Clinical trial NCT04848883: Infectious Diseases Experts as Part of the Antibiotic Stewardship Team in Primary Care
Official title: Infectious Diseases Experts as Part of the Antibiotic Stewardship Team in Primary Care: Protocol for a Cluster-randomised Blinded Study (IDASP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Infectious Disease
Keywords: Antimicrobial stewardship program
Primary care
Infectious disease specialist
Bacterial resistance
Lead sponsor: Institut d'Investigació Biomèdica de Bellvitge
Sponsor class: OTHER
First posted: 2021-04-19
Enrollment: 2600
Sex: ALL
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Six primary care centres will be randomised by conglomerates in 3 parallel groups. First group with three randomised centres will receive a conventional AMS, meanwhile the three other parallel randomised centres will include an infectious diseases specialist in the AMS group and a biweekly meetings.

List of study sites: El Castells from Castelldefels, Prat de Llobregat 2, Gava 1, Viladecans 2, Hospitalet de Llobregat 2 Sant Josep and Santa Eulàlia Nord.
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: A cluster-randomised multicentre blinded clinical trial will be performed in six primary care centres located in the southern metropolitan area of Barcelona (Spain). The objective is to assess whether including experts on infectious diseases (ID) within the antimicrobial stewardship (AMS) team of primary care achieves higher reductions on overall antibiotic consumption and increases the quality of prescription in diagnosed upper respiratory and urinary tract infections.

Centres will be randomly assigned to receive a standard-AMS or an advanced-AMS (intervention). Advanced-AMS includes all standard-AMS strategies plus general practitioner chance to discuss clinical cases by telephone to ID expert on working days (8:00 am to 8:00 pm), and by biweekly meetings.

Detailed description: STUDY DESIGN. A cluster-randomised, multicentre blinded clinical trial will be conducted in six primary care centres between June 2021 and June 2023.

This cluster-randomised trial uses primary care centres as a unit of analysis to avoid intracentre contamination.

SCOPE OF STUDY. Six primary care centres in the southern metropolitan area of Barcelona.

SUBJECTS OF STUDY. General practitioners of the participating centres. Paediatricians are excluded. Patients older than 14 years who have a diagnosis of upper respiratory tract or urinary tract infections will be prospectively follow up to assess information related to secondary outcomes. Each patient could be included more than once if the GP visit is 30 days or more apart from the initial medical assessment.

Eligible patients will be identified following the International Classification of Diseases (ICD-10) CM codes as follows:

Upper respiratory tract infection: J00, J01, J02, J03, J04, J05, J06, J31, J39, H60, H62, H65, H66, H67, H83 and H92.

Urinary tract infection: N10, N30, N39, N41, R82 and O23.

TIMELINE. From June to September 2021 standard-AMS will be promoted to increase understanding and acceptance of AMS by general practitioners. Baseline data collection will begin on October 2021 and will last six months. After these six months, on 1 April 2022, centres will be randomly assigned to receive an advanced-AMS, or to continue the standard-AMS. The intervention will be spanned 12 months, until 31 March 2023.

RANDOMISATION. A centralised electronic computer system will generate a random list based on permuted blocks. To ensure similar characteristics among centres permuted blocks will be created with stratification on the total number of referral population and the number of population older than 65 years old by centre. Investigators will be unaware of the block size and the permutation procedure.

STUDY GROUPS. The 6 centres will be assigned to receive an advanced AMS or a standard AMS, 3 in one and 3 in another. The standard AMS will receive an standard antibiotic optimization program based on:

1. Educational campaign addressed both, to patients and health professionals, to increase awareness about antibiotic indications and potential harms of its misuse.
2. Updated local antibiotic empirical guidelines for treating common infections according to local resistance patterns.
3. Promotion of delayed antibiotic prescription.
4. Promotion of Streptococcal pyogenes antigen test (Streptotest) if bacterial tonsillitis is suspected.
5. Daily microbiological report of resistant bacteria isolates to general practitioners.
6. Annual reports to prescribers of main AMS outcomes at centre-level.

The advanced AMS group will have the same standard AMS program, enhanced with:

* Telephone access to ID expert on working days (8:00 am to 8:00 pm).
* Biweekly meetings among GP and infectious diseases experts to discuss clinical cases.

More detailed data are placed forward in the document.

BLINDING. Two secondary end-points (unnecessary antibiotic therapy and adequacy of therapy), will be evaluated by two independent investigators who will be blinded to centre allocation. Discrepant decisions among them will be discussed with a third blinded physician to achieve consensus. The degree of agreement will be recorded with the kappa statistic analysis. The centre allocation will not be blinded for the participating centres and general practitioners.

OUTCOMES. Outcomes will be measured in each primary centre with a mensual periodicity during 12 consecutive months. These variables are:

* Main objective. To assess the impact of advanced-AMS on overall antibiotic consumption measured by defined daily dose of antibiotic per 1.000 inhabitants per day (DHD).
* Secondary objectives:

  * To assess the impact of the advanced-AMS on unnecessary antibiotic prescriptions in diagnosed upper respiratory and urinary tract infections.
  * To evaluate the impact of the advanced-AMS on the adequacy of antibiotic prescriptions.
  * To evaluate the impact of the advanced-AMS on the total number of re-attendance to general practitioners or emergency department for any reason within 30 days after the initial GP evaluation.
  * To evaluate the impact of the advanced-AMS on the number of hospital admissions for any reason within 30 days after the initial GP visit.

DEFINITIONS.

* DHD are calculated by the following the World Health Organisation criteria (https://www.who.int/tools/atc-ddd-toolkit/indicators).
* Unnecessary prescription will be considered as follows:

  * An antibiotic prescribed in upper respiratory infections, which is in disagreement with the local antibiotic guidelines.
  * An antibiotic is prescribed in asymptomatic bacteriuria, which is defined as having a positive urine culture with ≥ 10EXP5 CFU/ml of an uropathogen in patients without signs or symptoms of urinary tract infection (dysuria, urinary frequency or urgency, suprapubic pain, fevers, or flank pain). Pregnant women and patients undergoing urologic interventions are excluded from this definition.
* Adequacy of antibiotic therapy will be considered when prescription fulfils the local guidelines: type of antibiotic + dose, and length of therapy.

DATA COLLECTION AND MONITORING. Monthly DHD will be calculated based on the dispensing data of our electronic prescribing system of the Catalan Institute of Health.

To get information regarding secondary outcomes, patients who fulfil ICD-10 CM codes on the last working day of every month will be selected by a cross-sectional analysis. On these selected patients, information from electronic medical records (SAP logon® and eCAP) will be obtained. Investigator will obtain the following variables: demographics, Charlson score, type of infection, antibiotic prescribed, doses and length of antibiotic therapy, re-attendance to the general practitioner, attendance to the emergency department, and hospital admission. All the included patients will be followed up 30 days after the initial primary care physician visit. To ensure completeness of data, a telephone call will be allowed if any crucial data is missing in the electronic medical record.

Information regarding the burden of the intervention such as the number of telephone calls received by the ID expert per month and the number of participants to biweekly meetings with the ID will be also collected.

All data will be recorded by the study monitor on a standardized data abstraction form by using RedCap (Research Electronic Data Capture) hosted at IDIBELL, a secure web application for building and managing online databases.

SAMPLE SIZE. The intervention area has a total of 18 primary care centres and a reference population of 402 657 inhabitants. Six centres will be included, three in each study arm, implying an approximate coverage of 37% of the referral population (147 644 inhabitants). The consumption of antibiotics in 2017 was 8.94 DHD, and it's expected to reduce this consumption by 10% in the intervention group. The number of 3 clusters per arm will allow rejecting the null hypothesis of equal consumption with a power of 80%, assuming a moderate intra-cluster correlation of 0.2, an intra-cluster variance of 4, and a mean difference of 1 DHD. Type I error is set at 5%.

STATISTICAL ANALYSIS. A descriptive analysis will be performed on the monthly consumption of antibiotics expressed in DHD by the study group (control and intervention), period, and cluster. The monthly consumption of antibiotics evolution will be represented on a graph by months, and a smoothed curve will be estimated using locally weighted smoothing (LOESS).

Antibiotic consumptions will be compared according to the study group using a time series model. Where the dependent variable will be the monthly consumption of antibiotics expressed in DHDs and the independent variable will be the study group. In the estimation of the model, the seasonality, the trend, and the first and second-order lags of the series will be analyzed. Also, the use of hierarchical models due to cluster design will be taken into account.

A descriptive analysis of the demographic and clinical profile of the patients surveyed will be performed. A McNemar test will be used to compare, between the study groups, the percentage of patients with an unnecessary prescription for the upper respiratory and urinary tract, the percentage of patients with an adequate prescription according to the guidelines, the percentage of patients who revisit general practitioner or emergency room at 30 days, and the percentage of patients with hospital admission at 30 days. Also, log-binomial regression models will be performed, to estimate the effect of the intervention in terms of risk on the above-mentioned outcomes adjusting by patients' clinical profile. To estimate models it will be accounted that patients are nested in primary care clusters, so a correction of the standard errors is carried out through the variance-covariance matrix.

Data management and statistical analysis will be carried out with the statistical package R version 4.0.1 or higher.

LIMITATIONS. The study does not contemplate randomisation by prescribing physician, but by conglomerates to avoid possible contamination effects at the prescribing physician and patients in the same centre. As it is a cluster analysis, there could be differences in the degree of prescription of doctors within the same centre and between the different centres. In order to reduce this problem, the variability of prescribing intra-cluster and between clusters has been calculated during the period 2017 in a group of primary care centres in the intervention area, differences that have been taken into account for the calculation of the sample. Design of the present study does not include a third group without any AMS intervention due to department policies during 2019. However, to achieve the best result interpretation, an historic of the antibiotic consumption in the participating centres will act as a control group, and a baseline period with only an standard-AMS intervention will be performed.

Comparisons between all stages of the clinical trial will be performed to obtain more robust data.

ETHICAL ASPECTS. This research will be carried out under the standards of good clinical practices following the principles of the Declaration of Helsinki (Fortaleza, 2013), as well as the current legislation applicable to this type of study. This study has been approved by the Ethics Committee of Hospital Universitari de Bellvitge and the Foundation University Institute for Primary Health Care Research Jordi Gol i Gurina (IDIAPJGol) who waived the need to obtain informed consent since the intervention is mainly aimed at health-care professionals (general practitioners) who will be previously informed of the objective and other relevant aspects of the study (REF. PR277/19 - REF. 4R20/26).

Clinical data treatment of the included patients in the research project as well as that of associated professionals (primary care physicians) will be carried out following the established by the Organic Law 3/2018, of December 5, and by Regulation (EU) 2016/679 of the European Parliament and of the Council of April 27, 2016 on Data Protection (RGPD). Based on these regulations, the sponsor will guarantee the protection of the confidentiality of the participants in the program, both patients and doctors.

The data collection sheets will be identified with a code. The name of the doctor or patient will not appear in any document, or any publication or communication of the study results.

Eligibility criteria: All general practitioners of the 6 primary care centers will be included in our clinical trial, excepting paediatricians. Data collection will be performed on patients attended in these centres. Inclusion and exclusion criteria will be applied on the patients attended by general practitioners:

Inclusion criteria:

* Patients older than 14 years old diagnosed with respiratory infections: pharyngoamygdalitis, sinusitis and otitis.
* Patients older than 14 years old diagnosed with urinary tract infections: cystitis, prostatitis and pyelonephritis.

Exclusion criteria:

* Patients less than 14 years old.
* Patients with indwelling urinary catheter.
* Patients with congenital urinary tract abnormalities.

Primary outcomes:
measure: To asses the impact of implementing an advanced-AMS program (inclusion of infectious diseases specialists) on the overall antibiotic consumption.
timeFrame: Through study completion, an average of 1 year and a half
Secondary outcomes:
measure: Number of patients with unnecessary antibiotic prescriptions on high respiratory pathway infections.
timeFrame: Through study completion, an average of 1 year and a half
measure: Number of patients with unnecessary antibiotic prescriptions on urinary tract infections.
timeFrame: Through study completion, an average of 1 year and a half
measure: Number of patients with an adequate antibiotic treatment
timeFrame: Through study completion, an average of 1 year and a half
measure: Number of patients re-consulting after completing antibiotic therapy.
timeFrame: Through study completion, an average of 1 year and a half
measure: Number of cases who needs hospitalisation 30 days after antibiotic therapy.
timeFrame: Through study completion, an average of 1 year and a half
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Hospital Univeristari de Bellvitge
state: Cataluña
Study officials:
affiliation: Institut d'Investigació Biomèdica de Bellvitge
name: Ariadna Padullés, Pharmacyst
role: STUDY_DIRECTOR
affiliation: Institut d'Investigació Biomèdica de Bellvitge
name: Evelyn Shaw, Doctor
role: PRINCIPAL_INVESTIGATOR
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