This study aims to determine how CRP levels and Patient Information Leaflets (PILs) affect antibiotic prescribing in adults with acute respiratory symptoms in Kyrgyz primary care. It will evaluate the effectiveness of PILs in reducing antibiotic use and ensuring safety and assess the effectiveness and safety of three CRP thresholds (20, 40, 60 mg/L) for adults with acute respiratory tract infections. Conducted as a multicentre, open label, individually randomized controlled clinical trial with 21 days of blinded follow-up, the study will compare PIL to no PIL in a 1:1 ratio and assess antibiotic use and safety across the three CRP cut-offs in a 1:1:1 ratio, resulting in six groups. The trial will take place in 14 district primary healthcare centres in rural Kyrgyzstan and one urban primary healthcare centre in Bishkek.

BACKGROUND Antimicrobial resistance (AMR) poses a significant global health threat, particularly in Kyrgyzstan, where overuse and misuse of antibiotics have fueled the crisis. The easy over-the-counter availability of antibiotics has led to widespread misuse, escalating resistance among common pathogens. This undermines effective treatment for infections, increasing healthcare costs and mortality rates. Although Kyrgyzstan is part of the Central Asian and European Surveillance of Antimicrobial Resistance (CAESAR) network, it faces challenges such as inadequate data reporting, limited resources, and insufficient training in rational antibiotic use. Efforts are underway, including a national action plan and a CIS-wide joint initiative to address AMR, focusing on public education, vaccination, and healthcare training. Improved diagnostic tools like C-reactive protein (CRP) testing have shown promise in reducing unnecessary antibiotic prescriptions by distinguishing between bacterial and viral infections.

The COORDINATE trial in Kyrgyzstan demonstrated that CRP point-of-care testing (POCT) effectively reduces antibiotic use for respiratory tract infections (RTIs) without compromising patient safety. The study's findings prompted the Ministry of Health to plan nationwide implementation of CRP POCT in primary healthcare. However, further research is needed to establish appropriate CRP thresholds for adults. Complementary strategies such as antibiotic-free patient information leaflets (PILs) can educate the public on appropriate antibiotic use, promoting alternative symptom management and reducing patient demand for unnecessary prescriptions. Together, these measures can improve antibiotic stewardship, mitigate AMR, and enhance public health outcomes.

The research team will address these challenges in the 2CARE study:

1. an adequate understanding of the AMR context may work together with the use of CRP POCT to additionally lower antibiotic use. Hence, this understanding needs to be instilled in the patient. To aid in this, the use of written materials (PILs) in the consultation is evaluated in the present study.
2. What CRP-threshold to choose: a low threshold may not lower antibiotic use much, while a high threshold could significantly reduce antibiotic use, but possibly at the expense of a higher rate of adverse events (hospitalisations, longer recovery times) due to the risk of undertreatment of bacterial pneumonia. In order to identify relevant thresholds, guidelines are reviewed to assess which CRP values are applied in adult patients who present with acute respiratory infection.

AIM The study aims to determine how CRP levels and PILs affects antibiotic prescribing in adults presenting with acute respiratory symptoms in Kyrgyz primary care.

OBJECTIVES

1. To evaluate the effectiveness of PILs to reduce the participants' tendency to take antibiotics and the safety of PILs with respect to not increase hospitalisations.
2. To evaluate the effectiveness and safety of selected CRP thresholds (low, middle, high) for adults with acute respiratory tract infection.

STUDY SETTING The study will integrate healthcare centres (HCs) from the COORDINATE trial and newly selected sites, chosen based on logistical convenience, transport infrastructure, and patient flow. Primary healthcare workers (HCWs), including family doctors, nurses, and feldshers in rural clinics with limited equipment, will participate. HCWs from new sites will receive training in CRP testing, interpretation, and providing patient information leaflets (PILs), while those from COORDINATE sites will refresh their skills. Training will use the Aidian QuickRead Go device and cover CRP threshold values. Site-specific characteristics will be addressed in covariate analysis and subgroup analysis to understand their impact on healthcare delivery and outcomes.

PARTICIPANTS Adult patients aged 18 to 70 years with acute respiratory tract infections (ARTIs) and symptoms such as cough, shortness of breath, sore throat, stuffy nose, or wheezing lasting less than two weeks will be screened during normal working hours over two winter and early spring periods (2025 and 2026) at 15 selected primary healthcare centres. Eligible participants must provide written informed consent and comply with study requirements. Exclusion criteria include severe or terminal illness, immunosuppression, recent antibiotic use, pregnancy, inability to participate in follow-up, or unwillingness to provide consent.

PROCEDURES The research team will screen patients at healthcare centres to identify eligible participants, who will provide informed consent in written or oral form. Patients of any ethnicity and both sexes, aged up to 70 years, will be included due to the average life expectancy in Kyrgyzstan. Upon enrollment, the research team will contact an investigator at the central office in Bishkek to assign a unique participant ID and randomise the participant into one of six groups. All subsequent study procedures will take place in the healthcare worker's office, typically involving a physician or feldsher, often assisted by a nurse.

INTERVENTION All participants will undergo CRP POCT testing during their consultation with a pre-trained healthcare worker (HCW) using the Aidian QuickRead Go device. Antibiotic prescriptions will follow the assigned CRP cut-off subgroup (>20 mg/L, >40 mg/L, >60 mg/L), with results recorded in the case report form (CRF) and explained to patients in plain language. In Groups A (AX, AY, AZ), participants will also receive a patient information leaflet (PIL), regardless of antibiotic prescription, emphasizing the importance of avoiding antibiotics for low CRP levels when a viral infection is suspected. Follow-up calls will be conducted by blinded researchers on days 3, 7, 14, and 21, and all participants will be advised to seek further care if symptoms worsen or fail to improve, following standard ARTI management practices in Kyrgyzstan.

CRITERIA FOR DISCONDUCTING FOR MODIGYING INTERVENTIONS Each participant will be involved in the trial for 21 days to report any adverse events (AEs), with serious adverse events (SAEs) reviewed by a safety board comprising the primary investigator, a biostatistician, and three academic members (one Kyrgyz and two Danish). SAEs must be reported to the primary investigator within 24 hours and to the safety board within 14 days. The safety board can terminate the trial if safety concerns arise, and participants will be informed and provided follow-up care if the trial ends prematurely. Discontinuation from the trial may occur due to withdrawn consent or protocol violations, but participants are not required to provide reasons. AEs leading to discontinuation will be followed up, and data collected until discontinuation will be included in the analysis. Exclusion criteria met during the follow-up period will not automatically result in discontinuation, and participants will not be replaced.

SAMPLE SIZE AND POWER CALCULATION The study aims to recruit 1,050 participants to evaluate both primary outcomes while accounting for up to 5% loss to follow-up. To detect a 10 percentage point reduction in antibiotic use with patient information leaflets (PILs) (from 40% to 30%) with 90% power and 5% significance, 1,012 participants are required. For the safety outcome, ensuring non-inferiority with a 5 percentage point margin in hospitalisation rates (expected at 5%) requires 978 participants. These calculations ensure adequate power to assess the study's primary outcomes reliably.

STATISTICAL METHODS The study will analyze baseline characteristics, such as living place, age, sex, and occupation, using medians with interquartile ranges for continuous variables (tested with the Kruskal-Wallis test) and percentages for categorical variables (tested with chi-squared tests). Outcomes will be assessed as risk differences (RD) through linear regression and odds ratios (OR) via logistic regression, with adjustments for correlations using Generalized Estimating Equations (GEE). The effects of the PIL and CRP interventions will be analyzed separately, with adjustments for the other intervention. An interim analysis will be conducted after 500 participants (50% of the target), allowing for early trial termination if interventions show clear benefits, harm, or futility. Subgroup analyses will explore outcomes by age group (18-44/45-59/60-70), urban/rural settings, clinic type, and sex.

TRIAL STATUS Protocol version 2.1. December 2nd, 2024. Date of start recruitment estimated to be January 2025. Estimated end of recruitment March 2026

DECLARATIONS Ethics approval and consent to participate Ethical approval for the 2CARE RCT was obtained during a meeting of the Ethics Committee, which included the chairman and other members of the Ethics Committee of the National Centre of Cardiology and Internal Medicine named after academician M. Mirrakhimov. During the meeting, the study protocol was reviewed, and the principal investigator addressed questions regarding the intervention. The decision was documented and signed by each member (Ref. No 10 27.11.2024). As stated earlier, before inclusion in the study, the participant will be asked to sign an informed consent, otherwise the participant cannot be included in the study. The informed consent is on the first page of the CRF.

COMPETING INTERESTS There are no competing interests.

Inclusion Criteria:

• Adults aged 18 to 70 years with ARTI according to the attending HCW;

• Having at least one of the following respiratory symptoms lasting for less than 2 weeks (with or without a fever):

  • cough;
  • shortness of breath;
  • sore throat;
  • stuffy nose;
  • wheezing.

• Able and willing to comply with all study requirements.

• Able and willing to give informed consent.

Exclusion Criteria:

• Severely ill and in need of urgent referral where measurement of POCT CRP is not relevant or would delay the process;
• Terminally ill patients;
• Patients with known immunosuppression or severe chronic disease (HIV, liver failure, kidney failure, history of neoplastic disease, long term systemic steroid use or similar conditions as assessed by the health worker or research team);
• Patients who are not able to participate in follow-up procedures (lack of telephone etc.);
• Have taken antibiotics within 24 hours before the index consultation;
• Pregnant women;
• Unable or unwilling to provide informed consent.

This study does not plan to share individual participant data (IPDs).

Following the baseline consultation, follow-up calls will be made to the telephone number provided by the participants on days 3, 7, 14 and 21 (Figure 1) by a blinded researcher from the Bishkek office.