The goal of this clinical trial is to find out if giving certain medications once a day works just as well as giving them twice a day to treat infections around the lungs (called pleural infections). These medications-tissue plasminogen activator (tPA) and deoxyribonuclease (DNase)-are placed through a chest tube into the space between the lung and the chest wall to help clear out the infection.

The investigators are trying to learn:

• Does using the medicine once a day work just as well as using it twice a day?
• Are there any differences in outcomes between patients who get the medicine once a day versus twice a day?
• Does more or less fluid remain in the chest (seen on a chest x-ray) depending on how often the medicine is given?

Participants will:

• Have an infection around their lung and will already be getting normal hospital care, including a chest tube to drain the infected fluid around their lung.
• Be asked to give permission to join the study.
• Be randomly chosen (like flipping a coin) to get the medications either once a day or twice a day through the chest tube.

Inclusion Criteria:

• Written informed consent obtained from patient or patient's legally authorized representative (LAR) to participate in the study and HIPAA authorization for release of personal health information.

• Subject is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee.

• Age ≥ 18 years at the time of consent.

• Patient is admitted to the hospital and with a pleural effusion that is drained with a small-bore chest tube or one that allows for administration of IET

• Pleural fluid that is one of the following:

  (i) Macroscopically purulent or pleural fluid gram stain or culture positive for bacteria (ii) potential of hydrogen (pH) < 7.2 (iii) Pleural fluid glucose < 60mg/dL (iv) Pleural fluid Lactate Dehydrogenase (LDH) > 1,000 IU/L

• Patient is deemed a candidate to receive intrapleural enzyme therapy as defined by having a residual collection or persistent sepsis 24 hours after initial chest tube placement

Exclusion Criteria:

• Known pregnancy or lactating females
• Prisoners
• Age <18 years at time of consent
• Previous treatment with intra-pleural fibrinolytic agents, DNase, or both during the same hospital admission
• Known sensitivity or allergic reaction to DNAse or tPA
• Coincidental stroke, major hemorrhage (requiring blood transfusions within the last 5 days), major trauma, or major surgery within the last 5 days
• Previous pneumonectomy or active bronchopleural fistula on the affected side
• Therapeutic systemic anticoagulation or antiplatelet agents that cannot held for more than 48 hours prior to IET administration
• Expected survival of less than 3 months due to a pathologic condition other than that causing the pleural infection

Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.

Beginning 9/2026 and continuing for 36 months following publication

Investigator has approved IRB, IEC, or REB and an executed data use/sharing agreement with University of North Carolina (UNC).