Pneumonia

A Study of 2 Antiobiotic Regimens In The Treatment Of Community-Acquired Pneumonia: An Investigator-Blind, Randomized, Compartor-Controlled Study In Outpatients.

Study Design

Rationale for Study Design

This trial is to be conducted as an investigator-blind, randomized. comparative, multicenter study. The two treatments will be compared for equivalence. Although some measurements used to assess efficacy, such as microbiologic culture results, body temperature, pulse, respiration rate, WBC count, and chest x-ray can be interpreted objectively, whether the medication is blinded or not, investigator blinding will strengthen the clinical assessments by reducing possible bias.

Primary Objectives

To assess the clinical efficacy of linezolid when compared with cephalosporin therapy in the outpatient treatment of community-acquired pneumonia.

To assess the safety and tolerance of linezolid when compared with cephalosporin therapy in the outpatient treatment of community-acquired pneumonia.

The primary endpoint will be the clinical response to treatment (see Section 8, Efficacy and Safety Assessments). A secondary endpoint will be the microbiologic response. An overall response to treatment will be judged by a combination of the clinical and microbiologic criteria (Overall Outcome). See Section 10, Statistics, for more information. Safety endpoints will be evaluated for all patients who receive any study medication including physical examination findings, vital signs measurements, laboratory assay results, and adverse event monitoring.

Inclusion Criteria

To be eligible for this study, a valid, signed informed consent form must be obtained for each
patient and each must meet all of the following criteria.

1. At least 18 years of age.
2. Clinical picture compatible with community-acquired pneumonia (acquired in a community or nursing home setting) with at least two of the following signs and symptoms:

cough.
production of purulent sputum or a change (worsening) in character of the sputum.
auscultatory findings on pulmonary exam of rales and/or pulmonary consolidation (dullness on percussion, bronchial breath sounds, or egophony).
dyspnea, tachypnea. or hypoxemia, particularly if any or all of these are progressive in nature.
organism consistent with a respiratory pathogen isolated from respiratory, sputum, or blood cultures.

3. Deemed clinically appropriate by the investigator for outpatient therapy.
4. Expected to survive at least 60 days.
5. Each patient should also have at least one of the following:

fever, defined as body temperature 238°C (100.4°F) taken orally, 238.5°C (101.2°F) tympanically, or 239°C ( 102.2°F) rectally or hypothermia defined as body temperature <35.5°C (96°F) taken orally.
Elevated total peripheral white blood cell count (WBC) >10,000/mm3
>15% immature neutrophils (bands) regardless of total peripheral WBC.

6. Chest x-ray (PA and lateral) at baseline/screen or within 48 hours of initiation of treatment
      consistent with a diagnosis of pneumonia (new or progressive infiltrates, consolidation, or
      pleural effusion).
7. Provide a suitable sputum specimen for Gram's stain and culture. (See Section 7.3., Study
    Procedures for guidance regarding a suitable respiratory specimen.)
8. Willing to complete all study-related activities and a follow-up visit.

Exclusion Criteria

The presence of any of the following conditions at enrollment will exclude a patient from study
eligibility. Reasons why patients were not enrolled must be documented on the Screening and Enrollment Log.

1. Infection due to organisms known to be resistant to either of the study drug regimens before study entry.

2. History of mechanical ventilation within the previous month.

3. Loculated empyema or lung abscess.

4. Cystic fibrosis, bronchiectasis, or those with known or suspected active tuberculosis.

5. Known bronchial obstruction or a history of post-obstructive pneumonia. (This does not exclude patients who have chronic obstructive pulmonary disease.) Pheochromocytoma, untreated hyperthyroidism, untreated or uncontrolled hypertension, or carcinoid syndrome.

7. Known or suspected pulmonary conditions which are likely to preclude evaluation of therapeutic response, eg, granulomatous diseases, lung cancer, or another malignancy metastatic to the lungs.

8. Known or suspected meningitis, endocarditis, or osteomyelitis.

9. Current or anticipated use of high doses of systemic corticosteroids or prednisone dose > 15 mg/day.

10. CD4 cell count <200 cells/mm3 secondary to HIV infection.

11. Unstable psychiatric conditions or seizure disorders requiring chronic administration of medication without consultation and consent of the TCTL.

12. Previous antibiotic treatment for the current episode of pneumonia received for more than 24 hours, unless documented to be a treatment failure (72 hours treatment and not responding).

13. Females of child-bearing potential who are unable to take adequate contraceptive precautions, have a positive pregnancy test result within 24 hours prior to study entry, are otherwise known to be pregnant, or are currently breastfeeding an infant.

14. Another investigational drug received within the past 30 days.

15. Previous enrollment in this or any other protocol using linezolid.

16. Hypersensitivity to oxazolidinones or one of the excipients in the oral formulation of linezolid (see Section 7.1, Trial Medications)

17. Hypersensitivity to cephalosporins .

I8. Patients with known liver disease and total bilirubin >5 X ULN.

19. Patients with severe neutropenia (< 500 cells/mm3)

Note: Patients may receive the first 24 hours of treatment before obtaining the results of the laboratory assays in 18 & l 9 above. See Section 6.3, Discontinuation of Study Subjects.

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