PLoS ONE plos plosone PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0307784 PONE-D-24-28402 Study Protocol Medicine and health sciencesPharmacologyDrugsAntimicrobialsAntibiotics Biology and life sciencesMicrobiologyMicrobial controlAntimicrobialsAntibiotics Biology and life sciencesMicrobiologyMicrobial controlAntimicrobial resistance Medicine and health sciencesPharmacologyAntimicrobial resistance People and placesGeographical locationsAsia Biology and life sciencesMicrobiologyMicrobial controlAntimicrobial resistanceAntibiotic resistance Medicine and health sciencesPharmacologyAntimicrobial resistanceAntibiotic resistance People and placesGeographical locationsAsiaKazakhstan People and placesGeographical locationsEuropeKazakhstan People and placesPopulation groupingsProfessionsMedical personnelPharmacists Medicine and health sciencesPublic and occupational healthGlobal health Medicine and health sciencesHealth careHealth care providersPhysiciansGeneral practitioners People and placesPopulation groupingsProfessionsMedical personnelPhysiciansGeneral practitioners Optimizing antibiotic stewardship and reducing antimicrobial resistance in Central Asia: A study protocol for evidence-based practice and policy Reducing ARM in Central Asia https://orcid.org/0009-0002-0857-9857 Lim Lisa Conceptualization Funding acquisition Methodology Supervision Validation Writing – original draft Writing – review & editing 1 * Kassym Laura Methodology Writing – review & editing 2 Kussainova Assiya Methodology Writing – review & editing 1 Aubakirova Bibigul Methodology Writing – review & editing 3 Semenova Yuliya Conceptualization Funding acquisition Methodology Project administration Writing – original draft Writing – review & editing 1 Nazarbayev University, Astana, Kazakhstan Astana Medical University, Astana, Kazakhstan WHO Country Office in Kazakhstan, Astana, Kazakhstan Jakupi Arianit Editor University of Business and Technology, ALBANIA

The authors have decleared that no competing interests exist.

 * E-mail: lisa.lim@nu.edu.kz 16 1 2025 2025 20 1 e0307784 19 7 2024 6 11 2024 2025 Lim et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Antimicrobial resistance (AMR) poses a significant global health challenge, prompting the World Health Organization (WHO) to stress the importance of monitoring antibiotic consumption and sales to address AMR effectively. This study protocol aims to optimize antibiotic stewardship and combat AMR in Central Asia through evidence-based practices and policies. The protocol includes objectives such as conducting systematic reviews of interventions to promote judicious antibiotic use, assessing antibiotic consumption trends, and investigating antibiotic overuse practices among healthcare providers. The study aims to raise awareness among stakeholders to enhance appropriate antibiotic prescribing practices. By establishing regulatory frameworks, monitoring policies’ effectiveness, and providing training programs for healthcare professionals, this study seeks to contribute to the global efforts in combating AMR and promoting prudent antibiotic use.

 http://dx.doi.org/10.13039/501100012632 Nazarbayev University 211123CRP1609 Semenova Yuliya This work was supported by Nazarbayev University under Collaborative Research Program Grant No. 211123CRP1609 awarded to YS (PI) and LL (co-PI). Data Availability No datasets were generated or analyzed during the current study. All relevant data from this study will be made available upon study completion. 1. Introduction

Antimicrobial resistance (AMR) is a growing global health issue, hence, the World Health Organization (WHO) emphasizes the need for countries to monitor antibiotic consumption and sales to combat AMR [1,2]. In 2019, nearly 4.95 million deaths were linked to bacterial AMR, with a range of 3.62 to 6.57 million. Among these deaths, 1.27 million were specifically attributed to bacterial AMR, with a range of 0.911 to 1.71 million [3]. By 2050, it is projected that AMR would be accountable for causing 10 million deaths annually on a global scale [4]. Thus, the presence of effective antimicrobial medications are necessary to combat the emergence and global spread of emerging infectious diseases. Despite the discovery of the most recent groups of antibiotics in 1984 [5], there remain multiple challenges in the process of introducing new antibiotics into the market. Ineffectiveness of existing available drugs in combating bacterial infections may result in higher morbidity rates, increased usage of healthcare resources, and an elevated risk of premature deaths [6]. Particularly with the aging population and the rising rates of obesity and diabetes, the importance of possessing effective antibiotics cannot be emphasized enough. Besides, the problem of AMR is complex, and no single public health campaign can address the whole spectrum of challenges associated with the spread of bacterial agents that are resistant to existing available antibiotics. Due to a variety of factors, including the availability of generics at low cost and the use of antibiotics as growth promoters, the past few decades have been characterized by the misuse of antibiotics in both animal and human medicine [7,8]. The issue of AMR is further compounded by unregulated sale of drugs without a proper prescription over-the-counter (OTC) and a lack of information regarding the recommended dosage limits [9,10]. Thereby, several international agencies have proposed a number of initiatives aimed at raising global awareness, increasing financial resources available for infectious diseases, and promoting a One Health approach that aims to balance the health of people, animals, and the environment [11,12].

AMR issues can be mitigated by reducing inappropriate use of antibiotics. The AMR issue and improper use of antibiotics, as well as limited understanding of implementation of antimicrobial stewardship (AMS) [13,14] efforts and factors that influence these practices in primary care settings, remain largely unknown in Kazakhstan and other Central Asian countries [15,16]. There have been separate studies evaluating the prevalence of antibiotic-resistant strains in hospital facilities [17,18], as well as attempts to assess antibiotic consumption at the inpatient level with data available up to 2019 [19–21]. Yet there is a lack of data for the post-COVID period, and considering only the inpatient healthcare sector may result in significant underestimation of actual antibiotic consumption. This is because the majority of patients receive treatment at the community level, and further the extent of self-medication is unclear. A recent local study of public awareness of antibiotic consumption and resistance among the adult population of Kazakhstan revealed that about 40% of respondents had received antibiotics without a prescription within the past year, and nearly 65% of them were unaware of AMR [22]. Nevertheless, since the study exclusively focused on the general people within the East Kazakhstan region, the applicability of these findings to the wider population of Kazakhstan remains uncertain.

Our proposed project is the first study to assess the factors influencing antibiotic prescription practices by a general practitioner [1] (GP), who plays a crucial role in primary healthcare settings in Kazakhstan and other Central Asian countries. Besides, this study attempts to explore the role of pharmacists in OTC sales of antibiotics and their approaches to manage leftover antibiotics. On the basis of the WHO Access, Watch and Reserve (AWaRe) Classification in 2019, the majority of antibiotics consumed at the level of hospital care in Kazakhstan and Central Asia belonged to the "Watch" group (68%), and this trend was growing similar to the consumption of antibiotics from the "Reserve" group [23]. We will apply AWaRe methodology to evaluate antibiotic consumption across Access, Watch, and Reserve categories at the community level in Central Asia. We will evaluate practices of non-prudent use of antibiotics in primary care settings, monitor AMS activities in primary care settings, and identify factors influencing their implementation in Kazakhstan and other Central Asian countries. Ultimately, our project findings will inform policy measures to improve antibiotic stewardship and reduce AMR in Kazakhstan and Central Asia.

1.1. Study objectives and anticipated outcomes 1.1.1 Aims

Our project aim is to conduct evidence synthesis of best practices to improve antibiotic stewardship and inform policy options to reduce antimicrobial resistance (AMR) in Central Asia. The sub-goals of the study are as follows:

To investigate the drivers and determinants of non-prudent use and sales of antibiotics to develop targeted interventions at the community level to address AMR effectively in Central Asia.

To assess the consumption of antibiotic drugs in defined daily doses (DDD) both in the community and hospital sectors, as well as estimate time trends in Central Asia.

To generate in-depth knowledge of the reasons for over-the-counter (OTC) sales of antibiotics in the community pharmacies in order to evaluate the effectiveness of existing policies and regulations related to AMR control in Central Asian countries.

To investigate antibiotic overuse by exploring antibiotic prescribing practices among primary care providers for common infections such as upper respiratory tract infections, otitis, and sinusitis in Central Asia.

To conduct a comprehensive systematic review evaluating various interventions designed to promote judicious use of antibiotics among community members, general practitioners [24], and community pharmacists.

 1.1.2 Expected results

The study aims to raise awareness among a wide range of stakeholders, including representatives of the Ministry of Health (MoH), National Health Insurance Fund (NHIF), academia, and the general public, regarding key factors associated with AMR and antibiotic use in Kazakhstan. The results of the study will:

Establish a robust regulatory framework to conduct regular inspection of pharmacies, clinics, and other outlets where antibiotics are sold, including penalties for noncompliance with prescription requirements.

Establish mechanisms to monitor the effectiveness of reinforcement policies and assess their impact on reducing OTC antibiotic sales.

Provide comprehensive training programs and continuous medical education to healthcare professionals to enhance their knowledge of appropriate antibiotic prescribing practices.

Develop and strengthen surveillance systems to monitor antibiotic sales and consumption patterns.

Enhance the regulatory capacity for assessing the quality, safety, and efficacy of antibiotics available in the market.

Develop and implement interventions aimed at reducing non-prudent antibiotic use and sale, such as educational campaigns, AMS programs, and interventions targeting specific healthcare sectors or patient populations.

To achieve this goal, we will convene a country dialogue meeting, disseminate the knowledge generated from our research, and build on research and training programs to enhance local expertise in AMR surveillance, laboratory diagnostics, infection prevention and control in Central Asia. These accomplishments will have important socioeconomic benefits by reducing overall antibiotic consumption, curbing OTC sales, and slowing the spread of antibiotic-resistant bacteria throughout the country.

 2. Materials and methods 2.1 Study framework

The study procedure is depicted below in Fig 1, outlining the main areas of focus through a series of interconnected steps.

10.1371/journal.pone.0307784.g001 Illustration of primary areas in connected phases. 2.2 Data sources and methods for each target as follows

Objective 1: To investigate the drivers and determinants of non-prudent use and sale of antibiotics at the community level to develop targeted interventions to address the antimicrobial resistance (AMR) issues in Central Asia. Three related sub-studies will be implemented to identify the primary factors of antibiotic misuse among (i) adult residents, (ii) general practitioners, (iii) prospective medical doctors at the community level.

Sub-study 1 for Objective 1: To identify the key factors contributing to the non-prudent use of antibiotics in adult populations at the community level. This study involves community residents in both sexes aged 18 years and older. The survey will utilize the questionnaire presented in the WHO report “Antibiotic Resistance: Multi-country Public Awareness Survey” [25]. The questionnaire was previously piloted in a cohort of adult individuals aged 18 years and older from the East Kazakhstan province [22]. The calculations for the sample size will be conducted using the following methodology, with Kazakhstan serving as an illustrative example. The survey sample will comprise 683 individuals based on the calculation made with the help of EpiInfo7. The sample size calculation was based on the approximately 13,300,000 adult populations in Kazakhstan, an expected frequency of good knowledge of AMR (around 20%) [22], an acceptable margin of error (3%), a 95% confidence interval, and a design effect of 1.0. The sampling design will have two domains. The first domain will include all settlements except the largest cities, and the second domain will consist only of these largest cities. Four sampling stages will be used in the first domain. At the first stage, settlements will be selected using stratified sampling (SS), with selection probability based on population size. Stratification will be done by five geographic zones–central, north, east, south, and west. From each selected settlement, two electoral districts will be selected using simple random sampling (SRS). Dwelling units in each electoral district will be selected by SRS, with a total of 18 units per district. From each dwelling unit, one eligible person will be selected using the Kish Grid. The second domain will involve three sampling stages. At the first stage, a SS of electoral districts will be selected, with stratification based on the three largest cities. The second and third stages (sampling of dwelling units and individuals) will be identical to the first domain. Interviews will be conducted face-to-face in local languages, depending on the respondent’s choice. The study objectives will be clearly explained and communicated before the interview starts, and informed consent will be obtained.

Sub-study 2 for Objective 1: To evaluate the knowledge, attitudes, and behaviors of general practitioners with respect to antibiotics, antibiotic use, and antibiotic resistance. The survey will be used to evaluate the knowledge, attitudes and behaviors of general practitioners regarding antibiotics and AMR by using the questionnaire developed by the European Centre for Disease Prevention and Control (ECDC) [25]. The questionnaire was previously piloted in a cohort of GPs from Astana. The calculations for the sample size will be conducted using the following methodology, with Kazakhstan serving as an illustrative example. According to calculations made with the help of EpiInfo7, it has to include a minimum of 690 individuals in order for the study to be generalizable. This calculation is based on the number of general 5,000 practitioners in Kazakhstan, an expected frequency of an adequate knowledge around 75% of AMR [26], with an acceptable margin of 3% error, a 95% confidence interval, and a design effect of 1.0. The sampling frame for this study will be composed of members of the Kazakhstan Association of Family Physicians (KAFP). To select the study participants, 750 physicians will be randomly sampled from the sampling frame, and an invitation to participate in an online survey will be sent to them. The invitation will explain the survey aim, provide a declaration of informed consent, and offer a link to the questionnaires. The online questionnaires will be open for responses over a 6-week period, and will be available in both Russian and Kazakh languages. The same sampling size and frame will be used in other Central Asian countries.

Sub-study 3 for Objective 1: To evaluate the knowledge, attitudes, and behaviors of prospective medical doctors with respect to antibiotics, antibiotic use and antibiotic resistance. This study will involve final year medical students from all six medical schools in Kazakhstan. The survey will utilize a questionnaire developed by the ECDC, which includes a separate subsection for health students that focuses on the AMR training received in medical schools [26]. In addition to this subsection, the students will respond to questions from other subsections of the questionnaire, except for those related to prescribing practices. The calculations for the sample size will be conducted using the following methodology, with Kazakhstan serving as an illustrative example. In order for the study to be generalizable, it must include a minimum of 723 participants, which has been calculated using EpiInfo7. This calculation is based on the total number of final year medical students in Kazakhstan (7,500), an expected frequency of adequate knowledge of approximately 75% AMR [26], an acceptable margin of 3% error, a 95% confidence interval, and a design effect of 1.0. The final year medical students will be selected randomly, based on the lists provided by the deans of their respective medical schools. An invitation to participate in an online survey will be sent to 800 final year medical students. The invitation will provide details about the survey’s purpose, include a declaration of informed consent, and offer a link to the questionnaire. The online questionnaire will be available for responses over a 6-week period and will be provided in both Russian and Kazakh languages. The same sampling size and frame will be carried out in other Central Asian countries. Statistical analysis will be conducted using IBM Statistical Package for Social Sciences (SPSS) version 24 software and Microsoft Excel. Continuous variables will be presented as mean and standard deviation or median and interquartile range, depending on the data distribution, which will be evaluated by the Kolmogorov-Smirnov test and histograms. Categorical variables will be presented as absolute numbers and proportions. Pearson’s chi-square test will be used for between-group comparisons of categorical variables, while Student’s t-test/ANOVA or Mann-Whitney/Kruskal-Wallis test will be used for normally and non-normally distributed continuous variables, respectively. Five-point agreement responses will be collapsed into two categories: (i) agree, undecided/neither agree, nor disagree, disagree and (ii) once a day/more than once a day, once a week/more than once a week, and rarely/never. Logistic regression will be conducted to identify factors associated with non-prudent use of antibiotics.

Objective 2: To assess the consumption of antibacterial drugs in defined daily doses (DDD) in both the community and hospital sectors, as well as estimate time trends. The research team will conduct two distinct sub-studies to achieve the objective: (i) by assessing antibiotic consumption in the community and hospital sectors, and (ii) conducting a time-series analysis of country-level antibiotic consumption over a 10-year period.

Sub-study 1 for Objective 2: To assess antibiotic consumption in the community sector. A pharmaceutical consulting company “VIORTIS” collects data on sales of all medications in all pharmacies, as well as the data on the medicines supplied to hospital facilities. Therefore, this data can be used to evaluate the consumption of antibiotics both at the community and hospital sectors with high precision. The consumption of antibiotics (ATC group J01) will be expressed in DDD/1000 inhabitants/day (DID) following the ATC/DDD (Anatomical Therapeutic Chemical/Defined Daily Dose) methodology developed by the WHO [27]. The demographic data for the relevant years will be collected from the statistical compilations issued by the Bureau of National Statistics [28]. The AWaRe methodology [29] will be used to evaluate the distribution of antibiotics consumed within the three groups: Access, Watch, and Reserve.

Sub-study 2 for Objective 2: Conducting a time-series analysis of country-level antibiotic consumption over a 10- year period. The study will analyze 10 years’ worth of data (2015–2024) on country-level antibiotic consumption, disaggregated by the Access, Watch, and Reserve groups. Special attention will be given to antibiotic consumption during the COVID-19 pandemic when comparing with pre-pandemic and post pandemic periods. Statistical analysis will be conducted using the “Forecasting” package of IBM SPSS version 24 software and Microsoft Excel.

Objective 3: To generate in-depth knowledge of the reasons for OTC sales of antibiotics in the community in order to evaluate the effectiveness of existing policies and regulations related to AMR control in Central Asian countries. This objective aims to carry out three distinct sub-studies: (i) to monitor the practice of OTC antibiotic sales with different stakeholders in the community; (ii) to evaluate the effectiveness of reinforcement policies and assess their impact on reducing OTC antibiotic sales; and (iii) to conduct a desk review on the existing AMR policies, guidelines, and legislations, including implementation and assessment of national action plans (NAPs) on AMR.

Sub-study 1 for Objective 3: To investigate the practice of OTC antibiotic sales from the perspective of the community pharmacists. This qualitative study will employ in-depth interviews with community pharmacists working in metropolis, city, and rural areas. The sample for this study will be selected through convenience sampling, based on an equal distribution of urban and rural pharmacists, and their willingness to participate. Triangulation will be involved in utilizing different data collection order to check the consistency of the findings [30]. The investigation will utilize a flexible topic guide covering critical areas such as (i) the practice of and reasons for OTC antibiotic sales; (ii) knowledge and understanding of AMR and related antibiotic consumptions; (iii) awareness of existing legislation regarding OTC antibiotic sales; and (iv) the existence of legal regulations promoting the accurate dispensing of prescribed antibiotic pharmaceutical forms.

Sub-study 2 for Objective 3: To explore the mechanisms to evaluate the effectiveness of reinforcement policies and assess their impact on reducing OTC antibiotic sales. This study will be a qualitative study conducted through in-depth interviews with key stakeholders, including representatives from the MoH, the NHIF, professional associations, and public health experts. Our investigation will utilize a flexible topic guide to cover critical areas such as (i) NAPs on AMR and antibiotics; (ii) national laws or regulations aimed at reducing the non-prudent use of antibiotics, including surveillance and auditing, including penalties for non-compliance with prescription requirements and other relevant regulations; (iii) legal regulations encouraging the accurate dispensing of prescribed antibiotic pharmaceutical forms, prosecution of illegal means of obtaining antibiotics. Prior to the interview, all participants will provide oral informed consent, which will include an agreement for audio recording. The interviews will be conducted in local languages, depending on the interviewee’s preference. Recorded interviews will be transcribed verbatim and translated into English prior to coding. The transcribed text will be reviewed several times for familiarization. The inductive thematic analysis will be performed concurrently with data collection. A full and inclusive description of themes will be developed, and feedback from the participants will be sought to obtain verification of the authors’ understanding of data. Statistical analysis will be conducted using the Version 14 of the NVivo software.

Sub-study 3 for Objective 3: To conduct the desk literature review on the existing AMR policies, guidelines, and legislations, including implementation and assessment of the NAPs on AMR. The present study will involve a desk review of existing laws, rules, and regulations. The review will be conducted using the Google Search engine, employing the following search queries: (i) “antimicrobials”; (ii) “AMR”; (iii) “OTC sale”; and (iv) “measures.” Additionally, the national legislative databases managed by the Ministry of Justice will be accessed. The titles of all relevant documents will be evaluated, and their complete texts will be obtained and thoroughly examined. Data extraction and organization will be performed, utilizing tables specifically designed for this purpose.

Objective 4: To investigate antibiotic overuse by exploring antibiotic prescribing practices for common infections such as upper respiratory tract infections, otitis, and sinusitis in Central Asia among primary care providers. The provision of clinical care in Kazakhstan and other Central Asian countries is regulated by national standards of care, which are mandatory for all healthcare providers, including those in the private sector. These standards, referred to locally as “clinical protocols,” guide the management of various medical conditions. In the first phase of this study, we will create a comprehensive list of available clinical protocols for treating upper respiratory tract infections. In the second phase, we will extract provisions concerning the use of antibiotics and compare them with current international evidence-based clinical practice guidelines developed by established professional associations in the field. We will organize data on the indications for antibiotic prescription, type of antibiotic, recommended duration of treatment, and dosage into tables designed for this purpose. This will enable us to identify areas for improvement in aligning current standards of care with evidence based international practices.

Objective 5: To conduct a comprehensive systematic review of systematic reviews evaluating various interventions designed to promote judicious use of antibiotics among two key groups: (i) community members and (ii) General Practitioners (GPs) and community pharmacists. To achieve this objective, three academic databases, namely PubMed, Google Scholar, and Science Direct, will be searched without any restrictions on publication year. This approach is considered suitable as it provides a comprehensive overview of interventions and prevents the inclusion of redundant studies. In the initial step, two researchers will independently screen article titles and abstracts, and any discrepancies will be resolved by discussion with a third researcher. The study’s data will include the first author, year of review publication, types of interventions assessed, their effectiveness (if available), number of primary studies included in each review, time period, world region, and main conclusions. A quality assessment tool will be employed to evaluate the methodological quality of the systematic reviews included.

 2.3. Ethical consideration

This research will involve human subjects, and therefore all documents related to the study, including the application to the Nazarbayev University (NU) Institutional Research Ethics committee (IREC), informed consent forms, and questionnaires, will be submitted for approval by NU IREC. Data collection will only begin after approval has been granted. Informed consent will be obtained from each subject prior to data collection, and all documents as well as study results will be kept confidential. This study will not entail any physical activities or medical interventions, and will not address sensitive or personal topics. Data collection for Objectives 1, 2, and 4 will be anonymized, with no identifying information collected. Researchers responsible for the statistical analysis for Objectives 1–3 will be blinded. The research team will follow the principles of research ethics, avoiding scientific data fabrication, scientific fraud, plagiarism, false co-authorship, and scientific misconduct. Only questionnaires developed and made available for the general public for free by the WHO, WOAH, ECDC, and the European Commission will be used, and proper credit will be given to the developers upon utilization of these questionnaires. The recruitment period of this study will be August 2024-March 2025.

Institutional Review Board Statement (IREC): This study is being conducted in accordance with the Declaration of Helsinki. The approval for Objective 2 (To assess the consumption of antibacterial drugs in defined daily doses (DDD) in both the community and hospital sectors, as well as estimate time trends) was taken from the Nazarbayev University (NU) IREC (#802/23112023, December 1, 2023). In addition, the necessary authorizations to collect survey and interview data for other objectives were received from the NU IREC (survey data collection- #851/05022024) and interview data collection- #861/20022024).

 3. Discussion 3.1. The potential social and economic impact of the project for Central Asia

According to the WHO, antimicrobial resistance (AMR) constitutes one of the three greatest threats to human health in the coming decades [31]. The potential costs associated with the improper use of antibiotics are challenging to quantify. Estimates suggest that in the United States (USA) alone, the annual costs associated with AMR amount to 55 billion USD, with 20 billion USD attributed to direct healthcare expenses and approximately 35 billion USD representing productivity losses [23]. In the European Union (EU), AMR is responsible for 33,000 deaths per year and costs 1.5 billion EUR in additional healthcare expenses and productivity losses [31]. The O’Neill report projects that by 2050, drug-resistant diseases could cause 10 million deaths annually, equivalent to the economic impact of the 2008–2009 global financial crisis [3]. Furthermore, as many as 24 million people could be pushed into extreme poverty by 2030 [4]. We must address how AMR also impacts on environment, social, and economic targets in the Sustainable Development Goals (SDG) framework, including SDG 3 –good health and wellbeing of all ages [32].

Recently, the issue of AMR has received significant attention from the medical community in Kazakhstan. Kazakhstan has developed a national action plan (NAP) on AMR [33]. The NPA primarily focuses on AMR surveillance, but inadequate attention is paid to controlling antibiotic use. Therefore, urgent steps are required to prioritize the funding, implementation, and monitoring interventions aimed at promoting prudent use of antibiotics. It is crucial to coordinate efforts across sectors and engage a diverse range of stakeholders, as this is likely to yield favorable outcomes. However, no attempt was made to estimate the social and economic consequences of AMR in Kazakhstan, even though they are likely to be significant. The economic costs include loss of productivity and expenditures on additional diagnostics and treatments, while social impact includes decreased quality of life, an upsurge in morbidity and mortality rates, amplified poverty rates, and exacerbated gender inequities [34]. Despite the affordability of antibiotics for the majority of the population in Kazakhstan and other Central Asia nations, coupled with a low knowledge and awareness of the rationale for consumption of antibiotics, this issue is likely to worsen without interventions and policies. Furthermore, the period of the COVID-19 pandemic has been characterized by increased consumption of medicines, including antibiotics, and high rates of self-medication [35], suggesting that the magnitude of the problem may have increased even further.

 Supporting information Data management plan.

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 Study management plan.

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 Team composition.

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 Research alignment.

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I express my gratitude for the helpful discussions received from Nazarbayev University Graduate School of Public Policy and School of Medicine. I would also like to express my gratitude for the helpful discussions provided by the Department of Antimicrobial Resistance at the International Vaccine Institute.

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Available from: https://www.statisticssolutions.com/what-is-credibility-in-qualitative-research/ Fabbro E, Arnau Sánchez J, Del Pilar López Acuña M, Hukelová H, Alcaraz Quiñonero M, Pantosti A, et al. Where we are in the fight against Antimicrobial Resistance and Healthcare-Associated Infections. The opinion of the stakeholders of the European Joint Action on Antimicrobial Resistance and Healthcare-Associated Infections (EU-JAMRAI). Ann Ist Super Sanita. 2022;58(3):204–12. Jasovský D, Littmann J, Zorzet A, Cars O. Antimicrobial resistance-a threat to the world’s sustainable development. Ups J Med Sci. 2016 Aug;121(3):159–64. doi: 10.1080/03009734.2016.1195900 27416324 Antimicrobial resistance TrACSS Kazakhstan 2021 country profile [Internet]. [cited 2023 May 5]. Available from: https://www.who.int/publications/m/item/antimicrobial-resistance-tracss-kaz-2021-country-profile Antimicrobial resistance and causes of non-prudent use of antibiotics in human medicine in the EU ‐ Publications Office of the EU [Internet]. [cited 2023 May 10]. Available from: https://op.europa.eu/en/publication-detail/-/publication/970215eb-473e-11e7-aea8-01aa75ed71a1/language-en Semenova Y, Pivina L, Khismetova Z, Auyezova A, Nurbakyt A, Kauysheva A, et al. Anticipating the Need for Healthcare Resources Following the Escalation of the COVID-19 Outbreak in the Republic of Kazakhstan. J Prev Med Public Health. 2020 Nov;53(6):387–96. doi: 10.3961/jpmph.20.395 33296578 10.1371/journal.pone.0307784.r001 Decision Letter 0 Jakupi Arianit Academic Editor 2025 Arianit Jakupi This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 0

22 Oct 2024

PONE-D-24-28402Optimizing Antibiotic Stewardship and Reducing Antimicrobial Resistance in Central Asia:

A Study Protocol for Evidence-Based Practice and PolicyPLOS ONE

Dear Dr. Lim,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Arianit Jakupi, PhD

Academic Editor

PLOS ONE

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When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

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https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf.

2. Thank you for stating the following in your manuscript:

“This research is funded by the Nazarbayev University under the Collaborative Research Project (CRP) Grant № OPCRP2024008 of “Evidence-based practice and policy to improve antibiotic stewardship and reduce antimicrobial resistance in Central Asia”

We note that you have provided additional information within the Acknowledgements Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

 ” Grant program: Collaborative Research Project 2024-2026

Funder-Project Reference: 211123CRP1609”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

3. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process.

4. Please amend the manuscript submission data (via Edit Submission) to include authors Laura Kassym , Assiya Kussainova , Yuliya Semenova , and Bibigul Aubakirova.

5. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

6 Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

7. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Partly

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Partly

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The abstract you've written is clear and focused. The first sentence can be made more impactful by specifying why AMR is a global challenge. You mention the establishment of regulatory frameworks but don't detail the nature of these frameworks. Consider providing more specifics in the full text (not the abstract), but it’s good to leave a hint here. There are some areas where phrasing and structure could be slightly improved for a smoother read and alignment with academic expectations. Abstracts should not include abbreviations, if possible. Abbreviation Consistency: Ensure all abbreviations like AMS, DDD, and OTC are introduced at first mention and used consistently throughout the paper.

You introduce several study goals at once; it may help to break them down slightly for clearer readability. Consider clarifying who the stakeholders are. Are they healthcare providers, policymakers, or the general public? You mention the establishment of regulatory frameworks but don't detail the nature of these frameworks. Consider providing more specifics in the full text

Methodological Section: Consider reducing long sentences for ease of understanding. Certain sections would benefit from more specificity, particularly in sampling procedures and desk review methodologies. Additionally, clarity on how results will translate into policy recommendations or interventions would improve the impact and practical application of the findings.

Ethical Consideration: The ethical considerations outlined are appropriately thorough and reflect a strong commitment to maintaining high ethical standards. One suggestion would be to include a plan for how the anonymized data will be stored and managed post-study to ensure compliance with data protection regulations. Clarifying this, along with the process of obtaining informed consent would strengthen the ethical framework.

Discussion: The paper provides a solid foundation for understanding the urgency of addressing AMR in Central Asia, with well-structured objectives. However, more clarity on how the study findings will translate into policy recommendations or real-world interventions would enhance the impact of the research. The discussion could also benefit from a more comprehensive exploration of potential economic and social consequences specific to the region.

Take into consideration separating these two sections clearly (Discussion and Conclusion). This will allow the discussion to focus on analysis and exploration, while the conclusion to give final summary and closes the argument.

**********

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Reviewer #1: No

**********

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

 10.1371/journal.pone.0307784.r002 Author response to Decision Letter 0 Submission Version 1

31 Oct 2024

RESPONSE TO REVIEWERS

Reviewer’s comment 1

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf.

Response to comment 1:

The manuscript has been revised to comply with PLOS ONE’s style requirements, including appropriate file naming conventions.

• Page and line numbers were added,

• Used double-spaced, Removed Footnotes,

• Used “Vancouver” style for reference style

• Changed Level 1 Heading to Bold type, 18pt font

• Changed Level 2 Heading to Bold type, 16pt font

• Changed Level 3 Heading to Bold type, 14pt, font

Reviewer’s comment 2

Thank you for stating the following in your manuscript:

“This research is funded by the Nazarbayev University under the Collaborative Research Project (CRP) Grant № OPCRP2024008 of “Evidence-based practice and policy to improve antibiotic stewardship and reduce antimicrobial resistance in Central Asia”

Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

” Grant program: Collaborative Research Project 2024-2026 Funder-Project Reference: 211123CRP1609”.

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Response to comment 2:

All funding-related text has been entirely removed from the manuscript.

Reviewer’s comment 3.

When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process.

Response to comment 3:

We have included the data availability declaration.

Line 386-387

Data Availability Statement

The data used and analysed during the current study are available from the corresponding author upon reasonable request.

Reviewer’s comment 4

Please amend the manuscript submission data (via Edit Submission) to include authors Laura Kassym , Assiya Kussainova , Yuliya Semenova , and Bibigul Aubakirova.

Response to comment 4:

We have included the following statement regarding the data agreement below.

Line 21- 22

All authors have agreed to provide the data following the acceptance of the manuscript for publication.

Reviewer’s comment 5

Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

Response to comment 5:

Ethics statement appears in the Methods section of the manuscript only.

Line 317-338.

2.3 Ethical consideration

Instructional Review Board Statement (IREC)

Reviewer’s comment 6

Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Response to comment 6:

We've already incorporated captions for our supporting information in the manuscript accordingly, and ensured that all in-text citations match these captions.

Line 489-501

Supporting information

S1 Fig. This is the S1 Fig Title. This is the S1 Fig legend.

S1 Text. Data management plan.

S2 Fig. This is the S2 Fig Title. This is the S2 Fig legend.

S2 Text. Study management plan.

S3 Fig. This is the S3 Fig Title. This is the S3 Fig legend.

S3 Text. Team composition.

S4 Fig. This is the S4 Fig Title. This is the S4 Fig legend.

S4 Text. Research alignment.

Reviewer’s comment 7

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response to comment 7:

We have reviewed all reference list to ensure that it is complete and correct.

Submitted filename: RESPONSE TO REVIEWERS.docx

 10.1371/journal.pone.0307784.r003 Decision Letter 1 Jakupi Arianit Academic Editor 2025 Arianit Jakupi This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

6 Nov 2024

Optimizing Antibiotic Stewardship and Reducing Antimicrobial Resistance in Central Asia:

A Study Protocol for Evidence-Based Practice and Policy

PONE-D-24-28402R1

Dear Dr. Lim,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Arianit Jakupi, PhD

Academic Editor

PLOS ONE

 10.1371/journal.pone.0307784.r004 Acceptance letter Jakupi Arianit Academic Editor 2025 Arianit Jakupi This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

3 Jan 2025

PONE-D-24-28402R1

PLOS ONE

Dear Dr. Lim,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

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on behalf of

Dr Arianit Jakupi

Academic Editor

PLOS ONE