European Journal of Medicinal Chemistry 131 (2017) 185e195

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Review article

Recent updates of carbapenem antibiotics

Mohammed I. El-Gamal a, b, c, *, Imen Brahim a, Noorhan Hisham a, Rand Aladdin a,
Haneen Mohammed a, Amany Bahaaeldin a
a
College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
b
Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
c
Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt

a r t i c l e i n f o a b s t r a c t

Article history: Carbapenems are among the most commonly used and the most efficient antibiotics since they are
Received 23 January 2017 relatively resistant to hydrolysis by most b-lactamases, they target penicillin-binding proteins, and
Received in revised form generally have broad-spectrum antibacterial effect. In this review, we described the initial discovery and
1 March 2017
development of carbapenems, chemical characteristics, in vitro/in vivo activities, resistance studies, and
Accepted 14 March 2017
clinical investigations for traditional carbapenem antibiotics in the market; imipenem-cilastatin, mer-
Available online 16 March 2017
openem, ertapenem, doripenem, biapenem, panipenem/betamipron in addition to newer carbapenems
such as razupenem, tebipenem, tomopenem, and sanfetrinem. We focused on the literature published
Keywords:
Antibiotic resistance
from 2010 to 2016.
Carbapenems © 2017 Elsevier Masson SAS. All rights reserved.
b-lactams
b-lactamases

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
2. Carbapenems structure and properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
3. Older carbapenem antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
3.1. Imipenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
3.1.1. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
3.1.2. Imipenem in vivo, in vitro studies and clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
3.2. Meropenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
3.2.1. Resistance studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
3.2.2. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
3.2.3. In vitro/in vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
3.2.4. Pharmaceutical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
3.3. Ertapenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
3.3.1. Pharmacokinetics of ertapenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
3.3.2. Antibacterial activity and resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
3.4. Doripenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
3.4.1. Chemical structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
3.4.2. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
3.4.3. Antimicrobial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
3.5. Biapenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
3.5.1. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
3.5.2. In vivo/in vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
3.6. Panipenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

* Corresponding author. Department of Medicinal Chemistry, College of Phar-

macy, University of Sharjah, Sharjah 27272, United Arab Emirates.
E-mail address: drmelgamal2002@gmail.com (M.I. El-Gamal).

http://dx.doi.org/10.1016/j.ejmech.2017.03.022
0223-5234/© 2017 Elsevier Masson SAS. All rights reserved.
186 M.I. El-Gamal et al. / European Journal of Medicinal Chemistry 131 (2017) 185e195

3.6.1. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

3.6.2. Antimicrobial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
4. Newer carbapenem antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
4.1. Razupenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
4.1.1. Antibacterial activity and resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
4.1.2. Comparing razupenem to other agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
4.2. Tebipenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
4.2.1. Antibacterial activity and resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
4.3. Tomopenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
4.3.1. Biological activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
4.3.2. Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
4.3.3. Resistance to tomopenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
4.3.4. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
4.3.5. Postantibiotic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
4.4. Sanfetrinem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
4.4.1. In vivo/in vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

1. Introduction doripenem were a little bit effective against Gram-negative or-

ganisms [1e5]. All clinical trials demonstrated that carbapenems
Penicillins have been widely used to treat serious infections for have low oral bioavailability and must be administered intrave-
nearly 60 years due to their excellent efficacy and safety, and nously because they cannot cross the gastrointestinal membranes
tolerability profiles. This led to the emergence of bacterial resis- readily. In addition, imipenem-cilastatin and ertapenem can also be
tance, mainly through b-lactamases, that threatened their clinical administered intramuscularly. All these carbapenem antibiotics are
use. Because of that, scientists started to look for b-lactamase in- excreted via the kidney [1]. A classification scheme for carbapenem
hibitors. In 1976, scientists discovered the first b-lactamase in- has been suggested; Group 1: broad-spectrum carbapenems, with
hibitors, generated from Gram-positive bacteria, called olivanic limited activity against non-fermentative Gram-negative bacilli
acid. However, because of its poor stability and poor ability to that are particularly suitable for community-acquired infections
penetrate the bacterial cells, the scientists lost their interest in this (e.g. ertapenem), Group 2: imipenem, meropenem, and doripenem;
natural product. After that, the search for other b-lactamase in- broad-spectrum carbapenems, with activity against non-
hibitors has started over and ended up with two agents: clavulanic fermentative Gram-negative bacilli, have less sensitivity to base
acid and thienamycin (Fig. 1). Thienamycin was the first cabapenem hydrolysis in solution, and Group 3: carbapenems with clinical
to be produced and considered as the lead compound for carba- activity against methicillin-resistant Staphylococcus aureus (MRSA),
penems [1]. and it is under development [2e6].
Carbapenems have been proven to have wider spectrum against In general, carbapenems tend to have better stability against b-
bacteria in comparison with the available penicillin, cephalosporin, lactamase enzymes compared to other b-lactam antibiotics. For
and b-lactam/b-lactamase inhibitor combinations. In general, car- example, they tend to be highly active against b-lactamase-pro-
bapenems having different antibacterial activity such as imipenem, ducing Enterobacteriaciae species. However, several bacterial spe-
panipenem and doripenem were effective against Gram-positive cies are capable of resisting their activity by different mechanisms
bacteria, while meropenem, biapenem, ertapenem and including hydrolyzing enzymes. Class B b-lactamases as well as

Fig. 1. The nuclei of penams (penicillins), cephems (cephalosporins), and carbapenems (Fig. 1A), and the most important structural features of carbapenem antibiotics (Fig. 1B).
 M.I. El-Gamal et al. / European Journal of Medicinal Chemistry 131 (2017) 185e195
some infrequent b-lactamases from classes A (e.g.: SME, IMI, NMC,
GES, KPC) and D (enzymes in Pseudomonas aeruginosa and Acine-
tobacter baumannii) are able to hydrolyze carbapenems. Pseudo-
monas and several Acinetobacter species also tend to possess high
resistance to carbapenems via enzymatic hydrolysis. Lack of bac-
terial porins is another mechanism of bacterial resistance to car-
bapenems. Bacterial porins influence the permeability of bacterial
cell membrane; rendering bacteria less susceptible to the carba-
penem antibiotic [5].
In the present article, we reviewed the recent updates reported
in the literature mainly from 2010 to 2016, about the clinically-used
carbapenem antibiotics. We reviewed their chemical properties,
antibacterial activity, pharmacokinetic profiles, and bacterial
resistance to them.
2. Carbapenems structure and properties
Carbapenems are similar in structure to penicillins. Their
structure consists of unsaturated 5-membered ring fused with a b-
lactam ring (Fig. 1). The differences between penicillins and car-
bapenems are the C2-C3 double bond and carbon instead of sulfur
at C1. This carbon is important for the potency, spectrum of activity,
and stability of carbapenems against b-lactamases. Carbapenems
have a trans-1-hydroxyethyl substituent instead of the acylamino
substituent on the b-lactam ring. This side chain is extended under
the plane of b-lactam ring. It plays a role in resistance to hydrolysis
by b-lactamase and its stereochemistry is critical for activity.
Although carbapenems rapidly acrylate the serine residue on b-
lactamases, the hydrolysis of the acylated enzyme is very slow
because the trans-1-hydroxyethyl moiety displaces water that is
necessary for hydrolysis at the active site. Therefore, the enzyme
becomes acylated and inactive. Metallo-b-lactamases are an
exception here, since their activity does not require a covalent bond
with the b-lactam. 1-b-methyl group: most of agents have 1-b-
methyl group. Early developed agents were susceptible to hydro-
lysis by mammalian hydrolase at the renal brush border
dehydropeptidase-I (DHP-I). The 1-b-methyl group added to the
structure shields the carbonyl group of b-lactam and prevents hy-
drolysis by DHP-I. Clinically available carbapenems have R config-
uration at C8, which increases their potency. The trans
configuration at the C5-C6 bond which increases the potency and
helps in b-lactamases resistance. Another structural feature of
carbapenems is the positively charged side chain at position 2 due
to basic amine or amidine that get protonated at physiological pH
[5e11].
3. Older carbapenem antibiotics
3.1. Imipenem
Imipenem structure (Fig. 2) has the previously mentioned
backbone structure of carbapenems. It lacks the 1-b-methyl group,
therefore it must be administered with the DHP-I inhibitor cil-
astatin. Thienamycin instability was due to the intermolecular
interaction between the azetidinone and the cysteamine. When the
amino group was replaced with a less nucleophilic group, the
antipseudomonal activity decreased as the latter required a basic
group at the C2. Replacement with a stronger base, such as the N-
formimidoyl moiety in case of imipenem, increased the stability
and maintained antipseudomonal property [7].
3.1.1. Pharmacokinetics
Imipenen is not absorbed orally, so it is intravenously admin-
istered. It is extensively distributed to the tissues and body fluids. It
is metabolized by DHP-I enzyme so it must be given with cilastatin.
187
Renal excretion is the main route, and the dose must be adjusted in
kidney disorders. Its half-life is about 1 h, which is prolonged in
patients with renal impairment [12,13].
3.1.2. Imipenem in vivo, in vitro studies and clinical trials
Imipenem is the drug of choice in polymicrobial sepsis. Mean-
while, statins beside their hypocholesterolemic effect, they are
anti-inflammatory and immunomodulators. In a study carried out
on mice, imipenem and atorvastatin combination increased the
survival time from 20.00 ± 1.66 h to 56.00 ± 4.62 h because in case
of acute lung injury sepsis, they can improve vascular function and
reduce bacteria. That combination effectively reduced the total
bacterial count, lung homogenate bacteria, microvascular leakage
and cytokines [14]. An open-label randomized study was done to
study the efficacy of cefozopran, meropenem, imipenem/cilastatin
in febrile neutropenia, compared to cefepime. Almost all the four
agents had the same effect. In the sub-group which had neu-
tropenia for longer than 7 days the imipenem/cilastatin combina-
tion had better effect than cefepime [15]. Colistin methanesulfonate
is a prodrug of colistin. Due to reported side effects such as neph-
rotoxicity, colistin was neglected by the clinicians. But because of
limited drug choices for multidrug-resistant Acinetobacter bau-
mannii (MDRAB), it was re-introduced. Colistin has a synergistic
effect when combined with imipenem. It improves its activity at
lower serum levels of colistin hence, reducing toxicity and prevent
the possible heteroresistance when colistin is used alone. An
in vitro study was conducted to evaluate the activity of the com-
bination and the imipenem resistance reversal in imipenem-
nonsusceptible MDRAB. A significant reversal of imipenem resis-
tance was reported [16]. Acinetobacter species is resistant to all
available antibiotics due to its ability to form a biofilm. A study was
designed to assess Acinetobacter resistance to imipenem. Relying on
the minimum inhibitory concentration (MIC) results, 46% of 65
isolates showed imipenem resistance. Despite these results, imi-
penem is still considered the drug of choice in treating Acineto-
bacter infections [17]. To understand the cause of Pseudomonas
aeruginosa resistance to imipenem in southern China, isolates
where collected from 4 hospitals between 2011 and 2012. The re-
sults illustrated that the main reason for resistance is the loss of
OprD, lower expression of OprD genes and metallo -b-lactamase
production [18]. A pilot study was carried out to study the resis-
tance and cross resistance of imipenem and ciprofloxacin in Pseu-
domonas aeruginosa. Resistance to imipenem manifested in 18.5% of
the cases, 8.9% to ciprofloxacin, and 28.9% to both. Resistance to
imipenem as well as resistance to both agents were reported in
patients who received fluoroquinolone or carbapenem in the last 3
months. Unlike ciprofloxacin, imipenem did not lead to ciproflox-
acin and imipenem cross-resistance [19]. It was reported that up to
this date there was no large study to compare the efficacy, tolera-
bility and safety between imipenem/clavulanate and meropenem/
clavulanate in treatment of resistant tuberculosis (TB). An obser-
vational study stated that meropenem combination was more
effective than imipenem combination in treating multiple and
extensively drug resistant tuberculosis [20]. There are few evi-
dences about the effectiveness of regimens that contain imipenem/
clavulanate and linezolid in treatment of MDR and extensively drug
resistant tuberculosis. An observational study was carried out to
assess their therapeutic effect in resistant TB. It concluded that
there could be a role of imipenem/clavulanate treatment of MDR-
and extensively drug-resistant TB (XDR-tuberculosis). And that
regimens containing linezolid and imipenem/clavulanate are
considered safe and effective in treating multiple and extensively
drug resistant tuberculosis [21]. Streptomyces species K04-0144
produced cyslabdan that potentiated the activity of imipenem
against MRSA. This potentiation effect of cyslabdan was reported
188 M.I. El-Gamal et al. / European Journal of Medicinal Chemistry 131 (2017) 185e195

Fig. 2. Structures of the carbapenem antibiotics.

when combined with b-lactams among antibiotic classes and
particularly greater effect with carbapenems. It reduced the MIC
value of imipenem from 16 to 0.05 mg/mL. In addition to the dis-
covery of cyslabdan A from Streptomyces sp. K04-0144 broth, two
new cyslabdans were discovered; Cyslabdan B which potentiates
activity of imipenem against MRSA by 123 folds, and cyslabdan C by
533 folds. Comparing with cyslabdan A, the hydrophilic group at
the dimethyl moiety of the decalin ring was disadvantageous for
the activity [22,23]. Colistin is considered the drug of choice in
treatment of carbapenem resistant Klebsiella infections but resis-
tance to this antibiotic is growing as well. The efficacy of amikacin/
imipenem combination in treatment of infections caused by car-
bapenem resistant Klebsiella has been reported. Concluding that
the combination if a high dose of imipenem and amikacin was
advantageous in treating pneumonia and blood stream infections
caused by this pathogen. Continuous venovenous hemodiafiltration
 M.I. El-Gamal et al. / European Journal of Medicinal Chemistry 131 (2017) 185e195
can be used to prevent the aminoglycoside nephrotoxicity [24].
3.2. Meropenem
The central and renal toxicities of meropenem were massively
decreased while keeping the antipseudomonal activity maintained
by adopting a C2 side chain of a group called: dimethylcarbamoyl-
pyrrolidinylthio. Furthermore, the enhancement of DHP-I stability
in vivo and the anti-Haemophilus influenzae activity improvement.
were established by introducing 1-b-methyl group to the carba-
penem frame [25,26].
3.2.1. Resistance studies
A 2016 study showed that carbapenem (meropenem) cannot
fundamentally cause enhancing the transcription level of an efflux
pump (mexA) or a carbapenemase (blaNDM-1) gene in Pseudo-
monas aeruginosa. Hence, different variables may have a role in
promoting their transcription. More studies were important to
recognize such factors in order to aid clinicians to start proper
antimicrobial treatment in serious infections with this pathogen
[27]. In another 2016 study, the results confirmed that the high-
level resistance to carbapenems in P. aeruginosa should not be
blindly attributed to the production of carbapenemase. Intensive
susceptibility testing of both meropenem and imipenem is required
to figure out the most likely mechanisms contributing to carba-
penem resistance [28]. Furthermore, a 2010 study revealed that
susceptibility profiles of meropenem against various organisms
have stayed constant over the last six years. However, there is a
sharp drop in the activity of meropenem against Acinetobacter spp
[29].
3.2.2. Clinical studies
In a study done in 2014 on adult Japanese patients suffering
from bacterial meningitis, meropenem was found to be an effective,
well tolerated agent when given to those patients in a dose of 2 g
every 8 h in a treatment duration that ranged from 14 to 28 days
[30]. In another study performed in 2014, patients who suffered
from intra-pleural infection and/or refractory pneumonia were
given meropenem (3 g per day) the therapy was effective and
revealed a relatively good safety profile [31]. A further study in 2014
revealed that reports of myoclonus after administering meropenem
are rare. However, the epileptogenicity of meropenem must be
considered, especially patients presenting with a complex clinical
scenario [32]. In a study performed in 2013, it is found that when
treating severe skin and soft tissue infection caused by
carbapenem-resistant A. baumannii through IV therapy with the
combination of ampicillinesulbactam and meropenem, successful
cure on both microbiological and clinical levels was observed
without major acute complications or side effects [33]. In a 2013
study, when comparing the efficacy meropenem with that of the
combination of piperacillin/tazobactam in treating pneumonia, the
latter combination showed a slightly greater rate of efficacy than
meropenem, however both regimens were found safe [34]. In 2012,
a study showed that there is serious interaction between the
antiepileptic medication valproic acid and merpenem particularly
due to the extreme reduction of the valproic acid serum concen-
trations. And so giving them together should be avoided [35]. In
2010, a study concluded that meropenem induced less seizures and
that it showed somehow greater clinical efficacy in treating
neurological infections than imipenem [36].
3.2.3. In vitro/in vivo studies
In a study done in 2016, it was shown that using meropenem at
a high dose as monotherapy for treating P. aeruginosa that produces
verona integron-encoded metallo-b-lactamase caused a high rate
189
of resistance and poor pharmacodynamics profile. All of this
increased the need for a novel compound for treating this difficult
pathogen [37]. In 2015, a study revealed that synergism was
observed when plazomicin was combined with meropenem
against strains of enterobacteriacea [38]. Furthermore, in a 2014
study, data obtained suggest that the combination of meropenem
with rifampicin might be a suitable option for treating MDRAB due
to their synergetic activity that was shown in vitro and through
sepsis experimental model [39]. In another study done in 2014,
meropenem appeared to have greater resistance to the inoculum
effect of (extended spectrum b-lactamases (ESBL)- producing
klebsiella pneumoniae) than piperacillin-tazobactam both in vivo
and in vitro, and so in managing people with severe pneumonia
caused by ESBL-Kpn, meropenem may be the drug of choice for
achieving a successful treatment [40]. In 2013, a study showed that
meropenem was highly effective for treatment of meningitis with
b-lactamase-nonproducing ampicillin-resistant Haemophilus influ-
enza when given frequently at high doses [41]. In another study
done in 2016, the results reveal that combining meropenem with
colistin may be a promising therapeutically against carbapenem-
resistant Acinetobacter baumannii [42].
3.2.4. Pharmaceutical studies
In a study conducted in 2016 concluded that forming mer-
openem-b-cyclodextrin inclusion complex has a significantly
beneficial outcome on meropenem chemical stability. The protec-
tive impact of complexation additionally enhance the antibacterial
profile of against P. aeruginosa, whose extermination is a critical
clinical issue. The complex formation on a molecular level is as the
following: the carbonyl group in trans-b-hydroxyethyl at C6 and the
carboxylic moiety at C2 and additionally the carbonyl group at C7 of
4:5 fused bicyclic ring of meropenem interact with cyclodextrins
[43]. In another a study carried out in 2016 aiming at determining
stability of meropenem in a bacterial growing medium through
high-performance liquid chromatography, meropenem showed
just limited stability [44]. In 2013, a study showed that as a ther-
apeutic choice meropenem is found appropriate for treating pros-
tatitis from the view of pharmacokinetic and pharmacodynamic
evaluation [45].
3.3. Ertapenem
Ertapenem (Fig. 2) is parenteral 1-b-methyl carbapenem
developed in 2001. It is broad-spectrum b -lactam antibiotic with
the bactericidal property. Ertapenem binds to penicillin-binding
proteins (PBPs) located on the bacterial cell wall, in particular,
PBPs 2 and 3, thereby inhibiting the final transpeptidation step in
the synthesis of peptidoglycan, an essential component of the
bacterial cell wall. Inhibition results in a weakening and subsequent
lysis of the cell wall leading to cell death of Gram-positive and
Gram-negative aerobic and anaerobic pathogens. This agent is
stable against hydrolysis by a variety of b-lactamases, including
penicillinases, cephalosporinases, and ESBL. Ertapenem is more
stable against DHP-I inactivation than imipenem and therefore,
does not require the addition of a DHP-I inhibitor such as cilastatin
or betamipron (Fig. 3) [46]. Although ertapenem retains many of
the beneficial structure features of the other carbapenem, it differs
from other members of the class by the presence of the meta-
substituted benzoic acid substituent. This moiety increases the
lipophilic and changes the overall molecular charge, the carboxylic
acid moiety, ionized at physiological pH result in a net negative
charge [7].
3.3.1. Pharmacokinetics of ertapenem
Ertapenem is approximately 94% protein bound. Its long
190 M.I. El-Gamal et al. / European Journal of Medicinal Chemistry 131 (2017) 185e195
Fig. 3. Structures of the dehydropeptidase-I inhibitors, cilastatin and betamipron.
elimination half-life of approximately 4 h, allows for once-daily
dosing. The adult dose is 1 g parenterally once a day. Ertapenem
is not hepatically metabolized and is primarily eliminated by the
renal route; dose reduction to 0.5 g once a day is required in pa-
tients with severe renal insufficiency. Drugedrug interactions are
unlikely since ertapenem does not inhibit P-glycoprotein-mediated
or cytochrome P450-mediated drug clearance. The most common
adverse reactions reported with ertapenem were diarrhea, infused
vein complication, nausea, headache, vaginitis in females, phlebitis/
thrombophlebitis, vomiting and elevated aminotransferase levels.
Seizures were reported infrequently during parenteral study ther-
apy in all treatment groups [48,49].
3.3.2. Antibacterial activity and resistance
Ertapenem also has been considered as the first line effective
against ESBL-producing Gram-negative bacteria infections and it
has a wide spectrum of activity against community-acquired
pathogens involved in a variety of infections. It is clinically useful
for complicated acute pelvic infections as well as community-
acquired pneumonia. It also was active in almost all isolates that
had high levels of either AmpC b-lactamase, although MICs are
elevated compared with those for isolates lacking these enzymes,
this does not translate into resistance to ertapenem. However,
ertapenem has a limited activity against nosocomial pathogens
such as Pseudomonas aeruginosa, Acinetobacter species, Methicillin-
resistant staphylococci, and Enterococci [46]. Ertapenem is indi-
cated to treat patients with urinary tract infections (UTIs) caused by
the ESBL-producing organism by once daily parenteral injection
through outpatient parenteral antibiotic therapy (OPAT) program-
mer. Furthermore, the use of OPAT programmer proved to help in
cost saving by decrease the number of inpatient bed days required
for their successful treatment. However, the resistance of chronic
urinary tract infections (cUTIs) isolates to first-line antibiotics is
high [49,50]. Ertapenem ceftriaxone and levofloxacin in the treat-
ment of cUTIs had a great clinical reaction. Among the three agents,
ertapenem was the most effective in the treatment of cUTIs than
ceftriaxone and levofloxacin and was associated with shorter hos-
pital stays. However, using ceftriaxone in cUTIs was less costly [50].
Ertapenem has been designed as a first line antimicrobial treatment
of intra-abdominal infection, which is a complicated infection
commonly encountered in the community. The early diagnosis and
early use of adequate and effective antimicrobial therapy with a
combination surgical sours control showed to reduce inpatient
care. Ertapenem, is active in vitro against many aerobic and
anaerobic bacteria associated intra-abdominal infections. It is
administered as once-a-day parenteral dose. In addition, a combi-
nation therapy of ertapenem with metronidazole also showed ac-
tivity against the infection [51]. A 1 g once a day of Ertapenem was
highly effective for treatment of adults with serious infections
caused by Enterobacteriaceae. Moreover, no resistance has been
developed during treatment of these infections with ertapenem
[52]. Ertapenem was highly active in vitro against complicated skin
and skin-structure infections which are a result from polymicrobic
and they include both aerobic and anaerobic pathogens. However,
ertapenem showed only very moderate effects on the intestinal
microflora with no serious adverse events were encountered. In a
comparison between the activities of ertapenem and tigecycline,
ertapenem with or without vancomycin exerted higher efficacy
than the 150 mg once-daily regimen of tigecycline in treatment of
diabetic foot infections. For the sub-study in subjects with osteo-
myelitis, the cure rates for tigecycline were low [47]. Hypovolemia
is an event that may influence drug distribution and elimination.
The impact of hypovolemia on the plasma protein binding and
tissue distribution of ertapenem was explored in rats using
microdialysis. Ertapenem elimination changed in hypovolemic rats,
most likely because of diminished renal blood flow, however its
distribution characteristics not changed. Unbound concentrations
of ertapenem in blood and muscles were always virtually identical
[53]. Antibiotics used for treatment of complicated intra-abdominal
infections (cIAIs) should give broad-spectrum for both Gram-
positive and Gram-negative microorganisms. The PROMISE study
analyzed the clinical and bacteriological viability and safety of
moxifloxacin versus ertapenem for the treatment of cIAIs. The
outcomes show that moxifloxacin is a profitable treatment choice
for a range of community-acquired cIAIs with mild-to-moderate
severity [54]. An ertapenem-resistant Escherichia coli isolate was
recuperated from peritoneal fluid in a patient who had been treated
with imipenem/cilastatin for 10 days. Ertapenem resistance might
be clarified by a deformity in the outer membrane protein and
production of extended-spectrum b-lactamase CTX-M-2 [55].
Ertapenem susceptible and resistant extended-spectrum b-lacta-
mase-creating Enterobacter cloacae disconnects acquired from a
similar patient. Gene transcription of OmpD and OmpF was
decreased in the ertapenem resistante separate. An efflux pump
inhibitor diminished the MICs of ertapenem in the resistante strain,
proposing a potential part of efflux pumps in ertapenem resistance
[54]. Ertapenem resistance in Klebsiellae pneumoniae thus depen-
ded on production of particular -lactamases and defects in
permeability. In most strains loss of susceptibility was more
marked for ertapenem than for imipenem or meropenem. Extra
clinical disengages with this resistance phenotype have as of late
been accounted for [56].
3.4. Doripenem
Doripenem (Fig. 2) is a new carbapenem which has many unique
properties that make this drug on the top of the carbapenems class.
It is as active as imipenem against Gram-positive bacteria, and of
similar activity as meropenem against Gram-negative bacteria.
Doripenem does not need cilastatin to be co-administered due to
the presence of the 1-b-methyl functional group. It has good
tolerability and lowers tendency to cause seizure compared to
imipenem, a lower tendency for resistance and bacteria resistant to
carbapenems had a lower frequency and reduced MICs after addi-
tion to doripenem in comparison to imipenem or meropenem.
Doripenem also showed higher blood concentration and half-life
than both imipenem or meropenem [10,11].
3.4.1. Chemical structure
Doripenem has the same structure of meropenem with slight
modification by substituting dimethyl-carboxyl chain of mer-
openem with sulfamoxil-aminomethyl chain. Doripenem has 1-b-
methyl group that contributes to enhanced stability against DHP-I
enzyme. Doripenem has trans-a-1-hydroxyethyl group at position
6 which provides b-lactamase stability [57].
 M.I. El-Gamal et al. / European Journal of Medicinal Chemistry 131 (2017) 185e195
3.4.2. Pharmacokinetics
Data obtained from phase 1, 2, and 3 studies, a two-
compartment model used after giving doripenem by intravenous
route. Since doripenem is excreted by the kidney, creatinine
clearance was the most successful parameter to predict doripenem
clearance. Although doripenem clearance decreased in elderly due
to decrease in kidney function in that age group, however this
decrease was stabilized by the decrease in blood and tissue bind-
ing; so there was no need to adjust the dose in elderly. It was found
that the clearance increased in Latino-origin people compared with
caucasians. Caucasian volunteers/patients mean clearance was
estimated to range from 4.1 L/h in patients with a kidney defect to
22.9 L/h in volunteers with normally functioning kidney. Crea-
tenine clearance and age had positive effect on peripheral volume
of distribution (Vp). Because patients with kidney defect had
changed tissue and protein binding; so their Vp also changed. Due
to inverse relationship between age and creatinine clearance, and
between age and body weight; the effect on Vp would be low [58].
3.4.3. Antimicrobial activity
A recent meta-analysis was done to assess the safety and effi-
cacy of doripenem in treating different bacterial infections. In terms
of effectiveness, it was confirmed that doripenem had the same
efficacy as other comparators for treating cIAI, cUTI and nurse
practitioner infectious disease. On the other hand, in terms of
safety, side effects were higher in case of doripenem in comparison
with other comparators, however the difference was not very sig-
nificant. Eventhough, doripenem is still not approved by the FDA to
be used for treating nurse practitioner infectious disease and
ventilator-associated pneumonia (VAP), meta-analysis showed that
doripenem was safe and effective and it is non-inferior to other
comparators. A recent study showed that patients with VAP treated
with doripenem had an advantage over those treated with imipe-
nem by staying less in hospital so saving both time and money [59].
Doripenem was approved in Japan in 2011 to be given in high doses
(3 g daily) for treating pneumonia (third most fatal disease in
Japan). Studies on the safety and effectiveness of high doses of
doripenem showed that it is effective and relatively safe [60]. In a
study done to assess the in vitro efficacy of doripenem, it was
shown that doripenem had the same potency as meropenem
against E. coli, Acinetobacter spp and Pseudomonas aeruginosa. In
comparison with imipenem it was shown that doripenem at least
two times more potent against E. coli and it inhibits higher number
of Pseudomonas aeruginosa strains. The activity of doripenem was
higher than meropenem against imipenem-resistant Pseudomonas
aeruginosa, while meropenem did not inhibit these strains [11].
Another study was carried out to evaluate the in vitro activity of
doripenem in comparison with imipenem and meropenem against
multiple Gram-negative bacteria. Against Enterobacteriaceae, the
efficacy of doripenem was similar or higher than meropenem, and
4-folds higher than imipenem. Doripenem showed the highest ef-
ficacy when compared with imipenem and meropenem against
Pseudomonas aeruginosa [61]. In vitro activities of combination
therapy (doripenem, polymyxin B, and rifampin) were assessed
against some of the carbapenem-resistant bacteria showed that
this combination resulted in 90% bactericidal activity against
Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii
and Klebsiella pneumoniae. So this combination could be used for
patient with such carbapenem-resistant bacteria [62].
3.5. Biapenem
At C1 of Biapenem (Fig. 2), a b-methyl substitution is located to
decrease the chance of degradation by DHP-I enzyme attacking the
b-lactam unit [3]. A study showed that upon introducing a bicyclic
191
thiazolium moiety at C4 of the bicyclic 4:5 fused rings (which are
originally unstable), the stability of biapenem was improved. The
hydroxyethyl group present on C6 of carbapenem is responsible for
its resistance against b-lactamases [9].
3.5.1. Pharmacokinetics
Biapenem is not absorbed orally, and so is given parenterally. It
has a high distribution in tissues overall. The main excretion route
for biapenem is glomerular filtration [46].
3.5.2. In vivo/in vitro studies
Biapenem has a broad-spectrum and quick bactericidal activity
against both Gram-positive and Gram-negative bacterial species. In
a study to determine the in vitro activity of several antibiotics
against Gram-negative strains of bacteria, only biapenem was
found effective against 50% of Escherichia coli and Klebsiella species.
Biapenem shows higher stability towards hydrolysis by DHP-I en-
zymes than meropenem, giving it the advantage of being possibly
administered individually, unlike imipenem and panipenem. Bia-
penem was found to have an excellent activity against nursing- and
health care-associated pneumonia as well as proven safe and
effective in treating general pneumonia, both of which occurring in
the elderly. Biapenem was also found effective in treatment of
moderate and severe urinary tract and lower respiratory tract in-
fections, as well as in treatment of intra-abdominal infections [46].
Biapenem can also be used for treatment of bacterial cholangitis
and cholecystitis, and also for prophylaxis in biliary tract surgery
and endoscopic retrograde cholangiopancreatography [63].
3.6. Panipenem
Panipenem (Fig. 2) is a broad-spectrum antibiotic possessing
activity against Gram-positive and Gram-negative, aerobic and
anaerobic bacteria. It is little bit more stable than imipenem against
hydrolysis by DHP-I, however it is still susceptible to hydrolysis by
renal DHP-I. So administration of panipenem with a DHP-I inhibi-
tor, betamipron (Fig. 3), in a ratio of 1:1 is a must. Betamipron is a
kidney anion transport inhibitor that inhibits the panipenem
transport in the cortex of the kidney and decrease kidney toxicity
[46]. Panipenem contains 3-acetimidoylpyrrolidinyl substitution
and no methyl group introduced at C1 [64].
3.6.1. Pharmacokinetics
Panipenem is a parenterally administered drug. The rate of
urinary excretion was 30% of panipenem. Most of betamipron was
excreted unchanged in urine. So determining the function of the
kidney and the dose is required, and it showed low rates of protein
binding. Panipenem clearance in patients with end-stage renal
disease undergoing hydrolysis was 9.53 ± 1.26 L/h for panipenem
and 4.18 ± 0.643 L/h for betamipron, while the clearance in patients
without hydrolysis was 2.92 ± 0.238 L/h for panipenem and
0.615 ± 0.511 L/h for betamipron. After intravenous infusion of 0.5 g
and 0.75 g of both components (panipenem and betamipron) the
mean maximum blood concentration for panipenem were 37 and
61 mg/L respectively, and for betamipron were 24 and 39 mg/L,
respectively. The half-life after intravenous infusion administration
in children was 1.2 h panipenem and 0.9 h for betamipron. The drug
concentration in the cerebrum spinal fluid was 8-folds lower than
the concentration in the serum [46].
3.6.2. Antimicrobial activity
Panipenem/betamipron was effective for treatment of Strepto-
coccus pneumoniae infection, as the initial therapy with pan-
ipenem/betamipron showed advantage over other carbapenem
antibiotics in treating Streptococcus pneumoniae infection. Using
192 M.I. El-Gamal et al. / European Journal of Medicinal Chemistry 131 (2017) 185e195
panipenem/betamipron in elderly patients for treating pneumonia
was effective, safe and tolerable in most of the patients [65,66].
Against Gram-positive aerobic bacteria, panipenem showed good
antimicrobial activity. Panipenem had the same activity as imipe-
nem, and it was 2e4 times more active than meropenem. On the
other hand, panipenem activity against Gram-negative aerobic
bacteria was remarkable as the majority of Enterobacteriaceae were
susceptible to panipenem including Klebsiella species, Proteus spe-
cies. Enterobacter species., and Escherichia coli. Panipenem showed
the same activity as imipenem against Pseudomonas aeruginosa.
Against 61% of Pseudomonas aeruginosa strains, the panipenem MIC
was over 8 mg/mL, however against all Pseudomonas aeruginosa
strains that are resistant to ceftazidime, the MIC was 8 mg/mL.
Panipenem is effectively used for treating listerial meningitis in
paediatrics [46]. The clinical trials showed that high efficiency of
panipenem/betamipron against respiratory tract and urinary tract
infections in adults (the efficacy was similar to imipenem/cil-
astatin). The effect was demonstrated also in elderly patients with
respiratory tract infections. In addition, panipenem/betamipron
exerted good antibacterial effect in adults with surgical or gyne-
cological infections, and in pediatric patients with respiratory tract
and urinary tract infections in non-comparative trials [67]. Patients
with end-stage renal disease were recommended to take pan-
ipenem/betamipron as 500 mg/500 mg once daily since the results
were similar to patients with normal kidney function [68].
4. Newer carbapenem antibiotics
4.1. Razupenem
Razupenem (Fig. 2) is a novel carbapenem that is administered
parenterally. It is suggested that razupenem has a potential role in
the treatment of polymicrobial anaerobic infections. Unfortunately,
razupenem development was discontinued in America because of
the great rate of adverse events in phase II clinical trials [6].
4.1.1. Antibacterial activity and resistance
Razupenem showed broad-spectrum activity when it was
evaluated in vitro against anaerobes, it was also active against a
variety of aerobic bacteria including: penicillin-resistant Strepto-
coccus pneumoniae, vancomycin-resistant Enterococcus faecium,
ampicillin-resistant Haemophilus influenza, MRSA, and also against
ESBLs-producing bacteria [69]. In an in vitro study, when razupe-
nem was given at doses that are simulated to the human it revealed
a significant antibacterial effect on strains of methicillin-sensitive
Staphylococcus aureus and MRSA [69]. It is concluded that razupe-
nem is significantly active against ESBL producing bacteria, how-
ever it is affected by AmpC b-lactamases. Furthermore,
carbapenemases compromise the activity of razupenem. Razupe-
nem was found to be effective against ESBLs-producing strains,
however in a recent in vitro study, the activity of razupenem
significantly dropped by carbapenemases and AmpC enzymes.
Furthermore, the activity of razupenem against S. marcescens and B.
cepacia can be enhanced through combining it with other antibi-
otics such as ciprofloxacin or amikacin [45].
4.1.2. Comparing razupenem to other agents
Unlike other b-lactams, razupenem is not compromised by
decreased temperatures or increased concentrations of salt. In
addition, razupenem pharmacokinetics are superior in animals;
which suggests promising pharmacokinetics profile in human be-
ings, with even a longer half-life than the other carbapenems
available [4]. In a study done on murine models aiming at
comparing between the activity of razupenem and vancomycin, a
noticeable reduction in the number of the viable bacteria resulted
when using razupenem on murine suffering from hematogenous
bronchopneumonia that is due to vancomycin intermediate
Staphylococcus aureus and MRSA. Furthermore, the survival rate
was significantly higher with razupenem in comparison to vanco-
mycin. Moreover, in comparison with doripenem and meropenem,
it was found to be strongly active against non-fragilis Bacteroides
spp that was clinically isolated [45]. Razupenem produced excellent
activity against non-fragilis Bacteroides spp. in comparison to that of
other carbapenems, these species are detected in abdominal in-
fections post surgeries. Moreover, Razupenem's MICs against
Fusobacterium spp., Prevotella spp., and Porphyromonas spp., which
are usually isolated in head and neck space infections, abdomen,
and pleuropulmonary areas, were superior or comparable to those
of other antimicrobial agents [70].
4.2. Tebipenem
Tebipenem (Fig. 2), a broad-spectrum antibiotic, has been under
development as the world's first oral carbapenem antibiotic, it was
created as an alternative drug to combat bacteria that had devel-
oped resistance to usually used antibiotics. Tebipenem is formu-
lated as the ester, tebipenem pivoxil (Fig. 2). It is rapidly absorbed
into intestinal cells and has high bioavailability with favorable
pharmacokinetics. In addition, tebipenem is an active compound
that has been shown to exhibit in vitro and in vivo activity. Clinical
studies of the prodrug are under consideration in Japan [71].
4.2.1. Antibacterial activity and resistance
The preparatory acute toxicity measurement was carried out
in vivo in mice. Direct bacterial test models were then utilized as
they are nearer to real clinical states. Interestingly, single simulta-
neous tebipenem pivoxil oral administration significantly de-
creases the mortality of sepsis model mice tested with different
pathogenic microscopic organisms [71,72]. Tebipenem pivoxil
proved excellent protection in sepsis mouse models in vitro. In
addition, tebipenem pivoxil following oral administration had a
higher protective effect than meropenem in all the tried sepsis
models, which can be due to its great tissue distribution [73]. The
tebipenem pivoxil tablet was more powerful than the tebipenem
pivoxil granules for ensuring mortality of sepsis mice in some
sepsis models because of the higher bioavailability of this tablet
in vivo. Together, these discoveries showed powerful antibacterial
properties of tebipenem pivoxil against different pathogenic
microscopic organisms in vitro and in vivo, which gives some
exploratory proof to its application to treat sepsis in the facility [74].
The in vitro studies of the tebipenem proved that it has potent ac-
tivity against Neisseria gonorrhoeae and multidrug-resistant Strep-
tococcus pneumonia, the cause of community-acquired respiratory
tract infections. It was also shown that tebipenem has higher se-
lective antibacterial and bactericidal activities against b-lactamase-
nonproducing, ampicillin-resistant Haemophilus influenza, in addi-
tion, tebipenem appeared to be an excellent antibiotic for the
treatment of acute otitis media [75]. Burkholderia pseudomallei is a
Gram-negative bacterium causing melioidosis, that is pervasive in
Southeast Asia and Northern Australia. Many clinical trials proved
that tebipenem pivoxil could be considered as an alternative oral
antibiotic therapy for melioidosis [76]. Tebipenem is extremely
powerful against ESBL-delivering Escherichia coli. Oral administra-
tion of tebipenem pivoxil is safe and initiated high inhibitory and
bactericidal activity in serum and urine. Tebipenem pivoxil could be
a potent of oral drug for powerful treatment of ESBL-delivering
Escherichia coli contamination [77]. Tebipenem pivoxil was tested
for treatment of bacterial pneumonia in children, caused funda-
mentally by Streptococcus pneumoniae, Haemophilus influenzae and
Mycoplasma pneumonia. The clinical outcomes demonstrated
 M.I. El-Gamal et al. / European Journal of Medicinal Chemistry 131 (2017) 185e195 193

viability in all patients, and causative organisms beings were 100%
dispensed with no clinically dangerous unfavorable adverse effects,
and compliance was great. It is considered that these cases give
significant bits of knowledge into the personality of pathogenic
organism's forms of pneumonia in kids and the conceivable part of
tebipenem pivoxil in outpatient treatment [78]. The study sug-
gested that co-administration of tebipenem and valproic acid
should be avoided due to presenting with convulsive seizures. This
might be due to diminishment of valproic acid concentration in the
blood. This has been reported with the injectable carbapenem.
However, this is the primary report of such an association with
tebipenem, which is an orally-administered carbapenem antibiotic.
In spite of the fact that the component of drug interaction amongst
valproic acid and carbapenem antibiotic is not completely under-
stood, it is believed that valproic acid blood concentration di-
minishes because of enhanced creation of valproic acid glucuronic
acid conjugates being directly or indirectly affected by the carba-
penem antibiotic [79].
4.3. Tomopenem
Tomopenem (Fig. 2, CS-023 previously) is a new carbapenem
antibiotic that has a broad-spectrum of antibacterial activity. It was
tested against large number of isolates and found to be effective
against different Gram-positive and Gram-negative aerobes and
anaerobes most potently MRSA and Pseudomonas aeruginosa [5].
Tomopenem is a 1b-methylcarbapenem that has 5-substituted
pyrrolidin- 3-ylthio group that includes amidine moiety at the C2
position [80]. A 2-guanidinoacetylamino pyrrolidine moiety at
position 2 might be the reason behind its activity against MRSA.
This structural characteristic allows the molecule to bind to the
groove in a way that makes the acylation reaction occurs faster than
other commercially-available carbapenems. Newer compounds
which have longer side chain have higher affinity to penicillin-
binding protein 2A (PBP 2A) [81].
4.3.1. Biological activity
Several in vivo and in vitro studies were carried out to investigate
the activity of tomopenem against variety of clinical isolates in
comparison with other carbapenems and antibacterial agents. Re-
sults are summarized in Table 1.
4.3.2. Remarks
No safety issues in renal dysfunction but needs dose adjustment
as tomopenem and its metabolite clearance decrease with
increased disease severity [83]. The change in drug pharmacoki-
netics in elderly and women is minimal so there is no need for dose
adjustment [84].
4.3.3. Resistance to tomopenem
No emergence of resistance has been reported when 0.75 g and
1.5 g every 8 h simulations were used at 106 CFU/mL. Studies that
evaluate in vitro Staphylococcus aureus resistance to carbapenems
are rare. One study illustrated that there is low risk of resistance at
T > MICs of >30%, opposite to cases when the T > MIC is <10% [85].
4.3.4. Pharmacokinetics
Tomopenem has 15e17 L volume of distribution, a half-life
about 2 h, protein binding is 10%, and 69% of drug is excreted un-
changed in urine [85].
4.3.5. Postantibiotic effect
The post-antibiotic effects on methicillin-sensitive Staphylo-
coccus aureus and Pseudomonas aeruginosa were about 1 h, and they
were comparable to those of meropenem and longer than vanco-
mycin in MRSA [86].

Table 1
In vitro activities of Tomopenem.

Pathogen Results and comments

Methicillin-resistant Staphylococcus aureus - Potent activity

- MIC90 ¼ 8 mg/mL
- Active against all mutants (isolated in Germany)
- Greater activity than Vancomycin.
- Mechanism of action: inhibition of PBP 2A (not inhibited by available carbapenems)
Pseudomonas aeruginosa - Potent activity. MIC90 ¼ 4 mg/mL
- 4-fold greater than imipenem, meropenem and levofloxacin
- Active against all mutants (isolated in Germany)
- antibacterial due to strong intrinsic activity
Enterobacter cloacae Stable to b-lactamase
Proteus vulgaris Stable to b-lactamase
Enterobacteriaceae (e.g. Escherichia coli, Klebsiella, and - Potent activity comparable to meropenem and stronger than imipenem (except for Providencia rettgeri)
Proteus) - Stronger than cephems
Methicillin-susceptible S.aureus Very potent
Methicillin-susceptible S.epidermidis Very potent
Streptococci - High activity including penicillin-resistant Streptococcus pneumonia (PRSP)
- Similar efficacy to imipenem/cilastatin and vancomycin in a pneumonia model induced by two serotypes of
PRSP.
- Exception: streptococcus Streptococcus oralis and S.mitis
Enterococcus faecalis Potent but less than imipenem
- M.catarrhalis Similar activity to meropenem
-Ampicillin-susceptible influenza
Ampicillin-resistant influenza - Similar activity to meropenem
- 16 folds greater than imipenem
Bacteroides fragilis High activity
Stenotrophomonas maltophilia No activity
Enterobacteria (e.g. E.cloacae and P.vulgaris) Stable against two types b lactamases. This was suggested to be the cause of activity against Enterobacteria
Extended-spectrum b-lactamases Increase in MIC of tomopenem
(EM- and SHV-type ESBL genes in E. coli)
Anaerobics More potent than metronidazole [82].
194 M.I. El-Gamal et al. / European Journal of Medicinal Chemistry 131 (2017) 185e195
4.4. Sanfetrinem
Sanfetrinem (Fig. 2) is the first carbapenem trinem (tricyclic b-
lactam compounds) to be discovered. Sanfetrinem possesses broad-
spectrum bactericidal activity. Sanfetrinem cilexetil (Fig. 2) is an
orally-bioavailable prodrug of sanfetrinem [46].
4.4.1. In vivo/in vitro studies
Sanfetrinem is strongly effective against Staphylococcus aureus,
and has a greater activity against it and against Staphylococcus
pneumoniae than cefdinir, ceftram, cefuroxime, amoxicillin, and
levofloxacin. It also possesses an excellent activity against Bacter-
oides fragilis group bacteria. It may also be of use for the treatment
of pneumococcal infections like otitis media as it reaches adequate
levels to eradicate penicillin-resistant Pneumococci. The compound
is also effective against Proteus vulgaris and Klebsiella oxytoca
strains of bacteria, like imipenem, and is more effective against
penicillin-resistant Pneumococci than imipenem. In addition, it was
found successful in eradication of Klebsiella pneumonia and
Escherichia coli bacterial species. Enterococcus faecium, Enterococcus
faecalis, Streptococci, and Rhodococcus-like species are also among
the scope of its activity. A study showed Sanfetrinem's ability to
penetrate human polymorphonuclear leukocytes (PMNs), the
phagocytes that shield most bacterial pathogens, at all tested
concentrations of the compound [46]. Sanfetrinem is resisted by
zinc b-lactamases, e.g. L1 enzyme of Stenotrophomonas maltophilia
species and is even hydrolyzed by IMP-1 enzyme, another zinc b
-lactamase [87]. Sanfetrinem is absorbed orally and has a short
half-life [88,89].
5. Conclusion
Carbapenem antibiotics are considered as drug of choice in
many multidrug resistant infections. They are able to bind to PBP
and inhibit b-lactamase with the broadest spectrum of activity
among b-lactam antibiotics. The first carbapenems that were iso-
lated from Streptomyces were unstable due to hydrolysis by DHP-I.
For that reason the first available carbapenem, imipenem, must be
given with the DHP-I inhibitor, cilastatin. Imipenem is somewhat
more active than other carbapenems against Gram-positive bac-
teria and particularly very active against Pseudomonas aeruginosa
and Acinetobacter baumannii. Carbapenems under development
that had 1-b-methyl group rendered newer agents stable to DHP-I
such as meropenem that had almost similar activity to imipenem.
Ertapenem has a long half-life which gives it the advantage of once
daily dose regimen. It is useful for treatment of community-
acquired infections since it is very active against ESBL-producing
Gram-negative bacteria but limited activity against non-
fermentative Gram-negative bacteria. Biapenem compared to imi-
penem had similar activity against Gram-positive bacteria and
greater activity against Gram-negative bacteria. It is excellent for
treatment of intra-abdominal infections, complicated urinary tract
infections, and lower respiratory tract infections. Doripenem
showed the most potent in vitro activity against Pseudomonas aer-
uginosa. It has great efficacy in treatment of hospital-acquired
pneumonia. Newer carbapenems include tebipenem that has
higher selective antibacterial and bactericidal activities against b-
lactamase-nonproducing, ampicillin-resistant Haemophilus influ-
enza and Neisseria gonorrhoeae. Tomopenem is active against va-
riety of pathogens. It is very potent against MRSA and Pseudomonas
aeruginosa and it has a half-life longer than other carbapenems
except for ertapenem. Panipenem has a broad-spectrum activity
against Gram-positive and Gram-negative aerobic and anaerobic
bacteria but it is not active against Pseudomonas aeruginosa. It is
effective in treating respiratory tract and urinary tract infections.
Sanfetrinem is the first carbapenem trinem, tricyclic b-lactam
compounds, to be found. It acts as a broad-spectrum bactericidal
antibiotic. Razupenem is a novel carbapenem that is administered
parenterally. Many studies suggested that it can treat polymicrobial
anaerobic infections. Its development has been stopped due to
adverse events in phase II clinical trials. It is highly recommended
that the use of carbapenem antibiotics must be under restricted
control to avoid or decrease the emergence of bacterial resistance.
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