Study of Cefiderocol (S-649266) or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens

Inclusion Criteria

• Patients with clinically documented infection (HAP/VAP/HCAP, cUTI, or BSI/sepsis) caused by a Gram-negative pathogen with evidence of carbapenem resistance
• Patients who have been treated previously with an empiric antibiotic regiment and failed treatment, both clinically and microbiologically, are eligible for the study, if they have an identified carbapenem-resistant Gram-negative pathogen which has either been shown to be nonsusceptible in vitro to each of the antibiotic(s) of the empiric antibiotic regimen or been grown from a culture performed after at least 2 days of the empiric antibiotic regimen
• Patient is male (no contraception required) or female and meets one of the following criteria:
• Surgically sterile by hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy or tubal ligation for the purpose of contraception for at least 6 weeks with appropriate documentation of such surgery
• Postmenopausal (defined as older than 45 years of age with cessation of regular menstrual periods for 6 months and confirmed by a follicle-stimulating hormone level of > 40 mIU/mL, or amenorrhea for at least 12 months)
• 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
• Of childbearing potential and practice abstinence as a preferred and usual lifestyle, and agrees to continue practicing abstinence from Screening and for the entire duration of the study
• 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
• Patients meeting specific criteria for each infection site

Exclusion Criteria

• Patients who have a 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)
• Patients who need more than 3 systemic antibiotics as part of best available therapy (BAT) for the treatment of the Gram-negative infection (patients with mixed Gram-positive or anaerobic infections may receive appropriate concomitant narrow spectrum antibiotics [eg, vancomycin, linezolid, metronidazole, clindamycin])
• Patients with coinfection caused by invasive aspergillosis, mucormycosis or other highly lethal mold
• Patients who have central nervous system (CNS) infection (eg, meningitis, brain abscess, shunt infection)
• Patients with infection requiring > 3 weeks of antibiotic treatment (eg, bone and joint infection, endocarditis)
• Patients with cystic fibrosis or moderate to severe bronchiectasis
• Patients in refractory septic shock defined as persistent hypotension despite adequate fluid resuscitation or despite vasopressive therapy at the time of Randomization
• Patients with severe neutropenia, ie, polymorphonuclear neutrophils (PMNs) 30
• Patients who have received a potentially effective antibiotic regimen for the carbapenem-resistant Gram-negative infection for a continuous duration of more than 24 hours in cUTI, or 36 hours in HAP/VAP/HCAP or BSI/sepsis during the 72 hours leading to Randomization
• Patients with any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the patient or the quality of the study data
• Patients who have received another investigational drug or device within 30 days prior to study entry
• Patients who have previously been randomized in this study or received S-649266
• Patients receiving peritoneal dialysis
• Patients meeting specific exclusion criteria for each infection site