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Reducing Antimicrobial Overuse Through Targeted Therapy for Patients With Community-Acquired Pneumonia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05568654
Recruitment Status : Recruiting
First Posted : October 6, 2022
Last Update Posted : November 15, 2022
Sponsor:
Information provided by (Responsible Party):
Michael Rothberg, The Cleveland Clinic

Brief Summary:
The purpose of this study is to reduce the exposure of broad-spectrum antimicrobials by optimizing the rapid detection of CAP pathogens and improving rates of de-escalation following negative cultures. To accomplish this, we will perform a 3-year, pragmatic, multicenter 2 X 2 factorial cluster randomized controlled trial with four arms: a) rapid diagnostic testing b) pharmacist-led de-escalation c) rapid diagnostic testing + pharmacist-led de-escalation and d) usual care

Condition or disease Intervention/treatment Phase
Community-Acquired Pneumonia Antimicrobial Stewardship Point-of-Care Testing Diagnostic Test: Rapid Diagnostic Testing Other: Pharmacist-led de-escalation Not Applicable

Detailed Description:

Community-acquired pneumonia (CAP) is a leading cause of hospitalization and inpatient antimicrobial use in the United States. However, diagnostic uncertainty at the time of initial treatment and following negative cultures is associated with prolonged exposure to broad-spectrum antimicrobials. We propose a large multicenter cluster randomized controlled trial to test two approaches to reducing the use of broad-spectrum antibiotics in adult patients with CAP a) routine use of rapid diagnostic testing at the time of admission and b) pharmacist -led de-escalation after 48 hours for clinically stable patients with negative cultures.

When a patient is admitted with a diagnosis of pneumonia, it will trigger the admission order set and if the physician is in a hospital randomized to the rapid diagnostic testing arm, a CDSS-based alert will be generated in real time, and the form will append orders for viral and UAT testing. For physicians at a hospital randomized to the control condition, ordering will proceed as usual (standard-of-care). A second CDSS algorithm will identify study patients who have negative culture results (blood and/or sputum) for greater than 48 hours and generate a list for the antimicrobial stewardship pharmacist, who will be a member of the study team. The alerts will be audited by the clinical pharmacist daily on weekdays at a centralized location. In clinically stable patients from hospitals randomized to the de-escalation arm, the pharmacist will communicate their recommendations for de-escalation to the clinical providers via a phone call, Epic chat, or page. The primary outcome will be the duration of exposure to broad-spectrum antimicrobial therapy defined by the number of days of antibiotic therapy from initiation to discontinuation. Secondary outcomes will include detection of influenza/RSV, de-escalation and re-escalation to broad-spectrum antibiotics after de-escalation, total antibiotic duration, in-hospital mortality, ICU transfer after admission, healthcare-associated CDI and acute kidney injury after 48 hours.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12500 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description: To accomplish these two aims, we will perform a, pragmatic, multicenter 2 X 2 factorial cluster randomized controlled trial with four arms:
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Reducing Antimicrobial Overuse Through Targeted Therapy for Patients With Community-Acquired Pneumonia
Actual Study Start Date : November 1, 2022
Estimated Primary Completion Date : January 31, 2026
Estimated Study Completion Date : June 30, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Rapid diagnostic testing (RDT)
Rapid diagnostic testing: Eligible patients at hospitals randomized to this arm will undergo testing for viral pathogens (from November-April) and pneumococcal UAT testing. If the patient is not being admitted to the ICU, and the patient has an admitting diagnosis of pneumonia, the form will append orders for viral testing and UAT testing to providers in hospitals randomized to receive it.
Diagnostic Test: Rapid Diagnostic Testing
Eligible patients in hospitals randomized to this arm will undergo testing for viral pathogens (from November-April) and pneumococcal UAT testing. A CDSS-based alert will be generated in real time. If the patient is not being admitted to the intensive care unit, the form will append orders for viral pathogen and UAT testing.

Active Comparator: Pharmacist-led de-escalation
Pharmacist-led de-escalation: Another CDSS algorithm will identify CAP patients who meet study criteria and have negative culture results for > 48 hours and generate a list for the clinical pharmacist, who will be a member of the study team. The alerts will be audited by the pharmacist daily on weekdays at a centralized location. The pharmacist will attempt to determine whether each patient is clinically stable. The validated measures of clinical stability in patients with CAP are a) resolved vital sign abnormalities b) normal mental status c) ability to eat. If the patient appears stable, the pharmacist will communicate their recommendations for de-escalation to the clinical providers via a phone call or page.
Other: Pharmacist-led de-escalation
A CDSS algorithm will identify CAP patients who meet study criteria and have negative culture results for greater than 48 hours and generate a list for the antimicrobial stewardship pharmacist, who will be a member of the study team. The alerts will be audited by the pharmacist daily at a centralized location. The pharmacist will attempt to determine whether each patient is clinically stable. The validated measures of clinical stability in patients with CAP are a) resolved vital sign abnormalities (temperature, heart rate, oxygen saturation, blood pressure and respiratory rate) b) normal mental status and c) ability to eat. If the patient appears stable, the pharmacist will communicate their recommendations for de-escalation to the clinical providers via a phone call or page. The de-escalation recommendations made by the pharmacist will be based on a protocol developed by the research team.

Active Comparator: Rapid diagnostic testing (RDT) and Pharmacist-led de-escalation

Rapid diagnostic testing: Eligible patients at hospitals randomized to this arm will undergo testing for viral pathogens (from November-April) and pneumococcal UAT testing. If the patient is not being admitted to the ICU, and the patient has an admitting diagnosis of pneumonia, the form will append orders for viral testing and UAT testing to providers in hospitals randomized to receive it.

Pharmacist-led de-escalation: Another CDSS algorithm will identify CAP patients who meet study criteria and have negative culture results for >48-hours and generate a list for the clinical pharmacist, who will be a member of the study team. The alerts will be audited by the pharmacist daily on weekdays at a centralized location. The pharmacist will attempt to determine whether each patient is clinically stable. If the patient appears stable, the pharmacist will communicate their recommendations for de-escalation to the clinical providers via a phone call or page.

Diagnostic Test: Rapid Diagnostic Testing
Eligible patients in hospitals randomized to this arm will undergo testing for viral pathogens (from November-April) and pneumococcal UAT testing. A CDSS-based alert will be generated in real time. If the patient is not being admitted to the intensive care unit, the form will append orders for viral pathogen and UAT testing.

Other: Pharmacist-led de-escalation
A CDSS algorithm will identify CAP patients who meet study criteria and have negative culture results for greater than 48 hours and generate a list for the antimicrobial stewardship pharmacist, who will be a member of the study team. The alerts will be audited by the pharmacist daily at a centralized location. The pharmacist will attempt to determine whether each patient is clinically stable. The validated measures of clinical stability in patients with CAP are a) resolved vital sign abnormalities (temperature, heart rate, oxygen saturation, blood pressure and respiratory rate) b) normal mental status and c) ability to eat. If the patient appears stable, the pharmacist will communicate their recommendations for de-escalation to the clinical providers via a phone call or page. The de-escalation recommendations made by the pharmacist will be based on a protocol developed by the research team.

No Intervention: Usual care (no intervention)
Usual care



Primary Outcome Measures :
  1. Number of days of broad-spectrum antibiotic therapy [ Time Frame: first 21 days of admission ]
    duration of exposure to broad-spectrum antimicrobial therapy defined by the number of days of antibiotic therapy in the first 21 days of admission as per National Healthcare Safety Network (NHSN) guidelines


Secondary Outcome Measures :
  1. viral testing ordered (yes/no) [ Time Frame: Up to 48 hours ]
    Proportion of patients in whom viral testing was ordered. We will look at each virus individually as well as all viruses together (i.e. any viral testing)

  2. detection of influenza virus (yes/no) [ Time Frame: Up to 48 hours ]
    Proportion of patients who test positive for influenza

  3. detection of RSV (yes/no) [ Time Frame: up to 48 hours ]
    Proportion of patients who test positive for RSV

  4. detection of viruses/atypical bacteria in the respiratory panel (yes/no) [ Time Frame: up to 48 hours ]
    Proportion of patients who test positive for each of the viruses/atypical bacteria in the respiratory panel

  5. treatment with anti-viral medications [ Time Frame: up to 48 hours ]
    treatment with anti-viral medications (oseltamivir, zanamivir, peramivir, baloxavir, ribavirin, remdesivir, nirmatrelvir, COVID-19 medications)

  6. treatment with antiviral medications [ Time Frame: within 21 days ]
    treatment with antiviral medications (oseltamivir, zanamivir, peramivir, baloxavir, ribavirin, remdesivir, nirmatrelvir, COVID-19 medications)

  7. S. pneumoniae urinary antigen test (UAT) performed [ Time Frame: up to 48 hours ]
    Proportion of patients in whom UAT is performed

  8. positive pneumococcal UAT [ Time Frame: up to 48 hours ]
    Proportion of patients with positive pneumococcal UAT

  9. de-escalation by 72 hours from admission (yes/no) [ Time Frame: within 72 hours from admission. ]
    Proportion of patients whose broad spectrum antimicrobials (imipenem, meropenem, piperacillin-tazobactam, aztreonam, cefepime, ceftazidime, tobramycin, ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, cefiderocol, ceftaroline, tigecycline, eravacycline, amikacin, linezolid or vancomycin) are de-escalated

  10. re-escalation to broad-spectrum antibiotics after de-escalation (yes/no) [ Time Frame: by 21 days from admission ]
    Proportion of patients whose antibiotics were de-escalated and that were subsequently re-escalated to broad-spectrum antibiotics (imipenem, meropenem, piperacillin-tazobactam, aztreonam, cefepime, ceftazidime, tobramycin, ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, cefiderocol, ceftaroline, tigecycline, eravacycline, amikacin, linezolid or vancomycin).

  11. total duration of any antibacterial antibiotic [ Time Frame: up to 21 days ]
    Total duration of any antibacterial antibiotic treatment up to 21 days, including re-initiation of antibiotics

  12. 14-day mortality [ Time Frame: up to 14 days ]
    proportion of patients who die by 14 days

  13. 30-day mortality [ Time Frame: up to 30 days ]
    proportion of patients who die by 30 days

  14. ICU transfer after admission (> 24 hours after admission) [ Time Frame: up to 21 days ]
    proportion of patients transferred to the ICU >24 hours after admission up to 21 days

  15. healthcare-associated C.difficile Infection (CDI) (yes/no) [ Time Frame: after 72 hours of admission until discharge ]
    CDI after 72 hours of admission. Proportion of patients with CDI after 72 hours of admission (healthcare-associated CDI) until discharge

  16. acute kidney injury after 48 hours (yes/no) after 48 hours [ Time Frame: up to 21 days ]
    Proportion of patients with AKI after 48 hours of admission, up to 21 days

  17. total inpatient cost (from hospital's cost accounting system) [ Time Frame: from admission to discharge or 21 days, whichever comes first ]
    total inpatient cost (from hospital's cost accounting system) - from admission to discharge or 21 days, whichever comes first

  18. hospital length-of-stay (days, hours) [ Time Frame: days from the time of admission to the time of discharge ]
    length of stay will be calculated in days from the time of admission to the time of discharge

  19. empyema (yes/no) [ Time Frame: from 48 hours to 21 days ]
    empyema (pus in the pleural space)

  20. 30-day readmission (yes/no) [ Time Frame: up to 30 days after discharge ]
    30-day hospital readmission

  21. Infection with a resistant organism in the future (yes/no) [ Time Frame: up to 6 months after discharge ]
    up to 6 months after discharge. Resistance to CAP therapy will be defined as resistance to either a respiratory quinolone or to both a beta-lactam/3rd generation cephalosporin and a macrolide. Multi-drug resistance will be defined as any CAP bacterial isolate that tests either intermediate (I) or resistant (R) to at least one agent in three or more antimicrobial classes



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for patient's records:

  1. Men or women greater than or equal to 18 years of age
  2. Admitted to a participating (i.e. enrolled and randomized) hospital
  3. Admitting diagnosis of pneumonia

Exclusion Criteria:

  1. Admission to intensive care unit within 24 hours of hospital admission
  2. Comfort care measures only
  3. Cystic fibrosis
  4. Discharged from an acute care hospital in the past week
  5. Patients not eligible for empiric therapy due to a known pathogen (any positive blood or respiratory cultures in the 72 hours prior to admission)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05568654


Contacts
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Contact: Michael Rothberg, M.D. 216-445-0719 ROTHBEM@ccf.org
Contact: Abhishek Deshpande, M.D., PhD 216-445-6207 DESHPAA2@ccf.org

Locations
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United States, Ohio
Avon Hospital Recruiting
Avon, Ohio, United States, 44011
Contact: Rosa Solis, MD         
Fairview Hospital Recruiting
Fairview Park, Ohio, United States, 44111
Contact: Ali Acker Gantz, CNP         
Marymount Hospital Recruiting
Garfield Heights, Ohio, United States, 44125
Contact: Debasis Sahoo, MD         
Medina Hospital Recruiting
Medina, Ohio, United States, 44256
Contact: Shameer Khubber, MD         
Sponsors and Collaborators
The Cleveland Clinic
Investigators
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Principal Investigator: Michael Rothberg, M.D. The Cleveland Clinic
Publications:

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Responsible Party: Michael Rothberg, Staff Physician, The Cleveland Clinic
ClinicalTrials.gov Identifier: NCT05568654    
Other Study ID Numbers: 21-863
First Posted: October 6, 2022    Key Record Dates
Last Update Posted: November 15, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Pneumonia
Respiratory Tract Infections
Infections
Lung Diseases
Respiratory Tract Diseases