A Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CRE)
Condition: Bloodstream Infections (BSI) Due to CRE; Hospital-Acquired Bacterial Pneumonia (HABP) Due to CRE; Ventilator-Associated Bacterial Pneumonia (VABP) Due to CRE; Complicated Urinary Tract Infection (cUTI) Due to CRE; Acute Pyelonephritis (AP) Due to CRE
MeSH terms: Infections; Communicable Diseases; Pneumonia; Urinary Tract Infections; Sepsis; Pneumonia, Bacterial; Pyelonephritis
Intervention: plazomicin; colistin; meropenem; tigecycline; antibiotic of Investigator's choice
Intervention MeSH terms: Anti-Bacterial Agents; Meropenem; Colistin; Tigecycline
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 69.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Gram-negative; bacterial infection; antibacterial; antimicrobial; CRE; CPE; BSI; pneumonia; HABP; VABP; AP; cUTI; UTI

Summary:

      This was a Phase 3 study containing a randomized open-label superiority cohort (Cohort 1)
      comparing the efficacy and safety of plazomicin with colistin when combined with a second
      antibiotic (either meropenem or tigecycline) in the treatment of patients with bloodstream
      infection (BSI), hospital acquired bacterial pneumonia (HABP), or ventilator-associated
      bacterial pneumonia (VABP) due to CRE. An additional cohort of patients with BSI, HABP, VABP,
      complicated urinary tract infection (cUTI), or acute pyelonephritis (AP) due to CRE, not
      eligible for inclusion in the other cohort, were enrolled into a single arm (Cohort 2) and
      treated with plazomicin-based therapy. Therapeutic drug management (TDM) was used to help
      ensure that plazomicin exposures lie within an acceptable range of the target mean
      steady-state area under the curve (AUC).
    

Eligibility criteria:

        Key Inclusion Criteria:

          -  Cohort 1: APACHE II score between 15 and 30, inclusive; Cohort 2: BSI, HABP, VABP
             patients with an APACHE II score ≤30 (cUTI and AP patients do not need to have their
             APACHE II score calculated)

          -  Positive culture that was collected ≤96 hours prior to randomization indicating a CRE
             infection, or a high likelihood of a CRE infection

          -  Diagnosis of BSI as defined by at least one of the following: fever, hypothermia, new
             onset arterial hypotension, elevated total peripheral white blood cell (WBC) count,
             increased immature neutrophils (band forms), or leukopenia

          -  Or, diagnosis of HABP defined as clinical signs and symptoms consistent with pneumonia
             acquired after at least 48 hours of continuous stay in an inpatient acute or
             chronic-care facility, or acquired within 7 days after being discharged from a
             hospitalization of ≥3 days duration

          -  Or, diagnosis of VABP defined by clinical signs and symptoms consistent with pneumonia
             acquired after at least 48 hours of continuous mechanical ventilation

          -  Or, diagnosis of cUTI or AP defined by clinical signs and symptoms consistent with
             cUTI or AP assessed within 24 hours prior to enrollment

        Key Exclusion Criteria:

          -  Cohorts 1 and 2 BSI, HABP, and VABP patients: receipt of more than 72 hours of
             potentially effective antibacterial therapy; Cohort 2: cUTI and AP patients: receipt
             of any potentially effective antibacterial therapy in the 48 hours prior to enrollment

          -  Cohort 1 only: knowledge that index CRE infection is resistant to colistin prior to
             randomization

          -  Objective clinical evidence for any of the following clinical syndromes that
             necessitates study therapy for greater than 14 days: endovascular infection including
             endocarditis, osteomyelitis, prosthetic joint infection, meningitis and/or other
             central nervous system infections

          -  Objective clinical evidence of infectious involvement of intravascular material
             potentially due to the study qualifying pathogen and not intended to be removed within
             4 calendar days of the initial positive culture

          -  HABP or VABP patients only: pulmonary disease that precludes evaluation of therapeutic
             response including known bronchial obstruction or a history of post-obstructive
             pneumonia, tracheobronchitis, primary lung cancer or malignancies metastatic to the
             lung, bronchiectasis, known or suspected active tuberculosis

          -  cUTI or AP patients only: renal abscess, chronic bacterial prostatitis, orchitis or
             epididymitis, polycystic kidney disease, one functional kidney, vesicoureteral reflux,
             renal transplant, cystectomy or ileal loop surgery, fungal UTI or complete, permanent
             obstruction of the urinary tract

          -  Patients in acute renal failure at the time of randomization

          -  Patients receiving intermittent hemodialysis (IHD) at the time of screening

          -  Pregnant or breastfeeding female patient