Correction: Azithromycin consumption during the COVID-19 pandemic in Croatia, 2020.

[This corrects the article DOI: 10.1371/journal.pone.0263437.].

Azithromycin consumption during the COVID-19 pandemic in Croatia, 2020.

BACKGROUND: During the initial phase of the COVID-19 pandemic, there was great enthusiasm for the use of azithromycin with or without hydroxychloroquine. OBJECTIVES: We analyzed azithromycin consumption in Croatia in 2020 and compared this to the period 2017-2019. METHODS: Azithromycin consumption was evaluated using the IQVIA Adriatic d.o.o. database which collects data on azithromycin distribution from wholesale pharmacies to hospital and non-hospital pharmacies in Croatia. We analyzed data for the period from January 2017 to December 2020. Azithromycin distribution was measured as days of therapy (DOT) and reported as per 1000 inhabitants or per 1000 inhabitant-days. RESULTS: In the period 2017-2020, total azithromycin DOT in Croatia increased in 2017, 2018, 2019, and 2020 (1.76, 1.91, 1.91 and 2.01/1000 inhabitant-days, respectively). Non-hospital pharmacies received 2.18 times and hospital pharmacies 4.39 times more DOT units/1000 inhabitants of azithromycin in March 2020 compared to the average distribution rate in March 2017-2019. During the peak of the COVID-19 epidemic (November and December 2020) azithromycin distribution increased considerably in hospital (3.62 and 3.19 times, respectively) and non-hospital pharmacies (1.93 and 1.84 times, respectively) compared to the average consumption in the same months in 2017-2019. CONCLUSIONS: Our data showed increased azithromycin distribution in the period 2017-2020 which indicates azithromycin overuse. Preliminary information on COVID-19 treatments with a desire to offer and try what is available even in the absence of strong scientific evidence may have influenced practices of antimicrobial prescriptions.

Immunometabolic Modulatory Role of Naltrexone in BV-2 Microglia Cells.

Background: Naltrexone is an opioid receptor antagonist commonly used to treat opioid and alcohol dependence. The use of low dose naltrexone (LDN) was found to have anti-inflammatory properties for treatment of diseases such as fibromyalgia, Crohn's disease, multiple sclerosis and regional pain syndromes. Related to its anti-neuroinflammatory properties, the mechanism of action is possibly mediated via Toll-like receptor 4 antagonism, which is widely expressed on microglial cells. The aim of the present study was to assess the immunometabolic effects of naltrexone on microglia cells in in vitro conditions. METHODS: All experiments were performed in the BV-2 microglial cell line. The cells were treated with naltrexone at 100 µM concentrations corresponding to low dose for 24 h. Cell viability was assessed for every drug dose. To induce additional activation, the cells were pretreated with LPS and IFN-γ. Immunofluorescence was used to analyse the classical microglial activation markers iNOS and CD206, while Seahorse was used for real-time cellular metabolic assessments. mTOR activity measured over the expression of a major direct downstream target S6K was assessed using western blot. RESULTS: LDN induced a shift from highly activated pro-inflammatory phenotype (iNOShighCD206low) to quiescent anti-inflammatory M2 phenotype (iNOSlowCD206high) in BV-2 microglia cells. Changes in the inflammatory profile were accompanied by cellular metabolic switching based on the transition from high glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). LDN-treated cells were able to maintain a metabolically suppressive phenotype by supporting OXPHOS with high oxygen consumption, and also maintain a lower energetic state due to lower lactate production. The metabolic shift induced by transition from glycolysis to mitochondrial oxidative metabolism was more prominent in cells pretreated with immunometabolic modulators such as LPS and IFN-γ. In a dose-dependent manner, naltrexone also modulated mTOR/S6K expression, which underlies the cell metabolic phenotype regulating microglia immune properties and adaptation. CONCLUSION: By modulating the phenotypic features by metabolic switching of activated microglia, naltrexone was found to be an effective and powerful tool for immunometabolic reprogramming and could be a promising novel treatment for various neuroinflammatory conditions.

Implementation of medication management services at the primary healthcare level - a pilot study.

This study employed a mixed-method approach to enable the implementation of comprehensive medication management (CMM) services in Croatia's primary care setting. Drug therapy problems (DTPs) and factors associated with their occurrence were determined in patients with chronic diseases from January 2018 to April 2019. The pre-implementation stage established the foundations for the early implementation stage, in which the practice was set up, the patients' recruitment initiated and various challenges identified. During the study period, 86 patients were recruited for CMM provision. Overall, 2.8 DTPs (± 1.6) per patient were identified and the majority (96.2 %) presented with at least one DTP. Multiple regression analysis showed that type 2 diabetic patients (p = 0.025) and patients using five or more medications (p = 0.011) should be prioritized to receive CMM services as potentially they have a higher number of DTPs, and could, therefore, obtain a greater benefit from the service.