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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05568654
Other study ID # 21-863
Secondary ID
Status Recruiting
Phase N/A
First received
Last updated
Start date November 1, 2022
Est. completion date June 30, 2026

Study information

Verified date March 2023
Source The Cleveland Clinic
Contact Michael Rothberg, M.D.
Phone 216-445-0719
Email ROTHBEM@ccf.org
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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


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.


Recruitment information / eligibility

Status Recruiting
Enrollment 12500
Est. completion date June 30, 2026
Est. primary completion date January 31, 2026
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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)

Study Design


Intervention

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.

Locations

Country Name City State
United States Akron General Hospital Akron Ohio
United States Avon Hospital Avon Ohio
United States Cleveland Clinic Main Campus Cleveland Ohio
United States Lutheran Hospital Cleveland Ohio
United States Euclid Hospital Euclid Ohio
United States Fairview Hospital Fairview Park Ohio
United States Marymount Hospital Garfield Heights Ohio
United States Hillcrest Hospital Mayfield Heights Ohio
United States Medina Hospital Medina Ohio
United States Indian River Hospital Vero Beach Florida
United States South Pointe Hospital Warrensville Heights Ohio
United States Weston Hospital/Cleveland Clinic Florida Weston Florida

Sponsors (1)

Lead Sponsor Collaborator
The Cleveland Clinic

Country where clinical trial is conducted

United States, 

References & Publications (11)

Allgaier J, Lagu T, Haessler S, Imrey PB, Deshpande A, Guo N, Rothberg MB. Risk Factors, Management, and Outcomes of Legionella Pneumonia in a Large, Nationally Representative Sample. Chest. 2021 May;159(5):1782-1792. doi: 10.1016/j.chest.2020.12.013. Epub 2020 Dec 19. — View Citation

Belforti RK, Lagu T, Haessler S, Lindenauer PK, Pekow PS, Priya A, Zilberberg MD, Skiest D, Higgins TL, Stefan MS, Rothberg MB. Association Between Initial Route of Fluoroquinolone Administration and Outcomes in Patients Hospitalized for Community-acquired Pneumonia. Clin Infect Dis. 2016 Jul 1;63(1):1-9. doi: 10.1093/cid/ciw209. Epub 2016 Apr 5. — View Citation

Deshpande A, Richter SS, Haessler S, Lindenauer PK, Yu PC, Zilberberg MD, Imrey PB, Higgins T, Rothberg MB. De-escalation of Empiric Antibiotics Following Negative Cultures in Hospitalized Patients With Pneumonia: Rates and Outcomes. Clin Infect Dis. 2021 Apr 26;72(8):1314-1322. doi: 10.1093/cid/ciaa212. — View Citation

Haessler S, Lindenauer PK, Zilberberg MD, Imrey PB, Yu PC, Higgins T, Deshpande A, Rothberg MB. Blood Cultures Versus Respiratory Cultures: 2 Different Views of Pneumonia. Clin Infect Dis. 2020 Oct 23;71(7):1604-1612. doi: 10.1093/cid/ciz1049. — View Citation

Higgins TL, Deshpande A, Zilberberg MD, Lindenauer PK, Imrey PB, Yu PC, Haessler SD, Richter SS, Rothberg MB. Assessment of the Accuracy of Using ICD-9 Diagnosis Codes to Identify Pneumonia Etiology in Patients Hospitalized With Pneumonia. JAMA Netw Open. 2020 Jul 1;3(7):e207750. doi: 10.1001/jamanetworkopen.2020.7750. — View Citation

Jain S, Self WH, Wunderink RG, Fakhran S, Balk R, Bramley AM, Reed C, Grijalva CG, Anderson EJ, Courtney DM, Chappell JD, Qi C, Hart EM, Carroll F, Trabue C, Donnelly HK, Williams DJ, Zhu Y, Arnold SR, Ampofo K, Waterer GW, Levine M, Lindstrom S, Winchell JM, Katz JM, Erdman D, Schneider E, Hicks LA, McCullers JA, Pavia AT, Edwards KM, Finelli L; CDC EPIC Study Team. Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults. N Engl J Med. 2015 Jul 30;373(5):415-27. doi: 10.1056/NEJMoa1500245. Epub 2015 Jul 14. — View Citation

Klompas M, Imrey PB, Yu PC, Rhee C, Deshpande A, Haessler S, Zilberberg MD, Rothberg MB. Respiratory viral testing and antibacterial treatment in patients hospitalized with community-acquired pneumonia. Infect Control Hosp Epidemiol. 2021 Jul;42(7):817-825. doi: 10.1017/ice.2020.1312. Epub 2020 Dec 1. — View Citation

Madaras-Kelly K, Jones M, Remington R, Caplinger CM, Huttner B, Jones B, Samore M. Antimicrobial de-escalation of treatment for healthcare-associated pneumonia within the Veterans Healthcare Administration. J Antimicrob Chemother. 2016 Feb;71(2):539-46. doi: 10.1093/jac/dkv338. Epub 2015 Nov 3. — View Citation

Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, Cooley LA, Dean NC, Fine MJ, Flanders SA, Griffin MR, Metersky ML, Musher DM, Restrepo MI, Whitney CG. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-e67. doi: 10.1164/rccm.201908-1581ST. — View Citation

Musher DM, Thorner AR. Community-acquired pneumonia. N Engl J Med. 2014 Oct 23;371(17):1619-28. doi: 10.1056/NEJMra1312885. No abstract available. — View Citation

Schimmel JJ, Haessler S, Imrey P, Lindenauer PK, Richter SS, Yu PC, Rothberg MB. Pneumococcal Urinary Antigen Testing in United States Hospitals: A Missed Opportunity for Antimicrobial Stewardship. Clin Infect Dis. 2020 Sep 12;71(6):1427-1434. doi: 10.1093/cid/ciz983. — View Citation

* Note: There are 11 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Number of days of broad-spectrum antibiotic therapy 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 first 21 days of admission
Secondary viral testing ordered (yes/no) 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) Up to 48 hours
Secondary detection of influenza virus (yes/no) Proportion of patients who test positive for influenza Up to 48 hours
Secondary detection of RSV (yes/no) Proportion of patients who test positive for RSV up to 48 hours
Secondary detection of viruses/atypical bacteria in the respiratory panel (yes/no) Proportion of patients who test positive for each of the viruses/atypical bacteria in the respiratory panel up to 48 hours
Secondary treatment with anti-viral medications treatment with anti-viral medications (oseltamivir, zanamivir, peramivir, baloxavir, ribavirin, remdesivir, nirmatrelvir, COVID-19 medications) up to 48 hours
Secondary treatment with antiviral medications treatment with antiviral medications (oseltamivir, zanamivir, peramivir, baloxavir, ribavirin, remdesivir, nirmatrelvir, COVID-19 medications) within 21 days
Secondary S. pneumoniae urinary antigen test (UAT) performed Proportion of patients in whom UAT is performed up to 48 hours
Secondary positive pneumococcal UAT Proportion of patients with positive pneumococcal UAT up to 48 hours
Secondary de-escalation by 72 hours from admission (yes/no) 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 within 72 hours from admission.
Secondary re-escalation to broad-spectrum antibiotics after de-escalation (yes/no) 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). by 21 days from admission
Secondary total duration of any antibacterial antibiotic Total duration of any antibacterial antibiotic treatment up to 21 days, including re-initiation of antibiotics up to 21 days
Secondary 14-day mortality proportion of patients who die by 14 days up to 14 days
Secondary 30-day mortality proportion of patients who die by 30 days up to 30 days
Secondary ICU transfer after admission (> 24 hours after admission) proportion of patients transferred to the ICU >24 hours after admission up to 21 days up to 21 days
Secondary healthcare-associated C.difficile Infection (CDI) (yes/no) CDI after 72 hours of admission. Proportion of patients with CDI after 72 hours of admission (healthcare-associated CDI) until discharge after 72 hours of admission until discharge
Secondary acute kidney injury after 48 hours (yes/no) after 48 hours Proportion of patients with AKI after 48 hours of admission, up to 21 days up to 21 days
Secondary total inpatient cost (from hospital's cost accounting system) total inpatient cost (from hospital's cost accounting system) - from admission to discharge or 21 days, whichever comes first from admission to discharge or 21 days, whichever comes first
Secondary hospital length-of-stay (days, hours) length of stay will be calculated in days from the time of admission to the time of discharge days from the time of admission to the time of discharge
Secondary empyema (yes/no) empyema (pus in the pleural space) from 48 hours to 21 days
Secondary 30-day readmission (yes/no) 30-day hospital readmission up to 30 days after discharge
Secondary Infection with a resistant organism in the future (yes/no) 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 up to 6 months after discharge
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