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1.
Am J Trop Med Hyg ; 103(3): 960-964, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32705976

RESUMO

The world is currently facing a novel COVID-19 pandemic caused by SARS-CoV-2 that, as of July 12, 2020, has caused a reported 12,322,395 cases and 556,335 deaths. To date, only two treatments, remdesivir and dexamethasone, have demonstrated clinical efficacy through randomized controlled trials (RCTs) in seriously ill patients. The search for new or repurposed drugs for treatment of COVID-19 continues. We have witnessed anecdotal use of herbal medicines, including Artemisia spp. extracts, in low-income countries, and exaggerated claims of their efficacies that are not evidence based, with subsequent political controversy. These events highlight the urgent need for further research on herbal compounds to evaluate efficacy through RCTs, and, when efficacious compounds are identified, to establish the active ingredients, develop formulations and dosing, and define pharmacokinetics, toxicology, and safety to enable drug development. Derivatives from the herb Artemisia annua have been used as traditional medicine over centuries for the treatment of fevers, malaria, and respiratory tract infections. We review the bioactive compounds, pharmacological and immunological effects, and traditional uses for Artemisia spp. derivatives, and discuss the challenges and controversies surrounding current efforts and the scientific road map to advance them to prevent or treat COVID-19.


Assuntos
Artemisia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Artemisia/química , COVID-19 , Humanos , Pandemias , Extratos Vegetais/farmacologia , SARS-CoV-2 , Tratamento Farmacológico da COVID-19
2.
Eur Respir J ; 49(5)2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28526799

RESUMO

Cystic fibrosis (CF) patients receive chronic treatment with macrolides for their antivirulence and anti-inflammatory properties. We, however, previously showed that Pseudomonas aeruginosa, considered as naturally resistant to macrolides, becomes susceptible when tested in a eukaryotic medium rather than a conventional broth.We therefore looked for specific macrolide resistance determinants in 333 CF isolates from four European CF centres in comparison with 48 isolates from patients suffering from hospital-acquired pneumonia (HAP).Minimum inhibitory concentrations (MICs) of macrolides and ketolides measured in eukaryotic medium (RPMI-1640) were higher towards CF than HAP isolates. Gene sequencing revealed mutations at three positions (2045, 2046 and 2598) in domain V of 23S rRNA of 43% of sequenced CF isolates, but none in HAP isolates. Enzymes degrading extracellular polymeric substances also reduced MICs, highlighting a role of the mucoid, biofilm-forming phenotype in resistance. An association between high MICs and chronic azithromycin administration was evidenced, which was statistically significant for patients infected by the Liverpool Epidemic Strain.Thus, ribosomal mutations are highly prevalent in CF isolates and may spread in epidemic clones, arguing for prudent use of oral macrolides in these patients. Measuring MICs in RPMI-1640 could be easily implemented in microbiology laboratories to phenotypically detect resistance.


Assuntos
Antibacterianos/uso terapêutico , Fibrose Cística/microbiologia , Farmacorresistência Bacteriana/genética , Macrolídeos/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/genética , Administração Oral , Adolescente , Adulto , Membrana Celular/metabolismo , Criança , Pré-Escolar , Doença Crônica , Fibrose Cística/tratamento farmacológico , Europa (Continente) , Humanos , Lactente , Cetolídeos/uso terapêutico , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mutação , Permeabilidade , Fenótipo , Ribossomos/metabolismo , Análise de Sequência de DNA , Adulto Jovem
3.
Int J Antimicrob Agents ; 47(1): 77-83, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26691019

RESUMO

Increases in antibiotic minimum inhibitory concentrations (MICs) for Pseudomonas aeruginosa during treatment are commonly observed but their relationship to efflux overexpression remains poorly documented. In this study, pairs of first [at time of diagnosis (D0)] and last [during treatment (DL)] P. aeruginosa isolates were obtained from patients treated for suspicion of nosocomial pneumonia. Pair clonality was determined by repetitive extragenic palindromic PCR. Overexpression of mexA and mexX was assessed by real-time PCR, and expression of mexC and mexE was assessed by PCR. Antibiotics received by patients before and during treatment were determined from clinical charts. For D0 isolates, 24% were from patients without antibiotics for 1 month and 64% were negative for mexA/mexX overexpression and mexC/mexE expression. For DL isolates, approximately one-half of the patients had received piperacillin/tazobactam, amikacin, meropenem and/or cefepime, and 17% had received ciprofloxacin (alone or in combination); 38% did not show changes in expression of the four genes, whereas 38% showed increased expression for one gene (mainly mexA or mexX), 19% for two genes (mainly mexA and mexX) and 5% for three or four genes. Isolates overexpressing mexA or mexX had median MICs above EUCAST clinical resistance breakpoints for ciprofloxacin, cefepime and meropenem, or for ciprofloxacin, amikacin, cefepime and meropenem, respectively. mexA or mexX overexpression was statistically significantly associated with patients' exposure to ciprofloxacin and meropenem or cefepime and meropenem, respectively. Overexpression of genes encoding antibiotic transporters in P. aeruginosa during treatment is frequent and is associated with increases in MICs above EUCAST clinical susceptibility breakpoints.


Assuntos
Antibacterianos/metabolismo , Farmacorresistência Bacteriana , Proteínas de Membrana Transportadoras/genética , Pneumonia Bacteriana/microbiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Transporte Biológico , Expressão Gênica , Perfilação da Expressão Gênica , Genes Bacterianos , Humanos , Testes de Sensibilidade Microbiana , Reação em Cadeia da Polimerase , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/isolamento & purificação
4.
Antimicrob Agents Chemother ; 59(8): 4750-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26014952

RESUMO

The pyrrolocytosine RX-P873, a new broad-spectrum antibiotic in preclinical development, inhibits protein synthesis at the translation step. The aims of this work were to study RX-P873's ability to accumulate in eukaryotic cells, together with its activity against extracellular and intracellular forms of infection by Staphylococcus aureus and Pseudomonas aeruginosa, using a pharmacodynamic approach allowing the determination of maximal relative efficacies (Emax values) and bacteriostatic concentrations (Cs values) on the basis of Hill equations of the concentration-response curves. RX-P873's apparent concentration in human THP-1 monocytes was about 6-fold higher than the extracellular one. In broth, MICs ranged from 0.125 to 0.5 mg/liter (S. aureus) and 2 to 8 mg/liter (P. aeruginosa), with no significant shift in these values against strains resistant to currently used antibiotics being noted. In concentration-dependent experiments, the pharmacodynamic profile of RX-P873 was not influenced by the resistance phenotype of the strains. Emax values (expressed as the decrease in the number of CFU from that in the initial inoculum) against S. aureus and P. aeruginosa reached more than 4 log units and 5 log units in broth, respectively, and 0.7 log unit and 2.7 log units in infected THP-1 cells, respectively, after 24 h. Cs values remained close to the MIC in all cases, making RX-P873 more potent than antibiotics to which the strains were resistant (moxifloxacin, vancomycin, and daptomycin for S. aureus; ciprofloxacin and ceftazidime for P. aeruginosa). Kill curves in broth showed that RX-P873 was more rapidly bactericidal against P. aeruginosa than against S. aureus. Taken together, these data suggest that RX-P873 may constitute a useful alternative for infections involving intracellular bacteria, especially Gram-negative species.


Assuntos
Guanidinas/uso terapêutico , Monócitos/microbiologia , Inibidores da Síntese de Proteínas/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Pirimidinonas/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/uso terapêutico , Ceftazidima/uso terapêutico , Células Cultivadas , Ciprofloxacina/uso terapêutico , Daptomicina/uso terapêutico , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Fluoroquinolonas/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana/métodos , Moxifloxacina , Vancomicina/uso terapêutico
5.
Antimicrob Agents Chemother ; 59(1): 178-85, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25331703

RESUMO

Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [± standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 µM versus 6.4 ± 1.2 µM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies.


Assuntos
Antibacterianos/farmacocinética , Linezolida/farmacocinética , Mitocôndrias/efeitos dos fármacos , Oxazolidinonas/farmacocinética , Tetrazóis/farmacocinética , Animais , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Técnicas In Vitro , Linezolida/efeitos adversos , Linezolida/farmacologia , Masculino , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/biossíntese , Método de Monte Carlo , Síndromes Neurotóxicas/etiologia , Oxazolidinonas/efeitos adversos , Oxazolidinonas/farmacologia , Ratos Endogâmicos LEC , Tetrazóis/efeitos adversos , Tetrazóis/farmacologia , Testes de Toxicidade Crônica/métodos
6.
J Antimicrob Chemother ; 67(12): 2873-81, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23002174

RESUMO

OBJECTIVES: Phagocytosed methicillin-resistant Staphylococcus aureus (MRSA) are susceptible to ß-lactams because of an acid-induced conformational change of penicillin-binding protein (PBP) 2a within phagolysosomes. We have examined whether this mechanism applies to menD and hemB small-colony variants (SCVs) of the COL MRSA strain, using cloxacillin, meropenem, doripenem, and vancomycin as comparator. METHODS: Intracellularly, the change in cfu from post-phagocytosis inoculum was measured after 24 h of incubation with antibiotics combined or not with N-acetylcysteine (NAC; oxidant species scavenger); the relative potency (C(s)) was calculated from the Hill equation of concentration-response curves. Extracellularly, the effect of a pre-incubation with H(2)O(2) was determined on MICs and killing at pH 7.4 and 5.5. RESULTS: Intracellularly, the ß-lactam C(s) was similar for the COL strain and the hemB mutant and not modified or slightly decreased (2- to 16-fold) by NAC. In contrast, the C(s) was 100- to 900-fold lower for the menD mutant, but similar to that for the COL strain when NAC was present. Extracellularly, ß-lactam MICs were markedly reduced at pH 5.5 for the parental strain and the haemin-supplemented hemB mutant, with limited additional effect of pre-incubation with H(2)O(2). In contrast, MICs remained elevated at pH 5.5 for the menD mutant (supplemented with menadione sodium bisulphite or not), but were 7-10 dilutions lower after pre-incubation with H(2)O(2). Vancomycin MICs were unaltered in all conditions, with no marked effect of NAC on C(s). CONCLUSIONS: Cooperation between acidic pH and oxidant species confers high potency to ß-lactams against intracellular forms of menD SCVs of MRSA.


Assuntos
Ácidos Carboxílicos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Monócitos/microbiologia , Oxidantes/farmacologia , Vitamina K 3/metabolismo , beta-Lactamas/farmacologia , Antibacterianos/farmacologia , Linhagem Celular , Contagem de Colônia Microbiana , Experimentação Humana , Humanos , Concentração de Íons de Hidrogênio , Staphylococcus aureus Resistente à Meticilina/metabolismo , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Monócitos/imunologia , Fagocitose , Vacúolos/química , Vacúolos/microbiologia
7.
PLoS One ; 6(12): e28368, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22162766

RESUMO

Exposure of J774 mouse macrophages to stepwise increasing concentrations of ciprofloxacin, an antibiotic inhibiting bacterial topoisomerases, selects for resistant cells that overexpress the efflux transporter Abcc4 (Marquez et al. [2009] Antimicrob. Agents Chemother. 53: 2410-2416), encoded by the Abcc4 gene located on Chromosome 14qE4. In this study, we report the genomic alterations occurring along the selection process. Abcc4 expression progressively increased upon selection rounds, with exponential changes observed between cells exposed to 150 and 200 µM of ciprofloxacin, accompanied by a commensurate decrease in ciprofloxacin accumulation. Molecular cytogenetics experiments showed that this overexpression is linked to Abcc4 gene overrepresentation, grading from a partial trisomy of Chr 14 at the first step of selection (cells exposed to 100 µM ciprofloxacin), to low-level amplifications (around three copies) of Abcc4 locus on 1 or 2 Chr 14 (cells exposed to 150 µM ciprofloxacin), followed by high-level amplification of Abcc4 as homogeneous staining region (hsr), inserted on 3 different derivative Chromosomes (cells exposed to 200 µM ciprofloxacin). In revertant cells obtained after more than 60 passages of culture without drug, the Abcc4 hsr amplification was lost in approx. 70% of the population. These data suggest that exposing cells to sufficient concentrations of an antibiotic with low affinity for eukaryotic topoisomerases can cause major genomic alterations that may lead to the overexpression of the transporter responsible for its efflux. Gene amplification appears therefore as a mechanism of resistance that can be triggered by non-anticancer agents but contribute to cross-resistance, and is partially and slowly reversible.


Assuntos
Ciprofloxacina/uso terapêutico , DNA Topoisomerases Tipo II/química , Resistência a Medicamentos , Regulação Enzimológica da Expressão Gênica , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Inibidores da Topoisomerase/uso terapêutico , Animais , Anti-Infecciosos/farmacologia , Linhagem Celular , Cromossomos/efeitos dos fármacos , Citogenética , Relação Dose-Resposta a Droga , Células HEK293 , Proteínas de Choque Térmico HSP40/genética , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Camundongos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
8.
Int J Antimicrob Agents ; 36(6): 513-22, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20926262

RESUMO

Pseudomonas aeruginosa causes severe nosocomial pneumonia in Intensive Care Unit (ICU) patients, with an increased prevalence of multiresistant strains. We examined the impact of the use of antipseudomonal antibiotic(s) on the susceptibility of P. aeruginosa isolated from ICU patients with clinically suspected hospital-acquired pneumonia collected in five teaching hospitals (110 non-duplicate initial isolates; 62 clonal pairs of initial and last isolates during treatment). Minimum inhibitory concentrations (MICs) were determined for amikacin, ciprofloxacin, meropenem, piperacillin/tazobactam (TZP), cefepime and ceftazidime (used in therapy) as well as five reporter antibiotics (aztreonam, colistin, gentamicin, piperacillin and ticarcillin) using Clinical and Laboratory Standards Institute (CLSI) methodology. Susceptibility was assessed according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) and CLSI breakpoints. Resistance rates prior to treatment exceeded 25% for cefepime, ceftazidime, piperacillin, ticarcillin and aztreonam (EUCAST and CLSI) and for gentamicin, TZP and colistin (EUCAST only). The highest rates of cross-resistance were noted for ceftazidime and cefepime and the lowest rate for amikacin. Mean MIC values were systematically higher in isolates from patients previously exposed (1 month) to the corresponding antibiotic. For clonal pairs, a systematic increase in MIC between initial and last isolates (significant for amikacin, cefepime, meropenem and TZP) was noted. There was a significant correlation between the use of antibiotics (adjusted for respective proportional use of each drug) and loss of susceptibility at the population level when using EUCAST breakpoints. The high level of resistance of P. aeruginosa in ICU patients with nosocomial pneumonia as well as its further increase during treatment severely narrows the already limited therapeutic options. Further observational studies and the development of early diagnosis for resistant isolates are warranted.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Infecção Hospitalar/tratamento farmacológico , Farmacorresistência Bacteriana , Pneumonia Bacteriana/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Infecção Hospitalar/microbiologia , Hospitais de Ensino , Humanos , Unidades de Terapia Intensiva , Testes de Sensibilidade Microbiana , Pneumonia Bacteriana/microbiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação
9.
Bioorg Med Chem Lett ; 17(21): 5758-62, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17855088

RESUMO

Four small molecular receptors of vancomycin have been designed to make part of a novel biosensor device based on the FTIR-ATR detection: N-Boc (2a) or N-Ac (2b)-6-aminocaproyl-D-Ala-D-Ala and N-Boc (3a) or N-Ac (3b)-6-aminocaproyl-D-Ala-d-Ser. Using an original microbiological approach to assess the competition of compounds with the natural target of vancomycin in bacteria, EC(50) values of 6.3-8.0 x 10(-5)M (2a-b) and 7.1-9.3 x 10(-4)M (3a-b) were determined. Vancomycin:2b complex was characterized by MS.


Assuntos
Bactérias/química , Técnicas Biossensoriais , Parede Celular/química , Peptidoglicano/química , Vancomicina/análise , Cromatografia Líquida de Alta Pressão , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier
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