Study of Cefiderocol (S-649266) or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens
Condition: Healthcare-associated Pneumonia (HCAP); Bloodstream Infections (BSI); Hospital Acquired Pneumonia (HAP); Complicated Urinary Tract Infection (cUTI); Sepsis; Ventilator Associated Pneumonia (VAP)
MeSH terms: Infections; Communicable Diseases; Pneumonia; Sepsis; Urinary Tract Infections; Pneumonia, Ventilator-Associated; Healthcare-Associated Pneumonia
Intervention: Cefiderocol; Best Available Therapy
Intervention description: 2 g intravenously over 3 hours every 8 hours for a period of 7 to 14 days, or 2 g every 6 hours for participants with creatinine clearance >120 mL/min.; Standard of care with either a polymyxin-based or non-polymyxin-based regimen as determined by the investigator and consisting of one to three marketed antibacterial agent(s).
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 152.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: cefiderocol; Bloodstream infections (BSI); Complicated urinary tract infection (cUTI); Ventilator associated pneumonia (VAP); Hospital acquired pneumonia (HAP); Sepsis; multi-drug resistant pathogens; S-649266; Gram-negative pathogens; Healthcare-associated pneumonia (HCAP); carbapenem resistant pathogens

Summary:

      This study is designed to provide evidence of efficacy of cefiderocol in the treatment of
      serious infections in adult patients caused by carbapenem-resistant Gram-negative pathogens.
    

Eligibility criteria:

        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:

          1. 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)

          2. 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])

          3. Patients with coinfection caused by invasive aspergillosis, mucormycosis or other
             highly lethal mold

          4. Patients who have central nervous system (CNS) infection (eg, meningitis, brain
             abscess, shunt infection)

          5. Patients with infection requiring > 3 weeks of antibiotic treatment (eg, bone and
             joint infection, endocarditis)

          6. Patients with cystic fibrosis or moderate to severe bronchiectasis

          7. Patients in refractory septic shock defined as persistent hypotension despite adequate
             fluid resuscitation or despite vasopressive therapy at the time of Randomization

          8. Patients with severe neutropenia, ie, polymorphonuclear neutrophils (PMNs) < 100
             cells/μL

          9. Female patients who have a positive pregnancy test at Screening or who are lactating

         10. Patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) score > 30

         11. 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

         12. 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

         13. Patients who have received another investigational drug or device within 30 days prior
             to study entry

         14. Patients who have previously been randomized in this study or received S-649266

         15. Patients receiving peritoneal dialysis

         16. Patients meeting specific exclusion criteria for each infection site