International Journal of Antimicrobial Agents 53 (2019) 211–224

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International Journal of Antimicrobial Agents

journal homepage: www.elsevier.com/locate/ijantimicag

Review

Infections by multidrug-resistant Gram-negative Bacteria: What’s new

in our arsenal and what’s in the pipeline?
Despoina Koulenti a,b,c,∗, Andrew Song a, Aaron Ellingboe a, Mohd Hafiz Abdul-Aziz a,d,
Patrick Harris a,e,f, Emile Gavey a, Jeffrey Lipman a,b,g
a
UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia
b
Royal Brisbane Clinical Unit, Faculty of Medicine, The University of Queensland, Brisbane, Australia
c
2nd Critical Care Department, Attikon University Hospital, Athens, Greece
d
School of Pharmacy, International Islamic University, Malaysia, Kuantan, Malaysia
e
Pathology Queensland, Central Laboratory, Herston, Queensland, Australia
f
Infection Management Services, Princess Alexandra Hospital, Queensland, Australia
g
Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane

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

Article history: The spread of multidrug-resistant bacteria is an ever-growing concern, particularly among Gram-negative
Received 28 May 2018 bacteria because of their intrinsic resistance and how quickly they acquire and spread new resistance
Accepted 23 October 2018
mechanisms. Treating infections caused by Gram-negative bacteria is a challenge for medical practitioners
and increases patient mortality and cost of care globally. This vulnerability, along with strategies to tackle
Editor: Professor A. Tsakris antimicrobial resistance development, prompts the development of new antibiotic agents and exploration
of alternative treatment options. This article summarises the new antibiotics that have recently been
Keywords:
Ceftolozane/tazobactam approved for Gram-negative bacterial infections, looks down the pipeline at promising agents currently in
Ceftazidime/avibactam phase I, II, or III clinical trials, and introduces new alternative avenues that show potential in combating
Meropenem/vaborbactam multidrug-resistant Gram-negative bacteria.
Plazomicin © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
Eravacycline
Multidrug-resistant Gram-negative bacteria

1. Introduction length of hospital stay was increased by 5 days, and hospital cost
was increased by 35.9% compared with non-resistant GNBs ($144
Antibiotic-resistant bacteria are spreading fast and stealthily 414 and $106 293 USD, respectively; P<0.0 0 01) [4]. The special
around the world and are an ever-increasing health concern. Some concern about GNBs arises partly from their efficiency at upreg-
estimates indicate that 70 0 0 0 0 deaths per year can be attributed ulating or acquiring new genes encoding a diverse range of antibi-
to antimicrobial resistance [1]. Although quantification of future otic resistance mechanisms. GNBs can develop resistance through
excess morbidity and mortality is challenging, by 2050, mortality DNA mutations under selective pressure from antimicrobial agents
attributed to antibiotic resistance is estimated to increase to 10 (e.g. point mutations in DNA gyrase conferring fluoroquinolone re-
million deaths annually and a cost of 100 trillion USD [1,2]. sistance), or by acquisition from horizontal gene transfer (usually
Gram-negative bacteria (GNBs) are of particular concern. One via mobile genetic elements, such as plasmids, transposons or inte-
study placed the mortality risk ratio of healthcare-associated in- grons) [5]. These acquired resistance genes may produce antibiotic-
fections by multidrug-resistant (MDR) vs. non-MDR GNBs at 1.42 inactivating enzymes, such as extended-spectrum β -lactamases
[95%-confidence interval (CI) 1.31-1.54%] at 30 days and 1.48 [95%CI (ESBLs), and carbapenemases [5]. Carbapenem-resistant Enterobac-
1.39-1.57%] at 90 days showing significant elevation in mortality teriaceae (CRE) are particularly challenging to treat and usually
risk [3]. Another study of hospital-acquired infections reported that become carbapenem-resistant by acquisition of carbapenemases.
for patients infected with antibiotic-resistant GNBs, the median The most common (so called “Big Five”) carbapenemases include
Klebsiella pneumoniae carbapenemase (KPC), oxacillinase-type car-
bapenemase (OXA), and metallo-beta-lactamases (MBLs), which
∗
Corresponding author. Despoina Koulenti, MD, PhD, Internist-Intensivist, Burns, include imipenemase MBL (IMP), New Delhi MBL (NDM) and
Trauma and Critical Care Research Centre, University of Queensland Centre for Clini- Verona integron-encoded MBL (VIM) [6]. NDM-1, most frequently
cal Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia, encountered in Escherichia coli or K. pneumoniae, was first de-
Building 71/918, Herston.
scribed in Sweden from a traveller returning from India in 2008,
E-mail address: d.koulenti@uq.edu.au (D. Koulenti).

https://doi.org/10.1016/j.ijantimicag.2018.10.011
0924-8579/© 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
212 D. Koulenti, A. Song and A. Ellingboe et al. / International Journal of Antimicrobial Agents 53 (2019) 211–224

Table 1 cephalosporin ceftazidime but has a modified side chain that gives
Global priority list of antibiotic-resistant Gram-negative bacteria to guide re-
a more potent inhibition profile towards penicillin-binding proteins
search, discovery, and development of new antibiotics. World Health Organiza-
tion. 2017 [13]. (PBPs) [19]. Tazobactam is a penicillanic acid sulfone derivative
and an irreversible inactivator of β -lactamase [18]. It is exclusively
Priority 1: Critical Resistance spectrum
cleared renally [20].
Acinetobacter baumannii carbapenem-resistant
Pseudomonas aeruginosa carbapenem-resistant Ceftolozane has a minimum inhibitory concentration (MIC)
Enterobacteriaceae carbapenem-resistant, third-generation against P. aeruginosa that is 8- to 16-fold lower compared with
cephalosporin-resistant ceftazidime, imipenem, and ciprofloxacin [21]. The effectiveness
Priority 2: High of ceftolozane is limited by the production of ESBLs and AmpC
Helicobacter pylori clarithromycin-resistant
Campylobacter fluoroquinolone-resistant
β -lactamases, although stability to hydrolysis by AmpC enzymes
Salmonella spp. fluoroquinolone-resistant may be dependent on the level of expression as well as the spe-
Neisseria gonorrhoeae third-generation cephalosporin-resistant, cific organism and enzyme type [22,23]. To overcome this barrier,
fluoroquinolone-resistant tazobactam has been used to increase the coverage of ceftolozane.
Priority 3: Medium
The addition of tazobactam to ceftolozane elevates in vitro ac-
Haemophilus influenzae ampicillin-resistant
Shigella spp. fluoroquinolone-resistant tivity against β -lactamase-producing microorganisms and ESBL-
producers, such as E. coli, K. pneumoniae, and Proteus mirabilis,
as well as some inhibition against AmpC de-repressed Enterobac-
and NDM genes have since rapidly spread among different clonal ter and Citrobacter strains [17,24]. Ceftolozane/tazobactam has also
lineages and across a diverse range of Gram-negative species and demonstrated higher in vitro activity than available cephalosporins
are now globally distributed [7,8]. against Enterobacteriaceae but remains susceptible to hydrolysis by
Unfortunately, despite the implementation of strategies to MBLs and KPC enzymes [25,26]. One in vitro study also showed
tackle antibiotic resistance development, the rate of antibac- that ceftolozane/tazobactam is effective against P. aeruginosa in the
terial resistance is expected to increase inexorably [9,10]. The planktonic state, not the biofilm state [27].
widespread use of antibiotics in animals and humans, the increas- In vivo activities against neutropenic murine thigh infec-
ing global population and the rise of globalisation has helped tion models showed a 2:1 ratio of ceftolozane/tazobactam was
disseminate resistance throughout the world [11]. On the other the most effective formulation for both efficacy and MIC re-
hand, the rate of new antibiotic development has been decreas- duction [28]. In a prospective, randomised, double-blind, phase
ing every decade since the 1980s and drastically after the 20 0 0s II trial (ClinicalTrials.gov Identification Number: NCT01147640),
[12]. This led to initiatives, such as the ‘10 x 20 initiative’ set ceftolozane/tazobactam in combination with metronidazole was
by the Infectious Diseases Society of America (IDSA) to encour- compared against meropenem for complicated intra-abdominal
age more antibiotic research with the goal of having 10 new infections (cIAIs) [29]. The combination had microbiological suc-
antibiotic treatments by 2020 [12]. In the World Health Orga- cess against E. coli (89.5%), P. aeruginosa (100%), and K. pneu-
nization (WHO) Priority Pathogens List for Research & Develop- moniae (100%), and was found to be well tolerated with sim-
ment of New Antibiotics published in 2017 (Table 1), all bacte- ilar adverse event rates (50% vs. 48.8% in meropenem) [30].
ria in the Priority 1 Critical category are carbapenem-resistant In a randomised, double-blind, phase III trial (NCT01345929),
GNB strains, including carbapenem-resistant Acinetobacter bau- ceftolozane/tazobactam was superior to levofloxacin for compli-
mannii, carbapenem-resistant Pseudomonas aeruginosa, and third- cated urinary tract infections (cUTIs) [31]. The microbiological
generation cephalosporin-resistant Enterobacteriaceae, which in- eradication at the test-of-cure visit 5 to 9 days after treatment
cludes common pathogens such as E. coli, Enterobacter spp. and was 88.9% for ceftolozane/tazobactam compared with 77.4% [95%CI
K. pneumoniae [13,14]. Due to the emergence of GNB strains that 5.8-17.1%] for levofloxacin, and both were well tolerated with
cannot be treated with any existing marketed antibiotics, GNBs are 34.7% and 34.4% adverse event rates, respectively [31,32]. In 2014,
designated by the WHO as the most critical priority for antibiotic the U.S. Food and Drug Administration (FDA) approved the use
research and development [15]. of Zerbaxa for cUTIs and its combination with metronidazole
This review introduces some recently approved novel an- was approved for cIAIs [18]. In 2015, the European Medicines
tibiotics that can combat existing MDR GNBs, with drug in- Agency (EMA) approved ceftolozane/tazobactam for cIAIs, acute
formation summarised in Table 2 and chemical structures pyelonephritis, and cUTIs [33]. A randomised, double-blind, phase
summarised in the Supplementary material [16]. These novel III trial (NCT02070757) of ceftolozane/tazobactam compared with
antibiotics include ceftolozane/tazobactam, ceftazidime/avibactam, meropenem for patients with ventilator-acquired pneumonia (VAP)
meropenem/vaborbactam, plazomicin and eravacycline. The review completed its recruitment recently, and results are pending [34]. It
also explores some novel antibiotics that are currently in clini- should be noted that the dose used in the above trial is double
cal trials or development, and discusses alternative/complementary the approved dose for cIAIs and cUTIs as the epithelial lining fluid
management approaches that could potentially prove useful in (ELF)/plasma ratio is 50% [35].
the battle against MDR GNBs [16]. Finally, pharmacokinetic/ In summary, ceftolozane/tazobactam has good in vitro activ-
pharmacodynamic (PK/PD) strategies to optimise the use of our ity against most Enterobacteriaceae (including ESBL-producers) and
currently available antibiotics against GNBs will be briefly de- notable effectiveness against P. aeruginosa [36].
scribed.
2.1.2. Ceftazidime/avibactam
2. Novel approved antibiotics Ceftazidime/avibactam (trade name Avycaz (Allergan) in US
and Canada; Zavicefta (Pfizer) outside US and Canada) is a com-
2.1. β -Lactam/β -lactamase inhibitor combinations bination of the cephalosporin ceftazidime and the non-β -lactam
β -lactamase inhibitor avibactam [37]. Ceftazidime is an estab-
2.1.1. Ceftolozane/tazobactam lished third-generation cephalosporin with predominant activity
Ceftolozane/tazobactam (trade name Zerbaxa, developed by against Gram-negative bacilli, but ceftazidime-resistant GNBs have
Merck/MSD) is a combination of ceftolozane, a novel oxyimino- become increasingly more common [38]. Ceftazidime is resistant to
aminothiazolyl cephalosporin, and the β -lactamase inhibitor hydrolysis by many of the older narrow-spectrum β -lactamases
tazobactam [17,18]. Ceftolozane resembles the third-generation (such as TEM-1 or SHV-1); however, it is not stable against ES-
Table 2
Summary of novel antibiotics approved by FDA and EMA since 2010.

Drug Approval time Antibiotic class Company Inhibitor provides stability to β -lactamase1 Spectrum against organisms [15] Indication Dosage5

D. Koulenti, A. Song and A. Ellingboe et al. / International Journal of Antimicrobial Agents 53 (2019) 211–224
2 3
ESBL KPC OXA AmpC MBLs Effective against Ineffective against

Ceftolozane/ FDA: December Cephalosporin/ Merck & Co. (US, + - - +/- - MDR-P. aeruginosa4 , NDM- or FDA: cIAI, cUTI; 1 g/0.5 g by IV
Tazobactam 2014; EMA: β -lactamase Canada); Merck Enterobacteriaceae IMP-producing EMA: cIAI, cUTI infusion over 1 h
(Zerbaxa) September 2015 inhibitor Sharp & Dohme (including some Enterobacteri- every 8 h [18,33]
(MSD) (outside ESBL and AmpC aceae,
US & Canada) producers) CRAB
Ceftazidime/ FDA: February Cephalosporin/ Allergan Inc. (US, + + + + - Enterobacteriaceae NDM- or FDA: cIAI, cUTI; 2 g/0.5 g by IV
Avibactam 2015; EMA: June β -lactamase Canada); Pfizer (including ESBL, IMP-producing EMA: cIAI, cUTI, infusion over 2 h
(Avycaz in US, 2016 inhibitor (outside US & AmpC, KPC and Enterobacteri- HAP, VAP every 8 h [54,55]
Canada; Canada) OXA-48 producers), aceae,
Zavicefta MDR-P. aeruginosa4 CRAB
outside US &
Canada)
Meropenem/ FDA: August 2017 Carbapenem/ Rempex + + - + - Enterobacteriaceae MDR-P. aeruginosa4 FDA: cUTI 2 g/2 g by IV
Vaborbactam β -lactamase Pharmaceuticals (including KPC, (including CRPA), infusion over 3 h
(Vabomere) inhibitor Inc. ESBL and AmpC CRAB every 8 h [57]
producers, and
CRE)
Plazomicin FDA: June 2018 Aminoglycoside Achaogen Inc. N/A N/A N/A N/A N/A Enterobacteriaceae Organisms FDA: cUTI 15 mg/kg by IV
(Zemdri) (including CRE) producing 16S infusion over 30
rRNA methyl- min every 24 h
transferases, [80]
CRAB, CRPA
Eravacycline FDA: August 2018; Tetracycline Tetraphase N/A N/A N/A N/A N/A Enterobacteriaceae P. aeruginosa FDA: cIAI; EMA: 1 mg/kg by IV
(Xerava) EMA: October Pharmaceuticals (including CRE), A. (including CRPA), cIAI infusion over 1 h
2018 Inc. baumannii B. cenocepacia every 12 h
(including CRAB) [90,91]
Note:
1
‘+’ indicates positive protection, ‘-’ indicates no protection and ‘+/-’ indicates possible protection against β -lactamases.
2
OXA (oxacillinase) refers to OXA carbapenemases, e.g. OXA-48.
3
MBLs (metallo-beta-lactamases) include NDM (New Delhi metallo-β -lactamase), IMP (Imipenemase metallo-β -lactamase) and VIM (Verona integron-encoded metallo-β -lactamase).
4
MDR (multidrug-resistant)-P. aeruginosa utilises chromosomal AmpC β -lactamase, porin loss, and efflux pumps for its antibiotic resistant mechanisms.
5
Dosage refers to patients 18 years or older of age; For ceftolozane/tazobactam and ceftazidime/avibactam: dosage is for patients with CrCl greater than 50 mL/min. For meropenem/vaborbactam: dosage is for patients with
eGFR equal or greater than 50 mL/min/1.73 m2 . For plazomicin: dosage is for patients with CrCl equal or greater than 60 mL/min. For eravacycline: dosage is for patients without severe (Child-Pugh C) hepatic impairment.
Abbreviations: cIAI (complicated intra-abdominal infection), CRAB (carbapenem-resistant Acinetobacter baumannii), CrCl (creatinine clearance), eGFR (estimated glomerular filtration rate), CRPA (carbapenem-resistant Pseudomonas
aeruginosa), cUTI (complicated urinary tract infection), EMA (European Medicines Agency), ESBL (extended spectrum β -Lactamase), EU (European Union), FDA (United States Food and Drug Administration), HAP (hospital-
acquired pneumonia), IMP (imipenemase metallo-β -lactamase), IV (intravenous), KPC (Klebsiella pneumoniae carbapenemase), MBL (metallo-β -lactamase), MDR (multidrug-resistant), NDM (New Delhi metallo-β -lactamase), OXA
(oxacillinase), rRNA (ribosomal ribonucleic acid), US (the United States), VAP (ventilator-acquired pneumonia), VIM (Verona integron-encoded metallo-β -lactamase).
Bacteria abbreviations: A. baumannii (Acinetobacter baumannii), B. cenocepacia (Burkholderia cenocepacia), P. aeruginosa (Pseudomonas aeruginosa).

213
214 D. Koulenti, A. Song and A. Ellingboe et al. / International Journal of Antimicrobial Agents 53 (2019) 211–224

BLs, class C (AmpC-type) enzymes and carbapenemases, such as from destruction by serine β -lactamases that target carbapenems
KPCs and MBLs [39]. To protect against this susceptibility, cef- [60,61]. When tested in vitro against KPC-positive Enterobacte-
tazidime has been paired with avibactam, which is a diazabi- riaceae, meropenem/vaborbactam inhibited 99.0% of the isolates
cyclooctane that provides protection against class A and C β - [62]. Another study showed similar success at inhibiting KPC-
lactamases by binding covalently and inhibiting their actions [39]. positive Enterobacteriaceae and reported a 98.5% inhibition rate
Of note, avibactam (in contrast to tazobactam) binds reversibly [63]. However, when tested against A. baumannii producing primar-
to β -lactamases [37]. Ceftazidime/avibactam is primarily cleared ily class D (OXA-type) carbapenemases and P. aeruginosa with MDR
by the kidneys [40]. In vitro studies of ceftazidime/avibactam phenotypes mediated by porin changes and efflux mechanisms, the
have demonstrated inhibition against >99.9% of Enterobacteriaceae addition of vaborbactam did not increase bacterial susceptibility
and P. aeruginosa isolates that were resistant to meropenem, cef- [63].
tazidime and piperacillin/tazobactam [41]. Ceftazidime/avibactam In a randomised, double-blind, phase III trial (NCT02166476;
had activity against 100% of KPC and OXA-48 producers in urine ‘TANGO I’) comparing meropenem/vaborbactam against
isolates, the most prevalent carbapenemases in the study [42]. Cef- piperacillin/tazobactam in an intent-to-treat study against
tazidime/avibactam also had coverage against ESBLs and most KPCs cUTIs, patients who received meropenem/vaborbactam achieved
but not MBLs [43-45]. a clinical success rate of 98.4% compared with 94.0% for
A randomised, double-blind, superiority phase III trial piperacillin/tazobactam [64]. Additionally, the endpoint for the
(NCT01595438) comprising 1033 hospitalised adult patients who FDA (overall success at the end of the intravenous treatment visit),
were given either ceftazidime/avibactam or doripenem for cUTIs and the endpoint for the EMA (microbiological eradication) were
has been completed [46]. Ceftazidime/avibactam showed non- both met in this study [64]. Another open-label, randomised,
inferiority for the co-primary endpoints of symptom resolution and phase III trial (NCT02168946; ‘TANGO II’) was completed in 2017,
combined resolution/microbiological cure; superiority was shown and meropenem/vaborbactam demonstrated increased clinical
in the EMA endpoint (using a 5% significance level, which indicated cure rate and decreased 28-day all-cause mortality compared
superiority on the microbiological endpoint) [47]. In an open-label, with the best available treatment for cUTIs, HAP/VAP, and bac-
randomised, non-inferiority phase III trial (NCT01644643) of pa- teraemia caused by CRE [65]. Vabomere was approved by the
tients with cUTIs or cIAIs due to ceftazidime-resistant pathogens, FDA in 2017 for cUTIs [57]. The EMA has recommended grant-
ceftazidime/avibactam demonstrated similar cure rates at 91% ing a marketing authorisation for Vabomere in September 2018
for test-of-cure visits compared with best available therapy (97% [66]. A randomised, double-blind, comparative phase III trial
of the time this was a carbapenem) [48,49]. The adverse event (NCT03006679; ‘TANGO III’) comparing meropenem/vaborbactam
rate was 31% for ceftazidime/avibactam and 39% for carbapenem, against piperacillin/tazobactam in HAP/VAP is ongoing [67].
with gastrointestinal disorders the most frequently reported In summary, meropenem/vaborbactam has demonstrated suc-
[49]. A randomised, double-blind, phase III study (NCT01726023) cess against a wide range of KPC-positive Enterobacteriaceae and
from Asia comparing ceftazidime/avibactam plus metronidazole it is a viable option against MDR GNBs.
to meropenem in the treatment of cIAIs showed comparative
effectiveness with clinical cure rates of 93.8% and 94.0%, respec- 2.2. Aminoglycosides
tively [50]. A randomised, double-blind, non-inferiority phase III
trial (NCT01808092) for hospital-acquired pneumonia (HAP)/VAP 2.2.1. Plazomicin
showed 77.4% cure rate in the ceftazidime/avibactam-treated Plazomicin (trade name Zemdri, developed by Achaogen) is a
group compared with 78.1% in the meropenem-treated group, new aminoglycoside derivative of sisomicin that inhibits bacterial
which shows ceftazidime/avibactam as non-inferior and a potential protein synthesis [68]. The half-life of plazomicin is 2-3 h, and its
alternative to meropenem [51,52]. In 2015, ceftazidime/avibactam lung penetration is quite poor; the ratio of ELF to plasma area
was approved by the FDA to treat cUTIs, and its combination with under the concentration-time curve (AUC) is approximately 13%,
metronidazole was approved to treat cIAIs [53,54]. The EMA ap- which is similar to that of amikacin (14%) [69,70]. Plazomicin is
proved ceftazidime/avibactam in 2016 for the indications of cUTIs, eliminated via the kidneys [71]. Adverse effects associated with
cIAIs, HAP/VAP, and infections by GNBs when other treatments plazomicin include dizziness, hypoaesthesia, somnolence, nausea
might not work [55]. It should be highlighted that the infusion and transient mild-to-moderate hypotension [69]. No clinically sig-
time of ceftazidime/avibactam is 2 h and this can be considered nificant impairment of vestibular, cochlear or renal function was
an extended infusion and might contribute to its effectiveness observed [69]. The antibacterial spectrum of plazomicin covers
[54]. GNBs, including CRE, with minimal activity against P. aeruginosa
In summary, ceftazidime/avibactam has a wide range of activity and Acinetobacter spp. [72]. Plazomicin is active in vitro against
against GNBs, including most of the KPC- and OXA-48-producers CRE and aminoglycoside-resistant Enterobacteriaceae containing
[45,56]. aminoglycoside-modifying enzymes [73-76]. The combination of
plazomicin with colistin, meropenem or fosfomycin showed syner-
2.1.3. Meropenem/vaborbactam gistic activity against VIM-1- and KPC-2-producing K. pneumoniae
Meropenem/vaborbactam (trade name Vabomere, previously isolates [76]. However, it is not active against bacteria containing
named Carbovance; vaborbactam developed by Rempex Pharma- ribosomal methyltransferases found in most NDM-1-producing En-
ceuticals Inc., acquired by Melinta Therapeutics) is a combina- terobacteriaceae (E. coli, K. pneumoniae, Enterobacter spp.) that are
tion of the broad-spectrum carbapenem meropenem with the also resistant to amikacin, gentamicin and tobramycin [73,74,77].
β -lactamase inhibitor vaborbactam [57]. Meropenem is a bacte- In a multinational, randomised, double-blind, non-inferiority
ricidal β -lactam that inhibits cell wall synthesis by binding to phase III study (NCT02486627; Evaluating Plazomicin in cUTI
PBPs. Meropenem/vaborbactam is primarily excreted by the kid- [EPIC]), 388 (64%) of 609 enrolled patients were analysed in the
neys [57]. Meropenem is effective against both Gram-positive and microbiological modified intent-to-treat (mMITT) population [78].
Gram-negative bacteria, and it is resistant to hydrolysis by many At test-of-cure visit, in patients with cUTIs, microbiological erad-
β -lactamases, except carbapenemases such as KPCs [58,59]. To re- ication by plazomicin vs. meropenem was 86.9% vs. 75.6% (95%CI
sist degradation against these enzymes, a novel cyclic boronate 0.4-21.7%), and in patients with acute pyelonephritis was 85.7% vs.
β -lactamase inhibitor vaborbactam has been added. Vaborbactam 71.8% [95%CI 0.4-27.1%] [78]. Once-daily plazomicin also demon-
by itself has no antibacterial activity but it protects meropenem strated non-inferiority compared with meropenem, with a clinical
 D. Koulenti, A. Song and A. Ellingboe et al. / International Journal of Antimicrobial Agents 53 (2019) 211–224 215

cure rate of 87.9% vs. 91.6% in patients with cUTIs and 90.5% vs. 3. Antibiotics in phase III clinical trials
88.5% in patients with acute pyelonephritis [78]. Plazomicin was
generally well-tolerated, with the most common adverse events re- 3.1. β -Lactams or β -lactam/β -lactamase inhibitor combinations
ported to be diarrhoea, hypertension, headache, nausea and vomit-
ing [78]. The EPIC study supports the use of plazomicin as a po- 3.1.1. Sulopenem
tential new treatment option for cUTIs and acute pyelonephritis Sulopenem (CP-70,429, developed by Pfizer Japan) is a new
[78]. Another multicentre, randomised, open-label phase III trial broad-spectrum carbapenem that is potent against both Gram-
(NCT01970371; Combating Antibiotic-Resistant Enterobacteriaceae positive and Gram-negative bacteria. It is not active against
[CARE]) compared the efficacy of plazomicin with that of colistin Stenotrophomonas maltophilia or P. aeruginosa, which exhibit high
in the treatment of bloodstream infections (BSIs) or HAP/VAP due intrinsic resistance to sulopenem [93,94]. In vitro, sulopenem
to CRE based on day 28 all-cause mortality or significant disease- showed bactericidal activities against ESBL-producing Enterobacte-
related complications [79]. Both plazomicin and colistin were ad- riaceae (MIC50 0.015–0.125 μg/mL), and Gram-positive and Gram-
ministered in combination with adjunctive therapy of meropenem negative anaerobes [95,96]. In four different animal models, su-
or tigecycline [79]. In 39 patients with BSIs or HAP/VAP, pla- lopenem demonstrated dose-dependent activity, and was active
zomicin showed reduced all-cause mortality of 11.8% at day 28 against ESBL-producing K. pneumoniae and E. coli [97,98]. Pfizer
compared with 40.0% for colistin (90%CI 0.7-52.5%) [79]. In BSI Japan completed an extensive preclinical program, followed by a
patients, plazomicin also demonstrated favourable microbiological phase II trial of intravenous formulation of sulopenem in Japan
response rate compared with colistin (92.9% vs. 60.0% at End-of- and a phase II trial of its oral prodrug in community-acquired
Treatment; 92.9% vs. 53.3% at Test-of-Cure) [79]. In June 2018, the pneumonia (CAP) in the US [99]. Although the results were en-
FDA approved plazomicin for the indication of adult cUTIs includ- couraging, the development of sulopenem by Pfizer was aban-
ing pyelonephritis but not BSI [80]. The EMA also accepted an ap- doned, and Iterum Therapeutics obtained the license of sulopenem
plication from Achaogen in the same month [81]. and its prodrugs and restarted the development program in 2015
In summary, plazomicin is potent and has good synergistic ac- [99]. Although most carbapenems are administered intravenously,
tivity with colistin, meropenem or fosfomycin against VIM-1 and sulopenem can be administered both orally as a tablet form or
KPC-2 producing GNBs. However, plazomicin should be used only intravenously with good bioavailability [99]. Iterum Therapeutics
as a last resort when there are limited or no alternative treatment is commencing three phase III studies for the treatment of un-
options available [80]. complicated urinary tract infections (uUTIs) (NCT03354598), cUTIs
(NCT03357614), and cIAIs (NCT03358576) by the end of 2018, with
2.3. Tetracyclines a plan to file a New Drug Application (NDA) by late 2019 [99-102].

2.3.1. Eravacycline 3.1.2. Imipenem/cilastatin + relebactam (MK-7655)

Eravacycline (trade name Xerava, developed by Tetraphase Relebactam (developed by Merck/MSD) is a novel β -lactamase
Pharmaceuticals Inc.) is a novel fluorocycline with broad-spectrum inhibitor that inhibits class A and C β -lactamases [103]. It
antibacterial activity; it is a synthetic tigecycline analogue with is administered intravenously in combination with imipenem,
a pair of modifications to the D-ring core at C-7 and C-8 that a β -lactam cell wall inhibitor, and cilastatin, a dehydropep-
widens its activity [82,83]. In vitro studies have demonstrated tidase inhibitor, to prolong the antibiotic effect of imipenem
broad-spectrum antimicrobial activity against GNBs with the ex- [104]. Imipenem/relebactam was active against Enterobacteri-
ception of P. aeruginosa and Burkholderia cenocepacia [83]. Erava- aceae and non-fermenting GNBs. They include E. coli (ESBL-
cycline is resistant against expression of tetracycline-targeting ef- and KPC-producing strains), K. pneumoniae (ESBL, KPC, AmpC
flux channels, ribosomal protection mechanisms, and β -lactamases and OXA-positive strains), imipenem-resistant K. pneumoniae
[83]. It is notably successful against carbapenem-resistant A. bau- expressing AmpC β -lactamases or KPC carbapenemases, and
mannii and was more potent than any other drug tested in an P. aeruginosa isolates with either outer membrane porin protein
in vitro study [84]. Eravacycline is also effective against biofilms D (OprD) deficiency or expression of AmpC [105,106]. However,
formed by uropathogenic E. coli [85]. imipenem/relebactam is not active against imipenem-resistant En-
In a randomised, double-blind, non-inferiority phase III trial terobacteriaceae expressing IMPs, VIMs or NDM MBLs, A. bauman-
(NCT01844856; ‘IGNITE1’) comparing eravacycline with ertapenem, nii, or IMP- or VIM-producing P. aeruginosa [106].
the intent-to-treat populations receiving eravacycline had a cure In two recently completed randomised non-inferiority phase
rate of 86.8% vs. a cure rate of 87.6% for ertapenem, indicating non- II trials in patients with cIAIs or cUTIs caused by imipenem-
inferiority and demonstrating eravacycline as a promising alterna- resistant GNBs, imipenem-cilastatin/relebactam demonstrated
tive option for patients with cIAIs with MDR GNBs [86,87]. A re- non-inferiority compared with imipenem-cilastatin with similar
cently published post hoc analysis of the IGNITE1 trial and another tolerability and safety profiles [107,108]. Notably, both stud-
similar phase III trial (NCT02784704; ‘IGNITE4’) demonstrated a ies included only a very low number of imipenem-resistant
favourable microbiological response rate of 88.9% and 100% for er- strains, which represented an important limitation and high-
avacycline against ESBL-producing Enterobacteriaceae and A. bau- lighted the need for further trials, particularly involving patients
mannii, respectively [88,89]. The FDA and the EMA approved er- with CRE infections [107,108]. Specifically, in the cIAI study
avacycline for the indication of adult cIAIs in August and October (NCT01506271) only 36 patients (13% of the MITT popula-
2018, respectively [90,91]. Meanwhile, a randomised phase III trial tion) had at-baseline GNB strains non-susceptible to imipenem,
(NCT03032510; ‘IGNITE3’) comparing eravacycline with ertapenem whereas in the cUTI study (NCT01505634) only 10% of the
for cUTIs was recently completed and results are pending [92]. isolated strains were imipenem-non-susceptible [107,108]. More-
In summary, although not effective against P. aeruginosa, the ef- over, in both studies, the addition of relebactam did not restore
fectiveness of eravacycline against a wide variety of GNBs and the susceptibility to imipenem, presumably due to mechanisms
problematic organism A. baumanni has made it a helpful tool in other than β -lactamases vulnerable to relebactam inhibition
fighting MDR GNBs. [107,108]. In a randomised, double-blind, phase III trial
A summary of the newly approved antibiotics ceftolozane/ (NCT02452047) testing imipenem-cilastatin/relebactam against
tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, pla- imipenem-cilastatin/colistimethate sodium combination in the
zomicin and eravacycline is presented in Table 2. treatment of imipenem-resistant infections (HAP, VAP, cIAIs, cUTIs),
216 D. Koulenti, A. Song and A. Ellingboe et al. / International Journal of Antimicrobial Agents 53 (2019) 211–224

imipenem-cilastatin/relebactam demonstrated a higher favourable 3.2. Outer Membrane Protein Targeting Antibiotics (OMPTAs)
clinical response (71.4% vs. 40%) and a lower all-cause mortality
(9.5% vs. 30%) compared with cilastatin/colistimethate sodium 3.2.1. Murepavadin (POL7080)
[109]. Two phase III trials (NCT03583333, NCT02493764) are Murepavadin (POL7080, developed by Polyphor Pharmaceuti-
currently recruiting, investigating imipenem-cilastatin/relebactam cals) is a protein epitope mimetic belonging to a novel class of
vs. piperacillin/tazobactam for treatment of HAP/VAP in China antibiotics called the Outer Membrane Protein Targeting Antibi-
and multiple countries, respectively [110,111]. Specifically targeting otics (OMPTAs). It targets the lipopolysaccharide transport protein
β -lactamase-producing MDR GNBs, relebactam has exhibited D (LptD) on the outer membrane of P. aeruginosa, and is critical for
great potential in treating nosocomial infections. In 2014, the FDA lipopolysaccharide synthesis [124,125]. Therefore, it is highly spe-
designated imipenem-cilastatin/relebactam fast track status for the cific for P. aeruginosa, and has demonstrated activity against MDR
treatment of bacterial HAP, VAP, cIAIs and cUTIs [112]. P. aeruginosa in a murine pneumonia model [126]. A phase I clin-
ical trial showed that murepavadin was safe and well-tolerated
in healthy volunteers [127]. In a phase II study (NCT02096328),
murepavadin demonstrated good lung penetration and showed en-
3.1.3. Cefiderocol or S-649266
couraging results when given on top of standard-of-care in patients
Cefiderocol (developed by Shionogi & Co. Ltd.) is a novel
with VAP, with a cure rate of 80% and a 28-day all-cause mortality
siderophore cephalosporin with a catechol at the third position
of 8% [128]. A randomised, parallel phase III trial (NCT03409679) to
side chain [113]. Cefiderocol displays antibiotic activity against aer-
compare murepavadin combined with one anti-pseudomonal an-
obic GNBs as it binds to ferric ion, utilises the iron uptake sys-
tibiotic with the combination of two anti-pseudomonal antibiotics
tem and bypasses their outer membrane barriers [113]. Cefide-
in treating VAP is currently recruiting [129].
rocol is also stable against β -lactamases, including metallo- and
A summary of the antibiotics in phase III clinical trials is pre-
serine-carbapenemases, via passive diffusion through porin chan-
sented in Table 3.
nels [114]. Cefiderocol has demonstrated potent in vitro activity
against a large spectrum of GNBs, including Enterobacteriaceae and
Vibrio spp., and non-fermenting bacteria, such as Acinetobacter spp., 4. Antibiotics in phase II and phase I clinical trials
Pseudomonas spp., and Burkholderia spp. [115]. Cefiderocol was po-
tent in vitro as well as in vivo in a neutropenic murine thigh model 4.1. Phase II drugs
against P. aeruginosa resistant to other siderophore cephalosporins
[116]. 4.1.1. LYS228
There are two ongoing phase III trials and one completed phase LYS228 (developed by Novartis Pharmaceuticals) is a new
II trial. The completed randomised, double-blind, phase II trial monobactam that strongly binds PBP-3 and inhibits bacterial
(NCT02321800) compared cefiderocol with imipenem/cilastatin for peptidoglycan synthesis [130]. It is stable against NDM-1, KPCs,
cUTIs in hospitalised patients and demonstrated superiority of and most ESBLs, resulting in retained potency against ESBLs
cefiderocol against GNBs while being well tolerated [117]. One and CRE [131]. In vitro, LYS228 is potent against both wild-
ongoing randomised, open-label phase III trial (NCT02714595) type and β -lactamase-producing Enterobacteriaceae, regardless of
comparing cefiderocol against best available therapy is set to β -lactamases produced, and has potency similar to tigecycline
test the treatment with cefiderocol against a variety of se- [131]. With a broad spectrum against MDR GNBs, LYS228 has great
vere infections (BSIs, cUTIs, HAP/VAP) by carbapenem-resistant potential in treatment of nosocomial infections. It is currently in
GNBs [118]. A second ongoing randomised, double-blind, phase III two phase II trials (NCT03377426, NCT03354754) testing its PK,
trial (NCT03032380) comparing cefiderocol with meropenem for clinical response, safety and tolerability in patients with cUTIs and
HAP/VAP is estimated to be completed in 2019 [119]. The com- cIAIs, respectively [132,133].
pany plans to submit an NDA in late 2018 followed by a marketing
authorisation application to the EMA [120]. The wide spectrum of 4.1.2. Sulbactam/ETX2514 (ETX2514SUL)
activity of cefiderocol against siderosphore-resistant bacteria and ETX2514SUL (developed by Entasis Therapeutics Inc.) is a com-
non-fermenting bacteria demonstrates its great potential in fight- bination of sulbactam, a β -lactam antibiotic, and ETX2514, a di-
ing GNB infections. azabicyclooctane with wide-spectrum inhibition of class A, B,
and D β -lactamases, and potent in vivo efficacy against MDR
A. baumannii [134]. A phase I trial of ETX2514SUL has demon-
3.1.4. Cefepime/AAI101 strated positive PK and drug tolerance results, and a phase II trial
Cefepime, a fourth-generation cephalosporin with a wide range (NCT03445195) evaluating the safety and efficacy of intravenous
of Gram-positive and Gram-negative activity, is combined with ETX2514SUL in patients with cUTIs was concluded and results are
the β -lactamase inhibitor AAI101 (developed by Allecra) [121]. Ce- pending [135,136]. ETX2514SUL has been awarded Fast Track status
fepime is an established cephalosporin; however, there has been by the FDA, and a plan to move to phase III trials in early 2019 is
an increase of resistance in β -lactamase-producing Enterobacte- underway [135].
riaceae [121]. AAI101 is a novel β -lactamase inhibitor that has
inhibitory activities on a wide array of β -lactamases as well as 4.2. Phase I drugs
some class A and class B carbapenemases [121]. The combination
of cefepime/AA101 has been tested in vitro against highly resistant 4.2.1. WCK5222
K. pneumoniae and E. coli strains, and AA101 restored the suscep- WCK5222 (developed by Wockhardt Discovery) is a combina-
tibility of these organisms against cefepime [121]. A randomised, tion of cefepime, a cephalosporin, and zidebactam, which binds
double-blind, non-inferiority, phase II trial (NCT03680612) com- to Gram-negative PBP-2 and inhibits β -lactamases [137]. In vitro,
paring cefepime/AAI101 with cefepime in hospitalised adults with WCK5222 was potent against β -lactamase-producing Enterobacte-
cUTIs has been completed, pending results [122]. A randomised, riaceae and P. aeruginosa [137]. WCK5222 is potentially indicated
double-blind, non-inferiority phase III trial (NCT03687255) com- for HAP/VAP, BSI/sepsis, cIAIs and cUTIs [138]. A phase I study
paring cefepime/AAI101 with piperacillin/tazobactam in the treat- (NCT02707107) evaluating the safety, tolerability and PK of intra-
ment of cUTIs is currently recruiting [123]. venous WCK5222 has been completed, and results are pending for
Table 3
Summary of antibiotics with activity against Gram-negative bacteria currently in clinical trials.

Drug name Phase Company Drug class and MOA Spectrum against Gram-negative bacteria and enzymes [15] Potential Ongoing clinical trials
indications (ClinicalTrial.gov No.)
Effective against Ineffective against

Sulopenem III Pfizer and Iterum β -lactam ESBL-producing Enterobacteriaceae CRE, P. aeruginosa, cIAI, cUTI, uUTI NCT03354598,
Therapeutics Ltd. S. maltophilia NCT03357614,
NCT03358576
Imipenem/cilastatin III Merck Sharp & Dohme β -lactamase Enterobacteriaceae producing class A and C Imipenem-resistant cIAI, cUTI, HAP, NCT02493764,

D. Koulenti, A. Song and A. Ellingboe et al. / International Journal of Antimicrobial Agents 53 (2019) 211–224
+ Relebactam Corp. inhibitor + β -lactam/ β -lactamases: E. coli (ESBL- and KPC strains), Enterobacteriaceae VAP NCT03583333
(MK-7655) dehydropeptidase K. pneumoniae (ESBL, KPC, AmpC and OXA type expressing IMP, VIM
inhibitor carbapenemase strains) and P. aeruginosa isolates or NDM MBLs,
with either porin deficiency or over-expression A. baumannii, IMP- or
of chromosomal AmpC VIM-producing
P. aeruginosa
Cefiderocol or III Shionogi & Co. Ltd. Cephalosporin ESBL and AmpC-producing Enterobacteriaceae, CRE BSI, cUTI, HAP, NCT02714595,
S-649266 (irrespective of carbapenemase-production), VAP NCT03032380
carbapenem-resistant Acinetobacter spp.,
MDR-Pseudomonas spp., S. maltophilia and
Burkholderia spp.
Cefepime/AAI101 III AAI101: Allecra β -lactam + β -lactamase ESBL and carbapenemase-producing CRAB, CRPA cUTI NCT03687255
inhibitor Enterobacteriaceae
Murepavadin or III Polyphor Ltd. OMPTA CRPA CRAB, CRE HAP, VAP by NCT03409679
POL7080 P. aeruginosa
LYS228 II Novartis Ag. β -lactam Enterobacteriaceae-producing NDM-1, KPC, most CRAB, CRPA cIAI, cUTI NCT03377426,
ESBLs, CRE NCT03354754
Sulbactam/ETX2514 II Entasis Therapeutics β -lactam + β -lactamase Class A, B, and D β -lactamases, CRAB CRE, CRPA NCT03445195
(ETX2514SUL) Inc. inhibitor
Cefepime/Zidebactam I Wockhardt Ltd. Cephalosporin + ESBL-producing Enterobacteriaceae, CRE, CRPA BSI, cIAI, cUTI, NCT02707107,
(WCK 5222) β -lactamase inhibitor HAP, VAP NCT02942810,
NCT03554304 [191],
NCT03630094 [192]
SPR741 I Spero Therapeutics Inc. Polymyxin NCT03376529,
NCT03022175 [193]
SPR994 (Tebipenem) 1
I Spero Therapeutics Inc. β -lactam ESBL-producing E. coli and K. pneumoniae [194] cUTI [194] NCT03395249 [195]2
Nacubatam or I Meiji Seika Pharma Co. β -lactamase inhibitor CRE, Class A and C β -lactamases [196] CRAB NCT03182504 [197]2
OP0595/RG60801 Ltd.; Fedora
Pharmaceuticals Inc.
VNRX-51331 I VenatoRX β -lactamase inhibitor Serine β -lactamases, MBLs [198] NCT02955459 [199]2 ,
Pharmaceuticals NCT03332732 [200],
NCT03690362 [201]
GSK33428301 I GlaxoSmithKline plc Cephalosporin CRAB, CRE, CRPA NCT02751424 [202]2
β -lactam
TP-60761 I Tetraphase Tetracycline CRAB, Enterobacteriaceae, E. coli, K. pneumoniae CRPA NCT03691584 [204]
Pharmaceuticals [203]
Note:
1
SPR994 (Tebipenem), Nacubactam (OP0595/RG6080), VNRX-1533, GSK3342830 and TP-6076 are not included in the main text.
2
These clinical trials have been concluded as of 11 October 2018.
Abbreviations: BSI (blood stream infection), cIAI (complicated intra-abdominal infection), cUTI (complicated urinary tract infection), CRAB (carbapenem-resistant Acinetobacter baumannii), CRE (carbapenem-resistant Enter-
obacteriaceae), CRPA (carbapenem-resistant Pseudomonas aeruginosa), ESBL (extended spectrum β -Lactamase), GNBs (Gram-negative bacteria), HAP (hospital-acquired pneumonia), IMP (imipenemase metallo-β -lactamase), KPC
(Klebsiella pneumoniae carbapenemase), MBL (metallo-β -lactamase), MDR (multidrug-resistant), MOA (mechanism of action), NDM (New Delhi metallo-β -lactamase), OMPTA (outer membrane protein-targeting antibiotic), OXA
(oxacillin carbapenemases), uUTI (uncomplicated urinary tract infection), VAP (ventilator-acquired pneumonia), VIM (Verona integron-encoded metallo-β -lactamase).
Bacteria abbreviations: A. baumannii (Acinetobacter baumannii), E. coli (Escherichia coli), K. pneumoniae (Klebsiella pneumoniae), P. aeruginosa (Pseudomonas aeruginosa), S. maltophilia (Stenotrophomonas maltophilia).

217
218 D. Koulenti, A. Song and A. Ellingboe et al. / International Journal of Antimicrobial Agents 53 (2019) 211–224

another phase I study (NCT02942810) that investigates the PK of galactose reduced P. aeruginosa count in the sputum of cystic fibro-
WCK5222 in patients with renal impairment [139,140]. sis (CF) patients without impairing lung function [147]. This indi-
cates that the competitive inhibition of lectins is effective at facili-
tating the removal of bacteria via the mucociliary elevator and may
4.2.2. SPR741
provide an adjunctive treatment option, pending further research
SPR741 (developed by Spero Therapeutics Inc.) is a polymyxin
[147]. However, since this trial, investigations into lectin inhibition
derivative with little antibiotic activity but it enhances other an-
have stagnated.
tibiotics [141]. Polymyxins are five cationic charged lipopeptides
that attack the cell membrane of GNBs, and SPR741 is a derivative
of polymyxin B with the same cyclic portion but lacking the two-
5.3. Bacteriophages
cationic charged fatty acid tail [141]. A randomised phase I trial
(NCT03376529) was completed in 2018 investigating combinations
Use of bacteriophages to target certain bacteria was a very
of SPR741 with ceftazidime, piperacillin/tazobactam, or aztreonam
early idea that has recently undergone a renaissance. Bacterio-
showing favourable tolerability and PK profiles [142,143].
phages expressing endolysins can enter target cells when com-
bined with permeabilisers [148]. More recently, effective reduc-
4.2.3. Others tion of P. aeruginosa load in a biofilm-associated murine model
Other phase I drugs that are currently being developed of CF has been demonstrated with nebulised phage therapy [149].
include SPR994 (a broad-spectrum β -lactam), Nacubactam Nebulisation has been shown to be an effective delivery method
(OPO595/RG6080, a serine β -lactamase inhibitor), VNRX-5133, (an for bacteriophages, and has potential to be trialled in HAV/VAP
injectable β -lactamase inhibitor), GSK3342830 (a new siderophore cases [150]. A phase I/II clinical trial investigating bacteriophages
cephalosporin β -lactam) and TP-6076 (a tetracycline), as sum- (NCT02116010; ‘PhagoBurn’; Pherecydes Pharma) was launched in
marised in Table 3. June 2013, and was funded by the European Commission under
the Seventh Framework Programme for Research and Development
5. Emerging alternative management options for GNB [151]. However, it was stopped prematurely in January 2017 due
infections to insufficient efficacy of anti-P. aeruginosa bacteriophage PP1131
[152]. A major limitation of the study was that stability issues re-
Although antibiotics represent a significant avenue in infectious sulted in a lower than expected dose (10 0 0-fold to 10 0 0 0-fold)
disease management, exploring new treatment options is impera- of PP1131 in the phage group [152]. At low doses, PP1131 induced
tive to enhance the arsenal against MDR organisms. Areas of de- a slower clinical response than standard-of-care, and treatment-
velopment include targeting quorum-sensing systems, lectin in- resistant bacteria were also isolated in patients with failed treat-
hibition, bacteriophage-mediated endolysin delivery, and antibody ments [152]. However, some positive findings from this study, such
immune therapy. as a clinically-relevant reduced bacterial burden and fewer serious
adverse events in the phage group, warrant further investigations
with increased doses and a larger sample size [152].
5.1. Quorum-sensing inhibitors (QSI)

Developed by Nanyang Technological University, Singapore,

5.4. Immunotherapy
quorum sensing (QS) is utilised by bacteria to communicate in re-
sponse to stimuli. Bacteria may be triggered to synthesise small
Use of monoclonal antibodies (MABs) has great potential for
molecules that contribute to regulating gene expression [144]. The
highly targeted antibiotic therapy. The development of polymerase
regulation of various virulence factors by QS has led to investiga-
chain reaction (PCR) for use in diagnosing infections has over-
tions into QS as a therapeutic target. Two major mechanisms have
come the barrier of traditional culturing techniques [153]. A small
been proposed for the disruption of QS: intercepting the small sig-
phase II trial (NCT00851435, Kenta Biotech Ltd, n=31) was con-
nalling molecules with quorum-quenching enzymes (QQEs) and in-
ducted on patients with serotype O11 P. aeruginosa pneumonia
hibiting QS receptors with quorum-sensing inhibitors (QSIs) [144].
[154]. The study demonstrated that panobacumab, a MAB targeted
Las and rhl, two homologues of the largely conserved acylhomoser-
against pseudomonal lipopolysaccharides, combined with conven-
ine lactone-based QS signals, function in QS pathways in P. aerug-
tional therapy, decreased time to clinical resolution with no as-
inosa. One in vitro study explored using QQEs and QSIs to inhibit
sociated immunogenicity, which may justify further research into
gene expression regulated by las and rhl, and it found significant
adjunctive immunotherapy for HAP/VAP [155]. Another trial, spon-
reduction in the pathogenicity of P. aeruginosa with a combination
sored by KaloBios Pharmaceuticals, has investigated a fusion anti-
therapy [144]. Another study on P. aeruginosa explored the effects
body (FAB) KB001 targeted to another pseudomonal virulence fac-
of blocking las and rhl receptors with meta-bromo-thiolactone,
tor, the type-3 secretion system needle-tip protein PcrV [156]. This
which was shown to have protective effects on Caenorhabditis el-
trial indicated that the FAB KB001 was safe, with a favourable PK
egans and human lung epithelium against killing and biofilm for-
profile, but was not powered to explore clinical outcome [156].
mation by P. aeruginosa [145]. The promising results produced in
A subsequent phase II trial (NCT01695343, Humanigen, Inc.) has
vitro encourage progression to in vivo studies. Pending future re-
investigated the clinical efficacy of KB001 in CF patients with as-
sults, potential clinical trials may emerge involving QSI/QQE for
sociated pseudomonal infection [157]. In this study, KB001 demon-
HAP/VAP.
strated moderately improved forced expiratory volume in one sec-
ond (FEV1 ) and reduced inflammatory marker IL-8 compared with
5.2. Lectin inhibitors placebo [158]. Further immunotherapeutic research has yielded
MEDI3902, which is in a phase II trial (NCT02696902, Medimmune
P. aeruginosa expresses cell surface proteins called lectins. They LLC) [159]. This MAB also targets the PcrV component of the pseu-
play a key pathogenic role in two ways: by binding galactose domonal type III secretion system and is administered prophylac-
and fructose, respectively, in the glycocalyx of mammalian airways tically in VAP patients [160]. Outcomes for the trial will include
leading to adhesion, and by inactivating the mucociliary elevator safety and efficacy in reducing incidence of pseudomonal VAP and
[146]. A small clinical trial showed that inhalation of fructose and may direct further research [160].
 D. Koulenti, A. Song and A. Ellingboe et al. / International Journal of Antimicrobial Agents 53 (2019) 211–224 219

6. New dosing strategies to optimise efficacy of existing 7. Conclusions

antibiotics against Gram-negative bacteria
Despite increased efforts to develop new antibiotics, the num-
The rapid rise of MDR pathogens combined with a drying ber of drug approvals has dwindled in the last few years.
antibiotic pipeline has created an urgent need to optimise the Since 2010, only five new agents with activity against MDR
use of currently available antibiotics. The traditional goals of an- Gram-negative strains have been approved by the FDA and/or
tibiotic therapy were previously focused on maximising clinical the EMA, namely ceftolozane/tazobactam, ceftazidime/avibactam,
and microbiological outcomes, but not on minimising the emer- meropenem/vaborbactam, plazomicin and eravacycline. To safe-
gence of bacterial resistance [161]. Emerging PK/PD data indicate guard these antibiotics from resistance development, it is cru-
that the magnitude of antibiotic exposures for resistance suppres- cial to use them only as last-resort treatments when infections
sion is generally higher than the thresholds needed for optimal caused by microorganisms resistant to alternative options are con-
clinical and bacteriological outcomes [162-167]. Therefore, con- firmed or strongly suspected. Also, it should be noted that for
ventional antibiotic dosing, which primarily seeks to attain clin- the difficult-to-treat GNBs (such as MBL/NDM-1 producers, MDR-
ical success, may potentially amplify bacterial resistance by se- A. baumanni, etc.) the available options are still very limited and
lecting mutant bacterial strains with reduced drug susceptibility are expected to remain limited in the near future. Although there
[168-170]. Furthermore, as most antibiotic dosing recommenda- is a variety of agents currently in clinical trials, the vast majority
tions have been derived from healthy volunteers, different dos- of them are modifications of existing antibiotic classes addressing
ing approaches may be needed in patients with severe infections specific resistant mechanisms and are active only against specific
[171]. The altered dosing approaches may not only increase the pathogens or limited subsets of resistant strains [15]. On the other
likelihood of PK/PD target attainment and therapeutic success but hand, new alternative treatments, such as immunotherapy, bacte-
may also prolong the clinical lifespan of our existing antibiotic ar- riophages, QSIs and lectin inhibitors, are in their infancy for the
mamentarium. By way of example, maintaining effective β -lactam management of GNB infections, and their potential is yet to be ex-
exposure for extended periods via prolonged infusion (either con- plored. Finally, further research is needed to assess the PK/PD, effi-
tinuous or extended infusion) has been associated with the like- cacy, and applicability of these novel antibiotics in clinical practice.
lihood of clinical success and resistance suppression and, thus,
would be particularly suitable in critically ill patients with se- Acknowledgments
vere infections [162,172-174]. The theoretical basis for prolonged
β -lactam infusion in critically ill patients is well established with We would like to express our very great appreciation to Mr Lars
numerous preclinical and PK/PD data supporting this method of Eriksson, The University of Queensland, UQ Library, Herston Qld
administration over traditional bolus dosing in such a popula- 4006, Australia, for his valuable assistance with literature search.
tion [172]. Through robust PK/PD analysis, newer β -lactam an-
Funding
tibiotics (and their combinations), such as ceftazidime/avibactam,
doripenem and meropenem/vaborbactam, have been recognised to
None.
benefit from prolonged infusions in the earlier phase of develop-
ment. Furthermore, a recent individual patient data meta-analysis Competing interests
of three multicentre randomised controlled trials [175-177] com-
paring continuous and intermittent infusion of β -lactam antibiotics Author JL reports: Advisory Board with Bayer and MSD and
reported lower hospital mortality in the continuous infusion group, honorarium for lectures from Pfizer and MSD. Author PH reports
with the greatest benefits observed in patients with a higher level that he has received research support from Shionogi. All other au-
of sickness severity who were not receiving renal replacement thors (DK, AS, AE, MHA and EG) declare no competing interests.
therapy and were infected with non-fermenting GNBs [178]. Eight
recent meta-analyses have also reported significant patient bene- Ethical approval
fits with prolonged β -lactam infusions [179-186]. Importantly, the
BLING III trial (NCT03213990; a prospective, multinational, multi- Not required.
centre, open-labelled, phase III trial) is currently underway aiming
to recruit 70 0 0 patients to determine whether continuous infusion Supplementary material
of a β -lactam antibiotic results in significant patient benefits com-
pared with intermittent dosing in critically ill patients with severe Supplementary material associated with this article can be
sepsis [187]. found, in the online version, at doi:10.1016/j.ijantimicag.2018.10.
However, there are currently limited data describing the PK/PD 011.
exposure needed to prevent the emergence of resistance and ur- References
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