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

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 and fosfomycin
solution, delivered by aerosol to the lungs via the PARI Investigational eFlow Inline System
(eFlow Inline System). All patients will receive a standardized course of intravenous (IV)
antibiotics for a minimum of 7 days. Patients will be randomized to receive 10 days of
treatment with either AFIS or placebo, in addition to the IV therapy. The primary efficacy
endpoint is defined as the change from baseline in the Clinical Pulmonary Infection Score
(CPIS) during the 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

- 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