Texte

1072 www.thelancet.com/infection Vol 23 September 2023
Articles
Lancet Infect Dis 2023;
23: 1072–84
Published Online
May 11, 2023
https://doi.org/10.1016/
S1473-3099(23)00184-6
See Comment page 994
Division of Allergy,
Immunology and Infectious
Diseases, Robert Wood Johnson
Medical School,
New Brunswick, NJ, USA
(Prof K S Kaye MD); Pulmonary
and Critical Care Medicine,
MedStar Washington Hospital,
Washington, DC, USA
(Prof A F Shorr MD); Pulmonary
and Critical Care, Northwestern
University Feinberg School of
Medicine, Chicago, IL, USA
(Prof R G Wunderink MD); State
Key Laboratory of Complex,
Severe and Rare Diseases,
Medical ICU, Peking Union
Medical College Hospital,
Peking Union Medical College &
Chinese Academy of Medical
Sciences, Beijing, China
(Prof B Du MD); Entasis
Therapeutics, Waltham, MA,
USA (G E Poirier BS,
K Rana PharmD, A Miller PhD,
D Lewis MD, J O’Donnell BS,
S Srinivasan MD, R Isaacs MD,
D Altarac MD); Global
Development, Neuroscience,
Autoimmune and Infectious
Diseases, Zai Lab, Shanghai,
China (L Chen BE,
H Reinhart MD); Nimbus
Therapeutics, Cambridge, MA,
USA (G E Poirier); The Global
Antibiotic Research and
Development Partnership
(GARDP), Geneva, Switzerland
(S Srinivasan)
Efficacy and safety of sulbactam–durlobactam versus colistin
for the treatment of patients with serious infections caused
by Acinetobacter baumannii–calcoaceticus complex:
a multicentre, randomised, active-controlled, phase 3,
non-inferiority clinical trial (ATTACK)
Keith S Kaye, Andrew F Shorr, Richard G Wunderink, Bin Du, Gabrielle E Poirier, Khurram Rana, Alita Miller, Drew Lewis, John O’Donnell, Lan Chen,
Harald Reinhart, Subasree Srinivasan, Robin Isaacs, David Altarac
Summary
Background An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant
Acinetobacter baumannii–calcoaceticus complex (ABC). Sulbactam–durlobactam is a β-lactam–β-lactamase inhibitor
combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific,
randomised controlled trial, we compared the ecacy and safety of sulbactam–durlobactam versus colistin, both in
combination with imipenem–cilastatin as background therapy, in patients with serious infections caused by
carbapenem-resistant ABC.
Methods The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-
confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia,
or bloodstream infections were randomised 1:1 using a block size of four to sulbactam–durlobactam (1∙0 g of each
drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7–14 days. All patients
received imipenem–cilastatin (1∙0 g of each drug in combination over 1 h every 6 h) as background therapy. The
primary ecacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant
ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was
concluded if the upper bound of the 95% CI for the treatment dierence was less than +20%. The primary safety
endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease
criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at
ClinicalTrials.gov, NCT03894046.
Findings Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam–durlobactam or
colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated
pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC
isolates were included in the primary ecacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam–
durlobactam group and 20 (32%) of 62 in the colistin group, a dierence of –13·2% (95% CI –30·0 to 3·5), which met
criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0∙001) lower with sulbactam–durlobactam
than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the
sulbactam–durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events
leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam–durlobactam group
and 14 (16%) of 86 patients in the colistin group.
Interpretation Our data show that sulbactam–durlobactam was non-inferior to colistin, both agents given in
combination with imipenem–cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam–
durlobactam was well tolerated and could be an eective intervention to reduce mortality from serious infections
caused by carbapenem-resistant ABC, including multidrug-resistant strains.
Funding Entasis Therapeutics and Zai Lab.
Copyright © 2023 Elsevier Ltd. All rights reserved.
Introduction
The Acinetobacter baumannii–calcoaceticus complex
(ABC) comprises a group of closely related Gram-
negative Acinetobacter species that cause serious
dicult-to-treat infections.1 At present, many ABC
isolates are multidrug resistant, including to carba-
penems. Carbapenem-resistant ABC represents the
fourth leading cause of death attributable to antimicrobial

Articles
www.thelancet.com/infection Vol 23 September 2023 1073
Correspondence to:
Prof Keith S Kaye, Division of
Allergy, Immunology and
Infectious Diseases, Robert Wood
Johnson Medical School,
New Brunswick, NJ 08901, USA
[email protected]
resistance globally.2 A baumannii has been identified as
an urgent threat and a priority pathogen for the
development of new antibiotics.3
Due to high rates of antimicrobial resistance, patients
who develop serious infections caused by carbapenem-
resistant ABC, such as hospital-acquired bacterial
pneumonia, ventilator-associated bacterial pneumonia,
ventilated pneumonia, or bloodstream infections, often
receive inappropriate empirical antimicrobial treatment
and face poor outcomes and high medical costs.4,5
Optimal treatment for serious infections caused by
carbapenem-resistant ABC is unclear.6 Guidelines
support combination antibiotic therapy, including
colistin-based, tigecycline-based, minocycline-based,
and sulbactam-based combinations, depending on the
site of infection and in vitro susceptibilities.6,7 Treatment
with colistin, specifically, often results in dose-related
toxicity, especially nephrotoxicity.8 Additionally, colistin
has poor ecacy at recommended doses given its
inadequate tissue penetration.7
Sulbactam–durlobactam, a bactericidal β-lactam–
β-lactamase inhibitor combination, has promising
pharmacological properties that make it a suitable
candidate for clinical development. Sulbactam is an
established penicillin derivative used widely as a
β-lactamase inhibitor and in combination with a β-lactam
(eg, ampicillin–sulbactam). Sulbactam has direct
antibacterial activity against Acinetobacter spp, due to
inhibition of penicillin-binding proteins; however, it is
degraded by some common β-lactamases.9 Durlobactam
diers from other recently approved β-lactamase
inhibitors in that it has broad activity against Ambler
class A, C, and D β-lactamases (including OXA-type
carbapenemases expressed by carbapenem-resistant
ABC).10 In in-vitro studies, durlobactam has been shown
to restore the activity of sulbactam against multidrug
resistant A baumannii.10
In global surveillance studies, sulbactam–durlobactam
has shown potent in vitro activity against
carbapenem-resistant ABC isolates, with less than 4%
having a minimum inhibitory concentration (MIC) of
more than 4 µg/mL, the proposed susceptibility break-
point.11,12 In phase 1–2 clinical studies, sulbactam–
durlobactam was well tolerated and showed favourable
Research in context
Evidence before this study
Infections caused by carbapenem-resistant
Acinetobacter baumannii–calcoaceticus complex (ABC) are
associated with significant morbidity and mortality. Most
carbapenem-resistant ABC isolates are extensively drug-resistant,
with scarce treatment options. Combination antibiotic therapy
(with colistin or other existing drugs) is often used, with
suboptimal efficacy and safety. Treatment with colistin,
specifically, can result in dose-related nephrotoxicity.
Sulbactam–durlobactam is a novel β-lactam–β-lactamase
inhibitor combination with targeted activity against carbapenem-
resistant ABC. We searched PubMed for articles published from
database inception to Feb 01, 2023, using the terms “sulbactam-
durlobactam” or “ETX2514” and identified 15 research articles,
including ten in vitro studies and five clinical trials.
In vitro, sulbactam–durlobactam has shown potent activity
against globally diverse carbapenem-resistant ABC isolates,
including colistin-resistant and extensively drug resistant
isolates from several infection sources. In phase 1–2 clinical
studies, sulbactam–durlobactam was well tolerated when given
alone or in combination with imipenem–cilastatin in both
healthy adults and patients with complicated urinary tract
infections or acute pyelonephritis. Sulbactam–durlobactam has
also shown good penetration of the lung epithelium,
encouraging further study of this combination for the
treatment of carbapenem-resistant ABC pneumonia,
an infection with high mortality rates.
Added value of this study
ATTACK is a landmark, pathogen-specific, phase 3 randomised
clinical trial; the first to successfully evaluate an
investigational agent, sulbactam–durlobactam, targeting
carbapenem-resistant ABC in patients with hospital-acquired
bacterial pneumonia, ventilator-associated bacterial
pneumonia, ventilated pneumonia, and bloodstream
infections. The primary objectives of the trial were to compare
the efficacy of sulbactam–durlobactam versus colistin, both in
combination with imipenem–cilastatin as background
therapy, in patients with documented carbapenem-resistant
ABC infections and to compare the incidence of
nephrotoxicity, assessed using modified Risk, Injury, Failure,
Loss, End-stage renal disease criteria. The results showed that
sulbactam–durlobactam met criteria for non-inferiority versus
colistin for 28-day all-cause mortality when both were
combined with imipenem–cilastatin as background therapy
and was associated with substantial improvements in clinical
cure and microbiological favourable response in patients with
hospital-acquired bacterial pneumonia, ventilator-associated
bacterial pneumonia, ventilated pneumonia, and
bloodstream infections caused by carbapenem-resistant ABC.
Sulbactam–durlobactam was well tolerated by this critically ill
population, with a significantly lower incidence of
nephrotoxicity compared with colistin therapy.
Implications of all the available evidence
Sulbactam–durlobactam could be a promising new treatment
for hospitalised patients with serious multidrug resistant ABC
or carbapenem-resistant ABC infections, a susceptible patient
population with scarce therapeutic options.

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1074 www.thelancet.com/infection Vol 23 September 2023
pharmacokinetic properties when given alone or in
combination with imipenem–cilastatin in both healthy
adults13 and patients with complicated urinary tract
infections (UTIs) or acute pyelonephritis.14 Sulbactam–
durlobactam also showed good penetration of the lung
epithelium in healthy adults, supporting further study of
this novel compound for the treatment of pneumonia
caused by multidrug resistant A baumannii.15
Here, we report the results of the ATTACK trial, a
phase 3, pathogen-specific, randomised clinical trial
designed to evaluate the ecacy and safety of sulbactam–
durlobactam compared with colistin, both in combination
with imipenem–cilastatin as background therapy, for the
treatment of patients with serious infections caused by
ABC, including carbapenem-resistant ABC.
Methods
Study design
This phase 3, multinational, randomised, active-controlled,
non-inferiority trial was done from Sept 5, 2019, to
July 26, 2021. A total of 71 clinical sites screened patients
and 59 clinical sites randomised and enrolled patients in
16 countries (appendix pp 1–2).
This study was designed to enrol patients in two parts.
Part A was an assessor-blind, randomised study arm
that evaluated the ecacy and safety of sulbactam–
durlobactam compared with colistin, each combined with
imipenem–cilastatin as background therapy, in patients
with documented ABC hospital-acquired bacterial
pneumonia, ventilator-associated bacterial pneumonia,
ventilated pneumonia, or bloodstream infections.
Part B was an open-label (sulbactam–durlobactam plus
imipenem–cilastatin as background therapy), obser-
vational study arm that enrolled patients with ABC
infections who did not tolerate colistin–polymyxin B or
whose ABC pathogens were resistant to colistin–
polymyxin B. Imipenem–cilastatin was used as background
therapy in both treatment groups as it was predicted to be
eective therapy for most potential coinfecting pathogens.
A prespecified review of pharmacokinetic data for
30 patients in part A was done by an independent data
safety monitoring board before initiating part B to verify
that the planned sulbactam–durlobactam dose resulted in
predicted ecacious exposures in the targeted patient
population and was comparable with exposures observed
in previous clinical studies.13,14
The study protocol and amendments were approved by
the institutional review board or independent ethics
committee at participating study sites. The trial was
done in accordance with the principles of the Declaration
of Helsinki and in compliance with Good Clinical
Practice Guidelines. The full protocol and statistical
analysis plan are available in the appendix (pp 25–171).
Participants
Patients eligible for part A were adults aged 18 years or
older who were hospitalised with a confirmed diagnosis
of hospital-acquired bacterial pneumonia, ventilator-
associated bacterial pneumonia, ventilated pneumonia,
or bloodstream infections known to be caused by ABC on
the basis of cultures obtained from sputum, respiratory,
or blood samples collected within 72 h before
randomisation. Eligible patients had an Acute Physiology
and Chronic Health Evaluation (APACHE) II score
of 10–30 or a Sequential Organ Failure Assessment
(SOFA) score of less than 12. No more than 48 h of
potentially eective antimicrobial therapy (ie, Gram-
negative agent with activity against ABC) before the first
dose of study drug was allowed unless the patient was
clinically failing a previous treatment regimen (ie,
clinical deterioration or failure to improve after at least
48 h of antibiotic treatment).
Patients eligible for part B were adults who were
hospitalised with an infection (eg, hospital-acquired
bacterial pneumonia, ventilator-associated bacterial
pneumonia, ventilated pneumonia, bloodstream infec-
tions, complicated UTIs or acute pyelonephritis, or
surgical or post-traumatic wound) caused by ABC known
to be resistant to colistin or polymyxin B (defined as
laboratory-confirmed MIC ≥4 µg/mL by a non-agar-based
method) or with documented evidence of clinical failure
after at least 48 h of treatment with colistin or polymyxin
B, or with known intolerance to colistin or a condition
that contraindicated colistin (such as a neuromuscular
syndrome or acute kidney injury requiring renal
replacement therapy).
Patients were excluded if they had a history of
hypersensitivity or allergic reaction to any β-lactam, or
any contraindication to the use of imipenem–cilastatin
or pulmonary disease that precluded evaluation of
therapeutic response.
All sites were provided with the Biofire FilmArray 2.0
Pneumonia Panel (BPP; BioFire Diagnostics, Salt Lake
City, UT, USA) rapid test to enable early identification of
ABC pneumonia at screening (appendix p 12). If a
respiratory sample that tested positive for ABC by BPP
was not culture-positive for ABC at the local microbiology
laboratory, the patient was deemed ineligible and
withdrawn from study treatment. All patients or their
legally authorised representative provided written
informed consent before study participation.
Randomisation, masking, and treatment
In part A, eligible patients were randomised in a 1:1 ratio
using a web-based response system and a block size of
four to receive either sulbactam–durlobactam or colistin.
Patients were stratified by indication (ie, hospital-
acquired bacterial pneumonia or ventilator-associated
bacterial pneumonia or ventilated pneumonia vs
bloodstream infections), severity of illness (based
primarily on APACHE II scores [10–19 vs 20–30] at
screening), and geography (mainland China vs rest of the
world). If the APACHE II score was unavailable, the
SOFA (7–9 vs ≥10) or quick SOFA (2 vs 3) score was used.
See Online for appendix

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www.thelancet.com/infection Vol 23 September 2023 1075
Disease severity scores were prioritised for stratification
as: APACHE II, SOFA, then quick SOFA.
The study data were masked to data collectors and
analysers. On site, a masked designee entered the
participant’s information in the web response system,
which assigned participants to interventions on the basis
of the stratification data. The participants, site personnel
who assessed the clinical and safety outcomes, and the
study sponsor were masked to treatment group
assignments. Given the participant’s severity of illness
and complexity of regimens, the treating physician
(investigator) and pharmacist at each site were not
masked, and treatment group assignments were open
label.
Patients allocated to sulbactam–durlobactam (1∙0 g of
each drug in combination) received an intravenous
infusion over 3 h every 6 h; no loading dose was required.
Patients allocated to colistin received an initial loading
dose of 2∙5–5∙0 mg/kg (75 000–150 000 IU/kg), and then
2∙5 mg/kg (75 000 IU/kg) via intravenous infusion over
30 min every 12 h. All patients also received imipenem–
cilastatin (1∙0 g of each drug in combination) via
intravenous infusion over 1 h every 6 h. Dose adjustments
for sulbactam–durlobactam,16 colistin, and imipenem–
cilastatin were specified (per the label) for patients with
renal insuciency and for patients who developed an
imipenem-related seizure. Colistin dosing was adjusted
to ideal bodyweight and renal function. Treatment
duration was 7–14 days.
Outcomes
The primary ecacy endpoint was 28-day all-cause
mortality in patients with laboratory-confirmed
carbapenem-resistant ABC (microbiologically modified
ITT population). Patients who were randomised into part
A but then transferred into part B and patients who
withdrew consent before the assessment of survival status
were excluded from the analyses. Patients with missing
survival status were counted as a death. Prespecified
secondary ecacy endpoints were 28-day all-cause
mortality in the ITT, microbiologically modified ITT, and
carbapenem-resistant ABC microbiologically evaluable
populations; 14-day all-cause mortality in the carbapenem-
resistant ABC microbiologically modified ITT and
microbiologically modified ITT populations; and clinical
cure and microbiological favourable assessment at the
end of therapy, test of cure (7 ± 2 days after end of therapy),
and late follow-up (14 ± 2 days after end of therapy) visits in
all populations. Definitions of clinical and microbiological
outcomes varied by infection type (appendix p 15). A
refined population pharmaco kinetic model incorporating
pharmacokinetic data from patients in the ATTACK trial
will be presented in a separate publication.
Baseline pathogens were tested for susceptibility and
classified as multidrug resistant and extensively drug
resistant as previously defined.17 Pandrug resistance was
defined as non-susceptibility to all approved comparator
drugs tested by the central laboratory (amikacin, colistin,
cefepime, meropenem, imipenem, minocycline, and
sulbactam [based on breakpoints for ampicillin–
sulbactam from the Clinical and Laboratory Standards
Institute]).18 Dicult to treat was defined per Kadri and
colleagues.19
Safety outcomes, including treatment-emergent
adverse events (TEAEs), serious adverse events, and
nephrotoxicity, were monitored for 30 days after last dose
for all patients who received any amount of study drug
(safety population). The primary safety objective—
incidence of nephrotoxicity—was assessed with the
modified Risk, Injury, Failure, Loss, End-stage renal
disease (RIFLE) criteria, as measured by serum creatinine
level or glomerular filtration rate, but not urinary
volume.20,21 Nephrotoxicity was defined as meeting RIFLE
criteria at any visit after baseline; patients with multiple
RIFLE events were counted only once at the highest
severity. Patients with chronic haemodialysis at baseline
were excluded from the analysis of nephrotoxicity.
Analysis populations
The intention-to-treat (ITT) population included all
randomised patients; the modified ITT and safety
population included all randomised patients who
received any amount of study drug; the microbiologically
modified ITT population included patients with an ABC
organism isolated as the qualifying culture specimen, as
confirmed by the central or local microbiology laboratory.
The carbapenem-resistant ABC microbiologically modi-
fied ITT population was the primary ecacy population
and included patients who met micro biologically modified
ITT criteria and had a baseline ABC organism that was
confirmed to be carbapenem-resistant (defined as MIC of
imipenem–meropenem ≥8 µg/mL) by the central or local
laboratory. Patients were excluded from the carbapenem-
resistant ABC microbiologically modified ITT population
if they had isolates that were deemed by the
central laboratory to be non-susceptible to sulbactam–
durlobactam (MIC >4 µg/mL) or colistin (MIC ≥4 µg/mL),18
or if their blood culture or respiratory samples were
collected more than 72 h before randomisation. All
analysis populations, including the carbapenem-resistant
ABC micro biologically evaluable (per protocol) pop-
ulation, are defined in the appendix (p 13).
Statistical analysis
The non-inferiority margin (20%) was generated on
the basis of regulatory guidance and an estimated
colistin-based treatment eect in the range of 19–27%
(appendix pp 16–17). For the primary ecacy analysis, the
non-inferiority hypothesis test was based on a two-sided
95% CI computed using a continuity-corrected Z-statistic
for the dierence ([sulbactam–durlobactam + imipenem–
cilastatin] – [colistin + imipenem–cilastatin]) in 28-day all-
cause mortality between treatment groups in the
carbapenem-resistant ABC microbiologically modified

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1076 www.thelancet.com/infection Vol 23 September 2023
Figure 1: Trial profile
ABC=Acinetobacter baumannii–calcoaceticus complex. ITT=intention to treat. *Patients could have more than one reason for exclusion.
531 patients assessed for eligibility
Part A: randomised cohort (n=181)
92 assigned to sulbactam–durlobactam
1 not treated (did not meet inclusion and exclusion
criteria)
14 excluded from microbiologically modified ITT
analysis
13 no baseline ABC in qualified culture specimen
1 transferred to part B
14 excluded from carbapenem-resistant ABC
microbiologically modified ITT* primary analysis
4 baseline ABC organism not carbapenem-
resistant
2 baseline ABC organism resistant to
sulbactam–durlobactam
8 baseline ABC organism resistant to colistin
1 withdrew consent
91 received sulbactam–durlobactam
67 completed treatment
24 did not complete treatment
8 adverse events
2 deaths
1 comorbidity
7 no growth ABC
1 transferred to part B
5 other
77 included in microbiologically
modified ITT analysis
63 included in carbapenem-resistant
ABC microbiologically modified ITT
primary efficacy analysis at day 28
91 included in safety analysis
Part B: observational cohort (n=26)
89 assigned to colistin 26 directly enrolled
2 transferred from part A due to
colistin resistance
28 received sulbactam–durlobactam
22 completed treatment
6 did not complete treatment
3 adverse events
1 death
1 withdrew consent
1 other
28 included in carbapenem-resistant
ABC microbiologically modified ITT
analysis
3 not treated (death, consent withdrawn, no
growth ABC)
8 excluded from microbiologically modified ITT
analysis
7 no baseline ABC in qualified culture specimen
1 transferred to part B
16 excluded from carbapenem-resistant ABC
microbiologically modified ITT* primary analysis
4 baseline ABC organism not carbapenem-
resistant
4 baseline ABC organism resistant to
sulbactam–durlobactam
7 baseline ABC organism resistant to colistin
2 withdrew consent
86 received colistin
55 completed treatment
31 did not complete treatment
10 adverse events
4 deaths
1 liver event
2 renal toxicity
4 no growth ABC
1 transferred to part B
2 withdrew consent
7 other
78 included in microbiologically
modified ITT analysis
62 included in carbapenem-resistant
ABC microbiologically modified ITT
primary efficacy analysis at day 28
86 included in safety analysis 28 included in safety analysis
324 excluded
3 deaths
308 did not meet inclusion and exclusion criteria
11 withdrew consent
2 other