WHO's essential medicines and AWaRe: recommendations on first- and second-choice antibiotics for empiric treatment of clinical infections.

The WHO Model List of Essential Medicines (EML) prioritizes medicines that have significant global public health value. The EML can also deliver important messages on appropriate medicine use. Since 2017, in response to the growing challenge of antimicrobial resistance, antibiotics on the EML were reviewed and categorized into three groups: Access, Watch and Reserve, leading to a new categorization called AWaRe. These categories were developed taking into account the impact of different antibiotics and classes on antimicrobial resistance, and the implications for their appropriate use. The 2023 AWaRe classification provides empiric guidance on 41 essential antibiotics for over 30 clinical infections targeting both the primary health care and hospital facility setting. A further 257 antibiotics not included on the EML have been allocated an AWaRe group for stewardship and monitoring purposes. This article describes the development of AWaRe focussing on the clinical evidence base that guided the selection of Access, Watch or Reserve antibiotics as first and second choices for each infection. The overarching objective was to offer a tool for optimising the quality of global antibiotic prescribing and reduce inappropriate use by encouraging the use of Access antibiotics (or no antibiotics) where appropriate. This clinical evidence evaluation and subsequent EML recommendations are the basis for the AWaRe antibiotic book and related smartphone applications. By providing guidance on antibiotic prioritization, AWaRe aims to facilitate the revision of national lists of essential medicines, update of national prescribing guidelines and surveillance of antibiotic use. Adherence to AWaRe would extend the effectiveness of current antibiotics while helping countries to expand access to these life-saving medicines for the benefit of current and future patients, health professionals, and the environment.

Tackling potentially inappropriate prescriptions in older adults: development of deprescribing criteria by consensus from experts in Colombia, Argentina, and Spain.

BACKGROUND: Potentially inappropriate medication use is prevalent among older adults in primary care, leading to increased morbidity, adverse drug reactions, hospitalizations, and mortality. This study aimed to develop and validate a tool for identifying PIMs in older adults within the primary care setting. The tool is composed of a list of criteria and was created based on consensus among experts from three Spanish-speaking countries, including two from Latin America. METHODS: A literature review was conducted to identify existing tools, and prescription patterns were evaluated in a cohort of 36,111 older adults. An electronic Delphi method, consisting of two rounds, was used to reach a formal expert consensus. The panel included 18 experts from Spain, Colombia, and Argentina. The content validity index, validity of each content item, and Kappa Fleiss statistical measure were used to establish reliability. RESULTS: Round one did not yield a consensus, but a definitive consensus was reached in round two. The resulting tool consisted of a list of 5 general recommendations per disease, along with 33 criteria related to potential problems, recommendations, and alternative therapeutic options. The overall content validity of the tool was 0.87, with a Kappa value of 0.69 (95% CI 0.64-0.73; Substantial). CONCLUSIONS: The developed criteria provide a novel list that allows for a comprehensive approach to pharmacotherapy in older adults, intending to reduce inappropriate medication use, ineffective treatments, prophylactic therapies, and treatments with an unfavorable risk-benefit ratio for the given condition. Further studies are necessary to evaluate the impact of these criteria on health outcomes.

Safety Profile of Medicines Used for the Treatment of Drug-Resistant Tuberculosis: A Descriptive Study Based on the WHO Database (VigiBase®).

BACKGROUND: The introduction of new drugs that increase the usage of repurposed medicines for managing drug-resistant tuberculosis (DR-TB) comes with challenges of understanding, properly managing, and predicting adverse drug reactions (ADRs). In addition to the health consequences of ADRs for the individual, ADRs can reduce treatment adherence, thus contributing to resistance. This study aimed to describe the magnitude and characteristics of DR-TB-related ADRs through an analysis of ADRs reported to the WHO database (VigiBase) in the period from January 2018 to December 2020. METHODS: A descriptive analysis was performed on selected reports from VigiBase on the basis of medicine-potential ADR pairs. The ADRs were stratified by sex, age group, reporting country, seriousness, outcome of the reaction, and dechallenge and rechallenge. RESULTS: In total, 25 medicines reported to be suspected individual medicines or as a fixed-dose combination in the study period were included the study. Pyrazinamide (n = 836; 11.2%) was the most commonly reported medicine associated with ADRs, followed by ethionamide (n = 783; 10.5%) and cycloserine (n = 696; 9.3%). From the report included in this analysis, 2334 (31.2%) required complete withdrawal of the suspected medicine(s), followed by reduction of the dose (77; 1.0%) and an increased dose (4; 0.1%). Almost half of the reports were serious ADRs mainly caused by bedaquiline, delamanid, clofazimine, linezolid, and cycloserine that are the backbone of the DR-TB treatment currently in use. CONCLUSIONS: A third of the reports required medication withdrawal, which impacts treatment adherence and ultimately leads to drug resistance. Additionally, more than 40% of the reports indicated that ADRs appeared two months after the commencement of treatment, thus it's important to remain alert for the potential ADRs for the entire duration of the treatment.

Analysis of reported adverse liver reactions associated with drugs used to treat patients with coronavirus disease 2019

Abstract Hepatic injury has been documented in patients with coronavirus disease 2019 (COVID-19). However, pharmacotherapy can frequently impact liver alterations, given the known hepatotoxic potential of drugs not effective to treat COVID-19. The objective of the present study was to evaluate reports of suspected liver reactions to drugs used for treating COVID-19, compare their use for other indications among patients with COVID-19, and assess possible interactions between them. We obtained reports on drugs used to treat COVID-19 (tocilizumab, remdesivir, hydroxychloroquine, and/or lopinavir/ritonavir), registered on June 30, 2020, from the Food and Drug Administration Adverse Event Reporting System (FAERS) Public Dashboard. We then analyzed the risk of developing liver events with these drugs by calculating the reported odds ratios (ROR). We identified 662, 744, and 1381 reports related to tocilizumab, lopinavir/ ritonavir, and hydroxychloroquine use, respectively. The RORs (95% confidence intervals) were 6.32 (5.28-7.56), 6.12 (5.22-7.17), and 9.07 (8.00-10.29), respectively, demonstrating an increased risk of liver events among patients with COVID-19 when compared with uninfected patients. The elevated risk of reporting adverse liver events in patients with COVID-19 who receive these drugs, alone or in combination, highlights the need for careful drug selection and efforts to reduce drug combinations without notable benefits. Similar to any other condition, the use of drugs without established efficacy should be avoided.

Impact of a system to assist in clinical decision-making in primary healthcare in Catalonia: prescription Self Audit.

BACKGROUND: In 2008, in the context of a complete computerisation of medical records, the Institut Català de la Salut (ICS, Catalan Health Institute) implemented a system in its electronic clinical workstation (ECW) to assist decision-making at the prescription level. This system is known as Self Audit, and it supports physicians in reviewing the medication of their patients. Self Audit provides lists of patients presenting medication-related problems (MRPs) that have potential for improvement, and provides therapeutic recommendations that are easy to apply from the system itself. The aim of this study was to analyse the main results derived from the use of Self Audit in primary care (PC) in Catalonia, and the effect of an incentive-based safety indicator on the results obtained. METHODS: A descriptive cross-sectional study was carried out to analyse variations in the MRPs detected by Self Audit during 2016, 2017, and 2018 in PC in Catalonia. The effect of a safety indicator on the results obtained was also studied. This safety indicator includes the most clinically relevant MRPs (i.e., therapeutic duplications, safety alerts from the Spanish Medicines Agency, and incidences of polymedication in patients over 65 years of age). Variation in the MRPs was measured using the differences between two evaluation points (initial and final). An MRP was considered resolved if the recommendation specified in the alert was followed. The prescriptions of 6411 PC doctors of the ICS who use the ECW and provide their services to 5.8 million Catalans through 288 PC teams were analysed. RESULTS: Analysis of the total safety-based MRPs detected by Self Audit gave overall resolutions from April to December of 9% (21,547) in 2016, 7% (15,924) in 2017, and 1% (2392) in 2018 out of the total number of MRPs recorded in April each year. Examination of the 3 types of MRPs with the highest clinical relevance that were linked to the safety indicator gave overall resolutions of 41% in 2016 (17,358), 20% in 2017 (7655), and 21% in 2018 (8135). CONCLUSIONS: The ICS Self Audit tool assists in reducing the number of safety-based MRPs in a systematic manner, and yields superior results for the MRPs linked to a safety indicator included in the incentives of PC physicians.

Bleeding associated with self-medication in warfarin users: A prospective observational study in Ijuí (Brazil)

Abstract Warfarin has been associated with bleeding and venous thromboembolism. Objective: This study aimed to estimate the association between bleeding and concomitant self-medication, and the incidence of adverse drug reactions in patients using warfarin. Setting: the public health network of Ijuí, a municipality in southern Brazil. This was an open prospective cohort, conducted for a period of 18 months with users of warfarin, treated at the public health service. The association between bleeding and self-medication was evaluated by means of the Cox Model with left truncation, using the time variable. Main outcome measurement: bleeding reported in the follow-up. Cases of thromboembolism and death were also registered. All patients treated with warfarin in the public health system of the municipality (98) were identified. Sixty-eight were interviewed and followed up, of whom 63 completed follow-up and five died during the study. Bleeding rates of 37.7 /100 patients/year, thromboembolism of 4.8/100 patients / year and deaths of 4.8 /100 patients / year were observed. The results showed that patients, who take warfarin and self-medicated present a two-fold increased bleeding, compared with those who do not self-medicate. The bleeding risk associated with self-medication ranged from 2.001 to 2.685; those values maintained their significance even when adjusted for number of interactions, CYP polymorphism, TTR and age in COX analysis. These results greatly suggest the need for providing greater assistance to patients who take anticoagulant medications with the purpose of reducing self-medication and consequently, adverse reactions.

Safer prescription of drugs: impact of the PREFASEG system to aid clinical decision-making in primary care in Catalonia.

BACKGROUND: In 2008, the Institut Català de la Salut (ICS, Catalan Health Institute) implemented a prescription decision support system in its electronic clinical workstation (ECW), which automatically generates online alerts for general practitioners when a possible medication-related problem (MRP) is detected. This tool is known as PREFASEG, and at the time of beginning a new treatment, it automatically assesses the suitability of the treatment for the individual patient. This analysis is based on ongoing treatments, demographic characteristics, existing pathologies, and patient biochemical variables. As a result of the assessment, therapeutic recommendations are provided. The objective of this study is to present the PREFASEG tool, analyse the main alerts that it generates, and determine the degree of alert acceptance. METHODS: A cross-sectional descriptive study was carried out to analyse the generation of MRP-related alerts detected by PREFASEG during 2016, 2017, and 2018 in primary care (PC) in Catalonia. The number of MRP alerts generated, the drugs involved, and the acceptance/rejection of the alerts were analysed. An alert was considered "accepted" when the medication that generated the alert was not prescribed, thereby following the recommendation given by the tool. The MRP alerts studied were therapeutic duplications, safety alerts issued by the Spanish Medicines Agency, and drugs not recommended for use in geriatrics. The prescriptions issued by 6411 ICS PC physicians who use the ECW and provide their services to 5.8 million Catalans through 288 PC teams were analysed. RESULTS: During the 3 years examined, 67.2 million new prescriptions were analysed, for which PREFASEG generated 4,379,866 alerts (1 for every 15 new treatments). A total of 1,222,159 alerts (28%) were accepted. Pharmacological interactions and therapeutic duplications were the most detected alerts, representing 40 and 30% of the total alerts, respectively. The main pharmacological groups involved in the safety alerts were nonsteroidal anti-inflammatory drugs and renin-angiotensin system inhibitors. CONCLUSIONS: During the period analysed, 28% of the prescriptions wherein a toxicity-related PREFASEG alert was generated led to treatment modification, thereby helping to prevent the generation of potential safety MRPs. However, the tool should be further improved to increase alert acceptance and thereby improve patient safety.

Pharmacovigilance Data as a Trigger to Identify Antimicrobial Resistance and Inappropriate Use of Antibiotics: A Study Using Reports from The Netherlands Pharmacovigilance Centre.

(1) Background: Antimicrobial resistance (AMR) requires urgent multidisciplinary solutions, and pharmacovigilance has the potential to strengthen current antimicrobial stewardship strategies. This study aimed to characterize AMR-relevant adverse drug reaction (ADR) reports submitted to The Netherlands Pharmacovigilance Centre; (2) Methods: We carried out a descriptive analysis of ADR reports submitted to Lareb, coded with AMR-relevant MedDRA Preferred Terms (PTs); (3) Results: Between 1998 and January 2019, 252 AMR-relevant ADR reports were submitted to Lareb. The most frequent antibiotics were tobramycin (n = 89; 35%), colistin (n = 30; 11.9%), cipro-floxacin (n = 16; 6.3%), doxycycline (n = 14; 5.5%), and aztreonam (n = 12; 4.8%). The PTs used included off label use (n = 91; 36.1%), drug ineffective (n = 71; 28.2%), product use in unapproved indication (n = 28; 11.1%), pathogen resistance (n = 14; 5.6%), and drug resistance (n = 13; 5.2%). 54% of the reports were on Watch antibiotics and 19% were involved in the Reserve group. In the Watch group, "off label use" and "product use in unapproved indication" were the most frequent PTs and the majority of reports on Reserve antibiotics were coded as "Off label". A sharp increase in the number of reports was observed in the three consecutive years with 21 in 2013, 54 in 2014, and 83 in 2015; (4) Conclusions: In addition to existing AMR monitoring strategies, pharmacovigilance databases can serve as a source of data on suspected resistance and inappropriate use. Future research should explore how these AMR-relevant MedDRA Terms are used in resource-limited settings with less capacity to generate laboratory-confirmed resistance data.

Potential kidney damage associated with the use of remdesivir for COVID-19: analysis of a pharmacovigilance database.

The U.S. Food and Drug Administration (FDA) has stated that the prescription of remdesivir should be cautious for patients with estimated glomerular filtration rate (eGFR) < 30 and some studies reported risk of adverse renal events. The available information on the renal safety profile for remdesivir is limited, thus we analyzed the renal and urinary adverse reactions attributed to remdesivir reported in a large open pharmacovigilance database. We obtained reports of remdesivir and other drugs used to treat COVID-19 (tocilizumab, hydroxychloroquine, lopinavir/ritonavir) registered by September 30 2020, from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed the reporting odds ratios (RORs) for reports of adverse renal and urinary events for remdesivir and other drugs. We found 2,922 reports with remdesivir registered in FAERS for COVID-19. Among these, 493 renal and urinary adverse effects (16.9%) were reported. The most frequent events were acute kidney injury (338; 11.6%), renal impairment (86; 2.9%), and renal failure (53; 1.8%). Versus hydroxychloroquine, lopinavir/ritonavir, or tocilizumab, the use of remdesivir was associated with an increased chance of reporting renal and urinary disorders regardless of gender and age of patients (2.53; 95%CI: 2.10-3.06). The ROR remained significant when we restricted the analysis to hydroxychloroquine (4.31; 95%CI: 3.25-5.71) or tocilizumab (3.92; 95%CI: 2.51-6.12). Our results reinforce this already reported signal, emphasizing that it could be extremely useful for health professionals who prescribe this new antiviral to treat COVID-19, mainly knowing its low efficacy.

Pharmacovigilance network as an additional tool for the surveillance of antimicrobial resistance.

BACKGROUND: The WHO Programme for International Drug Monitoring (PIDM) is a large Pharmacovigilance network of countries sharing Adverse Drug Reaction (ADR) reports. Pharmacovigilance Experts have suggested that antimicrobial resistance (AMR) is an overlooked adverse event. We undertook this study to investigate the potential role of Pharmacovigilance databases in the surveillance of AMR. METHODS: Using the AWaRe (Access, Watch and Reserve) list and the WHO Priority Pathogens List, we established a list of antimicrobials and carried out a VigiBase search via VigiAccess, looking for ADR reports with Preferred Terms (PTs) that contained AMR-relevant information. Identified Terms were matched with codes from the Medical Dictionary for Regulatory Activities (MedDRA Version 21.1). RESULTS: Records on 86 drugs were retrieved with a total of 1 170 751 ADR reports submitted between 1968 and 2018. Seventeen PTs suggesting suspected resistance, ineffectiveness, inappropriate use, or medication error were used to code 15 250 reports. The most frequently used PTs were "Drug Ineffective" (45.6%), "Off label use" (9.5%) and "Pathogen Resistance" (8.9%). A group of six agents (Amoxicillin, Cefalotin, Ciprofloxacin, Clarithromycin, Levofloxacin and Daptomycin) accounted for 38% (n = 5806) of all 15 250 AMR-relevant ADR reports. The PTs most frequently used in 5806 reports were grouped in 4 categories: drug ineffectiveness (62.5%), resistance (19.2%), off-label use (12.1%) and prescription errors (6.2%). CONCLUSION: Our findings suggest that Pharmacovigilance databases could serve as a tool in tracking antimicrobial use and resistance especially in settings where laboratory capacity is still in its development stages. National Pharmacovigilance centers could play a proactive role in stimulating the reporting of AMR-relevant ADRs which can serve as a basis for resistance suspicion alerts. Further studies focusing on the narrative and other clinical pharmacology details in ADR reports are required.

Antimicrobial stewardship: can we add pharmacovigilance networks to the toolbox?

BACKGROUND: Antimicrobial resistance (AMR) is no longer an expected upcoming threat; it has become a real public health concern, challenging all existing control tools, requiring multidisciplinary innovative solutions. Antimicrobial stewardship (AMS) programs require a set of tools and skills which can be put to service by health systems. However, there is an immense capacity gap between health systems in developed countries compared to developing ones. Systems in developed countries can rely on well-established laboratory services that can carry out microbial cultures and drug susceptibility tests. For many low- and middle-income countries (LMICs) with limited laboratory resources, it will take time and long-term investments to have systems that can timely and reliably perform laboratory-based AMR monitoring. In the meantime, we must explore the possibility of using other indirect measures that can provide estimates of the growing burden of AMR in settings with weak laboratory capacity. OBJECTIVES: In this point of view, we describe the potential contribution of the global pharmacovigilance (PV) networkers in the process of mapping and estimating the AMR burden in settings with less laboratory coverage and capacity, within the framework of AMS. CONCLUSION: The heavy toll caused by AMR will not be brought down by a singular interventional approach, it will require a multidisciplinary and multifaceted set of strategies. Closing the laboratory capacity gap will require tremendous long-term investments, but the AMR data scarcity is a question that cannot wait any longer. The global pharmacovigilance network is a robust scientific community with experience in tracking suspected adverse events caused by new and old medicinal products. As AMR becomes a global health issue, AMS programs need all available tools to address resistance data scarcity and inform appropriate of antimicrobials. The solid global pharmacovigilance infrastructure could play an important role in countries with limited laboratory coverage and capacity.

Potential kidney damage associated with the use of remdesivir for COVID-19: analysis of a pharmacovigilance database / Potencial nefropatia associada ao uso do remdesivir para COVID-19: análise de uma base de dados de farmacovigilância / Potenciales lesiones renales asociadas con el uso de remdesivir para la COVID-19: análisis de una base de datos de farmacovigilancia

Abstract: The U.S. Food and Drug Administration (FDA) has stated that the prescription of remdesivir should be cautious for patients with estimated glomerular filtration rate (eGFR) < 30 and some studies reported risk of adverse renal events. The available information on the renal safety profile for remdesivir is limited, thus we analyzed the renal and urinary adverse reactions attributed to remdesivir reported in a large open pharmacovigilance database. We obtained reports of remdesivir and other drugs used to treat COVID-19 (tocilizumab, hydroxychloroquine, lopinavir/ritonavir) registered by September 30 2020, from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed the reporting odds ratios (RORs) for reports of adverse renal and urinary events for remdesivir and other drugs. We found 2,922 reports with remdesivir registered in FAERS for COVID-19. Among these, 493 renal and urinary adverse effects (16.9%) were reported. The most frequent events were acute kidney injury (338; 11.6%), renal impairment (86; 2.9%), and renal failure (53; 1.8%). Versus hydroxychloroquine, lopinavir/ritonavir, or tocilizumab, the use of remdesivir was associated with an increased chance of reporting renal and urinary disorders regardless of gender and age of patients (2.53; 95%CI: 2.10-3.06). The ROR remained significant when we restricted the analysis to hydroxychloroquine (4.31; 95%CI: 3.25-5.71) or tocilizumab (3.92; 95%CI: 2.51-6.12). Our results reinforce this already reported signal, emphasizing that it could be extremely useful for health professionals who prescribe this new antiviral to treat COVID-19, mainly knowing its low efficacy.

Resumo: De acordo com a Agência de Controle de Alimentos e Medicamentos dos Estados Unidos (FDA), a prescrição do remdesivir deve ser feita com cautela em pacientes com taxa de filtração glomerular estimada (TFGe) < 30, sendo que diversos estudos relatam risco de eventos adversos renais. São limitados os dados disponíveis sobre o perfil de segurança renal do remdesivir. Assim, analisamos as reações adversas renais e urinárias atribuídas ao remdesivir e notificadas em um grande base de dados abertos de farmacovigilância. Obtivemos notificações sobre remdesivir e outros medicamentos usados para tratar a COVID-19 (tocilizumabe, hidroxicloroquina, lopinavir/ritonavir) registradas até 30 de setembro de 2020 do Sistema de Notificação de Eventos Adversos da FDA (FAERS). Analisamos as razões de chances de notificação (RORs) para notificações de eventos adversos renais e urinários referentes ao remdesivir e outros medicamentos. Encontramos 2.922 notificações sobre remdesivir registradas no FAERS para COVID-19. Entre esses casos, foram notificados 493 efeitos adversos renais e urinários (16,9%). Os eventos mais frequentes foram lesão renal aguda (338; 11,6%), comprometimento renal (86; 2,9%) e insuficiência renal (53; 1,8%). Comparado com a hidroxicloroquina, lopinavir/ritonavir ou tocilizumabe, o uso do remdesivir esteve associado com um aumento das chances de notificação de transtornos renais e urinários, independentemente do sexo e idade dos pacientes (2,53; IC95%: 2,10-3,06). A ROR permaneceu significativo quando limitamos a análise à hidroxicloroquina (4,31; IC95%: 3,25-5,71) ou ao tocilizumabe (3,92; IC95%: 2,51-6,12). Nossos resultados corroboram outros estudos e destacam a utilidade para profissionais da saúde que usam esse novo antiviral para tratar a COVID-19, sobretudo em função de sua baixa eficácia.

Resumen: La Agencia Americana de Control de Alimentos y Medicamentos (FDA) ha destacado que la prescripción de remdesivir debe ser prudente con pacientes con tasa de filtración glomerular estimada (TGFe) < 30; además, algunos estudios informaron del riesgo de reacciones adversas renales. La información disponible sobre el perfil de seguridad renal, en el caso del remdesivir, es limitada. Por ello, analizamos las reacciones adversas renales y urinarias atribuidas al remdesivir e notificadas en una extensa base de datos abierta de farmacovigilancia. Obtuvimos las notificaciones de remdesivir y otros medicamentos usados para tratar la COVID-19 (tocilizumab, hidroxicloroquina, lopinavir/ritonavir) registrados el 30 de septiembre de 2020 por el Sistema de Notificación de Eventos Adversos de la FDA (FAERS). Analizamos las odds ratios informadas (RORs) en el caso de informes de eventos adversos renales y urinarios adversos relacionados con el remdesivir y otros medicamentos. En el FAERS, encontramos 2.922 notificaciones de remdesivir registradas como medicament sospechoso usado en COVID-19. De estos, habían 493 con efectos renales y urinarios adversos (16,9%). Los efectos adversos más frecuentes fueron lesiones renales agudas (338; 11,6%), insuficiencia renal (86; 2,9%), y fallo renal (53; 1,8%). Frente a hidroxicloroquina, lopinavir/ritonavir, o tocilizumab, el uso de remdesivir se asoció con un riesgo mayor de notificar alteraciones renales y urinarios, independientemente del género y edad de los pacientes (2,53; IC95%: 2,10-3,06). La ROR permaneció significativo al restringir el análisis a la hidroxicloroquina (4,31; IC95%: 3,25-5,71) o tocilizumab (3,92; IC95%: 2,51-6,12). Nuestros resultados corroboran datos previos, algo que podría ser extremadamente útil para los profesionales de la salud que decidan usar este nuevo antiviral para tratar la COVID-19, sobre todo conociendo su baja eficacia.

Development of a stepwise tool to aide primary health care professionals in the process of deprescribing in older persons.

OBJECTIVE: The aim of this study was to develop and validate a stepwise tool to aid primary health care professionals in the process of deprescribing potentially inappropriate medication in older persons. METHODS: We carried out a systematic review to identify previously published tools. A composite proposal of algorithm was made by following the steps from clinical experience to deprescribe medications. A 2-round electronic Delphi method was conducted to establish consensus. Eighteen experts from different countries (Colombia, Spain and Argentina) accepted to be part of the panel representing geriatricians, internists, endocrinologist, general practitioners, pharmacologists, clinical pharmacists, family physicians and nurses. Panel members were asked to mark a Likert Scale from 1 to 9 points (1= strongly disagree, 9= strongly agree). The content validity ratio, item-level content validity, and Fleiss' Kappa statistics was measured to establish reliability. The same voting method was used for round 2. RESULTS: A 7-question algorithm was proposed. Each question was part of a domain and conduct into a decision. In round 1, a consensus was not reached but statements were grouped and organized. In round 2, the tool met consensus. The inter-rater reliability was between substantial and almost perfect for questions with Kappa=0.77 (95% CI 0.60-0.93), for domains with Kappa= 0.73 (95%CI 0.60-0.86) and for decisions with Kappa= 0.97 (95%CI 0.90-1.00). CONCLUSIONS: This is a novel tool that captures and supports healthcare professionals in clinical decision-making for deprescribing potentially inappropriate medication. This includes patient's and caregiver's preferences about medication. This tool will help to standardize care and provide guidance on the prescribing/deprescribing process of older persons' medications. Also, it provides a holistic way to reduce polypharmacy and inappropriate medications in clinical practice.

Development of a stepwise tool to aide primary health care professionals in the process of deprescribing in older persons

OBJECTIVE: The aim of this study was to develop and validate a stepwise tool to aid primary health care professionals in the process of deprescribing potentially inappropriate medication in older persons. METHODS: We carried out a systematic review to identify previously published tools. A composite proposal of algorithm was made by following the steps from clinical experience to deprescribe medications. A 2-round electronic Delphi method was conducted to establish consensus. Eighteen experts from different countries (Colombia, Spain and Argentina) accepted to be part of the panel representing geriatricians, internists, endocrinologist, general practitioners, pharmacologists, clinical pharmacists, family physicians and nurses. Panel members were asked to mark a Likert Scale from 1 to 9 points (1= strongly disagree, 9= strongly agree). The content validity‏ ratio, item-level content validity, and Fleiss' Kappa statistics was measured to establish reliability. The same voting method was used for round 2. RESULTS: A 7-question algorithm was proposed. Each question was part of a domain and conduct into a decision. In round 1, a consensus was not reached but statements were grouped and organized. In round 2, the tool met consensus. The inter-rater reliability was between substantial and almost perfect for questions with Kappa=0.77 (95% CI 0.60-0.93), for domains with Kappa= 0.73 (95%CI 0.60-0.86) and for decisions with Kappa= 0.97 (95%CI 0.90-1.00). CONCLUSIONS: This is a novel tool that captures and supports healthcare professionals in clinical decision-making for deprescribing potentially inappropriate medication. This includes patient's and caregiver's preferences about medication. This tool will help to standardize care and provide guidance on the prescribing/deprescribing process of older persons' medications. Also, it provides a holistic way to reduce polypharmacy and inappropriate medications in clinical practice

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The "Square Box": Therapeutic Equivalence as a Foundation of the WHO Model List of Essential Medicines.

Every two years, the World Health Organization (WHO) updates its Model List of Essential Medicines, intended as a guide for countries to adopt or adapt in accordance with local priorities and treatment guidelines, for the development of national essential medicines lists. When more than one therapeutic option is available for a given indication, the WHO Model List often includes a single medicine as representative of a group of equivalent and interchangeable medicines. The representative medicine of that group is listed with an accompanying 'square box' symbol. The intended purpose of the square box is to highlight pharmacological classes or groups of medicines for which countries, institutions and health professionals can assume homogeneous therapeutic efficacy and safety and select the most appropriate single medicine based on price, local availability, and acceptability. Though this concept of therapeutic equivalence within a therapeutic class has been endorsed by most authoritative textbooks of pharmacology since Goodman & Gilman's The Pharmacological Basis of Therapeutics and evidence-based guidelines, marketing forces have often made claims on individual drugs to distinguish them beyond relevant differences shown by reliable evidence: this has generated the concept of "me-too drugs" with its double meaning-i.e., market latecomers differing minimally from products preceding them and whose marketing budgets have significant opportunity costs, or medicines which may be useful to substitute for equivalent products in the event of shortages. The square box concept is applied in the context of a comprehensive list: therapeutic equivalence or interchangeability cannot always be easily established. Different interpretations have been applied to different groups of medicines over the 40+ year history of the Model List. This paper presents the concept of the square box, provides key examples and guidance on how square box listings should be practically interpreted in the development and implementation of national essential medicine lists, considers the applicability of a square box listing concept to biologic medicines and proposes that an updated review of the square box concept and listings is warranted.

Patterns of Antibiotic Prescription in Colombia: Are There Differences between Capital Cities and Municipalities?

The use of antibiotics is the most important modifiable risk factor for the development of microorganism resistance. A cross-sectional study of outpatients receiving antibiotic prescriptions registered in a population database in Colombia was conducted. The characteristics of the consumption in capital cities and small municipalities was studied and the AWaRe classification was used. AWaRe classifies antibiotics into three stewardship groups: Access, Watch and Reserve, to emphasize the importance of their optimal use and potential harms of antimicrobial resistance. A total of 182,397 patients were prescribed an antibiotic; the most common were penicillins (38.6%), cephalosporins (30.2%) and fluoroquinolones (10.9%). 'Access' antibiotics (86.4%) were the most frequently prescribed, followed by 'Watch' antibiotics (17.0%). Being 18 or older, being male, living in a municipality, having one or more comorbidities and urinary, respiratory or gastrointestinal disorders increased the probability of receiving 'Watch' or 'Reserve' antibiotics. Penicillin and urinary antiseptic prescriptions predominated in cities, while cephalosporin and fluoroquinolone prescriptions predominated in municipalities. This analysis showed that the goal set by the WHO Access of mainly using Access antibiotics is being met, although the high use of Watch antibiotics in municipalities should be carefully studied to determine if it is necessary to design specific campaigns to improve antibiotics use.

Substandard Quality of the Antimicrobials Sold in the Street Markets in Haiti.

This pilot study was conducted to analyze the quality of the antimicrobials sold in the street markets in Port-au-Prince, Haiti. A total of 258 packs containing antimicrobials were bought in 28 street markets in Port-au-Prince (Haiti). Tablets and contents of capsules included in 196 packs were analyzed using a Raman handheld spectrometer (NanoRAM of BWTEK, Model: BWS456-785) during the first quarter of 2019. Three out of 11 antimicrobials (Amoxicillin, Metronidazole, and Cotrimoxazole) had a high spectral match with an HQI ≥ 90 to the respective authentic medicine for more than 95% of their tablets/capsules. For six antimicrobials (Tetracycline, Erythromycin, Cloxacillin, Azithromycin, Clarithromycin, and the combination Amoxicillin + Clavulanic Acid) none of their tablets/capsules showed a sufficient spectral match with the authentic medicine. This finding indicates that these products sold in the markets did not contain the labeled drug and/or contained a degraded drug. In addition to the fact that prescription antimicrobials can be purchased in street markets, the present field study found that for most of them (including "Watch" antimicrobials according to the AWaRe classification) were substandard, which contributes to the present antimicrobials resistance epidemic.

Prescription of Levofloxacin and Moxifloxacin in Select Hospitals in Uganda: A Pilot Study to Assess Guideline Concordance.

Background: In Uganda, national tuberculosis (TB) treatment guidelines were revised to include the newer generation fluoroquinolones among the second-line treatment options for multidrug-resistant TB. This study was designed to analyze if the prescription of these quinolones is compliant with country recommendations. Methods: This was an observational retrospective study of consumption data for 2017 and 2018 across four selected regional referral hospitals. The sources of consumption data were hospital pharmacy stock cards and the dispensing register. The medical files of patients who had been prescribed fluoroquinolones were also assessed to study compliance with the Uganda Clinical Guidelines and the British National Formulary (BNF). Results: None of the 371 levofloxacin prescriptions analyzed complied with the Uganda Clinical Guidelines, although 250 (67.3%) were prescribed for indications included in the BNF. According to WHO prescription indicators, only 220 (59.3%) prescriptions were appropriate. Conclusion: The prescription of levofloxacin and moxifloxacin increased in the hospitals studied, but in a high proportion of cases, they were not compliant with country recommendations. The findings call for the strengthening of national antimicrobial stewardship programs.

Adverse drug reactions to anti-diabetic drugs are commonest in patients whose treatment do not adhere to diabetes management clinical guidelines: cross-sectional study in a tertiary care service in sub-Saharan Africa.

AIMS: The study aimed to identify and describe adverse drug reactions and adherence to clinical guidelines in patients receiving treatment for type 2 diabetes mellitus (T2DM) in Cameroon. METHODS: The method used was a cross-sectional study at a tertiary diabetes care service in Yaoundé, Cameroon. Adult T2DM patients attending the diabetes clinic were interviewed using a pre-structured data collection form. Adverse drug reactions (ADRs) were self-reported by the patients. Naranjo's algorithm and Hartwig and Siegel's scale were used for assessment of causality and severity of ADRs, respectively. A blinded senior endocrinologist assessed whether treatment pattern of patients was "adherent" or not to local clinical guidelines for the management of diabetes. RESULTS: Of a total of 350 patients enrolled into the study 61.1% were on oral hypoglycaemic agents only, 24.9% were on both oral hypoglycaemic agents and insulin, while 13.4% were on insulin alone. Metformin was used by 96.3% of the patients. Ninety patients reported 101 suspected ADRs. The proportion of ADRs among patients with poor adherence to clinical guidelines was higher than ADRs reported among adherent patients (Chi-square test = 7.3273; p = 0.007). Hypoglycaemia was more frequent ADR among non-adherent (25.7% of the suspected ADR) than adherent participants (11.6%). In the participants whose treatment pattern did not adhere to local clinical guidelines, ADRs were definite in 63.9%, probable in 16.6%, doubtful in 13.9% and possible in 5.6% of the cases. ADRs were moderate in 61.1% and severe in 19.4% of cases whose treatment pattern was non-adherent to clinical guidelines. INTERPRETATION: Adverse drug reactions may be frequent in type 2 diabetes patients whose treatment pattern does not adhere to local clinical guidelines in Cameroon. Therefore, the promotion of active pharmacovigilance and the design of training activities to promote the appropriate use of medicines at hospital level in Cameroon could help to improve the management of diabetes and reduce the incidence of avoidable ADRs in the future.

Medicines in Western Sahara Refugee Camps in Tindouf: Prescriptions and self-medication mixing in the drawer.

Problems with access to medicines, either by shortage or excess can be especially relevant in refugee camps. In the present study, we describe the medicines found in a sample of the Western Sahara refugee households, with special emphasis on antimicrobials and their use. All households of the 2nd district of Mahbes daira, in the Smara wilaya of the Sahrawi Refugee Camps in Tindouf (Algeria) were visited during 10 days in April 2019 in order to know which medicines are kept at home. Seventy-six families were included in the study and 269 medicines were found. Eight (10.5%) did not have any medical product at home and the remaining 68 (89.5%) had a median of 3 drugs, ranging from 1 to 13. The most consumed drugs were analgesics (35.7%) and antimicrobials (15.6%). Most medicines had been prescribed, but in the case of antimicrobials, an incomplete consumption pattern was observed in 42.9% of the cases and, more worrying, one-third of them were used to treat viral or non-infectious diseases. This first drug utilization study in the Saharawi population highlighted the importance, not only to ensure appropriate access to medicines in refugee's camps, but also to watch over their appropriate use.