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

Community-Acquired Pneumonia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05568654
• Other study ID #: 21-863
• Status: Recruiting
• Phase: N/A
• 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
• 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)

Related Conditions & MeSH terms

• Antimicrobial Stewardship
• Community-Acquired Pneumonia
• Pneumonia
• Point-of-Care Testing

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 all — Click 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