Poulakou2008 - Doripenem - An Expected Arrival in The Treatment of Infections Caused by Multidrug - Resistant

Drug Evaluation
Doripenem: an expected arrival

in the treatment of infections
caused by multidrug-resistant
1. Overview of the market Gram-negative pathogens
2. Doripenem
3. Conclusions
Garyphallia Poulakou† & Helen Giamarellou
University General Hospital ATTIKON, National and Kapodistrian University of Athens
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by University of Notre Dame Australia on 06/25/13
4. Expert opinion
Medical School, 4th Department of Internal Medicine, 1 Rimini street, 124 62 Athens, Greece
Background: Potent new drugs against multidrug-resistant Gram-negative

bacteria, namely Pseudomonas aeruginosa and Acinetobacter spp. and
pan-drug-resistant Klebsiella pneumoniae, which constitute an increasing
medical threat, are almost absent from the future pharmaceutical pipeline.
Objective: This drug evaluation focuses on the position of doripenem, a
novel forthcoming carbapenem. Mechanisms of resistance and new drugs
with anti-Gram-negative activity are also briefly reviewed. Methods:
Literature search was performed for new carbapenems, new antibiotics,
doripenem, metallo-β-lactamase inhibitors, multidrug-resistant pathogens,
antipseudomonal antibiotics and multidrug-resistant epidemiology. Results:
Doripenem possesses a broad spectrum of activity against Gram-negative
For personal use only.
bacteria, similar to that of meropenem, while retaining the spectrum of

imipenem against Gram-positive pathogens. Against P. aeruginosa, doripenem
exhibits rapid bactericidal activity with 2 – 4-fold lower MIC values,
compared to meropenem. Exploitation of pharmacokinetic/pharmacodynamic
applications could offer a treatment opportunity against strains exhibiting
borderline resistance to doripenem. Stability against numerous β-lactamases,
low adverse event potential and more potent in vitro antibacterial
activity against P. aeruginosa and A. baumanni compared to the existing
carbapenems, are its principal features.
Keywords: Acinetobacter baumannii, antibiotic policy, antipseudomonal antibiotic,

colistin, doripenem, Klebsiella pneumonia, multidrug-resistant epidemiology,
multidrug-resistant pathogen, new antibiotic, Pseudomonas aeruginosa
Expert Opin. Investig. Drugs (2008) 17(5):749-771
1. Overview of the market
Doripenem (S-4661) is a novel parenteral carbapenem with a research history in

international meetings since 1994. It was developed by Shionogi & Co. Ltd
(Osaka Japan), approved in Japan in July 2005 and launched in September of
2005 [1]. Outside Japan, the rights were licensed to Peninsula Pharmaceuticals,
Inc. (Alameda, CA, USA) and acquired subsequently by Ortho-McNeil
Pharmaceutical, Inc. (New Brunswick, NJ, USA). Ortho-McNeil Pharmaceutical,
Inc. is a subsidiary of Johnson & Johnson [2].
1.1 Antimicrobial resistance and unmet need

Pseudomonas aeruginosa, a highly virulent microorganism, was recognised in the
1970s as the microorganism associated with lethal bacteraemia in the neutropenic
host. Today P. aeruginosa remains recognised as a major cause of nosocomial
bacteraemia and infections associated with invasive devices, mechanical ventilation,
10.1517/13543780802016332 © 2008 Informa UK Ltd ISSN 1354-3784 749

Doripenem
burn wounds or surgery, both in the immunocompromised resistance. In a recent retrospective matched cohort study,
and the immunocompetent host [3,4]. The worldwide clinical isolation of multidrug MDR A. baumannii was
emergence of multidrug-resistant (MDR) nosocomial clones demonstrated by multivariable analysis to be a significant
have added significantly to the ominous prognosis of predictor of mortality, need for mechanical ventilation and
P. aeruginosa infections. It has been reported that MDR reduced functional status on discharge [13]. National data
strains are associated with a 3-fold higher rate of mortality, from the NNIS indicate that the prevalence of
a 9-fold higher rate of secondary bacteraemia, a 2-fold Acinetobacter organisms among Gram-negative pathogens
increase in the length of hospital stay and a considerable causing pneumonia in ICUs has increased from 4.2% in
increase in cost [5]. The high virulent potential of MDR 1986 to 7.0% in 2003, with resistance to imipenem (increase
P. aeruginosa strains were also shown in current US data in in prevalence from 0 to 42%) and ceftazidime (increase in
which significantly greater mortality (30.7%) was observed in prevalence from 18 to 68%) rising substantially during
hospitalised patients receiving inadequate empiric therapy for the same period (NNIS data) [14]. Global data from the
bacteraemia compared with those who were given appropriate MYSTIC surveillance database for A. baumannii are also
therapy (17.8%, p = 0.018 for the comparison) [6]. shown in Table 1 [9].
According to data from the US National Nosocomial At present, increasing rates of Enterobacteriaceae harbouring
Infection Surveillance System (NNIS) published in 2004, extended-spectrum β-lactamases (ESBLs), including CTX-M,
report resistance rates among P. aeruginosa isolates to plasmid-mediated AmpC β-lactamases and carbapenemases,
imipenem and quinolone were at 21.1 and 29.5%, represent a new emerging threat. Escherichia coli isolates
respectively, for the period January – December 2003, with CTX-M ESBLs are spreading in the community and in
indicating an increase of 15 and 9%, respectively, from the hospitals [15,16]. Resistance to 3rd generation cephalosporins
period 1998 to 2002. In Intensive Care Unit (ICU) isolates, in Klebsiella pneumoniae strains was reported at 20.6%
the respective rates of resistance were even higher, with for the year 2003, with a worrisome 47% increase from
resistance rates of up to 51.6% for ciprofloxacin, 31.4% for the period 1998 through 2002 [7]. Recently, the emergence
piperacillin-tazobactam, 38% for imipenem and 23.6% for of K. pneumoniae producing metallo-β-lactamases (MBL)
ceftazidime among P. aeruginosa isolates [7]. Relevant has been witnessed in certain areas [17,18], resulting in
figures for ICU isolates of P. aeruginosa derived from Europe excessive empirical use of colistin. Colistin overuse sub-
are even worse, as from 1990 until 1999, resistance to sequently led to clusters of pan-drug-resistant Klebsiella
aminoglycosides reached 37 – 70%, to ceftazidime 57%, strains from various infections, mainly bacteraemia and
to piperacillin-tazobactam 53%, to ciprofloxacin 56% and VAP, mostly in patients with prolonged administration of
to imipenem 52% [8]. An estimation of the global current colistin [19]. Management of emerging MDR Gram-negative
resistance patterns of P. aeruginosa strains collected by pathogens seems [20].
the Meropenem Yearly Susceptibility Test Information
Collection programme (MYSTIC) is shown in Table 1 [9]. 1.2 Forthcoming and recently licensed compounds
Greece, Brazil, the Czech-Republic and Bulgaria possess the Antimicrobials already available are extensively reviewed else-
highest individual resistance rates to carbapenems, very where, although in-use carbapenems will be comparatively
probably indicating high consumption rates of the specific presented throughout this evaluation of doripenem. Only
antibiotics. However, meropenem, compared to imipenem, forthcoming compounds possessing an anti-Gram-negative
is more potent, being active against up to a third of spectrum of antimicrobial activity, particularly against the
imipenem-resistant strains, indicating that a considerable problematic pathogens mentioned in the previous section
percent of the strains should have lost the OprD porin that and the recently licensed tigecycline, will be presented.
is influential mainly against imipenem. On the other hand,
piperacillin/tazobactam seems to be less vulnerable to resistance 1.2.1 b-lactams
development in most countries and regions [10]. RO4908463/CS-023 (Roche, Basel, Switzerland) is a new
Acinetobacter spp., especially Acinetobacter baumannii, parenteral carbapenem, licensed from Sankyo (Tokyo,
has emerged as an important nosocomial pathogen within Japan) by Roche, undergoing Phase II clinical trials
the last two decades and is responsible for infections for pneumonia [21,22]. RO4908463/CS-023 demonstrated
among patients hospitalised in Intensive Care Units (ICU). in vitro activity against a broad spectrum of Gram-positive
A. baumannii has been implicated in ventilator-associated and -negative aerobes and anaerobes, including methicillin-
pneumonia (VAP), primary bacteremia, catheter-related resistant Staphylococcus aureus (MRSA), methicillin-resistant
infections, skin and soft tissue infections (SSTI), urinary Staphylococcus epidermidis (MRSE), penicillin-resistant
tract infections (UTI) and surgical site infections. Outbreaks Streptococcus pneumoniae (PRSP), β-lactamase-negative
have also been reported, predominantly among mechanically ampicillin-resistant Haemophilus influenzae and P. aeruginosa.
ventilated patients [11,12]. Although its virulence has been The compound demonstrated the most potent activity
debated in VAP, today it is recognised as an important among the comparators (imipenem, meropenem, ceftazidime,
contributor to morbidity, mainly due to its multidrug ceftriaxone, ampicillin, amikacin and levofloxacin) against
750 Expert Opin. Investig. Drugs (2008) 17(5)

Table 1. Global resistance surveillance of Acinetobacter baumannii and Pseudomonas aeruginosa isolated in the MYSTIC Program [9].
Region Gentamicin* Tobramycin* Pip/Tazo* Ceftazidime* Cefepime* Imipenem* Meropenem* Ciprofloxacin*

2000 – 2006 2000 – 2006 2000 – 2006 2000 – 2006 2000 – 2006 2000 – 2006 2000 – 2006 2000 – 2006
A. baumannii
Northern Europe‡ 28.89 – 8.33 20.29 – 6.9 26.67 – 7.04 68.54 – 66.18 6.45 – 9.68 1.11 – 4.23 6.67 – 0 35.36 – 23.94
Southern Europe§ 70 – 52.3 66.67 – 85 67.09 – 59.2‡‡ 71.25 – 71.7 0 – 51.52 20 – 35.85 13.75 – 16.98 78.48 – 84.91
Eastern Europe¶ 74.55 – 51.25 41.26 – 48.7 63.29 – 67.08 53.31 – 60.43 53.27 – 65.07 31.22 – 49.53 25.32 – 45.77 71.31 – 75.55
North America# 33.33 – 46.67 19.18 – 32.65 20.55 – 30.61 24.66 – 40.82 25.78 – 15.79 8.22 – 8.16 15.07 – 8.16 32.88 – 51.02
South America** 46.43 – 45.12 53.57 – 36.99 57.14 – 52.44 75 – 68.29 38.46 – 47.95 46.43 – 21.95 17.86 – 24.39 75 – 68.29
P. aeruginosa
Northern Europe‡ 22.63 – 19.3 6.72 – 8.11 11.68 – 10.39 16.35 – 17.38 14.44 – 29.72 19.42 – 20.07 11.68 – 10.39 16.93 – 22.4
Southern Europe§ 36.19 – 14.17 33.98 – 42.11 10.58 – 8.33 19.52 – 28.33 4.23 – 8.82 23.81 – 20.83 2.86 – 14.17 42.11 – 20.83
Eastern Europe¶ 42.2 – 31.78 51.49 – 41.38 25.38 – 24.11 40.37 – 22.19 42.7 – 27.79 42.2 – 31.71 25.38 – 24.11 34.88 – 35.83
North America# 10.38 – 13.7 8.66 – 11.54 12.34 – 13.23 12.34 – 16.6 9.71 – 7.59 12.07 – 13.62 10.04 – 7.65 21 – 22.44
Expert Opin. Investig. Drugs (2008) 17(5)

South America** 65.22 – 48.78 65.22 – 49.1 23.91 – 34.45 27.17 – 39.02 10.39 – 42.43 38.04 – 50.91 5.43 – 45.73 60.87 – 52.44
*All MIC values are expressed as µg/ml. The first value refers to 2000 and the second to 2006. Data derived from all hospital wards.
‡Resistance breakpoints (µg/ml): gentamicin ≥ 16, todramycin ≥ 16, Pip/Tazo ≥ 128, ceftazidine ≥ 32, cefepime ≥ 32, imipenem ≥ 16, meropenem ≥ 16, ciprofloxacin ≥ 4.
§Belgium, Finland, Germany, Sweden and UK.
¶Greece, Italy, Malta, Portugal, Spain and Switzerland.
#Bulgaria, Croatia, Chech Republic, Israel, Poland, Romania, Russia, Slovenia and Turkey.
**USA, Mexico and Canada.

‡‡Argentina, Brazil, Columbia, Peru and Venezuela.
MYSTIC: Meropenem Yearly Susceptibility Test Information Collection Program; Pip/Tazo: Piperacillin/tazobactam.
751
Poulakou & Giamarellou
Doripenem
P. aeruginosa and MRSA, but did not have activity treatment of intravascular infections or in cases of infections
against Enterococcus faecium, Burkholderia cepacia and with concomitant bacteraemia, particularly when the
Stenotrophomonas maltophilia [22,23]. RO4908463/CS-023 causative organism possesses an MIC near the Cmax, a
displayed stability against β-lactamases from situation that is quite common among A. baumannii
Enterobacter cloacae and Proteus vulgaris and ESBLs from strains. However, favourable pharmacokinetics of the
Escherichia coli. The in vivo efficacy of RO4908463/CS-023 compound in the tissues, including the epithelial-lining
was evaluated with a murine systemic infection model fluid of the lung, may prove an advantage in the treatment
induced by Gram-positive and Gram-negative pathogens of infections without concomitant bacteraemia [32-34].
and a lung infection model induced by strains of PRSP
with very encouraging results [24]. 1.2.3 Inhibitors of metallo-b-lactamases
A recent yet to be published study demonstrated stability The compound CP3242 is not a competitor but a possible
of RO4908463/CS-023 to purified Class A (SME-1 and companion. A fascinating future aspect has recently appeared
KPC-3), Class B (IMP-1, VIM-2, and VIM-6) and Class D as a poster presentation: CP3242, a novel inhibitor of
(OXA-23) carbapenemases. With the exception of IMP-1, metallo-β-lactamases was highly effective in combination
the Kcat/Km values of RO4908463/CS-023 were lower than with 3 carbapenems or ceftazidime against clinically isolated
those of imipenem and meropenem [25]. In another study, MBL-producing P. aeruginosa in vitro and in vivo [35].
in vitro activity of RO4908463/CS-023 was compared to CP3242 was effective in lowering the MIC50/MIC90 values
imipenem, panipenem, meropenem, biapenem, doripenem, of biapenem, imipenem, meropenem and ceftazidime.
ceftazidime and cefepime against 34 types of β-lactamase Time–kill studies revealed bactericidal activities relevant to
producing pathogens. RO4908463/CS-023 displayed MIC the MIC values of these antibiotics in combination with
values < 4 µg/ml against pathogens which produce Class A CP3242. In a murine systemic infection model studied
ESBL, or Class C or Class D β-lactamase. However, subsequently with IMP-1- or VIM-2-producing strain,
both meropenem and doripenem had MIC values ranging the ED50 values (mg/kg) of all four tested antibiotics were
from 8 – 256 µg/ml against pathogens producing lowered after addition of CP3242. This inhibitor merits
carbapenemases (IMP-1 and VIM metallo β-lactamases, as further evaluation in the future, as it seems to be one of the
well as class A or D β-lactamases with carbapenemase activity most promising advancements in the treatment of infections
such as SME-1, KPC-2, -3, OXA-23, -40 and -58) [26]. due to carbapenemase-producing pathogens.
Currently available data for RO4908463/CS-023 require
further evaluation of the compound in vitro and in 2. Doripenem
infections due to resistant Gram-negative pathogens.
At the time of the preparation of the manuscript, few
1.2.2 Glycylcyclines published articles relevant to doripenem were available.
Tigecycline, a new semisynthetic glycylcycline, was A large amount of data derives from unpublished studies,
licensed by the US Food and Drug Administration in presented as oral or poster presentations in several
June 2005 for complicated skin and skin structure conferences. The lack of peer-reviewed evidences prompted
infections (cSSSIs) and intra-abdominal infections (cIAIs) a lengthier and more descriptive presentation of scientific
in adults. It is a bacteriostatic agent, acting through inhi- data, which are subject to possible modifications following
bition of bacterial protein translation. Tigecycline is active future editorial procedures.
against a wide spectrum of aerobic and anaerobic bacteria,
including Gram-positive cocci (methicillin-sensitive 2.1 Chemistry of doripenem
Staphylococcus aureus [MSSA], MRSA, MRSE, penicillin- Doripenem is a new member of carbapenems, a class of
intermediate and-resistant Streptococcus pneumoniae, antibiotics derived from natural sources. Other members of
enterococci [vancomycin-sensitive and vancomycin-resistant the class include imipenem, meropenem and ertapenem.
Enterococcus faecium and faecalis]) and Gram-negative Faropenem and tebipenem and are being evaluated in
bacteria such as MDR A. baumannii, ESBL-producing clinical trials, whereas panipenem and biapenem are
Enterobacteriaceae spp., Klebsiella spp. and S. maltophilia marketed in Asia [36]. In view to treatment options against
strains [27-29]. However, P. aeruginosa and Proteus spp., as multiresistant Gram-negative pathogens, comparisons
well as Morganella spp., are not included in tigecycline’s throughout this doripenem evaluation will focus on
antibacterial spectrum, thus limiting the use of the drug in imipenem and meropenem, due to their similar spectrum of
patients with documented non-pseudomonal infections or activity. Thienamycin, the first carbapenem, possessing a
warranting the addition of an antipseudomonal agent in five-member ring attached to a β-lactam ring, originates
empirical regimens of patients with risk factors [30,31]. Nausea from Streptomycis cattleya [37]. The hydroxyethyl component
and vomiting are the most common adverse effects caused off position 6 confers stability against β-lactamases,
by tigecycline. Low tigecycline Cmax in the serum may especially due to its trans-conformation (Figure 1). The
compromise the drug’s use in clinical practice for the antipseudomonal activity of the class is attributed to

A. OH B. OH
H H H H
H
N2H N NH
S S
N N
O O
CO2H CO2H
C. OH D.
H H HO
H H
S
S NH2
N
N
O O S O
O
CO2H
O CO2H
N NH
H N
H
N
E. OH
H H
S
N
O
CO2H H
N CO2H
N
H
Figure 1. Chemical structures of thienamycin (A), imipenem (B), meropenem (C), doripenem (D) and ertapenem (E).
the alkythio side chain of position 2 of the five-member dimethyl-carbamoyl-pyrrolidynthio side chain of position 2
ring [38-40]. Chemical instability of thienamycin led to the of meropenem has been replaced in doripenem by a
synthesis of imipenem (N-formimidoyl-thienamycin), which sulfamoyl-aminomethyl-pyrrolidinylthio group which
retained potent antipseudomonal activity due to the amidine confers potency against S. aureus equivalent to that of
side chain [40]. However, imipenem was vulnerable to panipenem and imipenem, while preserving Gram-negative
hydrolysis by the renal enzyme dehydropeptidase-1, a potency similar to that of meropenem [45].
problem surpassed with the addition of cilastatin (an inhibitor
of dehydropeptidase-1) [41,42]. Imipenem/cilastatin was the 2.2 Mechanism of action
first carbapenem which entered the market in 1986 [43]. In Carbapenems, like all β-lactams act through inhibition of
meropenem, licensed in US in 1994, the hydrophobic the bacterial cell wall synthesis. In particular, they interact
dimethyl-carbamoyl-pyrrolidynthioside chain off position 2 with penicillin-binding proteins (PBPs), which are cytoplasmic
of the five-member ring, is responsible for the increased membrane proteins with a significant role in late peptidoglycan
activity against Gram-negative pathogens at the cost of a synthesis and conformation of bacterial cell wall [46].
relatively diminished activity against Gram-positive A characteristic that distinguishes carbapenems from other
pathogens compared to imipenem [44]. The chemical structure β-lactams is their stronger and specific affinity to PBP-1a
of doripenem is almost identical to that of meropenem and -1b of P. aeruginosa and E. coli, a fact that results in
(Figure 1). Doripenem, similar to meropenem and unlike more rapid bacterial killing [47,48]. Increased affinity to
imipenem, has a 1-β-melhyl side chain conferring resistance PBP-2 and -3 further differentiates the members within
to hydrolysis by dehydropeptidase-1. The hydrophobic the carbapenem class. Imipenem preferentially binds to
Expert Opin. Investig. Drugs (2008) 17(5) 753

Doripenem
PBP-2 of E. coli, leading to the formation of spherical and extrusion of a group of the β-lactams (carbenicillin,
or ellipsoid bacterial cells that lyse afterwards [48]. In ceftazidime, moxalactam and aztreonam) is specific to
P. aeruginosa, imipenem binds equally to both PBP-2 MexAB-OprM, which is the most commonly upregulated
and -3. Meropenem and ertapenem exhibit their strongest pump in P. aeruginosa. MexEF-OprN efflux pump, which
affinity for PBP-2 of E. coli; however, their binding to confers resistance to quinolones, chloramphenicol and
PBP-3 is more pronounced compared to imipenem [49]. trimethoprim, although not common, is co-regulated with
Against PBP-3 of P. aeruginosa, meropenem exerts a 3 to OprD mutation, conferring resistance also to carbapenems.
10-fold higher binding capacity than imipenem [50]. Metallo-β-lactamases have emerged as a key determinant of
Doripenem exhibits the same preference to PBP-2 of P. aeruginosa resistance to antimicrobials and inactivate all
E. coli as the other carbapenems; however its affinity to β-lactams except monobactams (aztreonam). The most
PBP-3 of P. aeruginosa is between that of imipenem and common representatives are the members of IMP and
meropenem. Interestingly, with doripenem, marked strain to VIM families. OXA-type β-lactamases possessing ESBL
strain variations have been reported, probably expressed as activity, which hydrolyse third generation cephalosporins
variable bactericidal and clinical outcomes. Imipenem binds and aztreonam, are not uncommon in P. aeruginosa.
avidly with PBP-1, -2, -3 and -4 of S. aureus, whereas Among other β-lactamases, encoded by plasmids or chromo-
meropenem shows 2 to 6-fold lower affinity for PBP-1, -2 somally integrated transposons, no single ESBL has become
and -4, and almost negligible for PBP-3, a fact that prevalent worldwide; VEB-1 has been reported from East
probably explains the reduced activity of meropenem against Asia, and OXA-10 and OXA-2 from Turkey and France.
S. aureus, compared to imipenem [47,50]. However, the PER-1 has been associated with outbreaks in Turkish hospitals
binding pattern of doripenem to PBPs of S. aureus is similar with poor therapeutic outcomes [54]. AmpC chromosomally-
to meropenem, thus failing to explain its near-imipenem encoded cephalosporinases may also play some role in the
antistaphylococcal activity [39]. Specific binding affinity spread of resistance among P. aeruginosa strains.
to the PBPs has been associated with variability in lipo- P. aeruginosa may also express a variety of aminoglycoside
polysaccharide (LPS) release from Gram-negative bacilli modifying enzymes (acetylases, adenylases and dephosphory-
and to bacterial cell morphology after exposure to an lases) that eliminate the effectiveness of aminoglycosides.
individual drug [51,52]. Their acquired genes are very often part of transferable
plasmids, together with integrons containing multiple drug
2.3Resistance mechanisms resistance determinants including metallo-β-lactamases.
2.3.1Overview of mechanisms of resistance among Point mutations in topoisomerase genes, gyrA and parC,
targeted Gram-negative pathogens are responsible for resistance to quinolones.
P. aeruginosa and Acinetobacter spp. are noted for their Finally, although not recognised as classical mechanism
intrinsic resistance to antibiotics and for their ability of resistance, biofilm formation by P. aeruginosa fre-
to acquire genes encoding resistance determinants. The quently involved in nosocomial infections where foreign
production of β-lactamases and aminoglycoside-modifying bodies are implicated (i.e., tracheal tubes, intravascular
enzymes, the diminished expression of outer membrane catheters) may be a major contributor to all the
proteins, mutations in topoisomerases and upregulation above-mentioned mechanisms [15,53].
of efflux pumps play an important role in antibiotic
resistance. The most prevalent mechanisms of resistance in 2.3.1.2 A. baumannii
P. aeruginosa, and A. baumannii are presented in Table 2. AmpC chromosomally-encoded cephalosporinase is a
key determinant of resistance in A. baumannii. Although
2.3.1.1 P. aeruginosa ubiquitously distributed, insertion elements (i.e., ISAba1)
The most common mechanism by which P. aeruginosa are recently considered responsible for the upregulation
becomes resistant to imipenem is the mutational loss of the of its expression.
outer membrane protein OprD. This porin change does not Various other β-lactamases have been found in
confer resistance to meropenem (although MIC values rise) A. baumannii (TEM-1, SHV, CTX-M, PER-1, and VEB-1).
or affect other β-lactams. Mutational loss of OprD is Their impact to resistance is difficult to be estimated in the
frequently described (up to 25%) during imipenem presence of AmpC. Many outbreaks of MDR A. baumannii
treatment. Efflux pumps are emerging as an important infections are attributed to loss of outer membrane porins.
mechanism of resistance in P. aeruginosa. All efflux The spread of class D OXA carbapenemases as
systems extrude a wide variety of antimicrobial agent ARI-1 (OXA-23) has resulted in outbreaks of carbapenem-
groups: quinolones, macrolides, tetracyclines, lincomycin, resistant A. baumannii; their action may be enhanced by
chloramphenicol, most penicillins (except carbenicillin), IS elements that act as promoters [55]. IMP and VIM
most cephems (except ceftazidime) and meropenem, but metallo-β-lactamases are also identified with increasing
none of them extrude polymyxin B or imipenem [53]. frequency. An RND efflux pump has been described in
Extrusion of aminoglycosides is specific to MexXY-OprM, A. baumannii, being involved in resistance to quinolones,

Table 2. Mechanisms of resistance among the key Gram-negative pathogens targeted by carbapenems [16,18,20,53-57].
Mechanism Description Frequency among Frequency among Frequency among

Pseudomonas aeruginosa Acinetobacter baumannii Enterobacteriaceae
isolates isolates
Reduced affinity Alteration of porin channels Prevalent Prevalent in outbreaks Porin deficiency rare*
to the target Mutational loss of OprD
Multidrug efflux pumps Prevalent Rare
Inactivating β-Lactamases Penicillinases, Rare Intrinsic AmpC prevalent‡ Prevalent chromosomal or
Enzymes cephalosporinases plasmid–mediated AmpC
Extended-spectrum- Rare (PER-1, VEB-1, OXA) Variable (TEM, SHV, Frequent (CTX-M, SHV, TEM)
β-lactamases (ESBL) CTX-M PER-1, VEB-1)
Carbapenemases Metallo-β-lactamases Frequent (IMP, VIM, SPM) Rare (IMP, VIM) IMP, VIM
Non-metallo-β-lactamases Rare Intrinsic OXA-51-like‡ Prevalent (KPC, OXA-48,
Frequent OXA-23, IMI/NMC, SME)
OXA-40, OXA-58
Aminoglycoside-modifying Acetylases, adenylases, Present§ Present§ Present§
emzymes dephosphorylases,

ribosomal methylases
Mutational Point mutations in gyrA, parC Present§ Present§ Present §
resistance topoisomerase genes
Regulatory mutations altering Present§ Present§ Present§
expression of intrinsic genes
and operons
*In combination with AmpC and ESBL, it confers resistance also to carbapenems.
‡Expression varies following activation by migration of ISAba1.
§Present at various frequencies.
755
Doripenem
tetracyclines, chloramphenicol, trimethoprim, erythromycin In another in vitro study, comparing activities of

and ethidium bromide. Mutations in gyrA and parC carbapenems against P. aeruginosa isolates with intrinsic
are responsible for quinolone resistance and three types of efflux-type resistance, doripenem MIC values were
aminoglycoside modifying enzymes (acetylating, adenylating 0.12 – 0.5 µg/ml, whereas meropenem and imipenem
and phosphorylating) are implicated in resistance MIC values were 0.25 – 0.5 µg/ml and 1 – 2 µg/ml,
to aminoglycosides [15,20,56]. respectively. In the same study, P. aeruginosa isolates with
acquired resistance were also tested (mutants with various
2.3.1.3 Enterobacteriaceae combinations of AmpC and OprD expression, PU21
Resistance to oxyiminocephalosporines has emerged among transconjugants with class A and D β-lactamases, and
Enterobacteriaceae through the selection of strains metallo-β-lactamases) [60]. The MIC values of doripenem
with hyperproduced or acquired AmpC enzymes and most were increased by the loss of OprD, but not by derepression of
importantly with ESBLs. Plasmid-mediated AmpC genes AmpC. Nevertheless, as with other carbapenems, the imper-
are increasingly prevalent among E. coli, Klebsiella spp. meability-determined resistance caused by the loss of OprD
and Salmonella spp. isolates, although less frequent than co-required AmpC activity and was lost in OprD mutants
ESBLs. Since the first description, in the mid-1980s, of also lacking AmpC. The TEM, PSE, PER and OXA enzymes
the first mutants of the TEM and SHV plasmid-mediated did not significantly compromise activity of doripenem.
penicillinases, ESBLs had become an increasing threat The presence of VIM and IMP metallo-β-lactamases was
among Enterobacteriaceae, being most prevalent among associated with doripenem MIC values of ≥ 16 µg/ml.
K. pneumoniae. The epidemiology of ESBLs nowadays Resistant mutants seemed to be harder to select with
is undergoing rapid change because of the spread of doripenem than with other carbapenems (or noncarbapenems),
CTX-M enzymes [53]. as shown by the fold increases in the MIC values, which
Carbapenem-resistance in Enterobacteriaceae, although were smaller for the resistant mutants. Single-step doripenem
rare, can arise either through the acquisition of permeability mutants were resistant only to carbapenems and had lost
in strains already possessing AmpC or ESBL enzymes, or Opr D, whereas multistep mutants had broader resistance,
through the acquisition of carbapenemases. Carbapenemases putatively including upregulated efflux mechanisms [60].
involved in acquired resistance of Enterobacteriaceae are The propensity of doripenem, meropenem and imipenem
mainly of Ambler molecular classes B (IMP or VIM series). in selecting carbapenem-resistant mutants was examined in
They have been reported worldwide but mostly from South P. aeruginosa strains at a concentration of ½ × MIC or ¼ × MIC
East Asia and Europe; their genes are plasmid and integron of each carbapenem [61]. Selection of mutants emerged with
located and they hydrolyse virtually all β-lactams, with the a frequency of 10-9 per cell per generation for doripenem,
exception of aztreonam. Class A, clavulanic acid-inhibited whereas for imipenem and meropenem, the respective
carbapenemases are either chromosomally encoded (NMC-A, frequencies were 10-7 to 10-9 per cell per generation.
Sme-1 to Sme-3, IMI-1) or plasmid encoded (KPC-1) Doripenem exhibited both the lowest drug concentration
and are rare [15,53]. KPC enzymes, identified particularly in and the narrowest range of drug concentration for selection
K. pneumoniae and E. cloacae are of great concern because of the carbapenem-resistant mutants.
they confer resistance to all β-lactams (carbapenems and The combination of doripenem plus an aminoglycoside
monobactams-included) [18,57]. was tested to determine the resistance selection during
subinhibitory passaging over seven consecutive days using
2.3.2 Data regarding resistance mechanisms derived six P. aeruginosa isolates [62]. The isolates included had MIC
from doripenem studies values near the susceptible breakpoints of both compounds
Doripenem like meropenem, is a substrate of the and one strain was highly resistant to gentamicin. The
MexAB-OprM, MexCD-OprJ and MexEF-OprN efflux results support that the combination may be an effective
pumps; the impact of their overexpression remains to be treatment of infections caused by P. aeruginosa with
elucidated [58]. In vitro studies with Gram-negative isolates elevated carbapenem MIC values with lower risk of
possessing selected resistance determinants have shown that selecting further resistance [62].
resistance to all carbapenems, including doripenem (MIC
values of 16 – 64 µg/ml), was seen in Acinetobacter isolates 2.4 Antimicrobial activity
with metallo-β-lactamases or OXA-carbapenemases. Isolates Doripenem is characterised in vitro by spectrum and potency
of Klebsiella and Serratia spp. with IMP, KPC and SME against Gram-positive cocci similar to imipenem and
β-lactamases also were resistant to doripenem (MIC values ertapenem, whereas against Gram-negatives it is mostly similar
of 8 – > 64 µg/ml) and to other carbapenems; for E. coli to meropenem, being two to four-fold superior to imipenem.
derivatives with cloned IMP-1 and NMC-A β-lactamases,
the continued apparent susceptibility (MIC values 2.4.1 Gram-negatives
of ≤ 0.5 µg/ml) suggested that carbapenem resistance might Against wild type P. aeruginosa isolates, doripenem was
require other factors besides the enzymes [59]. found two- and four-fold more potent than meropenem and

Table 3. Comparative activity of doripenem, imipenem and meropenem against non-fermenting

Gram-negative pathogens.
Organism Ref. [67] Ref. [70] Ref. [64]

Antibiotic N = 16,008 N = 907 N = 2,134
MIC50 MIC90 MIC50 MIC90 MIC50 MIC90
Pseudomonas aeruginosa n = 829 n = 107 n = 150

Doripenem 0.5 8 0.25 4 0.25 1
Meropenem 0.5 16 0.5 8 0.24 4
Imipenem 1 >8 1 16 1 2
Acinetobacter spp. n = 155 n = 47 n = 50
Doripenem 0.5 4 0.5 64 0.25 32
Meropenem 1 8 0.5 64 0.5 > 32
Imipenem ≤ 0.5 2 0.25 64 0.25 32
Burkholderia cepacia n = 20 n = 25
Doripenem 2 8 – – 4 8
Meropenem 2 4 – – 2 8
Imipenem 4 8 – – 8 32
Stenotrophomonas maltophilia n = 80 n = 25
Doripenem > 16 > 16 – – > 32 > 32
Meropenem > 16 > 16 – – > 32 > 32

Imipenem >8 >8 – – > 32 > 32
Aeromonas spp. n = 44
Doripenem 0.5 1 – – – –
Meropenem 0.12 1 – – – –
Imipenem ≤ 0.5 2 – – – –
–: Denotes data not available, or data presented in a manner non-comparable to the other studies.
MIC: Minimal inhibitory concentration (expressed as mg/l); N: Total number of isolates tested in the study; n: Number of tested species.
imipenem (MIC90 of 0.5 µg/ml versus 1 and 2 µg/ml, In another in vitro study, 20.8% of carbapenem-resistant
respectively) [63]. Similar results were reported after testing A. baumannii isolates (MIC ≥ 16 µg/ml for imipenem
2,137 bacterial isolates in vitro among which 150 were or meropenem) remained susceptible to doripenem at a
P. aeruginosa strains; range of MIC values, MIC50 and tentative susceptibility breakpoint of ≤ 4 µg/ml, whereas
MIC90 were lower for doripenem, compared to imipenem 29.4% of carbapenem-resistant P. aeruginosa strains were
and meropenem [64]. In another study, MIC values of MDR also inhibited [66]. Activity against Bulkholderia cepacia
P. aeruginosa strains isolated from cystic fibrosis patients was modest (MIC50/MIC90 of 2/8 µg/ml) and similar to
were higher, with no difference between mucoid (N = 200) meropenem (MIC50/MIC90 of 2/4 µg/ml) in one study,
and non-mucoid (N = 200) strains (MIC50/MIC90 at whereas in strains isolated from cystic fibrosis patients
8/32 and 8/64 µg/ml, respectively) [65]. Interestingly, in that doripenem MIC50/MIC90 were reported at 8 and 32 µg/ml,
study, doripenem was found active against 15 – 20% of the respectively [65,67]. Stenotrophomonas spp. strains displayed
strains resistant to imipenem and almost against 40% of resistance to doripenem, as with all carbapenems [67].
the strains characterised as resistant to ceftazidime, cefepime Comparative activity of doripenem, imipenem and
and aztreonam [65]. meropenem against non-fermenting Gram-negative pathogens
Doripenem demonstrated comparable activity to imipenem is presented in Table 3 [64,67-70].
against A. baumannii strains with MIC50 at 0.5 µg/ml Against members of the Enterobacteriaceae, doripenem
for both carbapenems and MIC90 at 16 and > 8 µg/ml, was generally more active than imipenem and the same
respectively, indicating a potential to inhibit a considerable or slightly less active than meropenem. Considerable
percentage of strains at achievable concentrations [63]. differences were noted among various species; doripenem

Doripenem
was 5 log2 dilutions more active than imipenem against tested in vitro with daptomycin against staphylococci,
Citrobacter freundii and 4 log2 dilutions more active enterococci and pneumococci [75].
than imipenem against ESBL-producing E. coli strains.
Conversely, doripenem was 3 log2 dilutions less active than 2.4.3 Antianaerobic activity
meropenem against Proteus mirabilis. Against the remainder The in vitro activities of doripenem against 364 anaerobic
of the species, MIC values of doripenem were comparable to isolates were measured and compared to those of ertapenem,
those of meropenem [64]. Klebsiella spp. strains (n = 1107) imipenem, meropenem, ceftriaxone and levofloxacin.
demonstrated considerable susceptibility to doripenem, All of the carbapenems were active against nearly all
with a MIC50/MIC90 of 0.03/0.06 µg/ml; in the presence Bacteroides fragilis group isolates. Doripenem was either
of confirmed ESBL (n = 155) the respective values were comparable to or slightly less active than imipenem and
0.06 and 0.12 µg/ml [67]. meropenem against most isolates, but more active than
H. influenzae and Moraxella catarrhalis were susceptible to the other penems against Clostridium difficile. Doripenem
doripenem, including β-lactamase-positive strains [65,67]. in general, appears to have excellent activity against a
However, β-lactamase-negative ampicillin-resistant or broad range of anaerobes [76].
ampicillin-intermediate H. influenzae strains demonstrated Similar results were obtained from a recent study
MICs of doripenem at 2 and 4 µg/ml [64]. A comparative presented as a conference abstract with microbiological
efficacy of doripenem, imipenem and meropenem data from diabetic foot infections; MIC values for all
against clinically important Gram-negative pathogens is 182 anaerobes were ≤ 1 µg/ml. MIC50 and MIC90 for
presented in Table 4 [64,67-71]. B. fragilis group were 0.25/1 µg/ml; and for Prevotella
and Porphyromonas spp. group were ≤ 0.015/0.125 µg/ml,
2.4.2 Gram-positives respectively [73]. In another study, doripenem demonstrated
Doripenem is comparable to other antipseudomonal excellent in vitro and in vivo antibacterial activities
carbapenems against methicillin-sensitive Gram-positive against strains of S.agalactiae, E.coli, Peptostreptococcus magnus,
pathogens, but may be more potent against MSSA Bacteroides fragilis and Prevotella bivia, which are major
and coagulase-negative Staphylococci. Its activity against pathogens in the fields of obstetrics and gynaecology [77].
enterococcal strains is modest, with better activity against
E. faecalis (MIC range of 0.5 – 16 µg/ml) than E. faecium 2.4.4 Susceptibility breakpoints
(MIC range of 0.5 – > 128) [63,71,72]. Vancomycin-resistant The Clinical and Laboratory Standards Institute (CLSI) has
Enterococcus spp., strains were resistant to doripenem not yet issued susceptibility breakpoints for doripenem.
with MIC values ≥ 8 µg/ml in another study [63]. Doripenem However, data from one of the largest in vitro studies
has shown similar activity with imipenem and higher permitted the proposition of tentative breakpoints of
than meropenem against S. pneumoniae. However, ‘susceptibility’ at MIC values of ≤ 2 µg/ml, ‘intermediate
MIC50/MIC90 values for the penicillin-resistant group resistance’ at 4 µg/ml and ‘resistance’ at ≥ 8 µg/ml. The disk
were 32- to 64-fold higher, compared to the penicillin- diffusion breakpoints were set at ≥ 21 mm for ‘susceptible’,
susceptible group, although all MIC90 values remained 18 – 20 mm for ‘intermediate’ and ≤ 17 mm for ‘resistant’
< 1 µg/ml [64,71]. Against penicillin-sensitive viridans isolates [64]. The use of surrogate testing agents is proposed
streptococci, doripenem was very potent (MIC90 = 0.06 µg/ml), until commercial testing devices acquire US FDA
whereas against penicillin-resistant strains the MIC90 approval [78]. Cross-susceptibility plots from simultaneous
value was at 4 µg/ml [72]. testing of a total of 19,308 organisms against doripenem,
Doripenem, like all tested carbapenems were extremely meropenem, ertapenem and imipenem elucidated
active against Streptococcus pyogenes (MIC90 ≤ 0.008 µg/ml); meropenem as the best predictor of cross-susceptibility
against Streptococcus agalactiae, doripenem and imipenem for Enterobacteriaceae, P. aeruginosa and Acinetobacter spp.,
were the most potent (MIC90 = 0.015 µg/ml) among the and ertapenem for H. influenzae and S. pneumoniae.
carbapenems tested [72]. Bacillus spp. and Listeria spp. strains Oxacillin was proposed as a surrogate for staphylococcal
demonstrated susceptibility to doripenem (MIC50/MIC90 strains testing. No doripenem surrogate marker can be
of 0.06/4 and 0.12/0.25 µg/ml, respectively), whereas recommended for enterococcal testing, according to the
Corynebacterium spp. strains were resistant (MIC90 values CLSI M100-S17 statement and the results obtained
> 16 µg/ml) [67]. Comparative efficacy of doripenem, with ampicillin in this study [78].
imipenem and meropenem against clinically important
Gram-positive pathogens is presented in Table 5 [63,67,70,71,73]. 2.4.5 Antimicrobial activity against selected
Synergy in vitro has been shown between doripenem and pathogens with resistance determinants
vancomycin or teicoplanin against S. aureus highly resistant Doripenem was tested in comparison to imipenem,
to carbapenems (27 MRSA strains) [74]. Additive effect or meropenem and ertapenem along with cephalosporins and
mild synergy has also been demonstrated in another study piperacillin-tazobactam, against over 250 clinical isolates,
presented as a conference poster, where doripenem was mutants and transconjugants of Enterobacteriaceae and

Table 4. Comparative efficacy of doripenem, imipenem and meropenem against clinically important Gram-negative pathogens.
Organism Ref. [67] Ref. [68] Ref. [70] Ref [69] Ref [64] Ref [71]
Antibiotic N = 16,008 N = 954 N = 907 N = 1,934 N = 2,137 N = 978
MIC50 MIC90 MIC50 MIC90 MIC50 MIC90 MIC50 MIC90 MIC50 MIC90 MIC50 MIC90
Escherichia coli n = 3,023 n = 666 n = 62 n = 45 n = 30 n = 29

Doripenem 0.03 0.03 ≤ 0.03 ≤ 0.03 ≤ 0.03 ≤ 0.03 ≤ 0.03 ≤ 0.03 0.03 0.03 0.016 0.032
Meropenem 0.016 0.03 ≤ 0.03 ≤ 0.03 ≤ 0.03 ≤ 0.03 ≤ 0.03 ≤ 0.03 0.03 0.03 0.016 0.016
Imipenem ≤ 0.5 ≤ 0.5 0.12 0.5 0.12 0.25 0.12 0.25 0.12 0.25 0.125 0.125
Klebsiella spp. n = 1,107 n = 54 n = 89 n = 64 n = 31 n = 30
Doripenem 0.03 0.06 0.06 0.25 ≤ 0.03 0.12 0.06 0.06 0.06 0.12 0.032 0.063
Meropenem 0.03 0.03 ≤ 0.03 0.12 ≤ 0.03 0.06 ≤ 0.03 ≤ 0.03 0.03 0.12 0.032 0.032
Imipenem ≤ 0.5 ≤ 0.5 0.25 0.5 0.25 0.5 0.25 0.5 0.25 0.5 0.125 0.5
Enterobacter spp. n = 601 n = 41 n = 51 n = 30
Doripenem 0.06 0.12 0.12 0.5 ≤ 0.03 0.06 – – – – 0.032 0.063
Meropenem 0.03 0.12 0.06 0.5 ≤ 0.03 0.06 – – – – 0.032 0.063
Imipenem ≤ 0.5 1 0.5 1 0.25 0.5 – – – – 0.25 0.5

Citrobacter spp. n = 136 n = 22
Doripenem 0.03 0.06 – – – – – – – – 0.032 0.063
Meropenem 0.03 0.06 – – – – – – – – 0.032 0.063
Imipenem ≤ 0.5 1 – – – – – – – – 0.025 0.5
Proteus mirabilis n = 307 n = 54 n = 15 n = 30
Doripenem 0.12 0.25 0.25 0.5 – – – – 0.25 1 0.25 0.5
Meropenem 0.06 0.06 0.06 0.12 – – – – 0.06 0.12 0.063 0.125
Imipenem 1 2 2 4 – – – – 2 4 2 4
759
760
Doripenem
Table 4. Comparative efficacy of doripenem, imipenem and meropenem against clinically important Gram-negative pathogens (continued).
Organism Ref. [67] Ref. [68] Ref. [70] Ref [69] Ref [64] Ref [71]
Antibiotic N = 16,008 N = 954 N = 907 N = 1,934 N = 2,137 N = 978
MIC50 MIC90 MIC50 MIC90 MIC50 MIC90 MIC50 MIC90 MIC50 MIC90 MIC50 MIC90
Indole-positive Proteae n = 148 n = 12 n = 30

Doripenem 0.12 0.5 – – – – – – 0.5 0.5 0.25 0.5
Meropenem 0.06 0.12 – – – – – – 0.12 0.5 0.125 0.125
Imipenem 2 4 – – – – – – 4 4 2 4
Serratia spp. n = 187 n = 24 n = 30
Doripenem 0.12 0.25 – – – – – – 0.25 0.5 0.125 0.25
Meropenem 0.03 0.06 – – – – – – 0.12 0.12 0.063 0.125
Imipenem ≤ 0.5 1 – – – – – – 1 2 0.25 1
Salmonella spp. n = 530 n = 19
Doripenem 0.06 0.06 – – – – – – 0.06 0.12 – –
Meropenem 0.03 0.03 – – – – – – 0.03 0.03 – –

Imipenem ≤ 0.5 ≤ 0.5 – – – – – – 0.25 0.25 – –
Shigella spp. n = 161 n = 20
Doripenem 0.03 0.06 – – – – – – 0.03 0.06 – –
Meropenem 0.03 0.03 – – – – – – 0.03 0.03 – –
Imipenem ≤ 0.5 ≤ 0.5 – – – – – – 0.25 0.25 – –
Table 5. Comparative efficacy of doripenem, imipenem and meropenem against clinically important
Gram-positive pathogens.
Organism Ref. [67] Ref. [64] Ref. [71] Ref. [73] Ref. [70]
Antibiotic N = 16,008 N = 2,137 N= N = 241 N = 907
MIC50 MIC90 MIC50 MIC90 MIC50 MIC90 MIC50 MIC90 MIC50 MIC90
Staphylococcus aureus (MSSA) n = 2,705 n = 75 n = 30 n = 41 n = 164

Doripenem 0.06 0.06 0.03 0.06 0.063 0.063 0.03 0.03 ≤ 0.03 0.06
Meropenem 0.12 0.12 0.12 0.12 0.125 0.125 1 4 0.06 0.12
Imipenem ≤ 0.5 ≤ 0.5 0.016 0.03 0.032 0.032 ≤ 0.015 0.03 ≤ 0.03 ≤ 0.03
CoNS n = 297 n = 148 n = 46 n = 15
Doripenem 0.03 0.06 0.06 4 0.032 0.063 0.25 2 – –
Meropenem 0.12 0.12 0.25 8 0.125 0.125 1 4 – –
Imipenem ≤ 0.5 ≤ 0.5 0.03 1 0.16 0.16 0.125 0.5 – –
Enterococcus faecalis n = 1,276 n = 26
Doripenem 4 8 – – 2 4 – – – –
Meropenem 8 16 – – 4 8 – – – –
Imipenem 1 4 – – 1 1 – – – –
Enterococcus faecium n = 198 n = 25
Doripenem > 16 > 16 – – 128 > 128 – – – –
Meropenem > 16 > 16 – – 128 > 128 – – – –

Imipenem >8 >8 – – 128 > 128 – – – –
Streptococcus pneumoniae n = 885 n = 290 n = 38
Doripenem 0.016 0.5 0.06 1 – – – – ≤ 0.03 0.5
Meropenem 0.016 0.5 0.12 1 – – – – ≤ 0.03 0.5
Imipenem ≤ 0.5 ≤ 0.5 0.06 1 – – – – ≤ 0.03 0.25
Viridans Group Streptococci n = 140 n = 42
Doripenem 0.03 0.5 – – ≤ 0.004 ≤ 0.004 – – – –
Meropenem 0.06 0.6 – – 0.008 0.008 – – – –
Imipenem ≤ 0.5 ≤ 0.5 – – ≤ 0.004 0.008 – – – –
β-Haemolytic streptococci n = 397
Doripenem ≤ 0.008 0.03 – – – – – – – –
Meropenem ≤ 0.008 0.06 – – – – – – – –
Imipenem ≤ 0.5 ≤ 0.5 – – – – – – – –
CoNS: Coagulase-negative Staphylococci; MIC: Minimal inhibitory concentration (expressed as mg/l); MSSA: Methicillin-susceptible Staphylococcus aureus;
N: Total number of isolates tested in the study; n: Number of tested species.
Acinetobacter spp. expressing various β-lactamases [59]. and were four- to eight-fold below those of imipenem.
Doripenem MIC values ranged from 0.03 to 0.25 µg/ml ESBL production did not raise the MIC values of
for Klebsiella spp. isolates, irrespective of the presence of doripenem for E. coli transconjugants; studies with known
ESBLs or plasmid-mediated AmpC or hyperproduced K1 expression mutants confirmed that neither inducible
β-lactamase. Similarly, MIC values of doripenem for both nor derepressed AmpC β-lactamase expression in E. cloacae,
AmpC-inducible and -derepressed Enterobacter spp. isolates Citrobacter freundii, Serratia marcescens, or Morganella morganii
ranged from 0.06 to 0.5 µg/ml. MIC values for control wild conferred resistance. Doripenem behaved similarly to
type Enterobacteriaceae were identical (± 1 dilution) to those meropenem and imipenem, whereas MIC values of ertapenem
of meropenem, were slightly lower than those of ertapenem, for many ESBL producers and AmpC-derepressed

Doripenem
Enterobacter and C. freundii isolates and mutants were raised. computerised simulation system [52]. Induction of LPS was
Against these pathogens expressing the above-mentioned measured after exposure of P. aeruginosa to either constant
determinants of resistance, all the other comparator agents concentration of the tested drugs or at simulated con-
exhibited high rates of resistance [59]. centration of the drug level pattern in human plasma.
In another in vitro study, multiple β-lactamase The computer-simulated concentrations model, reflected
(TEM, SHV, CTX-M, OXA, CMY types)-producing E. coli better in vivo conditions, according to the authors;
displayed doripenem MIC values at ≤ 0.016 µg/ml [79]. LPS production was associated with cell morphology
A study of MDR P. aeruginosa strains from cystic fibrosis (filamentous > spherical) following exposure to an individual
patients reported no difference between mucoid and drug. Following dose-dependent exposure to meropenem or
non-mucoid strains; however the displayed MIC values to doripenem, filamentous formation of bacterial cells turned
doripenem were higher, compared to P. aeruginosa isolates to spherical. Exposure to ceftazidime induced formation of
originating from other populations. Interestingly, in that merely filamentous long cells and was associated with higher
study, doripenem was active against 15 – 20% of the strains levels of LPS production. However, LPS peaked at 1 h for
resistant to imipenem and almost against 40% of the strains carbapenems, indicating rapid bacterial killing compared to
characterised as resistant to ceftazidime, cefepime and ceftazidime, for which the LPS release peaked at 4 h.
aztreonam [65]. Furthermore, among 34 carbapenem-resistant This observation is in line with previous publications [87].
and MDR P. aeruginosa strains from cystic fibrosis patients, Previous studies have elucidated the role of affinity of
the lowest rate of resistance (∼ 30%) was found for doripenem, the drugs to different PBPs, in the induction of LPS
indicating the possibility that infections caused by from Gram-negative bacilli [51].
carbapenem-resistant strains may be treatable with doripenem
based on pharmacokinetics/pharmacodynamics [66]. 2.6 Pharmacokinetics and metabolism
Doripenem, like all other carbapenems in use, is not
2.5 Pharmacodynamics absorbable from the intestinal tract; thus, it is formulated as
Doripenem, like other carbapenems exhibits a concentration- an intravenous formulation, to be given at a dose of 500 mg
independent, time-dependent bactericidal effect. The most every 8 h [88]. Detailed pharmacokinetic data from
critical pharmacodynamic parameter that predicts clinical large number of subjects are lacking. In a recent study
efficacy is the percentage of time that the drug levels remain investigating penetration of intravenous doripenem into
above the MIC of the targeted pathogen (time above MIC peritoneal exudate of ten abdominal-surgery patients, the
[T > MIC]) [80-82]. A bacteriostatic effect can be attained authors determined the drug concentrations in plasma and
targeting at T > MIC of 20% for carbapenems, whereas peritoneal fluid after a single doripenem dose of 500 mg
maximal bactericidal activity is achieved with 40%. Extended infused over 0.5 h, using HPLC. Non-compartmental
infusion (> 4 h) enhanced efficacy against selected strains pharmacokinetic analysis and three-compartment pharmaco-
of P. aeruginosa with MIC values of 4 µg/ml [83]. Scarce kinetic model were performed. Rapid and extensive drug-
data are available about postantibiotic effects of doripenem, exposure times in exudates was reported [89]. The AUC(0 – ∞)
indicating an approximate duration of 1.8 h in vitro and was 59.3 ± 7.2 mg⋅h/l (mean ± SD) in serum and
4.3 h in vivo for P. aeruginosa strains [84,85]. 49.3 ± 6.5 mg⋅h/l in exudate, and the exudate/serum ratio
In an yet to be published, in vitro study on anaerobe was 0.84 ± 0.13. The observed maximum concentration was
bactericidal activity of doripenem recently presented as a 46.9 ± 7.4 mg/l at 0.5 h in serum and 24.5 ± 6.5 mg/l at
meeting presentation, the authors examined the antianaerobic 0.7 ± 0.4 h in exudate, and the exudate/serum ratio
activity of doripenem, compared to imipenem, meropenem, was 0.53 ± 0.17. Volume of distribution at steady state
ertapenem, piperacillin/tazobactam, amoxicillin/clavulanate, (Vss in l) and total clearance of the drug (CLtot in l/h) were
ceftriaxone, clindamycin and metronidazole. Two 11.0 ± 1.7 and 8.56 ± 1.14, respectively. Serum t½, as
strains each of B. fragilis, Bacteroides thetaiotaomicron, estimated by γ half-live in the three compartment model
Prevotella intermedia, Fusobacterium nucleatum, was 1.62 ± 0.34 h. Interestingly, Cmax for peritoneal exudate
Finegoldia magna, Clostridium perfringens, and C. difficile was approximately half of the value for serum; on the contrary,
were tested. Doripenem had exhibited the lowest MIC the drug-exposure time in exudate was greater than or equal
values of all 4 carbapenems tested with MIC values ranging to the value for serum. This was attributed to the short
0.016 – 1 µg/ml. Doripenem and imipenem produced 99% difference in Tmax for the two sites (average time of 0.2 h),
kill of all strains at 48 h at the MIC. With the exception probably leading to concentrations which remained higher
of metronidazole, which was cidal at 2 × MIC against 13/14 in exudate than in serum. This pharmacokinetic property of
strains after 24 h, other drugs gave slower killing [86]. doripenem may come from a comparatively low molecular
The endotoxin-releasing capacity of doripenem in weight (438.5) and protein binding (9%).The average times
comparison to imipenem/cilastatin, meropenem/cilastatin above MIC for 1 and 4 mg/l in peritoneal exudate were
and ceftazidime was investigated in an in vitro study as a 78.2 and 41.5%, respectively. Taking into consideration:
surrogate marker of bacterial killing by use of an in vitro i) the anticipated MIC90 of doripenem against clinically

important isolates of E. coli, Streptococcus spp. and Bacteroides spp. over 1 h demonstrated antibacterial kill for P. aeruginosa
implicated in abdominal infections [67,76]; and ii) the T > MIC strains with MIC values of 0.125 – 8 µg/ml. Exposures
target value required for bactericidal effect of doripenem ≥ 40% f T > MIC resulted in the most pronounced
which like other carbapenems, is considered to be ∼ 40% of bactericidal effects while kill was variable for ∼ 20 – 30%
the dosing interval [82], an empirical regimen of 500 mg f T > MIC. Doses infused over 4 h enhanced efficacy against
every 8 h was indicated to provide sufficient bactericidal selected pseudomonal isolates with MIC values of 4 µg/ml.
exposure in the abdominal cavity. However, possible limitations The in vivo efficacy of doripenem was evaluated in a rat
of the study are the small number of subjects and the absence model of intrauterine infection, namely pyometra caused by
of documented infection within the studied group [89]. E. coli and B. fragilis. The results suggest that doripenem
In a Phase I, double-blind trial, 24 healthy volunteers may be useful for treating polymicrobial infections in the
received one of three dosing regimens of doripenem: a 4 h fields of obstetrics and gynaecology [77].
infusion of 500 mg every 8 h for 10 days (Cohort A); a

6 h infusion of 1000 mg every 12 h for 10 days (Cohort B); 2.7.2 Phase III clinical trials
or a 4 h infusion of 1000 mg every 8 h for 10 days A total of six trials were completed including two each of
(Cohort C) [90]. Steady-state was achieved in all cohorts complicated UTIs and/or pyelonephritis, complicated
after administration of doripenem for seven consecutive intra-abdominal infections and nosocomial pneumonia
days. Doripenem t½ was in the range of 0.65 – 1.65 h (including VAP) caused by a variety of micro-organisms [93].
(mean ∼ 1 h), AUC was 40.2 µg⋅h/ml, CL in the range In Phase II studies in 55 patients with chronic respiratory
of 15 – 36 l/h and Vdss in the range of 19 – 56 l. tract infections, doripenem in a variety of doses resulted
The mean doripenem concentration at steady-state (Css) in promising clinical result in 95.2% of patients with
was ∼ 3.3 µg/ml in Cohorts A and B, and ∼ 4.5 µg/ml in bacteriological eradication in 87.5% [94]. However, the
Cohort C. Doripenem was excreted mainly by the renal propensity of Pseudomonas strains to develop resistance
route (70%) [90]. Differences compared to the above- during therapy requires further studies.
mentioned published study may be attributed to the Results from a large (n = 531), prospective, multicenter,
different pharmacokinetic models used [89]. As renal open-label, Phase III trial were recently available as a poster
function decreased, t½ increased from 1 h to 5 h (severe presentation [95]. Adult VAP ICU patients were randomised
renal impairment) and up to 9 h (end stage renal failure). to 7 – 14 days of either extended intravenous infusion
Dialysis reduced systemic doripenem levels by 48 – 62% [91]. of doripenem, 500 mg every 8 h over 4 h, or standard intra-
Regarding the use of pharmacokinetic/pharmacodynamic venous imipenem 500 mg every 6 h or 1000 mg every 8 h
target attainment analysis and the Monte Carlo simulation for 30 or 60 min. At baseline, 13% (7/53) of P.aeruginosa
results, it was predicted that 500 mg of doripenem admini- isolates were resistant to imipenem but 0% to doripenem
stered over 1 h every 8 h would be effective against bacterial (MIC ≥ 16 mg/l). Clinical cure rates 7 – 14 days
strains with MIC values < 2 µg/ml, while less susceptible after completion of treatment were 68.3% for doripenem
strains need to be treated with prolonged infusions [82]. and 64.8% for imipenem in clinically evaluable patients
Doripenem in the infusate was stable for at least 12 h, (n = 249; difference: 3.5%; 95% CI: -9.1 to 16.6%), and
permitting extended infusion [92]. However, in vitro data, 59.0% (doripenem) and 57.8% (imipenem) in the clinical
as well as data derived from simulation techniques, have modified intent-to-treat (cMITT) population (n = 501;
to be confirmed in clinical trials in order to provide solid difference: 1.2%; 95% CI: -7.9 to 10.3%). Clinical cure
evidence and further support clinical recommendations. rates for patients with P. aeruginosa were 80% (doripenem)
versus 42.9% (imipenem), the respective microbiologic
2.7 Clinical efficacy cure rates being 65 versus 35.7%. Overall, 4/28 (14%)
2.7.1 In vivo animal studies pseudomonal strains in the doripenem arm and 13/25
In vivo efficacy of doripenem was determined in a mouse (52%) in the imipenem arm were either resistant at baseline
model of bactaeremia with S. aureus Smith strain. The ED50 or became resistant during the study. The authors conclude
of the drug was 0.066 mg/kg and was almost the same that in this Phase III study using an extended infusion,
as imipenem and lower than that of meropenem [71]. doripenem was clinically effective in patients with VAP and
In a recent animal pharmacokinetic/pharmacodynamic therapeutically established non-inferiority to imipenem [95].
study presented as a poster presentation, the authors assessed Pooled results from two Phase III randomised, double-
the pharmacokinetic profile of doripenem in infected blind, multicenter studies comparing 5 – 14 days of intra-
neutropenic mice to design regimens that approximated the venous doripenem (500 mg every 8 h over 60 min)
free time above MIC (f T > MIC) observed with doripenem to intravenous meropenem (1 g every 8 h as a bolus over
500 mg every 8 h given as either a 1-h or 4-h intravenous 3 – 5 min) in adults with complicated intra-abdominal
infusion in humans [83]. Clinical P. aeruginosa isolates with infections (cIAIs), also became available as a meeting poster
doripenem MIC values of 0.125 – 16 µg/ml were used. presentation [96]. A switch to oral amoxicillin/clavulanate
Simulated doses of doripenem 500 mg every 8 h infused after ≥ 9 doses of doripenem or meropenem was permitted.

Doripenem
A total of 962 patients in both studies were randomised; of imipenem patients, with only one among those assigned
486 received doripenem and 476 received meropenem. in the imipenem group being attributed to the drug therapy.
The clinical cure rates in the microbiologically evaluable Drug-related adverse events were reported as follows
population were 84.6% for doripenem and 84.1% for (doripenem vs imipenem): hepatic enzyme elevation 1.6
meropenem (difference 0.5%; 95% CI: -5.5 – 6.4), whereas versus 2.3%, diarrhea 1.9 versus 3.0%, rash 1.9 versus
the microbiological cure rates were 84.3 and 84.5%, 0.8%, vomiting 1.5 versus 0.8%, nausea 1.1 versus 2.3%,
respectively. In the microbiological modified intent-to-treat fungal infection 1.1 versus 1.5% and overall rate of one or
population, clinical cure rate was 76.2% for doripenem more adverse events 17.2 versus 17.5% [95].
and 77.3% for meropenem (difference: -1.1%; 95% In the two pooled clinical trials comparing doripenem
CI: -7.4 – 5.1). Microbiological cure rate for cIAI due to to meropenem in the treatment of cIAIs also recently
P. aeruginosa was 85% (34/40) versus 75% (24/32) for reported as a poster presentation, the most common
the comparator. According to the above-mentioned study drug-related adverse events were nausea (doripenem,
results, doripenem established non-inferiority compared 5.2%; meropenem, 1.9%) and diarrhea (doripenem, 4.4%;
to meropenem in the treatment of cIAIs. meropenem, 4.5%). No seizures were reported [96].
Finally, results from a randomised, open-label, multi- The association of seizures and carbapenems has been
centre study designed to establish the non-inferiority of identified since imipenem Phase III trials [100] with an
doripenem compared with piperacillin/tazobactam in incidence of 1 – 3%, but was also rarely observed with
nosocomial pneumonia became available as an oral conference ertapenem and meropenem [39,101-103]. The convulsive
presentation [97]. Adults (n = 448) with nosocomial potential of doripenem was extensively investigated in
pneumonia not associated with mechanical ventilation an article reporting several animal studies [104]. In intra-
or with early onset (< 5 days) VAP), were randomised venous injection studies in rats, imipenem/cilastatin,
to receive either a 1-h intravenous infusion of doripenem at 400/400 mg/kg produced seizure activity on electro-
500 mg every 8 h or a 30-min intravenous infusion of encephalogram (EEG) accompanied with clonic convulsions,
piperacillin/tazobactam 4.5 g every 6 h for a total of whereas meropenem showed only wet dog shaking
7 – 14 days. A switch to oral levofloxacin 750 mg q.d. behaviour at 200 and 400 mg/kg. Doripenem caused no
was permitted after ≥ 72 h of intravenous study drug, in changes in the EEG and behaviour in rats at 400 mg/kg.
eligible patients. Clinical cure rates in clinically evaluable Inva mouse model, intravenous imipenem/cilastatin potentiated
patients (n = 253) were 81.3% for doripenem and 79.8% the pentylenetetrazol -induced convulsions at 250/250 mg/kg,
for piperacillin/tazobactam (difference: 1.5%; 95% CI: -9.1 while meropenem, cefazolin panipenem/betamipron or
to 12.1%), whereas in the cMITT population (n = 429) doripenem did not cause any marked effects at up to
the respective clinical cure rates were 69.5 and 64.1% 500 mg/kg. In mouse intracerebroventricular (ICV)
(difference: 5.4%; 95% CI: -4.1 to 14.8%). Resistance injection studies, imipenem, panipenem and cefazolin
was substantially higher to piperacillin/tazobactam than induced clonic convulsions in a dose-dependent manner.
doripenem (MIC ≥ 16 µg/ml), especially among strains Doripenem and meropenem did not induce convulsions
of P. aeruginosa (27 vs 4%) and K. pneumoniae (43 vs 0%). at doses up to100 µg/mouse. In dog ICV injection studies,
Microbiological outcomes against Gram-negative pathogens imipenem produced generalised seizure discharge with clonic
were more favourable with doripenem than piperacillin/ convulsions at doses of 100 µg/dog. Meropenem also
tazobactam. Doripenem demonstrated therapeutically produced spikes or seizure discharges at 100, 300 and
non-inferiority to piperacillin/tazobactam [97]. 1000 µg/dog. However, doripenem had no effects on the
EEG and behaviour in dogs at any doses. In in vitro binding
2.8 Safety and tolerability experiments, imipenem, panipenem, cefazolin and
In general, doripenem was well tolerated in clinical trials. meropenem inhibited [3H]muscimol binding to the GABAA
The most common adverse event was headache, observed in receptor in mouse brain homogenates, while doripenem
33 and 50% of patients who received 500 mg every 8 h and did not cause any inhibition at up to 10 mM. Doripenem
1000 mg every 8 h of doripenem, respectively, versus 13% had no influence on the anticonvulsant actions of valproic
in the placebo recipients [98]. Infection site erythema was acid in the pentylenetatrazole- or bicuculine-induced
frequently reported [52], whereas gastrointestinal disorders convulsive model. The results of the study revealed no
expressed as nausea and diarrhoea were reported in 3.7 and convulsive activity for doripenem [104].
2.5%, respectively [99]. Somnolence and postural dizziness However, an earlier study has shown that doripenem, as
were also described at similar frequencies [90]. There was no well as the other studied carbapenems (panipenem and
evidence of a dose response in any adverse event [90]. meropenem), may lower plasma levels of and valproic acid
In a large Phase III clinical trial in VAP ICU patients (VPA), in accordance to previous clinical reports indicating
presented recently as a poster, comparing doripenem use that the co-administration caused seizures in epileptic
at > 4-h infusion to standard imipenem administration, patients due to lowered plasma levels of VPA [105]. In
seizures were reported in 1.1% of doripenem versus 3.8% this study, in vitro experiments using monkey liver slices

suggested that the apparent synthetic rate of VPA glucuronide 3. Conclusions

(VPA-G) increased in the presence of carbapenems. No such
increase was observed in the experiment using monkey liver The class of carbapenems has proved to be our last resort
microsomes. The authors elucidated that all tested carbapenems against evolving multidrug resistant Gram-negative
inhibited the hydrolytic enzyme, which is involved in the pathogens. Doripenem, the most recently FDA-approved
hydrolysis of VPA-G to VPA, resulting in a decrease of carbapenem, possesses an antimicrobial spectrum similar to
plasma concentration of VPA [105]. Although doripenem did meropenem against Gram-negatives and similar to imipenem
not prove to have convulsive activity, co-administration with against Gram-positive pathogens, while retaining 2 – 4-fold
VPA should not be used in epileptic patients [104]. lower MIC values. Interestingly, it retains activity against
Decreased renal function, history of seizures, presence of strains displaying OprD-mediated resistance to imipenem
other CNS lesions and excessive doses of imipenem are and also against many problematic strains with various
among the most commonly identified risk factors for resistant mechanisms. Against strains with isolated resistance to
seizures after carbapenem use. Dosage monitoring has imipenem (probably due to OprD mechanism), doripenem
diminished the incidence of convulsion in imipenem-treated would be a good option. In the case of MBL-mediated
patients to approximately 0.5%, which is the relevant resistance to meropenem and imipenem, the antibacterial
incidence observed with meropenem or ertapenem [100,106-108]. activity of doripenem is anticipated to be also affected.
It is anticipated that similar caution should be appropriate However, preliminary data indicate that pharmacokinetic/
with doripenem use. pharmacodynamic applications, by means of prolonged
Life threatening hypersensitivity reactions have not been infusion, supported by the relative stability of the infusate in
reported to the authors’ knowledge with doripenem use. ambient conditions, may help in the treatment of strains
However, the incidence of hypersensitivity to carbapenems with borderline MIC values, thus overcoming resistance.
among the general population (ranging from rash to The low adverse event potential and the favourable safety
anaphylactic shock) is estimated at 3% [39,109]. Pooled data profile of doripenem offer additional advantages in current
from two retrospective studies investigating the incidence clinical practice. Early clinical efficacy data from infections
of hypersensitivity of carbapenems in respect to history of caused by P. aeruginosa, the most virulent nosocomial patho-
penicillin-associated allergic reactions, indicate a cross- gen, reveal advantages of the new carbapenem over existing
sensitivity of 9 – 11% (263 pooled patients with penicillin- drugs, but need to be confirmed with large series.
associated allergy), compared to 3 – 4% (214 pooled patients
without history of penicillin-allergy) [39,110,111]. In line 4. Expert opinion
with this evidence, caution would be recommended with
doripenem use in patients with a history of hypersensitivity Resistance among Gram-negative pathogens, displaying
reactions to penicillin compounds. significant geographical variations has already become the
nightmare of nosocomial infections, particularly affecting
2.9 Regulatory status predisposed patients. There is a certain gap between
Doripenem is licensed from Shionogi & Co. Ltd, the accelerating rates of resistance among Gram-negative
which launched the product in Japan in September 2005 pathogens and the time-delay of new compounds to be
in an intravenous formulation as 250 mg vials [1]. Two new released. In the years to come, the future of antimicrobial
Phase II clinical trials were initiated: i) ‘A Randomized, chemotherapy seems ominous. Newer agents and approaches
Open-Label, Multicenter Study to Assess the Safety are needed to preserve the limited resources that we
and Tolerability of Doripenem Compared With Imipenem currently have available against multiple drug-resistant
in the Treatment of Subjects With Complicated Gram-negative pathogens. Decrease in unnecessarily
Intra-Abdominal Infections or Ventilator Associated prolonged duration of treatment would prevent the
Pneumonia’; and ii) ‘A Phase II Study of Doripenem In emergence of resistance, while adherence to a de-escalation
The Treatment of Nosocomial and Ventilator-Associated strategy once the susceptibilities of the infecting pathogen
Pneumonia In Hospitals’ [112,113]. become available, would further prove to be a critical
Doripenem was approved by the FDA for the treatment action towards the preservation of our armamentarium.
of complicated intra-abdominal and complicated urinary Based on in vitro activity and the available clinical data, it
tract infections on 16 September 2007 and will be marketed seems that doripenem could play an important role in
to US hospitals by Ortho-McNeil, Inc. The use of patients with serious nosocomial infections, including ICU
doripenem in the treatment of hospital-acquired (nosocomial) patients, particularly in hospital settings with high rates
pneumonia, including VAP, is under regulatory review in of MDR Gram-negatives where P. aeruginosa is prevalent.
the US, and the use of doripenem for complicated intra- However, doripenem’s potential of development in vivo
abdominal infections, complicated urinary tract infections resistance should be carefully studied.
and nosocomial pneumonia, including VAP, is under regulatory Exploitation of pharmacokinetic/pharmacodynamic
review in Europe [114,115]. properties of doripenem may help clinicians ‘buy time’,

Doripenem
while waiting for antimicrobials focusing on new targets. and epithelial cells by inhibiting nuclear factor-kappaB.
Extended infusion could probably provide maximum Large, randomised clinical trials for the management
bactericidal effect, especially in infections where the MIC of of these disorders with macrolides are not available, with
the pathogen is near the threshold of resistance. In the case the sole exception of four trials denoting benefit following
of isolated resistance to imipenem (probably due to OprD long-term administration of azithromycin in patients
mechanism) doripenem would be a good option. In the case with cystic fibrosis [119-122].
of resistance to meropenem and imipenem, an MBL pheno- Development of clinical vaccines may prove an
type would certainly discourage the use of doripenem. extremely useful adjuvant measure, to enhance clearance
However, if doripenem MIC values were within the zone of of P. aeruginosa in systemic and chronic infections [123].
susceptibility or borderline and no other treatment was Successful induction of protective antipseudomonal anti-
available, doripenem would be the only option; in that case bodies was achieved in burn and cystic fibrosis patients
we would encourage the extended intravenous infusion to injected with a recombinant vaccine of OprF and
overcome resistance. However, there is an evident need OprI [124,125]. In another study, combined oral vaccination
for clinical verification of those in vitro data, before their with Salmonella expressing P. aeruginosa O antigen, and
interpretation into clinical practice. Exploration of increase human monoclonal antibodies specific for mannuronic acid
of the dosage may also prove efficacious, given the excellent components of alginate, increased the survival of mice in an
safety profile of doripenem and its lowest seizure potential acute pneumonia model [126]. In a 10-year matched-control
among the carbapenem class of antibiotics. retrospective study, vaccination of young cystic fibrosis
Although preliminary and not yet published, coupling of patients with a polyvalent conjugate vaccine reduced
carbapenems with a metallo-β-lactamase inhibitor, seems to the frequency of chronic infection with P. aeruginosa and
be the most fascinating and promising near-future advance- ameliorated the preservation of lung function [127].
ment in the treatment of pseudomonal infections. A possible There is no doubt that in the same context we must
positive result in combination with doripenem, would offer explore ways for maintaining the use of colistin. In a recent
treatment opportunities in several critically ill patients outbreak of pan-drug-resistant P. aeruginosa among Greek
suffering from multidrug resistant strains and could preserve ICU patients with VAP, the sole independent predictors
the potency of the drug in the years to come [35]. However, elucidated by risk factor analysis were the administration of
the release of doripenem, by providing more options colistin for > 13 days or the combined use of a carbapenem
within the class of carbapenems, may decompress the for > 20 days. The outbreak resolved following reduction of
accumulation of MBL-producing P. aeruginosa strains, a colistin therapy and reinforcement of infection control
phenomenon reported in settings where a single carbapenem measures [128]. Although there is a paucity of published
is used [116]. studies addressing the development of resistance with colistin
The need to maintain the traditional antibiotic combi- use, it is now evident that duration of colistin therapy
nation of a broad spectrum antipseudomonal β-lactam should be re-addressed. However, lengthy co-administration
plus an aminoglycoside is still controversial. Two recent with a carbapenem should be better re-evaluated, in order to
meta-analyses showed that there was no advantage over prevent a deleterious collateral pressure in the patient’s flora,
monotherapy in terms of mortality, clinical efficacy or leading to the selection of unrivalled resistance.
prevention of resistance, while more adverse effects
and especially nephrotoxicity were observed in the combi- Acknowledgements
nations [117,118]. However, the analysis of P. aeruginosa
bacteremia subgroups, showed a significant survival benefit The authors thank D Plachouras, MD and I Katsarolis, MD
for the combination [118]. for the design of chemical structures.
A novel approach to P. aeruginosa infections may be to
attack the structure of the bacterial biofilm. Macrolides Declaration of interest
inhibit mobility and quorum sensing of P. aeruginosa; they
also decrease production of mucus by epithelial cells and The authors have no conflict of interest to declare and no
biosynthesis of pro-inflammatory cytokines from monocytes fee has been received for preparation of the manuscript.

Bibliography baumannii. Emerg Infect Dis amidine moiety. J Antibiot (Tokyo)

1. Anderson DL. Doripenem. 2005;11(1):22-9 2003;56(6):565-79
Drugs Today (Barc) 2006;42(6):399-404 12. Go ES, Urban C, Burns J, et al. 22. Guignard B, Entenza JM,
2. Johnson & Johnson announces agreement Clinical and molecular epidemiology Moreillon P. Beta-lactams against
to acquire Peninsula Pharmaceuticals, Inc. of acinetobacter infections sensitive only methicillin-resistant Staphylococcus aureus.
Available from: http://www.investor.jnj. to polymyxin B and sulbactam. Lancet Curr Opin Pharmacol 2005;5(5):479-89
com/releaseDetail.cfm?ReleaseID=160602 1994;344(8933):1329-32 23. Thomson KS, Moland ES. CS-023
&year=2005&textOnly=false 13. Abbo A, Carmeli Y, Navon-Venezia S, (R-115685), a novel carbapenem
3. Giamarellou H. Prescribing guidelines et al. Impact of multi-drug-resistant with enhanced in vitro activity against
for severe Pseudomonas infections. Acinetobacter baumannii on clinical oxacillin-resistant staphylococci
J Antimicrob Chemother outcomes. Eur J Clin Microbiol Infect Dis and Pseudomonas aeruginosa.
2002;49(2):229-33 2007;26(11):793-800 J Antimicrob Chemother

14. McDonald LC. Trends in antimicrobial 2004;54(2):557-62
4. Kipnis E, Sawa T, Wiener-Kronish J.
Targeting mechanisms of Pseudomonas resistance in health care-associated 24. Koga T, Abe T, Inoue H, et al. In vitro
aeruginosa pathogenesis. Med Mal Infect pathogens and effect on treatment. and in vivo antibacterial activities
2006;36(2):78-9 Clin Infect Dis 2006;42(Suppl 2):S65-71 of CS-023 (RO4908463),
15. Livermore DM, Woodford N. The a novel parenteral carbapenem.
5. Carmeli Y, Troillet N, Eliopoulos GM,
beta-lactamase threat in Enterobacteriaceae, Antimicrob Agents Chemother
Samore MH. Emergence of antibiotic-
Pseudomonas and Acinetobacter. 2005;49(8):3239-50
resistant Pseudomonas aeruginosa:
comparison of risks associated with Trends Microbiol 2006;14(9):413-20 25. Sugihara K, Ishii Y, Tateda K, Yamaguchi K.
different antipseudomonal agents. 16. Galani I, Souli M, Koratzanis E, Carbapenemase stability of CS-023
Antimicrob Agents Chemother et al. Emerging bacterial pathogens: (RO4908463) and other carbapenems
1999;43(6):1379-82 Escherichia coli, Enterobacter aerogenes [poster C1-92]. 47th Interscience
and Proteus mirabilis clinical isolates Conference on Antimicrobial Agents
6. Micek ST, Lloyd AE, Ritchie DJ,
harbouring the same transferable plasmid and Chemotherapy; 2007
et al. Pseudomonas aeruginosa
coding for metallo-beta-lactamase VIM-1 September 17 – 20; Chicago, IL

bloodstream infection: importance of
appropriate initial antimicrobial treatment. in Greece. J Antimicrob Chemother 26. Sugihara K, Ishii Y, Tateda K,
Antimicrob Agents Chemother 2007;59(3):578-579 Yamaguchi K. In vitro activity of CS-023
2005;49(4):1306-11 17. Karabinis A, Paramythiotou E, (RO4908463) against various β-lactamase
Mylona-Petropoulou D, et al. Colistin producing pathogens [poster C2-2055].
7. Anonymous. National Nosocomial
for Klebsiella pneumoniae-associated 47th Interscience Conference on
Infections Surveillance (NNIS) System
sepsis. Clin Infect Dis 2004;38(1):e7-9 Antimicrobial Agents and Chemotherapy;
Report, data summary from January 1992
2007 September 17 – 20; Chicago, IL
through June 2004, issued October 2004. 18. Bradford PA, Bratu S, Urban C, et al.
Am J Infect Control 2004;32(8):470-85 Emergence of carbapenem-resistant 27. Zhanel GG, Karlowsky JA, Rubinstein E,
Klebsiella species possessing the class A Hoban DJ. Tigecycline: a novel
8. Rossolini GM, Mantengoli E. Treatment
carbapenem-hydrolyzing KPC-2 and glycylcycline antibiotic. Expert Rev
and control of severe infections caused
inhibitor-resistant TEM-30 beta-lactamases Antiinfect Ther 2006;4(1):9-25
by multiresistant Pseudomonas
aeruginosa. Clin Microbiol Infect in New York City. Clin Infect Dis 28. Souli M, Kontopidou FV, Koratzanis E,
2005;11(Suppl 4):17-32 2004;39(1):55-60 et al. In vitro activity of tigecycline against
19. Antoniadou A, Kontopidou F, multiple-drug-resistant, including
9. The database of Meropenem Yearly
Poulakou G, et al. Colistin-resistant pan-resistant, gram-negative and
Susceptibility Test Information
isolates of Klebsiella pneumoniae gram-positive clinical isolates from Greek
Collection (MYSTIC) Program, provides
emerging in intensive care unit patients: hospitals. Antimicrob Agents Chemother
information regarding resistance
first report of a multiclonal cluster. 2006;50(9):3166-69
rates across several countries that
participate in the surveillance program. J Antimicrob Chemother 29. Noskin GA, Tigecycline: a new
Available from: http://www. 2007;59(4):786-90 glycylcycline for treatment of
infectionacademy.org/surveillance/ 20. Rice LB. Challenges in identifying serious infections. Clin Infect Dis
[Accessed on 18 November 2007] new antimicrobial agents effective for 2005;41(Suppl 5):S303-14
10. Turner PJ. Meropenem activity against treating infections with Acinetobacter 30. Cobo J, Morosini MI, Pintado V,
European isolates: report on the MYSTIC baumannii and Pseudomonas aeruginosa. et al. Use of tigecycline for the treatment
(Meropenem Yearly Susceptibility Test Clin Infect Dis 2006;43(Suppl 2):S100-5 of prolonged bacteremia due to
Information Collection) 2006 results. 21. Kawamoto I, Shimoji Y, Kanno O, a multiresistant VIM-1 and SHV-12
Diagn Microbiol Infect Dis et al. Synthesis and structure-activity beta-lactamase-producing Klebsiella
2008;60(2):185-92 relationships of novel parenteral pneumoniae epidemic clone.
carbapenems, CS-023 (R-115685) Diagn Microbiol Infect Dis
11. Abbo A, Navon-Venezia S,
and related compounds containing an 2008;60(3):319-22
Hammer-Muntz O, et al.
Multidrug-resistant Acinetobacter

Doripenem
31. Pliatsika V, Afkou Z, Protonotariou E, 43. Birnbaum J, Kahan FM, Kropp H, of in vitro and animal models.
Sofianou D. In vitro activity of Macdonald JS. Carbapenems, a new class J Antimicrob Chemother 2003;51(2):353-9
tigecycline against metallo-{beta}- of beta-lactam antibiotics. Discovery 53. Bonomo RA, Szabo D. Mechanisms
lactamase-producing Enterobacteriaceae. and development of imipenem/cilastatin. of multidrug resistance in Acinetobacter
J Antimicrob Chemother 2007 Am J Med 1985;78(6A):3-21 species and Pseudomonas aeruginosa.
32. Giamarellou H. Treatment options for 44. Sunagawa M, Matsumura H, Inoue T, Clin Infect Dis 2006;43(Suppl 2):S49-56
multidrug-resistant bacteria. Expert Rev et al. A novel carbapenem antibiotic, 54. Vahaboglu H, Ozturk R, Aygun G, et al.
Antiinfect Ther 2006;4(4):601-18 SM-7338 structure-activity relationships. Widespread detection of PER-1-type
33. Reid GE, Grim SA, Aldeza CA, et al. J Antibiot (Tokyo) 1990;43(5):519-32 extended-spectrum beta-lactamases
Rapid development of Acinetobacter 45. Iso Y, Irie T, Nishino Y, et al. A novel among nosocomial Acinetobacter and
baumannii resistance to tigecycline. 1 beta-methylcarbapenem antibiotic, Pseudomonas aeruginosa isolates in
Pharmacotherapy 2007;27(8):1198-201 S-4661. Synthesis and structure-activity Turkey: a nationwide multicenter study.
34. Peleg AY, Potoski BA, Rea R, et al. relationships of 2-(5-substituted pyrrolidin- Antimicrob Agents Chemother
Acinetobacter baumannii bloodstream 3-ylthio)-1 beta-methylcarbapenems. 1997;41(10):2265-9
infection while receiving tigecycline: a J Antibiot (Tokyo) 1996;49(2):199-209 55. Heritier C, Poirel L, Lambert T,
cautionary report. J Antimicrob Chemother 46. Edwards JR. Meropenem: a microbiological Nordmann P. Contribution of acquired
2007;59(1):128-31 overview. J Antimicrob Chemother carbapenem-hydrolyzing oxacillinases to
35. Osaki Y, Morinaka A, Mikuniya T, 1995;36(Suppl A):1-17 carbapenem resistance in Acinetobacter
et al. CP3242, a novel metallo-β-lactamase 47. Sumita Y, Fukasawa M, Okuda T. Affinities baumannii. Antimicrob Agents Chemother
inhibitor: in vitro and in vivo of SM-7338 for penicillin-binding 2005;49(8):3198-202
efficacy against clinically isolated proteins and its release from these 56. Livermore DM. The impact of
metallo-β-lactamase-producing P. proteins in Staphylococcus aureus. carbapenemases on antimicrobial
aeruginosa [poster F1-332]. 47th Antimicrob Agents Chemother development and therapy. Curr Opin
Interscience Conference on 1990;34(3):484-6 Investig Drugs 2002;3(2):218-24
Antimicrobial Agents and Chemotherapy; 48. Hashizume T, Ishino F, Nakagawa J, 57. Samra Z, Ofir O, Lishtzinsky Y, et al.
2007 September 17 – 20; Chicago, IL et al. Studies on the mechanism of action Outbreak of carbapenem-resistant
36. Zhanel GG, Wiebe R, Dilay L, et al. of imipenem (N-formimidoylthienamycin) Klebsiella pneumoniae producing KPC-3
Comparative review of the carbapenems. in vitro: binding to the penicillin-binding in a tertiary medical centre in Israel.
Drugs 2007;67(7):1027-52 proteins (PBPs) in Escherichia coli and Int J Antimicrob Agents 2007;30(6):525-9
37. Kahan JS, Kahan FM, Goegelman R, et al. Pseudomonas aeruginosa, and inhibition 58. Masuda N, Sakagawa E, Ohya S, et al.
Thienamycin, a new beta-lactam antibiotic. of enzyme activities due to the PBPs Substrate specificities of MexAB-OprM,
I. Discovery, taxonomy, isolation and in E. coli. J Antibiot (Tokyo) MexCD-OprJ, and MexXY-oprM efflux
physical properties. J Antibiot (Tokyo) 1984;37(4):394-400 pumps in Pseudomonas aeruginosa.
1979;32(1):1-12 49. Kohler J, Dorso KL, Young K, Antimicrob Agents Chemother
38. Norrby SR. Carbapenems. Med Clin et al. In vitro activities of the potent, 2000;44(12):3322-7
North Am 1995;79(4):745-59 broad-spectrum carbapenem MK-0826 59. Mushtaq S, Ge Y, Livermore DM.
(L-749,345) against broad-spectrum Comparative activities of doripenem versus
39. Lister PD. Carbapenems in the USA:
beta-lactamase-and extended-spectrum isolates, mutants, and transconjugants of
focus on doripenem. Expert Rev
beta-lactamase-producing Klebsiella Enterobacteriaceae and Acinetobacter spp.
Antiinfect Ther 2007;5(5):793-809
pneumoniae and Escherichia coli clinical with characterized beta-lactamases.
40. Moellering RC Jr, Eliopoulos GM, isolates. Antimicrob Agents Chemother Antimicrob Agents Chemother
Sentochnik DE: The carbapenems: new 1999;43(5):1170-6 2004;48(4):1313-9
broad spectrum beta-lactam antibiotics.
50. Kitzis MD, Acar JF, Gutmann L. 60. Mushtaq S, Ge Y, Livermore DM.
J Antimicrob Chemother
Antibacterial activity of meropenem Doripenem versus Pseudomonas aeruginosa
1989;24(Suppl A):1-7
against gram-negative bacteria with in vitro: activity against characterized
41. Kropp H, Sundelof JG, Hajdu R, a permeability defect and against isolates, mutants, and transconjugants
Kahan FM. Metabolism of thienamycin staphylococci. J Antimicrob Chemother and resistance selection potential.
and related carbapenem antibiotics by 1989;24(Suppl A):125-32 Antimicrob Agents Chemother
the renal dipeptidase, dehydropeptidase.
51. Jackson JJ, Kropp H, Hurley JC. Influence 2004;48(8):3086-92
Antimicrob Agents Chemother
of antibiotic class and concentration on the 61. Sakyo S, Tomita H, Tanimoto K,
1982;22(1):62-70
percentage of release of lipopolysaccharide et al. Potency of carbapenems for the
42. Norrby SR, Alestig K, Bjornegard B, et al. from Escherichia coli. J Infect Dis prevention of carbapenem-resistant
Urinary recovery of N-formimidoyl 1994;169(2):471-3 mutants of Pseudomonas aeruginosa:
thienamycin (MK0787) as affected by
52. Tsuji M, Matsuda H, Miwa H, Miyazaki S. the high potency of a new carbapenem
coadministration of N-formimidoyl
Antimicrobial-induced release of endotoxin doripenem. J Antibiot (Tokyo)
thienamycin dehydropeptidase inhibitors.
from Pseudomonas aeruginosa: comparison 2006;59(4):220-8
Antimicrob Agents Chemother
1983;23(2):300-307

62. Huynh HK, Biedenbach DJ, Jones RN. pneumonia and their susceptibility to Diagn Microbiol Infect Dis
Delayed resistance selection for doripenem doripenem (DOR) [poster E-265]. 2005;52(1):71-4
when passaging Pseudomonas aeruginosa 47th Interscience Conference on 80. Craig WA. Pharmacokinetic/
isolates with doripenem plus an Antimicrobial Agents and Chemotherapy; pharmacodynamic parameters:
aminoglycoside. Diagn Microbiol 2007 September 17 – 20; Chicago, IL rationale for antibacterial dosing
Infect Dis 2006;55(3):241-3 71. Tsuji M, Ishii Y, Ohno A, et al. In vitro of mice and men. Clin Infect Dis
63. Jones RN, Huynh HK, Biedenbach DJ, and in vivo antibacterial activities 1998;26(1):1-10; quiz 11-2
et al. Doripenem (S-4661), a novel of S-4661, a new carbapenem. 81. Burgess DS. Use of pharmacokinetics
carbapenem: comparative activity against Antimicrob Agents Chemother and pharmacodynamics to optimize
contemporary pathogens including 1998;42(1):94-9 antimicrobial treatment of Pseudomonas
bactericidal action and preliminary 72. Ge Y, Wikler MA, Sahm DF, et al. aeruginosa infections. Clin Infect Dis
in vitro methods evaluations. In vitro antimicrobial activity of 2005;40(Suppl 2):S99-104

J Antimicrob Chemother doripenem, a new carbapenem. 82. Bhavnani SM, Hammel JP, et al. Use of
2004;54(1):144-54 Antimicrob Agents Chemother pharmacokinetic-pharmacodynamic target
64. Brown SD, Traczewski MM. Comparative 2004;48(4):1384-96 attainment analyses to support phase 2
in vitro antimicrobial activity of a new 73. Goldstein E, Citron DM. In vitro activity and 3 dosing strategies for doripenem.
carbapenem, doripenem: tentative disc of doripenem plus six comparator drugs Antimicrob Agents Chemother
diffusion criteria and quality control. against 433 aerobic and anaerobic bacteria 2005;49(9):3944-7
J Antimicrob Chemother 2005;55(6):944-9 isolated from infected diabetic foot 83. Kim A, Banevicius MA, Nicolau DP.
65. Chen Y, Garber E, Zhao Q, et al. In vitro wounds [poster E-259]. 47th Interscience In vivo efficacy of doripenem human
activity of doripenem (S-4661) against Conference on Antimicrobial Agents simulated exposures against Pseudomonas
multidrug-resistant gram-negative bacilli and Chemotherapy; 2007 aeruginosa [poster A-28a]. 47th
isolated from patients with cystic fibrosis. September 17 – 20; Chicago, IL Interscience Conference on Antimicrobial
Antimicrob Agents Chemother 74. Kobayashi Y. Study of the synergism Agents and Chemotherapy; 2007
2005;49(6):2510-1 between carbapenems and vancomycin September 17 – 20; Chicago, IL
66. Jones RN, Huynh HK, Biedenbach DJ. or teicoplanin against MRSA, focusing on 84. Nishino N, Otsuki M, Izawa M. In vitro
Activities of doripenem (S-4661) against S-4661, a carbapenem newly developed and in vivo antibacterial activity of S-4661,
drug-resistant clinical pathogens. in Japan. J Infect Chemother a new carbapenem antibiotic [poster 115].
Antimicrob Agents Chemother 2005;11(5):259-61 36th Interscience Conference on
2004;48(8):3136-40 75. Mushtaq S, Warner M, GE Y, et al. In vitro Antimicrobial Agents and Chemotherapy;
67. Fritsche TR, Stilwell MG, Jones RN. interactions of doripenem with other 1996; New Orleans, LA
Antimicrobial activity of doripenem antimicrobials [poster E-307]. 45th 85. Totsuka K, Shiseki M, Uchiyama T, et al.
(S-4661): a global surveillance Interscience Conference on Antimicrobial In vitro post-antibiotic effect and in vivo
report 2003. Clin Microbiol Infect Agents and Chemotherapy; 2005; antimicrobial activity of novel carbapenem,
2005;11(12):974-84 Washington, DC S-4661 [poster 113]. 36th Interscience
68. Kaniga K, Redman R, Llorens L, 76. Wexler HM, Engel AE, Glass D, Conference on Antimicrobial Agents and
Friedland I. Prevalence of extended- Li C. In vitro activities of doripenem Chemotherapy; 1996; New Orleans, LA
spectrum beta-lactamase producers and comparator agents against 86. Credito K, Appelbaum PC. Comparative
(ESBLs) and fluoroquinolone-resistant 364 anaerobic clinical isolates. time-kill analysis of the anti-anaerobic
isolates from phase 3 Trials of complicated Antimicrob Agents Chemother activity of doripenem [poster E-261]. 47th
urinary tract infections (UTIs) including 2005;49(10):4413-7 Interscience Conference on Antimicrobial
pyelonephritis [poster E-925]. 77. Mikamo H, Izumi K, Hua YX, et al. Agents and Chemotherapy; 2007
47th Interscience Conference on In vitro and in vivo antibacterial activities September 17 – 20; Chicago, IL
Antimicrobial Agents and Chemotherapy; of a new injectable carbapenem, S-4661, 87. Simpson AJ, Opal SM, Angus BJ, et al.
2007 September 17 – 20; Chicago, IL against gynaecological pathogens. Differential antibiotic-induced endotoxin
69. Kaniga K, Umeh O, Llorens L, Friedland I. J Antimicrob Chemother 2000;46(3):471-4 release in severe melioidosis. J Infect Dis
Activity of doripenem against isolates 78. Jones RN, Sader HS, Fritsche TR, 2000;181(3):1014-9
from phase 3 trials of complicated Janechek MJ. Selection of a surrogate 88. Doripenem. S 4661. Drugs R&D
intra-abdominal infections [poster E-264]. beta-lactam testing agent for initial 2003;4(6):363-5
47th Interscience Conference on susceptibility testing of doripenem,
Antimicrobial Agents and Chemotherapy; 89. Ikawa K, Morikawa N, Urakawa N,
a new carbapenem. Diagn Microbiol
2007 September 17 – 20; Chicago, IL et al. Peritoneal penetration of doripenem
Infect Dis 2007
after intravenous administration
70. Kaniga K, Prokocimer P, Llorens L, 79. Jones RN, Sader HS, Fritsche TR. in abdominal-surgery patients.
Friedland I. Prevalence of extended- Comparative activity of doripenem and J Antimicrob Chemother
spectrum beta-lactamase (ESBL) and three other carbapenems tested against 2007;60(6):1395-7
fluoroquinolone-resistant isolates Gram-negative bacilli with various
from phase 3 trials of nosocomial 90. Floren L, Wikler M, Kilfoil T, et al. A
beta-lactamase resistance mechanisms.
phase 1, double-blind, placebo-controlled

Doripenem
study to determine the safety, 98. Thye D, Kilfoil T, Leighton A, et al. 109. Calandra GB, Wang C, Aziz M,
tolerability, and pharmacokinetics Doripenem: a phase 1 study to evaluate Brown KR. The safety profile of
of prolonged-infusion regimens of safety, tolerability and pharmacokinetics imipenem/cilastatin: worldwide clinical
doripenem in healthy subjects [pa-16]. in a Western healthy volunteer population experience based on 3470 patients.
44th Interscience Conference on [pa-21]. 43rd Interscience Conference on J Antimicrob Chemother
Antimicrobial Agents and Chemotherapy; Antimicorbial Agents and Chemotherapy; 1986;18(Suppl E):193-202
2004 October 30 – November 2; 2003 September 14 – 17; Chicago, IL 110. Prescott WA Jr, Depestel DD,
Washington, DC 99. Saito A, Inamatsu T, Shimada J. Clinical Ellis JJ, Regal RE. Incidence of
91. Floren L, Wikler M, Kilfoil T, et al. studies of S-4661, new parenteral carbapenem-associated allergic-type
A phase 1 open-label controlled study carbapenem antibiotic, in chronic reactions among patients with versus
to evaluate the safety, tolerability, and respiratory tract infections [PF-219]. patients without a reported penicillin
pharmacokinetics of doripenem 37th Interscience Conference on allergy. Clin Infect Dis 2004;38(8):1102-7
administered intravenously to subjects Antimicrobial Agents and Chemotherapy; 111. Sodhi M, Axtell SS, Callahan J,
with renal impairment [PA-17]. 44th 1997 September 28 – October 1; Toronto Shekar R. Is it safe to use carbapenems
Interscience Conference on Antimicrobial 100. Calandra G, Lydick E, Carrigan J, in patients with a history of allergy to
Agents and Chemotherapy; 2004 et al. Factors predisposing to seizures penicillin? J Antimicrob Chemother
October 30 – November 2; Washington, DC in seriously ill infected patients 2004;54(6):1155-7
92. Psathas P, Kuzmission A, Ikeda K, Ihara S. receiving antibiotics: experience 112. A safety and tolerability study of
Stability of doripenem for injection with imipenem/cilastatin. Am J Med doripenem in patients with abdominal
(500mg) in representative infusion 1988;84(5):911-8 infections or pneumonia. Available from:
fluids and containers [abstract 57E]. 101. Livermore DM, Sefton AM, http://clinicaltrials.gov/ct2/show/NCT005
American Society of Health-System Scott GM. Properties and potential 15034?term=doripenem&rank=1
Pharmacists; 2007 June 24 – 27; of ertapenem. J Antimicrob Chemother [Accessed on 18 November 2007]
San Francisco; CA, USA 2003;52(3):331-44 113. An effectiveness, safety, and microbiology
93. The official registry of clinical trials of 102. Linden P. Safety profile of meropenem: study of doripenem in patients with
NIH. Available from: http://clinicaltrials. an updated review of over 6,000 patients nosocomial (hospital-acquired) pneumonia.
gov/ct2/results?term=doripenem treated with meropenem. Drug Saf Available from: http://clinicaltrials.gov/ct2/
[Accessed on 18 November 2007] 2007;30(8):657-68 show/NCT00502801?term=doripenem&ra
94. Saito A, Inamatsu T, Shimada J. Clinical 103. Lunde JL, Nelson RE, Storandt HF. nk=7 [Accessed on 18 November 2007]
studies of S-4661, new parenteral Acute seizures in a patient receiving 114. FDA approves DORIBAX™ for the
carbapenem antibiotic, in chronic divalproex sodium after starting treatment of complicated intra-abdominal
respiratory tract infections [PF-219]. ertapenem therapy. Pharmacotherapy and complicated urinary tract infections.
37th Interscience Conference on 2007;27(8):1202-5 Available from: http://www.ortho-mcneil.
Antimicrobial Agents and Chemotherapy; com/ortho-mcneil/101507_press_release.
104. Horiuchi M, Kimura M, Tokumura M,
1997 September 28 – October 1; Toronto html [Accessed on 18 November 2007]
et al. Absence of convulsive liability of
95. Chastre J, Wunderink R, Prokocimer P, doripenem, a new carbapenem antibiotic, 115. The website of Johnson and Johnson
et al. Efficacy and safety of doripenem vs. in comparison with beta-lactam antibiotics. Pharmaceutical. Available from:
imipenem for ventilator-associated Toxicology 2006;222(1-2):114-24 http://www.jnj.com
pneumonia [poster L-486]. 47th
105. Nakajima Y, Mizobuchi M, Nakamura M, 116. Fujimura S, Nakano Y, Sato T, et al.
Interscience Conference on Antimicrobial
et al. Mechanism of the drug interaction Relationship between the usage of
Agents and Chemotherapy; 2007
between valproic acid and carbapenem carbapenem antibiotics and the incidence
September 17 – 20; Chicago, IL
antibiotics in monkeys and rats. of imipenem-resistant Pseudomonas
96. Solomkin JS, Umeh O, Jiang J, et al. Drug Metab Dispos 2004;32(12):1383-91 aeruginosa. J Infect Chemother
Doripenem vs. meropenem with an option 2007;13(3):147-50
106. Job ML, Dretler RH. Seizure activity with
for oral step-down therapy in the treatment
imipenem therapy: incidence and risk 117. Paul M, Benuri-Silbiger I, Soares-Weiser K,
of complicated intra-abdominal infections
factors. Dicp 1990;24(5):467-9 Leibovici L. Beta lactam monotherapy
[poster L-487]. 47th Interscience
107. Norrby SR, Gildon KM. Safety profile versus beta lactam-aminoglycoside
Conference on Antimicrobial Agents
of meropenem: a review of nearly combination therapy for sepsis in
and Chemotherapy; 2007
5,000 patients treated with meropenem. immunocompetent patients: systematic
September 17 – 20; Chicago, IL
Scand J Infect Dis 1999;31(1):3-10 review and meta-analysis of randomised
97. Réa-Neto Á, Niederman M, Prokocimer P, trials. BMJ 2004;328(7441):668
et al. Efficacy and safety of intravenous 108. Pestotnik SL, Classen DC, Evans RS,
et al. Prospective surveillance of 118. Safdar N, Handelsman J, Maki DG.
doripenem vs. piperacillin/tazobactam
imipenem/cilastatin use and associated Does combination antimicrobial therapy
in nosocomial pneumonia [poster L-731].
seizures using a hospital information reduce mortality in Gram-negative
47th Interscience Conference on
system. Ann Pharmacother bacteraemia? A meta-analysis.
Antimicrobial Agents and Chemotherapy;
1993;27(4):497-501 Lancet Infect Dis 2004;4(8):519-27
2007 September 17 – 20; Chicago, IL

119. Giamarellos-Bourboulis EJ. Macrolides 123. Holder IA, Neely AN, Frank DW. the proportion of patients infected and
beyond the conventional antimicrobials: PcrV immunization enhances survival of delays time to infection. Pediatr Infect
a class of potent immunomodulators. burned Pseudomonas aeruginosa-infected Dis J 2004;23(6):504-10
Int J Antimicrob Agents 2008;31(1):12-20 mice. Infect Immun 2001;69(9):5908-10 128. Mentzelopoulos SD, Pratikaki M,
120. Giamarellos-Bourboulis EJ, Adamis T, 124. Baumann U, Mansouri E, Von Specht BU. Platsouka E, et al. Prolonged use of
Laoutaris G, et al. Immunomodulatory Recombinant OprF-OprI as a vaccine carbapenems and colistin predisposes to
clarithromycin treatment of experimental against Pseudomonas aeruginosa infections. ventilator-associated pneumonia by
sepsis and acute pyelonephritis caused Vaccine 2004;22(7):840-7 pandrug-resistant Pseudomonas aeruginosa.
by multidrug-resistant Pseudomonas 125. Baumann U, Gocke K, Gewecke B, et al. Intensive Care Med 2007;33(9):1524-32
aeruginosa. Antimicrob Agents Chemother Assessment of pulmonary antibodies
2004;48(1):93-9 with induced sputum and bronchoalveolar Affiliation
121. Giamarellos-Bourboulis EJ, lavage induced by nasal vaccination Garyphallia Poulakou† MD, Attending Physician,
Antonopoulou A, Raftogiannis M, against Pseudomonas aeruginosa: a clinical Infectious Diseases Specialist &
et al. Clarithromycin is an effective phase I/II study. Respir Res 2007;8:57 Helen Giamarellou MD PhD,
immunomodulator when administered Professor of Internal Medicine and
126. Digiandomenico A, Rao J, Goldberg JB.
late in experimental pyelonephritis by Infectious Diseases
Oral vaccination of BALB/c mice with
†Author for correspondence
multidrug-resistant Pseudomonas Salmonella enterica serovar Typhimurium
aeruginosa. BMC Infect Dis 2006;6:31 University General Hospital ATTIKON,
expressing Pseudomonas aeruginosa O
National and Kapodistrian
122. Tramper-Stranders GA, Wolfs TF, Fleer A, antigen promotes increased survival in
University of Athens Medical School,
et al. Maintenance azithromycin treatment an acute fatal pneumonia model.
4th Department of Internal Medicine,
in pediatric patients with cystic fibrosis: Infect Immun 2004;72(12):7012-21
1 Rimini street, 124 62 Athens, Greece
long-term outcomes related to macrolide 127. Lang AB, Rudeberg A, Schoni MH, et al. Tel: +30 210 583 1990;
resistance and pulmonary function. Vaccination of cystic fibrosis patients Fax: +30 210 532 6446;
Pediatr Infect Dis J 2007;26(1):8-12 against Pseudomonas aeruginosa reduces E-mail: gpoul@med.uoa.gr

Poulakou2008 - Doripenem - An Expected Arrival in The Treatment of Infections Caused by Multidrug - Resistant

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Poulakou2008 - Doripenem - An Expected Arrival in The Treatment of Infections Caused by Multidrug - Resistant

Uploaded by

Copyright:

Available Formats

Drug Evaluation

Doripenem: an expected arrival

Background: Potent new drugs against multidrug-resistant Gram-negative

bacteria, similar to that of meropenem, while retaining the spectrum of

Keywords: Acinetobacter baumannii, antibiotic policy, antipseudomonal antibiotic,

Expert Opin. Investig. Drugs (2008) 17(5):749-771

1. Overview of the market

Doripenem (S-4661) is a novel parenteral carbapenem with a research history in

1.1 Antimicrobial resistance and unmet need

10.1517/13543780802016332 © 2008 Informa UK Ltd ISSN 1354-3784 749

750 Expert Opin. Investig. Drugs (2008) 17(5)

Region Gentamicin* Tobramycin* Pip/Tazo* Ceftazidime* Cefepime* Imipenem* Meropenem* Ciprofloxacin*

Expert Opin. Investig. Drugs (2008) 17(5)

§Belgium, Finland, Germany, Sweden and UK.

¶Greece, Italy, Malta, Portugal, Spain and Switzerland.

**USA, Mexico and Canada.

752 Expert Opin. Investig. Drugs (2008) 17(5)

Expert Opin. Investig. Drugs (2008) 17(5) 753

754 Expert Opin. Investig. Drugs (2008) 17(5)

Mechanism Description Frequency among Frequency among Frequency among

Expert Opin. Investig. Drugs (2008) 17(5)

§Present at various frequencies.

tetracyclines, chloramphenicol, trimethoprim, erythromycin In another in vitro study, comparing activities of

756 Expert Opin. Investig. Drugs (2008) 17(5)

Table 3. Comparative activity of doripenem, imipenem and meropenem against non-fermenting

Organism Ref. [67] Ref. [70] Ref. [64]

MIC50 MIC90 MIC50 MIC90 MIC50 MIC90

Pseudomonas aeruginosa n = 829 n = 107 n = 150

Meropenem > 16 > 16 – – > 32 > 32

Expert Opin. Investig. Drugs (2008) 17(5) 757

758 Expert Opin. Investig. Drugs (2008) 17(5)

Escherichia coli n = 3,023 n = 666 n = 62 n = 45 n = 30 n = 29

Expert Opin. Investig. Drugs (2008) 17(5)

Indole-positive Proteae n = 148 n = 12 n = 30

Expert Opin. Investig. Drugs (2008) 17(5)

Staphylococcus aureus (MSSA) n = 2,705 n = 75 n = 30 n = 41 n = 164

Meropenem > 16 > 16 – – 128 > 128 – – – –

Expert Opin. Investig. Drugs (2008) 17(5) 761

762 Expert Opin. Investig. Drugs (2008) 17(5)

infusion of 500 mg every 8 h for 10 days (Cohort A); a

Expert Opin. Investig. Drugs (2008) 17(5) 763

764 Expert Opin. Investig. Drugs (2008) 17(5)

suggested that the apparent synthetic rate of VPA glucuronide 3. Conclusions

Expert Opin. Investig. Drugs (2008) 17(5) 765

766 Expert Opin. Investig. Drugs (2008) 17(5)

Bibliography baumannii. Emerg Infect Dis amidine moiety. J Antibiot (Tokyo)

2002;49(2):229-33 2007;26(11):793-800 J Antimicrob Chemother

coding for metallo-beta-lactamase VIM-1 September 17 – 20; Chicago, IL

Expert Opin. Investig. Drugs (2008) 17(5) 767

768 Expert Opin. Investig. Drugs (2008) 17(5)

in vitro methods evaluations. In vitro antimicrobial activity of 2005;40(Suppl 2):S99-104

Expert Opin. Investig. Drugs (2008) 17(5) 769

770 Expert Opin. Investig. Drugs (2008) 17(5)

Expert Opin. Investig. Drugs (2008) 17(5) 771

You might also like