Breakpoints for the Classification of Anti-Candida Compounds in Antifungal Screening

Introduction. The absence of a standardized classification scheme for the antifungal potency of compounds screened against Candida species may hinder the study of new drugs. This systematic review proposes a scheme of interpretative breakpoints for the minimum inhibitory concentration (MIC) of bioactive compounds against Candida species in in vitro tests. Materials and Methods. A literature search was conducted in the PubMed, Scopus, Web of Science, Lilacs, and SciFinder databases for the period from January 2015 to April 2020. The following inclusion criterion was used: organic compounds tested by the microdilution technique according to the Clinical and Laboratory Standards Institute protocol against reference strains of the genus Candida. A total of 545 articles were retrieved after removing duplicates. Of these, 106 articles were selected after applying the exclusion criteria and were evaluated according to the number of synthesized molecules and their chemical classes, the type of strain (reference or clinical) used in the antifungal test, the Candida species, and the MIC (in μg/mL) used. Results. The analysis was performed based on the median, quartiles (25% and 75%), maximum, and minimum values of four groups: all strains, ATCC strains, C. albicans strains, and C. albicans ATCC strains. The following breakpoints were proposed to define the categories: MIC2000 μg/mL (no bioactivity). Conclusions. A classification scheme of the antifungal potency of compounds against Candida species is proposed that can be used to identify the antifungal potential of new drug candidates

Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine

Submitted by Nuzia Santos ([email protected]) on 2020-02-13T16:57:29Z No. of bitstreams: 1 Pharmacokinetics.pdf: 4762495 bytes, checksum: bf79584ac633b8db094ea9acfd3ce854 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2020-02-13T17:04:18Z (GMT) No. of bitstreams: 1 Pharmacokinetics.pdf: 4762495 bytes, checksum: bf79584ac633b8db094ea9acfd3ce854 (MD5)Made available in DSpace on 2020-02-13T17:04:18Z (GMT). No. of bitstreams: 1 Pharmacokinetics.pdf: 4762495 bytes, checksum: bf79584ac633b8db094ea9acfd3ce854 (MD5) Previous issue date: 2019Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Vice-Presidência de Pesquisa e Coleções Biológicas. Rio de Janeiro, RJ, Brasil / Liver-pool School of Tropical Medicine, Liverpool, UK.Liver-pool School of Tropical Medicine, Liverpool, UK.Tropical Medicine Research Center of Rondonia (CEPEM). Porto Velho, RO, Brazil / Universidade Federal de Rondonia. Porto Velho, RO, Brazil.Fundação Oswaldo Cruz. Instituto Leônidas & Maria Deane. Manaus, AM, Brazil / Fundação de Medicina Tropical Medicine Dr. Heitor Vieira Dourado. Manaus, AM, Brazil.Fundação de Medicina Tropical Medicine Dr. Heitor Vieira Dourado. Manaus, AM, Brazil.Fundação de Medicina Tropical Medicine Dr. Heitor Vieira Dourado. Manaus, AM, Brazil.Fundação Oswaldo Cruz. Instituto Nacional de Doenças Infecciosas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Presidência. Vice-Presidência de Produção e Inovação em Saúde. Laboratório de Farmacocinética. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Presidência. Vice-Presidência de Produção e Inovação em Saúde. Laboratório de Farmacocinética. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Presidência. Vice-Presidência de Produção e Inovação em Saúde. Laboratório de Farmacocinética. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou, Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou, Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou, Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou, Belo Horizonte, MG, Brasil.Liver-pool School of Tropical Medicine, Liverpool, UK.Liver-pool School of Tropical Medicine, Liverpool, UK.Background: Activation of hypnozoites of vivax malaria causes multiple clinical relapses, which contribute to the Plasmodium vivax burden and continuing transmission. Artemisinin-based combination therapy (ACT) is effective against blood-stage P. vivax but requires co-administration with primaquine to achieve radical cure. The therapeutic efficacy of primaquine depends on the generation of a therapeutically active metabolite via cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 metabolism has been associated with primaquine treatment failure. This study investigated the association between impaired CYP2D6 genotypes, drug-exposure to the long-acting ACT component (schizonticidal drugs) and tolerance and efficacy. Methods: Adult patients with acute vivax malaria were enrolled in a recently completed trial and treated with artesunate–mefloquine, chloroquine or artemether–lumefantrine. All received concomitant primaquine (0.5 mg/kg/day for 7–9 days). The association between efficacy and safety and drug exposure was explored using area-under-the-curve (AUC) and half-life (t1/2) estimates obtained by non-compartmental analysis of the long half-life drugs. Parasite recurrences by day 63 were categorized as related relapses or re-infections/unrelated hypnozoite activation by genotyping three microsatellite loci and two polymorphic loci of merozoite surface antigen-1. The CYP2D6 genotype was identified with Taqman assays by real-time PCR to 9 polymorphisms (8 SNPs and one deletion). Impaired CYP2D6 activity was inferred using the Activity Score System. Results: Most recurrences in the ASMQ (67%), CQ (80%) and AL (85%) groups were considered related relapses. Eight of nine (88.9%) of the patients with impaired CYP2D6 activity relapsed with related parasite compared to 18/25 (72%) with normal activity (RR = 1.23, 0.88; 1.72, p = 0.40). There were no associations between the measured PK parameters and recurrence. Patients with longer chloroquine half-lives had more pruritus (RR = 1.09, 1.03; 1.14, p = 0.001). Higher CQ AUCs were associated with reduced falls in haemoglobin by day 14 (Coef − 0.02, − 0.005; − 0.03, p = 0.01). All regimens were well tolerated. Conclusion: Genotyping of P. vivax showed that activation of related (homologous) hypnozoites was the most frequent cause of recurrence. The high proportion of the impaired CYP2D6 activity among patients with recurrent infections suggests that slow primaquine metabolism might influence related relapse rates in Brazil among patients receiving primaquine for radical cure, although confirmatory studies are needed. There was no association between drug exposure of the long-acting ACT component (schizonticidal drugs) and risk of related relapse. ACT was well tolerated. These results provide further re-assuranceabout the safety and efficacy of ACT when combined with short course primaquine to treat uncomplicated malaria vivax in Brazil

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H2O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p<0·0001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0·80 [95% CI 0·75-0·86]; p<0·0001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status