Hospital-acquired Bacterial Pneumonia, Ventilator-associatedBacterial Pneumonia, or Healthcare-associated BacterialPneumonia Caused by Gram-negative Pathogens

The primary objective of this study is to compare all-cause mortality at Day 14 in participants receiving cefiderocol with participants receiving the comparator, meropenem, in adults with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP) caused by Gram-negative pathogens.

S-649266

S-649266

vial

1g

Efficacy Assessment:
In addition to 14-day all-cause mortality (primary efficacy endpoint), both clinical and
microbiological outcomes will be assessed by the investigator at EA, EOT, TOC, and
FUP. If case study treatment duration is extended beyond 14 days, an additional clinical
and microbiological outcome will be assessed on Day 14.
Safety Assessments:
Subject safety will be assessed from the time of having signed informed consent to the
end of the study by identifying adverse events (AEs) with the addition of physical and
laboratory evaluations, which include multiple electrocardiograms obtained early in the
treatment with study drug.
In case treatment duration is extended beyond 14 days, additional safety assessments will
be conducted on Day 14. Safety surveillance will extend up to 28 days after the last dose
of the drug treatment.
Pharmacokinetic Assessments:
All subjects will have blood drawn for sparse pharmacokinetic (PK) assessment of
plasma concentrations of S-649266. The actual sampling date and time will be recorded.
PK blood sampling will be performed on Day 3 (after at least 6 doses of drug) at
4 timepoints: (1) just prior to the start of the 3-hour infusion, (2) 1 hour after the start of
infusion, (3) at the end of infusion, and (4) 1 hour after the end of infusion.
Pharmacokinetic blood sampling will be repeated in the event that the study dosage was
changed due to changes in renal function at EA.
If possible, a single blood sampling should be performed as soon as possible at EOT in
case of premature EOT.

Inclusion Criteria
Subjects who fulfill the following criteria at screening will be included in the study:
1. Subjects 18 years or older at the time of signing informed consent
2. Subjects who have provided written informed consent or their informed consent
has been provided by legal guardian (Note: Country-specific rules and local
Ethics Committee approval for legal guardian informed consent will determine
whether or not and how a subject unable to comprehend or sign the informed
consent is allowed to be enrolled in the study)
3. Subjects who meet the clinical diagnosis criteria for HABP/VABP/HCABP (see
above)
4. All subjects who fulfill at least 1 of the following clinical criteria at screening:
a. New onset or worsening of pulmonary symptoms or signs, such as cough,
dyspnea, tachypnea (eg, respiratory rate greater than 25 breaths/minute),
expectorated sputum production, or requirement for mechanical ventilation
b. Hypoxemia (eg, a partial pressure of oxygen [PaO2] less than 60 mm Hg while
the subject is breathing room air, as determined by arterial blood gas [ABG],
or worsening of the ratio of the PaO2 to the fraction of inspired oxygen
[PaO2/FiO2])
c. Need for acute changes in the ventilator support system to enhance
oxygenation, as determined by worsening oxygenation (ABG or PaO2/FiO2)
or needed changes in the amount of positive end-expiratory pressure
d. New onset of or increase in (quantity or characteristics) suctioned respiratory
secretions, demonstrating evidence of inflammation and absence of
contamination
5. All subjects must have at least 1 of the following signs:
a. Documented fever (ie, core body temperature [tympanic, rectal, esophageal]
greater than or equal to 38°C [100.4°F], oral temperature greater than or equal
to 37.5°C, or axillary temperatures greater than or equal to 37°C).
b. Hypothermia (ie, core body temperature [tympanic, rectal, esophageal] less
than or equal to 35°C [95.0°F], oral temperature less than or equal to 35.5°C
and axillary temperature less than or equal to 36°C).
c. Leukocytosis with a total peripheral white blood cell (WBC) count greater
than or equal to 10,000 cells/mm3
d. Leukopenia with total peripheral WBC count less than or equal to
4500 cells/mm3
e. Greater than 15% immature neutrophils (bands) noted on peripheral blood
smear
6. All subjects must have a chest radiograph during screening or have a previous
chest radiograph within 48 hours prior to randomization showing the presence of
new or progressive infiltrate(s) suggestive of bacterial pneumonia. A computed
tomography (CT) scan in the same time window showing the same findings could
also be acceptable.
7. All subjects must have evidence of a Gram-negative infection involving the lower
respiratory tract as documented by 1 or more of the following:
a. Gram stain of lower respiratory secretions showing Gram-negative bacteria,
either alone or mixed with Gram-positive bacteria at or within 72 hours prior
to randomization
b. Microbiologic culture of respiratory tract secretions within 72 hours prior to
randomization identifying Gram-negative aerobic bacteria
c. Microbiologic culture (culture obtained to identify infection) from blood, urine, or skin identifying a Gram-negative aerobic bacterial pathogen within
72 hours prior to randomization
d. Other diagnostic tests, including molecular tests, which provide evidence of
Gram-negative bacterial infection of the lower respiratory tract
e. Pneumonia highly suspected to be due to a Gram-negative bacteria based on
prior antibiotic use or local epidemiologic evidence of Gram-negative
infection outbreak
8. Subject is male (no contraception required) or female and meets one of the
following criteria:
 Surgically sterile (has had a hysterectomy and/or bilateral oophorectomy, or a
bilateral salpingectomy or tubal ligation for the purpose of contraception for at
least 6 weeks with appropriate documentation of such surgery), or
 Postmenopausal (defined as older than 45 years of age with cessation of
regular menstrual periods for at least 6 months and a follicle-stimulating
hormone level of > 40 mIU/mL, or amenorrhea for at least 12 months), or
 Of childbearing potential and using combined (estrogen and progestogen) or
progestogen-only hormonal contraception associated with inhibition of
ovulation (including oral, intravaginal, injectable, implantable, and
transdermal contraceptives), or an intrauterine device (IUD), or intrauterine
hormone-releasing system (IUS) for the entire duration of the study, or
 Of childbearing potential and practice abstinence as a preferred and usual life
style, and agrees to continue practicing abstinence from screening for the
entire duration of the study, or
 Of childbearing potential, whose sole heterosexual partner has been
successfully vasectomized and agrees to not have other heterosexual partners
for the entire duration of the study.

Exclusion Criteria
Subjects who meet any of the following criteria at screening will be excluded from the
study:
1. Subjects who have a known or suspected community-acquired bacterial
pneumonia (CABP), atypical pneumonia, viral pneumonia, or chemical
pneumonia (including aspiration of gastric contents, inhalation injury)
2. Subjects who have a documented history of any moderate or severe
hypersensitivity or allergic reaction to any β-lactam (Note: for β-lactams, a history
of a mild rash followed by uneventful re-exposure is not a contraindication to
enrollment) or linezolid
3. Subjects with a Gram-negative infection caused by a carbapenem resistant
pathogen, if known at the time of randomization (Note: subjects who have a
carbapenem-resistant pathogen identified after randomization should be evaluated
clinically before discontinuation of study treatment.)
4. Subjects with coinfection caused by invasive aspergillosis, mucormycosis or other
highly lethal mold
5. Subjects who have central nervous system (CNS) infection (eg, meningitis, brain
abscess, shunt infection)
6. Subjects with cystic fibrosis or bronchiectasis
7. Subjects in refractory septic shock defined as persistent hypotension despite
adequate fluid resuscitation or despite vasopressive therapy at the time of
randomization
8. Subjects with neutropenia (ie, polymorphonuclear neutrophils < 500 cells/µL)
9. Female subjects who have a positive pregnancy test at screening or who are
lactating
10. Subjects with acute physiology and chronic health evaluation II (APACHE
II) > 35
11. Subjects who have received potentially effective antibiotic therapy for a
continuous duration of more than 24 hours during the previous 72 hours prior to
randomization (Note: Subjects failing empiric therapy defined in inclusion criteria
No. 8 may be eligible for inclusion)
12. Subjects with any condition or circumstance that, in the opinion of the
investigator, would compromise the safety of the subject or the quality of the
study data
13. Subjects receiving peritoneal dialysis (hemofiltration and hemodialysis are
allowed to be in the study)
14. Subjects requiring continued treatment with methotrexate, procainamide,
probenecid, or monoamine oxidase inhibitors
15. Subjects who have received another investigational drug or device within 30 days
prior to study entry
16. Subjects who have previously been randomized in this study or have previously
received S-649266
17. One or more of the following laboratory abnormalities in baseline specimens:
aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline
phosphatase, or total bilirubin level greater than 3 times the upper limit of normal
(ULN), absolute neutrophil count less than 100/μL, platelet count less than
40,000/μL