Aerosolized Amikacin and Fosfomycin in Mechanically Ventilated Patients With Gram-negative Pneumonia

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