Economic evaluation of antimicrobial stewardship programme in primary care in Kosovo: study protocol

Abstract

Introduction

Antimicrobial resistance poses a major challenge to both public health and economic stability in many countries. In response, antimicrobial stewardship programmes are essential for optimising antibiotic use and reducing antimicrobial resistance, particularly in primary care settings where most antibiotics are prescribed. Kosovo, like many countries, is increasingly affected by the growing threat of antimicrobial resistance and must strengthen its strategies to address this problem. Although national action plans on antimicrobial resistance and stewardship have been completed, there is limited evidence on the economic impact of antimicrobial stewardship interventions in Kosovo, as is the case in many low- and middle-income country contexts. This study thus aims to evaluate the cost-effectiveness of antimicrobial stewardship programme in Kosovo, and the cost of implementing this programme in primary care settings in Kosovo.

Methods and analysis

First, for the cost-effectiveness component of the study, we will use a quasi-experimental interrupted time series design focusing on patients ≥18 years old diagnosed with upper respiratory tract infections at intervention and control sites in Kosovo’s primary care system, to analyse changes in antibiotic consumption measured in defined daily doses, and estimate the corresponding monetary value to determine cost-effectiveness. Second, we will use a bottom-up costing method to estimate the costs associated with implementing the antimicrobial stewardship programme, including resources required across intervention and control sites. Cost data for both components will be collected from the implementing institutions and the main family medicine centres, serving as the intervention and control sites.

Ethics and dissemination

The Ethical Committee of the Kosovo Chamber of Medical Doctors approved the protocol of our study (Number: 122/2024). Moreover, the results from this study will be published and disseminated as a peer-reviewed publication.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This study combines a quasi-experimental interrupted time series design with control groups and a bottom-up costing approach, enabling a comprehensive evaluation of both the cost-effectiveness and implementation costs of antimicrobial stewardship programme in primary care.

• The use of repeated measurements and standardised measures, such as defined daily doses, enables robust, comparable tracking of antibiotic consumption across multiple sites and over time.

• Inclusion of geographically diverse main family medicine centres supports the broader applicability of findings within Kosovo’s primary care system.

• The quasi-experimental design, while practical, does not fully eliminate the risk of confounding factors.

Introduction

Antimicrobial resistance (AMR) is a major and growing challenge affecting both public health and economic stability. In 2019, an estimated 1.27 million deaths were directly attributable to bacterial AMR and 4.95 million were associated with it worldwide, exceeding the annual mortality from HIV/AIDS or malaria.¹ Without effective action, this burden is projected to grow, with more than 39 million deaths estimated between 2025 and 2050². Earlier projections reported up to 10 million deaths per year by 2050.³ The burden falls disproportionately on low- and middle-income countries (LMICs), where limited diagnostic capacity, weaker regulation and constrained resources intensify both the drivers and the consequences of resistance.^{1 4 5} A principal driver is the overuse and misuse of antibiotics in humans, the majority of which are prescribed in primary and community care rather than in hospitals.^6–8 Prescribing at this level is directly associated with the subsequent emergence of resistant organisms in treated patients,⁹ making primary care a critical setting for containment. In response, AMR has risen to the top of the global policy agenda.¹⁰ The WHO adopted the Global Action Plan on Antimicrobial Resistance in 2015, committing all countries to develop National Action Plans,¹¹ underpinned by global surveillance through the Global Antimicrobial Resistance and Use Surveillance System.¹² This response has been reinforced by successive United Nations high-level commitments and by dedicated bodies such as the International Centre for Antimicrobial Resistance Solutions (ICARS), which partners with LMICs to co-develop context-specific, cost-effective interventions that advance implementation of their National Action Plans.^{13 14}

Kosovo, like many other countries, increasingly faces this threat and must develop effective strategies to reduce its impact. Despite having completed national action plans to address antimicrobial resistance and stewardship, the country continues to struggle with antibiotic misuse.^15–17 A recent rapid assessment found that 73.9% of patients with tonsillopharyngitis received antibiotics despite no microbiological confirmation of bacterial infection, highlighting the need to address inappropriate antibiotic use.¹⁸ Multiple factors contribute to this situation, including sector regulation, prescriber training, limited use of clinical guidelines and pressure from pharmaceutical companies.¹⁵ More recently, serious efforts have been made to change the situation. In 2023, the Ministry of Health (MoH) of the Republic of Kosovo approved a guideline on antibiotic use in primary healthcare.¹⁹ The guideline recommends the rational use of antibiotics, focusing on common infections in primary care, and follows international standards (eg, WHO and National Institute for Health and Care Excellence).

The antimicrobial stewardship (AMS) economic dimension is particularly significant. Globally, the cost of inaction on AMR over the next 30 years is projected to exceed the treatment costs due to the COVID-19 pandemic.^{1 4 20} Specifically, the direct costs of AMR globally already exceed US$66 billion annually and are projected to rise to US$159 billion, where resistance rates follow historical trends.²¹ In LMICs, AMR poses an even more severe economic burden.^{1 22 23} LMICs bear a disproportionate impact due to limited healthcare resources and economic constraints.^{22 23} While AMS programmes require initial investments, they have effectively reduced antibiotic consumption in hospital and community settings, lowering costs of treatment.^{1 4 23} For instance, AMS initiatives in low-resource settings have successfully reduced hospitalisations and mortality related to resistant infections and improved healthcare quality.²² Although there are no precise economic estimates of the burden of Upper Respiratory Tract Infections (URTIs) in Kosovo, the likelihood of this burden is real given the high level of antibiotic use.

In this context, the project ‘Addressing Antibiotic Overuse through Continuous Quality Improvement: Developing and Assessing Stewardship Interventions in Primary Care in Kosovo’ aims to reduce antibiotic misuse in primary care, focusing on acute URTIs, which are among the most common conditions for antibiotic prescription.^{16 24} It builds on the existing efforts of Kosovo institutions to tackle antibiotic overuse. Implemented by the National Institute of Public Health of Kosovo (NIPHK), alongside the MoH and local institutions, the project uses AMS programme and rapid diagnostic tools to enhance prescribing practices. This initiative, financially supported by the ICARS, runs from February 2024 to January 2027. The intervention focuses on raising awareness, strengthening training for healthcare providers and promoting adherence to new prescribing guidelines. The focus on primary care is essential, as 89% of patients surveyed use primary care as their first point of contact with health services.^{16 20 24}

Considering the need to evaluate the economic implications of the AMS programme in primary care in Kosovo, this study aims to evaluate the cost-effectiveness of antibiotic use following the implementation of the AMS programme in Kosovo and the cost of implementing the AMS programme in primary care settings. The implementation of the AMS programme could reduce the use of specific antibiotics²⁵ and lead to cost savings. The analyses will provide information on the economic impact (ie, cost differences) and cost of implementation of the programme in other sites, all of which are relevant for sustaining and scaling up the AMS intervention in other primary care facilities in the country. This study will inform relevant stakeholders on such impacts and support evidence-based decision-making regarding antibiotic prescribing practices for URTIs in the country.

Methods and analysis

Study design

This study aims to evaluate the effects of AMS adoption in antibiotic consumption, measured in defined daily doses (DDD), and the corresponding monetary value of these changes (cost-effectiveness component), as well as the costs of resources required to implement the programme (implementation cost component). The economic assessment is embedded within the broader theoretical framework of the AMS programme, which largely draws on implementation science frameworks, such as RE-AIM.^{16 24}

Cost-effectiveness analysis component

The cost-effectiveness component of the study will employ a quasi-experimental interrupted time series (ITS) design with control groups to evaluate the impact of the AMS programme on antibiotic prescribing costs in Kosovo’s primary care system. The study will include patients aged ≥18 years diagnosed with URTIs at intervention and control sites, with antibiotic use measured in DDD as the primary outcome. Data on antibiotic prescribing will be collected from health records using repeated measurements at multiple time points before, during and after implementation of the intervention to assess changes in prescribing patterns and costs over time. A quasi-experimental ITS design was selected as the most feasible and appropriate approach for assessing the intervention’s impact on antibiotic prescription costs, given its widespread use in AMS impact evaluations.^26–28

Cost of the implementation component

The implementation component will use an observational descriptive design to collect, analyse and present costs, alongside a bottom-up costing approach to estimate the costs of implementing the AMS programme across six intervention and six control sites within Kosovo’s primary care system. All study sites are main family medicine centres and will serve as the primary data source. Costs related to the AMS intervention will be categorised into three phases, design, implementation and maintenance, following Sohn’s conceptual framework.²⁹ Implementation costs, defined as expenses associated with developing and executing the AMS programme in Kosovo,³⁰ will include personnel, training, materials and programmatic activities. Costs will be analysed from the programme perspective, with support from the implementing partners, NIPHK and the Evidence Synthesis Group (ESG), using expenditure and audit reports, and presented in euros. For each phase, expenses will be classified as either central or site-specific, with site-specific costs capturing variations related to factors such as site size, patient volume and implementation needs, and central costs including programmatic, research and material costs. This approach will provide decision-makers with insight into scalability opportunities and potential cost variations when expanding the programme to other primary care settings.^{16 24}

Intervention

The AMS programme in primary care in Kosovo will establish AMS structures at national and facility levels, supported by Standard Operating Procedures developed by the MoH to standardise prescribing practices, monitoring protocols implementation and staff roles, with updates to tackle AMR informed by project findings. The intervention will include educational and training initiatives, Rapid Strep Test implementation, point prevalence surveys (PPS) and continuous monitoring through clinical audits (figure 1).

Figure 1. Intervention outline. AMR, antimicrobial resistance; AMS, antimicrobial stewardship; URTIs, upper respiratory tract infections; PESTLE, Political, Economic, Social, Technological, Legal and Environmental; SWOT, Strengths, Weaknesses, Opportunities and Threats.

Study sites

The AMS programme will include 12 Main Family Medicine Centres (MFMC) in total. Six will serve as the intervention sites, while six will serve as control sites. Control sites will provide baseline data on antibiotic prescribing, enabling comparison with intervention sites implementing the AMS programme. They will enrol in the AMS programme at a later stage. The facilities were chosen for their geographical diversity, infrastructure, patient volume and representativeness of the country’s healthcare landscape. Details on study sites are published elsewhere.^{16 24}

Source of data and data collection

Cost-effectiveness analysis

Initially, PPS with onsite data collection were planned as the primary data collection method. However, during piloting, it became evident that researchers’ presence at facilities was associated with immediate changes in antibiotic prescribing behaviour, suggesting a strong Hawthorne effect that would compromise the validity of baseline measurements. To preserve the integrity of the ITS design, we transitioned to retrospecitive PPS, using routine prescription records as the primary data source, thereby allowing unobtrusive longitudinal measurement without influencing clinical behaviour. Based on the initial assessment of data availability from records, this is a feasible option. We will collect data at different points during the project’s implementation period.

Before data collection, a 1-day training session will be held. Researchers will be provided with a pocket guide containing detailed instructions on data collection, their roles, timing, submission procedures and points of contact. This preparation will ensure data collection accuracy and standardisation. A final briefing will be held before the data collection. Researchers will collect data at MFMC, and data will be recorded on an electronic uniform sheet designed for this purpose. Basic patient information, such as age category, sex and presenting symptoms, will be recorded from the medical records. For patients receiving antimicrobial treatment, additional detailed data will be collected, including the specific antimicrobial agent used, dosage, frequency, route of administration, anatomical site of infection and indication for therapy. All data entries will be checked by a second researcher, and incomplete or inconsistent records will be resolved against the source records before the data are finalised.

Cost of implementation analysis

Cost data will derive from expenditure reports during the intervention. These will be collected continuously through spending records, budgets and accounting managers of the NIPHK and ESG. In addition, the primary healthcare centre’s financial departments might be consulted. Each expenditure will then be categorised within one of the phases within the chosen framework. Following a bottom-up approach, these costs will be further subcategorised into central and site-specific costs. Site-specific costs relate to activities at the facility level, in this case, primary health centres, and include expenses for site selection, troubleshooting, data monitoring, quality checks, site visits, operational adjustments and recruiting a study contact person for each site. Data will also include the general characteristics of the facilities and will be collected through facility records and direct engagement with service delivery sites. This analysis will not include indirect costs, such as potential changes in laboratory testing demands or infrastructure usage, unless data from existing financial reports or facility records directly identify and quantify them. This ensures that the costing remains focused on measurable, direct expenses.

Study participants—for the cost-effectiveness component only

Participants in this study will be patients diagnosed with URTIs across all intervention and control sites. These diagnoses include the common cold, sinusitis, pharyngitis, tonsillitis and otitis. Selection will consist of a consecutive sample in which all eligible patients presenting with URTIs symptoms during the study period will be considered for inclusion. This approach ensures that the sample is comprehensive and captures the typical patient demographic treated at the participating healthcare facilities. By combining consecutive sampling with health record data, the study will obtain a representative, unbiased sample, ensuring the validity and reliability of findings.

Planned analysis

Cost-effectiveness analysis

The primary objective of this analysis is to determine the effect of the AMS programme on antibiotic consumption and costs. To measure consumtion, we will calculate DDD, a standardised measure for tracking antibiotic use and monitoring antimicrobial prescribing trends across different healthcare settings. To ensure consistent measurement across varying prescription patterns, the total DDD for each prescription is determined by calculating the total amount of the antibiotic prescribed and dividing it by its specific WHO-defined DDD value.

$${\displaystyle {\displaystyle \mathrm{T}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l}\mathrm{D}\mathrm{D}\mathrm{D}=\frac{\mathrm{D}\mathrm{o}\mathrm{s}\mathrm{e}(\mathrm{g})\times \mathrm{D}\mathrm{o}\mathrm{s}\mathrm{e}\mathrm{s}\mathrm{p}\mathrm{e}\mathrm{r}\mathrm{d}\mathrm{a}\mathrm{y}\times \mathrm{D}\mathrm{u}\mathrm{r}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{o}\mathrm{n}(\mathrm{d}\mathrm{a}\mathrm{y}\mathrm{s})}{\mathrm{W}\mathrm{H}\mathrm{O}\mathrm{D}\mathrm{D}\mathrm{D}(\mathrm{g})}}}$$

For example, if a patient is prescribed oral amoxicillin 0.5 grams three times daily for 5 days for URTI, the total daily dose is 1.5 g (0.5 g $\times$ 3). Over the 5-day course, the total amount prescribed is 7.5 g. Since the WHO DDD for oral amoxicillin is defined as 1.5 g per day, dividing the total amount by this reference value yields exactly 5 DDD for the entire course.³¹

Following individual calculations, the data will be aggregated to determine the total DDD for all URTI prescriptions within each primary health centre per time interval over the 3-year study period. To standardise and enable meaningful comparisons across sites with varying patient volumes, we will calculate the DDD per 1000 patient visits using the following formula:

$${\displaystyle {\displaystyle \mathrm{D}\mathrm{D}\mathrm{D}\mathrm{p}\mathrm{e}\mathrm{r}1000\mathrm{p}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{e}\mathrm{n}\mathrm{t}\mathrm{v}\mathrm{i}\mathrm{s}\mathrm{i}\mathrm{t}\mathrm{s}=\left(\frac{\mathrm{T}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l}\mathrm{D}\mathrm{D}\mathrm{D}}{\mathrm{T}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l}\mathrm{p}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{e}\mathrm{n}\mathrm{t}\mathrm{v}\mathrm{i}\mathrm{s}\mathrm{i}\mathrm{t}\mathrm{s}}\right)\times 1000}}$$

Subgroup analyses will be conducted, focusing on specific antibiotics, such as amoxicillin or ceftriaxone, to identify patterns of overprescription or other significant trends in antimicrobial use.

Parallel to tracking antibiotic consumption, the analysis will also calculate the total costs of antibiotics. This is achieved by multiplying the total DDDs by the average cost per DDD for each antibiotic. These metrics will be analysed before and after implementing AMS strategies to evaluate the effectiveness of the programme in reducing unnecessary antibiotic use and associated costs. Drug prices are based on public prices in Kosovo presented in euros. We will monitor whether prices remain constant throughout the study period and report changes. We will not adjust for inflation.

Finally, we will determine the economic efficiency of the programme by calculating the cost-effectiveness ratio, defined as:

$${\displaystyle {\displaystyle \mathrm{C}\mathrm{o}\mathrm{s}\mathrm{t}\mathrm{e}\mathrm{f}\mathrm{f}\mathrm{e}\mathrm{c}\mathrm{t}\mathrm{i}\mathrm{v}\mathrm{e}\mathrm{n}\mathrm{e}\mathrm{s}\mathrm{s}\mathrm{r}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{o}=\frac{\mathrm{T}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l}\mathrm{i}\mathrm{n}\mathrm{t}\mathrm{e}\mathrm{r}\mathrm{v}\mathrm{e}\mathrm{n}\mathrm{t}\mathrm{i}\mathrm{o}\mathrm{n}\mathrm{c}\mathrm{o}\mathrm{s}\mathrm{t}\mathrm{s}}{\mathrm{\Delta }\mathrm{D}\mathrm{D}\mathrm{D}}}}$$

Cost of implementation analysis

The collected data will be systematically organised into a comprehensive table to facilitate analysis and visualisation of the costs. The columns will record cost description, phase (design, implementation and maintenance), type (central or site-specific), financial source and total amount (in euros). Additional columns will record the unit cost, quantity and supporting documentation, such as procurement or expenditure reports. Each row will represent a specific expense or activity. For example, under the design phase, rows will include materials for brainstorming sessions, venue rental and logistics. For the implementation phase, rows will document training session costs, staff salaries and venue costs. In the maintenance phase, rows will capture expenses for follow-up activities, such as quality assurance checks, site visits and operational adjustments. Site-specific costs will be detailed for each primary health centre, including expenses for data monitoring, troubleshooting and recruitment of site-specific personnel. Data will be presented in a report for stakeholders.

Ethics and dissemination

The Ethical Committee of the Kosovo Chamber of Medical Doctors approved the study protocol (Number: 122/2024). Moreover, the results from this study will be disseminated as a peer-reviewed publication.

Discussion

Relevance of the study

This study is relevant in the context of rising AMR and persistent antibiotic overuse in primary care settings in Kosovo. By generating evidence on both the cost-effectiveness and implementation costs of an AMS programme, it addresses a critical gap in low- and middle-income country settings where economic evaluations of such interventions remain limited. The findings will provide policymakers and healthcare stakeholders with data on the financialimpact of AMS implementation, supporting more efficient resource allocation and evidence-based decision-making. Ultimately, the study should inform strategies to optimise antibiotic prescribing for common conditions such as URTIs and contribute to the scalability and sustainability of AMS intervention within Kosovo’s primary care system.

Strengths and limitations

This study has several notable strengths. It applies a quasi-experimental ITS design with control groups alongside a bottom-up costing approach, enabling a comprehensive assessment of both the cost-effectiveness and implementation costs of AMS in primary care. The use of repeated measurements, combined with standardised measures such as DDD, enables consistent and comparable monitoring of antibiotic use across multiple sites and over time. In addition, the inclusion of geographically diverse MFMC strengthens the external validity of the findings and supports their applicability across Kosovo’s primary care system.

However, as a quasi-experimental study, the design is inherently susceptible to residual confounding and the potential influence of underlying secular trends, which may affect antibiotic prescribing patterns independently of the intervention. Additionally, reliance on health record data may introduce variability in data completeness and accuracy across study sites, thereby posing risks to measurement validity and the overall precision of the estimates.

⁴

Publication policy

This study will be published as a peer-reviewed publication. The report is primariy intended for stakeholders such as NIPHK and MoH and should provide valuable insights and actionable information directly relevant to the stakeholders' interests and needs. All the investigators will review drafts of the manuscripts, abstracts, press releases and any other publications arising from the study. The authors will acknowledge that ICARS funded the study. Authorship will be determined by the relevant guidelines, and other contributors will be acknowledged.

Data statement

The data supporting this study will be available from the corresponding author upon reasonable request

Reflexivity statement

The research question arose from a locally identified need to strengthen antimicrobial stewardship in primary care. The majority of the author team is affiliated with Kosovo institutions and was responsible for the study's conception, design, data collection, analysis, and implementation within the Kosovo primary care system. International coauthors contributed specialist expertise in health economics and cost-effectiveness methodology, supporting rather than directing the study's scientific direction. Authorship was determined in accordance with ICMJE criteria, and the whole team agreed on contributor roles. The study is designed to generate locally relevant evidence and to strengthen in-country research and stewardship capacity. Findings will be disseminated to Kosovo's health authorities, clinicians, and policymakers to inform national primary care and antimicrobial resistance strategy.