Clinical Trials to Reduce the Risk of Antimicrobial Resistance

The goal of this clinical study is to demonstrate that the application of pharmacodynamic
dosing principles to the antibiotic treatment of hospitalized subjects with
culture-documented pneumonia (including HABP, VABP and HCAP) requiring mechanical ventilation
can inhibit the emergence of antibiotic-resistant organisms during treatment and therefore
may improve the rate of a satisfactory clinical response. Antibiotic resistance is defined as
an increase in meropenem or aminoglycoside MIC by two tube dilutions (fourfold) from
baseline. In animal models of infection, the pharmacodynamic driver for bactericidal effect
by β lactam antibiotics such as meropenem is the proportion of the dosing interval during
which plasma drug levels are maintained above the MIC of the causative pathogen. The
hypothesis of this study is that prolongation of time above MIC by increasing total meropenem
dose and the duration of infusion will counter-select for the emergence of antimicrobial
resistance during the treatment of hospitalized subjects with pneumonia (i.e. HABP, VABP and
HCAP) caused by P.aeruginosa, Acinetobacter species (spp), or other pathogens with
intermediate susceptibility to meropenem, and that the addition of parenteral aminoglycosides
(amikacin, tobramycin or gentamicin) and nebulized aminoglycoside (tobramycin) given along
optimal pharmacodynamic principles will further reduce the likelihood of resistance
emergence, particularly among the non-fermenting Gram-negative bacilli, such as Pseudomonas
aeruginosa and Acinetobacter spp. The observed incidence of resistance emergence to meropenem
will be compared across therapeutic regimens.

Inclusion criteria:

Written informed consent by the subject/subject's LAR.

Hospitalized males or females ≥ 18 yrs with respiratory failure requiring mechanical
ventilation and clinical suspicion of HABP, HCAP or VABP.

Onset or exacerbation of pneumonia at least 48 hours after admission to any patient health
care facility or onset of pneumonia in a nursing home or rehabilitation facility with
subsequent transfer to an acute care facility

Women of childbearing potential if their pregnancy test is negative

Subjects who have received previous antibacterial therapy within 14 days of pre-treatment
bronchoscopy entry may be entered only if the subject has not responded clinically.). While
less than 24 hours of pre-treatment antibiotics is preferential, recovery of >104 CFU/ml in
the quantitative Bronchoscopic BAL will be seen as primary evidence that the prior therapy
was not efficacious and enrollment will be allowed.)

Patients should have clinical findings that support a diagnosis of HABP/VABP/HCAP:

Within 48 hours before starting empiric therapy a subject's chest radiograph should show
the presence of a NEW or progressive infiltrate, cavitation, or effusion suggestive of
pneumonia

Within 36 hours before the start of empiric study therapy, a quantitative culture of
Bronchoscopic BAL fluid must be obtained.

Patients with VABP should have a Clinical Pulmonary Infection Score of >/= 5.

Exclusion Criteria:

Subjects with pneumonia caused by pathogens resistant to meropenem (MIC greater than or
equal to 16µg/ml) or a prior meropenem therapy failure.

Subjects with contra-indications to ANY study medication, in particular with known or
suspected allergy or hypersensitivity.

Women who are pregnant or lactating.

Subjects taking anticonvulsant medications for a known seizure disorder.Patients with a
history of seizures, AND who are stabilized on anti-seizure medication, may be enrolled
into the study at the discretion of the site investigator.

Subjects with known or suspected community acquired bacterial pneumonia (CABP) or viral
pneumonia; or Subjects with acute exacerbation of chronic bronchitis without evidence of
pneumonia.

Subjects with primary lung cancer or another malignancy metastatic to the lungs.

Subjects who were previously enrolled in this study.

Subjects who have had an investigational drug or have used an investigational device within
30 days prior to entering the study.

Subjects with another focus of infection requiring concurrent antibiotics that would
interfere with evaluation of the response to study drug.

Subjects with cystic fibrosis, AIDS with a CD4 lymphocyte count <200 cells/µl, neutropenia
(absolute neutrophil count <500 cells/ml), known or suspected active tuberculosis.

Subjects with little chance of survival for the duration of study therapy.

Subjects with an APACHE II score >35.

Subjects with underlying condition(s) which would make it difficult to interpret response
to the study drugs.

Subjects with hypotension or acidosis despite attempts at fluid resuscitation. Subjects
requiring ongoing treatment with vasopressors will be eligible for the study if their
hypotension is controlled and acidosis has resolved. Subjects with intractable septic shock
are not eligible for enrollment.

Subjects who have undergone bone marrow transplantation.

Subjects with profound hypoxia as defined by a PaO2/FiO2 ratio <100.