7% for cefotaxime and 64.8 to 99.2 for
ceftazidime. In particular, meropenem was more
active against Enterobacteriaceae than imipenem,
with a 4- to 16-fold difference in MIC90 values
(≤0.06 to 0.5 mg/L and 0.25 to 8 mg/L, respec-
tively). Meropenem was also active against a sub-
set of 746 ceftazidime-resistant isolates, with 87.5
to 100% inhibited at ≤4 mg/L. Data from MYSTIC
indicate that MIC90 values were lower with
meropenem than with imipenem (0.13 to 1 mg/L vs
1 to 4 mg/L, respectively; table II), although all
Drugs 2000 Mar; 59 (3)
Meropenem: A Review 659

Table I. Overview of the in vitro activity of meropenem against pathogens commonly implicated in ICU infections (data for selected pathogens
taken from Pfaller & Jones)[11]
Species Europe North America
% Sa (no. of strains tested) MIC90 (mg/L) % Sa (no. of strains tested) MIC90 (mg/L)

Gram-negative aerobes
Acinetobacter baumanii 100 (116) 1.0 98.7 (152) 2.0
Citrobacter freundii 99.8 (445) 0.13 99.1 (433) 0.06
C. koseri 100 (85) 0.13 99.5 (205) <0.06
Enterobacter aerogenes 100 (167) 0.25 99.1 (535) 0.13
E. cloacae 100 (683) 0.25 99.5 (1014) 0.25
Escherichia coli 100 (2228) 0.06 99.7 (2126) <0.06
Haemophilus influenzae 100 (727) 0.13 99.4 (527) 0.13
Klebsiella oxytoca 100 (354) 0.06 99.7 (334) 0.06
K. pneumoniae 100 (860) 0.06 99.3 (1206) 0.06
Morganella morganii 100 (372) 0.25 99.4 (320) 0.25
Proteus mirabilis 100 (997) 0.13 100 (750) 0.25
P. vulgaris 100 (266) 0.13 100 (150) 0.25
Providencia rettgeri 100 (118) 0.25 100 (111) 0.25
P. stuartii 100 (192) 0.5 99.4 (167) 0.25
Pseudomonas aeruginosa 91.0 (2184) 4.0 91.0 (1870) 4.0
Serratia marcescens 99.7 (394) 0.13 98.8 (654) 0.25

Gram-positive aerobes
Enterococcus faecalis 70.8 (901) 8.0 78.8 (523) 8.0
E. faecium 23.4 (175) 128 31.5 (54) 64
Staphylococcus aureus (MS) 99.1 (1478) 0.25 98.6 (1691) 0.25
S. epidermidis (MS) 92.6 (476) 4.0 88.0 (533) 8.0
Streptococcus pneumoniaeb 93.9 (473) 0.06 78.1 (498) 0.5

Anaerobes
Bacteroides fragilis 98.2 (1130) 0.5 99.4 (161) 0.5
Clostridium perfringens 100 (230) <0.06 100 (108) 0.06
C. difficile 100 (106) 2.0 100 (34) 2.0
a Percentage of organisms considered to be susceptible (S) to meropenem at the breakpoint set by the National Committee for Clinical
Laboratory Standards (≤4 mg/L).
b Includes penicillin-resistant strains.
ICU = intensive care unit; MIC90 = minimum drug concentration required to inhibit the growth of 90% of bacterial strains; MS =
methicillin-sensitive.

Enterobacteriaceae were still susceptible to im-
ipenem.[19]
Other Gram-Negative Aerobic Bacteria
Other Gram-negative bacteria considered to be
highly susceptible to meropenem (MIC90 ≤1 mg/L)
in the review by Pfaller and Jones included
Haemophilus influenzae and Neisseria meningi-
tidis.[11] Those considered susceptible (MIC90 ≤4
mg/L) included Acinetobacter baumanii and P.
aeruginosa (although in the MYSTIC review of
data from 13 European ICUs, isolates of these bac-
teria had higher MIC90 values;[19] see table II). Steno-
trophomonas maltophilia, which is resistant to im-
ipenem, was also resistant to meropenem (MIC90
≥16 mg/L).[11]
Meropenem was more effective than imipenem
against P. aeruginosa: 91% of all isolates were sus-
ceptible to meropenem, with an MIC90 value of 4
mg/L, compared with 79.6% of European and
86.2% of North American isolates that were sus-
ceptible to imipenem (MIC90 values were 16 mg/L
for both groups).[11] Data from MYSTIC indicate
that isolates of P. aeruginosa from ICUs were of

© Adis International Limited. All rights reserved. Drugs 2000 Mar; 59 (3)
660 Hurst & Lamb

Table II. Comparative in vitro activity of meropenem against isolates from 13 European ICUs[19]
Species (no. of isolates) MIC90 (mg/L)
meropenem imipenem ceftazidime cefepime piperacillin/ gentamicin tobramycin
tazobactam

Gram-negative aerobes
Acinetobacter baumanii (95) 8 8 64 64 128 >128 32
Enterobacter aerogenes (22) 0.13 1 >128 4 64 128 16
E. cloacae (58) 0.5 4 >128 4 128 32 16
Escherichia coli (153) 0.13 2 2 0.5 16 16 8
Klebsiella oxytoca (27) 1 2 32 8 128 >128 >128
K. pneumoniae (62) 0.13 2 128 8 128 >128 64
Proteus mirabilis (44) 0.13 4 2 0.5 8 2 2
Pseudomonas aeruginosa (171) 8 16 32 32 128 >128 32
Serratia marcescens (41) 0.25 2 16 2 128 16 16

Gram-positive aerobes
Enterococcus faecalis (128) 32 8 >128 >128 32 >128 >128
Staphylococcus aureus (MS) 0.25 2 16 4 8 4 4
(276)
ICU = intensive care unit; MIC90 = minimum drug concentration required to inhibit the growth of 90% of bacterial strains; MS = methicillin-sen-
sitive.

intermediate susceptibility to meropenem and re- 2.1.2 Gram-Positive Aerobic Bacteria

sistant to all other agents tested (see table II);[19]
meropenem was more active against P. aeruginosa
than comparators (including imipenem, cipro-
floxacin, and ceftazidime), with susceptibility rates
of 89 to 100%, in 3 other studies involving isolates
from ICU patients[17,21] or patients with serious in-
fections.[18]
The percentages of Pseudomonas spp. (other than
P. aeruginosa) that were susceptible to meropenem
ranged from 50 to 95% in the few studies that in-
cluded these data;[16-18,22] however, 2 studies found
higher susceptibility rates with other agents (cefta-
zidime,[16,17] ciprofloxacin,[17] cefepime[16] and
piperacillin[17]).
North American studies found that meropenem had
more activity than imipenem against H. influenzae
(99.4 and 85.3% susceptible, respectively), al-
though no marked difference was evident in Eu-
ropean studies (100 and 98.2%, respectively).[11]
Meropenem and imipenem were the most effective
agents tested against Acinetobacter spp. (94% sus-
ceptible).[18]
Gram-positive bacteria that were highly suscep-
tible to meropenem (MIC90 ≤1 mg/L) included
methicillin-sensitive S. aureus and Streptococcus
pneumoniae (table I). Methicillin-sensitive S.
epidermidis was also susceptible (MIC90 ≤4 mg/L).
Meropenem had variable activity against Entero-
coccus faecalis (MIC90 ≤8 mg/L) and no activity
against methicillin-resistant staphylococci or E.
faecium (MIC90 values ≥16 mg/L).[11]
Meropenem was less active than imipenem
against E. faecalis and S. epidermidis (2- to 4-fold
and 4- to 8-fold differences in MIC90, respec-
tively).[11] In ICU patients, meropenem was less
active than imipenem against isolates of E. faecalis
(MIC90 32 and 8 mg/L, respectively; see table
II).[19] However, MIC90 values for methicillin-sen-
sitive S. aureus were 8-fold lower with meropenem
than with imipenem in ICU isolates (see table II).
In the review by Pfaller and Jones, North Amer-
ican isolates of S. pneumoniae were 2- to 4-fold
less susceptible to meropenem than to imipenem
and cefotaxime (MIC90 values 0.5, 0.13 and 0.25
mg/L, respectively); this difference was not seen in

© Adis International Limited. All rights reserved. Drugs 2000 Mar; 59 (3)
Meropenem: A Review
the European results (MIC90 values 0.06, 0.06 and
0.25, respectively).[11] The higher prevalence of
penicillin-resistant S. pneumoniae in North Amer-
ica was thought to be responsible (27% of isolates
vs 10% in Europe). However, although only 60%
of all isolates of penicillin-resistant S. pneumoniae
were susceptible to meropenem at concentrations
of ≤0.12 mg/L, 97% were susceptible at ≤1 mg/L
(MIC90 values for penicillin-resistant S. pneu-
moniae were not given).[11]
2.1.3 Anaerobic Bacteria
Overall, 99.1% of 2257 isolates of anaerobic
bacteria were susceptible to meropenem in the re-
view by Pfaller and Jones.[11] Clostridium per-
fringens and Bacteroides fragilis were highly sus-
ceptible (MIC90 ≤0.5 mg/L); C. difficile was also
susceptible (100% inhibited at 2 mg/L). More Eu-
ropean isolates of C. difficile were susceptible to
meropenem (100%) than imipenem (67.9%), al-
though in North American studies 100% of isolates
were susceptible to both drugs (table I).
2.2 Mechanisms of Resistance
Resistance to β-lactam antibacterial agents can
result from a number of mechanisms and may be
intrinsic or acquired.[23] Reduced susceptibility to
the carbapenems, although less common than with
other β-lactam agents, has been observed in bacte-
ria (such as P. aeruginosa) that exhibit multiple
resistance mechanisms;[24] in addition, there are in-
creasing numbers of reports of organisms with ac-
quired carbapenemases.[25] In spite of the wide-
spread use of meropenem, there has been no
clinically significant resistance seen in P. aerugin-
osa or Klebsiella, Enterobacter or Serratia spp.[26]
The potential of antibacterial agents to select
resistant strains and the incidence of cross-resis-
tance should also be considered when choosing an
antibacterial agent, although data are limited. In 1
in vitro study, meropenem selected for resistant
strains of Enterobacter cloacae to a greater degree
than imipenem (although data from MYSTIC indi-
cate that meropenem is highly active against this
pathogen; see table II);[27] in another study, neither
meropenem nor imipenem selected for mutant iso-
© Adis International Limited. All rights reserved.
661
lates of P. aeruginosa that were cross-resistant to
other β-lactam agents.[28] Cross-resistance data
from isolates of P. aeruginosa, however, suggest
that imipenem-resistant strains are more likely to
be susceptible to meropenem than vice versa.[29-32]
2.2.1 Production of β-Lactamases
The production of enzymes capable of hydro-
lysing β-lactam rings enables certain bacteria to
inactivate β-lactam antibacterial agents. Car-
bapenems such as meropenem are highly resistant
to hydrolysis by serine-based β-lactamases (such
as the chromosomal and plasmid-mediated β-
lactamases produced by most Gram-negative bac-
teria).[33,34] This may be of clinical significance; 1
study (reported as an abstract) found that mortality
rates in 80 patients infected with extended spec-
trum β-lactamase producing strains of K. pneu-
moniae were significantly lower in those who re-
ceived a carbapenem in the first 5 days of treatment,
compared with those who received other antibac-
terial agents (5 vs 43%, p = 0.01).[35]
However, carbapenems are susceptible to the
metallo-β-lactamases (Bush groups 3a and 3b) and
clavulanic acid-inhibited carbapenemases (group 2f)
produced by S. maltophilia and some Flavobacte-
rium spp.[33,34] Acquired metallo-β-lactamases
conferring resistance or decreased susceptibility to
carbapenems have been reported in resistant iso-
lates of P. aeruginosa from 1 patient in Italy[36] and
Japan;[25] a specific metallo-β-lactamase (IMP-1)
has also been reported in Japanese isolates of Ser-
ratia marcescens[25] and, in 1 case, a Japanese isolate
of K. pneumoniae.[25] Carbapenemase resistance is
also increasingly common in clinical isolates of
Acinetobacter, with plasmid-mediated carbapen-
emases and metallo-β-lactamases reported.[25,37,38]
Hyperproduction of β-lactamases by Escher-
ichia coli,[30,39,40] P. aeruginosa,[28] K. pneu-
moniae[41-43] and Citrobacter freundii[44] was also
associated with decreased susceptibility to mero-
penem when expressed in combination with de-
creased permeability due to porin deficiencies (see
section 2.2.2).
Drugs 2000 Mar; 59 (3)
662
2.2.2 Alterations in Permeability
Carbapenems enter Gram-negative bacteria by
passive diffusion through porins in the cell mem-
brane.[45] The zwitterionic nature and low molecu-
lar weight of meropenem mean that it is able to
penetrate most cells;[46] however, organisms that
lack porins can have decreased susceptibility to
carbapenems because of the reduction in perme-
ability. Deficiency of outer membrane porin protein
D2 is associated with decreased susceptibility to
carbapenems, but not other β-lactam agents;[45,47]
in addition, a number of different porin deficien-
cies associated with decreased susceptibility have
been described in isolates of P. aeruginosa.[23,48-50]
One in vitro study also found that meropenem se-
lected for porin-deficient mutants of K. pneu-
moniae;[50] however, clinical data indicate that iso-
lates of K. pneumoniae are still highly susceptible
to meropenem (section 2.1.1). Some organisms
with these deficiencies may demonstrate a reduc-
tion in susceptibility only if they also hyperproduce
β-lactamases (see section 2.2.1).
Multidrug efflux pumps capable of excreting
antibacterial agents have been detected in some
Gram-negative bacteria, including P. aeruginosa,
and these can also contribute towards decreased
susceptibility to carbapenems.[23,51] These pumps
are usually capable of excreting a broad range of
antibacterial agents, including β-lactams, fluoro-
quinolones and tetracyclines; it is unclear how
common they are among resistant bacterial iso-
lates.
2.2.3 Alterations in Penicillin-Binding Proteins
Some bacteria, such as E. faecium, have penicil-
lin-binding proteins (PBPs) that confer inherent re-
sistance to β-lactam antibacterial agents. In addi-
tion, many isolates of methicillin-resistant S.
aureus produce supplementary PBPs that make
them resistant to carbapenems or other β-lactam
agents.[45] However, meropenem and imipenem
differ in their affinities for bacterial PBPs; in par-
ticular, meropenem has a greater affinity for PBP3
than imipenem.[52] In 1 study (reported in abstract
form), imipenem resistance in isolates of H. in-
fluenzae appeared to relate to the low affinity of
© Adis International Limited. All rights reserved.
Hurst & Lamb
imipenem for PBP4 and PBP5, as these isolates were
still susceptible to meropenem.[53]
2.3 Other Properties
2.3.1 Effect on Endotoxin Release
Endotoxin release from Gram-negative bacteria
plays a major part in the pathogenesis of septic
shock; the overall mortality rate in patients with
this condition is approximately 45%.[54] Antibacte-
rials, although vital in the treatment of such infec-
tions, have been shown experimentally to induce
endotoxin release because of their ability to disrupt
bacterial outer membranes.[54] It is important to
note, however, that the clinical significance of
these in vitro findings is unknown, and the choice
of an antibacterial agent should still be based on
efficacy against the likely pathogens.
Some in vitro studies[55-60] and animal models,[61]
however, have shown that meropenem causes sig-
nificantly less endotoxin release from P. aerugin-
osa, E. coli, S. marcescens and K. pneumoniae than
non-carbapenems (including ceftazidime, ceftri-
axone, cefepime and ciprofloxacin); in 1 study in
P. aeruginosa, endotoxin concentrations were 2.7-
to 10-fold lower with meropenem than with
ceftazidime.[55] The effects of meropenem were
generally similar to those seen with imipenem in
these studies. However, in an in vitro study mero-
penem caused more endotoxin release from P.
aeruginosa than either imipenem or panipenem.[61]
In addition, an animal model of Gram-negative
sepsis (using E. coli and mice pretreated with hep-
atotoxin) found that endotoxin release was greater
with meropenem than with imipenem; however,
both agents were given as single doses and only 5
mice received meropenem.[62]
2.3.2 Postantibiotic Effect
Meropenem, like imipenem and unlike most other
β-lactam antibacterial agents, has a postantibiotic
effect against Gram-negative bacilli.[63] Delayed
regrowth following exposure to meropenem has
been reported in Enterobacteriaceae,[64-66] S. au-
reus,[67] P. aeruginosa,[64-66,68] B. fragilis[69] and E.
faecalis[70]; however, duration depends on the
method of assessment used.[65]
Drugs 2000 Mar; 59 (3)
Meropenem: A Review
2.3.3 Additive/Synergistic Effects
Combining meropenem with teicoplanin,[71]
vancomycin,[71] piperacillin or various other β-
lactams (including cefazolin and ampicillin)[72] re-
sulted in additive or synergistic activity in vitro
against methicillin-resistant S. aureus. Meropen-
em exhibited synergistic activity against E. faecalis
with teicoplanin.[73] Additive or synergistic activity
was also demonstrated with meropenem and
aminoglycosides (amikacin,[74,75] tobramycin,[73]
gentamicin[73] or netilmicin[73]) against P. aerugin-
osa (including multidrug-resistant strains[74,75]).
3. Pharmacokinetic Profile
Although most studies have involved healthy
volunteers, the pharmacokinetic properties of
meropenem have also been assessed in patients
with serious infections as well as those with renal
or hepatic failure. The pharmacokinetic properties
of meropenem in a variety of patient groups are
summarised in table III.
Meropenem has linear pharmacokinetics, with
both the area under the plasma concentration-time
curve (AUC) and the peak plasma concentration
(Cmax) increasing with dosage.[82,85] An inhibitory
effect on organisms is seen when the plasma con-
centration is above MIC for approximately 33 to
40% of the dosing interval.[85] Meropenem pene-
trates rapidly and widely into a range of body fluids
and tissues;[9,92-94] mean Cmax values after single
intravenous doses of meropenem 1g were 0.54 to
6.39 mg/L in the respiratory tract, 2.01 to 14.6
mg/L in intra-abdominal tissue and 5.3 to 8.76
mg/L in skin and skin structures.[93] Meropenem
also penetrates into CSF although, as with other
β-lactam agents, permeability is greater in patients
with meningeal inflammation.[92]
Plasma concentrations of meropenem in healthy
volunteers were similar 1 hour after administration
of 1g intravenously as either a bolus (over 5 min-
utes) or an infusion (over 30 minutes).[86] In addi-
tion, another study found similar plasma concen-
trations 10 minutes after bolus injections over 2, 3
or 5 minutes.[95]
© Adis International Limited. All rights reserved.
663
Meropenem is primarily excreted by the kidney,
with 54 to 79% of a 1g dose excreted unchanged
in the urine and a further 19 to 27% excreted as a
microbiologically inactive open β-lactam metabo-
lite.[82-86] Unlike imipenem, meropenem is stable
against hydrolysis by human renal dehydro-
peptidase-1 (DHP-1), and concomitant administra-
tion with cilastatin or another DHP-1 inhibitor is
not required.[96,97]
3.1 Special Patient Groups
3.1.1 Patients with Serious Infections
Pharmacokinetic studies of meropenem in pa-
tients with serious infections are limited. One
study in 12 patients with intra-abdominal infec-
tions found that mean values for Cmax (47.6 mg/L)
and AUC (57.5 mg/L • h) after meropenem 1g were
lower than those seen in healthy volunteers in other
studies (54.8 to 61.6 mg/L and 66.9 to 77.5 mg/L • h,
respectively), whereas values for Vd were in-
creased (26.7L vs 12.5 to 23L; table III[88]); how-
ever, these changes were thought to result from
physiological changes following surgery rather
than the infections themselves.[88] Similar conclu-
sions were drawn from a study involving 11 pa-
tients with moderate or severe infection; although
AUC values were greater than those seen in healthy
volunteers (see table III), they did not change dur-
ing the course of treatment.[89]
3.1.2 Renal and Hepatic Impairment
As creatinine clearance decreases, both the total
body and renal clearance of meropenem decrease,
and the elimination half-life (t1⁄2) increases, in
keeping with the predominantly renal clearance of
this agent (table III). Dosage reductions are recom-
mended in the event of renal impairment (see sec-
tion 6). The recommended dosage in patients with
creatinine clearance of <0.6 L/h is meropenem
500mg administered once daily (half the standard
dose). However, in patients undergoing continuous
veno-venous haemofiltration, an estimated 45.3 to
47.2% of the dose was removed by haemofiltra-
tion, giving an estimated daily dosage requirement
of 862 to 898mg in these patients.[98,99] Increasing
Drugs 2000 Mar; 59 (3)
664 Hurst & Lamb

Table III. Pharmacokinetics of meropenem (administered as an intravenous infusion over 30 minutes)

Patient group [no. Dose (g) AUC (mg/L • Cmax (mg/L) Vd (L) t1⁄2 (h) CL (L/h) CLr (L/h) References
of pts] h)

Single dose
Healthy volunteers
Adults [4-8] 0.5 28-39.6 21.1-35.6 11.7-26.1 0.8-1.54 11.2-19.8 7.6-15.1 [76-80]
Adults [6-30] 1 66.9-77.5 54.8-61.6 12.5-23 1.0-1.4 11.3-16.8 7.9-11.9 [81-87]
Elderly [8] 0.5 58.3 37 13.2a 1.3 8.3a 5.9a [80]
Pts with renal impairment
Pts with mild renal 0.5 74.6-89.8 31.7-37.3 14.2-16.8 1.9-3.4 4.4-7.7 2.5-2.8 [77-79]
impairment (CrCL
1.6-3 L/h) [4-6]
Pts with moderate 0.5 140.5-156 25.4-33.1 17.5-26.7 4.6 3.2-4.6 1.3-1.7 [76,77,79]
renal impairment
(CrCL 0.6-1.5 L/h)
[3-10]
Pts with severe 0.5 203-256.1 27.2 19.7 5.6-5.7 2.0-2.5 0.4-0.7 [76,77]
renal impairment
(CrCL <0.6 L/h)
[2-10]
Pts requiring 0.5 360-416 40.3-53.1 11.4-17.6 9.7-10 1.1-1.5 NA [76,78,79]
haemodialysis [5-6]

Multiple doseb
Pts with serious infections
Pts with 1 57.5 47.6 26.7 1.0 18.9 8.2 [88]
intra-abdominal
infections [12]
Surgical pts with 1 100 NR 20.7 1.3 11.4 NR [89]
moderate/severe
infections [11]
Pts with renal or hepatic impairment
Pts with renal 1 118-344 28.1-205.1 18-29.5 2.3-4.5 3.2-8.6 NR [90,91]
failure requiring
CVVH [9]
Pts with liver 0.5 78.6 55 18.8 1.2 13.1 NR [87]
disease [8]
a Corrected to 1.73m2 of body surface area.
b Most studies did not specify on what day of treatment pharmacokinetic analysis was performed.
AUC = area under the plasma concentration-time curve; CL = total body clearance from plasma; CLr = renal clearance from plasma; Cmax
= peak plasma concentration; CrCL = creatinine clearance; CVVH = continuous veno-venous haemofiltration; NA = not applicable; NR = not
reported; pts = patients; t1⁄2 = elimination half-life; Vd = volume of distribution.

the dosage in this patient group to at least 1g daily
was suggested in all studies.[98-101]
No significant differences in pharmacokinetic
parameters for meropenem were seen between 8
patients with chronic stable alcoholic cirrhosis and
8 matched controls (table III; data for controls are
incorporated into overall range for healthy
adults).[87] Patients received meropenem 1g ini-
tially, followed 24 hours later by 5 additional doses
of 1g every 6 hours.
3.1.3 Children and the Elderly
No age- or dose-related effects on any pharma-
cokinetic parameters were observed in a single-
dose study involving 73 children (aged 2 months to
12 years) who received meropenem 20 mg/kg.[102]
Values for t1⁄2 and Vd were 1.1 hours and 0.4 L/kg,
respectively; total body clearance was 0.31 L/h/kg
and renal clearance was 0.12 L/h/kg. However, in
35 newborn infants, Vd after a single dose of
meropenem (dosage not stated) was 0.52 L/kg, and

© Adis International Limited. All rights reserved. Drugs 2000 Mar; 59 (3)
Meropenem: A Review
the t1⁄2 ranged from 5.48 to 7.81 hours (study re-
ported in abstract form).[103]
Values for t1⁄2 and AUC after single-dose mero-
penem 0.5g were higher in elderly volunteers (aged
67 to 80 years) than in young healthy volunteers
(1.3 hours and 58.3 mg/L • h vs 0.8 hours and 39.6
mg/L • h, respectively), whereas values for Cmax
were similar (37.0 vs 35.6 mg/L, respectively).[80]
These differences were attributed to the reductions
in renal excretion rate associated with age.
4. Clinical Efficacy
Studies have assessed the efficacy of initial em-
pirical monotherapy with meropenem in compari-
son with other commonly used regimens in a range
of serious infections in adults, children and neo-
nates, including those requiring ICU treatment.
Primary end-points in these studies were the per-
centages of patients experiencing a satisfactory
clinical or bacteriological response. A satisfactory
clinical response was defined as either cure or im-
provement of symptoms at the completion of treat-
ment; satisfactory bacteriological response was de-
fined as proven or presumptive eradication of the
causative organism(s), although 3 studies consid-
ered partial responses (eradication of at least 1 of
the original pathogens) to be satisfactory.[104-106]
Mortality, although recorded, was not used as a
primary end-point and none of the deaths that oc-
curred during treatment (2.9 to 13.2% of mero-
penem recipients, compared with 2.5 to 13.3% of
those who received other drugs) were considered
to be treatment-related.[104,105,107-111]
Although all these studies included patients
with severe infections, not all stated where the pa-
tients were treated; in addition, descriptions of ill-
ness severity varied in both detail and terminology.
Clinical studies in adults were included in this re-
view if either all[104,109,112] or most[107,108] of the
patients involved received treatment in an ICU.
Studies which did not state whether patients were
treated in ICUs were included if a significant pro-
portion of the patients were in a poor or critical
condition (42%; other studies generally involved
≤20%)[110] or required mechanical ventilation
© Adis International Limited. All rights reserved.
665
(70%);[105] another trial was included because the
mean Acute Physiology and Chronic Health Eval-
uation (APACHE) II scores for the 2 treatment
groups were 18 and 20, indicating serious ill-
ness.[111]
4.1 Adults
The majority of patients in these studies were
diagnosed with lower respiratory tract infections
(LRTIs; 52 to 78% of patients[104,107-111]), most of
which were hospital-acquired; 2 studies included
only patients with hospital-acquired LRTIs.[105,112]
Other diagnoses included intra-abdominal infec-
tions (11 to 42% of patients) and septicaemia (6 to
21%).[104,107-111] Patients with 2 or more infections
were included in some studies[107-111] (13.6[107] and
35%[108] of all patients in the 2 trials to give this
information).
4.1.1 Compared with Imipenem/Cilastatin
Clinical and bacteriological response rates were
similar in patients who received either meropenem
or imipenem/cilastatin (both 1g every 8 hours;
these are the recommended dosages for empirical
treatment) in 4 randomised multicentre trials (table
IV).[104,107-109] Satisfactory clinical responses to
treatment were observed in 76 to 88% of patients
who received meropenem compared with 68 to
85% of imipenem/cilastatin recipients; ranges for
satisfactory bacteriological responses were 67 to
94% and 60 to 88%, respectively.
Overall, more Gram-negative organisms were
eradicated with meropenem (70 to 100%) than with
imipenem/cilastatin (64 to 84%; table V) in the 3
studies that included this information.[104,107,109]
However, in 1 of the 3 studies eradication rates
were higher with imipenem/cilastatin (78 vs 70%,
respectively)[107] and there were no statistical com-
parisons in any of the studies. Eradication rates for
Gram-positive organisms were higher with im-
ipenem/cilastatin than with meropenem (87 to 96%
vs 69 to 83%, respectively); again, there were no
statistical comparisons. The 2 treatments appeared
equally effective against anaerobic isolates.
Drugs 2000 Mar; 59 (3)
666 Hurst & Lamb

Table IV. Comparative efficacy of meropenem (MEM) in the empirical treatment of patients with serious infections; summary of randomised
nonblind multicentre studies. All drugs were administered intravenously (bolus or infusion) every 8 hours unless otherwise stated

Study Diagnosis and patient status Drug and daily dosage Percentage of pts with satisfactory
[no. of pts enrolled] responsea [no. of evaluable pts]
clinical bacteriological

Compared with imipenem/cilastatin (IPM/C)

Colardyn et al.[107] Serious bacterial infections; 67% of MEM 3g 76 [90] 77b [61]
clinically evaluable pts in ICUs[204] IPM/C 3g 77 [87] 83b [54]
Garau et al.[108] Severe nosocomial infections; 90% MEM 3g 87c [66] 79c [42]
of pts in ICUs [151] IPM/C 3g c
74 [67] 71c [42]
[104]
Hartenauer et al. Serious bacterial infections; all pts MEM 3g 88 [34] 94 [17]
in ICUs [80] IPM/C 3g 85 [39] 88 [25]
Verwaest et al.[109] Serious bacterial infections; all pts MEM 3g 77 [87] 67 [73]
in ICUs [212] IPM/C 3g 68 [91] 60 [73]

Compared with ceftazidime (CAZ) plus amikacin (AN) or tobramycin (TM)

Alvarez-Lerma et al.[112] Mechanical ventilation-associated MEM 3g 83* [59] 74* [53]
pneumonia; all pts in ICU [140] CAZ 6g + AN 15 mg/kg 66 [59] 54 [48]
q12h
Mouton et al.[110] Serious bacterial infections; 42% of MEM 3g 93 [43]d 100 [30]d
pts in poor/critical condition [237] 81 [37] e
71 [24]e
f
83 [12] 100 [12]f
g
87 [15] 56 [9]g
CAZ 6g + AN 15 mg/kg q8 79 [39] d
87 [30]d
or 12h
72 [32]e 76 [17]e
f
94 [17] 100 [17]f
g
100 [25] 100 [12]g
Sieger et al.[105] Nosocomial LRTIs; 70% of pts MEM 3g 89* [63] 89** [63]
required mechanical ventilation CAZ 6g + TM 3 mg/kg 72 [58] 67 [58]
[211]

Compared with cefuroxime (CXM) plus gentamicin (GM)

Jaspers et al.[111] Serious infections in the elderly; MEM 3g 70 [37] 68 [22]
mean APACHE II score 18 for CXM 4.5g + GM 4 mg/kgh 73 [33] 63 [19]
MEM recipients, 20 for CXM + GM
recipients [79]
a Clinical response was satisfactory if either cure or improvement of symptoms occurred. Bacteriological responses were satisfactory if
proven or presumptive eradication of the causative organism(s) took place. Responses were assessed at the end of treatment.
b Percentage calculated on the number of clinical isolates obtained from these patients; 110 isolates from MEM recipients, 109 from
IPM/C recipients.
c Weighted to allow for different sites of infection.
d Results for community-acquired LRTI.
e Results for nosocomial-acquired LRTI.
f Results for septicaemia.
g Results for complicated UTI.
h Ten patients also received metronidazole 500mg q6h.
APACHE = Acute Physiology and Chronic Health Evaluation; ICU = intensive care unit; LRTI = lower respiratory tract infection; pts = patients;
qxh = every x hours; UTI = urinary tract infection; * p < 0.05, ** p = 0.006 vs comparator.

© Adis International Limited. All rights reserved. Drugs 2000 Mar; 59 (3)
Meropenem: A Review 667

Table V. Comparative efficacy of meropenem against Gram-positive, -negative and anaerobic bacteria in randomised nonblind multicentre
trials in patients with serious infections. All drugs were administered intravenously every 8 hours unless otherwise stated
Study Drug and daily dosage Organisms eradicated (%) [total number of isolates]
Gram-negative Gram-positive anaerobic

Compared with imipenem/cilastatin (IPM/C)

Colardyn et al.[107] MEM 3g 70 [64] 83 [30] 94 [16]
IPM/C 3g 78 [67] 87 [31] 100 [11]
Hartenauer et al.[104] MEM 3g 100 [14] 69 [16] NR
IPM/C 3g 84 [25] 96 [24] NR
Verwaest et al.[109] MEM 3g 82 [71] 70 [30] 100 [8]
IPM/C 3g 64 [85] 96 [28] 94 [18]

Compared with ceftazidime (CAZ) plus amikacin (AN) or tobramycin (TM)

Alvarez-Lerma et al.[112] MEM 3g 83 [54] 89 [18] NR
CAZ 6g + AN 15 mg/kg q12h 72 [47] 62 [13] 100 [1]
Mouton et al.[110] MEM 3g 79 [58] 97 [34] NR
CAZ 6g + AN 15 mg/kg q8 or 12h 86 [65] 96 [28] NR
Sieger et al.[105] MEM 3g 93 [80] 80 [15] NR
CAZ 6g + TM 3 mg/kg 79 [78] 65 [23] NR
NR = not reported; pts = patients; qxh = every x hours.

4.1.2 Compared with
Cephalosporin-Based Regimens
Significantly more patients with serious noso-
comial respiratory infections experienced a satis-
factory clinical and bacteriological response with
meropenem (1g every 8 hours) than with ceftaz-
idime (2g every 8 hours) and either amikacin (7.5
mg/kg twice daily)[112] or tobramycin (1 mg/kg ev-
ery 8 hours)[105] in 2 randomised multicentre stud-
ies (table IV, fig. 2). Satisfactory clinical responses
were observed in 83 and 89% of evaluable
meropenem recipients compared with 66 and 72%
of those who received ceftazidime and either ami-
kacin (p = 0.035) or tobramycin (p = 0.04). Eradi-
cation or presumptive eradication of pathogens oc-
curred in 74 and 89% of meropenem recipients
(compared with 54 and 67% with ceftazidime and
either amikacin or tobramycin, respectively; p =
0.042 and 0.006, respectively)[table IV]. Mero-
penem was more effective than ceftazidime-based
treatments in eradicating both Gram-negative (83
and 93% vs 72 and 79%, respectively) and Gram-
positive (89 and 80% vs 62 and 65%, respectively)
organisms in these studies, although there were no
statistical comparisons (table V).
In contrast, 2 other studies found no significant
differences in clinical and bacterial responses be-
tween patients who received meropenem and those
who received cephalosporin-based treatments (ta-
ble IV); only 1 of these studies included data relat-
ing to effects on Gram-negative and Gram-positive
organisms, which were similar between treatments
(table V).[110] However, patients in these studies
had been diagnosed with a range of infections, in-
cluding respiratory, intra-abdominal, urinary tract
and bloodstream. One of these studies involved only
patients aged ≥65 years (see section 4.2.3).[111]
4.2 Special Patient Groups
4.2.1 Children
Meropenem is effective in the treatment of a
range of serious non-CNS infections in children
(also reviewed in Bradley et al.[113]). It can be ad-
ministered as an intravenous bolus (see sections 3
and 6), making it useful in paediatric treatment
where small intravenous volumes are often re-
quired; this type of administration has been well
tolerated clinically (see section 5.2).
In 3 nonblind multicentre trials in children
(aged 1 month to 15 years) with serious bacterial
infections (not including meningitis), meropenem
monotherapy (10 to 20 mg/kg every 8 hours) was
as effective as either ceftazidime monotherapy (10
to 30 mg/kg every 8 hours) or cefotaxime-based

© Adis International Limited. All rights reserved. Drugs 2000 Mar; 59 (3)
668
100
Patients experiencing satisfactory response (%)
* **
80
60
40
20
0 children had been previously treated unsuccess-
Clinical Bacteriological
[105]
Sieger et al.
Fig. 2. Comparative efficacy of meropenem (MEM) and
ceftazidime (CAZ)-based treatments in 2 randomised nonblind
clinical trials in patients with nosocomial lower respiratory tract
infections (LRTIs).[105,112] Percentage of patients experiencing
satisfactory clinical (cure or improvement of symptoms) or bac-
teriological (presumed or confirmed eradication of causative or-
ganisms) responses. One trial involved 140 patients with
mechanical ventilation-associated pneumonia who received ei-
ther MEM (1g every 8 hours) or CAZ (2g every 8 hours) plus
amikacin (7.5 mg/kg twice daily); 118 patients were clinically
evaluable and 101 were bacteriologically evaluable.[112] The
other involved 211 patients with hospital-acquired LRTIs who
received either MEM 1g or CAZ 2g and tobramycin 1 mg/kg (all
drugs given every 8 hours); 63 MEM recipients and 58 CAZ-
based tretment recipients were evaluable clinically and bacteri-
ologically.[105] * p < 0.05, ** p = 0.006 vs CAZ-based treatment.
therapies (100 to 160 mg/kg daily in 2 to 4 divided
doses)[table VI].[106,114,115] However, these trials
did not state whether these patients were in ICUs
and only 2 of them included information on patient
condition. In 1 trial,[115] 36% of the children were
considered to be in poor condition and in the other
approximately 10% of patients were described as
poor or critical,[106] although similar rates of satis-
factory clinical and bacteriological responses were
seen in all 3 studies (97 to 98% and 88 to 97% with
meropenem vs 93 to 96% and 89 to 93% with com-
parators)[table VI].
The most common diagnosis in all studies was
that of LRTI (43 to 63% of patients), although chil-
dren with urinary tract, intra-abdominal, skin and
© Adis International Limited. All rights reserved.
Hurst & Lamb
MEM bloodstream infections were also included. Only 2
CAZ-based
studies included a break-down of bacteriological
* response according to the nature of the organism;
* meropenem treatment eradicated 93 to 100% of
Gram-negative isolates and 92 to 94% of Gram-
positive isolates, compared with 80 to 95% and 83
to 100%, respectively, with cefotaxime-based ther-
apies.[106,115]
Cure or improvement was observed in 16 of 20
paediatric ICU patients (aged 1 month to 14 years)
who received meropenem, either as monotherapy
or in combination with other agents; 18 of these
Clinical Bacteriological fully with other antibacterial agents.[116] Most pa-
[112]
Alvarez-Lerma et al. tients were diagnosed with sepsis (11); the most
common pathogens were Acinetobacter spp., Pseu-
domonas spp. and Enterobacter.
4.2.2 Neonates
Although not formally approved for use in neo-
nates, meropenem has been used with success in 4
small noncomparative studies (3 reported in ab-
stract form[117-119]) in neonatal ICU patients with a
range of serious infections.[117-120] Pneumonia and
sepsis were the most common diagnoses, with P.
aeruginosa and Enterobacter, Klebsiella and
Acinetobacter spp. most commonly isolated as
causative pathogens. In 2 studies (n = 15[120] and
n = 7[117]), all of the neonates showed clinical im-
provement; in the others, 16 of 24[118] and 13 of
15[119] patients were cured or improved with mero-
penem. Total daily doses of meropenem ranged
from 15 mg/kg to 120 mg/kg, usually given in 3
divided doses; in 1 of the studies,[118] 6 of the 24
patients received meropenem in combination with
vancomycin or a cephalosporin. Most or all of the
neonates involved in these studies had failed to re-
spond to previous antibacterial therapy.
4.2.3 Elderly Patients
Meropenem was as effective as cefuroxime plus
gentamicin (with or without metronidazole) in 79
patients with serious bacterial infections aged ≥65
years (see table IV).[111] Clinical responses were
satisfactory in 70% of meropenem recipients and
73% of patients who received cefuroxime-based
treatment; bacterial responses were satisfactory in
Drugs 2000 Mar; 59 (3)
Meropenem: A Review 669

68 and 63% of patients, respectively. Most patients
had been diagnosed with pneumonia (52%) or in-
tra-abdominal infection (13%). Treatment location
was not stated, but mean APACHE II scores for
both patient groups indicated severe illness.
5. Tolerability
There are no meta-analyses that assess the tol-
erability of meropenem in patients in ICU alone.
However, a recent review of the tolerability profile
of meropenem analysed data from 46 clinical trials
involving 9514 hospitalised patients with serious
bacterial infections.[121] All except 1 of the trials
were prospective, controlled and randomised (the
exception being a noncomparative study in bone
and joint infections) and compared meropenem
(5026 treatment exposures) with either cephalo-
sporin-based treatments (2423 treatment expo-
sures), imipenem/cilastatin (1802 treatment expo-
sures) or clindamycin and an aminoglycoside (527
treatment exposures). The most common infections
were LRTIs (2196 treatment exposures), intra-
abdominal infections (2131 treatment exposures)
and urinary tract infections (1192 treatment expo-
sures); patients with febrile neutropenia (772 treat-
ment exposures) and children (926 treatment expo-
sures) were also included in the analysis.
Overall, the total incidences of adverse events
and drug-related adverse events were similar with
all treatment regimens (fig. 3a), although no statis-
tical data were provided. The most frequently
reported drug-related adverse events with mero-
penem were diarrhoea (2.3% of treatment expo-
sures), rash (1.4%), nausea and vomiting (1.4%)
and inflammation at the injection site (1.1%) [fig.
3b]. Imipenem/cilastatin was associated with more
nausea and vomiting than other treatments, and
cephalosporin-based treatments with less; how-
ever, there were no statistical comparisons.
Other adverse events associated with mero-
penem which were considered to be drug-related
(headache, sepsis, abdominal pain and pruritus) all
occurred in 0.1 to 0.4% of treatment exposures.[121]
Analysis by dosage did not indicate any significant
difference in the incidence of diarrhoea, rash, pru-
ritus and nausea and vomiting. However, oral
thrush appeared to be more common in patients
receiving >50 mg/kg/day (approximately 1 vs

Table VI. Comparative efficacy of meropenem (MEM) in the empirical treatment of children with serious infections; summary of multicentre
randomised nonblind studies. All drugs were administered intravenously (as a bolus or an infusion) every 8 hours unless otherwise stated
Study Diagnosis and patient status No. of pts Treatment (mg/kg) Response ratea (%) [no. of evaluable pts]
[age range] enrolled clinical bacteriological
Principi & Marchisio Severe acute bacterial 98 MEM 20 97 [90] 88 [16]
[114]
infections [4mo- 15.2y] 87 CAZ 10 to 30 95 [85] 93 [14]
Schuler[115] Hospitalised with bacterial 119 MEM 10 or 20 98 [96] 89 [28]
infections requiring 51 CTXb 100 to 150c 93 [46] 90 [10]
parenteral therapy; 36% in
poor condition, ≈50% with
pre-existing disorders
[4mo-12.9y]
Snedden et al.[106] Non-CNS infections, ≈10% 253 MEM 20 98 [205] 97 [112]
in poor or critical condition 252 CTXd 40 q6h 96 [178] 89 [48]
[1mo-13y]
a Clinical response was satisfactory if either cure or improvement of symptoms occurred. Bacteriological responses were satisfactory if
proven or presumptive eradication of the causative organism(s) took place.
b 35 children received CTX alone, 5 received CTX and metronidazole 7.5 mg/kg q8h and 11 received CTX and amikacin 15 mg/kg daily (in
2 to 3 equal doses).
c In 2 to 4 equal doses.
d Clindamycin 10 mg/kg and/or tobramycin 2 to 2.5 mg/kg (both administered q8h) could be added at the discretion of the investigator;
80% of pts received CTX alone.
CAZ = ceftazidime; CTX = cefotaxime; pts = patients; qxh = every x hours.

© Adis International Limited. All rights reserved. Drugs 2000 Mar; 59 (3)
670 Hurst & Lamb

a
50
MEM
IPM/C
CPH-based
CLN + AMG
40

30

20

10
Incidence (% of treatment exposures)

0
All Drug-related Withdrawal Mortality
adverse events adverse events

b
4

0
Diarrhoea Rash Nausea/vomiting Injection site
inflammation

Fig. 3. Comparative tolerability of meropenem (MEM). Data from a meta-analysis of 46 clinical trials in patients with serious bacterial
infections.[121] (a) Percentage of treatment exposures associated with adverse events, drug-related adverse events, treatment with-
drawal and death, (b) drug-related adverse events occurring in >1% of patients receiving MEM. Patients received either MEM (5026
treatment exposures), imipenem/cilastatin (IPM/C; 1802 treatment exposures), cephalosporin-based treatment (CPH-based; 2423
treatment exposures) or clindamycin and an aminoglycoside (CLN + AMG; 527 treatment exposures); all except 1 of these trials were
comparative and randomised. Most adult MEM recipients received either 1g (2391 patients) or 500mg (1215 patients) every 8 hours;
dosages of comparators were those recommended by the manufacturers.

© Adis International Limited. All rights reserved. Drugs 2000 Mar; 59 (3)
Meropenem: A Review
0.1% with 25 to 50 mg/kg/day and 0.3% with <25
mg/kg/day) and injection site inflammation was
more common in patients receiving <25 mg/kg/day
(approximately 2.6% vs 1.2% with 25 to 50
mg/kg/day and 0.5% with >50 mg/kg/day) [all val-
ues estimated from a graph].
Comparative studies involving patients with se-
rious infections (ICU-acquired or otherwise; see
section 4) that included adverse event data also
reported similar incidences of adverse events
with meropenem to those seen with either imi-
penem/cilastatin or cephalosporin-based treat-
ments.[104,105,107-109,111,122] Individual event fre-
quencies were similar to those seen in the general
population.
Nausea and vomiting during treatment with im-
ipenem/cilastatin relates to the speed of drug ad-
ministration as well as the dose.[123,124] This rela-
tionship is not seen with meropenem, which can be
administered more rapidly; in 3 clinical studies in
adults with serious infections (most not treated in
ICUs) where meropenem 1g was given as a bolus
to 114 patients, only 1 case of drug-associated nau-
sea and vomiting was reported.[110,125,126] In addi-
tion, in 2 studies meropenem was administered to
children as a bolus injection in 40 to 55% of pa-
tients without any reports of nausea and vomit-
ing.[114,115]
Laboratory tests indicated similar incidences of
adverse events with meropenem, cephalosporin-
based treatments and imipenem/cilastatin.[121]
Drug-related elevations in hepatic enzymes (AST,
ALT and alkaline phosphatase) and thrombocyto-
sis were observed in 1.5 to 4.3% of patient expo-
sures to meropenem; all other laboratory abnor-
malities considered to be associated with
meropenem occurred in <1% of patients. Similar
findings were seen in comparative trials in ICU
patients.[104,105,107-109,111,122]
5.1 CNS Toxicity
Animal[127,128] and human[124,129,130] data show
that meropenem is well tolerated by the CNS in
doses of up to 2g every 8 hours, even in patients
with bacterial meningitis. In contrast, although the
© Adis International Limited. All rights reserved.
671
overall incidence of seizures in hospitalised pa-
tients receiving treatment with imipenem/ cila-
statin ranged from 0.2 to 1.5% in large reviews, the
higher incidences reported in some studies in pa-
tients with CNS pathology and/or renal impair-
ment (20 to 32%) or children with meningitis
(48%) mean that this agent is not recommended for
use in these groups; in other patients, the maximum
recommended dosage of imipenem/cilastatin is 4g
daily.[131] However, in a recent comparative
randomised double-blind study in patients with se-
vere pneumonia, 11 of the 200 patients (6%) who
received imipenem/cilastatin 1g every 8 hours ex-
perienced seizures (all during treatment), com-
pared with 3 of the 202 patients (1%) receiving
ciprofloxacin (p = 0.028).[132]
In a meta-analysis of data from 46 clinical trials
involving 9514 patients with serious bacterial in-
fections, 4 patients without meningitis (0.08%) ex-
perienced seizures that were thought to be related
to meropenem treatment compared with 5 (0.28%)
imipenem/cilastatin recipients (fig. 4); patients
with a history of CNS disorders were excluded
from the trials.[121] All 4 patients who experienced
seizures during meropenem treatment were elderly
(aged >70 years) and 2 had renal impairment [cre-
Incidence (% of treatment exposures)
0.6
All seizures
Drug-related seizures
0.5
0.4
0.3
0.2
0.1
0
MEM IPM/C CPH-based CLN + AMG
Fig. 4. Comparative incidence of seizures with meropenem
(MEM) and other antibacterial regimens. All seizures and those
considered to be drug-related occurring during treatment with
either MEM, imipenem/cilastatin (IPM/C), cephalosporin-based
regimens (CPH-based) or clindamycin and an aminoglycoside
(CLN + AMG) in patients with serious infections other than men-
ingitis (9235 treatment exposures); data from a meta-analysis
of 46 clinical trials (see fig. 3 legend for further details).[121]
Drugs 2000 Mar; 59 (3)
672
atinine clearance (CLCR) 2.5 and 3.1 L/h]. In a sub-
group of largely paediatric patients with meningitis
(n = 540), meropenem was compared with cepha-
losporin-based therapies only, as imipenem/
cilastatin is contraindicated in this group; no drug-
related seizures were reported with either treat-
ment. None of the 5 seizures reported during treat-
ment with meropenem in clinical trials involving
adult patients with serious or ICU-acquired infec-
tions were considered to be drug-related,[105,108,109]
and there were no drug-related seizures in children
or neonates with serious infections who received
meropenem in clinical trials.[106,114-118]
5.2 Special Patient Groups
A recent review analysing results from 26 phase
III studies found that, in general, renal impairment
(CLCR <3.1 L/h) had little effect on the frequency
of drug-related adverse events experienced with ei-
ther meropenem or comparators (imipenem/
cilastatin or cephalosporin-based treatments), al-
though there were no statistical comparisons.[133]
Vomiting during meropenem therapy was slightly
more common in renally impaired patients (1.4 vs
0.2% in patients without renal impairment).
Comparative clinical studies in children with se-
rious infections found no significant differences in
incidences of adverse events experienced by recip-
ients of either meropenem or cephalosporin-based
therapies,[106,114,115] nor was there any evidence of
any association between age or dosage and adverse
event incidence.[115] No adverse effects were re-
ported during meropenem treatment (total daily
doses of 15 mg/kg to 120 mg/kg) in 4 small studies
in neonates.[117-120]
An analysis of data from 26 clinical trials found
that patients aged >65 years who received mero-
penem experienced more adverse events than
younger patients (45 vs 39%), although frequencies
of drug-related adverse events (17.9 vs 18%) and
withdrawals for drug-related adverse effects (2 vs
1%) were similar in both groups.[133] Similar pat-
terns were seen in comparator groups who received
either imipenem/cilastatin or cephalosporin-based
treatments.
© Adis International Limited. All rights reserved.
Hurst & Lamb
A comparative study involving 79 patients aged
≥65 years found similar types and frequencies of
adverse events with meropenem to those with cefur-
oxime-based treatments; adverse events were re-
ported in 49 and 45% of patients, respectively.[111]
6. Dosage and Administration
For empirical treatment of most serious infec-
tions (including nosocomial pneumonia, septicae-
mia and peritonitis), meropenem (when used em-
pirically) should be administered at a dosage of 1g
intravenously every 8 hours.[46,134] It can be given
as a bolus (over 5 minutes) or as an infusion (over
30 minutes). If pathogen susceptibilities are
known, it may be appropriate to reduce the dosage
by half, as with imipenem/cilastatin; in contrast to
imipenem/cilastatin, however, increased meropenem
dosages of up to 2g every 8 hours can be used if
necessary (for example, in the treatment of organ-
isms with intermediate resistance).[129] Appropri-
ate dose selection in serious infections is important
in reducing the risk of resistance developing during
treatment.[107]
Meropenem dosage should be reduced in pa-
tients with renal impairment (CLCR ≤3 L/h); those
with a CLCR of 1.6 to 3 L/h should receive
meropenem 1g every 12 hours and those with a
CLCR of 0.6 to 1.5 L/h should receive meropenem
500mg every 12 hours. Patients with CLCR <0.6
L/h should receive meropenem 500mg every 24
hours.[134] As meropenem is cleared by haemo-
dialysis (see section 3.1.2), it should be adminis-
tered after completion of haemodialysis at a dosage
appropriate to the type and severity of the infec-
tion.[134]
Children aged 3 months to 12 years should re-
ceive meropenem 10 to 20 mg/kg every 8 hours,
depending on the severity and type of infection and
the susceptibility of the pathogen; 40 mg/kg is rec-
ommended for children with meningitis. Children
weighing >50kg should receive adult dosages.[134]
Elderly patients with normal renal function and pa-
tients with hepatic impairment do not require dos-
age adjustment.[134]
Drugs 2000 Mar; 59 (3)
Meropenem: A Review
7. Place of Meropenem in the
Management of Patients in
Intensive Care
Infections in ICU patients are a common prob-
lem that can have serious consequences. Patients
with severe sepsis[5] or nosocomial infections[1,7]
have higher mortality rates than patients without
infections. One study in 213 ICU patients reported
mortality rates of 53% in those with infections
compared with 20% in those without.[5] Significant
increases in mortality in patients with ICU-ac-
quired pneumonia [odds ratio (OR) 1.91; 95% con-
fidence interval (CI) 1.6 to 2.29], clinical sepsis
(OR 3.5; 95% CI 1.71 to 7.18) or bloodstream in-
fection (OR 1.73; 95% CI 1.25 to 2.41) were also
found in a point-prevalence survey of 10 038 Eu-
ropean ICU patients,[1] although another study
found that primary nosocomial bloodstream infec-
tions did not increase mortality rates (35.3 vs
30.9% in uninfected patients).[6] Patients with ven-
tilator-associated pneumonia had significantly
higher mortality rates than those without (37.2 vs
8.5%, p < 0.001).[135]
Not surprisingly, infections in the ICU are also
associated with increases in costs. Primary noso-
comial bloodstream infections in ICU patients
were associated with significant increases in direct
costs [mean difference $US34 508 (1999 values)
per admission, p = 0.008] versus those for matched
patients without infections.[6] In another study, the
median cost of all patients with infection was ap-
proximately 6-fold greater than that for patients
without infection [$US10 622.65 vs 1 666.87
(1999 dollars); no p value given]; this study in-
volved 213 patients admitted consecutively to an
adult general ICU in the UK.[5] The increases in
costs were attributed to the longer lengths of stay
and greater numbers of therapeutic interventions
required in patients with infections.
In addition, infections in ICUs are more likely
to be serious than those acquired elsewhere. Sever-
ity of infection depends on the virulence and num-
bers of the micro-organisms as well as the integrity
of host defences of the patient;[8] patients in ICUs
often have impaired host defences because of con-
© Adis International Limited. All rights reserved.
673
current illness, medications or the use of such in-
vasive devices as mechanical ventilators or vascu-
lar catheters.[2] High usage of antibacterials in
ICUs has resulted in higher rates of antibacterial
resistance than those observed in isolates from gen-
eral wards;[136] although frequencies of resistant bac-
teria vary between countries, multidrug-resistant
staphylococci, drug-resistant enterococci (especially
vancomycin-resistant; these accounted for almost 14%
of ICU isolates in the US in 1994[137]) and cepha-
losporin-resistant Enterobacteriaceae[136,138-140] are
of particular concern. Organisms not previously
considered to be serious pathogens, such as
Acinetobacter spp., are also becoming increasingly
common.[136]
A number of strategies and treatment guidelines
have been put forward in order to minimise the
impact of these pathogens and/or prevent their
emergence.[137,141-144] These include general meas-
ures to minimise resistance, such as handwashing
and isolation of affected patients, in addition to
considerations that are specific for antibacterials,
such as ensuring that the pathogen is sensitive to a
given agent and that the dosages used are adequate.
Surveillance programmes are also very important
in monitoring trends in resistance development
both locally and internationally. In ICUs, other pre-
ventative measures used have included antibiotic-
impregnated vascular catheters and selective de-
contamination of the digestive tract (SDD).[145]
However, recent placebo-controlled studies have
not found any benefits from SDD, and in addition
there are concerns regarding the development of
drug-resistant bacteria and superinfection.[146]
In serious infections it is often necessary to be-
gin treatment before any or all pathogens have
been isolated.[8] Ideally, any initial treatment
should cover all likely pathogens and local resis-
tance patterns until the organism or organisms re-
sponsible are identified. This may involve mono-
therapy with a broad spectrum antibacterial agent
or combination therapy; each approach has its own
advantages and disadvantages, with no clear clini-
cal evidence as to which is best.[147,148] Combina-
tions of antibacterial agents can provide a broad
Drugs 2000 Mar; 59 (3)
674
spectrum of activity and also provide the opportu-
nity to exploit any synergism between the chosen
agents; however, compared with monotherapy,
these regimens take more time to prepare and ad-
minister, may require the additional inconvenience
and expense of drug monitoring (if aminoglycos-
ides are used) and may be associated with more
adverse effects (such as physical drug incompati-
bility and altered gastrointestinal flora).[148]
Although there have been no randomised trials
in this area, a prospective survey of 490 episodes
of nosocomial pneumonia found that modification
of empirical therapy occurred significantly more
often in those patients receiving combination treat-
ment compared with those who received monother-
apy (relative risk 1.29; 95% CI 1.02 to 1.65, p =
0.021).[149] Overall, empirical antibacterial treat-
ment was modified in 43.7% of cases; the most
frequent reasons for modification were isolation of
a micro-organism that was not covered by treat-
ment (62.1%), poor clinical response (36%) and
detection of a resistant strain during treatment
(6.6%).
In ICU infections, commonly used empirical
treatment combinations include a cephalosporin
(second- or third-generation) and/or an aminogly-
coside and/or metronidazole and/or a glycopep-
tide.[148] Quinolones, piperacillin/tazobactam and
newer cephalosporins (such as cefepime) have
been used as monotherapy, although breadth of
spectrum and trends in resistance development
with these agents may limit their usefulness in cer-
tain infections (such as those caused by P. aerugin-
osa and anaerobes).[148] Novel forms of treatment
such as host defence cationic peptides, immuno-
logical modulators and antiendotoxin strategies are
being investigated with mixed results.[54,150-152]
Meropenem is a carbapenem antibacterial with
in vitro activity against a wide range of Gram-pos-
itive and -negative aerobic and anaerobic organ-
isms (section 2.1). It was more active against En-
terobacteriaceae isolated from general and ICU
patients than any other agent tested, including im-
ipenem (section 2.1.1). ICU isolates of P. aerugin-
osa were intermediately susceptible to meropenem
© Adis International Limited. All rights reserved.
Hurst & Lamb
and resistant to all other agents tested; ICU isolates
of A. baumanii were intermediately susceptible to
both meropenem and imipenem, but resistant to all
other agents tested (see table II). Imipenem was
more active than meropenem against Gram-posi-
tive bacteria, with differences in MIC90 against S.
aureus, E. faecalis and S. epidermidis of 2- to 8-
fold (section 2.1.2). Both carbapenems were highly
active against B. fragilis and other anaerobes (sec-
tion 2.1.3).
Although resistance to the carbapenems is un-
common, some organisms (including S. maltophila
and E. faecium) possess intrinsic resistance (sec-
tions 2.2.1 and 2.2.3), and reduced susceptibility to
meropenem has been observed in organisms exhib-
iting multiple resistance mechanisms (section 2.2).
Careful monitoring and appropriate usage are nec-
essary to ensure that the efficacy of meropenem is
preserved; full results from programmes such as
the MYSTIC study are awaited with interest.[19]
There is evidence that increased use of car-
bapenems may select for greater numbers of infec-
tions caused by resistant organisms such as S.
maltophilia.[153]
In comparative trials, empirical monotherapy
with meropenem was as effective as imipenem/
cilastatin in the treatment of a range of serious in-
fections in adults, including patients in ICUs (sec-
tion 4.1.1). Clinical cure or improvement was ob-
served in 76 to 88% of patients compared with 68
to 85% with imipenem/cilastatin; bacteriological
efficacy (presumed or proven eradication of patho-
gens) occurred in 67 to 94% and 60 to 88% of pa-
tients, respectively. Although in vitro results sug-
gest that meropenem is more active than imipenem
against Gram-negative organisms and less active
against Gram-positive organisms, there was no sta-
tistically significant evidence for this in these clin-
ical trials.
Significantly more satisfactory clinical and bac-
terial responses, including eradication of Gram-
negative and Gram-positive organisms, were seen
with meropenem than with ceftazidime plus ami-
kacin or tobramycin in 2 trials involving patients
with nosocomial lower respiratory tract infections,
Drugs 2000 Mar; 59 (3)
Meropenem: A Review
although 2 similar studies in patients with a range of
infections failed to find any significant differences
between meropenem and cephalosporin-based
treatments (section 4.1.2).
Meropenem monotherapy was as effective as
cephalosporin-based treatments in children with
serious infections (section 4.2.1); however, fewer
critically ill patients were involved than in adult
trials. According to 4 small noncomparative stud-
ies, meropenem has also been used successfully in
neonates (section 4.2.2).
Meropenem is well tolerated in both adults and
children, whether administered as an infusion or as
a bolus (section 5); incidences and types of adverse
events were similar to those seen with cephalospo-
rin-based treatments. Incidences of drug-related
seizures during meropenem treatment are low, even
in patients with predisposing factors such as men-
ingitis, and similar to those seen with cephalospo-
rin-based treatments (section 5.1). For this reason
meropenem, unlike imipenem/cilastatin, is ap-
proved for use in the treatment of bacterial menin-
gitis. No drug-related seizures have been reported
with meropenem in clinical trials involving chil-
dren or neonates with serious infections (including
meningitis; section 5.1). Unlike imipenem/cilas-
tatin, meropenem is not associated with nausea and
vomiting related to dosage and/or rapidity of ad-
ministration.[123]
In conclusion, meropenem is an important agent
for the empirical monotherapy of serious infec-
tions in adults and children in ICUs. It is active
against most common ICU pathogens. In compar-
ative trials, meropenem was as effective as im-
ipenem/cilastatin (both 1g every 8 hours) in pa-
tients with serious infections (including those
acquired in ICU) and can be given as a bolus. Com-
pared with cephalosporin-based combination treat-
ments, meropenem monotherapy appears as well
tolerated and may be more effective in the treat-
ment of nosocomial LRTIs; it also offers the con-
venience of monotherapy. Meropenem can be
given in doses of up to 2g every 8 hours if neces-
sary. Meropenem has an important role in the em-
© Adis International Limited. All rights reserved.
675
pirical treatment of serious infections in adults and
children in ICUs.
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Correspondence: Miriam Hurst, Adis International Limited,
41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auck-
land 10, New Zealand.
E-mail: demail@adis.co.nz
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