Aerosolized Amikacin and Fosfomycin in Mechanically Ventilated Patients With Gram-negative Pneumonia
Condition: Pneumonia, Bacterial
MeSH terms: Pneumonia; Pneumonia, Bacterial
Intervention: Amikacin fosfomycin inhalation solution; Aerosolized placebo
Intervention description: 300 mg of amikacin and 120 mg of fosfomycin twice daily for 10 days to be administered by aerosol via the eFlow Inline System; Placebo twice daily for 10 days to be administered by aerosol the eFlow Inline System
Intervention MeSH terms: Amikacin; Fosfomycin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 143.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Gram-negative pneumonia; Aerosol antibiotics; Mechanical ventilation; Amikacin; Fosfomycin; Pneumonia, Bacterial; Pneumonia; Bacterial Infections; Lung Diseases; Respiratory Tract Diseases; Respiratory Tract Infections; Anti-Bacterial Agents; Anti-Infective Agents; Therapeutic Uses; Pharmacologic Actions

Summary:

      To demonstrate the safety and efficacy of adjunctive therapy with the Amikacin fosfomycin
      inhalation system (AFIS) versus aerosolized placebo to treat Gram-negative pneumonia in
      mechanically ventilated patients receiving IV antibiotics.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Males and non-pregnant, non-lactating females, ≥ 18 years and ≤ 80 years of age

          -  Intubated and mechanically ventilated

          -  Diagnosis of pneumonia, defined as presence of a new or progressive infiltrate(s) on
             the most recent chest radiograph prior to screening, as determined by the treating
             physician

          -  Signs of infection (within 24 hours prior to screening):

               1. Fever (> 38ºC or > 100.4ºF); or

               2. Leukopenia (< 4,000 WBC/mm3) or leukocytosis (≥ 12,000 WBC/mm3)

          -  Impaired oxygenation (within 24 hours prior to screening):

             a. PaO2/FiO2 ≤ 350 mmHg

          -  Acute Physiology and Chronic Health Evaluation (APACHE) II score > 10 (within 24 hours
             prior to screening)

          -  Presence, or high suspicion, of Gram-negative organism(s) by either Gram stain or
             culture of respiratory secretions from a sample obtained within the previous 7 days
             (enrollment can occur before culture results are available)

        Exclusion Criteria:

          -  History of hypersensitivity to amikacin, other aminoglycosides, fosfomycin, imipenem,
             meropenem, or colistin

          -  Received systemic antibiotic therapy for this episode of Gram-negative pneumonia for
             greater than 72 hours at the time of randomization

          -  PaO2/FiO2 ≤ 100 mmHg and diffuse infiltrates on Chest X-ray

          -  Refractory septic shock (severe sepsis plus unstable hypotension, in spite of adequate
             fluid resuscitation and vasopressors)

          -  Any of the following conditions that interfere with the assessment or interpretation
             of the diagnosis or response to therapy:

               1. chest trauma with ongoing loss of stability of the thoracic cage following a
                  fracture of the sternum, ribs, or both;

               2. increased amounts of fluid in the lung cavities requiring chest tube drainage;

               3. lung cancer within the last 2 years;

               4. lung abscess(s);

               5. anatomical bronchial obstruction;

               6. suspected atypical pneumonia;

               7. chemical pneumonitis (e.g., inhalation injury);

               8. cystic fibrosis

          -  Immunocompromised patients, including those with neutropenia NOT due to the current
             infection (absolute neutrophil count < 500/mm3), leukemia, lymphoma, human
             immunodeficiency virus (HIV) infection with CD4 count < 200 cells/mm3, or splenectomy;
             those who are early post-transplantation (< 3 months post-transplant, or > 3 months
             post-transplant with evidence of organ rejection by clinical criteria, pathologic
             confirmation, or modification of immunosuppression within the past 4 weeks), are on
             cytotoxic chemotherapy, or are on high-dose steroids (e.g., > 40 mg of prednisone or
             its equivalent [> 160 mg hydrocortisone, > 32 mg methylprednisolone, > 6 mg
             dexamethasone, > 200 mg cortisone] daily for > 2 weeks)

          -  Evidence of significant renal impairment (serum creatinine > 4.0 mg/dL within 24 hours
             prior to screening). If serum creatinine is >2.0 mg/dL, site must be capable of
             performing continuous renal replacement therapy, if clinically indicated. Patients
             with serum creatinine > 4.0 mg/dL and being treated with continuous renal replacement
             therapy (continuous venous-venous hemofiltration or continuous venous-venous
             hemodialysis) or chronic hemodialysis are eligible

          -  Evidence of ototoxicity (history of hearing aid use prior to current hospitalization)

          -  Evidence of hepatotoxicity (alanine aminotransferase [ALT] or aspartate
             aminotransferase [AST] >3X the upper limit of normal value within 24 hours prior to
             screening)

          -  Positive urine and/or serum beta-hCG pregnancy test (only in women of reproductive
             age)

          -  On mechanical ventilation for > 28 days

          -  Glasgow Coma Scale score =3 at Screening

          -  Participating in or has participated in other investigational interventional studies
             (drug or device) within the last 30 days (or 5 times the half-life of the previously
             administered investigational compound, whichever is longer) prior to study treatment