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REVIEW

CURRENT
OPINION Current evidence for therapy of ceftriaxone-
resistant Gram-negative bacteremia
David L. Paterson a,b, Andrew Henderson a,c, and Patrick N.A. Harris a,d

Purpose of review
This article aims to give a state-of-the-art assessment of treatment options for bloodstream infection because
of ceftriaxone-resistant Gram-negative bacilli, especially those caused by extended-spectrum beta-lactamase
(ESBL) or AmpC-producing Enterobacteriaceae. In particular, this review assesses whether current data
support ‘carbapenem-sparing options’ for treatment of these serious infections.
Recent findings
The MERINO trial refuted earlier observational studies some of which showed equivalence in outcomes
Downloaded from http://journals.lww.com/co-infectiousdiseases by BhDMf5ePHKbH4TTImqenVHT0Rm60g2jqIumURmnSSitIJtIrB1lvRKyB6RcmdDftq+U3EZMf3us= on 12/15/2019

between beta-lactam/beta-lactamase inhibitor combinations and carbapenems for treatment of bloodstream

infection because of ceftriaxone-resistant Escherichia coli or Klebsiella spp. Although numerous factors
influence mortality following bloodstream infection, the variability in piperacillin/tazobactam MICs
observed in the MERINO trial make this a less secure option than meropenem. However, the search for
carbapenem-sparing options continues with four randomized controlled trials (RCTs) in progress and a
number of other options in clinical development.
Summary
Hard outcomes from RCTs are still needed before intravenous carbapenems can be displaced as the
treatment of choice for ceftriaxone-resistant Gram-negative bacilli.
Keywords
bloodstream infections, carbapenems, carbapenem-sparing, ceftriaxone-resistance, extended-spectrum
beta-lactamases

INTRODUCTION that carbapenems pose a substantial risk of

Ceftriaxone-resistant Gram-negative bacilli are
increasingly commonplace, with 25% of Enterobac-
teriaceae worldwide estimated to now be resistant [1].
In Enterobacteriaceae, ceftriaxone resistance is
typically mediated by bacterial production of
extended-spectrum beta-lactamases (ESBLs) or AmpC
beta-lactamases. As an indication of the importance
of this antibiotic resistance problem, it was recently
estimated that over 290 000 isolates of ESBL-produc-
ing Enterobacteriaceae occur in patients admitted to
hospitals in the United States each year [2]. In recent
surveillance studies from Asia, the incidence of infec-
tions with ceftriaxone-resistant organisms is likely
to be much higher as almost 50% of Escherichia coli
and over 25% of Klebsiella pneumoniae isolates causing
significant infection are ESBL-producing [3].
Carbapenem antibiotics (for example, merope-
nem) are reliably active in vitro against ESBL-
producing organisms. However, notwithstanding a
lack of high-quality evaluations of the effects on the
human microbiome, there is a general perception
collateral damage [4]. This could take the form
of selection for carbapenem-resistant organisms (such
as carbapenem-resistant Enterobacteriaceae – CRE,
carbapenem-resistant Pseudomonas aeruginosa, carba-
penem-resistant Acinetobacter baumannii, or intrinsi-
cally carbapenem-resistant Gram-negative bacilli,
such as Stenotrophomonas maltophilia) or selection
for vancomycin-resistant enterococci, methicillin-
resistant Staphylococcus aureus or Candida spp.
a
University of Queensland Centre for Clinical Research, bInfectious
Diseases Unit, Royal Brisbane and Women’s Hospital, cInfection Man-
agement Services, Princess Alexandra Hospital and dCentral Microbiol-
ogy Laboratory, Pathology Queensland, Brisbane, Australia
Correspondence to David L. Paterson, University of Queensland Centre
for Clinical Research, Faculty of Medicine, The University of Queensland,
Level 8, Building 71/918, UQCCR, RBWH Campus, Herston, QLD
4029, Australia. Tel: +61 7 3346 5500; fax: +61 7 3346 5509;
e-mail: d.paterson1@uq.edu.au
Curr Opin Infect Dis 2019, 32:000–000
DOI:10.1097/QCO.0000000000000623

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Special commentary
KEY POINTS
 Bloodstream infections because of ESBL or AmpC-
mediated ceftriaxone-resistant Gram-negative bacilli are
incredibly common.
 The MERINO trial demonstrated that mortality at
30 days after bloodstream infection was lower with
meropenem than with piperacillin/tazobactam.
 Likely explanations for mortality following bloodstream
infections because of ceftriaxone-resistant Gram-
negative bacilli include underlying comorbidities, the
source of the infection and also the in-vitro activity of
the antibiotic used.
 For piperacillin/tazobactam, the in-vitro activity against
ESBL and AmpC producers is highly variable, which
may explain its suboptimal clinical activity.
 A large range of alternatives to intravenous
carbapenems are being studied in treatment of
ceftriaxone-resistant organisms.
In view of the potential problems of carbapenem
overuse, there is a search for ‘carbapenem-sparing’
alternatives, which can be used for treating sus-
pected or proven ceftriaxone-resistant organisms.
Beta-lactam/beta-lactamase inhibitor combinations
are the most apparent antibiotics to potentially fit
the mantle of ‘carbapenem sparers’.
THE MERINO TRIAL: FINDINGS,
EXPLANATIONS AND UNANSWERED
QUESTIONS
Over 20 observational studies have been undertaken,
which have evaluated outcome when patients with
bloodstream infections with ESBL-producing organ-
isms were treated with beta-lactam/beta-lactamase
inhibitor combinations (especially piperacillin/
tazobactam) or carbapenems [5]. Although some
studies showed superiority of carbapenems [6], taken
collectively, these observational studies have sug-
gested that no significant difference in outcome
occurs when beta-lactam/beta-lactamase inhibitor
combinations were used as compared with carbape-
nems [5]. However, observational studies are fraught
with potential biases, and therefore, randomized
controlled trials (RCTs) are needed to determine if
the results of observational studies can be applied to
clinical practice.
In September 2018, we reported the results of
the MERINO trial – the world’s first large RCT of a
carbapenem-sparing option (piperacillin/tazobac-
tam) versus a carbapenem (meropenem) for patients
with ceftriaxone-resistant E. coli or K. pneumoniae
2 www.co-infectiousdiseases.com
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&&
bloodstream infection [7 ]. The study was per-
formed at 26 hospitals in 9 countries (Singapore,
Australia, Turkey, New Zealand, Italy, South Africa,
Saudi Arabia, Lebanon, Canada). We enrolled 379
patients of whom 378 were assessed for the primary
outcome (30-day all-cause mortality). 12.3% (23 of
187) patients randomized to piperacillin/tazobac-
tam died within 30 days of randomization com-
pared with 3.7% (7 of 191) randomized to
meropenem. We concluded that the use of pipera-
cillin/tazobactam in this setting was not supported.
As an accompanying editorial by Hayden and Won
&
[8 ] concluded, the search (for a carbapenem-
sparing option for ESBL producers) continues.
Importantly, the MERINO trial studied whether
piperacillin/tazobactam was noninferior to merope-
nem as definitive treatment for ceftriaxone-resistant
E. coli or K. pneumoniae bloodstream infections.
Investigators could enrol a patient up to 72 h after
collection of the initial positive blood culture, and
patients could only be enrolled if their hospital’s
laboratory determined that the organism was resis-
tant to ceftriaxone and susceptible to both pipera-
cillin/tazobactam and meropenem. There were no
restrictions on the choice of empiric antibiotics used
prior to randomization. This trial, therefore, differed
substantially from trials performed for registrational
purposes, which typically limit the duration of ‘free
choice’ empiric therapy to 24 h or less. From a
pragmatic clinical perspective, however, clinicians
are faced with a choice of definitive therapy once
ceftriaxone resistance is confirmed. It would be
extremely inefficient to enrol patients into a trial
before bloodstream infection or antibiotic suscepti-
bility is confirmed.
An important question, which has been asked of
the MERINO trial investigators is whether piperacil-
lin/tazobactam was dosed as an extended infusion
or as a conventional infusion. From a pharmacoki-
netic/pharmacodynamics (PK/PD) perspective, tar-
get attainment would be expected to be superior if
piperacillin/tazobactam was given as an extended
infusion. We chose to administer both drugs as a
conventional 30 min infusion since a 7000þ patient
RCT of ICU antibiotics as extended or conventional
infusion is currently underway [9]. The results of
that trial are awaited with interest.
The primary endpoint of the MERINO trial was
30-day all-cause mortality. A criticism of the
MERINO trial has been that many patients appeared
not to have infection as a cause of death [10]. It has
been speculated that imbalance in baseline charac-
teristics may have led to an apparent trend to a
higher mortality in patients treated with piperacil-
lin/tazobactam [10]. Of importance is our finding
that only 9/23 (39.1%) of those who received
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piperacillin/tazobactam and died had clinical and
microbiologic success (defined as survival, resolu-
tion of fever, normalized white cell count and neg-
ative blood cultures) at 4 days from receipt of study
drug, compared with 112/154 (72.7%) of those who
received piperacillin/tazobactam and survived and
138/185 (74.6%) of all those who received merope-
nem. We believe that failure of piperacillin/tazobac-
tam to resolve infection with ESBL producers
‘pushes’ patients with comorbidities ‘over the edge’
resulting in premature death, even if infection is not
clearly the proximate cause of death.
There may also be microbiologic explanations
for our findings. In the MERINO trial, patients were
randomized on the basis of resistance to ceftriaxone
and susceptibility to both piperacillin/tazobactam
and meropenem as tested by their local microbiology
laboratories. Importantly, laboratories were asked to
perform antimicrobial susceptibility testing (AST)
according to their standard laboratory methods,
reported by most laboratories as Vitek 2 AST (Bio-
Merieux) or disk diffusion zone of inhibition. Labo-
ratories performing AST for enrolling sites in the
MERINO trial also varied between Clinical & Labo-
ratory Standards Institute (CLSI) and European
Committee on Antimicrobial Susceptibility Testing
(EUCAST) breakpoints for piperacillin/tazobactam
and meropenem (piperacillin/tazobactam suscepti-
ble breakpoint 8 mg/l EUCAST and 16 mg/l CLSI;
meropenem susceptible breakpoint 2 mg/l
EUCAST and 1 mg/l CLSI) [11,12]. At the conclu-
sion of the trial, the blood culture isolates were sent
to a central laboratory where minimum inhibitory
concentrations (MIC) were determined by gradient
diffusion testing and broth microdilution testing.
Additionally, antibiotic resistance genes were
sought by whole-genome sequencing. Three find-
ings became clear with this additional analysis.
Firstly, susceptibility testing for piperacillin/
tazobactam was prone to a higher than expected rate
of very major errors at the local level (that is, local
methods showed piperacillin/tazobactam suscepti-
bility whereas reference broth microdilution testing
showed that the isolates were in fact, resistant).
Secondly, the co-production of the OXA-1 beta-
lactamase in addition to CTX-M type ESBLs typically
led to an increase in piperacillin/tazobactam MIC.
OXA-1 is a commonly observed beta-lactamase pro-
&
duced by E. coli [13 ]. It is co-produced with ESBLs,
predominantly CTX-M-15 amongst subclade C2
sequence type (ST) 131 E. coli, in up to 50% of
bloodstream isolates – it is a penicillinase with weak
affinity for inhibitors, and therefore, compromises
activity of piperacillin/tazobactam (and amoxicil-
&
lin/clavulanate) [13 ,14]. Just as in Livermore’s
study, for piperacillin/tazobactam the modal MIC
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Therapy of ceftriaxone-resistant bacteremia Paterson et al
rose from 2 mg/l in the absence of blaOXA-1 to
&
8–16 mg/l in its presence [13 ].
Finally, it appears that a mix of piperacillin/
tazobactam MIC, patient comorbidity and source
of bacteremia contribute to outcome of patients
with ESBL or AmpC producers treated with piper-
acillin/tazobactam. Given that meropenem MICs
are substantially below the susceptibility break-
point, we believe that meropenem is a more reliable
antibiotic for treatment of ceftriaxone-resistant
Gram-negative bacilli.
TRIALS IN PROGRESS
To our knowledge, four RCTs are currently planned
or in progress to address the question of alternatives
to carbapenems for treatment of BSI because of
ceftriaxone-resistant organisms. These are the
MERINO-2 (NCT02437045), MERINO-3, PETER PEN
(NCT03671967), and FOREST (NCT02142751) trials.
The MERINO-2 trial is a pilot RCT comparing
piperacillin/tazobactam with meropenem as defini-
tive treatment for bloodstream infections because of
Enterobacter spp., Serratia marcescens, Citrobacter
freundii, Providencia spp. and Morganella morganii.
Investigators could enrol a patient up to 72 h after
collection of the initial positive blood culture, and
patients could only be enrolled if their hospital’s
laboratory determined that the organism was
susceptible to both piperacillin/tazobactam and
meropenem. When the results of the MERINO trial
became available, enrolment was paused. The
MERINO-2 trial was restarted with the restriction
that the patient’s organism must be susceptible to
third generation cephalosporins, to obviate the
possibility of strains also expressing ESBLs or
demonstrating a de-repressed AmpC phenotype.
At the time of writing, results of the trial are not
yet available.
The MERINO-3 trial is a pragmatic RCT of cefto-
lozane/tazobactam versus meropenem for patients
with bloodstream infection because of Enterobacter
spp., S. marcescens, C. freundii, Providencia spp. and
M. morganii and third-generation cephalosporin-
resistant E. coli or K. pneumoniae. Ceftolozane–
tazobactam was chosen as a potential carbapenem-
sparing option as MICs of this antibiotic are consid-
erably lower than those of piperacillin–tazobactam
[15]. Recently, several articles have also highlighted
key PK/PD indices between tazobactam concentra-
tions required for piperacillin and ceftolozane to
inhibit ESBL enzymes, with the tazobactam concen-
tration required for ceftolozane much lower for
CTX-M type ESBLs [16–18]. Enrolled patients
in the MERINO-3 trial must have confirmed
susceptibility to both ceftolozane/tazobactam and
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Special commentary
meropenem. At the time of writing, this trial was still
in preparation.
The PETERPEN trial is a three-country (Israel,
Italy, and Spain) RCT comparing piperacillin/
tazobactam with meropenem for more than 1000
patients with ceftriaxone-resistant E. coli or
K. pneumoniae bloodstream infection. Planned
exclusion criteria make the PETERPEN study popu-
lation of lower severity of illness than the MERINO
trial population. Additionally, each piperacillin/
tazobactam dose will be given as an extended infu-
sion over 3 h instead of the conventional 30 min
infusion used in the MERINO trial. At the time of
writing, this trial was still in preparation.
The FOREST trial is a Spanish RCT comparing
fosfomycin with meropenem for treatment of
E. coli bloodstream infection of urinary tract origin
[19]. Oral therapy is allowed from the fifth day of
therapy if clinical improvement is achieved. This
constitutes oral fosfomycin trometamol in the
fosfomycin arm and one of ciprofloxacin, amoxi-
cillin/clavulanate or trimethoprim/sulfamethoxa-
zole in the meropenem arm. Study enrolment has
been completed, with some modifications to the
originally published protocol because of slow
recruitment. The findings of the study are awaited
with interest.
EXPERIENCE WITH RELATIVELY NEW
BETA-LACTAM/BETA-LACTAMASE
INHIBITOR COMBINATIONS
Ceftolozane–tazobactam is active against close to
90% of bloodstream isolates of ESBL-producing
Enterobacteriaceae [20]. The antibiotic combination
has undergone three phase III randomized clinical
trials for registrational purposes for the indications
of complicated UTI (cUTI), complicated intra-
abdominal infections (cIAI) and hospital-acquired
pneumonia requiring mechanical ventilation
[21,22]. Popejoy et al. evaluated the outcome of
ceftolozane–tazobactam versus comparator drugs
(levofloxacin for cUTI and meropenem for cIAI)
for the subset of patients with infections because
&
of ESBL-producing organisms [23 ]. In total, 150 of
1346 (11.1%) patients involved in these studies were
infected with ESBL producers. Clinical cure rates
were 97.4% (76/78) for those randomized to cefto-
lozane–tazobactam, 82.6% (38/46) for those ran-
domized to levofloxacin and 88.5% (23/26) for
those randomized to meropenem.
The number of enrolled patients with ESBL pro-
ducers is too small from these studies to conclude
that ceftolozane–tazobactam is effective for serious
infections with ceftriaxone-resistant organisms. The
MERINO-3 trial (see above) will, therefore, be vital in
4 www.co-infectiousdiseases.com
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determining whether ceftolozane–tazobactam is a
carbapenem-sparing option.
Ceftazidime–avibactam has been compared
with ‘best available therapy’ (BAT) for cUTI or cIAI
because of ceftazidime-resistant Enterobacteriaceae
&
or P. aeruginosa [24 ]. Ninety-six percent of those
receiving ‘best available therapy’ received carbape-
nem monotherapy. Clinical cure was observed in
91% of patients in each arm of this 333 patient
study. Only 10 patients in this open-label RCT
had bloodstream infection. Cure rates by enzyme
type were 92.5% for ceftazidime/avibactam and
92.9% for BAT in the subset of patients infected
with isolates harboring blaCTX-M whereas for
patients with baseline isolates carrying AmpC genes
(plasmid-mediated AmpC and/or overexpression of
intrinsic AmpC), clinical cure rates were 80 and
89.5% for ceftazidime–avibactam and BAT arms,
respectively [25].
There are no trials currently planned for cefta-
zidime–avibactam versus meropenem for blood-
stream infections because of ceftriaxone-resistant
organisms. Due to the drug’s cost in many countries,
it is likely to be reserved for infections with Klebsi-
ella pneumoniae carbapenemase (KPC)- producing
organisms rather than for ESBL producers. Further-
more, recent observations suggest that widespread
use of ceftazidime–avibactam was associated with a
change in epidemiology of carbapenemase pro-
ducers from KPC to metallobeta-lactamases [26].
48.1% (13/27) with a ceftazidime–avibactam-
resistant K. pneumoniae bloodstream isolate had pre-
viously received the antibiotic [26].
Meropenem–vaborbactam and imipenem–
relebactam have also been recently studied in
registrational trials, but the use of these antibiotic
combinations for ceftriaxone-resistant organisms
would seem ‘overkill’ given the generic availability,
and narrower spectrum, of carbapenems alone.
EXPERIENCE WITH
OXYIMINOCEPHALOSPORINS,
TEMOCILLIN, CEPHAMYCINS AND
NONBETA-LACTAM ANTIBIOTICS
Isolates with cefepime MICs greater than 2 mg/l and
8 mg/l or less are currently considered susceptible
dose-dependent (SDD) according to CLSI break-
points, whilst EUCAST now classifies isolates with
cefepime MICs greater than 1 mg/l and 4 mg/l or less
as susceptible, increased exposure [12]. Essentially
both CLSI and EUCAST use these definitions to
categorize ESBL isolates with low-cefepime MICs
as susceptible at higher than standard doses. Enter-
obacteriaceae isolates with cefepime MICs in this
range typically represent ESBLs as cefepime is stable
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to the effect of AmpC enzymes [11]. The current
breakpoints were included to provide cefepime as a
carbapenem-sparing option for ESBLs, however,
clinical evidence to support this is limited. Several
retrospective studies have reported higher mortality
rates with patients treated with cefepime than car-
bapenems, particularly where isolates had cefepime
MICs between 2 and 8 mg/l [27–29].
In contrast, ceftazidime does not have a SDD
breakpoint with CLSI but isolates with MICs 4 mg/l
or less are considered susceptible [11]. Compara-
tively for EUCAST, isolates with ceftazidime MICs
greater than 1 mg/l and 4 mg/l or less are considered
susceptible, increased exposure [12]. Both EUCAST
and CLSI indicate that isolates should be reported as
susceptible (or susceptible, increased exposure),
with the presence of an ESBL gene not influencing
reporting. Similar to cefepime, studies have gener-
ally reported higher mortality rates with ceftazidime
compared with carbapenems [30,31]. Some ESBL
genes such as CTX-M-14 have MICs 4 mg/l or less
at standard inocula but often become resistant at
higher inocula; however, the clinical effect of this
phenomenon is not known [32].
Temocillin
Temocillin is a derivative of ticarcillin, with stability
to hydrolysis by ESBL and AmpC enzymes. As a result,
it has been recently revisited as a potential treatment
option for strains expressing these enzymes. It is
worth noting that temocillin has no stability to
OXA-48-like carbapenemases or metallobeta-lacta-
mases and its efficacy is diminished by alteration
in porins or efflux mechanisms [33]. Although the
drug was initially licensed in the UK, it was later
withdrawn because of limited market interest, but
has continued to be used in some European countries
(e.g. Belgium, Luxembourg). It has primarily been
considered as a treatment option for UTI as it achieves
high concentrations in the urine. In-vitro data
have shown good activity against ESBL producers,
de-repressed AmpC phenotypes and K1 hyper-
producing strains of Klebsiella oxytoca [34–36].
Although there are no current EUCAST or CLSI sus-
ceptibility breakpoints, guidelines from the British
Society for Antimicrobial Chemotherapy (BSAC)
have recommended different susceptibility break-
points for both systemic (8 mg/l) and urinary tract
infections (32 mg/l) [37]. Temocillin is usually
dosed in adults at 4 g daily, given twice a day or as
continuous infusion, although a dose increase to 6 g a
day is recommended in more severe infections [33].
However, published clinical evidence for the use of
temocillin in systemic ESBL infections is sparse. One
retrospective study from the UK looked at clinical and
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Therapy of ceftriaxone-resistant bacteremia Paterson et al
microbiological cure rates in 92 patients treated with
temocillin for UTI (n ¼ 42), bloodstream infection
(n ¼ 42) or hospital-acquired pneumonia (n ¼ 8),
where 58% of isolates were ESBL producers or had
a de-repressed AmpC phenotype [38]. Although clin-
ical cure rates of 89% and microbiological cure rates
of 84% for patients infected with ESBL or AmpC
producers were reported [38], the lack of a compara-
tor group makes interpretation difficult. At the pres-
ent time, until more robust clinical evidence is
available, temocillin has an uncertain status for the
treatment of more severe infections caused by ESBL
producers other than uncomplicated UTI.
Pivmecillinam, althogh highly effective against
UTIs caused by ESBL-producing organisms (Table 1)
would not be an appropriate choice for bloodstream
&
infections [39 ].
Cephamycins, such as cefoxitin or flomoxef, are
not substrates for ESBLs and so are typically active
in vitro against ESBL producers [40]. Flomoxef has
had some use for bloodstream infections because of
ESBL producers in countries, such as Taiwan [41]. No
RCTs have yet been performed comparing cepha-
mycins and carbapenems.
Aminoglycosides, tetracycline derivatives, fosfo-
mycin and fluoroquinolones are variably active
against ceftriaxone-resistant organisms and play a
role in treating bloodstream infection (Table 2).
However, none have been tested in RCTs specifically
for bloodstream infection because of ceftriaxone-
resistant organisms.
The aminoglycoside, plazomicin, was compared
with meropenem in treatment of cUTI [42]. Of
patients with an infection because of E. coli with
an ESBL phenotype, microbiologic eradication
occurred in 82.4% (42/51) treated with plazomicin
and 75%% (45/60) treated with meropenem. Com-
parable microbiologic eradication rates for K. pneu-
moniae with an ESBL phenotype were 75% (15/20)
treated with plazomicin and 76.9% (20/26) treated
with meropenem. As with other trials in cUTI, the
Table 1. Orally administered antibiotics for urinary tract
infections because of extended-spectrum beta-lactamase
producers
Amoxicillin–clavulanate
Fosfomycin
Nitrofurantoin
Pivmecillinam
Ceftibuten with amoxicillin–clavulanate
Tebipenem (investigational)
Sulopenem (investigational)
Orally administered cephalosporins with investigational beta-
lactamase inhibitors (e.g. VNRX-7145, QPX-7728, ETX-0282)
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Special commentary
Table 2. Antibiotic options for serious infections because
of extended-spectrum beta-lactamase producers (e.g.
bloodstream infections, hospital-acquired pneumonia, intra-
abdominal infections)
Carbapenems
Meropenem
Imipenem
Ertapenem
Potential carbapenem-sparing options
Ceftolozane–tazobactam
Ceftazidime–avibactam
Cefiderocol
Fosfomycin (intravenous)
Plazomicin
Tigecycline
Eravacycline
number of patients with bloodstream infection was
very small.
Tigecycline, eravacycline and omadacycline are
tetracycline derivatives with significant activity
against ceftriaxone-resistant Gram-negative bacilli
[43]. Eravacycline has recently been evaluated in
an RCT for patients with cIAI. Participants were
randomized to either eravacycline 1 mg/kg q12 h
or meropenem 1 g q8 h, both given intravenously.
In patients with ESBL-producing Enterobacteria-
ceae, clinical cure rates were 87.5% (14/16) and
84.6% (11/13) in the eravacycline and meropenem
groups, respectively [44]. As expected, few patients
in this trial had bloodstream infection.
Fosfomycin, administered intravenously, has
been compared to piperacillin/tazobactam in treat-
ment of cUTI [45]. Cure rates for cUTI because of
ESBL producers were high (93% in both arms). How-
ever, the number of patients with bloodstream
infection in this trial were small. It is hoped that
the FOREST trial will also provide more information
about the place of intravenous fosfomycin in the
treatment of ESBL producers [19,46]. It is notewor-
thy that the FOREST trial allowed step-down to oral
fosfomycin trometamol if there has been clinical
improvement.
POTENTIAL NEW DRUGS
A variety of antibiotics are under development,
which could play a future role in treatment of blood-
stream infection because of ceftriaxone-resistant
Gram-negative bacilli (Table 3). These include
cefiderocol, cefepime/zidebactam, cefepime/VNRX-
5133, new polymyxins (e.g. SPR-206) and combina-
tions with the new beta-lactamase inhibitor
6 www.co-infectiousdiseases.com
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Table 3. Investigational options for treatment of extended-
spectrum beta-lactamase producers
Carbapenems
Tebipenem (orally administered)
Sulopenem (orally administered)
Beta-lactam/beta-lactamase inhibitor combinations
Cefepime–enmetazobactam
Cefepime/tazobactam
Cefepime/zidebactam
Cefepime/VNRX-5133
Ceftibuten/VNRX-7145 (orally administered)
Cephalosporins with QPX-7728 or ETX-0282 (orally administered)
Siderophore cephalosporins
Cefiderocol
QPX-7728 [47]. However, all of these options cover
carbapenem-resistant Gram-negative bacilli and
would seem unnecessarily broad as targeted therapy
against ESBL or AmpC-producing organisms.
A smaller number of antibiotics under develop-
ment have activity specifically targeted against ESBL
or AmpC-producing organisms. Cefepime/tazobac-
tam (also known as WCK-4282) is active against at
least 94% of Enterobacteriaceae producing ESBLs or
AmpC [48]. It is being developed at high dose (2 g of
both cefepime and tazobactam). Cefepime–enmeta-
zobactam (also known as AAI101) is a novel pen-
icillanic acid sulfone b-lactamase inhibitor similar
in structure to tazobactam [49]. However, enmeta-
zobactam possesses a strategically placed methyl
group that gives the inhibitor a net neutral charge,
enhancing bacterial cell penetration [50]. This com-
bination has commenced clinical trials for cUTI but
not yet for bloodstream infection.
The concept of using orally administered anti-
biotics to complete definitive therapy for ceftriaxone-
resistant organisms is increasingly being considered
[51]. Orally administered carbapenems, such as tebi-
penem and sulopenem are highly active against
ESBL-producing and AmpC-producing Enterobacter-
iaceae and have now entered phase 3 trials for com-
plicated (NCT03788967) and uncomplicated UTI
(NCT03354598), respectively [52,53]. Ceftibuten in
combination with amoxicillin–clavulanate has been
successfully used in UTIs because of ESBL producers
[54]. Ceftibuten has also been combined with clav-
ulanate alone, and oral beta-lactamase inhibitors
VNRX-7145 [55] and QPX-7728 [56,57]. Cefpodox-
ime has been combined with a new beta-lactamase
inhibitor, ETX-0282, for similar indications and is
now in clinical development. It remains to be deter-
mined how these orally administered antibiotics
might be deployed for treatment of bloodstream
infections.
Volume 32  Number 00  Month 2019
CE: Tripti; QCO/330111; Total nos of Pages: 8;
QCO 330111
CONCLUSION
The MERINO trial showed that intravenous carba-
penems, such as meropenem, are still the treat-
ment of choice for bloodstream infection because
of ceftriaxone-resistant Gram-negative bacilli.
However, there is an active search for alternatives
to intravenous carbapenems. Four RCTs are cur-
rently in progress – it is clear that data from RCTs
and not observational studies will be needed to
displace the role of intravenous carbapenems for
this infection.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
D.P. has received honoraria or research grants from
Merck, Pfizer, Achaogen, Shionogi, QPex and Entasis.
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