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QCO 320601

REVIEW

CURRENT
OPINION Carbapenem-sparing strategy: carbapenemase,
treatment, and stewardship
Silvia Corcione a, Tommaso Lupia a, Alberto Enrico Maraolo b
Simone Mornese Pinna a, Ivan Gentile b, and Francesco G. De Rosa a

Purpose of review
describing the current role of carbapenems and carbapenem-sparing strategies in the setting of
antimicrobial stewardship programs.
Downloaded from https://journals.lww.com/co-infectiousdiseases by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3HsbbxaSipcNThgg4eS87naQ1M9h5WkSgQUjy6hCmfEk= on 10/23/2019

Recent findings
sparing carbapenems with other drugs appears to be an interesting perspective for a variety of reasons in
the current context of the multidrug-resistant (MDR) pandemic. Specific algorithms should also be precisely
investigated to define better how to spare carbapenems within empiric and targeted regimens, with
combination treatment or monotherapies, aiming at the best use of the new drugs and improving de-
escalation as soon as possible for most of the patients.
Summary
stewardship programs may be useful in reducing probable misuse and overuse of antibiotics, which has
probably contributed to the emergence of carbapenem-resistant bacteria worldwide. The proposal of
carbapenem-sparing strategies has then generated substantial scientific debate and, overall, the concept of
sparing these drugs is well advocated together with judicious use of novel drugs, appropriate measures of
infection control and prevention as well as in stewardship programs to curb the spread of MDR and XDR-
strains in healthcare facilities.
Keywords
Acinetobacter, antimicrobial stewardship, carbapenem, carbapenem sparing, carbapenemase, carbapenem-
resistant Enterobacteriaceae, Pseudomonas

INTRODUCTION infection control, prevention, and stewardship pro-

Antimicrobial resistance is one of the most serious
public health menaces worldwide [1,2]. Among the
biggest threats, multidrug-resistant (MDR) or exten-
sively drug-negative (XDR) Gram-negative bacteria
such as carbapenem-resistant Enterobacteriaceae
(CRE), extended-spectrum b-lactamase producing
(ESBL) Enterobacteriaceae, Pseudomonas aeruginosa
and Acinetobacter baumannii have been labeled as
the most serious or urgent [3–5].
With regard to MDR and XDR-Gram-negative
bacteria, the use of carbapenems, alone or in combi-
nation with other agents, is one the most controver-
sial issue: on the one hand their efficacy is well
established in many scenarios (for instance, infec-
tions by ESBL-Enterobacteriaceae), on the other hand,
their misuse and overuse (both as empiric or targeted
therapy) has resulted in the emergence of CRE which
represent a paramount therapeutic challenge [6–8].
Furthermore, carbapenem-sparing strategies have
generated substantial debate and are advocated with
judicious use of novel antibiotics, proper measures of
grams [9,10].
The present review is aimed at describing the
current role of carbapenems and carbapenem-
sparing strategies in the setting of infections and
proper antimicrobial therapy management dealing
with difficult-to-treat Gram-negative infections.
MECHANISMS OF RESISTANCE
Several mechanisms of antibiotic resistance have
been described for Gram-negative bacteria (Table 1):
a
Department of Medical Sciences, Infectious Diseases, University of
Turin, Turin and bDepartment of Clinical Medicine and Surgery, Section
of Infectious Disease, University of Naples Federico II, Naples, Italy
Correspondence to Francesco G. De Rosa, MD, Department of Medical
Sciences, Infectious Diseases, University of Turin, Turin, Italy.
E-mail: francescogiuseppe.derosa@unito.it
Curr Opin Infect Dis 2019, 32:000–000
DOI:10.1097/QCO.0000000000000598

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Gram-negative infections

(1) Enzymatic inactivation:

KEY POINTS
 Antimicrobial Stewardship Programs were pivotal to
reduce excessive or misuse of antibiotics in the struggle
against MDR and XDR-bacteria.
 Carbapenem-sparing strategy concept has the aim to
profess to save of these drugs and judicious use of
novel drugs not forgetting appropriate measures of
infection control and prevention.
 Antibiotic resistance passes through several
mechanisms: enzymatic inactivation, efflux pumps,
reducing permeability, and target modifications.
 The rediscovery of molecules set aside, the synergistic
association between drugs and new weapons in the
pipeline will be the present and the hopeful future of
difficult-to-treat pathogens such as ESBLs, CR-E, and
resistant Pseudomonas and Acinetobacter spp.
 Improving de-escalation, as soon as possible, is another
focal point that does not worsen clinical outcome in the
selected population.
(a) Class A b-lactamases include penicillinases
and cephalosporinases, such as (i.e., TEM,
SHV, CTX-M, PER, VEB, GES, and IBC) with
development of resistance to carboxypeni-
cillins, ureidopenicillins, and aztreonam
[11,12]. This class also comprises Klebsiella
pneumoniae carbapenemases (KPC) enzymes
and GES-2 that can hydrolyze carbapenems
[12,13].
(b) Class B are defined metallo-b-lactamases
(MBL), including IMP, verone integron-
encoded metallo-beta-lactamase (VIM),
New Delhi metallo-beta-lactamases (NDM),
SPM, and GIM, born in Asian countries and
after disseminated among Enterobacteriaceae
worldwide [13–15].
(c) Class C comprises intrinsic and inducible
resistance mechanisms, like AmpC-type
cephalosporinase, not inhibited by clavu-
lanic acid, tazobactam, and sulbactam.
The structural modifications of AmpC,
can confer reduced susceptibilities to new

Table 1. Enzymes involved in carbapenems resistance in Enterobacteriaceae, Pseudomonas spp., and Acinetobacter spp.
Susceptibility to carbapenems
Mechanism of Resistance CRE Pseudomonas spp. Acinetobacter spp.

Enzymatic inactivation Between ‘()’ the most Between ‘()’ the most Between ‘()’ the most
important of the class important of the class important of the class
Class ‘A’ enzymes

(KPC, GES) (GES) (KPC and GES)

Class ‘B’ enzymes

(IMP, VIM, and NDM) (IMP, VIM, NDM, SPM, (IMP, VIM, NDM,
and GIM) and SIM)
Class ‘C’ enzymes

(AmpC together with (AmpC together with other (AmpC together with other
other mechanism mechanism reported, mechanism reported,
reported, e.g. Porins) e.g. Porins) e.g. Porins)
Class ‘D’ enzymes

(OXA, e.g. OXA-48, 181) (OXA, e.g. OXA-198) (OXA, e.g. OXA-51, 48)
Efflux pumps

(RND) (RND, e.g. MexAB-OprM) (RND, e.g. AdeABC)

Porins

(Omp33-36 OmpA, OmpK) (OprD, e.g. OprD2) (Omp33-36)

Target modifications

(PBPs alterations) (PBPs alterations) (PBPs alterations)

CR-E, carbapenem resistant Enterobacteriaceae; KPC, Klebsiella pneumoniae carbapenemases; NDM, New Delhi metallo-beta-lactamases; OMP, outer membrane
porin; OXA, oxacillin; PBP, penicillin-binding protein; RND, resistance-nodulation-division; VIM, verone integron-encoded metallo-beta-lactamase.

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§ C/T +/- Fosfomycin or AG
§ C/A +/- Fosfomycin or AG
§ PTZ +/- AG
For less severe infecons
§ Cefepime +/- AG
§ Tigecycline +/- AG
§ Tigecycline +/- FQ
For UTI no complicated
§ Fosfomycin
§ AG ESBL
§ Nitrofurantoin
CR-E
§ C/A + Fosfomycin
§ C/A + Tigecycline
§ C/A + AG
§ C/A + Aztreonam
§ Colisn + Fosfomycin (plus/or Tigecycline)
§ Tigecycline + Fosfomicin (plus/or AG)
FIGURE 1. Carbapenem sparing strategies in the setting of suspected infections by extended-spectrum b-lactamase producing,
P. aeruginosa (PA), A. baumannii (AB), carbapenem-resistant Enterobacteriaceae (CR-E). AG, aminoglycoside; C/A,
ceftazdime/avibactam; C/T, ceftolozane/tazobactam; FQ, fluoroquinolones.
b-lactam-b-lactamase inhibitor (BLBLI),
ceftolozane/tazobactam, and ceftazidime/
avibactam [13,16].
(d) Class D oxacillinases provide resistance to
all penicillins, 3 and 4-generation cephalo-
sporines (3GC) and aztreonam [13,17].
Other OXA enzymes, such as OXA-198,
are known mechanisms of carbapenem
resistance [13,17], other OXAs b-lacta-
mases, mainly OXA-48, express low activity
against the carbapenems, better hydrolyz-
ing imipenem than meropenem [13,17].
(2) Efflux pump and reduced permeability:
(a) Resistance-nodulation-division (RND) fam-
ily are membrane proteins, including the
main efflux pumps responsible for increased
resistance of P. aeruginosa to a wide range of
agents commonly used. They rarely occur
individually but are often flanked by other
resistance mechanisms [18]. Lost or modifi-
cation of OprD2 may increase the MIC for
carbapenems, especially imipenem [19,20].
(3) Target modifications:
(a) Mainly, four classes of antimicrobials are
involved in mechanisms of resistance because
of change of the molecule target for P. aeru-
ginosa such as aminoglycosides (methylation
of 16S), b-lactams (penicillin-binding
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Carbapenems sparing strategy Corcione et al.
If Suscepble Strains Consider:
§ PTZ +/- AG
§ PTZ +/- Fosfomycin
§ Ceazidime +/- AG
§ C/T +/- AG
§ C/A +/- AG
If High Risk of MDR/XDR Strains Consider:
PA §
§
C/T + Colisn (plus/or Fosfomycin)
C/A + Colisn (plus/or Fosfomycin)
AB
§ Colisn+ Fosfomycin
§ Colisn + Tigecycline
§ Colisn + Rifampin
§ Colisn + Aztreonam
proteins alterations), quinolones (mutations
in DNA gyrase and topoisomerases IV), and
polymixins (LPS alterations) [21].
CARBAPENEMS IN THE SETTING OF
EXTENDED-SPECTRUM b-LACTAMASE
PRODUCING INFECTIONS
Carbapenem utilization has been fueled because of
the spread of ESBL, inciting a dangerous vicious
circle in empiric and targeted treatment because
of their efficacy against ESBL, but the quest for safe
and effective alternatives has been representing a
&
significant area of research [22 ,23]. BLBLI combi-
nations (e.g., piperacillin-tazobactam (PTZ) and
amoxicillin-clavulanic acid), cephamycins, amino-
glycosides, fosfomycin, tigecycline, may show
potential activity: nevertheless, many of these
options can be used just under specific circumstan-
&&
ces [24 ,25] (Fig. 1). Among long-standing drugs in
the antibiotic armamentarium, cefepime is probably
a useful option for not severe scenarios, for instance,
urinary tract infections, whereas conflicting results
are reported in case of severe clinical picture with
&&
high bacterial inoculum [24 ,26]. In this specific
setting, if strains are susceptible, valuable options
are fosfomycin and nitrofurantoin [27].
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Gram-negative infections
’Old’ BLBLIs (primarily upon PTZ) in observa-
tional studies definitely did not show their inferior-
ity when compared with carbapenems against ESBL
& &
infections in terms of mortality [28,29,30 ,31], and
recently the missing piece in the ESBL puzzle was
studied by a randomized controlled trial (RCT), the
&&
MERINO study [32 ] in which 391 patients with BSI
by Escherichia coli or K. pneumoniae not susceptible to
ceftriaxone were assigned (ratio 1:1) either to the
meropenem arm (1 g each 8 h) or to the PTZ arm
(4.5 g each 6 h). The MERINO trial showed higher
mortality in the latter group (12.3%) than in the
former (3.7%); therefore the results do not support
the noninferiority of PTZ to meropenem [32 ].
&&
Does the MERINO trial put an end to the use of
‘old’ BLBLI against ESBL-E? It did, although some
points deserve further clarification [33].
First, PTZ was administered at intermittent
intervals, in contrast with meta-analytic evidence
of significantly better outcomes with extended/con-
tinuous infusion and the same goes to meropenem,
especially in critically ill patients. [34,35].
Second, generic lots of drugs may widely vary in
terms of potency in comparison with branded prod-
ucts and could have influenced the trial’s results [36].
Third, ESBLs are not a homogenous group with
relevant differences among the different ß-lacta-
mases: the prevalence of some types, poorly inhib-
ited by tazobactam, may undermine the efficacy of
&
PTZ [37 ,38].
Perhaps the main question regarding the
MERINO trial is the higher mortality in the PTZ
arm, albeit the randomized sample showed, as base-
line characteristics, low Pitt and Charlson Comorbid-
&&
ity Index scores [32 ,33]. Furthermore, two-thirds of
patients randomized to PTZ received an appropriate
treatment according to susceptibility testing within
&&
5.5 h after collecting blood culture [32 ,33]; in the
same arm the proportion of infections from urinary
source was high (54.8%), which is traditionally the
main clinical scenario of ESBL invasive infections and
the ideal setting for PTZ [29]. In contrast, the median
MIC of PTZ was 2 mg/l, whereas values above this
threshold have been associated with the poor out-
&
come under PTZ therapy [37 ,38]. Of note, randomi-
zation was performed at day 3 in patients with severe
infections, a frame time in which the response to
empirical treatment is clinically evaluable.
However, the new frontier of noncarbapenem b-
Lactams for ESBL invasive infections, to pursuit a
carbapenem-sparing strategy, is nowadays repre-
sented by novel BLBLIs, ceftolozane/tazobactam
& &
and ceftazidime/avibactam [39 ,40 ,41].
Ceftolozane/tazobactam shows good activity in
vitro against ESBL, barring carbapenem-resistant phe-
& &
notypes [39 ,40 ]. Recent guidelines underline its role
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as a carbapenem-sparing strategy for complicated
abdominal or urinary tract ESBL infections, with
caution against Klebsiella spp. and encouraged versus
P. aeruginosa [40 ]. Ceftolozane/tazobactam may hap-
pen also as empiric therapy when there is a high
&
likelihood of serious infections by ESBL or CRE [40 ].
Ceftazidime/avibactam, whose spectrum of activ-
ity also covers CRE (except metallo-b-Lactamases) may
serve more appropriately as an alternative to carbape-
nems for severe and invasive infections with ESBL or
also with AmpC-producing Enterobacteriaceae [41].
CARBAPENEMS FOR THE MANAGEMENT
OF P. aeruginosa INFECTIONS
Acute invasive infections caused by P. aeruginosa are
associated with high mortality rates, above 40%,
especially in the case of MDR/XDR strains [42].
Generally, there has been considerable debate
regarding the benefit of combination therapy over
monotherapy against invasive infections by P. aer-
uginosa [43]. Data from literature highlight no dif-
ference between the two options, but it is difficult to
draw inferences regarding MDR and XDR-isolates
&
[44,45,46 ].
A great problem is posed by carbapenem-resis-
tant P. aeruginosa (CR-PA): death risk is significantly
higher in patients infected by CR-PA than among
patients infected by their sensitive counterparts, as
demonstrated by meta-analytic data (crude
OR ¼ 1.64; 95% CI ¼ 1.40, 1.93; adjusted OR ¼ 2.38;
95% CI ¼ 1.53, 3.69) [47].
Zusman et al. [48] reported in-vitro data about
combination therapy for MDR P. aeruginosa with a
synergistic effect of carbapenems (especially doripe-
nem), with polymixins. Bactericidal effects (>3 logs
reduction) increased from 10% to 49% with this
combination, and the result persisted even when
the isolate was both resistant to colistin and the
carbapenem [49,50]. New insights in the use of
carbapenem regimens is based on optimizing anti-
biotic combinations: Yadav et al. [51] reported that
clinically relevant concentrations of imipenem and
an aminoglycoside provided synergistic bacterial
killing and suppression of resistance against a high
inoculum of clinical isolates of carbapenem-resis-
tant P. aeruginosa. A precious help has been repre-
sented by the introduction in clinical practice of the
new BLBLI ceftolozane/tazobactam and ceftazi-
dime/avibactam: the first is ranked first as antipseu-
domonal b-lactam in recent Spanish guidelines
specifically addressing acute invasive infections by
P. aeruginosa [52]. Ceftolozane/tazobactam is con-
sidered the main backbone of the empiric approach
to suspected MDR-PA infections because of its
marked stability versus many mechanisms of
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QCO 320601
resistances employed by P. aeruginosa, including
resistance to carbapenems, as long as not mediated
by carbapenemases [53–55]. Montero et al. [56]
reported bacterial suppression using a combination
of ceftolozane/tazobactam and high dose merope-
nem against a strain of XDR P. aeruginosa recovered
from a Spanish patient, whereas microbiological fail-
ure occurred when molecules were individually
tested. A recent study found a synergism in vitro with
a combination of ceftolozane/tazobactam with colis-
tin or fosfomycin against MDR P. aeruginosa [57].
CARBAPENEMS FOR THE MANAGEMENT
OF Acinetobacter baumannii INFECTIONS
Carbapenems, the cornerstone of anti-acinetobacter
baumannii susceptible strains [58,59], show highly
bactericidal activity in many clinical scenarios
(pneumonia, bloodstream infections – BSI) but also
reported vital factors for the development of CR-AB
strains [60].
Colistin probably represents the paramount
weapon in the armamentarium in these cases, but
its toxicity often poses relevant challenges [61] on
the other hand tigecycline, is intriguing alternative,
but its use has several limitations [62]: bacteriosta-
tism, suboptimal lung penetration and it received a
black box warning by the Food and Drug Adminis-
tration [62,63].
Currently, carbapenems are often employed in
the case of CR-AB infection in the framework of
combination regimens, using the synergistic activity
with other drugs such as colistin [64,65]. The advan-
tage of combination therapies over monotherapies
against MDR and XDR-AB has not been established,
as showed, for instance, by the seminal Italian RCT
comparing colistin versus colistin and rifampin for
life-threatening infections because of XDR-AB: in
spite of an higher microbiological eradication rate,
the addition of rifampin did not reduce 30-day mor-
tality [65]. Lopes-Cortes et al. [66], in their multi-
centre prospective cohort did not find benefits in
clinical outcome from combination therapy.
Recently two network meta-analyses (NMA), have
tried to identify the best antimicrobial regimen against
difficult-to-treat A. baumannii infections [67,68].
The first one, focusing on pneumonia in criti-
cally ill patients by MDR or XDR-AB was developed
upon intravenous (IV) colistin as a common com-
parator and data showed that the best treatment for
reducing all-cause mortality was the treatment with
sulbactam monotherapy [67]. Furthermore, sulbac-
tam was significantly superior to the comparator
for lowering all-cause mortality (OR ¼ 0.27; 95%
CI ¼ 0.06–0.91). Of note, the only combination
therapy based on two different drugs ranking higher
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Carbapenems sparing strategy Corcione et al.
than IV colistin alone was fosfomycin and IV colis-
tin; the concomitant use of IV also showed a better
clinical outcome than the comparator and inhaled
colistin [67]. Fosfomycin does not display activity
per se against A. baumannii, but its synergistic effects
with other drugs turn out to be very useful [69].
The second NMA [68], compared efficacy and
safety of treatment options for MDR and XDR-AB
infections of any anatomical site: about the clinical
cure, the combination of colistin, tigecycline and
sulbactam was not superior to IV colistin monother-
apy. Regarding all-cause mortality, triple combination
therapy based on colistin, tigecycline and a third drug
ranked first, but it was not superior to IV colistin
monotherapy (RR ¼ 0.27; 95% CI ¼ 0.02–4.09); more-
over, tigecycline based-therapies were far less effective
when considering microbiological eradication (in this
case sulbactam monotherapy had the highest ranking)
or important subgroup such as BSI patients [68].
A very recent multicentre RCT had tested the
superiority of meropenem and colistin versus colistin
alone against carbapenem-resistant Gram-negative
bacteria as a cause of severe infections [70]. Overall,
no difference in terms of clinical failure was observed
between the two arms, and this was confirmed in the
subgroup (widely prevalent, 312 patients) of CR-AB
infections [70]. Interestingly, in a subsequent analysis
of this trial only concerning CR-AB cases, the death
rate was significantly lower in patients with infections
by isolates resistant also to colistin (OR ¼ 0.285; 95%
CI ¼ 0.118–0.686), probably because of a loss of fitness
and virulence by the bacterial strains [71]. The real
unexpected result was the higher mortality, in this
subset of patients, associated with the addition of
meropenem to colistin, compared with colistin mono-
therapy (OR ¼ 3.065; 95% CI ¼ 1.021–9.202) [70,71].
The explanation was unclear: the authors suggested a
possible modification in gene expression induced by
carbapenems, thereby restoring bacterial virulence
overcoming the fitness cost of colistin-resistance
[70,71].
CARBAPENEMS FOR THE TREATMENT OF
CARBAPENEM-RESISTANT
Enterobacteriaceae
Carbapenem paradox: high dosage and
double carbapenem
The time the plasma drug concentration is main-
tained above the MIC (t>MIC) is the most crucial
pharmacodynamics parameter predicting in-vivo
efficacy of b-lactams, including carbapenems [72].
In general, for a bacteriostatic and bactericidal
effect, the carbapenems require a t more than
MIC of approximately 20% and 40%, respectively
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Gram-negative infections
[72,73]. For CRE exhibiting MIC more than 4 mg/l,
the extended infusion of meropenem over 3–4 h at
the standard dose of 1 g every 8 h provides higher
probabilities of target attainment than conven-
tional 30 min infusion [74]. Furthermore, the same
dosing infused over 4 h may provide adequate expo-
sure for organisms with MICs more than 8 mg/l
[74,75]. These studies suggested that prolonging
the infusion time for over 1 h allowed target attain-
ment 1 dilution higher than shorter infusions [76].
High-dose meropenem (i.e., 2 g every 8 h) may be
able to achieve better PK/pharmacodynamics target
than standard dose [77,78]. One study reporting 4 h
infusions of this regimen have shown to achieve
adequate exposure for organisms with MICs up to
16 mg/l [78]. Continuous infusions strategies of mer-
openem following a 3 g daily dose have been found to
achieve median concentrations of 7 mg/l. By increas-
ing this dosage to 6 g in three doses may provide
adequate exposure for organisms with MICs up to
16 mg/l [79]. Giannella et al. [80] pointed out that
high-dose carbapenem-containing regimens were
associated with better outcomes in CRE-related infec-
tions. In 595 patients with CR-Kp BSI, analyzed, 77%
of isolates showed a carbapenem MIC at least 16 mg/l,
428 (71.9%) received HD carbapenem-based combi-
nation therapy. HD carbapenem use (HR ¼ 0.69, 95%
CI ¼ 0.47–1.00, P ¼ 0.05) was protective factor and
adjusted for the propensity score, showed a greater
protective effect (HR ¼ 0.64, 95% CI ¼ 0.43–0.95,
P ¼ 0.03). After stratification benefit of HD carbape-
nem was also observed for strains with carbapenem
MIC at least 16 mg/l [80].
Following the first reports of patients with infec-
tions because of carbapenemases-producing Entero-
bacteriaceae treated with a double carbapenem
combination, a growing number of case series have
been published, accompanied by observational stud-
ies conducted in Europe and in the United States [81–
84] despite that the sample size is frequently small
and RCTs are lacking. The rationale of such a combi-
nation is based on the possibility that the adminis-
tration of ertapenem, will serve as a suicidal inhibitor,
allowing the second carbapenem to reach concen-
trations exceeding the MIC or a sort of ‘double-hit’ in
which the first antibiotic should reduce bacterial load
in the site of infection, allowing the second medica-
tion acting on a decreased bacterial volume [81,82].
The proposed two carbapenems-based schemes may
be supported by a third antibiotic from a different
class (polymyxins, aminoglycosides, tigecycline, and
fluoroquinolones) [85,86]. With the advent of new
molecules, double-carbapenem regimens have been
partly set aside, and it can be considered as salvage
therapy when no other options are available.
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Carbapenems as part of combination therapy
for carbapenem-resistant
Enterobacteriaceae
The role of carbapenems in the treatment of CRE has
long been debated: some studies reported lower
mortality in patients treated with high dose mero-
penem combined with other agents for CR-Kp infec-
tions when the carbapenem MIC was more than
8 mg/l [87,88]. Results by Del Bono et al. [79] suggest
that meropenem might retain some bactericidal
activity on CR-Kp strain with up to 32 mg/l in some
cases. Synergisms between carbapenem and co-
administered agents could have supported this use
even if PK/pharmacodynamics targets were not
reached, in line with previous reports of synergistic
effects with meropenem [89].
The introduction of the new b-lactamase inhib-
itor ceftazidime/avibactam has changed the clinical
scenario (Fig. 1). Several case series described a better
survival at 30 and 90 days in patients treated with
ceftazidime/avibactam-based regimens than carba-
penem and other agents, including patients treated
with ceftazidime/avibactam monotherapy [90].
Tumbarello et al. [91] recently found similar results
in a retrospective series of patients with CP-Kp
infections treated with ceftazidime/avibactam
within a compassionate-access-program. Neverthe-
less, in a study of 37 patients infected by CRE,
Schields et al. [92] described low clinical success,
especially in patients with pneumonia because of
CRE treated by ceftazidime/avibactam without dif-
ference between monotherapy and combination
regimen. Ceftazidime/avibactam use produced
encouraging results in the CR-Kp BSIs with thirty-
day survival rates of 59.1% in monotherapy versus
63.1% with a carbapenem associated [91,92].
NEW CARBAPENEM COMBINATIONS
The introduction of the novel b-lactamase inhibitors
vaborbactam and relebactam, has provided additional
therapeutic options for CRE infections [93]. Of note,
these new b-lactamase inhibitors are not active against
all major carbapenemases, but these novel b-lacta-
mase inhibitor combinations will also provide carba-
penem-sparing options for the treatment of MDR
bacteria. The combination of meropenem with a
boronic acid beta-lactamase, vaborbactam (M/V),
has shown an increase in-vitro activity against class
A and class C serine b-lactamases, although Class B
(e.g., NDM, VIM) and class D (e.g., OXA-48) carbape-
nemases are not inhibited by vaborbactam [93]. The
efficacy, tolerability and safety of M/V was first
assessed in TANGO I [94] a multicenter, double-blind,
randomized, phase III, noninferiority trial versus P/T
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CE: Namrta; QCO/320601; Total nos of Pages: 11;
QCO 320601
for the treatment of cUTIs and TANGO II [95], in
which M/V was compared to best available treatment
(BAT) in a series of infections because of suspected or
known CRE (notably cUTI, hospital-acquired or ven-
tilator-associated pneumonia – HABP/VABP, compli-
cated intrabdominal infections – cIAI, bacteremia):
because of superiority of M/V compared to BAT this
study was terminated prematurely. A phase III trial
called TANGO III, in which M/V was compared to PTZ
for the treatment of HABP/VABP, was withdrawn by
sponsor decision [96].
Imipenem/cilastatin with relebactam (I/R),
combines an approved carbapenem with a novel
b-lactamase inhibitor [93]. The in-vitro addition of
relebactam showed increased activity of imipenem
against ESBLs, serine b-lactamases, and P. aerugi-
nosa; however, relebactam cannot inhibit Class D
OXA-48 [93]. A phase II study assessed efficacy,
tolerability and safety I/R versus imipenem/cilasta-
tin in cIAI and cUTI [97], furthermore two phase III
study, RESTORE-IMI 1 [98] and RESTORE-IMI 2 [99],
are currently evaluating I/R in different settings.
RESTORE-IMI 1 is a multicenter, randomized, dou-
ble-blind, comparator-controlled trial, comparing
the efficacy and safety of IMI/REL versus colistin
Empiric Treament
ESBL
Empiric Treament
CR-E
If High Risk Of CR-E
Colonizaon
Targeted Treament
CR-E
Sparing
Carbapenems
FIGURE 2. Role of carbapenem in the setting of empiric or target therapy for extended-spectrum b-lactamase producing and
carbapenem-resistant Enterobacteriaceae (CR-E).
0951-7375 Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Carbapenems sparing strategy Corcione et al.
and imipenem/cilastatin (COL þ IMI) in patients
with imipenem-nonsusceptible bacterial infec-
tions, including HABP, VABP, cIAI and cUTIs [98].
In the RESTORE-IMI 2 trial I/R was compared to PTZ
(both arms with the addition of Linezolid) in HABP/
VABP [99].
Nacubactam is a novel member of the diaza-
bicyclooctane inhibitor family with a dual-mode
of action, acting as a b-lactamase inhibitor and an
antibacterial agent employing PBP2 inactivation
[100]. The combination of meropenem with nacu-
bactam is still in a phase I status but is potentially
active against carbapenem-resistant Enterobacter-
iaceae isolates expressing serine b-lactamases
(theoretically also ceftazidime/avibactam resis-
tant strains), OXA-48 and metallo b-lactamases
[101].
ANTIMICROBIAL STEWARDSHIP OF
CARBAPENEMS
Carbapenems are a powerful weapon against Gram-
negative bacteria but sparing carbapenems usage
can have interesting microbiological effects as well
[102] (Fig. 2).
Targeted Treament
ESBL
Empiric Treament
CR-E
If low risk of CR-E
Colonizaon
Favourable
www.co-infectiousdiseases.com 7
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QCO 320601
Gram-negative infections
Gut colonization is the main reservoir of CR-Kp
among patients, and intestinal carriage is associated
with increased risk for developing successive CRE
infections [103]. Not surprisingly, carbapenems use
is among the critical determinant for CRE acquisi-
tion, is associated with a higher rate of superinfec-
tion compared with noncarbapenem therapies and a
higher risk of developing resistance through selec-
tive pressure that gives resistant strains the chance
to overwhelm their sensitive counterparts. [104].
Several strategies for wiser use of carbapenem are
needed: antimicrobial stewardship program should
be focused on the education of physicians in
addressing the indication for using carbapenems
and when and how treatment can be de-escalated
[105].
From an antimicrobial stewardship perspective,
the lower 30-day mortality with carbapenems
described in the MERINO trial could support the
hypothesis of saving carbapenems as a target ther-
apy for patients at high risk for ESBL infections,
therefore reducing their use as empiric therapy, a
&&
setting which PTZ may still have a role [32 ].
Another focal point is therapy duration and the
role of de-escalation. Recent data point out that
short-course treatment (< 10 days) for Enterobacter-
iaceae BSI does not worsen clinical outcomes [106]
and this has also been confirmed in a setting
wherein the proportion of ESBL was more than
25% [107]. A Japanese study in another setting
endemic for ESBL and investigating a cohort of
300 patients showed that a de-escalation strategy
from carbapenems, whenever possible according to
predefined criteria related to either empiric or tar-
geted treatment, did not impair clinical outcomes,
achieving instead a reduction of CDI and of CR-AB
acquisition [108].
Experiences from other countries all converge
on the feasibility of carbapenem-sparing strategies,
displaying a favorable impact on clinical, economic,
and ecological outcomes [109,110]. Of note, the
studies mentioned above were carried out before
the marketing of new drugs that can act as valid
alternatives to carbapenems in serious infections
wherein the latter are the benchmark as therapeutic
options, namely invasive infections by ESBL.
Moreover, the selective pressure exerted by
antimicrobials on the gut microbiota promotes
the carriage of MDR bacteria and recent data
described as carbapenems are a stronger driver of
intestinal dysbiosis [111,112]: saving carbapenems
in favor of certain nonb-lactam drugs with limited
impact on the intestinal microbiota, when feasible,
may also have a role in the management of MDR
infections.
8 www.co-infectiousdiseases.com
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CONCLUSION
In the current context of the MDR pandemic and
increasing opportunities for carbapenem-sparing
initiatives, the respective impacts of relevant clinical
parameters, such as dosing regimen, combination
therapies with nonb-lactam drugs, length of treat-
ment exposure and the sequence of antimicrobial
use, should be precisely investigated to better define
the positioning of carbapenem-sparing b-lactams
in antimicrobial stewardship programs and de-
escalation algorithms for patients.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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