Aerosolized Amikacin and Fosfomycin in Mechanically Ventilated Patients With Gram-negative and / or Gram-positive Bacterial Colonization

The primary purpose of this study is to demonstrate the safety and efficacy of the amikacin
fosfomycin inhalation system (AFIS). AFIS consists of amikacin solution (AMS) and
fosfomycin solution (FFS), delivered by aerosol to the lungs via the Investigational eFlow
AFIS Inline System (AFIS Inline System) with tamper evident reservoir. Patients will be
randomized to receive 5 days of treatment with either AFIS or placebo, followed by all
patients receiving open label AFIS for five days. The primary efficacy endpoint is the
change from baseline in tracheal aspirate Gram-negative and/or Gram-positive bacterial
density at the end of the 5-day randomized course of study drug.

Inclusion Criteria:

- Males and non-pregnant, non-lactating females, ≥ 18 years and ≤ 80 years of age

- Intubated and mechanically-ventilated

- Presence of Gram-negative and/or Gram-positive organism(s) by culture of respiratory
secretions from a sample obtained within the previous 7 days

Exclusion Criteria:

- History of hypersensitivity to amikacin or fosfomycin.

- Diagnosis of pneumonia, defined as presence of a new or progressive infiltrate(s) on
chest radiograph (within 7 days prior to screening), as determined by the treating
physician

- Use of systemic antibiotics with efficacy against likely respiratory tract pathogens
at the time of randomization

- Severe acute respiratory distress syndrome (defined as 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)

- 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)

- Any of the following conditions that interfere with the assessment or interpretation
of the diagnosis or response to therapy: chest trauma with loss of stability of the
thoracic cage following a fracture of the sternum, ribs, or both; increased amounts
of fluid in the lung cavities requiring chest tube drainage; lung cancer within the
last 2 years; lung abscess(s); anatomical bronchial obstruction; suspected atypical
pneumonia; chemical pneumonitis (e.g., inhalation injury); cystic fibrosis;
congestive heart failure (leading to a PaO2/FiO2 ratio ≤ 100 mmHg and diffuse
infiltrates on Chest X-ray)

- 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, 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)

- Positive urine and/or serum beta-hCG pregnancy test (only in women of reproductive
age)

- 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