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Expert Opinion on Drug Safety
ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20
Antimicrobial resistance and treatment: an unmetclinical safety need
Matteo Bassetti, Alessandro Russo, Alessia Carnelutti, Alessandro La Rosa &Elda Righi
To cite this article: Matteo Bassetti, Alessandro Russo, Alessia Carnelutti, Alessandro La Rosa& Elda Righi (2018): Antimicrobial resistance and treatment: an unmet clinical safety need, ExpertOpinion on Drug Safety, DOI: 10.1080/14740338.2018.1488962
To link to this article: https://doi.org/10.1080/14740338.2018.1488962
Accepted author version posted online: 13Jun 2018.
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Publisher: Taylor & Francis
Journal: Expert Opinion on Drug Safety
DOI: 10.1080/14740338.2018.1488962
Antimicrobial resistance: an unmet clinical safety need
Matteo Bassetti1,*, Alessandro Russo1, Alessia Carnelutti1, Alessandro La Rosa1, Elda Righi1
Affiliations
1Infectious Diseases Division, Santa Maria Misericordia Hospital, Udine, Italy
*Corresponding author:
Phone +39 0432 559355 ; Fax +39 0432 559360 ; Email: [email protected]
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Abstract
Introduction Infections due to multidrug-resistant (MDR) bacteria are burdened by high
mortality rates. The development of new compounds to face the global threat of resistance is
urgently needed. Combination regimens including “old” high-dose antimicrobials are
currently limited by the risk of toxicity, resistance selection, and reduced efficacy.
Following the Infectious Diseases Society of America call to develop 10 new antibacterials
by 2020, new molecules are currently under development or have become available for use
in clinical practice.
Areas covered We have reviewed safety characteristics and tolerability of old
antimicrobials that are currently employed in combination regimens as well as new
antimicrobials, including beta-lactams/beta-lactamase inhibitors, new cephalosporins,
quinolones, and aminoglycosides.
Expert opinion
The availability of new compounds that show in vitro efficacy against MDR represents a
unique opportunity to face the threat of resistance and to optimize the current use of
antimicrobials, potentially reducing toxicity. Among agents that are potentially active
against MDR Gram-negatives are ceftozolane/tazobactam, new carbapenems and
cephalosporins, the combination of avibactam with ceftazidime, and plazomicin. Further
data from clinical trials and post-marketing studies for drugs targeting MDR pathogens are
crucial to confirm their efficacy and safety.
Keywords: multidrug-resistant Gram-negative infections, drug toxicity, colistin, tigecycline,
fosfomycin, new antibiotics
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Article highlights
• The use of increased doses and prolonged regimens in to overcome resistance to Gram-
negative bacteria has been associated over the years with reports of relevant adverse
effects
• Among old antibiotics, regimens including aminoglycosides and high-dose colistin have
been associated by increased rates of nephrotoxicity
• New antimicrobials that are currently used in clinical practice (e.g.,
ceftolozane/tazobactam, ceftazidime/avibactam) are usually well tolerated
• Novel antimicrobials that are currently under development showed favorable safety
profiles in clinical trials, but real-world studies are needed to confirm their efficacy and
safety
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1. Introduction
The emergence of multidrug-resistant (MDR) Gram-negative bacteria (GNB) has led to a
global public health emergency [1]. Severe infections due to MDR GNB pose a great threat
due to their high mortality and associated prolonged hospitalizations [2]. In 2017, the World
Health Organization (WHO) published a list of pathogens presenting relevant resistance
issues, highlighting as a priority the research and development of new antibiotics targeting
carbapenem-resistant Acinetobacter, Pseudomonas, and Enterobacteriaceae species [3]. In
the past decades, the emergence of MDR strains of Pseudomonas aeruginosa and extended-
spectrum-beta-lactamases (ESBLs)-producing Enterobacteriaceae has greatly limited the
choices for an adequate antimicrobial regimen, affecting patients’ outcome [4]. Furthermore,
until recently the increase in MDR bacteria was not compensated by the development of
new molecules targeting carbapenem resistance [5]. Newer compounds that are now
available in clinical practice, such as ceftolozane/tazobactam and ceftazidime/avibactam,
have demonstrated high in vitro efficacy against selected MDR GNB and good tolerability
in clinical trials and preliminary post-marketing reports (Table 1) [6].
While awaiting the availability of newer compounds, clinicians aiming to target severe
infections had to rediscover the use of “old” drugs that retain in vitro activity against MDR
GNB, such as fosfomycin or polymixins [7]. High doses of broad-spectrum antimicrobials,
such as carbapenems or tigecycline, have been used in combination regimens including two
or three antimicrobials, to attain pharmacokinetics (PK)/pharmacodynamics (PD) targets,
showing therapeutic benefit in observational studies [8-10]. These strategies, however, have
been correlated to an increase in drug-related toxicity and present negative implications for
antimicrobial stewardship.
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Here we discuss the safety and tolerability of “old” and new compounds used for the
treatment of MDR GNB, including molecules that are under development and are
completing Phase 3 clinical trials.
2. Safety profiles of “old” antibiotics for MDR Gram-negative infections
2.1 Polymixins: colistin
Polymyxins are “old” polypeptide antibiotics commonly used in the 1950s for the treatment
of complicated urinary tract infections (cUTIs) [11]. This class exerts its antibacterial
activity through the interaction of a polycationic peptide ring with the lipid A of the
lipopolysaccharides (LPS), causing disorganization and loss of the membrane integrity and
bacterial cell death [11, 12]. Due to frequent reports of neurotoxicity and nephrotoxicity
associated with their use, polymyxin use was limited in the past years [13-15]. Attempts to
generate polymyxin derivatives that are less toxic have been made, but they all lacked a
significant antibacterial effect [16].
Recently, due to the spread of carbapenem-resistant GNB that showed in vitro sensitivity to
polymyxins, this class has been resumed as part of combination treatments, especially for
severe infections due to carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) [6,
17]. Despite their widespread use over the years, polymyxins retain in vitro activity against
carbapenemase-producing strains of Enterobacteriaceae, MDR Pseudomonas aeruginosa
and Acinetobacter spp., including most of the pandrug-resistant (PDR) strains [18]. Two
polymyxins are currently available for use, polymyxin B and colistin (polymyxin E).
Polymyxin B is currently used in North and South America while colistin is frequently used
in Europe. Colistimethate sodium (CMS) represents colistin’s inactive prodrug and is
available for parenteral use or for nebulization [19]. Since CMS is rapidly degraded to its
active form, the PK of colistin remains only partially understood, especially in difficult-to-
treat populations such as critically ill patients [20, 21]. Furthermore, there are different
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dosages and potency definitions associated with colistin according to different marketed
products, leading to a lack of universally adopted dose recommendations [22,23]. Based on
recent studies, however, higher dosages than those previously reported (e.g., a loading dose
of 9 MIU of CMS followed by a maintenance dose of 4.5 MIU every 12 h) have been
proposed in order to timely achieve a PK target [24]. Adjustments based on patient’s renal
function are suggested, although studies in patients on continuous hemodiafiltration have
shown that colistin dose should not be reduced [21]. Overall, a correct dose regimen and the
use of polymyxins only as part of combination regiments for the treatment of carbapenem-
resistant (CR) Enterobacteriaceae are recommended to limit the emergence of antimicrobial
resistance [8, 25].
Early reports associated total cumulative colistin dose and longer treatments with kidney
damage [26-28]. Studies performed after the reintroduction of colistin reported rates of mild
reversible nephrotoxicity in the range of 0–40%, without confirming the high levels of
toxicity reported in the 1970s [29]. Other adverse events (AEs), such as neurotoxicity or
bronchospasm following colistin nebulization for respiratory infections, were also extremely
rare [30].
A meta-analysis including 6 controlled studies and 14 single arm studies Florescu et al.
aimed to assess the efficacy and safety of colistin in the treatment of ventilator-associated
pneumonia (VAP). Data from controlled trials did not confirm a cumulative toxicity of
colistin [30]. Overall nephrotoxicity from 5 studies encompassing 344 patients did not differ
significantly between colistin and comparators (OR, 1.14, 95% CI, 0.59–2.20, P =0.69) [31-
35]. Neurotoxicity, assessed in 3 studies involving 183 patients was similar between groups
(OR, 1.39 [95% CI, .17–11.61; P = .76) [31,32,35].
Recent studies analyzing colistin-associated AEs following the use of higher daily doses
compared to the previous recommended ones have shown higher incidence of
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nephrotoxicity, usually appearing within the first week of treatment [36-38].
Specifically, results from PK and observational studies analyzing colistin safety highlighted
that particular attention to the patient’s actual bodyweight is important to reduce
nephrotoxicity, and showed frequent overdosing associated with obesity [21, 28]. Overall,
data from single studies and meta-analyses have highlighted how neurotoxicity does not
seem to be an issue during colistin treatment regimens, although higher occurrence has been
reported in patients with renal impairment [26, 27, 30]. The use of aerosolized CMS has
been associated with possible AEs, including bronchospasm, chest tightness and apnea, but
they are considered rare [30]. Patients with a history of pre-existing bronchial hyper-
reactivity or chronic obstructive pulmonary disease (COPD) are more subject to
bronchospasm that can be prevented but inhalation of beta2-agonists before the use of
aerosolized colistin [39].
In conclusion, colistin-associated nephrotoxicity represents an independent predictor or
treatment failure and mortality in severe MDR infections. For these reasons, factors that may
enhance colistin nephrotoxicity (i.e., shock, hypoalbuminemia, concomitant use of
nephrotoxic drugs such as aminoglycosides) should be limited whenever possible [37].
Renal function should be closely monitored during colistin treatment and dose adjustments
should be performed in case of renal impairment.
2.2 Fosfomycin
Fosfomycin belongs, similarly to colistin, to the group of “old” antibiotics that were
employed in clinical practice decades ago to treat various infections, especially UTIs. An
oral formulation of fosfomycin is also available for the treatment of cystitis. Fosfomycin
retains, despite the widespread use over the years, good activity against Gram-positive
bacteria (GPB) and multidrug-resistant GNB, especially those involved in UTIs [40].
Fosfomycin mechanism of action regards the inhibition of an early step in the bacterial cell
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wall synthesis involving phosphoenolpyruvate synthetase [41]. Fosfomycin in vitro activity
includes PDR strains of K. pneumoniae, while its activity remains moderate against P.
aeruginosa [40].
Fosfomycin has a hydrophilic character and is eliminated almost entirely by glomerular
filtration. For this reason, intensive care unit (ICU) patients with difficult-to-predict blood
concentrations due to augmented renal clearance may present fosfomycin subtherapeutic
concentrations that can affect clinical outcomes and/or promote selection of resistance [42].
Clinical studies employing fosfomycin as part of combination regimens to treat MDR Gram-
negative infections have not raised safety concerns so far. In a prospective study of 11
patients receiving fosfomycin as a part of combination regimens, no AEs were reported [43].
A multicenter prospective study involving 11 Greek ICUs included 68 fosfomycin-treated
patients with bacteremia and VAP due to MDR pathogens [44]. Successful clinical outcome
was observed in 54.2% of patients and bacterial eradication in 56.3% No major AEs were
noted, while among minor events the most common was the occurrence of reversible
hypokalemia. Various studies have evidenced the efficacy along with excellent tolerability
of oral fosfomycin in less serious infections, including the treatment of recurrent cystitis in
pregnant and non-pregnant women [45-48]. A recent review of the literature aiming at
characterizing the AEs associated with fosfomycin use showed a prevalence of AEs
consistent with its safety profile. In the study, a total of 23 trials (8 comparative and 15 non-
comparative trials) of intra-venous (IV) fosfomycin were selected, including 1242 patients.
For oral fosfomycin, 28 prospective comparative trials in 2743 patients were included. The
most frequent AEs associated with parenteral fosfomycin were rash, peripheral phlebitis,
hypokalemia, and gastrointestinal disorders. Serious AEs such as aplastic anemia,
anaphylaxis, and liver toxicities were reported infrequently. Gastrointestinal disorders were
the most common AEs associated with oral fosfomycin [49]. Overall, the oral formulation of
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fosfomycin is considered to have a favorable safety profile with gastrointestinal disturbances
being the most commonly associated AE. These comprise mainly transient and mild
symptoms, including diarrhea (10%), nausea (5%), abdominal pain (2%), and dyspepsia (1–
2%) [50]. Other AEs reported were headache, dizziness, back pain, and weakness. The IV
formulation of fosfomycin, fosfomycin disodium, is associated with a high sodium intake
(e.g., 1 g of intravenous fosfomycin corresponds to 0.33 g or 14.4 mEq of sodium) that has
to be taken into consideration when treating patients with heart failure or on hemodialysis
[41]. Other rare AEs associated with IV fosfomycin include nausea, neutropenia,
hypereosinophilia, and local phlebitis [51, 52] Recently, Florent et al. reported as mild and
transient AEs associated with IV fosfomycin among 72 patients the occurrence of
hypokalemia (26%), injection-site reaction (4%) and hypertension (3%) [53].
2.3 Tigecycline
Tigecycline belongs to the semisynthetic tetracycline derivative class of the glycylcyclines,
and acts inhibiting the bacterial protein synthesis [54]. Tigecycline use has been commonly
associated with presentation of mild AEs, mainly including nausea (ranging from 30 to
55%) and vomiting (ranging from 18 to 28%) [55]. Apart from gastrointestinal disturbances,
tigecycline is well tolerated and does not require dose adjustments for renal impairment or
mild-to-moderate hepatic failure (Child–Pugh scores B and C) [56, 57]. Compared to older
tetracyclines, tigecycline presents a wider spectrum of activity including Staphylococcus
aureus, vancomycin-resistant Enterococcus, tetracycline-resistant Escherichia coli and
certain ESBL-producing strains [58]. Tigecycline has also in vitro activity against
Clostridium difficile [59]. No activity has been reported, instead, against P. aeruginosa,
Proteus spp. and Providencia spp. Tygecycline has bacteriostatic activity and its use as
monotherapy in severe infections has been discussed. Specifically, an increased risk of
mortality associated with tigecycline use in the treatment of serious infections was reported
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by the Food and Drug Administration (FDA) in 2010 [60]. Data supporting this hypothesis
included the analysis of a pooled group of randomized clinical trials including various
infections. Despite the warning, tigecycline’s microbiological profile has supported its use
as part of combination treatments in severely ill patients with MDR GNB, especially KPC-
Kp mediated infections [61].
Clinically significant organ toxicity has not been reported in clinical trials employing
tigecycline. In Phase 1 studies, no relevant AEs were observed [55,62], although transient
elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and
alkaline phosphatase (ALP) levels occurred in some test subjects. In a Phase 2 clinical trial
encompassing 160 hospitalized patients, one case of paresthesia and one case of mild skin
reaction were associated with tigecycline use [63]. In a larger Phase 3 study, 1383 patients
received tigecycline for skin and skin-structure infections (SSTIs). No hematologic or
laboratory abnormalities were associated with use of tigecycline [64], although activated
partial thromboplastin or prothrombin time was prolonged in 3% of patients. In a study
analyzing the efficacy of tigecycline among patients with cIAI, only few changes in
hematologic or serum chemistry test results, vital signs, or electrocardiogram data were
associated with tigecycline treatment [65].
Nausea and vomiting, especially in younger subjects and women, remain the most common
AEs associated with tigecycline use and appears improved by the use of antiemetics at the
time of administration [55, 62]. Nausea usually occurs in the first two days of treatment and
is often mild and transient. In a clinical trial, overall discontinuation rate during tigecycline
treatment was 5% and was most frequently associated with nausea (1.3%) and vomiting
(1.0%). Diarrhea was reported in a significant number of patients (13%) in Phase 3 clinical
trials, but no patient treated with tigecycline tested positive for C. difficile toxin [66].
Various studies support the use of high-dose tigecycline (200 mg initially, and then 100 mg
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twice daily compared to 100 mg loading dose followed by 50 mg every 12 hours) to achieve
higher cure rates [67-70]. No major issues of toxicity have been reported at high doses so
far, although the tolerability of high-dose tigecycline has only been assessed in small trials
3. Safety profiles of new compounds for the treatment of MDR Gram-negative
infections
3.1 Ceftazidime/avibactam
Ceftazidime is a third-generation cephalosporin binding a variety of penicillin binding
proteins (PBPs) including the PBP3 of GNB such as Pseudomonas aeruginosa. Conversely,
avibactam is a semi-synthetic, non-beta-lactam, beta-lactamase inhibitor (BLI) and differs
from other BLI, such as clavulanic acid, sulbactam and tazobactam, in three aspects,
including structure, mechanism of inhibition, and spectrum of inhibition [71]. Avibactam in
vitro inhibits the activity of Ambler class A (ESBL and KPC), class C (AmpC) and some
class D (OXA-48) enzymes, but it is not active against metallo-beta-lactamases (NDM,
VIM, IMP), or against Acinetobacter OXA-type carbapenemases [72].
The emergence of resistance during treatment with ceftazidime/avibactam has been reported.
In a preliminary, real-world study including 37 patients, three patients developed resistance
early during treatment for KPC-producing K. pneumoniae [73]. For this reason, the use of
ceftazidime/avibactam in combination with other antimicrobials has been advocated and
often reported in subsequent studies [73-76]. The efficacy of ceftazidime/avibactam
monotherapy compared to combination therapies, however, has not been assessed yet and
larger studies are needed to give clear direction to clinicians on this point.
Data about the safety of ceftazidime/avibactam include experience from Phase 1 and Phase 2
trials, and recent Phase 3 trials. In the Phase 2 studies, AEs were similar between both
ceftazidime/avibactam and comparators (Table 3). Overall, ceftazidime/avibactam was well
tolerated and no differences were reported in the study conducted in patients with cUTI in
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terms of AEs between ceftazidime/avibactam and imipenem/cilastatin [77]. Most common
laboratory findings were increases in ALP, ALT and AST. Most of these AEs were mild to
moderate and some of these could be attributable to other patients’ comorbidities or
concomitant metronidazole therapy [78].
The clinical indications for ceftazidime/avibactam, based on Phase 3 non-inferiority trials,
are in the setting of cUTI, cIAI, and hospital acquired pneumonia (HAP), including VAP.
In Phase 3 clinical trials, adverse events were similar between ceftazidime/avibactam and
comparators (Table 3). The RECLAIM study, comparing ceftazidime/avibactam with
meropenem in cIAI showed a similar number of adverse events between groups. Most
common AEs for ceftazidime/avibactam included diarrehea (7.6%), nausea (6.8%), vomiting
(4.5%(, and pyrexia (4.5%) [79]. In the RECAPTURE clinical trial showing non-inferiority
of ceftazidime/avibactam compared to doripenem in the treatment of cUTI, ceftazidime-
avibactam had a safety profile consistent with that of ceftazidime alone. Headache and GI
disorders were the most commonly reported AEs [80] In the REPROVE study, adverse
events occurred in 75% of patients in patients with HAP/VAP in the ceftazidime-avibactam
compared to 74% in the meropenem group and were mostly mild or moderate in intensity
and mainly unrelated to study treatment [81].
In a recent study in UTIs, ceftazidime-avibactam showed 100% of susceptibility in KPC and
OXA-48 producers, and rates of susceptibility in carbapenemase-producing
Enterobacteriaceae non-susceptible to ceftazidime or meropenem were 92.1% and 96.9%,
respectively [82]. Overall, the efficacy of ceftazidime/avibactam in severe infections due to
carbapenem-resistant Enterobacteriaceae (CRE) in real world studies appeared promising
and superior compared to colistin and other combination treatments, especially for KPC-
producing strains [73-76]. Ceftazidime-avibactam currently represents a reasonable choice
in the treatment of K. pneumoniae carbapenemase-producing infections, including patients
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with documented bacteremia. No concerns regarding clinical safety have emerged from real-
world studies, although the number of patients treated with ceftazidime/avibactam is still
limited and more data is awaited to confirm its tolerability in clinical practice.
3.2 Ceftolozane/tazobactam
Ceftolozane/tazobactam is a beta-lactam/beta-lactamase inhibitor combination that exhibits
bactericidal activity through inhibition of bacterial cell wall biosynthesis, mediated through
PBPs. Ceftolozane is highly active against P. aeruginosa, showing lower MICs than
ceftazidime and retaining activity for MDR strains, including major route of resistance such
as de-repressed AmpC or upregulated efflux pumps [83]. The addition of tazobactam
provides enhanced activity against ESBL-producing Enterobacteriaceae and anaerobic
organisms [84].
Based on data from clinical trials, AEs due to ceftolozane/tazobactam do not differ
considerably from other cephalosporins, being the most common nausea, diarrhea,
headache, and pyrexia. In a Phase 2 cUTI study, AEs in the ceftolozane vs. comparator arms
were similar and included mainly constipation, sleep disorder, and diarrhea [85]. Of
importance, in patients with moderate renal failure (creatinine clearance, 30–50 mL/minute),
a numerically lower cure rate was noted in the Phase 3 intra-abdominal infection trial: 11 of
23 (48%) in the ceftolozane/tazobactam plus metronidazole arm vs. 9 of 13 (69.2%) in the
meropenem arm. The decreased cure rate among patients aged ≥65 years (69% vs. 82%) was
also thought to be secondary to changes in renal clearance. On this basis, FDA included a
warning in the package insert of ceftolozane/tazobactam to monitor renal function at least
daily in patients with changing renal function and to change ceftolozane/tazobactam dosing
as needed. Reported AEs included hypokalemia (2.9%), headache (2.5%), and increased
ALT (2.5%) and AST (1.6%) levels [86].
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Ceftolozane/tazobactam is a beta-lactam/beta-lactamase inhibitor combination that is
currently approved for the treatment of cIAI and cUTI. However, considering the specific
action against MDR Pseudomonas aeruginosa was explored its possible role in severe
infections caused by MDR and extensively drug-resistant (XDR) P. aeruginosa [87, 88], and
the cure of pulmonary exacerbation in patients with cystic fibrosis, also for its good profile
of tolerability [89].
Finally, a recent study reported the role of ceftolozane/tazobactam in the treatment of
osteomyelitis and skin and soft tissue infections (SSTIs) due to P. aeruginosa strains [90].
3.3. Imipenem/relebactam
Relebactam, formerly known as MK-7655 is a IV, class A – and class C - beta-lactamase
inhibitor and is currently under evaluation in combination with imipenem/cilastatin for the
treatment of resistant GNB infections [91]. In vitro studies have demonstrated relebactam to
restore imipenem’s activity against KPC-producing carbapenem-resistant
Enterobacteriacae, including K. pneumoniae, and to lower imipenem minimal inhibitory
concentrations (MICs) in P.aeruginosa, particularly in strains with depressed OprD
expression and increased AmpC expression [92]. Conversely, the addiction of relebactam to
imipenem seems not to provide any adjunctive benefit against A.baumanii and S.maltophilia
[93].
Safety and efficacy of imipenem/relebactam have been evaluated in two Phase 2 trials in the
setting of cIAI and cUTI (NCT01506271 and NCT01505634) (Table 3).
In a double-blind, Phase 2 study, 351 patients with cIAIs were randomized to receive either
relabactam 250 mg, relabactam 125 mg, or placebo, each given intravenously in
combination with imipenem 500 mg every 6 hours for 4 to 14 days. Diarrhea, nausea and
vomiting were the most commonly reported AEs and occurred in 6.0%, 6.8% and 6.0% in
relabactam 250 mg + imipenem treatment arm, 6.0%, 7.8% and 7.8% in relabactam 125 mg
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+ imipenem treatment arm and in 4.4%, 7.0% and 2.6% in placebo + imipenem treatment
arm, respectively [94].
In a similar Phase 2 study, imipenem/ relabactam was evaluated for the treatment of adult
patients with cUTI or acute pyelonephritis. The most common adverse events were
represented by headache, diarrhea and nausea, and occurred with no significant differences
in incidence rates across the three groups. Particularly, haeadache, diarrhea and nausea
occurred in 7.1%, 5.1% and 4.0% in relabactam 250 mg + imipenem treatment arm, 3.0%,
2.0% and 6.1% in relabactam 125 mg + imipenem treatment arm and in 4.0%, 4.0% and
4.0% in placebo + imipenem treatment arm, respectively [95].
A Phase 3 study evaluating the efficacy and safety of imipenem/relabactam (200/100 mg to
500/250 mg depending on renal function) compared to CMS for the treatment of IMI-
resistant bacterial infections, including HAP, VAP, cIAI and cUTI, has recently been
completed (NCT02452047).
A non-inferiority, Phase 3 trial evaluating the efficacy and safety of imipenem/relabactam
compared to piperacillin/tazobactam for the treatment of HAP and VAP (NCT02493764)
and a Phase 3 trials evaluating the efficacy and safety of imipenem/relabactam in Japanese
patients with cIAI or cUTI (NCT03293485) are currently ongoing.
3.4 Meropenem/vaborbactam
Vaborbactam, formerly known as RPX7009, is a novel class A - and class C - beta-
lactamase inhibitor and is currently in Phase 3 clinical development in combination with
meropenem for the treatment of infections due to MDR GNB [96]. Vaborbactam is a cyclic
boronic acid pharmacophore and is a potent inhibitor of serine beta-lactamases due to the
high affinity between the serine-based active sites of beta-lactamases and boronates, leading
to the formation of a covalent complex and inhibition of beta-lactamases enzymes [97].
Particularly, vaborbactam was found to be effective in lowering the meropenem MIC50 from
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32 to 0.06 μg/ml and the MIC90 from 32 to 1 μg/ml in a study encompassing 991 isolates of
KPC-producing Enterobacteriaceae collected in 2014 and 2015 [97, 98].
A Phase 1 study investigated safety, tolerability and PK of vaborbactam following single
and multiple ascending doses in healthy adult subjects (NCT01751269). Overall,
vaborbactam was well tolerated and no serious safety concerns were identified. Most
commonly reported AEs were headache and catheter site complications (i.e., infusion site
phlebitis, catheter site pain, catheter site hematoma and catheter site phlebitis), with similar
incidence in subjects who received treatment and in patients who received placebo.
Moreover, no correlation between administered vaborbactam dose and AEs incidence was
found. Mild lethargy was described only among patients receiving high vaborbactam doses
(1000 mg or 2000 mg) [99].
Meropenem/vaborbactam has recently been approved by FDA on August 2017 for the
treatment of cUTI, based on the results of the TANGO1 trial, showing the superiority of
MER/VAB (2g/2g every 8 hours) compared with piperacillin/tazobactam (4g/0.5g every 8
hours) for the treatment of cUTI and acute pyelonephritis in adult patients (NCT02166476).
MER/VAB was well tolerated and headache, diarrhea and infusion site phlebitis were the
most frequently reported adverse events, occurring in 8.8%, 3.3% and 2.2% of cases,
respectively. Discontinuations from study drug due to an AE occurred in 7 (2.6%) patients
in the MER/VAB arm and 14 (5.1%) receiving piperacillin/tazobactam.
A Phase 3 study evaluating efficacy, safety and tolerability of meropenem/vaborbactam
compared to best available therapy for the treatment of infections due to carbapenem-
resistant Enterobacteriacae has recently been completed and results are pending
(NCT02168946).
3.5 Plazomycin
Plazomicin is a new generation aminoglycoside that is not affected by most clinically
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relevant aminoglycoside-modifying enzymes and is currently under investigation for the
treatment of MDR Gram-negative infections. Plazomycin demonstrated in vitro activity
against MDR Enterobacteriaceae, including aminoglycoside-resistant isolates, ESBL-
producing bacteria and CRE [100].
In a randomized double-blind Phase 2 study IV plazomicin (administered as 10 or 15 mg/kg)
efficacy and safety were compared to IV levofloxacin (750 mg once daily) in the treatment
of cUTI including acute pyelonephritis [101]. Treatment duration was 5 days and 145
patients were included in the study. Microbiological eradication and clinical cure were
comparable between the groups.
In the plazomicin 10 mg/kg, 15 mg/kg, and levofloxacin groups, respectively, AEs were
reported in 31.8%, 35.1%, and 47.7% of patients. Serum creatinine values were stable over
the course of the study. No sensorineural, conductive, or mixed hearing loss at audiometry
was documented among plazomicin-treated patients.
In the CARE study [102] 17 patients were treated with plazomicin (15 mg/kg once daily)
and compared with 20 patients treated with colistin in combination with adjunctive therapy
of meropenem or tigecycline� in the treatment of BSI or HAP/VAP due to CRE. Primary
endpoints included all cause mortality at 28 days or significant disease-related
complications, such as worsening acute respiratory distress syndrome (ARDS), new lung
abscess or empyema, new-onset septic shock, persistence or new-onset bacteremia. All
cause mortality or related complications appeared lower in the plazomicin arm (23.5% vs.
50%, difference 26.5%, range -0.7 to 51.2). Drug-related AEs were 42.9 vs. 27.8 in the
colistin vs. plazomycin group, respectively. Higher serious adverse events (SAE) were also
more common in the colistin compared to plazomycin arm (19 vs. 5.6 respectively). Serum
creatinine increase ≥0.5 mg/dL while on IV therapy was 37.5% and 8.3% in patients treated
with colistin vs. plazomycin, respectively. Overall, more favorable safety profile was
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reported for plazomicin-treated patients compared with colistin when used as part of a
combination regimen for the treatment of life-threatening infections due to CRE.
A recent FDA briefing document on plazomicin has supported its role in cUTI based on
efficacy and safety data, but did not recognize substantial evidence for recommending
plazomicin use in BSI for patients with limited or no treatment options [103].
3.6 Cefiderocol
Cefiderocol is an investigational siderophore new cephalosporin antibiotic with activity
against CR organisms, including metallo-beta-lactamases producing strains. Cefiderocol
demonstrated a favorable side effect profile in clinical trials [104].
Cefiderocol has promising activity against GNB, including MDR Pseudomonas aeruginosa,
Acinetobacter baumannii, and Klebsiella pneumoniae [105]. The PK, safety, and tolerability
of cefiderocol after single and multiple dosing by IV infusion over 60 min in healthy adult
subjects were assessed in a Phase 1 trial [106]. Single-ascending doses of 100, 250, 500,
1000, and 2000 mg were administered in 40 healthy Japanese males and females (6 active
and 2 placebo per cohort). A multiple-ascending-dose study at doses of 1000 (two groups),
and 2000 mg every 8 h (q8h) was conducted in 30 healthy Japanese and Caucasian males (8
active and 2 placebo per cohort). There were no serious or clinically significant AEs
observed in either study. A single subject receiving 1000 mg cefiderocol withdrew from the
study due to AEs. In the single-dose study, 9 AEs in the cefiderocol groups were considered
potentially related to study treatment, including diarrhea, rash, abdominal pain, blood
present in urine, leukocytosis, and leukocyturia. In the multiple-dose study, 16 AEs reported
by 7 subjects in the cefiderocol 1000 mg group were considered possibly or probably related
to the study treatment, most common being rash (n=5 events), increased blood thyroid-
stimulating hormone (TSH) (n=3), and pyrexia (n=2). In the cefiderocol 1000 mg 2 and
2000 mg groups, 22 AEs were reported by 12 subjects. All of the AEs were mild in
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intensity, except for one, pyrexia, considered moderate. No deaths, SAEs, abnormal
electrocardiogram (ECG) findings were reported. Overall, there was no dose-related
association in the incidence of AEs. In a Phase 1 study encompassing 38 subjects,
cefiderocol were studied in patients with renal impairment (including various degree of renal
impairment and end�stage renal disease, ESRD, requiring hemodialysis) compared with
healthy controls following a single 1000 mg IV infusion [107]. Approximately 60% of
cefiderocol was removed by hemodialysis. The incidence of AEs did not correlate with the
degree of renal impairment and single 1000 mg intravenous doses of cefiderocol were
generally well tolerated in subjects with impaired renal function. No deaths or SAEs were
reported during the study. One subject from the moderate renal impairment cohort presented
with urticaria during administration, which led to discontinuation of the study medication
and was considered related to the study drug. Only nausea was reported as an AE by more
than one subject per cohort. AEs in various groups included 4 subjects (50%) in the
moderate impairment cohort, 3 (37.5%) in the ESRD cohort (predialysis, period 1), 2 (25%)
in the mild and severe impairment cohorts, and 1 (12.5%) each in the healthy and ESRD
cohorts.
3.7 Eravacycline
Eravacycline is a novel fluorocycline similar to tigecycline but not affected by resistance
mechanisms that cause tetracycline resistance, such as efflux pumps and ribosomal
protection proteins [108]. Eravacycline is characterized by a broad-spectrum activity against
both Gram-positive and Gram-negative bacteria, including MRSA, vancomycin-resistant
Enterococci, multidrug resistant Enterobacteriacae (e.g., ESBL, KPC and OXA) and
A.baumanii [109]. Eravacycline is in Phase 3 of clinical development for cIAI and cUTI and
showed efficacy of both intravenous and oral formulations, representing an attractive option
for step-down therapy in patients with infections due to MDR Gram-negative bacteria [110].
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A randomized, double-blind, multicenter study demonstrated eravacycline non-inferiority
compared to ertapenem in cIAI [111]. A Phase 1 study in 20 healthy adult volunteers
showed that eravacycline was well tolerated, with no serious adverse events and no
treatment discontinuations [112]. In the cIAI trial, eravacycline demonstrated an overall
favorable profile. Compared to ertapenem, patients in the eravacycline arm had higher
number of episodes of nausea and phlebitis (8.1% vs. 0.7% and 3% vs. 0.4%, respectively).
The number of patients who experienced treatment-emergent adverse events such as
vomiting, anemia, pyrexia, and diarrhea as well as the number of SAE was similar in the two
groups (n = 13) [111].
3.8 Omadacycline
Omadacycline is the first aminomethylcycline, a class of semisynthetic antibiotics related to
the tetracycline [113]. Similar to eravacycline, the chemical structure of omadacycline
allows to overcome the mechanisms of tetracycline resistance. Omadacycline is effective
against Gram-positive aerobes, including methicillin-resistant strains and Gram-negative
aerobes [114]. A Phase 3 trial comparing the efficacy and safety of intravenous and oral
omadacycline to moxifloxacin in patients with community-acquired pneumonia confirmed
omadacycline non-inferiority [115]. Omadacyline was generally safe and well tolerated with
overall safety profiles similar to that of moxifloxacin, but with low incidence of diarrhea and
no reported cases of C. difficile.
4. Conclusions
We have reviewed the most common AEs associated with “old” and newer molecules used
in the treatment of MDR GNB infection reported by clinical trials and real-world data.
Combination regimens based on “old” antibiotics appear limited by increased toxicity,
potential selection of further resistance, and suboptimal PK/PD. New compounds present
favorable safety data and promising efficacy in the treatment of MDR GNB infections,
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although definitive data is awaited.
5. Expert opinion
The increase in drug resistance among GNB represents a challenge for clinicians due to the
high mortality associated with these infections and the high risk of treatment failure. Recent
studies support the use of combination regimens, often including high-dose carbapenems or
nephrotoxic drugs such as colistin and/or gentamycin. The potential toxicity associated with
double or triple antimicrobial regimens along with limited safety data from real-world
studies on new compounds constitute an unmet clinical safety need.
Although colistin nephrotoxicity appeared less relevant than initially described, recent
reports of higher doses regimens used for PK/PD optimization (9 MIU followed by 4.5 MIU
every 12 hours compared to 3 MIU every 12 hours) have been associated with reduced CrCl.
Patients receiving high-dose colistin, especially if associated with other nephrotoxic drugs,
such as diuretics or aminoglycosides, require strict follow up, drug adjustments, and
aminoglycosides therapeutic drug monitoring (TDM). Furthermore, careful clinician’s
judgment is required to avoid treatment failure due to nephrotoxicity but also occurrence of
resistance or limited clinical response associated with colistin reduced or inappropriate
dosing. Fosfomycin appears well tolerated without relevant associated AEs. Tigecycline has
been classically associated with occurrence of nausea and vomiting that often require co-
administration of antiemetic drugs, but other relevant AEs are uncommon and no dose
adjustments are required in case of renal or hepatic impairment (Table 2). The use of
increased tigecycline doses (e.g., 100 mg every 12 hours instead of 50 mg every 12 hours) in
combination regimens against KPC-Kp infections has not been associated with a higher
occurrence of AEs. New compounds are now available for use in the treatment of infections
caused by MDR resistant P. aeruginosa (e.g., ceftolozane/tazobactam) and KPC-Kp (e.g.,
ceftazidime/avibactam), although not all resistant strains, in particular metallo-beta-
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lactamase-producing bacteria are not covered by these compounds. Safety and tolerability
data of new drugs from clinical trials appeared favorable or similar to comparators. Most
common adverse events reported among patients receiving ceftazidime/avibactam were
headache, gastrointestinal symptoms (e.g., abdominal pain, vomiting, nausea and
constipation), and infusion-site reactions. Recent reports analyzing ceftazidime/avibactam
efficacy among patients with KPC-Kp infections have reported the occurrence of early onset
of resistance to ceftazidime/avibactam during antimicrobial treatment. For this reason,
ceftazidime/avibactam has been often used in association with other “old” drugs with in
vitro activity against MDR GNB (e.g., carbapenems, aminoglyscosides, tigecycline), thus
posing a new concern of potential toxicity associated with combination therapies.
Ceftolozane/tazobactam AEs did not significantly differ from other cephalosporins,
including mainly nausea, diarrhea, headache, and pyrexia. A careful monitoring of creatinine
serum levels is recommended in patients receiving ceftolozane/tazobactam with renal
function changes during treatment. Other beta-lactams or beta-lactams/beta-lactamase
inhibitors (e.g., cefiderocol, imipenem/relebactam, meropenem/vaborbactam) did not
present significant tolerability concerns in clinical trials.
Plazomycin, a new aminoglycoside, appeared less nephrotoxic than colistin in recent trials.
Safety and tolerability of new compounds, however, need to be confirmed in future trials
and large real-world studies.
Funding
This paper has not been funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment, consultancies, honoraria, stock
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ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosure
Peer reviewers on this manuscript have no relevant financial or other relationships to
disclose.
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Table 1. Recently developed molecules with activity against multidrug-resistant Gram-
negative bacteria approved for clinical use or in late stage of development [5,16].
Molecule Class Spectrum Clinical indication
Ceftolozane/ Tazobactam*
BLBLI
Enterobacteriaceae ESBL-producers, MDR P.
aeruginosa (no MBLs)
cIAI (in association with metronidazole),
cUTI
Ceftazidime/ Avibactam*
BLBLI
Carbapenem-resistant Enterobacteriaceae and
P. aeruginosa (no MBLs)
cIAI, cUTI, HAP, VAP
Cefiderocol Cephalosporin
Carbapenem-resistant (including MBLs),
Enterobacteriaceae, P. aeruginosa, MDR A.
baumannii
cIAI, cUTI, HAP, VAP
Imipenem/ relebactam
BLBLI Carbapenem-resistant Enterobacteriaceae (no
MBLs)
cIAI, cUTI, HAP, VAP
Meropenem/ Vaborbactam
* BLBLI
Carbapenem-resistant Enterobacteriaceae (no
MBLs) cUTI
Plazomycin Aminoglycosid
es
Carbapenem-resistant Enterobacteriaceae (no
MBLs)
cUTI, VAP and HAP (as
combination therapy)
BLBLI= beta-lactam/beta-lactamse inhibitor, MDR= multidrug resistant, ESBL= extended-spectrum beta-lactamases, MBLs= metallo-beta-lactamases, c=complicated, IAI= intra-abdominal infections, UTI= urinary tract infections, HAP= hospital acquired pneumonia, VAP= ventilator-associated pneumonia
* FDA approved
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Table 2. Adverse effects associated with old antimicrobials used for multidrug-resistant
Gram-negative infections and suggested management
Drug Reported adverse effects (incidence)
Characteristics Management References
Colistin • Neprotoxicity (mild, reversible 0-40%)
• Neurotoxicity (rare) • Bronchospasm
(inhaled, rare)
• Associated with high doses (4.5 MU q12h)
• Increased by concomitant causes of nephrotoxicity
• Dose adjustments • Renal function
monitoring • Avoid other causes of
nephrotoxicity (aminoglycosides, shock, hypoalbuminemia)
[26,27, 30,39]
Fosfomycin • IV formulation: reversible hyperkalemia (26%); increased Na intake
• Oral formulation: diarrhea (10%), nausea (5%), abdominal pain (2%), and dyspepsia (1–2%)
• Usually reversible and mild
• Na and K monitoring • Caution in patients
with cardiac failure and hemodialysis
[50,53]
Tigecycline • Nausea (30 to 55%) and vomiting (18 to 28%)
• Mild • Clinical monitoring • Concomitant
antiemetic medications
• Slow IV administration (>1 hour)
[55, 64-67]
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Table 3. Common adverse events and serious adverse events reported during relevant
clinical trials of new compounds used in the treatment of multidrug-resistant Gram-
negative infections
Drug Study type Common adverse
effects SAE (%) Reference
Plazomycin
Phase 3 randomized trial for BSI, HAP/VAP due to CRE vs. colistin (CARE)
Total AE (88.9 vs. 100) Renal-related (27.8 vs. 42.9)
Total 5.6 vs. 19 Renal 11.1 vs. 28.6
[101]
Cefiderocol
Phase 1 ascending single doses in healthy subjects Phase 1 ascending multiple doses in healthy subjects
Any (20), diarrhea (7), abdominal pain (3), rash (7) Any (75), diarrhea (12.5), abdominal pain (6), pyrexia (12.5), headache (6), rash (12.5)
None [106,107]
Ceftolozane/
tazobactam
Phase 3 CT/TAZ 1000/500 mg iv q8h vs. levofloxacin in cUTI (ASPECT-cUTI) Phase 3 CT/TAZ 1000/500 mg plus metronidazole vs. MER in cIAI (ASPECT-cIAI)
75 CAZ/AVI vs. 74 levofloxacin 44 CT/TAZ vs. 42.7 MER
19 CT/TAZ vs. 13 levofloxacin 8.1 CT/TAZ vs. 7.2 MER
[85,86]
Ceftazidime/
Avibactam
(CAZ/AVI)
Phase 2 CAZ/AVI 500/125 mg q8h vs. IMI/cilastatin in cUTI/pyelonephritis Phase 2 CAZ/AVI 2000/500 mg q8h + metronidazole vs. MER in cIAI Phase 3 CAZ/AVI 2000/500 mg iv q8h vs. MER (REPROVE) in HAP/VAP Phase 3 CAZ/AVI 2000/500 mg iv q8h
67.6 CAZ/AVI vs. 76.1 IMI 64.4 CAZ/AVI vs. 57.8 MER 75 CAZ/AVI vs. 74 MER 45.9 CAZ/AVI vs. 42.9 MER
8.8 CAZ/AVI vs. 3 IMI 8.9 CAZ/AVI vs. 10.8 MER 19.0 CAZ/AVI vs. 13.0 MER 7.9 CAZ/AVI vs. 7.6 MER
[77-81]
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vs. MER (RECLAIM) in cIAI Phase 3 CAZ/AVI 2000/500 mg iv q8h vs. MER (RECAPTURE) in cUTI
36.2 CAZ/AVI vs. 31.0 DOR
4.1 CAZ/AVI vs. 2.4 MER
Imipenem/
Relebactam
(IMI/REL)
Phase 2 REL 250 mg vs. 125 mg vs. placebo in cUTI Phase 2 (REL 250 mg vs. 125 mg vs. placebo in cIAI
28.3 REL 250 mg vs. 29.3 REL 125 mg vs. 30.0 placebo 48.7 REL 250 mg vs. 47.4 REL 125 mg vs. 41.2 placebo
N/A 3.4 REL 250 mg vs. 9.5 REL125 mg vs. 7.0 placebo
[94,95]
Meropenem/vaborb
actam (MER/VA
B)
Phase 3 MER/VAB (2g/2g) iv every 8h ± levofloxacin 500 mg every 24h vs. piperacillin/tazobactam (± levofloxacin 500 mg every 24h (TANGO1) in cUTI
39 MER/VAB vs. 35.5% levofloxacin
4.0 MER/VAB vs. 4.4 levofloxacin
[116]
AE= adverse events; SEA=serious adverse effects CAZ/AVI= ceftazidime/avibactam; CT/TAZ= ceftolozane/tazobactam; cUTI= complicated urinary tract infections; cIAI= complicated intra-abdominal infection; VAP= ventilator-associated pneumonia; cUTI= complicated urinary tract infections; IMI/REL= imipenem/relebactam MER/VAB= meropenem/vaborbactam
Acknowledgements: none
Conflict of interest: In the past five years MB has participated in advisory boards and/or received speaker honoraria from Achaogen, Angelini, Astellas, AstraZeneca, Bayer, Basilea, Cidara, Gilead, Melinta, Menarini, MSD, Nabriva, Paratek, Pfizer, Roche, The Medicine Company, Shionogi, Tetraphase, VenatoRX, and Vifor. The remaining authors have no conflicts of interest.
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References
*=of importance, **= of considerable importance
1. Ventola CL, MS. The Antibiotic Resistance Crisis Part 1: Causes and Threats. P T.
2015,40(4):277–283
2. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M,
Spellberg B, Bartlett J. Bad bugs, no drugs: no ESKAPE! Clin Infect Dis 2009,48:1-
12.
3. World Health Organization. Global Priority List of Antibiotic-resistant Bacteria to
Guide Research, iscovery, and Development of New Antibiotics, 2017. Available at:
http://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-
ET_NM_WHO.pdf. Accessed February 4th, 2018
4. Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against resistant
gram-negative organisms: extended-spectrum beta-lactamase-producing
Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-
resistant Pseudomonas aeruginosa. Mayo Clin Proc 2011,86:250-259.
5. Hersh AL, Newland JG, Beekmann SE, Polgreen PM, Gilbert DN. Unmet medical
need in infectious diseases. Clin Infect Dis 2012,54:1677-1678.
6. Bassetti M, Righi E. New antibiotics and antimicrobial combination therapy for the
treatment of gram-negative bacterial infections. Curr Opin Crit Care 2015,21(5):402-
411.
7. Poulakou G, Bassetti M, Righi E, Dimopoulos G. Current and future treatment
options for infections caused by multidrug-resistant Gram-negative pathogens.
Future Microbiol. 2014,9(9):1053-1069.
8. Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, et al.
Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae:
Accep
ted M
anus
cript
30
superiority of combination antimicrobial regimens. Antimicrob Agents Chemother
2012,56:2108-13.
9. Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti
M, et al. Infections caused by KPC-producing Klebsiella pneumoniae: differences in
therapy and mortality in a multicentre study. J Antimicrob Chemother 2015,70:2133-
2143.
10. Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou
A, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections:
lowering mortality by antibiotic combination schemes and the role of carbapenems.
Antimicrob. Agents Chemother. 2014,58:2322-2328.
11. Storm DR, Rosenthal KS, Swanson PE. Polymyxin and related peptide antibiotics.
Annu Rev Biochem. 1977,46:723–763.
12. Koyama Y, Kurosasa A, Tsuchiya A, Takakuta K. A new antibiotic "colistin"
produced by spore-forming soil bacteria. J Antibiot (Tokyo) 1950,3:457–458.
13. Brown JM, Dorman DC, Roy LP. Acute renal failure due to overdosage of colistin.
Med J Aust1970,2:923–924.
14. Koch-Weser J, Sidel VW, Federman EB, Kanarek P, Finer DC, Eaton AE. Adverse
effects of sodium colistimethate. Manifestations and specific reaction rates during
317 courses of therapy. Ann Intern Med 1970,72:857–868.
15. Wolinsky E, Hines JD. Neurotoxic and nephrotoxic effects of colistin patients with
renal disease, N Engl J Med 1962, 266 :759-762.
16. Kurihara T, Takeda H, Ito H, Sato H, Shimizu M. Studies on the compounds related
to colistin. IX. On the chemical deacylation of colistin and colistin derivatives.
Yakugaku Zasshi 1974,94:1491–1494.
17. Giamarellou H, Poulakou G. Multidrug- resistant Gram-negative infections: what
Accep
ted M
anus
cript
31
are� the treatment options? Drugs 2009,69:1879–1901.
18. Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, et al. Colistin:
the re-emerging antibiotic for multidrug- resistant Gram-negative bacterial
infections. Lancet Infect Dis 2006,6:589–601. �
19. Bergen PJ, Li J, Rayner CR, Nation RL. Colistin methanesulfonate is an inactive
prodrug of colistin against Pseudomonas aeruginosa. Antimicrob. Agents
Chemother. 2006,50:1953–1958.
20. Karaiskos I, Friberg LE, Pontikis K, Ioannidis K, Tsagkari V, Galani L, et al.
Colistin population pharmacokinetics after application of a loading dose of 9 MU
colistin methanesulfonate in critically ill patients. Antimicrob Agents Chemother
2015,59:7240-7248.
21. Garonzik SM, Li J, Thamlikitkul V, Paterson DL, Shoham S, Jacob J, et al.
Population pharmacokinetics of colistin methanesulfonate and formed colistin in
critically ill patients from a multicenter study provide dosing suggestions for various
categories of patients. Antimicrob Agents Chemother 2011,55:3284-3294.
22. Institute for Safe Medication Practices. Warning! Dosing confusion with
colistimethate for injection. Available at:
www.ashp.org/DocLibrary/Policy/PatientSafety/NANAlert-
Colistimethatesodium.aspx. Accessed February 1st, 2018
23. Nation RL, Li J, Cars O, Gobin P, Balayn D, Marchand S, et al. Consistent global
approach on reporting of colistin doses to promote safe and effective use. Clin Infect
Dis 2014,58: 139–141.
24. Mohamed AF, Karaiskos I, Plachouras D, Karvanen M, Pontikis K, Jansson B,�et
al. Application of a loading dose of colistin methanesulfonate in critically ill patients:
Accep
ted M
anus
cript
32
population pharmacokinetics, protein binding, and prediction of bacterial kill.
Antimicrob. Agents Chemother 2012,56:4241–4249.
25. Vicari G, Bauer SR, Neuner EA, Lam SW. Association between colistin dose and
microbiologic outcomes in patients with multidrug-resistant gram-negative
bacteremia. Clin Infect Dis 2013,56:398–404. �
26. Kwon JA, Lee JE, Huh W, Peck KR, Kim YG, Kim DJ, et al. Predictors of acute
kidney injury associated with intravenous colistin treatment. Int J Antimicrob Agents
2010,35: 473–477.
27. Hartzell JD, Neff R, Ake J, Howard R, Olson S, Paolino K, et al. Nephrotoxicity
associated with intravenous colistin (colistimethate sodium) treatment at a tertiary
care medical center. Clin Infect Dis 2009,48:1724–1728.
28. Gauthier TP, Wolowich WR, Reddy A,�Cano E, Abbo L, Smith LB. Incidence and
predictors of nephrotoxicity associated with intravenous colistin in overweight and
obese patients. Antimicrob Agents Chemother 2012,56:2392–2396.
29. Falagas ME, Kasiakou SK. Toxicity of polymyxins: a systematic review of the
evidence from old and recent studies. Crit Care 2006,10: R27.
30. *Florescu DF, Qiu F, Mccartan MA, Mindru C, Fey PD, Kalil AC. What is the
efficacy and safety of colistin for the treatment of ventilator-associated pneumonia?
A systematic review and meta-regression. Clin Infect Dis 2012,54:670–680. �
* Systematic review on the safety of colistin in VAP
31. Garnacho-Montero J, Ortiz-Leyba C, Jimenez-Jimenez F, Barrero-Almodóvar
AE, García-Garmendia JL, Bernabeu-WittelI M, et al. Treatment of multidrug-
resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with
intravenous colistin: a comparison with imipenem-susceptible VAP. Clin Infect Dis
2003,36:1111-1118
Accep
ted M
anus
cript
33
32. Betrosian AP, Frantzeskaki F, Xanthaki A, Douzinas EE. Efficacy and safety of
high-dose ampicillin/sulbactam vs. colistin as monotherapy for the treatment of
multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia. J
Infect 2008,56:432-436).
33. Rattanaumpawan P, Lorsutthitham J, Ungprasert P, Angkasekwinai
N, Thamlikitkul V. Randomized controlled trial of nebulized colistimethate sodium
as adjunctive therapy of ventilator-associated pneumonia caused by gram-negative
bacteria. J Antimicrob Chemother 2010, 65:2645-2649.
34. Kallel H, Hergafi L, Bahloul M, George Dimopoulos, José Miguel Cisneros. Safety
and efficacy of colistin compared with imipenem in the treatment of ventilator-
associated pneumonia: a matched case-control study. Intensive Care
Med 2007,33:1162-1167.
35. Nakwan N, Wannaro J, Thongmak T, Pornladnum P, Saksawad R, Nakwan N, et
al. Safety in treatment of ventilator-associated pneumonia due to extensive drug-
resistant Acinetobacter baumannii with aerosolized colistin in neonates: a
preliminary report. Pediatr Pulmonol 2011,46:60-66
36. Paul M, Bishara J, Levcovich A, Chowers M, Goldberg E, Singer P, et
al. Effectiveness and safety of colistin: prospective comparative cohort study. J
Antimicrob Chemother 2010,65:1019-27).
37. *Rocco M, Montini L, Alessandri E, Venditti M, Laderchi A, De Pascale G, et al.
Risk factors for acute kidney injury in critically ill patients receiving high
intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics:
a retrospective cohort study. Crit Care 2013:17(4),R174. �
* Retrospective study analyzing risk factors associated with renal toxicity duing
colistin use
Accep
ted M
anus
cript
34
38. Pogue JM, Lee J, Marchaim D, Yee V, Zhao JJ, Chopra T, et al. Incidence of and
risk factors for colistin-associated nephrotoxicity in a large academic health system.
Clin Infect Dis 2011,53:879-84.
39. Michalopoulos A, Papadakis E. Inhaled anti-infective agents: emphasis on colistin.
Infection 2010,38:81–88. �
40. Matthews PC, Barrett LK, Warren S, Stoesser N, Snelling M, Scarborough M, et al.
Oral fosfomycin for treatment of urinary tract infection: a retrospective cohort study.
BMC Infect Dis 2016,16:556.
41. Michalopoulos AS, Livaditis IG, Gougoutas V. The revival of fosfomycin
International J Infect Dis 2011,15:e732-e739.
42. Parker S, Lipman J, Koulenti D, Dimopoulos G, Roberts JA. What is the relevance
of fosfomycin pharmacokinetics in the treatment of serious infections in critically ill
patients? A systematic review. Int J Antimicrob Agents 2013,42:289–293. �
43. Michalopoulos A, Virtzili S, Rafailidis P, Chalevelakis G, Damala M, Falagas ME.
Intravenous fosfomycin for the treatment of nosocomial infections caused by
carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective
evaluation. Clin. Microbiol. Infect. 2010:16:184–186. �
44. Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, Katsiari M et al.
Outcomes of critically ill intensive care unit patients treated with fosfomycin for
infections due to pandrug-resistant and extensively drug-resistant carbapenemase-
producing Gram-negative bacteria. Int J Antimicrob Agents 2014,43:52–59.
45. Falagas ME, Vouloumanou EK, Togias AG, Karadima M, Kapaskelis AM,
Rafailidis PI, et al. Fosfomycin versus other antibiotics for the treatment of cystitis: a
meta-analysis of randomized controlled trials. J Antimicrob Chemother 2010,
65:1862-1877.
Accep
ted M
anus
cript
35
46. Pullukcu H, Tasbakan M, Sipahi OR, Yamazhan T, Aydemir S, Ulusoy S.
Fosfomycin in the treatment of extended spectrum beta-lactamase-producing
Escherichia coli-related lower urinary tract infections. Int J Antimicrob Agents.
2007, 29:62-65.
47. Rodríguez-Baño J, Alcalá JC, Cisneros JM, Grill F, Oliver A, Horcajada JP, et al.
Community infections caused by extended-spectrum beta-lactamase-producing
Escherichia coli. Arch Intern Med 2008,168:1897-1902.
48. Schito GC. Why fosfomycin trometamol as first line therapy for uncomplicated UTI?
Int J Antimicrob Agents, 2003, 22:79-83.
49. *Iarikov D, Wassel R, Farley J, Nambiar S. Adverse Events Associated with
Fosfomycin Use: Review of the Literature and Analyses of the FDA Adverse Event
Reporting System Database. Infect Dis Ther 2015, 4:433-458
* Review analyzing adverse effects associated with fosfomycin use
50. Patel SS, Balfour JA, Bryson HM. Fosfomycin tromethamine. A review of its
antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-
dose oral treatment for acute uncomplicated lower urinary tract infections. Drugs
1997, 53:637-656.
51. Mirakhur A, Gallagher MJ, Ledson MJ, Hart CA, Walshaw MJ. Fosfomycin therapy
for multiresistant Pseudomonas aeruginosa in cystic fibrosis. J Cyst Fibros, 2003:19-
24.
52. Meissner A, Haag R, Rahmanzadeh R. Adjuvant fosfomycin medication in chronic
osteomyelitis Infection 1989,17:146-151.
53. Florent A, Chichmanian RM, Cua E, Pulcini C. Adverse events associated with
intravenous fosfomycin. Int J Antimicrob Agents, 2011,37:82-83.
54. Greer ND. Tigecycline (Tygacil): the first in the glycylcycline class of antibiotics.
Accep
ted M
anus
cript
36
Proc (Bayl Univ Med Cent) 2006,19:155–161.
55. Muralidharan G, Micalizzi M, Speth J, Raible D, Troy S. Pharmacokinetics of
tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents
Chemother 2005,49:220-229.
56. Barbour A, Schmidt S, Ma B, Schiefelbein L, Rand KH, Burkhardt O, et al. Clinical
pharmacokinetics and pharmacodynamics of tigecycline. Clin. Pharmacokinetics
2009,48:575–584.
57. Giamarellou H, Poulakou G. Pharmacokinetic and pharmacodynamic evaluation of
tigecycline. Expert Opin Drug Metab Toxicol 2011,7:1459–1470.
58. Petersen PJ, Jacobus NV, Weiss WJ, Sum PE, Testa RT. In vitro and in vivo
antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative
of minocycline (GAR-936). Antimicrob Agents Chemother 1999,43:738–744.
59. Gales AC, Jones RN. Antimicrobial activity and spectrum of the new glycylcycline,
GAR-936 tested against 1,203 recent clinical bacterial isolates. Diagn Microbiol
Infect Dis 2000,36:19–36.
60. FDA Drug Safety Communication. Increased risk of death with Tygacil (tigecycline)
compared to other antibiotics used to treat similar infections.
www.fda.gov/Drugs/DrugSafety/ucm224370.htm
61. Livermore DM, Warner M, Mushtaq S, Doumith M, Zhang J, Woodford N. What
remains against carbapenem-resistant Enterobacteriaceae? Evaluation of
chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin,
temocillin and tigecycline. Int J Antimicrob Agents 2011,37:415–419.
62. Sun HK, Ong CT, Umer A, Harper D, Troy S, Nightingale CH, et
al. Pharmacokinetic profile of tigecycline in serum and skin blister fluid of healthy
Accep
ted M
anus
cript
37
subjects after multiple intravenous administrations. Antimicrob Agents
Chemother 2005,49:1629-1632.
63. Postier RG, Green SL, Klein SR, Ellis-Grosse EJ, Loh E. Results of a multicenter,
randomized, open-label efficacy and safety study of two doses of tigecycline for
complicated skin and skin-structure infections in hospitalized patients. Clin
Ther 2004,26:704-714.
64. **Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E. The efficacy and
safety of tigecycline in the treatment of skin and skin-structure infections: results of
2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect
Dis 2005,41:341-353.
** Phase 3 randomized study evaluating the safety and efficacy of tigecycline in the
treatment of cSSSI
65. Babinchak T, Ellis-Grosse E, Dartois N, Rose GM, Loh E. The efficacy and safety
of tigecycline for the treatment of complicated intra-abdominal infections: analysis
of pooled clinical trial data. Clin Infect Dis 2005,41:354-66).
66. Stein GE. Safety of newer parenteral antibiotics. Clin Infect Dis 2005,41 Suppl
5:293-302.
67. Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, Mcgovern PC.
Randomized Phase 2 trial to evaluate the clinical efficacy of two high-dosage
tigecycline regimens versus imipenem- cilastatin for treatment of hospital-acquired
pneumonia. Antimicrob Agents Chemothe. 2013,57:1756–1762.
68. Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al.
Comparison of tigecycline with imipenem/ cilastatin for the treatment of hospital-
acquired pneumonia. Diagn Microbiol Infect Dis 2010,68:140–151.
Accep
ted M
anus
cript
38
69. Docobo-Perez F, Nordmann P,�Dominguez-Herrera J, López-Rojas R, Smani
Y, Poirel L, et al. Efficacies of�colistin and tigecycline in mice with�experimental
pneumonia due to NDM-1- producing strains of Klebsiella pneumoniae�and
Escherichia coli. Int J Antimicrob Agents�2012,39:251–254. �
70. Geng TT, Xu X, Huang M. High-dose tigecycline for the treatment of nosocomial
carbapenem-resistant Klebsiella pneumoniae bloodstream infections: A retrospective
cohort study. Medicine (Baltimore) 2018,97(8):e9961.
71. Sader HS, Castanheira M, Flamm RK, Farrell DJ, Jones RN. Antimicrobial activity
of ceftazidime-avibactam against Gram-negative organisms collected from U.S.
medical centers in 2012. Antimicrob Agents Chemother 2014,58:1684–1692
72. Keepers TR, Gomez M, Celeri C, Nichols WW, Krause MK. Bactericidal activity,
absence of serum effect, and time–kill kinetics of ceftazidime-avibactam against b-
lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob
Agents Chemother 2014,58: 5297–305.
73. Shields RK, Potoski BA, Haidar G, Hao B, Doi Y, Chen L, et al. Clinical Outcomes,
Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among
Patients Treated for Carbapenem-Resistant Enterobacteriaceae Infections. Clin Infect
Dis 2016,15;63:1615-1618.
74. Van Duin D, Lok JJ, Earley M, Cober E, Richter SS, Perez F, et al. Antibacterial
Resistance Leadership Group. Colistin Versus Ceftazidime-Avibactam in the
Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae. Clin
Infect Dis 2018,66:163-171.
75. *Shields RK, Nguyen MH, Chen L, Press EG, Potoski BA, Marini RV, et al.
Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against
Carbapenem-Resistant Klebsiella pneumoniae Bacteremia. Antimicrob Agents
Accep
ted M
anus
cript
39
Chemother 2017,61:8.
* Post-marketing study on ceftazidime/avibactam efficacy and safety in infections
due to carbapenem-resistant K. pneumoniae
76. King M, Heil E, Kuriakose S, Bias T, Huang V, El-Beyrouty C, et al. Multicenter
Study of Outcomes with Ceftazidime-Avibactam in Patients with Carbapenem-
Resistant Enterobacteriaceae Infections. Antimicrob Agents Chemother.
2017,27;61(7).
77. **Vazquez JA, Gonza´ lez Patza´n LD, Stricklin D, Duttaroy DD, Kreidly Z, Lipka
J, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in
the treatment of complicated urinary tract infections, including acute pyelonephritis,
in hospitalized adults: results of a prospective, investigator-blinded, randomized
study. Curr Med Res Opin 2012,28:1921–31.
** Phase 2 randomized study evaluating the safety and efficacy of ceftazidime-
avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract
infections
78. Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the
efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem
in the treatment of complicated intra-abdominal infections in hospitalized adults:
results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother
2013,68: 1183–92.
79. Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, et al.
Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus
Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results
From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Infect Dis.
2016 Jun 1; 62(11): 1380–1389
Accep
ted M
anus
cript
40
80. Florian M, Wagenlehner FM, Sobel JD, Newell P, Armstrong J, Huang X, et al.
Ceftazidime-avibactam Versus Doripenem for the Treatment of Complicated Urinary
Tract Infections, Including Acute Pyelonephritis: RECAPTURE, a Phase 3
Randomized Trial Program. Clin Infect Dis. 2016 Sep 15; 63(6): 754–762.
81. **Torres A, Zhong N, Pachl J, Timsit JF, Kollef M, Chen Z, et al. Ceftazidime-
avibactam versus meropenem in nosocomial pneumonia, including ventilator-
associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-
inferiority trial. Lancet Infect Dis. 2017,10:747-8.
** Phase 3 randomized study evaluating the safety and efficacy of ceftazidime-
avibactam versus meropenem in nosocomial pneumonia, including ventilator-
associated pneumonia
82. García-Castillo M, García-Fernández S, Gómez-Gil R, Pitart C, Oviaño M, Gracia-
Ahufinger I, et al. Activity of ceftazidime-avibactam against carbapenemase-
producing Enterobacteriaceae from urine samples obtained during the infection-
carbapenem resistance evaluation surveillance trial (iCREST) in Spain. Int J
Antimicrob Agents. 2018, 10.1016.
83. Livermore DM, Mushtaq S, Ge Y, Warner M. Activity of cephalosporin CXA-101
(FR264205) against Pseudomonas aeruginosa and Burkholderia cepacia group
strains and isolates. Int J Antimicrob Agents 2009; 34: 402–6.
84. Armstrong ES, Farrell DJ, Palchak M, Steenbergen JN. In vitro activity of
Ceftolozane-Tazobactam against anaerobic organisms identified during the
ASPECT-cIAI study. Antimicrob Agents Chemother. 2015,60:666-8.
85. Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO.
Ceftolozane/tazobactam compared with levofloxacin in the treatment of complicated
urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase
Accep
ted M
anus
cript
41
3 trial (ASPECT-cUTI). Lancet 2015,385:1949–1956.
86. **Solomkin J, Hershberger E, Miller B, Popejoy M, Friedland I, Steenbergen J, et al.
Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal
infections in an era of multidrug resistance: results from a randomized, double-blind,
phase 3 trial (ASPECT-cIAI). Clin Infect Dis 2015,60:1462–1471.
** Phase 3 trial analyzing ceftolozane/tazobactam plus metronidazole safety and
efficacy in complicated intra-abdominal infections
87. Xipell M, Bodro M, Marco F, Martínez JA, Soriano A. Successful treatment of three
severe MDR or XDR Pseudomonas aeruginosa infections with
ceftolozane/tazobactam. Future Microbiol. 2017,12:1323-1326.
88. Munita JM, Aitken SL, Miller WR, Perez F, Rosa R, Shimose LA, et al. Multicenter
Evaluation of Ceftolozane/Tazobactam for Serious Infections Caused by
Carbapenem-Resistant Pseudomonas aeruginosa. Clin Infect Dis. 2017,65(1):158-
161.
89. Monogue ML, Pettit RS, Muhlebach M, Cies JJ, Nicolau DP, Kuti JL. Population
Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis
Patients Admitted with Acute Pulmonary Exacerbation. Antimicrob Agents
Chemother. 2016,60:6578-6584.
90. Dietl B, Sánchez I, Arcenillas P, Cuchi E, Gómez L, González de Molina FJ, et al.
Ceftolozane/tazobactam in the treatment of osteomyelitis and skin and soft tissue
infections due to extensively drug-resistant Pseudomonas aeruginosa: clinical and
microbiological outcomes. Int J Antimicrob Agents. 2017, doi:10.1016.
91. Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the
treatment of infections caused by carbapenem-resistant Enterobacteriaceae.
Virulence. 2017,8(4):403-416.
Accep
ted M
anus
cript
42
92. Livermore DM, Warner M, Mushtaq S. Activity of MK-7655 combined with
imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J Antimicrob
Chemother. 2013,68(10):2286-90.
93. Lapuebla A, Abdallah M, Olafisoye O, Cortes C, Urban C, Landman D, et al.
Activity of Imipenem with Relebactam against Gram-negative pathogens from New
York City. Antimicrob Agents Chemother. 2015,59(8):5029-31.
94. Lucasti C, Vasile L, Sandesc D, Venskutonis D, McLeroth P, Lala M, et al. Phase 2,
Dose-ranging study of Relebactam with Imipenem-Cilastatin in subjects with
complicated intra-abdominal infection. Antimicrob Agents Chemother.
2016,60(10):6234-43.
95. Sims M, Mariyanovski V, McLeroth P, Akers W, Lee YC, Brown ML, et al.
Prospective, randomized, double-blind, Phase 2 dose-ranging study comparing
efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin
alone in patients with complicated urinary tract infections. J Antimicrob Chemother
2017,72(9):2616-2626.
96. Castanheira M, Huband MD, Mendes RE, Flamm RK. Meropenem-Vaborbactam
tested against contemporary gram-negative isolates collected worldwide during
2014, including carbapenem-resistant, KPC-Producing, multidrug-resistant, and
extensively drug-resistant Enterobacteriaceae. Antimicrob Agents Chemother
2017,61(9).
97. Hackel MA, Lomovskaya O, Dudley MN, Karlowsky JA, Sahm DF. In Vitro
Activity of Meropenem-Vaborbactam against clinical isolates of KPC-positive
Enterobacteriaceae. Antimicrob Agents Chemother 2017,62(1).
98. Sun D, Rubio-Aparicio D, Nelson K, Dudley MN, Lomovskaya O. Meropenem-
Vaborbactam resistance selection, resistance prevention, and molecular mechanisms
Accep
ted M
anus
cript
43
in mutants of KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother
2017,61(12).
99. Griffith DC, Loutit JS, Morgan EE, Durso S, Dudley MN. Phase 1 study of the
safety, tolerability, and pharmacokinetics of the β-lactamase inhibitor Vaborbactam
(RPX7009) in healthy adult subjects. Antimicrob Agents Chemother 2016,60:6326-
32.
100. Walkty A1, Adam H, Baxter M, Denisuik A, Lagacé-Wiens P, Karlowsky JA, et al.
In vitro activity of plazomicin against 5,015 gram-negative and gram-positive
clinical isolates obtained from patients in canadian hospitals as part of the
CANWARD study, 2011-2012. Antimicrob. Agents Chemother 2014,58(5):2554-63
101. Connolly LE, Riddle V, Cebrik D, Armstrong ES, Miller LG. Efficacy and safety of
Plazomicin compared with Levofloxacin in the treatment of complicated urinary tract
infection and acute pyelonephritis: A multicenter, randomized, double-blind, Phase 2
study. Antimicrob Agents Chemother 2018, AAC.01989-17.
102. Connolly LE, Jubb AM, O’Keeffe B, Serio AW, Smith A, Gall J, et al. Plazomicin Is
associated with improved survival and safety compared with colistin in the treatment
of serious infections due to carbapenem-resistant Enterobacteriaceae: results of the
CARE study. Presented at 27th European Congress of Clinical Microbiology and
Infectious Diseases (ECCMID), Vienna, Austria, April 22-25, 2017.
103. FDA Briefing Document. Plazomicin sulfate Injection Meeting of the Antimicrobial
Drugs Advisory Committee (AMDAC) May 02, 2018. Available at
https://www.fda.gov, accessed June 10, 2018
104. Gorska A, Sloderbach A, Marszaff MP. Siderophore�drug complexes: potential
medicinal applications of the “Trojan horse” strategy. Trends Pharmacol Sci
2014,35(9):442–449.
Accep
ted M
anus
cript
44
105. Ito A, Kohira N, Bouchillon SK, West J, Rittenhouse S, Sader HS, et al. In vitro
antimicrobial activity of S�649266, a catechol substituted siderophore
cephalosporin, when tested against non�fermenting Gram�negative bacteria. J
Antimicrob Chemother 2016,71(3):670–677.
106. Saisho Y, Katsube T, White S, Fukase H, Shimada J. Pharmacokinetics, safety, and
tolerability of Cefiderocol, a novel siderophore cephalosporin for gram-negative
bacteria, in healthy subjects. Antimicrob Agents Chemother 2018,62(3): e02163-17.
107. Katsube T, Echols R, Ferreira JCA, Krenz HK, Berg JK, Galloway C. Cefiderocol,
a siderophore cephalosporin for gram�negative bacterial infections:
pharmacokinetics and safety in subjects with renal impairment J Clin Pharmacol
2017,57: 584–591.
108. Clark RB, Hunt DK, He M, et al. Fluorocyclines. 2. Optimization of the C-9 side-
chain for antibacterial activity and oral efficacy. J Med Chem 2012; 55:606 – 622.
109. Zhanel GG, Baxter MR, Adam HJ, et al. In vitro activity of eravacycline against
2213 Gram-negative and 2424 Gram-positive bacterial pathogens isolated in
Canadian hospital laboratories: CANWARD surveillance study 2014-2015. Diagn
Microbiol Infect Dis. 2018 May;91(1):55-62
110. Bassetti M, Righi E. Eravacycline for the treatment of intra-abdominal infections.
Expert Opin Investig Drugs 2014;23:1575 – 1584
111. Solomkin J, Evans D, Slepavicius A, Lee P, et al. Assessing the Efficacy and Safety
of Eravacycline vs Ertapenem in Complicated Intra-abdominal Infections in the
Investigating Gram-Negative Infections Treated With Eravacycline (IGNITE 1)
Trial: A Randomized Clinical Trial. JAMA Surg. 2017;152:224-232.
112. Connors KP, Housman ST, Pope JS, et al. Phase I, open-label, safety and &
pharmacokinetic study to assess bronchopulmonary disposition of intravenous
Accep
ted M
anus
cript
45
eravacycline in healthy men and women. Antimicrob Agents Chemother 2014;
58:2113 – 2118
113. Honeyman L, Ismail M, Nelson ML, et al. Structure-activity relationship of the
aminomethylcyclines and the discovery of omadacycline. Antimicrob Agents
Chemother. 2015;59):7044-7053
114. Macone AB, Caruso BK, Leahy RG, et al. In vitro and in vivo antibacterial activities
of omadacycline, a
115. Sun H, Ting L, Machineni S, et al. Randomized, Open-Label Study of the
Pharmacokinetics and Safety of Oral and Intravenous Administration of
Omadacycline to Healthy Subjects. Antimicrob Agents Chemother. 2016;60:7431-
7435 novel aminomethylcycline. Antimicrob Agents Chemother. 2014;58:1127-35
116. Loutit J, Fusaro K, Zhang S, Morgan E, Alexander E, Griffith D, et al. Meropenem-
Vaborbactam compared with Piperacillin-Tazobactam in the treatment of adults with
complicated urinary tract infections (cUTI), including acute pyelonephritis in a Phase
3 randomized, double-blind, double-dummy trial (TANGO 1) Open Forum Infect
Dis 2016,3:LB-7