Quality control of antibiotic stewardship

ISRCTN	ISRCTN48029287
DOI	https://doi.org/10.1186/ISRCTN48029287
Secondary identifying numbers	V2

Submission date: 09/02/2022
Registration date: 16/06/2022
Last edited: 04/12/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Respiratory

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Pneumonia is a leading cause of illness and death worldwide. It can be categorized into two main groups as community-acquired (CAP) or hospital-acquired (HAP), with HAP being defined as pneumonia occurring 48 hours or more after hospitalisation. Clinical presentation cannot distinguish between the wide variety of causes. One of the most important prognostic factors in pneumonia is early and adequate antibiotic treatment. Therefore, initial empirical antibiotic treatment is chosen to cover the suspected range of bacteria. Identification of the causative agent is pivotal to adjusting the empirical antibiotic treatment to targeted treatment, a primary goal of antimicrobial stewardship. Antimicrobial stewardship targets the best clinical outcomes while keeping unnecessary or inappropriate antibiotic use to a minimum in order to decrease side effects, reduce the emergence of resistance and for cost-effectiveness purposes. Optimal antibiotic treatment includes escalation or de-escalation according to microbiological results, discontinuation and taking allergies into account, whereas inappropriate therapy is empirical therapy in discordance with susceptibility testing, without clinical response or with a too broad a spectrum for the identified pathogen. The aim of this study is to evaluate whether a rapid multiplex polymerase chain reaction (PCR) testing of the bronchoalveolar lavage (BAL) can decrease the time on inappropriate antimicrobial treatment in patients with a lower respiratory tract infection compared to conventional microbiological tests alone. BAL is a procedure in which a bronchoscope is passed through the mouth or nose into the lungs and fluid is squirted into a small part of the lung and then recollected for analysis.

Who can participate?
Patients aged 18 years in hospital undergoing bronchoscopy for respiratory tract infection

What does the study involve?
Participants will be randomly allocated to BAL culture or BAL culture and PCR. Antibiotic treatment will be assessed based on microbiology/PCR results. The follow-up period encompasses the whole duration of hospitalization up to a maximum of 30 days.

What are the possible benefits and risks of participating?
Routine microbiologic testing methods to identify the causative agent are culture-based and results take 48 to 72 hours. In addition to the time delay, they are not suitable to detect atypical pathogens. The yield of sputum cultures is variable, generally low and influenced by several factors such as specimen collection, transport, time of processing, and previous antibiotic treatment with the highest yield in patients before the start of antibiotic treatment. BAL has a higher yield than sputum culture, and is of additional value in identifying the causative agent, especially in patients without sputum production and those non-responsive to empirical treatment. However, in patients already receiving antibiotic treatment the diagnostic yield in BAL is also reduced. With multiplex PCR methods, the rate of pathogen detection can be improved significantly, especially in antibiotic exposed patients, with the potential to enable targeted treatment.

Where is the study run from?
1. University Hospital Basel (Switzerland)
2. Universitätsklinikum Freiburg (Germany)

When is the study starting and how long is it expected to run for?
January 2021 to January 2024

Who is funding the study?
University Hospital Basel (Switzerland)

Who is the main contact?
Prof. Daiana Stolz
Daiana.Stolz@usb.ch

Contact information

Prof Daiana Stolz
Principal Investigator

Petersgraben 4
Basel
4031
Switzerland

ORCID ID	0000-0003-0099-882X
Phone	+41 (0)612655184
Email	daiana.stolz@usb.ch

Ms Vivian Suarez Domenech
Scientific

University Hospital Basel
Clinic of Respiratory Medicine and Pulmonary Cell Research
Petersgraben 4
Basel
4031
Switzerland

Phone	+41 61 328 69 17
Email	vivian.suarezdomenech@usb.ch

Study information

Study design	Randomized controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a participant information sheet
Scientific title	Quality control of antibiotic stewardship
Study acronym	Flagship IV
Study objectives	The purpose of this quality control project is to evaluate whether a rapid multiplex PCR of the bronchoalveolar lavage (BAL) can decrease time on inappropriate antimicrobial therapy in patients with lower respiratory tract infection (LRTI) compared to conventional microbiological investigations alone as used in the clinical routine of a tertiary care institution.
Ethics approval(s)	Approved 15/04/2021, Ethikkommission Nordwest- und Zentralschweiz (EKNZ, Hebelstrasse 53, 4056 Basel, Switzerland; +41 (0)612681350; eknz@bs.ch), ref: 2021-00451
Health condition(s) or problem(s) studied	Lower respiratory tract infection (LRTI)
Intervention	The BIOFIRE® FILMARRAY® Pneumonia plus Panel tests for 18 bacteria (11 Gram-negative, 4 Gram-positive and 3 atypical), 7 antibiotic resistance markers, and 9 viruses that cause pneumonia and other lower respiratory tract infections. It offers an overall sensitivity and specificity for BAL-like samples of 96,2% and 98.3%, respectively. The Biofire Pneumonia Panel is run on the BIOFIRE® FILMARRAY® System, a US FDA, CE-IVD, and TGA certified multiplex PCR system. The system integrates sample preparation, nucleic acid extraction and purification, amplification, detection and analysis into one simple system that requires just 2 minutes of hands-on time, with a total run time of about 75 to 90 minutes. The new panel complements the existing BIOFIRE® FILMARRAY® Respiratory Panel 2+ to provide a comprehensive diagnostic tool for pneumonia and other lower respiratory tract infections. Rapid and accurate identification of the causative agent of both community and health-care associated respiratory tract infections can help improve patient management through timely and effective antimicrobial therapy. A rapid diagnosis can assist with directing appropriate infection control practices thereby aiding in the prevention of the secondary spread of infection, shortening hospital stays, reducing ancillary testing, and reducing overall health care costs. The disposable cartridge is compatible with standard waste disposal procedures of hospitals and laboratories. Hospitalized patients undergoing bronchoscopy for respiratory tract infection will be randomized to BAL culture or BAL culture and PCR. Antibiotic therapy will be assessed based on microbiology/PCR results. The follow-up period encompasses the whole duration of hospitalization up to a maximum of 30 days.
Intervention type	Other
Primary outcome measure	Time on inappropriate therapy in hours, recorded daily up to a total of 30 days, defined as anti-microbial therapy: 1. With no identifiable pathogen or 2. Not active according to in-vitro susceptibility testing of the identified pathogen or 3. With known intrinsic resistance of the identified pathogen to the given therapy or 4. Having a spectrum too broad for the identified pathogen (antimicrobial therapy considered broad when switching to a different antimicrobial therapy with a narrower spectrum continues to show a favourable clinical course) and in the case where there is a lack of evidence suggesting resistance of the microorganism to a narrower antimicrobial therapy or 5. Continuation of the antimicrobial therapy beyond the guideline-suggested duration e.g. for pneumonia 5 to 7 days
Secondary outcome measures	Clinical outcomes measured using patients’ medical records daily up to a total of 30 days: 1. Time to clinical stability (in hours) 2. Length of hospital stay (in hours) 3. Mortality 4. Adverse events
Overall study start date	26/01/2021
Completion date	31/01/2024

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	740
Key inclusion criteria	1. Age ≥18 years 2. Clinical indication for diagnostic bronchoscopy with bronchoalveolar lavage 3. Suspicion of lower respiratory tract infection – in immunocompetent patients infiltrate must be confirmed; in immunocompromised patients an infiltrate is not required 4. Evidence of systemic inflammation (such as abnormal white blood cell count – either leukocytosis (>10.0x10e9/l) or leukopenia (<4.0x10e9/l) – or C-reactive protein (CRP) or procalcitonin (PCT) values above the local upper limit
Key exclusion criteria	1. Ambulatory patients 2. Patients intubated at the time of inclusion 3. Neutropenic patients as defined by neutrophils <0.5x10e9/l 4. Haemodynamic instability or signs of life-threatening infection precluding a narrowing of antimicrobial therapy 5. Prior enrolment in an intervention study within the last 30 days 6. Women who are pregnant or breastfeeding
Date of first enrolment	01/02/2022
Date of final enrolment	31/12/2023

Locations

Countries of recruitment

Germany
Switzerland

Study participating centres

University Hospital Basel

Clinic of Pneumology and Respiratory Cell Research
Petersgraben 4
Basel
4031
Switzerland

Universitätsklinikum Freiburg, Klinik für Pneumologie

Kilianstrasse 5
Freiburg im Breisgau
79106
Germany

Sponsor information

University Hospital of Basel
Hospital/treatment centre

Clinic of Pneumology and Respiratory Cell Research
Petersgraben 4
Basel
4031
Switzerland

Phone	+41 (0)612655184
Email	daiana.stolz@usb.ch
Website	https://www.unispital-basel.ch/
"ROR"	https://ror.org/04k51q396

Funders

Funder type

Hospital/treatment centre

Universitätsspital Basel
Government organisation / Other non-profit organizations

Alternative name(s): University Hospital Basel, University Hospital of Basel, The University Hospital Basel, Hôpital Universitaire de Bâle, L’Hôpital universitaire de Bâle, Das Universitätsspital Basel, UHB
Location: Switzerland

Results and Publications

Intention to publish date	31/01/2025
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not expected to be made available
Publication and dissemination plan	Planned publication in high-impact peer-reviewed journal
IPD sharing plan	Due to technical incompatibilities the researchers don’t expect the dataset to be made available. Data will be stored at the University Hospital Basel.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol file	version 3.0	16/09/2022	17/03/2023	No	No

Additional files

ISRCTN48029287_Protocol_v3.0_16September2022.pdf

Editorial Notes

04/12/2024: Contact details updated.
17/03/2023: The following changes have been made:
1. Uploaded protocol (not peer reviewed).
2. The participant information sheet was updated from blank to "Not available in web format, please use the contact details to request a participant information sheet".
18/05/2022: Trial's existence confirmed by the Ethikkommission Nordwest- und Zentralschweiz (EKNZ).