PERSPECTIVE

New Perspectives on Antimicrobial Agents: Imipenem-

Relebactam
J. Nicholas O’Donnell,a Thomas P. Lodisea

Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York, USA
a

ABSTRACT Imipenem (IMI)/cilastatin/relebactam (REL) (I/R) is a novel b -lactam/

b -lactamase inhibitor combination with expanded microbiologic activity against
carbapenem-resistant non-Morganellaceae Enterobacterales (CR-NME) and difficult-
to-treat (DTR) Pseudomonas aeruginosa. Relebactam, a bicyclic diazabicyclooctane,
has no direct antimicrobial activity but provides reliable inhibition of many Ambler
class A and class C enzymes. It is currently approved for the treatment of adult
patients with hospital-acquired bacterial pneumonia and ventilator-associated bac-
terial pneumonia (HABP/VABP) and those with complicated urinary tract infections
(cUTIs) and complicated intra-abdominal infections (cIAIs) when limited or no alter-
native treatments are available. Given the number of recently approved b -lactams
with expanded activity against highly resistant Gram-negative pathogens, this
review summarizes the published literature on I/R, with a focus on its similar and
distinguishing characteristics relative to those of other recently approved agents.
Overall, available data support its use for the treatment of patients with HABP/
VABP, cUTI, and cIAI due to CR-NME and DTR P. aeruginosa. Data indicate that I/R
retains some activity against CR-NME and DTR P. aeruginosa isolates that are resist-
ant to the newer b -lactams and vice versa, suggesting that susceptibility testing
be performed for all the newer agents to determine optimal treatment options for
patients with CR-NME and DTR P. aeruginosa infections. Further comparative PK/PD
and clinical studies are warranted to determine the optimal role of I/R, alone and
in combination, for the treatment of patients with highly resistant Gram-negative
infections. Until further data are available, I/R is a potential treatment for patients
with CR-NME and DTR P. aeruginosa infections when the benefits outweigh the
risks.

KEYWORDS imipenem-relebactam, multidrug resistance, pharmacokinetics,

pharmacodynamics, Enterobacterales, Pseudomonas aeruginosa, clinical trials

mipenem (IMI)/cilastatin/relebactam (REL) (I/R) is a novel b -lactam/ b -lactamase inhibi-

I tor (BL/BLI) combination with expanded microbiologic activity against multidrug-resist-
ant Gram-negative pathogens, including carbapenem-resistant non-Morganellaceae
Copyright © 2022 American Society for
Enterobacterales (CR-NME) and difficult-to-treat (DTR) Pseudomonas aeruginosa. Relebactam,
Microbiology. All Rights Reserved.
a bicyclic diazabicyclooctane, has no direct antimicrobial activity but provides reliable inhibi- Address correspondence to Thomas P. Lodise,
tion of many Ambler class A and class C enzymes (1). For example, relebactam effectively Thomas.lodise@acphs.edu.
inhibits Klebsiella pneumoniae carbapenemase (KPC) and Pseudomonas-derived cephalospor- The authors declare a conflict of interest. T.P.L.
has received consultant honoraria and
inases (PDCs), which are Ambler class A and C enzymes, respectively. Relebactam differs
investigator-initiated grant support from Merck
from other diazabicyclooctane BLIs in that it carries a positively charged side chain that has & Co. J.N.O. has received investigator-initiated
been shown to limit its efflux (2). The addition of relebactam to IMI restores its in vitro activity grant support from Merck & Co.
against a substantial number of CR-NME and DTR P. aeruginosa isolates. Consistent with Received 16 February 2022
Returned for modification 28 March 2022
most new b -lactams except cefiderocol, I/R does not have expanded activity against Accepted 20 May 2022
Acinetobacter baumannii or metallo-b -lactamase (MBL)-producing Gram-negative bacteria Published 21 June 2022
relative to IMI alone (3, 4).

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Imipenem/cilastatin/relebactam is currently approved by the Food and Drug

Administration (FDA) for the treatment of adult patients with hospital-acquired bac-
terial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), com-
plicated urinary tract infections (cUTI), including pyelonephritis, or complicated intra-
abdominal infections (cIAI) who have limited or no alternative treatment options (5).
In the European Union, it is approved in adult patients for the treatment of HABP/
VABP, suspected or documented bacteremia due to HABP/VABP, and infections due
to aerobic Gram-negative bacteria with limited treatment options (6). The United
States- and European Union-approved I/R dose is 500 mg/250 mg infused overed 30
min every 6 h, with renal dose adjustments for patients with creatinine clearances of
,60 mL/min (5, 6). The current FDA and Clinical and Laboratory Standards Institute
(CLSI) I/R susceptibility breakpoints for P. aeruginosa and Enterobacterales are #2/4 mg/L
and #1/4 mg/L, respectively, while the EUCAST susceptibility breakpoints for both P. aer-
uginosa and Enterobacterales are #2/4 mg/L (7, 8).
Given the number of recently approved b -lactams with activity against highly re-
sistant Gram-negative pathogens, this review on I/R summarizes the published litera-
ture on its in vitro susceptibility against highly resistant Gram-negative isolates across
surveillance programs, mechanisms of resistance, pharmacokinetics (PK), pharmacoki-
netics/pharmacodynamics (PK/PD) in preclinical models of infections, and clinical data.
As part of the review, we focus on the similar and distinguishing characteristics of I/R
relative to those of other recently approved b -lactams (i.e., BL/BLIs and cefiderocol).
We also discuss its overlapping and differential potential roles in therapy within the
current antibiotic landscape. Finally, we provide some considerations for future studies
to help better define the role of I/R in the treatment of patients with highly resistant
infections relative to those of other recently approved b -lactams.

MICROBIOLOGY
In vitro activity and mechanisms of resistance. The addition of REL to IMI expands
the in vitro spectrum of activity of I/R to include NME that produce class A b -lactamases,
including KPC and several serine extended-spectrum b -lactamases, and class C b -lacta-
mases, including the PDCs and AmpC enzymes (Table 1) (2, 9). It is largely unaffected by
porin channel-mediated resistance due to OprD loss or efflux pump-mediated resistance
(eg, MexAB, MexCD, MexXY) in P. aeruginosa (Table 2). Of note, I/R also appears to retain in
vitro activity against isolates with KPC-3 or PDC mutations that result in resistance to cefta-
zidime-avibactam (CZA) or ceftolozane-tazobactam (C/T). Resistance to I/R has been
observed in isolates expressing OXA-48 or MBLs and with combinations of porin altera-
tions and hyperexpression of carbapenemase enzymes. As with IMI alone, activity against
Acinetobacter sp. and Morganellaceae (i.e., Proteus spp., Providencia spp., and Morganella
spp.) is limited (2, 9). Among large surveillance studies, I/R typically exhibits activity against
.90% of NME and P. aeruginosa isolates (10–14). Most notably, REL provides significant
restoration of IMI activity against KPC-producing NME, lowering the MIC90 up to 16-fold (2,
9). It is also highly active against DTR P. aeruginosa isolates (15).
While I/R is highly active against most CR-NME and multidrug-resistant (MDR) P. aerugi-
nosa isolates, it does not have activity against MBL-producing isolates (e.g., NDM, IMP,
VIM), Serratia marcescens isolates that express SME carbapenemases, VEB-type extended-
spectrum b -lactamase (ESBL)-producing P. aeruginosa, and GES-like carbapenemase-pro-
ducing P. aeruginosa (2, 16–18). Relebactam also exhibits variable, but limited, inhibition of
OXA-48-like enzymes (19–22). Among isolates exhibiting I/R resistance, production of
OXA-48-like enzymes is relatively common, with the largest study to date suggesting that
only 16% (22/137) of isolates with OXA-48 production and without MBL production were
susceptible to I/R (21). Among K. pneumoniae isolates, disruption of OmpK36 combined
with production of KPC enzymes has also been associated with I/R resistance as have porin
alterations in combination with increased blaKPC copy number (i.e., increased KPC expres-
sion) (4, 23, 24). Data are more limited on the effect of disruption of Enterobacter species
porin OmpC, which serves functions similar to those of OmpK36, on I/R susceptibility.

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 TABLE 1 Susceptibility of carbapenem-nonsusceptible Enterobacterales to imipenem/relebactam and rate of metallo- b -lactamase productiona
Susceptibility (%)
CLSI or EUCAST %
Perspective

Study Database, location (yr[s]) breakpoints Population (n isolates) % MBL Morganellaceae IMI MERd I/R CZAd M/V COL/PMBd AMKd
Maraki 2022 (25) Greece (2017–2020) EUCAST CR-K. pneumoniae (266) 17.3% 0.0% 0.0% 0.0% 76.7% 79.7% 80.1% 65.8% NRd
Bail 2022 (37) Brazil (2013–2020) CLSI IMI/MER-R 0.0% 4.0% 0.0% 8.0% 96.0% NR NR 65.0% 67.0%
Enterobacterales (300)
Kuo 2021 (27) Taiwan (2012–2018) CLSI IMI-NS E. coli (17) 7.2%b 0.0% 0.0% 52.9% 70.6% 70.6% 94.1% 94.1% 94.1%

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IMI-NS K. pneumoniae 0.0% 0.0% 27.6% 76.1% 90.8% 81.6% 87.1% 76.7%
(163)
Bhagwat 2021 (29) Greece (2014–2018) EUCAST Enterobacterales (563) 33.0% 6.6% 9.9% 10.3% 61.0% 59.8% NR 47.4% 36.9%
Yang 2021 (83) Taiwan (2012–2015) CLSI Carbapenem-NS E. coli 4.8% 0.0% 29.3% 28.7% 87.8% NR NR NR NR
(188)
Carbapenem-NS K. 3.0% 0.0% 18.9% 23.1% 82.2% NR NR NR NR
pneumoniae (472)
Vazques-Ucha 2021 (19) Spain (2018) EUCAST CPE (401) 14.0% 0.0% 72.3% 68.8% 85.8% 83.8% NR 86.5% 75.8%
Yang 2020 (84) SMART, China (2015–2018) CLSI IMI-NS NR 0.0% 0.0% NR 66.3% NR NR 83.6% 50.9%
Enterobacteriaceae
(1,165)
Karlowsky 2020 (30) Global (2014–2016) CLSI Carbapenem-NS 21.0% 0.0% NR 4.4% 64.1% 77.5% NR 78.1% NR
Enterobacterales
(1,018)
Karlowsky 2021 (14) Global (2015–2017) CLSI KPC-producing NME 0.2% 0.0% 0.0% NR 96.2% NR NR 74.8% 71.5%
(1,081)
Nelson 2020 (32) Global (2001–2017) CLSI CPE (non-MBL) (374) 0.0% 0.3% 2.9% 24.6% 69.5% 90.6% 76.7% NR NR
Non-CP-EBE (50) 0.0% 0.0% 20.0% 51.2% 64.0% 86.0% 74.0% NR NR
Karlowsky 2021 (15) SMART, USA (2015–2017) CLSI DTR EBE (102) NR 1.0% 0.0% 0.0% 82.4% NR NR 84.3% 79.4%
Johnston 2020 (20) USA (2002–2017) CLSI CR E. coli (203) 7.9% 0.0% 44.0% 75.0% 89.0% NR NR 99.0% 80.0%
Lob 2020 (21) Europe (2015–2017) EUCAST IMI-NS NME (474) 30.8% 0.0% 0.0% NR 42.4% NR NR 67.1% 54.0%
Karlowsky 2020 (17) SMART, USA (2015–2017) CLSI IMI-R NME (170) 0.0% 0.0% 0.0% NR 66.4% NR NR NR NR
Karlowsky 2020 (85) SMART, USA (2015–2017) CLSI IMI-NS NME (154) 1.3% 0.0% 0.0% NR 77.9% NR NR 61.0% 88.3%
Carpenter 2019 (33) USA (2013–2017) CLSI IMI-NS CPE isolates (200) 0.0% 0.0% 0.0% NR 96.5% 100.0% NR 46.1%c NR
Galani 2019 (34) Greece (2014–2016) EUCAST KPC-producing K. 0.0% 0.0% 0.0% 0.3% 98.0% 99.7% NR 60.7% NR
pneumoniae (295)
Karlowsky 2018 (9) SMART, USA (2016) CLSI IMI-R NME (130) NR 0.0% 0.0% 0.0% 78.5% NR NR 41.5% 97.7%
Karlowsky 2018 (86) SMART, Europe (2015) EUCAST IMI-NS K. pneumoniae 22.9% 0.0% 0.0% NR 54.2% NR NR NR 41.9%
(179)
IMI-NS Enterobacter spp. 73.5% 0.0% 0.0% NR 26.5% NR NR NR 88.2%
(34)
Lapuebla 2015 (87) USA, (2013–2014) CLSI KPC-producing K. 0.0% 0.0% 9.0% NR 97.0% NR NR NR NR
pneumoniae (111)
aTable limited to studies with .100 carbapenem-nonsusceptible isolates.
bMBL-production reported for E. coli and K. pneumoniae together.
cTested against 180 non-Serratia species isolates.

dCOL, colistin; PMB, polymyxin B; AMK, amikacin; MER, meropenem; NR, not reported.

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 TABLE 2 P. aeruginosa susceptibility to imipenem/relebactam and prevalence of metallo- b -lactamase production
Susceptibility (%)
Perspective

Study Database, location (yr[s]) Phenotype (n isolates) % MBL IMI MER I/R C/T CAZ CZA M/V COL/PMB AMK
Bail 2022 (37) Brazil (2013–2020) IMI/MER-R (carbapenemase 0% 2% 6% 63% 80% 53% NR NR 98% 64%
non-producing) (229)
Sader 2021 (10) SENTRY Global (2020) MER-NS (54) NR NR 0% 88.9% 90.6% NR 92.6% 61.1% NR NR
IMI-R (48) NR 0% NR 87.5% 91.5% NR 93.8% 56.3% NR NR

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Sader 2022 (11) SENTRY, Europe (2020) MER-R (70) NR NR 0% 58.6% 57.1% NR 69.9% 5.7% NR NR
IMI-R (155) NR 0% NR 78.7% 81.9% NR 87% 59.4% NR NR
Zhang 2021 (3) SMART, China (2015–2018) IMI-NS (835) NR 0% NR 64.4% NR% NR NR NR NR NR
MDR (835) NR 25.2% NR 65.8% NR NR NR NR NR NR
Lob 2021 (13) SMART, USA (2018–2019) IMI-R (43) NR 0% 46.5% 79.1% NR 72.1% NR NR NR 95.4
Lob 2021 (12) SMART, USA (2017–2019) DTR ICU (72) NR 0% 0% 54.2% 61.1% 0% NR NR NR 83.3%
DTR non-ICU (56) NR 0% 0% 57.1% 69.6% 0% NR NR NR 82.1%
Kuo 2021 (27) Taiwan (2018) IMI-NS (81) 4.93% 0% 28.4% 85.2% NR 43.2% 81.5% 42% 69.3% 95%
Bhagwat 2021 (29) Greece (2014–2018) IMI-NS (172) 64% 0% 9.9% 28.5% 25.6% 0% 33.7% NR 64.5% 34.9%
Karlowsky 2020 (30) Global (2014–2016) MDR (262) 35.90% 0% 1.9% 17.2% 21.8% NR 26.3% NR 99.6% NR
Karlowsky 2021 (14) SMART, Global (2015–2017) Pediatric MDR (281) 15.3% 28.5% NR 70.5% NR 19.9% NR NR 98.6 72.2%
Adult MDR (4,927) 13.7% 28% NR 68.3% NR 23.4% NR NR 98.9% 72%
Karlowski 2021 (15) SMART, USA (2015–2017) DTR (230) NR 0% 0% 62.2% 67.5% 0% NR NR 98.7% 84.8%
Lob 2020 (21) Europe (2015–2017) IMI-NS (469) 18.30% 0% NR 74.4% NR 35.6% NR NR 64.6% 99.6%
Karlowsky 2020 (17) SMART, USA (2015–2017) IMI-R (219) NR 0% NR 77.2% NR NR NR NR NR NR
Karlowsky 2020 (85) SMART, USA (2015–2017) IMI-NS (193) NR 0% NR 85% NR NR NR NR NR NR
Young 2019 (2) SMART (2009–2016) IMI-R (3,747) 13.50% 0% NR 68% NR NR NR NR NR NR
Karlowski 2019 (88) SMART, USA (2015–2017) IMI-NS (766) NR 0% NR 78.3% NR NR NR NR NR NR
Asempa 2019 (89) USA (2017–2018) Carbapenem-NS (189) NR 6.4% 22.2% 75.7% NR 58.2% 84.7% NR NR NR
Lob 2018 (90) SMART, Europe (2015–2017) IMI-NS (1,668) NR 0% NR 75.2% NR NR NR NR NR NR
Mushtaq 2021 (18) England (2012–2019) VEB-producing (97) 0% 3.1% NR 10.3% 1% 0% 2.1% NR NR NR
GES-5 (carbapenemase) 0% 0% NR 0% 8.1% 8.1% 94.6% NR NR NR
producing (37)

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Perspective Antimicrobial Agents and Chemotherapy

Finally, I/R exhibited very limited in vitro activity against P. aeruginosa isolates producing a
VEB-type ESBL (18).
Comparisons of in vitro susceptibility between I/R and CZA have been conducted in
several surveillance studies (10, 11, 18, 19, 22, 23, 25–34). Typically, susceptibility results
are similar, or slightly favor CZA. Differences in activity against Enterobacterales are typ-
ically ,10% of tested isolates and are mostly driven by the prevalence of OXA-48 pro-
duction, Morganellaceae, and Serratia marcescens. To date, I/R does appear unaffected
by KPC-3 mutations that render CZA ineffective (4, 24). While the exact mechanism of
these mutations’ effect on avibactam are unclear, it has been suggested that they may
result in increased affinity for ceftazidime and decreased affinity for avibactam. It is
also worth noting that these mutations are also associated with significant decreases
in carbapenem MICs, often with restoration of carbapenem susceptibility as a solitary
mechanism (35, 36). It appears, however, that these mutations in combination with
porin alterations in K. pneumoniae may result in increases in MICs with M/V but not
with I/R (24). Activity against DTR-P. aeruginosa is also similar between these agents,
though I/R does not appear to exhibit activity against GES-5-producing P. aeruginosa
whereas CZA does (18).
Comparisons with meropenem-vaborbactam (M/V) and C/T are more limited than
CZA, and scant comparative susceptibility data are available with cefiderocol (10, 11,
15, 18, 22, 24–30, 32). Overall, M/V appears to exhibit activity against NME similar to
that of I/R, though M/V may have improved activity against OXA-48 producers relative
to that of I/R (10, 11, 22, 25–27, 32). I/R exhibits significantly increased activity against
P. aeruginosa relative to that of M/V. I/R also appears to exhibit activity against KPC-
producing K. pneumoniae isolates that exhibit M/V resistance via KPC production com-
bined with OmpK35 and OmpK36 mutations (24). Against P. aeruginosa, I/R and C/T
exhibited similar susceptibility profiles (10, 11, 15, 18, 22, 28–30, 37). One study of non-
carbapenemase-producing P. aeruginosa from Brazil, however, identified activity of C/T
substantially higher than that of I/R (80 versus 63%), though the cause of this discrep-
ancy is unknown (37). Of note, some DTR-P. aeruginosa isolates that develop resistance
to C/T also develop cross-resistance to CZA (28). It appears that these mutations, often
driven by mutations in PDCs, have a limited effect on I/R susceptibility.

PHARMACOKINETICS
Most published data on the PK of I/R were ascertained in phase I and II studies of
noninfected patients. In phase I and II studies, I/R exhibited linear PK with a dose-inde-
pendent terminal half-life (t1/2) ranging from 1.35 to 1.85 h (38). Data from single- and
multiple-dose studies indicated that I/R is predominately cleared by the kidneys (IMI,
;200 mL/min; REL, ;150 mL/min) with the fraction excreted in urine ranging from
94.7% to 100%. There was no appreciable accumulation with multiple doses, and the
observed apparent volume of distribution (;20 L) indicated that I/R largely distributed
in extracellular fluid. No drug-drug interactions between IMI and REL were observed,
and their PK profiles were similar, supporting their use as coadministered agents (38).
In a phase 1 PK study of patients with impaired renal function, including patients on
hemodialysis (HD), plasma exposures of IMI and REL increased as the estimated glo-
merular filtration rate (eGFR) decreased, and all 3 compounds exhibited comparable PK
alterations in patients with mild, moderate, and severe renal impairment and were sim-
ilarly removed by HD (39). These data were used, in part, to derive the current renal
dosing recommendations for patients with renal impairment, including HD (5). In
healthy subjects, the area under the curve from zero to infinity (AUC0–1) in epithelial
lining fluid (ELF) for both IMI and REL was ;55% of free plasma AUCs (40).

PHARMACOKINETICS AND PHARMACODYNAMICS

Overview. The PK/PD profile of I/R has been informed in 8 preclinical models of infec-
tions: neutropenic murine disseminated and pulmonary infection models (K. pneumoniae
and P. aeruginosa) (41), neutropenic mouse thigh infection model (K. pneumoniae and P.

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aeruginosa) (42, 43), in vitro one-compartment infection model (K. pneumoniae, P. aerugi-
nosa, and Escherichia coli) (44, 45), and hollow fiber infection model (HFIM; K. pneumoniae
and P. aeruginosa) (46–48). A mix of IMI-resistant and IMI-susceptible strains were eval-
uated across the preclinical PK/PD studies. Limited information on the susceptibility of the
evaluated isolates against newer b -lactams was included in the studies. In the two studies
that provided data, most isolates were susceptible to ceftazidime-avibactam (CZA) and cef-
tolozane-tazobactam (C/T) (43, 45). Standard starting inocula were evaluated across all
studies (49). All preclinical PK/PD studies were 24 h except two in vitro PK/PD model pub-
lished studies, which evaluated durations of 3, 7, and 14 days (44, 48). Across most preclini-
cal PK/PD studies, the FDA-European Union-approved I/R dose was simulated using the I/R
free maximum concentration (fCmax) and half-life (t1/2) observed in healthy human volun-
teers (38), and none include a newer b -lactam as a comparator. Given that the dosing (50)
and PK/PD profile (51, 52) of IMI are well established, humanized REL dose escalation and
fractionation studies (46, 47) were performed (REL doses were varied from 0 to 3,000 mg
every 1.5 to 24 h) to ascertain the REL in the presence of IMI PK/PD indices for a 1- to 2-log
kill, the PK/PD targets associated with clinical outcomes (53).
PK/PD targets for REL in the presence of IMI in preclinical PK/PD models of
infections. Two PK/PD targets for REL in the presence of IMI have been identified across
the preclinical PK/PD infection models of infection (46, 47). In the 24-h dose-escalation and
fractionation translational semimechanistic HFIM of IMI-resistant P. aeruginosa (n = 5 iso-
lates with I/R MICs of 2/4 to 16/4 mg/L) study by Bhagunde and colleagues, the PK/PD
index was found to be the fAUC0–24/MIC, and the magnitude of fAUC0–24/MIC for stasis,
1-log, and 2-log kill was 2.7, 4.7, and 7.5, respectively (46). Most patient fAUC0–24/MIC at a
250 mg REL dose exceeded 7.5, suggesting that the I/R 500 mg/250 mg dose every 6 h
was sufficient to provide .2-log kill for IMI-resistant P. aeruginosa isolates with potentiated
I/R MIC (the MIC of IMI in the presence of REL 4 mg/L) of #4 mg/L. The findings from this
HFIM study aligned with an earlier mouse thigh P. aeruginosa infection model study, which
suggested that the PK/PD-linked variable for REL in the presence of IMI was fAUC (42). It is
consistent with the PK/PD driver for meropenem-vaborbactam (M/V; vaborbactam fAUC:
MIC ratio of 18 to 35 associated with 1 log10 CFU/mL killing) (54) but differs from the
PK/PD driver (i.e., percent time above a threshold) for CZA and aztreonam-AVI (ATM-AVI)
(55, 56). Further study is needed, but the differences in PK/PD drivers could be due to
altered enzyme-binding kinetics; REL is an irreversible BLI while AVI is a reversible inhibitor.
As an irreversible BLI, degree of b -lactamase inhibition is likely a function of the magni-
tude of exposure over time while maintenance of a critical concentration would be more
critical for a reversible inhibitor like AVI (57).
A second dose-escalation HFIM of IMI-resistant P. aeruginosa and K. pneumoniae
that was 72 h in duration also found an association between fAUC/MIC and bacterial
killing, and the fAUC/MIC ratios required to achieve static, 1-log, and 2-log drops using
the potentiated I/R MIC were 8.2, 12, and 18, respectively (47). However, the percent-
age of time that I/R exceeds the dynamic MIC (%T . MICdynamic) was found to be a
more informative PK/PD driver. Data from checkboard experiments performed as part
of the study indicated that the potentiated I/R MIC of an isolate changes in a concen-
tration-dependent manner with increasing concentrations of REL, and the MICdynamic
reflects the potentiated I/R MIC at a given point in time based on the REL concentra-
tion present (58). Employing a maximum-effect (Emax) model to describe the relation-
ship between the potentiated I/R MIC and the REL concentration, the authors found
that the clinically administered dose of I/R (500 mg/250 mg intravenously [i.v.] every
6 h as a 0.5-h infusion) demonstrated a 65.5% fT . MICdynamic, which was well above
the identified 48- and 72-h fT . MICdynamic thresholds for sustained $2-log killing and
regrowth suppression.
Probability of target attainment profiles of United States- and European
Union-approved I/R dosing regimens. The probability of target attainment (PTA) pro-
file of I/R was evaluated as part of the population PK study that included PK data from
patients in the multicenter, randomized, double-blind trial comparing efficacy and
safety of imipenem/relebactam (RESTORE-IMI-1 and RESTORE-IMI-2) randomized

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clinical trials (RCTs) (59). Using data from 12 completed phase I to III clinical studies
(1,197 total patients with quantifiable plasma PK samples), a two-compartment zero-
order i.v. infusion model with first-order linear elimination with a proportional error
term was identified as the optimal base PK model (59). Covariates retained in the final
REL PK model included pneumonia and creatinine clearance (CLCR), expressed as a
power function, on CL and ventilation status, pneumonia, and total weight (power
function) on apparent central volume (V1). For IMI, significant covariates included
pneumonia, CLCR (power function), and body weight (power function) on CL and venti-
lation status, pneumonia, and total body weight (power function) on V1.
With the final population PK model (59), simulations of I/R exposure profiles in non-
ventilated and ventilated pneumonia patients (n = 1,000 per renal function category)
based on the covariate patterns observed in RESTORE-IMI-2 and MODIFY I/II (end-stage
renal disease [ESRD] patients only) (60) were performed. For the I/R 500/250-mg and
renal function-adjusted dosing regimens, free plasma concentrations at steady-state
conditions were simulated to characterize the joint I/R PTA profile. The PK/PD targets
in the joint PTA analyses were 30% fT . MIC for IMI and fAUC/MIC $ 8 for REL (46).
Safety analyses were also performed to assess the percentage of patients within each
renal function group that remained below the upper limit safety exposure thresholds
for IMI (AUC0–24, 3229.8 m Mh; Cmax, 625.1 m M) and REL (AUC0–24, 2941.0 m Mh; Cmax,
367.9 m M) (38, 61). In the primary analysis, joint PTA was .90% for all renal function
subgroups at the current I/R MIC breakpoint of 2/4 mg/L, regardless of ventilation sta-
tus. In a sensitivity joint PTA analysis that employed an IMI PK/PD target of 40%
fT . MIC, PTA across renal function subgroups still exceeded 90% for I/R MIC values of
#2/4 mg/L. In the safety analysis, less than 1% of patients in any renal function group
exceeded the AUC0–24 and Cmax thresholds when renal function-adjusted doses of I/R
were simulated, except the ESRD group in which 12.2% of patients exceeded the
threshold for REL AUC0–24.
Performance of approved I/R dosing regimens in preclinical PK/PD infection
model studies. Several preclinical PK/PD studies have been performed to assess the effi-
cacy of the now-approved I/R regimen when it is administered alone and in combination.
In the neutropenic mouse thigh infection model of P. aeruginosa study that examined
humanized I/R exposures, a $2-log reduction in bacterial density was observed in 27/29
(93%) of the IMI-resistant isolates with 500 mg/250 mg every 6 h (43). For the two isolates
with ,2-log reduction in CFU, one was VIM producing (I/R MIC . 32 mg/L) and the sec-
ond produced a GES-20 carbapenemase (I/R MIC = 32 mg/L). In a 24-h in vitro one-com-
partment PK/PD model of P. aeruginosa, the mean reductions in CFU/mL at hour 24 were
22.52, 21.49, 21.15, and 20.61 log10 CFU/mL against isolates with potentiated I/R MICs
of 1, 2, 4, and 8 mg/L, respectively (45). However, regrowth at hour 24 with I/R was com-
monplace and I/R-resistant subpopulations (at 3 the baseline MIC) were observed in one
isolate that exhibited intermediate susceptibility (4/4 mg/L) to I/R at baseline. The combi-
nation of I/R plus colistin resulted in synergistic or additive effects against three of the six
isolates, while the addition of amikacin to I/R achieved only indifferent effects against all
isolates. For the I/R and colistin combination regimen, no resistant subpopulations devel-
oped to either drug, whereas the addition of amikacin to I/R prevented the emergence of
amikacin-resistant subpopulations but the I/R-resistant populations remained for the one
isolate. Similarly, P. aeruginosa regrowth was observed in the 7-day one-compartment
PK/PD infection model study by Noel and colleagues with I/R 500 mg/250 mg i.v. every
6 h despite significant drops in CFU/mL counts during the first 24 h (44). Regrowth
through 7 days was not associated with an increase in I/R MICs. However, regrowth of
P. aeruginosa was greater than the starting inoculum by day 14 and increases in I/R MICs
among evaluated isolates were observed. Addition of amikacin to this infection model
study prevented development of resistance to I/R and regrowth. In a 72-h HFIM by Hirsch
et al. that evaluated 500 mg of REL in combination with 500 to 1,000 mg of IMI every 6 h,
I/R demonstrated rapid bacterial killing and sustained suppression of bacterial growth for
up to 72 h against a K. pneumoniae isolate harboring the KPC-2 carbapenemase and TEM-
and SHV-like extended-spectrum b -lactamases. Against P. aeruginosa, $2-log reduction in

July 2022 Volume 66 Issue 7 10.1128/aac.00256-22 7

Perspective Antimicrobial Agents and Chemotherapy

bacterial burden was observed consistently at 24 h but regrowth by 72-h was observed in
2 of the 3 P. aeruginosa isolates evaluated with I/R 500 mg/500 mg i.v. every 6 h (48).

CLINICAL EXPERIENCE
Clinical trial data. To date, I/R has been evaluated in 2 prospective, randomized, dou-
ble-blind, dose-ranging phase II RCTs (62, 63), 2 prospective, randomized, double-blind
phase III RCTs (64, 65), one open-labeled noncomparator phase III trial (66), and 2 real-
world evidence studies (Table 3) (67). The FDA and European Union approvals of I/R were
based, in large part, on the results of RESTORE-IMI-1 and RESTORE-IMI-2 (64, 65). RESTORE-
IMI-1 was a pathogen-focused randomized, double-blind phase III RCT that investigated
the efficacy of I/R and IMI plus colistin against IMI-nonsusceptible infections (65). In this
noninferential, descriptive phase III RCT, hospitalized patients with HABP/VABP, cUTIs, or
cIAIs caused by IMI-nonsusceptible (colistin- and I/R-susceptible) pathogens were random-
ized 2:1 to 5 to 21 days of I/R or IMI plus colistin (loading dose to achieve 300 mg colistin
base activity [CBA] and then up to 150 mg CBA every 12 h). The safety population included
enrolled patients who received $1 dose of study treatment. The microbiologic modified
intent-to-treat (mMITT) population was the primary efficacy population, which comprised
all randomized patients who received $1 dose of study treatment and had a central labo-
ratory-confirmed IMI Gram-negative pathogen from the primary infection site. The primary
efficacy endpoint was overall response, which was defined based on the infection type
per regulatory guidance (HABP/VABP, 28-day all-cause mortality [ACM]; cIAI, day 28 clinical
response; and cUTI, composite clinical and microbiologic response at early follow-up
[EFU]) (68–70). Secondary endpoints were day 28 clinical response (mMITT population), 28-
day all-cause mortality (mMITT population), and treatment-emergent nephrotoxicity
(safety population).
Overall, 50 patients were enrolled, 47 patients (31 I/R versus 16 IMI plus colistin)
received $1 dose of assigned study treatment (safety population), and 31 patients (21
I/R versus 10 IMI plus colistin) met the criteria for the MITT population. Treatment
groups were reasonably well matched at baseline in the MITT population: 36%
were $ 65 years of age, 23% had renal impairment (CLCR , 60 mL/min), 29% had an
APACHE-II score of .15 (71), 36% had HABP/VABP, 51% had a cUTI, and 13% had a
cIAI. The most common pathogens were P. aeruginosa (77%), Klebsiella spp. (16%), and
other Enterobacterales (6%). Detected b -lactamases included AmpC (84% of mMITT
patients), ESBLs (35%), KPC (16%), and OXA-48 (3%).
In the MITT population, favorable outcomes were observed in 71% of patients in
the I/R group versus 70% of patients in the IMI plus colistin group (90% confidence
interval [CI], 227.5, 21.4). Favorable overall response against P. aeruginosa was
observed in 81% (13/16) of patients in the I/R group and 63% (5/8) of patients in the
IMI plus colistin group. Against Enterobacterales, favorable response rates were 40% (2/5)
for I/R and 100% (2/2) for IMI plus colistin, respectively. Day 28 ACM overall was 9.5% (2/
21) and 30% (3/10) in the I/R and IMI plus colistin (adjusted difference, 220.5 [90% CI,
246.5, 6.7]), respectively. Clinical response at day 28 was 71% in the I/R group and 40%
in the IMI plus colistin group (adjusted difference, 31.4 [90% CI, 1.3, 51.5]). All-cause mor-
tality and clinical response at day 28 by pathogen were not provided. Prior meropenem
therapy did not affect overall response, and there were no instances of treatment-emer-
gent I/R-nonsusceptible isolates. Serious adverse events (AEs) occurred in 10% and 31%
of I/R and IMI plus colistin patients, respectively. Three patients (19%) in the IMI plus coli-
stin arm (drug-related blood creatinine increase, drug-related CLCR increase, and treat-
ment-emergent infection; n = 1 each) and none in the I/R arm discontinued treatment
due to AEs. Treatment-emergent nephrotoxicity was significantly less frequent with I/R
than with IMI plus colistin (10% and 56%, respectively; adjusted difference, 245.9 [95%
CI, –69.1% to –18.4%). By the Kidney Disease Improving Global Outcomes (KDIGO) crite-
ria, none of the patients in the I/R arm and 31.3% in the IMI plus colistin group experi-
enced stage III acute kidney injury, and two patients who received IMI plus colistin
required initiation of dialysis during the study period. In a secondary analysis in

July 2022 Volume 66 Issue 7 10.1128/aac.00256-22 8

 TABLE 3 Summary of published clinical dataa
Study design and population
Prospective, randomized, double-
blind, dose-ranging phase II study
comparing efficacy and safety of I/R
with IMI alone in patients with cUTIs
(63)
July 2022 Volume 66 Issue 7
Prospective, randomized, double-
blind, dose-ranging phase II study
comparing efficacy and safety of I/R
with IMI alone in patients with cIAI
(62)
10.1128/aac.00256-22
9
Comparators
I/R 250 mg, I/R 125 mg, or IMI
500 mg alone
Treatment was administered over
30 minutes every 6 hours for 4–
14 days (step-down to oral
ciprofloxacin after 4 days was
permitted)
I/R 250 mg, I/R 125 mg, or IMI
500 mg alone
Treatment was administered over
30 minutes every 6 hours for
4–14 days in all groups
Key primary and secondary
endpoints
The primary endpoint was favorable
microbiological response rate at
DCIV in the ME population
Secondary efficacy endpoints, all
assessed in the ME population:
 Microbiological responses at EFU
and LFU
 Microbiological response at DCIV
in patients with IMI-resistant
pathogens
 Clinical response at DCIV, EFU and
LFU
The primary endpoint was favorable
clinical response at DCIV in the
ME population at 28–42 days
after i.v. study therapy (LFU)
Secondary endpoints included
clinical response at EFU and LFU
visits and global response
at day 28
Key baseline characteristics
Of the 302 patients randomized,
298 were treated and 230
(77.2%) were ME at DCIV
 71 in the I/R 250 mg group
 79 in the I/R 125 mg group
 80 in the IMI group
In the ME at DCI population, groups
were well balanced at baseline:
 40% were $65 yrs
 52% were female
 52% had a cUTI vs AP only.
The most common baseline
pathogens:
 E. coli (62%)
 K. pneumoniae (15%)
Among the patients with a
confirmed Gram-negative
pathogen (n = 220):
 34.1% were NS to at least one
third-generation cephalosporin
 11.4% had an IMI NS isolate
 6.8% had an I/R NS isolate
Of the 351 subjects randomized,
277 were included in the MITT
population, and 255 (72.6%)
were included in the ME
population
 83 in the I/R 250 mg group
 87 in the I/R 125 mg group
 85 in the IMI group
In the ME population, groups were
well balanced at baseline:
 55% were male
 79% were ,65 yrs old
 95% had an APACHE-II score of
#15
 53% had complicated
appendicitis and 17% had
complicated cholecystitis
The most common pathogens
identified at baseline:
 E. coli (171 isolates)
 K. pneumoniae (38 isolates)
Major findings
At DCIV, .95% of ME patients in
each treatment arm had
favorable microbiological
responses, and both I/R dosing
regimens (500/250 mg and the
500/125 mg) were found to be
noninferior to IMI
All patients with an IMI-NS Gram-
negative baseline pathogen in
the ME population achieved a
favorable microbiological
response at DCIV
A favorable clinical response in ME
population at DCIV exceeded
95% for all treatment groups
Microbiological and clinical
response rates were similar
between all three treatment
groups at the EFU and LFU visits
At the DCIV visit, the proportion of
subjects in the ME population
with a favorable clinical response
was .95% for the 3 treatment
groups, and both I/R doses were
found to be noninferior to IMI
alone
All patients with an IMI
nonsusceptible pathogen in the
ME population (n = 34) had a
favorable microbiological
response at the DCIV visit
Clinical response rates at the EFU
and LFU visits were similar
between all treatment groups
Global response at 28 days
postrandomization in the MITT
population was similar (.85%)
between all treatment groups
Other findings and comments
Perspective
Four patients had treatment-related
AEs leading to discontinuation of
study drug
 2.0% with I/R 250 mg
 1.0% with I/R 125 mg
 1% with IMI
One patient each in the 250 and
125 mg I/R groups experienced
liver enzyme elevation (i.e., ALT or
AST) of $5% ULN
The most common AEs were nausea,
vomiting, and diarrhea
Drug-related AE events leading to
discontinuation:
 1 subject who received I/R 125 mg
(decreased CLCR)
 3 subjects who received IMI alone
(thrombocytosis, nausea, and
increased ALT)
4 patients experienced liver enzyme
elevations (i.e., AST and ALT
of $5)
 2 with I/R 250
 2 with IMI alone
One patient who received I/R
250 mg met the criteria for Hy’s
law (day 2 of treatment), and it
was deemed to be unrelated to
treatment
Three fatal adverse events occurred
(septic shock, ventricular
(Continued on next page)
Antimicrobial Agents and Chemotherapy
 TABLE 3 (Continued)
Study design and population
Pathogen-focused randomized,
double-blind descriptive phase III
study that investigated the efficacy
July 2022 Volume 66 Issue 7
of I/R and IMI plus colistin in
hospitalized patients with HABP/
VABP, cUTIs, or cIAIs caused by
IMI-non-susceptible (colistin-
and I/R-susceptible) pathogens
(RESTORE-IMI-1) (65)
Randomized, double-blind,
multicenter trial comparing efficacy
and safety of I/R vs TZP in adults
with HABP or VABP (RESTORE-IMI 2
study) (64)
10.1128/aac.00256-22
10
Comparators
Patients were randomized 2:1 to 5–
21 days of I/R 250 mg over
30 minutes every 6 hours or IMI
500 mg over 30 minutes every
6 hours plus colistin (loading
dose to achieve 300 mg CBA then
up to 150 mg CBA every
12 hours)
Patients were randomized in a 1:1
ratio to I/R 250 mg over
30 minutes every 6 hours or TZP
4.5 g over 30 minutes every
6 hours for 7–14 days
All patients received empirical
intravenous linezolid for $7 days
unless baseline LRT cultures
confirmed the absence of MRSA
Key primary and secondary
endpoints
The primary efficacy endpoint was
overall response in the mMITT
population (comprised all
randomized patients who
received $1 dose of study
treatment and had a central
laboratory-confirmed IMI non-
susceptible Gram-negative
pathogen from the primary
infection site)
The primary efficacy endpoint was
defined based on the infection
type per regulatory guidance
(HABP/VABP: 28-day all-cause
mortality; cIAI, day 28 clinical
response; and cUTI, composite
clinical and microbiologic
response at EFU)
Secondary endpoints were day 28
clinical response (mMITT
population), 28-day all-cause
mortality (mMITT population),
and treatment-emergent
nephrotoxicity (safety
population)
The primary endpoint was day 28
all-cause mortality (ACM) in the
modified intent-to-treat (MITT)
population (patients who
received study therapy, excluding
those with only Gram-positive
cocci at baseline)
Key secondary endpoint was clinical
response at the EFU (7–14 days
after completing therapy) in the
MITT population
Other secondary endpoints included
28-day ACM in mMITT
population), microbiologic
response at EOT and EFU (mMITT
population), and clinical response
at EFU (clinically evaluable [CE]
population)
Key baseline characteristics
 P. aeruginosa (37 isolates)
36 subjects (13%) had IMI-
resistant Gram-negative
infections at baseline in MITT
population
50 patients were enrolled:
 47 patients (31 I/R vs 16 IMI plus
colistin) received $1 dose of
assigned study treatment (safety
population)
 31 patients (21 I/R vs 10 IMI plus
colistin) met the criteria for the
MITT population
Treatment groups were reasonably
well matched at baseline in the
MITT population:
 36% were $65 yrs old
 23% had renal impairment
(creatinine clearance ,60 mL/
min)
 29% had an APACHE-II score of
.15
 36% had HABP/VABP
 51% had a cUTI
 13% had a cIAI
The most common pathogens were
P. aeruginosa (77%), Klebsiella
spp. (16%), and other
Enterobacterales (6%)
Detected b -lactamases included
AmpC (84% of mMITT patients),
ESBLs (35%), KPC (16%), and
OXA-48 (3%)
Of 537 randomized patients:
 535 (266 I/R, 269 TZP) received $1
dose of study treatment
 531 (264 IMI/REL, 267 TZP) were
included in the MITT population
Treatment groups were reasonably
well matched at baseline in the
MITT population
 43% were .65 yrs old
 66% were in the ICU
 49% had ventilated HABP/VABP
 48% had APACHE-II score of $15
(70)
 17% had augmented renal
clearance and 25% had moderate/
severe renal impairment
Most frequent Gram-negative
pathogens:
 K. pneumoniae (26%)
 P. aeruginosa (19%)
 Acinetobacter calcoaceticus-
baumannii complex (16%)
 E. coli (16%)
Among MITT patients with $1
identified Gram-gram LRT
Major findings
Favorable outcomes were observed
in 71% of patients in the I/R
group vs 70% of patients in the
IMI plus colistin group (90% CI,
227.5, 21.4) in mMITT population
Favorable overall response against
P. aeruginosa was observed in
81% (13/16) of patients in the I/R
group and 63% (5/8) of patients
in the IMI plus colistin group
Favorable response against
Enterobacterales was 40% (2/5)
for I/R and 100% (2/2) for IMI plus
colistin
Day 28 ACM was 9.5% (2/21) and
30% (3/10) in the I/R and IMI plus
colistin (adjusted difference,
220.5 [90% CI, 246.5, 6.7]),
respectively
Clinical response at day 28 was 71%
in the I/R group and 40% in the
IMI plus colistin group (adjusted
difference, 31.4 [90% CI 1.3, 51.5])
In the MITT population, 28-day ACM
was 15.9% with I/R and 21.3%
TZP (adjusted treatment
difference, 25.3% [95% CI,
211.9% to 1.2%]); noninferiority
P , .001)
For patients who had all confirmed
baseline LRT pathogens
susceptible to both study drugs,
28-day ACM was 16% for I/R and
19% for TZP (adjusted treatment
difference, 24.8 (95% CI, 216.1,
6.1)
In clinically relevant patient
subgroup analyses, 28-day ACM
was similar between treatment
groups except for patients with
ventilated HABP/VABP and
APACHE-II score of $15
 Ventilated HABP/VABP: 20% for I/R
and 31% for TZP (adjusted
treatment difference, 211.2 [95%
CI, 221.6, 20.5)
 APACHE-II score $ 15: 20% for I/R
and 35% for TZP (adjusted
Other findings and comments
Perspective
fibrillation, and intestinal
infarction) among patients in the
I/R 125 mg group, and all deaths
were considered non-drug
related
Prior meropenem therapy did not
affect overall response
There were no instances of
treatment-emergent I/R
nonsusceptibility
Serious adverse events occurred in
10% and 31% of I/R and IMI plus
colistin patients, respectively
3 patients (19%) in the IMI plus
colistin arm (drug-related blood
creatinine increase, drug-related
CLCR increase, and treatment-
emergent infection; n = 1 each)
and 0 in the I/R arm discontinued
treatment due to AEs
Treatment-emergent nephrotoxicity
was significantly less frequent
with I/R than with IMI plus colistin
(10% and 56%, respectively,
adjusted difference 245.9, [95%
CI, –69.1% to –18.4%])
KDIGO criteria, 0 of the patients in
the I/R arm and 31.3% in the IMI
plus colistin group experienced
stage 3 acute kidney injury
2 patients who received IMI plus
colistin required initiation of
dialysis during the study period
(day 3)
The most reported drug-related AEs
with I/R were diarrhea, increased
aspartate aminotransferase, and
increased alanine
aminotransferase (each drug-
related AE was ,3%)
Six I/R patients (2.3%) and 4 TZP
patients (1.5%) discontinued
treatment due to drug-related
AEs
Serious drug-related AEs were
reported in 1.1% of I/R vs 0.7% of
TZP patients
There were 40 deaths (15%) in the
I/R group and 57 deaths (21%) in
the TZP group; no deaths were
considered drug related
(Continued on next page)
Antimicrobial Agents and Chemotherapy
 TABLE 3 (Continued)
Study design and population
July 2022 Volume 66 Issue 7
Phase 3, multicenter, open-label,
noncomparative study of I/R in
Japanese patients with cUTIs or cIAIs
suspected or confirmed to be
caused by I/R-susceptible Gram-
negative pathogens (66)
aDCIV:discontinuation of intravenous therapy; EFU: early follow-up; LFU; late follow-up; ME: microbiologic evaluable; NS: nonsusceptible; ALT: alanine transaminase; AST: aspartate aminotransferase; MRSA: methicillin-resistant
Staphylococcus aureus; EOT: end of treatment; TOC: test of cure; CE: clinically evaluable; I/R: imipenem/relebactam; IMI: imipenem; cUTI: complicated urinary tract infections; DCIV: discontinuation of intravenous therapy; AEs:
adverse events; ULN: upper limit of normal; cIAI: complicated intra-abdominal infections; IV: intravenous; MITT: microbiologic intention to treat; HABP; hospital-acquired bacterial pneumonia; VABP: ventilator-associated bacterial
pneumonia; CBA: colistin base activity; mMITT: modified microbiologic intent-to-treat; CI: confidence interval; KDIGO: Kidney Disease Improving Global Outcomes; ACM: all-cause mortality; TZP: piperacillin/tazobactam; ICU:
intensive care unit; APACHE-II: acute physiology and chronic health evaluation-II.
10.1128/aac.00256-22
11
Comparators
I/R 250 mg over 30 minutes every
6 hours for 5–14 days
Key primary and secondary
endpoints
Primary efficacy endpoints were
assessed in the ME population:
 Clinical response at EOT for
patients with cIAI
 Microbiological response at EOT
for patients with cUTI
Secondary efficacy endpoints:
 Clinical response at TOC for cIAI
 Microbiological response at TOC
for cUTI
Key baseline characteristics
pathogen and susceptibility
interpretation available
(n = 380), 80% of I/R patients and
66% of TZP patients had all
susceptible isolates
Of 87 patients screened, 83 (cIAI,
n = 39; cUTI, n = 44) were
enrolled in the study
 81 patients (cIAI, n = 37; cUTI,
n = 44) were included in the MITT
population
 67 patients (cIAI, n = 28; cUTI,
n = 39) were included in the ME
population
Baseline characteristics in cIAI
patients:
 62% were male
 46% were $ 65 yrs
 62% had a complicated
appendicitis
Baseline characteristics in cIAI
patients
 68% were female
 62% were $ 65 yrs
 50% had an uncomplicated AP
 The most common baseline
pathogen isolated was E. coli
 51% of cIAI patients
 71% of cUTI patients
Major findings Other findings and comments
Perspective
treatment difference, 215.4 [95%
CI, 226.2, 24.4])
Baseline pathogen subgroup
analyses of 28-day ACM
 Enterobacterales: 12% for I/R and
20% for TZP (adjusted treatment
difference, 28.5 [95% CI, 221.9,
23.3])
 P. aeruginosa: 33% for I/R and 12%
for TZP (adjusted treatment
difference, 221.3 [95% CI, 24.5,
48.9])
In the secondary endpoint analyses,
favorable clinical response at EFU
was 61.0% with I/R and 55.8%
with TZP (adjusted treatment
difference, 5.0% [95% CI, 23.2%
to 13.2%]); noninferiority
P , .001
Other secondary endpoints (i.e., 28-
day ACM in MITT population,
favorable microbiologic response
at EFU in mMITT population, and
favorable clinical response at EFU
in CE population) were
comparable between treatment
groups
Favorable clinical and Drug-related AEs occurred in 18.5%
microbiological responses in the of patients in the MITT
ME population at EOT: population
 cUTI: favorable clinical response 3.7% of patients discontinued
was 100% and favorable therapy due to a drug-related AE
microbiologic response was 100% (hypoesthesia [two patients],
 cIAI: favorable clinical response dizziness, tremor, and blurred
was 85.7% and favorable vision)
microbiologic response was 85.7% Serious AEs occurred in 9 patients,
Favorable clinical and including one death, but none
microbiological responses in the were considered treatment
ME population at TOC: related
 cUTI: favorable clinical response
was 92.3% and favorable
microbiologic response was 59.0%
 cIAI: favorable clinical response
was 82.1% and favorable
microbiologic response was 82.1%
Antimicrobial Agents and Chemotherapy
Perspective Antimicrobial Agents and Chemotherapy

RESTORE-IMI-1, similar outcomes were observed in primary mMITT population (n = 31),

where eligibility was based on central laboratory susceptibility testing, and the supple-
mental mMITT (SmMITT) population, where eligibility was based on local, site-level test-
ing (n = 41) (72).
I/R was also compared with piperacillin-tazobactam (TZP) in RESTORE-IMI 2, a multi-
center, randomized, phase III noninferiority trial of adult patients with HABP/VABP (64).
In RESTORE-IMI 2, adult patients with nonventilated HABP, ventilated HABP, or VABP
were randomized (stratified by nonventilated HABP versus ventilated HABP/VABP and
by APACHE-II score [,15 versus $15] [71]) in a 1:1 ratio to I/R or TZP 44.5 g, intrave-
nously (30-minute infusion) every 6 h for 7 to 14 days. All patients received empirical
intravenous linezolid for $7 days unless baseline LRT cultures confirmed the absence
of methicillin-resistant Staphylococcus aureus. The primary endpoint was day 28 all-
cause mortality (ACM) in the MITT population (patients who received study therapy,
excluding those with only Gram-positive cocci at baseline). The key secondary end-
point was clinical response at the EFU (7 to 14 days after completing therapy) in the
MITT population. Other secondary endpoints included 28-day ACM in mMITT popula-
tion, microbiologic response at EOT and EFU (mMITT population), and clinical response
at EFU (clinically evaluable [CE] population).
Overall, 537 patients were randomized and 531 (264 I/R, 267 TZP) were included in
the MITT population. Among patients in the MITT population, 43% were .65 years old,
66% were in the intensive care unit (ICU), 49% had ventilated HABP/VABP, 48% had
APACHE-II score of $15 (71), 17% had augmented renal clearance, and 25% had mod-
erate to severe renal impairment. Most frequent Gram-negative pathogens were K.
pneumoniae (26%), P. aeruginosa (19%), Acinetobacter calcoaceticus-baumannii complex
(16%), and Escherichia coli (16%). Among MITT patients with $1 identified Gram-gram
LRT pathogens and susceptibility interpretation available (n = 380), 80% of I/R patients
and 66% of TZP patients had all susceptible isolates. Mean treatment duration was
8.7 days with I/R and 8.3 days with TZP.
In the MITT population, 28-day ACM was 15.9% with I/R and 21.3% with TZP
(adjusted treatment difference, 25.3% [95% CI, 211.9% to 1.2%]; noninferiority P ,
0.001). For patients who had all confirmed baseline LRT pathogens susceptible to both
study drugs, 28-day ACM was 16% for I/R and 19% for TZP (adjusted treatment differ-
ence, 24.8 [95% CI, 216.1, 6.1]). No data were provided on 28-ACM rates for patients
with nonsusceptible LRT Gram-negative pathogens to treatment received. In the clini-
cally relevant patient subgroups analyses, 28-day ACM was similar between treatment
groups except for patients with ventilated HABP/VABP and APACHE-II score of $15.
Among ventilated HABP/VABP patients, 28-ACM was 20% for I/R and 31% for TZP
(adjusted treatment difference, 211.2 [95% CI, 221.6, 20.5]). For the subgroup of
patients with an APACHE-II score of $15, 28-ACM was 20% for I/R and 35% for TZP
(adjusted treatment difference, 215.4 [95% CI, 226.2, 24.4]). In the baseline pathogen
subgroup analyses, 28-day ACM for patients with Enterobacterales (I/R [n = 68] versus
TZP [n = 66]) was 12% for I/R and 20% for TZP (adjusted treatment difference, 28.5
[95% CI, 221.9, 23.3]). For patients with P. aeruginosa (I/R [n = 15] versus TZP [n = 25]),
28-day ACM was 33% for I/R and 12% for TZP (adjusted treatment difference, 221.3
[95% CI, 24.5, 48.9]).
In the secondary endpoint analyses, I/R was found to be noninferior to TZP for
favorable clinical response at EFU (61.0% with I/R and 55.8% with TZP [adjusted treat-
ment difference, 5.0% {95% CI, 23.2% to 13.2%}; noninferiority P , .001]). Other sec-
ondary endpoints (i.e., 28-day ACM in MITT population, favorable microbiologic
response at EFU in mMITT population, and favorable clinical response at EFU in CE
population) were also comparable between treatment groups. Drug-related AEs
occurred in 11.7% of patients who received I/R and 9.7% of patients who received TZP.
The most reported drug-related AEs with I/R were diarrhea, increased aspartate amino-
transferase, and increased alanine aminotransferase (each drug-related AE was ,3%).
Six I/R patients (2.3%) and 4 TZP patients (1.5%) discontinued treatment due to drug-

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Perspective Antimicrobial Agents and Chemotherapy

related AEs. Serious drug-related AEs were reported in 1.1% of I/R versus 0.7% of TZP
patients. There were 40 deaths (15%) in the I/R group and 57 deaths (21%) in the TZP
group; no deaths were considered drug related.
Real-world data. Published real-world evidence with I/R is currently limited to two
noncomparator case reviews (67, 73). The first was a multicenter observational study of
21 patients with doses of I/R ranging from 500/250 to 1,250/625 mg every 6 h (67). The
most common infection types were respiratory tract infections, including HABP and
VABP (52%), UTIs (14%), and invasive prosthetic device infections (14%). Pseudomonas
aeruginosa was the predominant pathogen (76%), followed by K. pneumoniae; 29%
were polymicrobial infections and 29% had concurrent bacteremia. Multidrug-resistant
pathogens were common; 3/8 (38%) patients with Enterobacterales had a carbapenem-
resistant Enterobacterales (CRE) infection, and 15/16 (94%) P. aeruginosa cases were
MDR. Only 52% of cases had I/R MICs performed (mostly Etest), with an MIC range of
0.125/4 to $32/4 (73% were susceptible). The median (IQR) duration of I/R therapy was
8 (4.5 to 14) days, and combination therapy was commonplace (29%). Thirty-day mor-
tality and clinical cure were 33% and 62%, respectively. Nonsusceptibility to I/R devel-
oped on treatment in 1 of 9 isolates with subsequent MIC testing post-index culture
(nonsusceptible organism not identified, but the patient had a CRE/CR P. aeruginosa
pneumonia). Microbiological recurrence occurred in 24% (5/21) of patients, and 2 of
the 5 patients with recurrence had an initial P. aeruginosa I/R-susceptible isolate but a
nonsusceptible I/R isolate on subsequent culture. Two adverse events were reported (1
gastrointestinal [nausea, vomiting, diarrhea] and 1 encephalopathic [altered mental
status, somnolence, new-onset seizures]), but neither resulted in drug discontinuation.
The second real-world evidence study described the experience of 19 patients who
were treated with I/R for an MDR P. aeruginosa HABP/VABP (73). Among these 19
patients, 5 had emergence of I/R-nonsusceptible P. aeruginosa during treatment or
within 30 days posttreatment. All 5 patients with recovered emergent I/R-nonsuscepti-
ble P. aeruginosa were managed in the ICU and had failed prior antibiotic regimens,
including two patients who received I/R after treatment-emergent resistance to C/T.
Baseline I/R MICs ranged from 0.5 to 1 mg/L, and postexposure I/R MICs ranged from 4
to 32 mg/L following 10- to 28-day treatment courses. Whole-genome sequencing
(WGS) was performed, and each recovered P. aeruginosa isolate across the 5 patients
had a unique sequence type (ST), including two patients with high-risk MDR clones
ST235 and ST244 (74). Genomic sequence analyses identified treatment-emergent
mutations in MexAB-OprM and/or MexEF-OprN efflux operons (mutations in both
membrane transporter and transcriptional regulator genes) that arose independently
in each patient and across the distinct P. aeruginosa STs. There were no clear associations
between emergent I/R-nonsusceptible isolates and mutations in porin genes or genes
encoding penicillin-binding proteins. Furthermore, no isolates harbored MBLs or other
b -lactamase enzymes known to confer I/R resistance (74). Testing with efflux-inhibitor
PA b N restored I/R susceptibility against all but 1 I/R-nonsusceptible isolate that had a
mutation in ampC, suggesting that the MexAB-OprM and MexEF-OprN operons potentially
work in concert to extrude REL and result in I/R-nonsusceptible strains, most likely in the
presence of other upregulated resistance mechanisms (i.e., downregulated OprD porin
channels and ampC overexpression). Alternatively, as REL differs from other diazabicy-
clooctane BLIs in that it carries a positively charged side chain believed to limit drug efflux
(5), an alternative explanation for the observed findings was that mutations in MexEF-
OprN may have limited REL entry into P. aeruginosa isolates largely by downregulating
OprD porin channels.

ROLE OF IMIPENEM-RELEBACTAM IN CLINICAL PRACTICE

Overall, published preclinical PK/PD infection model, susceptibility surveillance, and
clinical data for I/R are highly favorable and indicate that I/R is a welcomed addition to
our antibiotic armamentarium against CR-NME and DTR P. aeruginosa. Consistent with
best antibiotic stewardship practices, I/R use should be limited to clinical situations in

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Perspective Antimicrobial Agents and Chemotherapy

which a CR-NME or DTR P. aeruginosa infection is highly suspected or documented.

Like the other recently approved b -lactams, I/R demonstrated noninferior efficacy for
the treatment of adults with HABP/VABP, and its safety profile was consistent with
those of other b -lactams (5, 6, 62–66). Although it was a descriptive, small-scale RCT,
RESTORE-IMI-2 suggested that I/R may be associated with similar or improved 28-day
response rates and less nephrotoxicity relative to those of IMI and colistin combination
therapy for the treatment of adult patients with IMI-resistant NME and P. aeruginosa
infections (65). Available preclinical PK/PD (43, 46, 47) and PTA data (59) provide
adequate support for the current I/R and renal function-adjusted dosing regimens at
the current CLSI and EUCAST susceptibility breakpoints for P. aeruginosa and NME.
Across its phase II and III RCTs, no cases of treatment-emergent I/R resistance were
reported, lending further support for the adequacy of the I/R FDA- and European
Union-approved I/R dosing regimen. However, regrowth and resistance emergence
were observed in two in vitro PK/PD models of P. aeruginosa infections (44, 45), and
two recent case series revealed treatment-emergent I/R resistance during therapy
among extensively antibiotic experienced patients with infections due to CR/DTR P.
aeruginosa (67, 73). The preclinical infection model and clinical I/R treatment-emergent
resistance findings with MDR/CR/DTR P. aeruginosa are highly consistent with the other
recently approved novel b -lactams (28, 75–78) and highlight the critical importance of
susceptibility testing of baseline and subsequent isolates when considering one of the
newer b -lactam agents, especially among patients not responding to therapy or with
recurrent infections.
Given the current lack of comparator clinical data between the newer b -lactams,
the most informative way to differentiate between the recently approved b -lactams is
by comparison of their microbiologic in vitro susceptibility profiles. Unlike the other
recently approved b -lactams, I/R lacks activity against Morganellaceae (5). It also exhib-
its limited microbiologic activity against MBL-producing NME and P. aeruginosa and CR
Acinetobacter sp., which is consistent with the recently approved b -lactams except
cefiderocol (3, 17, 21). In comparative surveillance programs, I/R in vitro activity was
similar to that of CZA and M/V for CR-NME and C/T and CZA for MDR/CR/DTR P. aerugi-
nosa. Subtle differences in susceptibility results among the newer b -lactams were
observed across several comparative surveillance studies with I/R retaining some
microbiologic activity against CR-NME and MDR/CR/DTR P. aeruginosa isolates that are
resistant to some of the newer b -lactams and vice versa. Data suggest that I/R may
retain activity against CR-NME isolates that develop resistance to CZA via KPC-3 muta-
tions and DTR P. aeruginosa isolates that develop resistance to C/T and CZA due to
PDC mutations (37). Conversely, I/R is typically nonsusceptible to NME and/or P. aeruginosa
isolates that produce SME b -lactamases, OXA-48-like b -lactamases, GES-like carbapenemase,
and VEB-producing b -lactamases in contrast to some newer b -lactams (2, 16–18).
Expression of multiple resistance mechanisms simultaneously (i.e., downregulated or deleted
porins, b -lactamase hyperproduction, upregulated efflux pumps, etc.) may also result in dis-
cordant susceptibility patterns for the newer b -lactams, as some resistance expression pat-
terns have a higher propensity to result in resistance to certain b -lactams more so than
others (28, 73, 75). Additional data are needed to fully elucidate the role of concurrently
expressed resistance mechanisms in causing nonsusceptibility against each of the newer
b -lactam agents (2, 4, 14, 23).
Unfortunately, the resistance mechanism(s) present in a CR-NME or DTR P. aerugi-
nosa infection are infrequently known at baseline, even with use of rapid diagnostics
(rapid diagnostic testing can detect the presence of only select resistance genes). From
a clinical practice standpoint, susceptibility testing should ideally be performed for all
the newer agents for patients with CR-NME and DTR P. aeruginosa infections to deter-
mine the best available treatment options. In the absence of near real-time antibiotic
susceptibility results, institution-specific antibiogram data should guide early targeted
treatment decisions for patients with CR-NME and CR P. aeruginosa infections. In a clin-
ical situation in which some or all newer agents are active against the recovered CR-

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Perspective Antimicrobial Agents and Chemotherapy

NME and/or DTR P. aeruginosa isolate(s), there are no comparator data to indicate that
one should be preferentially used over another, and selection of a I/R relative to
another agent should be made on a case-by-case basis at this time. Of note, unlike the
newer b -lactams, I/R had reliable microbiologic activity against ampicillin-susceptible
Enterococcus sp. and Gram-negative anaerobes, making it a potentially preferred agent
in patients with polymicrobial infections that include Enterococcus sp., CR-NME, and/or
DTR P. aeruginosa (5).

FUTURE DIRECTIONS
Additional real-world data are needed to determine the optimal place for I/R ther-
apy in our antibiotic arsenal. Comparative preclinical PK/PD and clinical data are
needed between newer BL/BLIs to determine optimal treatment of CR-NME and DTR P.
aeruginosa infections. Currently, differences in in vitro activity among newer BL/BLIs
appear to be limited, and overall differences in coverage are driven by the intrinsic ac-
tivity of the b -lactam agent (i.e., IMI exhibits coverage against Enterococci but does not
have activity against Morganellaceae and CR-NME that express certain b -lactamases).
An emerging theme with newer agents is the development of resistance during or
shortly after therapy, particularly among patients with DTR P. aeruginosa infections
and extensive antibiotic exposure (28, 73, 76). In patients with DTR P. aeruginosa infec-
tions who develop resistance on C/T, there is some suggestion that I/R retains activity
in treatment-emergent infections; however, a recent case series suggests that subse-
quent I/R resistance may develop (73). There is a need to better understand the PK/PD
target for resistance selection against borderline-resistant and hypermutable strains,
particularly for P. aeruginosa. To date, most I/R preclinical PK/PD infection model stud-
ies have examined only standard inocula, short courses, and isolates that were not re-
sistant to the newer agents at baseline. There may be some flexibility with use of a
higher dose of I/R (safety has been evaluated with doses of IMI 1,000 mg and REL up to
1,000 mg every 6 h), and it may be that higher doses are ultimately needed to treat
patients with high inoculum infections that are resistant to other newer b -lactams at
baseline (38).
There is also a need to establish optimal combination therapy given reports of
treatment-emergent resistance and overall lack of activity against certain resistance ge-
notypes. Limited preclinical PK/PD with amikacin and colistin suggests that use of com-
bination therapy may enhance killing and minimize resistance emergence against P.
aeruginosa in vitro (43, 45). However, while both combinations showed synergy in
static concentration time kills, only combinations with colistin were additive or syner-
gistic against six MDR P. aeruginosa isolates tested in a dynamic infection model (45).
Ultimately, it may be that newer agents need to be paired with a second active drug,
especially with P. aeruginosa infections, given the high rates of resistance emergence
observed in recent real-world evidence studies. As part of combination therapy studies,
there needs to be an assessment of aztreonam (ATM) with I/R for isolates producing
MBLs. Limited in vitro studies have suggested that aztreonam plus I/R exhibits synergy
against MBL-producing K. pneumoniae and P. aeruginosa that constitutively produce
PDCs (79, 80).
I/R may also have a role in the treatment of Mycobacterium abscessus complex infec-
tions (81, 82). IMI remains one of the mainstays of care for the treatment of this highly
resistant pathogen, and REL appears to have a beneficial, though modest, effect on IMI
susceptibilities. Combinations of I/R with amoxicillin have shown particularly good ac-
tivity in vitro (82). To date, data on I/R against M. abscessus are limited to in vitro stud-
ies, though this may prove to be a promising step forward in the treatment of these
infections.

CONCLUSIONS
Available preclinical PK/PD infection model, microbiologic surveillance, PTA, and
clinical data for I/R support the use and current dosing of I/R for the treatment of

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Perspective
patients with HABP/VABP, cUTI, and cIAI due to highly resistant NME and P. aeruginosa.
From a microbiologic in vitro activity perspective, I/R is most comparable to CZA and
M/V for CR-NME and C/T and CZA for MDR/CR/DTR P. aeruginosa. Data indicate that I/R
retains some activity against CR-NME and MDR/CR/DTR P. aeruginosa isolates that are
resistant at baseline or emerge during therapy to the newer b -lactams and vice versa,
suggesting that susceptibility testing be performed for all the newer agents for
patients with CR-NME and DTR P. aeruginosa infections to identify the most viable
treatment options. Further comparative PK/PD and clinical studies are warranted to
determine the optimal role of I/R, alone and in combination, for the treatment of
patients with highly resistant Gram-negative infections. Until further data are available,
I/R is a reasonable early targeted treatment option in patients with suspected or docu-
mented infections due to CR-NME and DTR P. aeruginosa infections when the benefits
outweigh the risks.
ACKNOWLEDGMENTS
No funding was received for this publication.
T.P.L. has received consultant honoraria and investigator-initiated grant support from
Merck & Co. J.N.O. has received investigator-initiated grant support from Merck & Co.
REFERENCES
1. Blizzard TA, Chen H, Kim S, Wu J, Bodner R, Gude C, Imbriglio J, Young K,
Park YW, Ogawa A, Raghoobar S, Hairston N, Painter RE, Wisniewski D,
Scapin G, Fitzgerald P, Sharma N, Lu J, Ha S, Hermes J, Hammond ML.
2014. Discovery of MK-7655, a beta-lactamase inhibitor for combination
with Primaxin(R). Bioorg Med Chem Lett 24:780–785. https://doi.org/10
.1016/j.bmcl.2013.12.101.
2. Young K, Painter RE, Raghoobar SL, Hairston NN, Racine F, Wisniewski D,
Balibar CJ, Villafania A, Zhang R, Sahm DF, Blizzard T, Murgolo N,
Hammond ML, Motyl MR. 2019. In vitro studies evaluating the activity of
imipenem in combination with relebactam against Pseudomonas aerugi-
nosa. BMC Microbiol 19:150. https://doi.org/10.1186/s12866-019-1522-7.
3. Zhang H, Jia P, Zhu Y, Zhang G, Zhang J, Kang W, Duan S, Zhang W, Yang
Q, Xu Y. 2021. Susceptibility to imipenem/relebactam of Pseudomonas
aeruginosa and Acinetobacter baumannii isolates from Chinese intra-ab-
dominal, respiratory and urinary tract infections: SMART 2015 to 2018.
Infect Drug Resist 14:3509–3518. https://doi.org/10.2147/IDR.S325520.
4. Haidar G, Clancy CJ, Chen L, Samanta P, Shields RK, Kreiswirth BN, Nguyen
MH. 2017. Identifying spectra of activity and therapeutic niches for cefta-
zidime-avibactam and imipenem-relebactam against carbapenem-resist-
ant Enterobacteriaceae. Antimicrob Agents Chemother 61. https://doi
.org/10.1128/AAC.00642-17.
5. Anonymous. 2019. RECARBRIOTM (imipenem, cilastatin, and relebactam)
for injection, for intravenous use. Merck Sharp & Dohme LLC, Rahway, NJ, USA.
https://www.merck.com/product/usa/pi_circulars/r/recarbrio/recarbrio_pi.
pdf. Accessed on February 1, 2022.
6. Anonymous. 2020. Recarbrio - EMEA/H/C/004808 - N/0010. European Medi-
cines Agency, Amsterdam, The Netherlands. https://www.ema.europa.eu/en/
documents/product-information/recarbrio-epar-product-information_en.pdf.
Accessed on February 1, 2022.
7. Clinical and Laboratory Standards Institute. 2005. The Clinical and Laboratory
Standards Institute (CLSI) has published M100—performance standards for
antimicrobial susceptibility testing, 31st ed. Clinical and Laboratory Stand-
ards Institute, Wayne, PA.
8. EUCAST. 2022. Clinical breakpoints–breakpoints and guidance. https://
www.eucast.org/clinical_breakpoints/.
9. Karlowsky JA, Lob SH, Kazmierczak KM, Young K, Motyl MR, Sahm DF.
2018. In vitro activity of imipenem-relebactam against clinical isolates of
Gram-negative bacilli isolated in hospital laboratories in the United States
as part of the SMART 2016 program. Antimicrob Agents Chemother 62.
https://doi.org/10.1128/AAC.00169-18.
10. Sader HS, Castanheira M, Duncan LR, Mendes RE. 2021. Antimicrobial activ-
ities of ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebac-
tam, meropenem/vaborbactam, and comparators against Pseudomonas
aeruginosa from patients with skin and soft tissue infections. Int J Infect Dis
113:279–281. https://doi.org/10.1016/j.ijid.2021.10.022.
July 2022 Volume 66 Issue 7
Antimicrobial Agents and Chemotherapy
11. Sader HS, Carvalhaes CG, Shortridge D, Castanheira M. 2022. Comparative
activity of newer beta-lactam/beta-lactamase inhibitor combinations
against Pseudomonas aeruginosa from patients hospitalized with pneu-
monia in European medical centers in 2020. Eur J Clin Microbiol Infect Dis
41:319–324. https://doi.org/10.1007/s10096-021-04363-7.
12. Lob SH, DePestel DD, DeRyke CA, Kazmierczak KM, Young K, Motyl MR,
Sahm DF. 2021. Ceftolozane/tazobactam and imipenem/relebactam cross-
susceptibility among clinical isolates of Pseudomonas aeruginosa from
patients with respiratory tract infections in ICU and non-ICU wards-SMART
United States 2017–2019. Open Forum Infect Dis 8:ofab320. https://doi.org/
10.1093/ofid/ofab320.
13. Lob SH, Hackel MA, Young K, Motyl MR, Sahm DF. 2021. Activity of imipe-
nem/relebactam and comparators against Gram-negative pathogens
from patients with bloodstream infections in the United States and Can-
ada - SMART 2018–2019. Diagn Microbiol Infect Dis 100:115421. https://
doi.org/10.1016/j.diagmicrobio.2021.115421.
14. Karlowsky JA, Lob SH, Young K, Motyl MR, Sahm DF. 2021. In vitro activity
of imipenem/relebactam against Gram-negative bacilli from pediatric
patients-study for monitoring antimicrobial resistance trends (SMART)
global surveillance program 2015–2017. J Pediatric Infect Dis Soc 10:
274–281. https://doi.org/10.1093/jpids/piaa056.
15. Karlowsky JA, Lob SH, Raddatz J, DePestel DD, Young K, Motyl MR, Sahm DF.
2021. In vitro activity of imipenem/relebactam and ceftolozane/tazobactam
against clinical isolates of Gram-negative bacilli with difficult-to-treat resist-
ance and multidrug-resistant phenotypes-study for monitoring antimicrobial
resistance trends, United States 2015–2017. Clin Infect Dis 72:2112–2120.
https://doi.org/10.1093/cid/ciaa381.
16. Biagi M, Shajee A, Vialichka A, Jurkovic M, Tan X, Wenzler E. 2020. Activity
of imipenem-relebactam and meropenem-vaborbactam against carbape-
nem-resistant, SME-producing Serratia marcescens. Antimicrob Agents
Chemother 64. https://doi.org/10.1128/AAC.02255-19.
17. Karlowsky JA, Lob SH, Kazmierczak KM, Young K, Motyl MR, Sahm DF.
2020. In-vitro activity of imipenem/relebactam and key beta-lactam
agents against Gram-negative bacilli isolated from lower respiratory tract
infection samples of intensive care unit patients - SMART Surveillance
United States 2015–2017. Int J Antimicrob Agents 55:105841. https://doi
.org/10.1016/j.ijantimicag.2019.10.022.
18. Mushtaq S, Meunier D, Vickers A, Woodford N, Livermore DM. 2021. Activity
of imipenem/relebactam against Pseudomonas aeruginosa producing ESBLs
and carbapenemases. J Antimicrob Chemother 76:434–442. https://doi.org/
10.1093/jac/dkaa456.
19. Vazquez-Ucha JC, Seoane-Estevez A, Rodino-Janeiro BK, Gonzalez-Bardanca
M, Conde-Perez K, Martinez-Guitian M, Alvarez-Fraga L, Arca-Suarez J, Lasarte-
Monterrubio C, Gut M, Gut I, Alvarez-Tejado M, Oviano M, Beceiro A, Bou G,
GEMARA-SEIMC/REIPI Enterobacterales Study Group. 2021. Activity of imipe-
nem/relebactam against a Spanish nationwide collection of carbapenemase-
10.1128/aac.00256-22 16
Perspective
producing Enterobacterales. J Antimicrob Chemother 76:1498–1510. https://
doi.org/10.1093/jac/dkab043.
20. Johnston BD, Thuras P, Porter SB, Anacker M, VonBank B, Vagnone PS,
Witwer M, Castanheira M, Johnson JR. 2020. Activity of imipenem-rele-
bactam against carbapenem-resistant Escherichia coli isolates from the
United States in relation to clonal background, resistance genes, coresist-
ance, and region. Antimicrob Agents Chemother 64. https://doi.org/10
.1128/AAC.02408-19.
21. Lob SH, Karlowsky JA, Young K, Motyl MR, Hawser S, Kothari ND, Sahm
DF. 2020. In vitro activity of imipenem-relebactam against resistant phe-
notypes of Enterobacteriaceae and Pseudomonas aeruginosa isolated
from intraabdominal and urinary tract infection samples—SMART Surveil-
lance Europe 2015–2017. J Med Microbiol 69:207–217. https://doi.org/10
.1099/jmm.0.001142.
22. Senchyna F, Gaur RL, Sandlund J, Truong C, Tremintin G, Kultz D, Gomez
CA, Tamburini FB, Andermann T, Bhatt A, Tickler I, Watz N, Budvytiene I,
Shi G, Tenover FC, Banaei N. 2019. Diversity of resistance mechanisms in
carbapenem-resistant Enterobacteriaceae at a health care system in
Northern California, from 2013 to 2016. Diagn Microbiol Infect Dis 93:
250–257. https://doi.org/10.1016/j.diagmicrobio.2018.10.004.
23. Gomez-Simmonds A, Stump S, Giddins MJ, Annavajhala MK, Uhlemann
AC. 2018. Clonal background, resistance gene profile, and porin gene
mutations modulate in vitro susceptibility to imipenem-relebactam in
diverse Enterobacteriaceae. Antimicrob Agents Chemother 62. https://
doi.org/10.1128/AAC.00573-18.
24. Lombardo D, Ambretti S, Lazzarotto T, Gaibani P. 2022. In vitro activity of
imipenem-relebactam against KPC-producing Klebsiella pneumoniae re-
sistant to ceftazidime-avibactam and/or meropenem-vaborbactam. Clin
Microbiol Infect 28:749–751. https://doi.org/10.1016/j.cmi.2022.01.025.
25. Maraki S, Mavromanolaki VE, Magkafouraki E, Moraitis P, Stafylaki D, Kasimati
A, Scoulica E. 2022. Epidemiology and in vitro activity of ceftazidime-avibac-
tam, meropenem-vaborbactam, imipenem-relebactam, eravacycline, plazo-
micin, and comparators against Greek carbapenemase-producing Klebsiella
pneumoniae isolates. Infection 50:467–474. https://doi.org/10.1007/s15010
-021-01735-1.
26. Castanheira M, Doyle TB, Deshpande LM, Mendes RE, Sader HS. 2021. Ac-
tivity of ceftazidime/avibactam, meropenem/vaborbactam and imipe-
nem/relebactam against carbapenemase-negative carbapenem-resistant
Enterobacterales isolates from US hospitals. Int J Antimicrob Agents 58:
106439. https://doi.org/10.1016/j.ijantimicag.2021.106439.
27. Kuo SC, Wang YC, Tan MC, Huang WC, Shiau YR, Wang HY, Lai JF, Huang
IW, Lauderdale TL. 2021. In vitro activity of imipenem/relebactam, mero-
penem/vaborbactam, ceftazidime/avibactam, cefepime/zidebactam and
other novel antibiotics against imipenem-non-susceptible Gram-negative
bacilli from Taiwan. J Antimicrob Chemother 76:2071–2078. https://doi
.org/10.1093/jac/dkab141.
28. Rubio AM, Kline EG, Jones CE, Chen L, Kreiswirth BN, Nguyen MH, Clancy CJ,
Cooper VS, Haidar G, Van Tyne D, Shields RK. 2021. In vitro susceptibility of
multidrug-resistant Pseudomonas aeruginosa following treatment-emer-
gent resistance to ceftolozane-tazobactam. Antimicrob Agents Chemother
65. https://doi.org/10.1128/AAC.00084-21.
29. Bhagwat SS, Legakis NJ, Skalidis T, Loannidis A, Goumenopoulos C, Joshi
PR, Shrivastava R, Palwe SR, Periasamy H, Patel MV, Chatzipanagiotou S,
Hellenic Cefepime/Zidebactam Study Group. 2021. In vitro activity of
cefepime/zidebactam (WCK 5222) against recent Gram-negative isolates
collected from high resistance settings of Greek hospitals. Diagn Micro-
biol Infect Dis 100:115327. https://doi.org/10.1016/j.diagmicrobio.2021
.115327.
30. Karlowsky JA, Hackel MA, Bouchillon SK, Sahm DF. 2020. In vitro activity
of WCK 5222 (cefepime-zidebactam) against worldwide collected Gram-
negative bacilli not susceptible to carbapenems. Antimicrob Agents Che-
mother 64. https://doi.org/10.1128/AAC.01432-20.
31. Bhagwat SS, Hariharan P, Joshi PR, Palwe SR, Shrivastava R, Patel MV,
Devanga Ragupathi NK, Bakthavatchalam YD, Ramesh MS, Soman R,
Veeraraghavan B. 2020. Activity of cefepime/zidebactam against MDR
Escherichia coli isolates harbouring a novel mechanism of resistance
based on four-amino-acid inserts in PBP3. J Antimicrob Chemother 75:
3563–3567. https://doi.org/10.1093/jac/dkaa353.
32. Nelson K, Rubio-Aparicio D, Sun D, Dudley M, Lomovskaya O. 2020. In vitro
activity of the ultrabroad-spectrum-beta-lactamase inhibitor QPX7728
against carbapenem-resistant Enterobacterales with varying intrinsic and
acquired resistance mechanisms. Antimicrob Agents Chemother 64. https://
doi.org/10.1128/AAC.00757-20.
July 2022 Volume 66 Issue 7
Antimicrobial Agents and Chemotherapy
33. Carpenter J, Neidig N, Campbell A, Thornsberry T, Truex T, Fortney T, Zhang
Y, Bush K. 2019. Activity of imipenem/relebactam against carbapenemase-
producing Enterobacteriaceae with high colistin resistance. J Antimicrob Che-
mother 74:3260–3263. https://doi.org/10.1093/jac/dkz354.
34. Galani I, Souli M, Nafplioti K, Adamou P, Karaiskos I, Giamarellou H,
Antoniadou A, Study Collaborators. 2019. In vitro activity of imipenem-
relebactam against non-MBL carbapenemase-producing Klebsiella pneu-
moniae isolated in Greek hospitals in 2015–2016. Eur J Clin Microbiol
Infect Dis 38:1143–1150. https://doi.org/10.1007/s10096-019-03517-y.
35. Shields RK, Chen L, Cheng S, Chavda KD, Press EG, Snyder A, Pandey R,
Doi Y, Kreiswirth BN, Nguyen MH, Clancy CJ. 2017. Emergence of ceftazi-
dime-avibactam resistance due to plasmid-borne blaKPC-3 mutations
during treatment of carbapenem-resistant Klebsiella pneumoniae Infec-
tions. Antimicrob Agents Chemother 61. https://doi.org/10.1128/AAC
.02097-16.
36. Haidar G, Clancy CJ, Shields RK, Hao B, Cheng S, Nguyen MH. 2017. Muta-
tions in blaKPC-3 that confer ceftazidime-avibactam resistance encode
novel KPC-3 variants that function as extended-spectrum beta-lacta-
mases. Antimicrob Agents Chemother 61. https://doi.org/10.1128/AAC
.02534-16.
37. Bail L, Ito CAS, Arend L, Nogueira KDS, Tuon FF. 2022. Activity of imipenem-
relebactam and ceftolozane-tazobactam against carbapenem-resistant Pseu-
domonas aeruginosa and KPC-producing Enterobacterales. Diagn Microbiol
Infect Dis 102:115568. https://doi.org/10.1016/j.diagmicrobio.2021.115568.
38. Rhee EG, Rizk ML, Calder N, Nefliu M, Warrington SJ, Schwartz MS, Mangin
E, Boundy K, Bhagunde P, Colon-Gonzalez F, Jumes P, Liu Y, Butterton JR.
2018. Pharmacokinetics, safety, and tolerability of single and multiple
doses of relebactam, a beta-lactamase inhibitor, in combination with imi-
penem and cilastatin in healthy participants. Antimicrob Agents Chemo-
ther 62:e00280-18. https://doi.org/10.1128/AAC.00280-18.
39. Bhagunde P, Colon-Gonzalez F, Liu Y, Wu J, Xu SS, Garrett G, Jumes P,
Lasseter K, Marbury T, Rizk ML, Lala M, Rhee EG, Butterton JR, Boundy K.
2020. Impact of renal impairment and human organic anion transporter
inhibition on pharmacokinetics, safety and tolerability of relebactam
combined with imipenem and cilastatin. Br J Clin Pharmacol 86:944–957.
https://doi.org/10.1111/bcp.14204.
40. Rizk ML, Rhee EG, Jumes PA, Gotfried MH, Zhao T, Mangin E, Bi S, Chavez-
Eng CM, Zhang Z, Butterton JR. 2018. Intrapulmonary pharmacokinetics
of relebactam, a novel beta-lactamase inhibitor, dosed in combination
with imipenem-cilastatin in healthy subjects. Antimicrob Agents Chemo-
ther 62. https://doi.org/10.1128/AAC.01411-17.
41. Powles MA, Galgoci A, Misura A, Colwell L, Dingley KH, Tang W, Wu J,
Blizzard T, Motyl M, Young K. 2018. In vivo efficacy of relebactam (MK-7655)
in combination with imipenem-cilastatin in murine infection models. Antimi-
crob Agents Chemother 62. https://doi.org/10.1128/AAC.02577-17.
42. Mavridou E, Melchers RJ, van Mil AC, Mangin E, Motyl MR, Mouton JW.
2015. Pharmacodynamics of imipenem in combination with beta-lacta-
mase inhibitor MK7655 in a murine thigh model. Antimicrob Agents Che-
mother 59:790–795. https://doi.org/10.1128/AAC.03706-14.
43. Reyes S, Abdelraouf K, Nicolau DP. 2020. In vivo activity of human-simu-
lated regimens of imipenem alone and in combination with relebactam
against Pseudomonas aeruginosa in the murine thigh infection model. J
Antimicrob Chemother 75:2197–2205.
44. Noel AR, Bowker KE, Attwood M, MacGowan AP. 2019. Antibacterial effect
of imipenem/relebactam on aerobic Gram-negative bacilli: in vitro simu-
lations of 7 or 14 day human exposures. J Antimicrob Chemother 74:
1945–1951. https://doi.org/10.1093/jac/dkz114.
45. Chen IH, Nicolau DP, Kuti JL. 2020. Imipenem/cilastatin/relebactam alone
and in combination against Pseudomonas aeruginosa in the in vitro phar-
macodynamic model. Antimicrob Agents Chemother 64. https://doi.org/
10.1128/AAC.01764-20.
46. Bhagunde P, Zhang Z, Racine F, Carr D, Wu J, Young K, Rizk ML. 2019. A
translational pharmacokinetic/pharmacodynamic model to characterize
bacterial kill in the presence of imipenem-relebactam. Int J Infect Dis 89:
55–61. https://doi.org/10.1016/j.ijid.2019.08.026.
47. Wu J, Racine F, Wismer MK, Young K, Carr DM, Xiao JC, Katwaru R, Si Q,
Harradine P, Motyl M, Bhagunde PR, Rizk ML. 2018. Exploring the pharma-
cokinetic/pharmacodynamic relationship of relebactam (MK-7655) in
combination with imipenem in a hollow-fiber infection model. Antimi-
crob Agents Chemother 62. https://doi.org/10.1128/AAC.02323-17.
48. Hirsch EB, Ledesma KR, Chang KT, Schwartz MS, Motyl MR, Tam VH. 2012.
In vitro activity of MK-7655, a novel beta-lactamase inhibitor, in combi-
nation with imipenem against carbapenem-resistant Gram-negative
10.1128/aac.00256-22 17
Perspective
bacteria. Antimicrob Agents Chemother 56:3753–3757. https://doi.org/
10.1128/AAC.05927-11.
49. Bulitta JB, Hope WW, Eakin AE, Guina T, Tam VH, Louie A, Drusano GL,
Hoover JL. 2019. Generating robust and informative nonclinical in vitro
and in vivo bacterial infection model efficacy data to support translation
to humans. Antimicrob Agents Chemother 63. https://doi.org/10.1128/
AAC.02307-18.
50. Anonymous. 2016. PRIMAXIN (imipenem and cilastatin) for injection, for in-
travenous use. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/050587s074lbl
.pdf.
51. Drusano GL. 2004. Antimicrobial pharmacodynamics: critical interactions
of 'bug and drug'. Nat Rev Microbiol 2:289–300. https://doi.org/10.1038/
nrmicro862.
52. Craig WA. 1998. Pharmacokinetic/pharmacodynamic parameters: ration-
ale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–10.
https://doi.org/10.1086/516284.
53. European Medicines Agency. 2016. Guideline on the use of pharmacoki-
netics and pharmacodynamics in the development of antimicrobial me-
dicinal products (EMA/CHMP/594085/2015). Committee for Medicinal
Products for Human Use, London, UK.
54. Griffith DC, Sabet M, Tarazi Z, Lomovskaya O, Dudley MN. 2019. Pharma-
cokinetics/pharmacodynamics of vaborbactam, a novel beta-lactamase
inhibitor, in combination with meropenem. Antimicrob Agents Chemo-
ther 63. https://doi.org/10.1128/AAC.01659-18.
55. Berkhout J, Melchers MJ, van Mil AC, Seyedmousavi S, Lagarde CM,
Schuck VJ, Nichols WW, Mouton JW. 2016. Pharmacodynamics of ceftazi-
dime and avibactam in neutropenic mice with thigh or lung infection.
Antimicrob Agents Chemother 60:368–375. https://doi.org/10.1128/AAC
.01269-15.
56. Singh R, Kim A, Tanudra MA, Harris JJ, McLaughlin RE, Patey S, O’Donnell JP,
Bradford PA, Eakin AE. 2015. Pharmacokinetics/pharmacodynamics of a
beta-lactam and beta-lactamase inhibitor combination: a novel approach for
aztreonam/avibactam. J Antimicrob Chemother 70:2618–2626. https://doi
.org/10.1093/jac/dkv132.
57. Crass RL, Pai MP. 2019. Pharmacokinetics and pharmacodynamics of
beta-lactamase inhibitors. Pharmacotherapy 39:182–195. https://doi.org/
10.1002/phar.2210.
58. Bhagunde P, Chang KT, Hirsch EB, Ledesma KR, Nikolaou M, Tam VH.
2012. Novel modeling framework to guide design of optimal dosing strat-
egies for beta-lactamase inhibitors. Antimicrob Agents Chemother 56:
2237–2240. https://doi.org/10.1128/AAC.06113-11.
59. Patel M, Bellanti F, Daryani NM, Noormohamed N, Hilbert DW, Young K,
Kulkarni P, Copalu W, Gheyas F, Rizk ML. 2021. Population pharmacoki-
netic/pharmacodynamic assessment of imipenem/cilastatin/relebactam
in patients with hospital-acquired/ventilator-associated bacterial pneu-
monia. Clin Transl Sci 15:396–408. https://doi.org/10.1111/cts.13158.
60. Yee KL, Kleijn HJ, Kerbusch T, Matthews RP, Dorr MB, Garey KW, Wrishko
RE. 2019. Population pharmacokinetics and pharmacodynamics of bezlo-
toxumab in adults with primary and recurrent Clostridium difficile infec-
tion. Antimicrob Agents Chemother 63. https://doi.org/10.1128/AAC
.01971-18.
61. Anonymous. 2016. PRIMAXIN (imipenem and cilastatin). US Prescribing
information. Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USA.
62. Lucasti C, Vasile L, Sandesc D, Venskutonis D, McLeroth P, Lala M, Rizk ML,
Brown ML, Losada MC, Pedley A, Kartsonis NA, Paschke A. 2016. Phase 2,
dose-ranging study of relebactam with imipenem-cilastatin in subjects
with complicated intra-abdominal infection. Antimicrob Agents Chemo-
ther 60:6234–6243. https://doi.org/10.1128/AAC.00633-16.
63. Sims M, Mariyanovski V, McLeroth P, Akers W, Lee YC, Brown ML, Du J,
Pedley A, Kartsonis NA, Paschke A. 2017. Prospective, randomized, dou-
ble-blind, phase 2 dose-ranging study comparing efficacy and safety of
imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in
patients with complicated urinary tract infections. J Antimicrob Chemo-
ther 72:2616–2626. https://doi.org/10.1093/jac/dkx139.
64. Titov I, Wunderink RG, Roquilly A, Rodriguez Gonzalez D, David-Wang A,
Boucher HW, Kaye KS, Losada MC, Du J, Tipping R, Rizk ML, Patel M,
Brown ML, Young K, Kartsonis NA, Butterton JR, Paschke A, Chen LF. 2021.
A randomized, double-blind, multicenter trial comparing efficacy and
safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam
in adults with hospital-acquired or ventilator-associated bacterial pneu-
monia (RESTORE-IMI 2 study). Clin Infect Dis 73:e4539–e4548. https://doi
.org/10.1093/cid/ciaa803.
July 2022 Volume 66 Issue 7
Antimicrobial Agents and Chemotherapy
65. Motsch J, Murta de Oliveira C, Stus V, Koksal I, Lyulko O, Boucher HW,
Kaye KS, File TM, Brown ML, Khan I, Du J, Joeng HK, Tipping RW, Aggrey
A, Young K, Kartsonis NA, Butterton JR, Paschke A. 2020. RESTORE-IMI 1: a
multicenter, randomized, double-blind trial comparing efficacy and safety
of imipenem/relebactam vs colistin plus imipenem in patients with imi-
penem-nonsusceptible bacterial infections. Clin Infect Dis 70:1799–1808.
https://doi.org/10.1093/cid/ciz530.
66. Kohno S, Bando H, Yoneyama F, Kikukawa H, Kawahara K, Shirakawa M,
Aoyama N, Brown M, Paschke A, Takase A. 2021. The safety and efficacy
of relebactam/imipenem/cilastatin in Japanese patients with complicated
intra-abdominal infection or complicated urinary tract infection: a multi-
center, open-label, noncomparative phase 3 study. J Infect Chemother
27:262–270. https://doi.org/10.1016/j.jiac.2020.09.032.
67. Rebold N, Morrisette T, Lagnf AM, Alosaimy S, Holger D, Barber K, Justo
JA, Antosz K, Carlson TJ, Frens JJ, Biagi M, Kufel WD, Moore WJ, Mercuro
N, Raux BR, Rybak MJ. 2021. Early multicenter experience with imipenem-
cilastatin-relebactam for multidrug-resistant Gram-negative infections.
Open Forum Infect Dis 8:ofab554. https://doi.org/10.1093/ofid/ofab554.
68. US Department of Health and Human Services, Food and Drug Adminis-
tration Center for Drug Evaluation and Research. 2014. Community-
acquired bacterial pneumonia: developing drugs for treatment, guidance
for industry. Center for Drug Evaluation and Research, Silver Spring, MD.
69. US Department of Health and Human Services, Food and Drug Adminis-
tration Center for Drug Evaluation and Research. 2018. Guidance for
industry. Complicated intra-abdominal infections: developing drugs for
treatment. Center for Drug Evaluation and Research, Silver Spring, MD.
70. US Department of Health and Human Services, Food and Drug Adminis-
tration Center for Drug Evaluation and Research. 2015. Guidance for
industry. Complicated urinary tract infections: developing drugs for treat-
ment. Center for Drug Evaluation and Research, Silver Spring, MD.
71. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. 1985. APACHE II: a se-
verity of disease classification system. Crit Care Med 13:818–829. https://
doi.org/10.1097/00003246-198510000-00009.
72. Kaye KS, Boucher HW, Brown ML, Aggrey A, Khan I, Joeng HK, Tipping
RW, Du J, Young K, Butterton JR, Paschke A. 2020. Comparison of treat-
ment outcomes between analysis populations in the RESTORE-IMI 1
phase 3 trial of imipenem-cilastatin-relebactam versus colistin plus imipe-
nem-cilastatin in patients with imipenem-nonsusceptible bacterial infec-
tions. Antimicrob Agents Chemother 64. https://doi.org/10.1128/AAC
.02203-19.
73. Shields RK, Stellfox ME, Kline EG, Samanta P, Van Tyne D. 2022. Evolution
of imipenem-relebactam resistance following treatment of multi-drug re-
sistant Pseudomonas aeruginosa pneumonia. Clin Infect Dis ciac097.
https://doi.org/10.1093/cid/ciac097.
74. Del Barrio-Tofino E, Lopez-Causape C, Oliver A. 2020. Pseudomonas aeru-
ginosa epidemic high-risk clones and their association with horizontally-
acquired beta-lactamases: 2020 update. Int J Antimicrob Agents 56:
106196. https://doi.org/10.1016/j.ijantimicag.2020.106196.
75. Tamma PD, Beisken S, Bergman Y, Posch AE, Avdic E, Sharara SL,
Cosgrove SE, Simner PJ. 2021. Modifiable risk factors for the emergence
of ceftolozane-tazobactam resistance. Clin Infect Dis 73:e4599–e4606.
https://doi.org/10.1093/cid/ciaa1306.
76. Simner PJ, Beisken S, Bergman Y, Posch AE, Cosgrove SE, Tamma PD.
2021. Cefiderocol activity against clinical Pseudomonas aeruginosa iso-
lates exhibiting ceftolozane-tazobactam resistance. Open Forum Infect
Dis 8:ofab311. https://doi.org/10.1093/ofid/ofab311.
77. Naseer S, Weinstein EA, Rubin DB, Suvarna K, Wei X, Higgins K, Goodwin
A, Jang SH, Iarikov D, Farley J, Nambiar S. 2021. US Food and Drug Admin-
istration (FDA): benefit-risk considerations for cefiderocol (Fetroja(R)). Clin
Infect Dis 72:e1103–e1111. https://doi.org/10.1093/cid/ciaa1799.
78. Poirel L, Sadek M, Kusaksizoglu A, Nordmann P. 2022. Co-resistance to
ceftazidime-avibactam and cefiderocol in clinical isolates producing KPC
variants. Eur J Clin Microbiol Infect Dis 41:677–680. https://doi.org/10
.1007/s10096-021-04397-x.
79. Maraki S, Mavromanolaki VE, Moraitis P, Stafylaki D, Kasimati A,
Magkafouraki E, Scoulica E. 2021. Ceftazidime-avibactam, meropenen-
vaborbactam, and imipenem-relebactam in combination with aztreonam
against multidrug-resistant, metallo-beta-lactamase-producing Klebsiella
pneumoniae. Eur J Clin Microbiol Infect Dis 40:1755–1759. https://doi
.org/10.1007/s10096-021-04197-3.
80. O'Donnell JN, Putra V, Belfiore GM, Maring BL, Young K, Lodise TP. 2022.
In vitro activity of imipenem/relebactam plus aztreonam against metallo-
b -lactamase producing, OprD-deficient Pseudomonas aeruginosa with
varying levels of Pseudomonas-derived cephalosporinase production. Int
10.1128/aac.00256-22 18
Perspective
J Antimicrob Agents 59:106595. https://doi.org/10.1016/j.ijantimicag
.2022.106595.
81. Le Run E, Atze H, Arthur M, Mainardi JL. 2020. Impact of relebactam-medi-
ated inhibition of Mycobacterium abscessus BlaMab beta-lactamase on
the in vitro and intracellular efficacy of imipenem. J Antimicrob Chemo-
ther 75:379–383. https://doi.org/10.1093/jac/dkz433.
82. Lopeman RC, Harrison J, Rathbone DL, Desai M, Lambert PA, Cox JAG. 2020.
Effect of amoxicillin in combination with imipenem-relebactam against
Mycobacterium abscessus. Sci Rep 10:928. https://doi.org/10.1038/s41598
-020-57844-8.
83. Yang TY, Hsieh YJ, Kao LT, Liu GH, Lian SH, Wang LC, Lin IL, Wang HY,
Tseng SP, Lu PL. 2021. Activities of imipenem-relebactam combination
against carbapenem-nonsusceptible Enterobacteriaceae in Taiwan. J
Microbiol Immunol Infect 55:86–94. https://doi.org/10.1016/j.jmii.2021.02
.001.
84. Yang Q, Zhang H, Yu Y, Kong H, Duan Q, Wang Y, Zhang S, Sun Z, Liao K, Gu
L, Jiang X, Wu A, Huang W, Shan B, Kang M, Hu F, Yu H, Zhang W, Xu Y. 2020.
In vitro activity of imipenem/relebactam against Enterobacteriaceae isolates
obtained from intra-abdominal, respiratory tract, and urinary tract infections
in china: study for monitoring antimicrobial resistance trends (SMART), 2015–
2018. Clin Infect Dis 71:S427–S435. https://doi.org/10.1093/cid/ciaa1519.
85. Karlowsky JA, Lob SH, Kazmierczak KM, Young K, Motyl MR, Sahm DF.
2020. In vitro activity of imipenem/relebactam against Enterobacteria-
ceae and Pseudomonas aeruginosa isolated from intraabdominal and
July 2022 Volume 66 Issue 7
Antimicrobial Agents and Chemotherapy
urinary tract infection samples: SMART Surveillance United States 2015–
2017. J Glob Antimicrob Resist 21:223–228. https://doi.org/10.1016/j.jgar
.2019.10.028.
86. Karlowsky JA, Lob SH, Kazmierczak KM, Hawser SP, Magnet S, Young K,
Motyl MR, Sahm DF. 2018. In vitro activity of imipenem/relebactam
against Gram-negative ESKAPE pathogens isolated in 17 European coun-
tries: 2015 SMART surveillance programme. J Antimicrob Chemother 73:
1872–1879. https://doi.org/10.1093/jac/dky107.
87. Lapuebla A, Abdallah M, Olafisoye O, Cortes C, Urban C, Landman D,
Quale J. 2015. Activity of imipenem with relebactam against Gram-nega-
tive pathogens from New York City. Antimicrob Agents Chemother 59:
5029–5031. https://doi.org/10.1128/AAC.00830-15.
88. Karlowsky JA, Lob SH, Young K, Motyl MR, Sahm DF. 2019. Activity of imi-
penem-relebactam against multidrug-resistant Pseudomonas aeruginosa
from the United States—SMART 2015–2017. Diagn Microbiol Infect Dis
95:212–215. https://doi.org/10.1016/j.diagmicrobio.2019.05.001.
89. Asempa TE, Nicolau DP, Kuti JL. 2019. Carbapenem-nonsusceptible Pseu-
domonas aeruginosa isolates from intensive care units in the United
States: a potential role for new beta-lactam combination agents. J Clin
Microbiol 57. https://doi.org/10.1128/JCM.00535-19.
90. Lob SH, Karlowsky JA, Young K, Motyl MR, Hawser S, Kothari ND, Gueny ME,
Sahm DF. 2019. Activity of imipenem/relebactam against MDR Pseudomo-
nas aeruginosa in Europe: SMART 2015–17. J Antimicrob Chemother 74:
2284–2288. https://doi.org/10.1093/jac/dkz191.
10.1128/aac.00256-22 19