Review
Recent developments in
1. Introduction
2. Chemistry of carbapenems
3. Mechanism of action
4. Mechanisms of resistance
5. Clinical use
6. Conclusion and expert opinion
Ashley Publications
www.ashley-pub.com
carbapenems
Giovanni Bonfiglio†, Giovanni Russo & Giuseppe Nicoletti
Dipartimento di Scienze Microbiologiche, Università di Catania, Via Androne 81, 95124, Catania,
Italy
Carbapenems are β-lactam antibiotics characterised by the presence of a β-
lactam ring with a carbon instead of sulfone in the 4-position of the thyazo-
lidinic moiety. The first carbapenem to be utilised in therapy was imipenem,
the N-formimidoyl derivative of thienamycin. Imipenem is coadministered
with cilastatin, an inhibitor of human renal dehydropeptidase I, as imipenem
is hydrolysed by this enzyme. Meropenem was the first carbapenem with a
1-β-methyl group and 2-thio pyrrolidinyl moiety, which renders this antibi-
otic stable to renal dehydropeptidase I. Other carbapenems for parenteral
administration later discovered include biapenem, panipenem, ertapenem,
lenapenem, E-1010, S-4661 and BMS-181139. Carbapenems which are orally
administered include sanfetrinem, DZ-2640, CS-834 and GV-129606. Carbap-
enems have an ultra-broad spectrum of antibacterial activity and stability to
almost all clinically relevant β-lactamases. This differentiates them from all
other currently available classes of β-lactam antibiotics. However, Class B β-
lactamases, along with some rare Class A and D enzymes, are able to hydro-
lyse these antibiotics. Although Class B enzymes are generally chromosoma-
lly-encoded (isolated from Stenotrophomonas maltophilia, Aeromonas spp.,
Bacillus cereus, Bacteroides fragilis, Flavobacterium spp. and Legionella gor-
manii), plasmid-metallo-β-lactamases now are appearing in B. fragilis, Pseu-
domonas aeruginosa, Acinetobacter baumannii and members of
Enterobacteriaceae such as Serratia marcescens and Klebsiella pneumoniae.
The number of these enzymes compared to the number of other β-lactamase
types is still low, however, it is likely that they will spread due to the
increased selective pressure of carbapenem use. The very broad spectrum of
antimicrobial activity associated with a good clinical efficacy and a favoura-
ble safety profile makes the carbapenems valuable as ‘first-line’ antibiotics
in initial empirical therapy for the treatment of severe infections.
Keywords: antibiotics, β-lactams, carbapenemases, carbapenems, serious infections
Expert Opin. Investig. Drugs (2002) 11(4):529-544
1. Introduction
The β-lactam antibiotics comprise more than half of all antimicrobial drugs. The
extraordinary efficacy and tolerability of this class of antibiotics justifies their ample
development and they represent the most commonly prescribed antibacterial agents.
Until 1970, penicillins and cephalosporins were the only examples of naturally-
occurring β-lactam antibiotics. The discovery of 7-α-methoxy-cephalosporins from
Streptomyces in 1971, stimulated the search for novel β-lactam antibiotics from
microbes or by laboratory synthesis. Today this class of antibiotics can be divided
into several groups according to their structure, namely monobactams, cephems
(cephalosporins), oxacephems, carbacephems, penams (penicillins), oxapenams,
penems and carbapenems.
β-Lactam antibiotics share a common structural similarity, the four-membered
lactam ring. In most β-lactam antibiotics, the β-lactam ring is fused through the
2002 © Ashley Publications Ltd ISSN 1354-3784 529
Recent developments in carbapenems
R2
1
R3
2 O
R1 6 5
7 N4 3
O OH
Figure 1. Basic chemical structure of the carbapenems.
nitrogen and the adjacent tetrahedral carbon atoms to a sec-
ondary ring structure. A thiazolidine ring is present in penicil-
lins and a dihydrothiazine ring in cephalosporins. Penicillins
have asymmetric centres at carbon C-5 and C-6, which corre-
spond to the asymmetric centres present at C-6 and C-7 in
cephalosporins.
2. Chemistry of carbapenems
2.1 Chemical structure
The carbapenems consist of a series of β-lactam antibiotics
characterised by a nuclear structure that differs from the
penam nucleus of the penicillins as a carbon atom replaces
sulfur at position 1 and an unsaturated bond is present
between carbon atoms 2 and 3 in the 5-membered ring (thia-
zolidinic) (Figure 1). Carbapenems are derived from 7-oxo-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. Many com-
pounds exist as stereoisometric forms. In general, those com-
pounds that exist with an R1 substituent and R2 = H have cis
stereochemistry whilst those with an R2 substituent and
R1 = H have trans stereochemistry.
The first carbapenems discovered were olivanic acids pro-
duced by Streptomyces olivaceus. This was followed by the dis-
covery of thienamycin. The latter was found in the course of a
soil-screening programme to identify inhibitors of peptidogly-
can synthesis [1,2]. Thienamycin was produced by a previously
unknown Streptomyces spp. which was named Streptomyces cat-
tleya as the pigment in its aerial mycelium resembled the col-
our of the cattleya orchid. Its structure was determined by
Albers-Schonberg et al. [3] and is remarkable not only for its
nucleus but for nature and conformation of hydroxyethyl side
chain in the trans (α) configuration in position 6. The classic
penicillins and cephalosporins have side chains in the cis (β)
configuration at positions 6 and 7 relative to one other.
The major difference between the olivanic acids and thien-
amycins is that the former tend to be cis and the latter form
tend to be trans. Olivanic acids (MM 4550, MM 13902,
MM17880, MM 22380, MM 22381, MM 22382 and MM
22383) were originally found as a part of a screen for β-lacta-
mase inhibitors, as noted above, by Beecham Research Labo-
ratories [4]. In addition to their ability to inhibit different β-
lactamases, they also showed a broad spectrum activity [5,6].
However, they were chemically unstable, so have not been
used clinically.
Other natural carbapenems have been discovered and semi-
synthetic derivatives have been synthesised, for example,
530 Expert Opin. Investig. Drugs (2002) 11(4)
asparenomycins derived from Streptomyces tokunonesis and
Streptomyces argenteolus [7]. The presence of an exocyclic meth-
ylene-linked side chain at position 6, as in the asparenomy-
cins, destroys any stereochemistry at this site. These
compound appeared unstable and have not been developed
for clinical use.
Pluracidomycin A (SF 2103A) derived from Streptomyces
sulfonofaciens, appears to have only weak antimicrobial activ-
ity [8-10]. Carpetimycins (A, B, C, D) were isolated from Strep-
tomyces KC-6643 [11]. Carpetimycin B is sulfated at position
8 whereas carpetimycin A is not sulfated. Carpetimycin C
and D differ from A and B, respectively, by having an unsatu-
rated side chain at position 2. All of these compounds have
β-lactamase inhibitor activity but do not exhibit high anti-
bacterial activity.
Other carbapenems include the PS series from Streptomyces
cremosus [12,13] and SQ 27860 isolated from Serratia spp. and
Erwinia spp. [14]. PS-5, -6, -7 and -8 differ in the 2-carbon
substituent at C-6 and the satured (PS-5, PS-6) or unsatured
(PS-7, PS-8) side chain at C-2. More of these compounds are
chemically instable and consequently they have not been clin-
ically employed.
Epithienamycin A has a hydroxyethyl chain in the cis (β)
position. Epithienamycins D and C are stereoisomers of N-
acetyl thienamycin and N-acetyl dehydrothienamycin,
respectively.
The configuration of the optically-active side chains at C-8
influences intrinsic antimicrobial activity and the stereochemis-
try across C-5 to C-6 influences both activity and β-lactamase
stability [15]. The presence of a sulfate in position 8 also appears
to enhance β-lactamase stability. A typical example is olivanic
acid, MM22380, which is a potent antibiotic but lacks the β-
lactamase stability of its stereoisomer N-acetyl thienamycin.
Chemical instability is one of the biggest problems with the
majority of the carbapenems so far discovered. The instability
has been related to the terminal free amino group on the C-2
side chain. Thienamycin is also highly unstable as a result of
cleavage of the β-lactam ring of one molecule by the primary
amine in the 2′ side chain of another and its derivative the N-
formimidoyl thienamycin (known as imipenem) was synthe-
sised [16] bearing the more basic amidine function, which is
protonated at physiological pH and thus unable to take part
in such nucleophilic attack. This compound was therapeuti-
cally used, being more stable both in the solid state and in
concentrated solution, and it was the first of a new class of
antibiotic [17]. However, an additional instability to a mamma-
lian hydrolase, renal dehydropeptidase-I (DHP-I), led to the
development of an additional compound, cilastatin, to be
coadministered with imipenem in order to prevent hydrolysis
by DHP-I [18]. A further advantage of the addition of cilasta-
tin was a reduction in the nephrotoxicity seen in animals
dosed with imipenem alone [19]. Cilastatin has a serum half-
life similar to that of imipenem in man [20]. This was the start
of the discovery of a new subclass of compounds for potential
clinical use.
 Bonfiglio, Russo & Nicoletti

R1 R2 R3

Me
H OH
MM 4550 H 8
H NHCOMe
S
HO3 SO H

Me
H
Epithienamycin A H NHCOMe
8 S
HO

Me
H
Epithienamycin C H NHCOMe
8 S
HO

Me
H
Epithienamycin D H NHCOMe
8 S
HO

Me
H
Epithienamycin E H NHCOMe
8 S
HO3SO

OH
H
Thienamycin H NH2
8 S
Me

OH
H
N-Acetyl-thienamycin H NHCOMe
8 S
Me

OH
H
N-Acetylyldehydrothienamycin H NHCOMe
8 S
Me

PS-5 H CH3CH2 NHCOMe

S

Expert Opin. Investig. Drugs (2002) 11(4) 531

Recent developments in carbapenems

R1 R2 R3

H3 C
PS-6 H NHCOMe
S
H3 C

PS-7 H CH3CH2 NHCOMe

S

H3 C
PS-8 H NHCOMe
S
H3 C

OH OH
OH
Asparenomycin A NHCOMe
S
H
Me Me

OH OH
OH
Asparenomycin B NHCOMe
S
H
Me Me

OH OH NHCOMe
S
Asparenomycin C

Me Me

OH
Me OH
Carpetimycin A H NHCOMe
8 S
Me H

OSO3H OH
Me
Carpetimycin B H NHCOMe
8 S
Me H

Me
H
Pluracidomycin A 8 H SO3H
HO3SO

SQ 27,860 H H H

OH
N-Fomimidoyl thienamycin H
H NHCH=NH
(imipenem) 8 S
Me
O
OH N
H
Meropenem H
8
Me S
NH

532 Expert Opin. Investig. Drugs (2002) 11(4)

 Bonfiglio, Russo & Nicoletti

R1 R2 R3

OH
H S
Panipenem H
8 NH
N
Me H
Me

OH +
H N
Biapenem H S N
8
N
Me

H
OH N CO2
H S
Ertapenem H
8 NH
Me Na
OH
OH H
H
Lenapenem H
NHMe
8
Me S
NH

OH
OH H
H
NH HCl
E-1010 H
8
Me S
NH

OH H
H N NH2
S-4661 H S S
8
Me NH O O

OH S
H
BMS-181139 NH+
NHC 8
NH2 Me N

OH O
H
CS 834 H S
8
Me NH

Figure 2. Chemical structures of carbapenems.

Panipenem (RS-533) also has a N-substituted pyrrolidine
thio-side chain at C-2 and boasts a spectrum of activity that
parallels that of imipenem. This antibiotic which was the
second carbapenem introduced into clinical practice in
Japan in 1993, is susceptible to hydrolysis by DHP-I and
requires the coadministration of an inhibitor of this enzyme,
betamipron [21,22]. Panipenem differs chemically from imi-
penem as it has a N-acetamidoyl pyrrolidinyl thio side chain
at C-2 position.
Stability to human renal DHP-I can be achieved by the
introduction of a 1-β-methyl substituent at C-1 [23]. The
combination of this feature with a precise stereochemistry in
the pendent pyrrolidinyl ring at the 2 position to ensure sus-
tained antibacterial potency, led to the synthesis of mero-
Expert Opin. Investig. Drugs (2002) 11(4)
penem (SM7338) [24,25]. This compound resembles
imipenem in structure, as it has a 6-α-hydroxyethyl group,
but differs by having a methyl group attached at C-1 and a
dimethyl-carbamoyl-pyrrolidine-thio side chain attached at
C-2. This antibiotic was chemically stable to hydrolysis by
DHP-I and could therefore be developed as a single product.
Meropenem was the first carbapenem antibiotic synthesised
to promote DHP-I stability and increase antimicrobial activ-
ity. The addition of substituted pyrrolidinyl-containing side
chains at C-2 yields stable compounds with enhanced activ-
ity of its compound against P. aeruginosa and other Gram-
negative microrganisms. Moreover, C-2 substituents may also
influence serum protein binding of carbapenems. Carbapen-
ems with pyridinium-4-yl side chains are more efficiently
533
Recent developments in carbapenems
Table 1. Natural resistance of common aerobic bacterial
pathogens to carbapenems.
Carbapenem-susceptible
bacteria
Gram-positive
Streptococcus pneumoniae
pen-S
S. pneumoniae pen-R
Enterococcus faecalis
Staphylococcus aureus
methicillin-S
Coag-negative staphylococci
methicillin-S
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus sanguis
Streptococcus spp.
Gram-negative
Escherichia coli
Citrobacter spp.
Salmonella spp.
Shigella spp.
Klebsiella spp.
Enterobacter spp.
Serratia spp.
Hafnia alvei
Proteus spp.
Morganella morganii
Providencia spp.
Yersinia enterocolitica
Plesiomonas shigelloides
Pasteurella multocida
Pseudomonas aeruginosa
Pseudomonas spp.
Acinetobacter spp.
Burkholderia cepacia
Other microrganisms
Haemophilus spp.
Neisseria spp.
534
Carbapenem-resistant
bacteria
Staphylococcus aureus
methicillin-R
Coag-negative staphylococci
methicillin-R
Enterococcus faecium
About 10% are resistant to
imipenem and susceptible to
meropenem
About 20 – 30% resistant to
carbapenems
Stenotrophomonas maltophilia
Expert Opin. Investig. Drugs (2002) 11(4)
bound to human serum albumin than compounds with
pyridinium-3-yl substituents [26].
Biapenem (LJC10,627) also has a methyl radical at the 1- β
position of the carbapenem skeleton making the coadminis-
tration of a DHP inhibitor unnecessary [27-29]. It has also a
bicyclic triazolium moiety attached to the sulfur at the site
chain of the second site instead of a substituted pyrrolidinyl
residue or N-formimidoyl.
Ertapenem (MK-0826) [30], lenapenem (BO-2727) [31] and
S-4661 [32] are 1-β-methyl carbapenems more resistant than
imipenem to DPH-I inactivation and therefore do not require
the addition of a DPH-I inhibitor such as cilastatin or betami-
pron. Ertapenem possesses a longer apparent elimination half-
life in comparison to imipenem and meropenem. S-4661 has
a basic group in the side chain at position 2 and is less basic
than other carbapenems.
A primary difference between structure of BMS-181139
and those of other known carbapenems (imipenem, mero-
penem, biapenem and panipenem) is the absence of a basic
group at position 2 and the presence of a basic group at posi-
tion 1 [33].
2.2 Oral carbapenems
The introduction of oral activity has also been possible with,
for example, the ester prodrugs CS 834 and sanfitrinem cilex-
etil (GV-104326).
CS-834 [34], the first oral carbapenem, is a 1β-methyl car-
bapenem and is an ester-type prodrug with a pivaloyloxyme-
thyl group. Its active metabolite, R-95867, is released into
blood when CS-834 is absorbed from intestinal wall.
Sanfitrinem [35] exemplifies the new class of trinems, in
which an extra carbocyclic ring has been attached.
DZ2640, a new oral carbapenem, is a pivaloyloxymethyl
ester prodrug and becomes de-esterified to produce an active
form, DU-6681a. DZ-2640 has a bicyclic imidazole ring as a
side chain which affects its pharmacokinetics after oral
administration [36].
The use of esters and prodrugs highlights the problems of
identifying parent molecules with good bioavailability follow-
ing oral administration. In the absence of specific uptake sys-
tem, agents must rely on passive diffusion for transport through
the intestinal wall and this requires an uncharged, lipophilic
molecule. In consequence, the ionised carboxilylic acid is best
masked by the use of prodrugs, through modest absorption of
the parent may be possible. The presence of basic groups that
will protonate (imipenem) or of intrinsically-charged functions
(biapenem) is not compatible with good diffusion.
3. Mechanism of action
Carbapenems show an excellent in vitro activity due to their
efficient penetration into bacteria, stability to hydrolysis by
almost all clinically important serine β-lactamases and high
affinity for essential penicillin-binding proteins (PBPs) of
Gram-negative bacteria.
 Bonfiglio, Russo & Nicoletti

Table 2. Production of carbapenem-hydrolysing β-lactamase in naturally occurring isolates.

Molecular

Class β-lactamase Bush's group Microorganisms Enzyme produced

Class A 2f Enterobacter cloacae IMI-1
Class A 2f E. cloacae NOR-1
Class A 2f Serratia marcescens Sme-1
Class A 2f Klebsiella pneumoniae KPC-1
Class B 3 Bacillus cereus II
Class B 3 Bacteroides fragilis CfiA/CcrA
Class B 3 Stenotrophomonas maltophilia L-1
Class B 3 Aeromonas hydrophila A2h
Class B 3 A. hydrophila CphA
Class B 3 A. hydrophila ACP
Class B 3 Aeromonas salmonicida ASA-1
Class B 3 Aeromonas jandaei AsbM1
Class B 3 Aeromonas sobria ImiS
Class B 3 Burkolderia cepacia PCM-1
Class B 3 Pseudomonas aeruginosa IMP*
Class B 3 P. aeruginosa VIM
Class D - Acinetobacter baumannii OXA-24
*Found also in S. marcescens, K. pneumoniae and A. baumannii.

3.1 Interaction with penicillin-binding proteins
The interaction of carbapenems with PBPs is different
depending on the molecule studied. When Gram-negative
bacilli are exposed to imipenem, they rapidly transform into
small spheres or ellipsoid forms which proceed to lyses, with-
out the production of long filamentous forms as is often seen
with penicillins and cephalosporins. This appears to be the
result of the high affinity of imipenem for PBP-2 (inhibition
of which is responsible of production of round cells) and its
low affinity for PBP-3 (inhibition of which is responsible of
elongated filament) in Gram-negative bacilli [37]. Other stud-
ies have confirmed the high affinity of imipenem for the PBP-
1a and PBP-1b components in Escherichia coli (eight times
more than ampicillin) as well as for PBPs 4 and 5. Thienamy-
cin binds to all the PBPs of E. coli, showing the greatest affin-
ity for PBP-2 and the lowest for PBP-3 [38]. The preferential
binding of PBP-2 explains the distinctive morphological
effects of imipenem reported for this antibiotic. Moreover, the
relevance of binding to PBP-2 to the mode of action of thien-
amycin was established by the study an E. coli mutant with an
altered PBP-2 protein. In this mutant the susceptibility to
thienamycin decreased significantly and the activity of cephal-
oridine, which has no affinity for PBP-2, remained
unchanged [39]. Thienamycin also binds to PBP-1 of E. coli
and its ability to inhibit this enzyme is approximately 8-fold
more potent than ampicillin. In E. coli, both imipenem and
meropenem bind with highest affinity to PBP-2 and PBP4
[40].Analysis of the morphological changes induced by these
antibiotics indicates that PBP-2 is the primary target in this
microorganism [41]. The affinity of lenapenem for PBP-2 of E.
coli is twice that of imipenem [42]. In P. aeruginosa, mero-
penem binds primarily to PBP-2 and has considerably high
affinity for PBP-3 [41], whereas imipenem retains PBP-2 as its
prime target and also bestows affinity for PBP-1a [41]. BMS-
181139 has a higher affinity for PBP-2 relative to imipenem
and meropenem. Conversely, it shows lower affinity for PBP-
1a than do the other two carbapenems [43].
Imipenem and meropenem bind to all four PBPs identified
in Staphylococcus aureus, although meropenem has a relatively
low affinity for PBP-3 [44].
3.2 Interaction with β-lactamases
Stability to hydrolysis of carbapenems by serine-based β-lacta-
mases has been extensively studied for almost all carbapenems.
Many old carbapenems have been reported as β-lactamase
inhibitors and inactivators. These include asparenomycins [45],
olivanic acids [46], carpetimycins [47], C-19393 S2 and H2 [48],
and PS-5 [49]. Asparenomycin A shows a good inhibitory β-
lactamase activity of Class C enzyme and is ≥ 100 times more
potent than clavulanic acid [45]. The compound has an inhibi-
tory potency similar to clavulanic acid against other bacterial
β-lactamases.
The inhibitory activity of imipenem has been extensively
studied [50-53]. Like imipenem, meropenem also appears to be

Expert Opin. Investig. Drugs (2002) 11(4) 535

Recent developments in carbapenems
unaffected by various types of β-lactamases, including the
extended spectrum β-lactamases (ESBLs) [54,55], which are
responsible for third generation cephalosporin resistance. The
activity of meropenem against strains possessing specific β-
lactamases, its resistance to hydrolysis and activity as an enzyme
inhibitor have been reported. Meropenem, as imipenem, is a
weak substrate for Class C enzymes. Moreover, the drugs have
some ability to inactivate these enzymes. Biapenem also behaves
as a very poor substrate or as a transient inhibitor of these
enzymes [56]. Biapenem and meropenem behave as competitive
inhibitors of the Class A (TEM and SHV) enzymes [52,56],
whereas imipenem appears less reactive [54].
4. Mechanisms of resistance
Although imipenem has been used clinically for several
years, resistance to the carbapenems has been observed in
very few species as shown in Table 1. Carbapenem resistance
among clinically important species has been infrequent and
largely non-β-lactamase mediated. In fact, only PBP insensi-
tivity is responsible of resistance to carbapenems, as well as
to other β-lactams, in methicillin-resistant staphylococci and
in some enterococci.
4.1 Carbapenemase
Two different families of β-lactam-degrading enzymes,
which catalyse the same reaction, i.e., the opening of the β-
lactam ring by hydrolysis of the amide bond, but which are
structurally and mechanistically unrelated, have evolved in
bacteria. These are active site serine-β-lactamases and metal-
loβ-lactamases [57-58]. The latter enzymes were identified
25 years after the serine-β-lactamases and have remained
less common among pathogenic bacteria [57,59,60]. Neverthe-
less, they are potentially very dangerous as resistance effec-
tors due to their efficient hydrolysis of carbapenem
antibiotics [61].
On a molecular level, these enzymes can belong either to
Class A of β-lactamases of Ambler’s classification [62] or group
2f of Bush’s classification [57], which have serine at the active
site, or to Class B or group 3 enzymes that represent the only
metallo-β-lactamases to have been identified. Moreover, some
Class C cephalosporinases have been reported to hydrolyse
imipenem [63], although imipenem does not represent a major
substrate in their hydrolytic profile. Recently, some Class D
enzymes with carbapenemase activity have been reported [64].
Most of carbapenemases are single subunit Zn2+-depend-
ent enzymes, with exception of S. maltophilia enzyme,
which has a tetrameric structure with molecular weights of
25,00 – 35,000 [65]. Aside from their carbapenemase activity,
most are penicillinases and cannot hydrolyse monobactams,
such as aztreonam [61,65,66].
β-Lactamase-mediated resistance to carbapenems is still
rare in clinically important species. Strong carbapenemase
activity has been described for only a few β-lactamases. Most
of these are metallo-enzymes. Unlike the serine β-lactamases,
536 Expert Opin. Investig. Drugs (2002) 11(4)
the metallo-β-lactamases use an active site zinc ion to hydro-
lyse the β-lactam ring. They are inactivated by chelating
agents, such as EDTA, which sequester the zinc.
Few species have chromosomally-mediated zinc-β-lacta-
mases and very few were coded by transferable plasmids.
Most known metallo-β-lactamases are encoded by chromo-
somal genes of some bacterial species that are primarily mem-
bers of the environmental microbiota, whereas some
unknown environmental species are the most likely sources of
the mobile metallo-β-lactamase determinants that recently
appeared among Gram-negative pathogens. Therefore, envi-
ronmental bacteria could be an important reservoir of similar
resistance determinants.
S. maltophilia is a typical example of an intrinsically carbap-
enem-resistant microrganism. Its resistance is due to the pro-
duction of a chromosomally-mediated carbapenemase (L-1 β-
lactamase) [67,68] belonging to the Class B.
Strains of A. sobria, A. hydrophila (cphA β-lactamase) and
B. cereus (II β-lactamase) produce Class B enzymes capable of
hydrolysing carbapenems [61]. They are produced in combi-
nation with other β-lactamases, including cephalosporinases,
in Stenotrophomonas (L-2 an Ambler Class A enzyme) and
Aeromonas and a strict penicillinase in B. cereus (I β-lacta-
mase) [69].
Zinc β-lactamases are ubiquitous in some Legionella spp.
and carbapenem-hydrolysing β-lactamase was found in L. gor-
manii [70], Myroides odoratus (formerly, Flavobacterium odora-
tum) [71] and Chryseobacterium spp. [72,73]. Only one type of
metallo-β-lactamase with carbapenemase activity (CfiA/CcrA)
has been found in B. fragilis, although minor variants of the
enzyme are known [61,74].
Results of the screening performed in some work indicated
that metallo-β-lactamase-producing bacteria are widespread
in the environmental microbiota, such as Janthinobacterium
lividum [75].
Only few plasmid-mediated carbapenemase have so far
been described. This enzyme, found in P. aeruginosa, was first
isolated in Japan in 1988 [76] and metallo- β-lactamases of the
IMP and VIM families are now increasing sources of resist-
ance to carbapenems in P. aeruginosa [77-80]. The IMP enzymes
have also been found in some clinical isolates of Serratia marc-
escens [81], K. pneumoniae [82] and A. baumannii [83].
Some carbapenemases of Class A are chromosomally
encoded (such as, NMC-A, Sme1 and 2, IMI-1) isolated in
Enterobacter cloacae and S. marcescens. These enzymes hydro-
lyse imipenem faster than meropenem and biapenem result-
ing in higher MIC values of imipenem for the organisms
producing them [61].
A Class A, group 2f, plasmid encoded carbapenemase called
KPC-1 (K. pneumoniae carbapenemase-1) was isolated in K.
pneumoniae [84]. The MIC values of imipenem and mero-
penem were of 16 mg/l and the strain was also resistant to
extended spectrum cephalosporins and aztreonam. Further-
more, weak carbapenemases belonging to molecular Class D
(such as, OXA-24) are emerging in A. baumannii worldwide

A classification of carbapenemase enzymes has been pro-
[64].
posed by Galleni et al. [85].
In conclusion, under the selective pressure of carbapenems
and extended spectrum cephalosporins use, the carbapene-
mase genes might spread and became epidemic, as is the case
for ESBLs. In fact, the recent appearance of plasmid mediated
β-lactamases in member of the Enterobacteriaceae family
demonstrate the ability of carbapenem-hydrolysing enzymes
to be transferred among localised hospitals [86].
4.2 Diminished permeability
Many P. aeruginosa strains show resistance to imipenem which
is not mediated by β-lactamase production. The mechanism
of such resistance is due to the lack or diminished production
of a 45 or 48 kDa outer membrane protein (OprD protein,
initially called D2 porin) [87-90]. The primary role of this pro-
tein is in the passive uptake of basic amino acids across the
outer membrane [91] but it forms pores that are also permeable
to carbapenems, though not to other β-lactams. Its loss is
responsible for imipenem resistance. The MIC values of non-
carbapenems are unaffected. Meropenem [92], biapenem [93],
panipenem [94] lenapenem [33] and BMS-181139 [43] are less
active against imipenem-resistant strains of P. aeruginosa,
though in some strains this decreased activity is still within
the susceptibility range. In particular, lenapenem seems more
active than meropenem against imipenem-resistant P. aerugi-
nosa strains irrespective of the existence of β-lactamase [95].
BMS-181139 differs from the other carbapenems in its
uptake into P. aeruginosa [43]. Although the pathway used by
BMS-181139 has not been identified, it seems that it does not
share the same route of permeation used by other carbapen-
ems. In fact, the absence of OprD protein does not affect the
activity of BMS-181139 against P. aeruginosa. Moreover,
BMS-181139 was not cross-resistant with imipenem and
meropenem in clinical or laboratory-derived mutants of
P. aeruginosa. The absence of a basic group at position 2 of
BMS-181139 is probably consistent with its lack of depend-
ence on OprD protein [43].
4.3 Efflux system activation
Intrinsic resistance is expressed to a variable degree by all
P. aeruginosa isolates and involves an interplay of impermea-
bility with multi-drug efflux system mediated by Mex-A-
MexB-OprM [96]. The efflux system is composed of MexB
protein, which is a pump located in the cytoplasmic mem-
brane, the OprM protein, a pore forming protein in the outer
membrane and the MexA protein, which links these compo-
nents. Increased MIC values of penicillins, cephalosporins
and quinolones but not those of imipenem are due to an
upregulation of Mex-A-MexB-OprM as a result of the nalB
mutation at the mexR locus [97]. The lack of activity against
imipenem may be due to its lack of a heterocyclic side chain.
The upregulation of Mex-A-MexB-OprM reduces susceptibil-
ity without conferring resistance to meropenem. It is inferred
that meropenem can use the OprD pathway to enter the
Expert Opin. Investig. Drugs (2002) 11(4)
Bonfiglio, Russo & Nicoletti
P. aeruginosa and that is recognised and ejected by Mex-B-
mediated efflux because of its 2´ heterocyclic side chain.
Imipenem resistance in P. aeruginosa is principally due to
loss of OprD, whereas meropenem resistance codepends on
upregulation of Mex-A-MexB-OprM. Thus, it is harder to
obtain resistance to meropenem in P. aeruginosa than to imi-
penem, since two mutations (loss of OprD and upregulation
of Mex-A-MexB-OprM) are required.
Upregulation of another efflux system, MexE-MexF-OprN
is associated with raised MIC values of both carbapenems as
well as fluoroquinolones [98]. However, it is not clear whether
this pump recognises carbapenems or whether the association
reflects coregulation of MexE-MexF-OprN with OprD [99].
5. Clinical use
5.1 Antibacterial activity
Carbapenems have a broad spectrum of antimicrobial activity
which exceeds that of most other classes of antimicrobial [100].
5.1.1 Gram-negative microorganisms
Carbapenems show strong activity against all enterobacte-
riaceae. They retain activity against both ceftazidime-resistant
enterobacteriaceae for ESBL production or de-repression of
chromosomal Class C β-lactamases [101-103].
Meropenem shows the greatest activity against Gram-nega-
tive microorganisms and its activity is from 4- to 16-fold
more potent than imipenem [104-106]. The other carbapenems
also demonstrate very good activity against Gram-negative
microorganisms. The activity of lenapenem seems to be simi-
lar to that of biapenem [107].
Since the introduction of imipenem, new carbapenems
antibiotics have been discovered with one objective: to over-
come the resistance of P. aeruginosa. Several in vitro studies
have demonstrated that, worldwide, meropenem is more
active than imipenem against P. aeruginosa [108-113]. The differ-
ence in the MIC values of imipenem and meropenem for
these strains has been attributed to either the poorer β-lacta-
mase-inducing ability of meropenem, the improved β-lacta-
mase stability of meropenem, the higher affinity of
meropenem for PBP-3 or the possibility that meropenem dif-
fuses through the outer membrane by the non-specific and
imipenem-specific pathways. One or more of these mecha-
nisms could result in higher steady-state periplasmic concen-
trations for meropenem and thus in a reduced MIC.
BMS-181139 differs from other carbapenems due to its
lack of cross-resistance with imipenem. This difference
could be explained by the permeation of BMS-181139
through a non-D2 channel, compared to the preferential
uptake of other carbapenems by the D2 porin [43]. E-1010
(ER-35786) and lenapenem [33] are especially active against
imipenem or meropenem-resistant strains of P. aeruginosa,
although cross-resistance between E-1010 and other carbap-
enems was observed [114]. S-4661 shows an excellent activity
against imipenem-resistant P. aeruginosa [115]. The oral car-
537
Recent developments in carbapenems
bapenems DU-6681a and CS-804 do not have any activity
against P. aeruginosa [116].
5.1.2 Gram-positive microorganisms
Imipenem shows better activity than any other carbapenem
against Gram-positive microorganisms. Comparatively, mero-
penem generally has two to fourfold less activity than imi-
penem against most Gram-positive bacteria [117], although this
is unlikely to be of clinical significance [118].
Carbapenems, as with all other β-lactam antibiotics, do
not seem likely as useful drugs in the treatment of diseases
caused by methicillin-resistant staphylococci and Enterococ-
cus faecium.
5.1.3 Anaerobes
All the carbapenems demonstrate potent anaerobic activity
against a wide range of clinical anaerobic isolates. In a recent
study against anaerobes, with exception of Bilophila wadswor-
thia, the activity of imipenem and ertapenem against 1001
anaerobes isolated from human intra-abdominal infections
was similar [119]. Imipenem seems to have similar or slightly
less activity (up to four-fold) than meropenem against anaer-
obes [105]. The anti-anaerobic in vitro activity of ertapenem
[119] and biapenem [120] against anaerobic Gram-negative and
-positive rods is comparable to that of meropenem and
slightly more active than imipenem.
Also, oral carbapenems, such as CS-834 [34,121] and san-
fetrinem [35,122], show very good activity against anaerobes. A
full cross-resistance between imipenem and sanfetrinem was
shown against these microorganisms [122]. Another trinem for
parenteral use, GV129606, demonstrated a good in vitro activ-
ity against Clostridium perfringens and B. fragilis [123].
5.2 Carbapenems in clinical practice
Effective empirical treatment of serious bacterial infections
requires the use of bactericidal antibiotics with a wide spec-
trum of activity. Monotherapy of serious infections is a desira-
ble aim offering fewer interventions, easier patient
management in terms of control and administration, a poten-
tial for better cost-efficiency and a lower potential for side
effects. Successful empirical therapy also requires potent anti-
infective drug with activity against Gram-negative, Gram-pos-
itive and anaerobic microorganisms. Consequently, the good
clinical efficacy and favourable safety profiles associated with
the broad spectrum antibacterial activity of carbapenems,
which exceeds that of most other antimicrobial classes, make
them valuable as initial empirical therapy in the treatment of
serious infections.
5.2.1 Intensive care units infection
Nosocomial bacterial infections are a major cause of morbid-
ity in hospitalised patients, particularly those in the inten-
sive care units (ICUs). Moreover, the prevalence of
antimicrobial resistance in nosocomial isolates is increasing
worldwide. Empirical antibiotic therapy should be initiated
538 Expert Opin. Investig. Drugs (2002) 11(4)
promptly in severely ill infected patients. A regimen with a
broad spectrum antibiotic encompassing the most common
pathogens found in this setting, Enterobacteriaceae, P. aeru-
ginosa, S. aureus and anaerobes must be employed. Carbap-
enem antibiotics may offer a potential of monotherapy for
nosocomial infections [124-127].
The stability of the carbapenems to AmpC or ESBL β-lacta-
mase hydrolysis makes them an appropriate monotherapy for
nosocomial infections in the ICU. Since carbapenems are not
prone to determine the insurgence of resistance during treat-
ment, initial monotherapy with carbapenems is a good option
until results of susceptibility tests coming from laboratory are
known and a final decision on definitive therapy can be made.
5.2.2 Febrile neutropenia
Patients with cancer often have one or more predisposing fac-
tors for infection. Infections in neutropenic patients are usually
caused by aerobic Gram-positive and Gram-negative microor-
ganisms, including staphylococci, streptococci, Klebsiella spp.
E. coli and P. aeruginosa. Antibiotic-resistant microorganisms
tend to be more prevalent in neutropenic patients because they
are exposed to prolonged course of broad spectrum antibiotics.
Examples include ESBLs producers and fluoroquinolone-resist-
ant Enterobacteriaceae other than vancomycin-resistant entero-
cocci and methicillin-resistant staphylococci.
Options for the treatment of febrile neutropenia, following
recommendations by the Infectious Disease Society of Amer-
ica [128], include duotherapy with β-lactam plus aminoglyco-
side or β-lactam plus vancomycin or monotherapy with
carbapenem or extended spectrum cephalosporins.
Several studies demonstrated that meropenem can be used
as monotherapy in the first-line empirical treatment of
febrile episodes in neutropenic patients, including those
with profound neutropenia and underlying haematological
malignancies [129-132].
5.2.3 Lower respiratory tract infections
Serious lower respiratory tract infections (LRTI) include exac-
erbations of chronic obstructive pulmonary disease and severe
community- and hospital-acquired pneumonias.
Bacterial pneumonia is one of the most common infections
and one most often associated with significant morbidity and
mortality. The patient who is intubated or has a tracheostomy is
particularly susceptible to respiratory tract infections. Optimal
choice of antibiotics for bacteria pneumonia is problematic as a
result of the multitude of potential bacterial pathogens and the
difficulty in making a specific aetiological diagnosis.
Imipenem and meropenem have demonstrated excellent
clinical efficacy in severe LRTI in several clinical trials [133].
Several studies support the clinical efficacy of carbapenems as
monotherapy in the treatment of serious polymicrobial infec-
tions [134-137]. However, monotherapy with imipenem should
be checked when this antibiotic is used for the treatment of
serious pseudomonas infections. Indeed, imipenem resistant
P. aeruginosa can develop during therapy.
 Bonfiglio, Russo & Nicoletti

5.2.4 Intra-abdominal infections Meropenem should be considered as an alternative in mon-

Carbapenems have potential utility in the treatment of intra-
abdominal infections, which are often polymicrobial, since
they show high activity against almost all of the pathogens
likely to be encountered. In fact, antibiotic regimens suitable
for the treatment of intra-abdominal infections must be active
against Enterobacteriaceae and anaerobes. Different antibiot-
ics have been employed for this purpose but several trials have
demonstrated that monotherapy with carbapenems can be
useful for the treatment of intra-abdominal infections [138-143].
Meropenem and imipenem show similar efficacy in the
treatment of patients with moderate-to-severe intra-abdomi-
nal infections. The efficacy of empirical monotherapy with
meropenem in hospitalised patients with intra-abdominal
infections has been assessed in several comparative clinical tri-
als [144-146]. In these trials, patients receiving meropenem had
response rates ranging from 96 – 100%, corresponding
response rates in imipenem/cilastatin recipients ranged from
94 – 97%. At follow-up, clinical responses in valuable patients
were similar to those obtained at the end of treatment [144-146].
5.2.5 Paediatric meningitides
In meningitis, it is very important to have high serum con-
centrations of β-lactam antibiotics in order to ensure effec-
tive levels of antibiotic reach the site of infection by
penetration across meninges. Meropenem is the only car-
bapenem extensively evaluated in children. Worldwide, pae-
diatric clinical trials of meropenem have include > 1200
children [147]. The results demonstrated that the mono-
therapy with meropenem in the treatment of serious paedi-
atric infections, including meningitides, give a response rate
of 90 – 100% of children treated.
otherapy to the currently recommended combination regi-
mens of either ceftriaxone/vancomycin or cefotaxime/
vancomycin for treatment of presumptive pneumococcal
meningitis [148]. Moreover, meropenem is FDA approved in
the US for use in children with meningitis.
6. Conclusion and expert opinion
Although development of new carbapenems has been relatively
difficult, the in vitro and in vivo experience with imipenem and
meropenem have been so favourable that there are strong incen-
tives to develop new and even better members of this class of
antibiotics. Biapenem and lenapenem have been tested in
patients but have not have progressed towards registration [149].
The rate of development of bacterial resistance to car-
bapenems is likely to parallel the extent to which carbapen-
ems are used, as has been demonstrated with other
antibiotics. In general carbapenems should not be used for
the routine therapy of community-acquired infections.
Other antibiotics that are equally effective and safe and
that exhibit a more narrow spectrum of activity should be
preferentially used.
Very few β-lactamases are able to hydrolyse this class of
antibiotic, the majority of which are chromosomally
encoded. This has certainly contributed to the slow spread
of these enzymes and thus to the slow increase in β-lacta-
mase-mediated resistance to carbapenems. Although the
number of these enzymes compared to the number of other
β-lactamase types is very low it is likely that they will spread
due to the increased selective pressure of inappropriate car-
bapenem use.

Bibliography antibiotics with β-lactamase inhibitory 10. YAMAGUCHI A, HIRATA T, SAWAI T:

Papers of special note have been highlighted as
either of interest (•) or of considerable interest (••)
to readers.
1. KAHAN JS, KAHAN FM, GOEGELMAN
R et al.: Thienamycin, a new β-lactam
antibiotic: I. Discovery, taxonomy, isolation
and physical properties. J. Antibiot. (1979)
32:1-12.
2. KAHAN FM, KROPP H, SUNDELOF JG
et al.: Thienamycin: development of
imipenem-cilastatin. J. Antimicrob.
Chemother. (1983) 12(Suppl. D):1-35.
3. ALBERS-SCHONBERG G, ARISON BH,
HENSENS DD et al.: Structure and absolute
configuration of thienamycin. J. Americ.
Chemich. Soc. (1978) 100:6491-6499.
4. •BASKER MJ: The carbapenem family. J.
Antimicrob. Chemother. (1982) 10:4-7.
5. HOOD JD, BOX SJ, VERALL MS:
Olivanic acids, a family of β-lactam
properties produced by Streptomyces sp. II.
Isolation and characterisation of MM 4550,
MM 17880. J. Antibiot. (1979) 32:295-304.
6. BASKER MJ, BOON RJ, HUNTER PA:
Comparative antibacterial properties in vitro
of seven olivanic acid derivatives-MM 4550,
MM 13902, MM17880, MM 22380, MM
22381, MM 22382 and MM 22383. J.
Antibiot. (1980) 33:878-884.
7. TSUJI N, KONDO E, MAYAMA M et al.:
Asparenomycin A, a new carbapenem
antibiotic. J. Antibiot. (1981) 34:909-911.
8. TSUJI N, NAGASHIMA K, KOBAYASHI
M, TERUI Y, MATSUMOTO K, KONDO
E: The structure of pluracidomycins, new
carbapenem antibiotics. J. Antibiot. (1982)
3:536-540.
9. ITO T, EZAKI N, OHBA K et al.: A novel
β-lactamase inhibitor, SF-2103A, produced
by a Streptomyces. J. Antibiot. (1982) 35:533-
535.
Novel carbapenem derivative SF2103A:
studies on the mode of β-lactamase
inactivation. Antimicrob. Agents Chemother.
(1984) 25.348-353.
11. NAKAYAMA M, IWASAKI A, KIMURA S
et al.: Carpetimycin A e B, new β-lactam
antibiotics. J. Antibiot. (1980) 32:1388-
1390.
12. SHIBAMOTO N, KOKI A, NISHINO M
et al.: PS-6 and PS-7, new β-lactam
antibiotics. Isolation physiochemical
properties and structures. J. Antibiot. (1980)
33:1128-1137.
13. SHIBAMOTO N, NISHINO M,
OKAMURA K, FUGAGAWA Y,
ISHIKARA T: PS-8, a minor carbapenem
antibiotic. J. Antibiot. (1982) 35:763-765.
14. PARKER WL, RATHNUM ML, WELL JS,
TREJO WH, PRINCIPE PA, SYKES RB:
SQ 27860, a simple carbapenem produced
by species of Serratia and Erwinia. J. Antibiot.

Expert Opin. Investig. Drugs (2002) 11(4) 539

Recent developments in carbapenems
(1982) 35:563-660.
15. ••WISE R: In vitro and pharmacokinetic
properties of the carbapenems. Antimicrob.
Agents Chemother. (1986) 30:343-349.
16. KROPP H, SUNDELOFF JG, KAHAN JS,
KAHAN F, BIRNBAUM J: MK0787 (N-
formimidoyl thienamycin): evaluation of
in vitro and in vivo activities. Antimicrob.
Agents Chemother. (1980) 17:993-1000.
17. BARZA M: Imipenem: first of a new class of
antibiotic. Ann. Inter. Med. (1985) 103:552-
560.
18. KROPP H, SUNDELOFF JG, HAJDU R,
KAHAN FM: Metabolism of thienamycin
and related carbapenem antibiotics by the
renal dipeptidase, dehydropeptidase-I.
Antimicrob. Agents Chemother. (1982) 22:62-
70.
19. •BIRNBAUM J, KAHAN F, KROPP H,
MACDONALD JS: Carbapenems, a new
class of β-lactam antibiotics. Discovery and
development of imipenem/cilastatin. Am. J.
Medic. (1985) 78:3-21.
20. •KAHAN F, KROPP M, SUNDELOF JG,
BIRNBAUM J: Thienamycin: development
of imipenem-cilastatin. J. Antimicrob.
Chemother. (1983) 12(Suppl. D):1-35.
21. NAGANUMA H, TOKIWA H,
HIROUCHI Y et al.: Nephroprotective
effect and its mechanism of betamipron (2)-
Relationships of renal excretion. Chemother.
(1991) 39(Suppl. 3):178-189.
22. TAKAHAGI H, HIROTA T
MATSUSHITA Y, MURAMATSU S,
TANAKA M, MATSUO E: In vitro
dehydropeptidase-1 activity and its
hydrolytic activity of panipenem in several
tissue in animal species and their influence
on the disposition of panipenem in vivo.
Chemother. (1991) 39(Suppl. 3):236-241.
23. SHIH DH, BAKER F, CAMA L,
CHRISTENSEN BG: Synthetic carbapenem
antibiotics. I. 1-β-methylcarbapenem.
Heterocycles. (1984) 21:29-40.
24. FUKASAWA M, SUMITA Y, HARABE ET
et al.: Stability of meropenem and effect of
1β-methyl substitution on its stability in the
presence of renal dehydropeptidase.
Antimicrob. Agents Chemother. (1992)
36:1577-1579.
25. EDWARDS JR, TURNER PJ, WANNOP
C, WITHNELL ES, GRINDEY AJ, NAIRN
K: In vitro antibacterial activity of SM-7338,
a carbapenem antibiotic with stability to
dehydropeptidase-I. Antimicrob. Agents
Chemother. (1989) 33:215-222.
26. OGBORNE KT, HITCHCOCK MJM:
540
Radiolabeled quaternary carbapenems and
their interactions with human serum
albumin. Antimicrob. Agents Chemother.
(1988) 32:186-189.
27. HIKIDA M, KAWASHIMA K, YOSHIDA
M, MITSUHASHI S: Inactivation of new
carbapenem antibiotics by dehydropeptidase-
I from porcine and human renal cortex. J.
Antimicrob. Chemother. (1992) 30:129-134.
28. PETERSEN PJ, JACOBUS NV, WEISS WJ,
TESTA RT: In vitro and in vivo activities of
LJC10,627, a new carbapenem with stability
to dehydropeptidase I. Antimicrob. Agents
Chemother. (1991) 35:203-207.
29. HIKIDA M, KAWASHIMA K, NISHIKI K
et al.: Renal dehydropeptidase-I stability of
LJC-10,627, a new carbapenem antibiotic.
Antimicrob. Agents Chemother. (1992)
36:481-483.
30. GILL CJ, JACKSON JJ, GERCKENS LS
et al.: In vitro activity and pharmacokinetic
evaluation of a novel long acting carbapenem
antibiotic, MK-826 (L-748,345). Antimicrob.
Agents Chemother. (1998) 42:1996-2001.
31. NAKAGAWA S, HASHIZUME T,
MATSUDA K et al.: In vitro activity of a new
carbapenem antibiotic, BO2727, with potent
antipseudomonal activity. Antimicrob. Agents
Chemother. (1993) 37:2756-2759.
32. ISO Y, IRIE T, NISHINO Y, MOTOKAWA
K, NISHITANI Y: A novel 1β-
methylcarbapenem antibiotic, S-4661:
synthesis and structure-activity relationships
of 2-(5-substituted pyrrolidin-3-ylthio)-1β-
methylcarbapenems. J. Antibiot. (1996)
49:199-209.
33. KESSLER RE, FUNG-TOMC J, KOLEK B
et al.: In vitro activity of BMS-181139, a new
carbapenem with potent antipseudomonal
activity. Antimicrob. Agents Chemother.
(1995) 39:380-385.
34. FUKUOKA T, OHYA S, UTSUI Y et al.:
In vitro and in vivo antibacterial activities of
CS-834, a new oral carbapenem. Antimicrob.
Agents Chemother. (1997) 41:2652-2663.
35. DI MODIGANO E, ERBETTI I,
FERRARI L, GALASSI G, HAMMOND D,
XERRI L: In vitro activity of the tribactam
GV104326 against Gram-positive, Gram-
negative and anaerobic bacteria. Antimicrob.
Agents Chemother.(1994) 38:2362-2368.
36. NISHI T, ISHIDA Y, SUGITA K et al.: DZ-
2660, a new oral carbapenem antibiotic, 1
:structure activity relationships and in vitro
activity. In: Program and Abstracts of the
Thirty-Fifth Interscience Conference on
Antimicrobial Agents and Chemotherapy.
Expert Opin. Investig. Drugs (2002) 11(4)
Abstract F133. American Society for
Microbiology, Washington, DC, USA
(1995).
37. SPRATT BG, TOBANPUTRA V,
ZIMMERMANN W: Binding of
thienamycin and clavulanic acid to the
penicillin-binding proteins of Escherichia coli
K-12. Antimicrob. Agents Chemother. (1977)
12:406-409.
38. •SPRATT BG: Properties of penicillin-
binding proteins of Escherichia coli K-12.
Europ. J. Biochem. (1977) 72:341-352.
39. SPRATT BG: Escherichia coli resistance to β-
lactam antibiotics through a decresed in the
affinity of a target for lethality. Nature (1978)
274:713-715.
40. YANG Y, BHACHECH N, BUSH K:
Biochemical comparison of imipenem,
meropenem and biapenem: permeability,
binding to penicillin-binding proteins and
stability to hydrolysis by β-lactamases. J.
Antimicrob. Chemother. (1995) 35:75-84.
41. SUMITA Y, FUKOSAWA M, OKUDA T:
Comparison of two carbapenems, SM-7338
and imipenem: affinities for penicillin-
binding proteins and morphological changes.
J. Antibiot. (1990) 43:314-320.
42. KATO Y, OTSUKI M, NISHINO T:
Antibacterial properties of BO-2727, a new
carbapenem antibiotic. J. Antimicrob.
Chemother. (1997) 40:195-203.
43. FUNG-TOMC JC, GRADELSKI E,
KOLEK B et al.: Activity of carbapenem
BMS-181139 against Pseudomonas aeruginosa
is not dependent on porin protein D2.
Antimicrob. Agents Chemother. (1995)
39:386-393.
44. SUMITA Y, FUKOSAWA M, OKUDA T:
Affinities of SM-7338 for penicillin-binding
proteins and its release from these proteins in
Staphylococcus aureus. Antimicrob. Agents
Chemother. (1990) 34:484-486.
45. MURAKAMI K, DOI M, YOSHIDA T:
Asparenomycins A, B and C, new
carbapenems antibiotics. V. Inhibition of β-
lactamases. J. Antibiot. (1982) 35:39-45.
46. CHARMAS RL, KNOWELS JR: Inhibition
of RTEM β-lactamase from Escherichia coli.
Interactions with derivatives of olivanic acids.
Biochemistry (1981) 20:2732-2737.
47. KOBAYASHI F, SAINO Y, KOSHI T et al.:
Antimicrobial and β-lactamases activities of
carpetimycins A and B, new carbapenem
antibiotics. Antimicrob. Agents Chemother.
(1982) 21:536-544.
48. OKONOGI K, NOZAKI Y, IMADA A,
KUNG M: C-19393 S 2 and H2, new

carbapenem antibiotics. IV. Inhibitory
activity against β-lactamases. J. Antibiot.
(1981) 34: 212-217.
49. OKAMURA K, SAKAMOTO M,
ISHIKURA T: PS-5 inhibition of a β-
lactamase from Proteus vulgaris. J. Antibiot.
(1980) 33:293-302.
50. RICHMOND MH: The semi-synthetic
thienamicin derivative MK-0787 and its
properties with respect to a range of β-
lactamases from clinically important bacterial
species. J. Antimicrob. Chemother. (1981)
7:279-285.
51. SAWAI T, TSUKAMOTO K: Cefoxitin, N-
formimidoyl thienamycin, clavulanic acid
and penicillanic sulfone as suicide inhibitors
for different types of β-lactamases produced
by Gram-negative bacteria. J. Antibiot.
(1982) 35:1594-1602.
52. MONKS J, WALEY SG: Imipenem as
substrate and inhibitor of β-lactamases.
Biochem. J. (1988) 253:323-328.
53. LABIA R, MORAND A, GUIONIE M:
Beta-lactamase stability of imipenem. J.
Antimicrob. Chemother. (1986) 18(Suppl.
E):1-8.
54. LABIA R, MORAND A, TIWARI K,
SIROT D, CHANAL C: Interactions of
meropenem, with β-lactamases, including
enzymes with extended spectrum activity
against third generation cephalosporins. J.
Antimicrob. Chemother. (1989)
24(Suppl.A):219-223.
55. •SANDERS CC, SANDERS Jr WE,
THOMSON KS, IACONIS JP:
Meropenem: activity against resistant Gram-
negative bacteria and interactions with β-
lactamases. J. Antimicrob. Chemother. (1989)
24(Suppl.A):187-196.
56. •FELICI A, PERILLI M, SEGATORE B
et al.: Interactions of biapenem with active-
site serine and metallo-β-lactamases.
Antimicrob. Agents Chemother. (1995)
39:1300-1305.
57. BUSH K, JACOBY GA, MEDEIROS AA: A
functional classification scheme for β-
lactamases and its correlation with molecular
structure. Antimicrob. Agents Chemother.
(1995) 39:1211-1233.
58. •FRERE JM: Beta-lactamases and bacterial
resistance to antibiotics. Mol. Microbiol.
(1995) 16:385-395.
59. •BUSH, K: Metallo-β-lactamases: a class
apart. Clin. Infect. Dis. (1998) 27:S48-S53.
60. ••LIVERMORE DM: β-Lactamases in
laboratory and clinical resistance. Clin.
Microbiol. Rev. (1995) 8:557-584.
61. ••RASSMUSSEN BA, BUSH K:
Carbapenem-hydrolyzing β-lactamases.
Antimicrob. Agents Chemother. (1997).
41:223-232.
62. ••AMBLER RP: The structure of β-
lactamases. Philos. Trans. R. Soc. Lond. B.
Biol. Sci. (1980) 289:321-331.
63. BUSH K, TANAKA SK, BONNER DP,
SYKES RB: Resistance caused by decreased
penetration of β-lactam antibiotics into
Enterobacter cloacae. Antimicrob. Agents
Chemother. (1985) 27:555-560.
64. BOU G, OLIVER A, MARTINEZ-
BELTRAN J: OXA-24, a novel class D beta-
lactamase with carbapenemase activity in an
Acinetobacter baumannii clinical strain.
Antimicrob. Agents Chemother. (2000)
44:1556-1561.
65. •LIVERMORE DM: Carbapenemases. J.
Antimicrob. Chemother. (1992) 29:609-616.
66. •FELICI A, AMICOSANTE A, ORATORE
R et al.: An overview of the kinetic
parameters of class B β-lactamases. Biochem.
J. (1993) 291:151-155.
67. SAINO Y, KOBAYASHI F, INOUE M,
MITSUASHI S: Purification and properties
of inducible penicillin β-lactamase isolated
from Pseudomonas maltophilia. Antimicrob.
Agents Chemother. (1982) 22:564-570.
68. BICKNELL R, EMANUEL EL, GAGNON
J, WALEY SG: The production and
molecular properties of the zinc β-lactamase
from Pseudomonas maltophilia IID 1275.
Biochem. J. (1985) 229:791-797.
69. IACONIS JP, SANDERS CC: Purification
and characterization of inducible β-
lactamases in Aeromonas spp. Antimicrob.
Agents Chemother. (1990) 34:44-51.
70. FUJII T, SATO K, MIYATA K, INOUE M
MITSUASHI S: Biochemical properties of β-
lactamase produced by Legionella gormanii.
Antimicrob. Agents Chemother. (1986)
29:925-926.
71. SATO K, FUJII R, OKATOMO R, INOUE
M, MITSUASHI S: Biochemical properties
of β-lactamases produced by Flavobacterium
odoratum. Antimicrob. Agents Chemother.
(1985) 27:612-614.
72. BELLAIS S, LEOTARD S, POIREL L,
NAAS T, NORDMANN P: Molecular
characterization of a carbapenem-hydrolyzing
beta-lactamase from Chryseobacterium
(Flavobacterium) indologenes. FEMS
Microbiol. Lett. (1999) 171:127-132.
73. BELLAIS S, AUBERT D, NAAS T,
NORDMANN P: Molecular and
biochemical heterogeneity of class B
Expert Opin. Investig. Drugs (2002) 11(4)
Bonfiglio, Russo & Nicoletti
carbapenem-hydrolyzing β-lactamases in
Chryseobacterium meningosepticum.
Antimicrob. Agents Chemother. (2000)
44:1878-1886.
74. CUCHURAL GJ, MALAMY MH, TALLY
FP: β-Lactamase-mediated imipenem
resistance in Bacteroides fragilis. Antimicrob.
Agents Chemother. (1986) 30:645-648.
75. ROSSOLINI GM, CONDEMI MA,
PANTANELLA F, DOCQUIER JD,
AMICOSANTE G, THALLER MC:
Metallo-β-Lactamase Producers in
Environmental Microbiota: New Molecular
Class B Enzyme in Janthinobacterium
lividum. Antimicrob. Agents Chemother.
(2001) 45:837-844.
76. •WATANABE M, IYOBE S, INOUE M,
MITSUASHI S: Transferable imipenem
resistance in Pseudomonas aeruginosa.
Antimicrob. Agents Chemother. (1991)
25:891-902.
77. CORNAGLIA G, RICCIO ML,
MAZZARIOL A, LAURETTI L,
FONTANA R, ROSSOLINI G: Appearance
of IMP-1 metallo-beta-lactamase in Europe.
Lancet (1999) 353:899-900.
78. LAURETTI L, RICCIO ML,
MAZZARIOL A et al.: Cloning and
characterization of blaVIM, a new integron-
borne metallo-β-lactamase gene from a
Pseudomonas aeruginosa clinical isolate.
Antimicrob. Agents Chemother. (1999)
43:1584-1590.
79. POIREL L, NAAS T, NICHOLAS D et al.:
Characterization of VIM-2, a carbapenem-
hydrolyzing metallo-β-lactamase and its
plasmid- and integron-borne gene from a
Pseudomonas aeruginosa clinical isolate in
France. Antimicrob. Agents Chemother. (2000)
44:891-897.
80. PALLECCHI L, RICCIO ML,
DOCQUIER JD, FONTANA R,
ROSSOLINI GM: Molecular heterogeneity
of bla(VIM-2)-containing integrons from
Pseudomonas aeruginosa plasmids encoding
the VIM-2 metallo-beta-lactamase. FEMS
Microbiol. Lett. (2001) 195:145-50.
81. OSANO E, ARAKAWA Y,
WACHAROTAYANKUN R et al.:
Molecular characterization of an
enterobacterial metallo-β-lactamase found in
a clinical isolate of Serratia marcescens that
shows imipenem resistance. Antimicrob.
Agents Chemother. (1994) 38:71-78.
82. KOH TH, BABINI G, WOODFORD N,
SNG LH, HALL LM, LIVERMORE DM:
Carbapenem-hydrolyzing IMP-1 β-lactamase
in Klebsiella pneumoniae from Singapore.
541
Recent developments in carbapenems
Lancet (1999) 353:819.
83. RICCIO ML, FRANCESCHINI N,
BOSCHI L et al.: Characterization of the
metallo-β-lactamase determinant of
Acinetobacter baumannii AC-54/97 reveals
the existence of bla(IMP) allele variants
carried by gene cassettes of different
phylogeny. Antimicrob. Agents Chemother.
(2000) 44:1229-1235.
84. YGIT H, QUEENAM AM, ANDERSON
GJ et al.: Novel carbapenem-hydrolyzing β-
lactamase, KPC-1, from a carbapenem-
resistant strain of Klebsiella pneumoniae.
Antimicrob. Agents Chemother. (2001)
45:1151-1161.
85. GALLENI M, LAMOTTE-BRASSEUR J,
ROSSOLINI GM, SPENCER J,
DIDEBERG O, FRERE JM, AND THE
METALLO-β-LACTAMASE WORKING
GROUP: Standard numbering scheme for
Class B β-lactamases. (2001) Antimicrob.
Agents Chemother. 45:660-663.
86. ITO H, ARAKAWA Y, OHSUKA S,
WACHARATAYANKUN R, KATO N,
OHTA M: Plasmid-mediated dissemination
of the metallo-β-lactamase gene blaIMP
among clinically isolated strains of Serratia
marcescens. Antimicrob. Agents Chemother.
(1995) 39:824-829.
87. QUINN JP, STUDEMEINSTER AE,
DIVINCENZO CA, LERNER SA:
Resistance to imipenem in Pseudomonas
aeruginosa: clinical observations and
biochemical mechanism. Rev. Infect. Dis.
(1988) 10:892-898.
88. •TRIAS J, DUFRESNE J, LEVESQUE RC,
NIKAIDO H: Decreased outer membrane
permeability in imipenem-resistant mutants
in Pseudomonas aeruginosa. Antimicrob. Agents
Chemother. (1989) 33:1201-1206.
89. •TRIAS J, NIKAIDO H: Outer membrane
protein D2 channel catalyses facilitated
diffusion of carbapenems and penems
through the outer membrane of Pseudomonas
aeruginosa. Antimicrob. Agents Chemother.
(1990) 34:52-57.
90. SATAKE S, YONEYAMA H, NAKAE T:
Role of OmpD2 and chromosomal β-
lactamase in carbapenem resistance in clinical
isolates of Pseudomonas aeruginosa. J.
Antimicrob. Chemother. (1991) 32:199-207.
91. TRIAS J, NIKAIDO H: Protein D2 channel
of the Pseudomonas aeruginosa outer
membrane has a binding site for basic amino
acids and peptides. J. Biol. Chem. (1990)
265:15680-15684.
92. SUMITA Y, FUKASAWA M: Meropenem
542
resistance in Pseudomonas aeruginosa.
Chemother. (1996) 42:47-56.
93. BONFIGLIO G, MACCARONE G,
MEZZATESTA ML et al.: In vitro activity of
biapenem against recent clinical isolates.
Chemother. (1997) 43:393-399.
94. SHIMADA K: Overview of a new
carbapenem, panipenem/betamipron. Drugs
Exp. Clin. Res. (1994) 20:241-245.
95. TSUJI M, ISHII Y, OHNO A, MIYAZAKI
S, YAMAGUCHI: In vitro and in vivo
antibacterial activities of S-4661, a new
carbapenem. Antimicrob. Agents Chemother.
(1998) 42:94-99.
96. •LI XZ, ZHANG L, POOLE K: Interplay
between the MexA-MexB-OprM multidrug
efflux system and the outer membrane barrier
in the multiple antibiotic resistance of
Pseudomonas aeruginosa. J. Antimicrob.
Chemother. (2000) 45:433-436.
97. •SRIKUMAR R, PAUL CJ, POOLE K:
Influence of mutations in the mexR repressor
gene on expression of the MexA-MexB-
OprM multidrug efflux system of
Pseudomonas aeruginosa. J. Bacteriol. (2000)
182: 1410-1414.
98. MASEDA H, YONEYAMA H, NAKAE T:
assignment of the substrate-selective subunits
of the MexE-MexF-OprN multidrug efflux
pump of Pseudomonas aeruginosa. Antimicrob.
Agents Chemother. (2000) 44:658-664.
99. KOHLER T, EPP SF, CURTY LK,
PECHERE JC: Characterization of the
MexT, the regulator of the MexE-MexF-
OprN multidrug efflux system of
Pseudomonas aeruginosa. J. Bacteriol. (1999)
181:6300-6305.
100. MOELLERING Jr RC, ELIOPOULOS
GM, SENTOCHNIK ED: The
carbapenems: new broad spectrum β-lactam
antibiotics. J. Antimicrob. Chemother. (1989)
24(Suppl.A):1-7.
101. ALONSO R, FDEZ-ARANGUIZ A,
COLOM et al.: In vitro activity of biapenem
against beta-lactamase producing
Enterobacteriaceae. Eur. J. Clin. Microbiol.
Infect. Dis. (1994) 13:820-822.
102. ASAHI YA, MIYAZAKI S, YAMAGUCHI
K: In vitro and in vivo antibacterial activities
of BO-2727, a new carbapenem. Antimicrob.
Agents Chemother. (1995) 39:1030-1037.
103. LIVERMORE DM, YANG Y: Comparative
activity of meropenem against Pseudomonas
aeruginosa strains with well-characterised
resistance mechanisms. J. Antimicrob.
Chemoth. (1989) 24(Suppl. A):149-159
104. •EDWARDS JR: Meropenem: a
Expert Opin. Investig. Drugs (2002) 11(4)
microbiological overview. J Antimicrob
Chemother. (1995) 36(Suppl. A):1-17.
105. PFALLER MA, JONES RN: A review of the
in vitro activity of meropenem and
comparative antimicrobial agents tested
against 30,254 aerobic and anaerobic
pathogens isolated worldwide. Diagnost.
Microb. Inf. Dis. (1997) 28:157-163.
106. TURNER PJ: MYSTIC (meropenem yearly
susceptibility test information collection): a
global overview. J. Antimicrob. Chemother.
(2000) 46(topic T2):9-23.
107. INOUE K, HAMANA Y, MITSUASHI S:
In vitro antibacterial activity and β-lactamase
stability of a new carbapenem, BO-2727.
Antimicrob. Agents Chemother. (1995)
39:2331-2336.
108. •EDWARDS JR, TURNER PJ: Laboratory
data which differentiate meropenem and
imipenem. Scand. J. Infect. Dis . (1995)
96(Suppl.):5-10.
109. CHEN HY, YUAN M, IBRAHIM-
ELMAGBOUL IB, LIVERMORE DM:
National survey of susceptibility to
antimicrobials amongst clinical isolates of
Pseudomonas aeruginosa. J. Antimicrob.
Chemother. (1995) 35:521-524.
110. BONFIGLIO G, CARCIOTTO V, RUSSO
G et al.: Antibiotic resistance in Pseudomonas
aeruginosa. An Italian survey. J. Antimicrob.
Chemother. (1998) 41:307-310.
111. BONFIGLIO G, LAKSAI Y, FRANCHINO
L, AMICOSANTE G, NICOLETTI G:
Mechanisms of β-lactam resistance in Italian
isolates of Pseudomonas aeruginosa. J.
Antimicrob. Chemother. (1998) 42:697-702.
112. PFALLER MA, JONES RN, FOR THE
MYSTIC STUDY GROUP (AMERICAS):
MYSTIC (meropenem yearly susceptibility
test information collection) results from the
Americas: resistance implications in the
treatment of serious infections. J. Antimicrob.
Chemother. (2000) 46(Topic T2):25-37.
113. GOOSSENS H, FOR THE MYSTIC
STUDY GROUP (EUROPEAN CENTRES
ONLY): MYSTIC (Meropenem Yearly
Susceptibility Test Information Collection)
results from the Europe: comparison of
antibiotic susceptibilities between countries
and centre types. J. Antimicrob. Chemother.
(2000) 46(Topic T2):39-52.
114. HAZUMI N, FUSE A, MATSUDA K,
HASHIZUME T, SANADA M: Mechanism
of enhanced antipseudomonal activity of
BO-2727, a new injectable 1-β-methyl
carbapenem. Antimicrob. Agents Chemother.
(1995) 39:702-706.

115. OHBA F, NAKAMURA-KAMIJO M,
WATANABE N-A, KATSU: In vitro and
in vivo antibacterial activities of ER-35786, a
new antipseudomonal carbapenem.
Antimicrob. Agents Chemother. (1997)
41:298-307.
116. OKUDA J, OTSUKI M, OH T, NISHINO
T: In vitro activity of DU-6681a, an active
form of the new oral carbapenem compound
DZ-2640, in comparison with that of R-
95867, faropenem and oral cephalosporins. J.
Antimicrob. Chemother. (2000) 46:101-108.
117. KITZIS MD, ACAR JF, GUTMANN L:
Antibacterial activity of meropenem against
Gram-negative bacteria with a permeability
defect and against staphylococci. J.
Antimicrob. Chemother. (1989) 24(Suppl.
A):125-132.
118. FISH DN, SINGLETARY TJ: Meropenem a
new carbapenem antibiotic. Pharmacotherapy
(1997) 17:644-669.
119. GOLDSTEIN EJC, CITRON DM,
MERRIAM CV, WARREN Y TYRREL KL:
Comparative in vitro activities of ertapenem
(MK-0826) against 1,001 anaerobes isolated
from human intra-abdominal infections.
Antimicrob. Agents Chemother. (2000)
44:2389-2394.
120. WEXLER KM, MOLITORIS E,
FINGOLD SM: The in vitro activity of L-
627 against anaerobic bacteria. J. Antimicrob.
Chemother. (1994) 33:629-634.
121. KATO N, TANAKA K, KATO H,
WATANABE K: In vitro activity of R-95867,
the active metabolite of a new oral
carbapenem, CS-834, against anaerobic
bacteria. J. Antimicrob. Chemother. (2000)
45:357-361.
122. BETRIUC C, GOMEZM, PALAN ML,
SANCHEZ A, PICAZO JJ: Activities of new
antimicrobial agents (trovafloxacin,
moxifloxacin, sanfetrinem and quinupristin-
dalfopristin) against Bacteroides fragilis group:
comparison with the activities of 14 other
agents. Antimicrob. Agents Chemother. (1999)
43:2320-2322.
123. DI MODUGANO E, BROGGIO R,
ERBETTI I, LOWTHER J: In vitro and
in vivo antibacterial activities of GV129606,
a new broad spectrum trinem. Antimicrob.
Agents Chemother.(1997) 41:2742-2748.
124. COLARDYN F, FAULKNER KL, FOR
THE MEROPENEM SERIOUS
INFECTION STUDY GROUP:
Intravenous meropenem versus imipenem/
cilastatin in the treatment of serious bacterial
infections in hospitalised patients. J.
Antimicrob. Chemother. (1996) 38:523-537.
125. GARAU J, BLANQUER J, COBO L et al.:
Prospective, randomised, multicentre study
of meropenem versus imipenem/cilastatin as
empiric monotherapy in severe nosocomial
infections. Eur. J. Clin. Microbiol. Infect. Dis.
(1997) 16:789-796.
126. MOUTON YJ, BEUSCART C,
MEROPENEM STUDY GROUP:
Empirical monotherapy with meropenem in
serious bacterial infections. J. Antimicrob.
Chemother. (1995) 36(Suppl. A):145-156.
127. DIRKSEN MSC, WINTERMANS RFG,
BOEREMA JBJ, GIMBRERE JSF:
Imipenem as monotherapy in the treatment
of intensive care patients with severe
infections. J. Antimicrob. Chemother. (1986)
18(Suppl. E):145-151.
128. HUGHES WT, ARMSTRONG D, BODEY
G et al.: Guidelines for the use of
antimicrobial agents in neutropenic patients
with unexplained fever. Infectious Diseases
Society of America. Clin. Infect. Dis. (1997)
25:551-557.
129. COMETTA A, GLAUSER MP: Empiric
antibiotic monotherapy with carbapenems in
febrile neutropenia: a review. J. Chemother.
(1996) 8:375-381.
130. LINDBLAD R, RODJER S,
ADRIANSSON M et al.: Empiric
monotherapy for febrile neutropenia – a
randomised study comparing meropenem
with ceftazidime. Scand. J. Infect. Dis. (1998)
30: 237-243.
131. BEHRE G, LINK H, MASCHMEYER G
et al.: Meropenem monotherapy versus
combination therapy with ceftazidime and
amikacin for empirical treatment of febrile
neutropenic patients. Ann. Hematol. (1998)
76:73-80.
132. LAMB HM, GOA KL: Management of
febrile episodes in neutropenic patients. Dis.
Manage Health Outcomes. (1999) 5:101-116.
133. HAMACHER J, VOGELL F, LICHEY J
et al. Treatment of acute bacterial
exacerbations of chronic obstructive
pulmonary disease in hospitalised patients, a
comparison of meropenem and imipenem/
cilastatin: COPD Study Group. J Antimicrob
Chemother. (1995) 36(Suppl. A):121-133.
134. AMERICAN THORACIC SOCIETY:
Hospital-acquired pneumonia in adults:
diagnosis, assessment of severity, initial
antimicrobial therapy, and preventive
strategy. Am. J. Respir. Crit. Care. (1996)
153:1711-1725.
135. SIEGER B, BERMAN SJ, GECKLER RW,
FARKAS SA: Empiric treatment of hospital-
Expert Opin. Investig. Drugs (2002) 11(4)
Bonfiglio, Russo & Nicoletti
acquired lower respiratory tract infections
with meropenem or ceftazidime with
tobramycin: a randomised study:
Meropenem Lower Respiratory Infection
Group. Crit. Care Med. (1997) 25:1663-
1670.
136. FINCH RG, PENBERTON K, GILDON
KM. Pneumonia: the impact of risk factors
on the outcome of treatment with
meropenem and ceftazidime. J. Chemother.
(1998) 10:35-46.
137. •BRADLEY JS, GARAU J, LODE H,
ROLSTON KVI, WILSON SE, QUINN
JP: Carbapenems in clinical practice: a guide
to their use in serious infection. Intern. J.
Antimicrob. Agents. (1999) 11:93-100.
138. POENARU D, SANTIS M, CHRISTOU
NV: Imipenem versus tobramycin-
antianaerobe antibiotic therapy in intra-
abdominal infections. Can. J. Surg. (1990)
33:415-422.
139. SOLOMKIN JS, DELLINGER EP,
CRISTOU NV, BUSUTTIL RW: Results of
a multicenter trial comparing imipenem/
cilastatin to tobramycin/clindamycin for
intraabdominal infections. Ann. Surg. (1990)
212:581-591.
140. HESELTINE PNR, YELLIN AE,
APPLEMAN MD et al.: Imipenem therapy
for perforated and gangrenous appendicitis.
Surg. Gynecol. Obstet. (1986) 162:43-48.
141. BRISMAR B, AKERLUND J-E,
SJOSTEDT S et al.: Biapenem versus
imipenem/cilastatin in the treatment of
complicated intra-abdominal infections:
report from Swedish study group. Scand.J.
Infect. Dis. (1996) 28:507-512.
142. CONDON RE, WALKER AP, SIRINEK
KR et al.: Meropenem versus tobramycin
plus clindamycin for treatment of
intrabdominal infections: results of a
prospective, randomised, double-bind
clinical trial. Clin. Infect. Dis. (1995) 21:
544-550.
143. •WILSON SE: Meropenem in the treatment
of intra-abdominal infection: review of the
clinical trials. Adv. Ther. (1997) 14:110-115.
144. KEMPF P, BAUERNFEIND A, MULLER
A, BLUM J: Meropenem monotherapy
versus cefotaxime plus metronidazole
combination treatment for serious intra-
abdominal infections. Infection (1996)
24:473-479.
145. ZANETTI G, HARBARTH SJ, TRAMPUZ
A et al.: Meropenem (1.5 g/day) is as effective
as imipenem/cilastatin (2 g/day) for the
treatment of moderately severe intra-
543
Recent developments in carbapenems

abdominal infections. Int. J. Antimicrob.

Agents. (1999) 11:107-113.
146. KANELLAKOPOULOU K,
GIAMMARELLU H,
PAPADOTHOMAKOS P et al.:
Meropenem versus imipenem/cilastatin in
the treatment of intraabdominal infetions
requiring surgery. Eur. J. Clin Microbiol.
Infect. Dis. (1993) 12:449-453.
147. BRADLEY JS: Selecting therapy for serious
infections in children : maximizing safety and
efficacy. Diagn. Microb. Infect. Dis. (1998)
31:405-410.
148. KLUGMAN KP, DAGAN R AND THE
MEROPENEM MENINGITIS STUDY
GROUP: A randomised comparison of
meropenem with cefotaxime for the
treatment of bacterial meningitis. Antimicrob.
Agents Chemother. (1995) 39:1140-1146.
149. •EDWARDS JR, BETT MJ: Carbapenems:
the pinnacle of the β-lactam antibiotics or
room for improvement? J. Antimicrob.
Chemother. (2000) 45:1-4.

Affiliation
Giovanni Bonfiglio†, Giovanni Russo & Giuseppe
Nicoletti
Dipartimento di Scienze Microbiologiche,
Università di Catania, Via Androne 81, 95124,
Catania, Italy
Tel: +39 095327485; Fax: +39 095312798;
E-mail: bonfigio@mbox.unict.it

544 Expert Opin. Investig. Drugs (2002) 11(4)