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1.
Antivir Chem Chemother ; 28: 2040206620961712, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972196

RESUMO

Macrolides are a large group of antibiotics characterised by the presence of a macro-lactone ring of variable size. The prototype of macrolide antibiotics, erythromycin was first produced by Streptomyces and associated species more than half a century ago; other related drugs were developed. These drugs have been shown to have several pharmacological properties: in addition to their antibiotic activity, they possess some anti-inflammatory properties and have been also considered against non-bacterial infections. In this review, we analysed the available clinical evidences regarding the potential anti-viral activity of macrolides, by focusing on erythromycin, clarithromycin and azithromycin. Overall, there is no significant evidences so far that macrolides might have a direct benefit on most of viral infections considered in this review (RSV, Influenza, coronaviruses, Ebola and Zika viruses). However, their clinical benefit cannot be ruled out without further and focused clinical studies. Macrolides may improve the clinical course of viral respiratory infections somehow, at least through indirect mechanisms relying on some and variable anti-inflammatory and/or immunomodulatory effects, in addition to their well-known antibacterial activity.


Assuntos
Antibacterianos/farmacologia , Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Macrolídeos/farmacologia , Pneumonia Viral/tratamento farmacológico , Animais , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Antivirais/farmacocinética , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Humanos , Macrolídeos/farmacocinética , Macrolídeos/uso terapêutico , Pandemias
2.
Nat Commun ; 11(1): 4450, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895379

RESUMO

Hollow multishelled structures (HoMSs), with relatively isolated cavities and hierarchal pores in the shells, are structurally similar to cells. Functionally inspired by the different transmission forms in living cells, we studied the mass transport process in HoMSs in detail. In the present work, after introducing the antibacterial agent methylisothiazolinone (MIT) as model molecules into HoMSs, we discover three sequential release stages, i.e., burst release, sustained release and stimulus-responsive release, in one system. The triple-shelled structure can provide a long sterility period in a bacteria-rich environment that is nearly 8 times longer than that of the pure antimicrobial agent under the same conditions. More importantly, the HoMS system provides a smart responsive release mechanism that can be triggered by environmental changes. All these advantages could be attributed to chemical diffusion- and physical barrier-driven temporally-spatially ordered drug release, providing a route for the design of intelligent nanomaterials.


Assuntos
Antibacterianos/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Portadores de Fármacos/química , Nanoestruturas/química , Antibacterianos/farmacocinética , Preparações de Ação Retardada/farmacocinética , Difusão , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Microesferas , Tiazóis/administração & dosagem , Tiazóis/farmacocinética
3.
Int J Nanomedicine ; 15: 4991-5004, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764931

RESUMO

Introduction: Various materials and approaches have been used to reduce the mesh-induced inflammatory response and modify the mesh with tissue-matched mechanical properties, aiming to improve the repair of abdominal wall defects. Materials and Methods: In this study, we fabricated a polycaprolactone (PCL)/silk fibroin (SF) mesh integrated with amoxicillin (AMX)-incorporating multiwalled carbon nanotubes (MWCNTs) via electrospinning, grafting and crosslinking, developing a sustainable antibiotic and flexible mesh. AMX was loaded into the hollow tubular MWCNTs by physical adsorption, and a nanofibrous structure was constructed by electrospinning PCL and SF (40:60 w/w). The AMX@MWCNTs were then chemically grafted onto the surfaces of the PCL/SF nanofibers by treating with 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) solution for simultaneous crosslinking and coating. The incorporation of AMX into the MWCNTs (AMX@MWCNTs) and the integration of the AMX@MWCNTs with the PCL/SF nanofibers were characterized. Then, the functional mesh was fabricated and fully evaluated in terms of antibacterial activity, mechanical properties and host response. Results: Our results demonstrated that the PCL/SF nanofibrous structure was fabricated successfully by electrospinning. After integrating with AMX@MWCNT by grafting and crosslinking, the functional mesh showed undeformed structure, modified surface hydrophilicity and biocompatible interfaces, abdominal wall-matched mechanical properties, and a sustained-release antibiotic profile in E. coli growth inhibition compared to those of PCL/SF mesh in vitro. In a rat model with subcutaneous implantation, the functional mesh incited less mesh-induced inflammatory and foreign body responses than PCL/SF mesh within 14 days. The histological analysis revealed less infiltration of granulocytes and macrophages during this period, resulting in the loosely packed collagen deposition on the functional mesh and prominent collagen incorporation. Discussion: Therefore, this designed PCL/SF-AMX@MWCNT nanofibrous mesh, functionalized with antibacterial and tissue-matched mechanical properties, provides a promising alternative for the repair of abdominal wall defects.


Assuntos
Amoxicilina/química , Antibacterianos/química , Nanofibras/química , Nanotecnologia/métodos , Telas Cirúrgicas , Amoxicilina/farmacocinética , Amoxicilina/farmacologia , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Colágeno/química , Colágeno/metabolismo , Reagentes para Ligações Cruzadas/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Fibroínas/química , Inflamação/etiologia , Masculino , Teste de Materiais , Camundongos , Nanotubos de Carbono/química , Poliésteres/química , Ratos Sprague-Dawley , Telas Cirúrgicas/efeitos adversos
4.
Bull World Health Organ ; 98(6): 406-412F, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32514214

RESUMO

Objective: To compare dosing guidance in the paediatric formularies of high- and middle-income countries for 32 commonly prescribed antibiotics on the World Health Organization's (WHO's) 2017 Model list of essential medicines for children. Methods: We identified paediatric antibiotic guidelines that were either widely used internationally or originated from countries in which antibiotic use has increased markedly in recent years (i.e. Brazil, China, India, the Russian Federation and South Africa). Findings: The study analysis considered five leading antibiotic guidelines: (i) the Manual of childhood infections: the blue book; (ii) the BNF (British national formulary) for children; (iii) the Red book®: 2018-2021 report of the committee on infectious diseases; (iv) WHO's Pocket book of hospital care for children; and (v) Indian National treatment guidelines for antimicrobial use in infectious diseases. There was marked heterogeneity in the recommended dosing (i.e. daily dose, age dosing bands and dose frequency) for most commonly used antibiotics. The rationale for dosing recommendations was generally unclear. Conclusion: The pharmacokinetic, pharmacodynamic and clinical evidence supporting paediatric antibiotic dosing, particularly on total doses and on age or weight dosing bands, needs to be improved. Future research should consider whether the variations in guidance identified stem from different clinical disease patterns, varying levels of antibiotic resistance or drug availability rather than historical preferences. Interested global parties could collaborate with WHO's Model list of essential medicines antibiotic working group to develop an evidence-based consensus and identify research priorities.


Assuntos
Antibacterianos/administração & dosagem , Pediatria/normas , Guias de Prática Clínica como Assunto/normas , Fatores Etários , Antibacterianos/farmacocinética , Peso Corporal , Relação Dose-Resposta a Droga , Saúde Global , Humanos , Organização Mundial da Saúde
5.
J Vet Sci ; 21(3): e35, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32476311

RESUMO

BACKGROUND: Despite common use of tylosin in turkeys, the pharmacokinetic (PK) data for this drug in turkeys is limited. Within a few months of growth, PK of drugs in turkeys undergoes changes that may decrease their efficacy due to variable internal exposure. OBJECTIVES: The objective of this study was to investigate the influence of age on the PK of a single intravenous (i.v.) and oral administration of tylosin to turkeys at a dose of 10 and 50 mg/kg, respectively. METHODS: Plasma drug concentrations were measured using high-performance liquid chromatography with UV detection. The PK parameters were assessed by means of non-compartmental approach and were subjected to allometric analysis. RESULTS: During a 2.5-month-long period of growth from 1.4 to 14.7 kg, the median value for area under the concentration-time curve after i.v. administration increased from 2.61 to 7.15 mg × h/L and the body clearance decreased from a median of 3.81 to 1.42 L/h/kg. Over the same time, the median elimination half-life increased from 1.03 to 2.96 h. For the oral administration a similar trend was noted but the differences were less pronounced. Bioavailability was variable (5.76%-21.59%) and age-independent. For both routes, the plasma concentration of the major tylosin metabolite, tylosin D, was minimal. Protein binding was age-independent and did not exceed 50%. Allometric analysis indicated a relatively poor predictivity of clearance, volume of distribution and elimination half-life for tylosin in turkeys. CONCLUSIONS: Age has a significant impact on tylosin PK in turkeys and dosage adjustment may be needed, particularly in young individuals.


Assuntos
Antibacterianos/farmacocinética , Perus/metabolismo , Tilosina/farmacocinética , Administração Intravenosa/veterinária , Administração Oral , Fatores Etários , Animais , Antibacterianos/administração & dosagem , Peso Corporal , Cromatografia Líquida de Alta Pressão/veterinária , Masculino , Modelos Biológicos , Polônia , Perus/crescimento & desenvolvimento , Tilosina/administração & dosagem
6.
CPT Pharmacometrics Syst Pharmacol ; 9(8): 435-443, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32511867

RESUMO

Azithromycin (AZ), a broad-spectrum macrolide antibiotic, is being investigated in patients with coronavirus disease 2019 (COVID-19). A population pharmacokinetic model was implemented to predict lung, intracellular poly/mononuclear cell (peripheral blood monocyte (PBM)/polymorphonuclear leukocyte (PML)), and alveolar macrophage (AM) concentrations using published data and compared against preclinical effective concentration 90% (EC90 ) for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The final model described the data reported in eight publications adequately. Consistent with its known properties, concentrations were higher in AM and PBM/PML, followed by lung tissue, and lowest systemically. Simulated PBM/PML concentrations exceeded EC90 following the first dose and for ~ 14 days following 500 mg q.d. for 3 days or 500 mg q.d. for 1 day/250 mg q.d. on days 2-5, 10 days following a single 1,000 mg dose, and for > 20 days with 500 mg q.d. for 10 days. AM concentrations exceeded the 90% inhibitory concentration for > 20 days for all regimens. These data will better inform optimization of dosing regimens for AZ clinical trials.


Assuntos
Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Antibacterianos/farmacocinética , Azitromicina/farmacocinética , Relação Dose-Resposta a Droga , Humanos , Leucócitos Mononucleares/metabolismo , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Modelos Biológicos , Neutrófilos/metabolismo , Pandemias , Distribuição Tecidual
7.
Ceska Slov Farm ; 69(1): 17-23, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32460506

RESUMO

Early and appropriate antibiotic therapy remains the key intervention for successful treatment of infection in critically ill patients, particularly in the current era of increasing antibiotic resistance. Optimization of the antimicrobial dosing regimens to achieve therapeutic plasma concentrations and concentrations at the site of infection is crucial for maximizing the therapeutic response and minimizing the risk of organ toxicity and is also an important tool to avoid the resistance emergence. Beta-lactam antibiotics have been considered relatively safe and, as opposed to aminoglycosides, therapeutic drug monitoring as a tool conventionally used primarily to minimize toxicity in drugs with narrow therapeutic window or complex pharmacokinetics, has not been provided routinely yet. However, emerging data suggest that optimal antibiotic exposure may not be achieved with traditional dosing strategies in a significant number of critically ill patients and, on the contrary, concerns about insufficient plasma concentrations leading to microbiological and clinical failure are warranted. The treatment of infections in the intensive care unit (ICU) patients is often challenging because of disease complexity, pathophysiologic alterations they undergo and reduced susceptibility of nosocomial pathogens. Therefore, it is of paramount importance to update current recommendations on dosing of beta-lactam antibiotics in severe infections and therapeutic drug monitoring may be regarded as the only exact method to ensure pharmacodynamics target achievement. Na Homolce Hospital is one of the first medical institutions in the Czech Republic where the practice of routine TDM of beta-lactam antibiotics in ICU-patients has been established. In this paper, we introduce our experience and first case reports.


Assuntos
Antibacterianos/farmacocinética , Infecções Bacterianas/tratamento farmacológico , Unidades de Terapia Intensiva , beta-Lactamas/farmacocinética , Estado Terminal , República Tcheca , Monitoramento de Medicamentos , Humanos
8.
Yonsei Med J ; 61(4): 301-309, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32233172

RESUMO

PURPOSE: Few studies have been investigated the in vivo efficacy of generic vancomycin products available outside of the United States. In this study, we aimed to compare the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of five generic vancomycin products available in Korea with those of the innovator. MATERIALS AND METHODS: The in vitro vancomycin purity of each product was examined using high-pressure liquid chromatography. Single-dose PK analyses were performed using neutropenic mice. The in vivo efficacy of vancomycin products was compared with that of the innovator in dose-effect experiments (25 to 400 mg/kg per day) using a thigh-infection model with neutropenic mice. RESULTS: Generic products had a lower proportion of vancomycin B (range: 90.3-93.8%) and a higher proportion of impurities (range: 6.2-9.7%) than the innovator (94.5% and 5.5%, respectively). In an in vivo single-dose PK study, the maximum concentration (Cmax) values of each generic were lower than that of the innovator, and the geographic mean area under the curve ratios of four generics were significantly lower than that of the innovator (all p<0.1). In the thigh-infection model, the maximum efficacies of generic products reflected in maximal effect (Emax) values were not significantly different from the innovator. However, the PD profile curves of some generic products differed significantly from that of the innovator in mice injected with a high level of Mu3 (all p≤0.05). CONCLUSION: Some generic vancomycin products available in Korea showed inferior PK and PD profiles, especially in mice infected with hetero-vancomycin-resistant Staphylococcus aureus.


Assuntos
Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/uso terapêutico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/farmacocinética , Vancomicina/uso terapêutico , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Modelos Animais de Doenças , Medicamentos Genéricos/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , República da Coreia , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Coxa da Perna/microbiologia , Falha de Tratamento , Vancomicina/farmacologia
9.
Ecotoxicol Environ Saf ; 197: 110626, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32339959

RESUMO

The objective of this study was to evaluate the tissue distributions of antibiotics in the fish, the bioaccumulation and trophic transfer in freshwater food web in Taihu Lake, a large shallow freshwater lake. Twenty four out of 41 antibiotics were detected in the biotas of the food web; and antibiotic concentrations followed the orders: fish plasma ~ fish muscle < fish liver ~ fish bile and fish < invertebrates ~ plankton. Antibiotic concentrations in the liver of piscivores were higher than those in omnivores and planktivores. Most bioaccumulation factors (BAFs) of sulfonamides (SAs), macrolides (MLs), ionophores (IPs) and lincomycin (LIN) were less than 2000 L/kg, indicating low bioaccumulation ability of these compounds in fish. Fluoroquinolones (FQs) were frequently detected in fish liver, invertebrates and plankton with much of BAFs great than 5000 L/kg, indicating that FQs have the potential of bioaccumulation in fish. Relationship analysis between BAFs and physicochemical properties of antibiotics showed that the bioaccumulation of antibiotics in the biota was related with their adsorption ability. Generally, the antibiotics in the food web of Lake Taihu including plankton, invertebrates and fish showed trophic dilution. The normalized estimated daily intake (EDI) values are less than the acceptable daily intake (ADI) values, and then hazard quotients were much less than 1. This result suggests the consumption of fish, crab and shrimp in Lake Taihu would probably not pose direct detrimental effects on humans.


Assuntos
Antibacterianos/análise , Organismos Aquáticos/metabolismo , Monitoramento Ambiental/métodos , Lagos/química , Poluentes Químicos da Água/análise , Animais , Antibacterianos/farmacocinética , Organismos Aquáticos/efeitos dos fármacos , China , Crustáceos/metabolismo , Peixes/metabolismo , Cadeia Alimentar , Humanos , Plâncton/metabolismo , Medição de Risco , Poluentes Químicos da Água/farmacocinética
10.
J Med Microbiol ; 69(5): 676-684, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32228800

RESUMO

Introduction. Quantification of bacterial load in tissue homogenates in in vivo pharmacodynamic studies is cumbersome and time-consuming.Aim. We therefore developed a new method for quantifying bacterial load in tissue homogenates of animals treated with a ß-lactam and ß-lactamase inhibitor using growth curves.Methods. The log10 colony-forming units (c.f.u.) ml-1 of 184 thigh and lung homogenates from female CD-1 mice infected intranasally and intramuscularly with 4 Pseudomonas aeruginosa, 4 Klebsiella pneumoniae, 3 Enterobacter cloacae and 2 Escherichia coli strains treated with a ß-lactam drug and tazobactam were calculated using the standard approach of serial quantitative cultures and analysis of growth curves. Growth curves were obtained with continuous (every 10 min) monitoring of optical density at 630 nm (OD630) after 20 µl tissue homogenates were inoculated in total volume of 200 µl Mueller-Hinton broth in 96-well microtitration plates and incubated at 37 °C for 18 h.Results. The best correlation between log10 c.f.u. ml-1 determined with the serial quantitative cultures and growth curves was found at the time point corresponding to an OD630 of 0.25 increase above the baseline OD (average of first five timepoints) (R 2=0.918-0.999). The median (range) differences between the two methods was -0.19 (-1.79-1.69) with 86-97 % of all isolates and species being within 1 log10 c.f.u. ml-1 with 1 h hands-on-time and <13 h of incubation for 96 samples. Pharmacodynamic analysis showed similar dose-response relationships and 1 log kill dose estimations (paired t-test, P=0.112).Conclusion. The new technique resulted in comparable c.f.u. counts to those for the standard serial dilution/culture technique with minimal hands-on and turnaround times.


Assuntos
Antibacterianos/farmacocinética , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Carga Bacteriana , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana
11.
Int J Nanomedicine ; 15: 2011-2026, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32273699

RESUMO

Introduction: The bone regeneration of endosseous implanted biomaterials is often impaired by the host immune response, especially macrophage-related inflammation which plays an important role in the bone healing process. Thus, it is a promising strategy to design an osteo-immunomodulatory biomaterial to take advantage of the macrophage-related immune response and improve the osseointegration performance of the implant. Methods: In this study, we developed an antibacterial silver nanoparticle-loaded TiO2 nanotubes (Ag@TiO2-NTs) using an electrochemical anodization method to make the surface modification and investigated the influences of Ag@TiO2-NTs on the macrophage polarization, osteo-immune microenvironment as well as its potential molecular mechanisms in vitro and in vivo. Results: The results showed that Ag@TiO2-NTs with controlled releasing of ultra-low-dose Ag+ ions had the excellent ability to induce the macrophage polarization towards the M2 phenotype and create a suitable osteo-immune microenvironment in vitro, via inhibiting PI3K/Akt, suppressing the downstream effector GLUT1, and activating autophagy. Moreover, Ag@TiO2-NTs surface could improve bone formation, suppress inflammation, and promote osteo-immune microenvironment compared to the TiO2-NTs and polished Ti surfaces in vivo. These findings suggested that Ag@TiO2-NTs with controlled releasing of ultra-low-dose Ag+ ions could not only inhibit the inflammation process but also promote the bone healing by inducing healing-associated M2 polarization. Discussion: Using this surface modification strategy to modulate the macrophage-related immune response, rather than prevent the host response, maybe a promising strategy for implant surgeries in the future.


Assuntos
Autofagia/efeitos dos fármacos , Transportador de Glucose Tipo 1/metabolismo , Fatores Imunológicos/administração & dosagem , Macrófagos/efeitos dos fármacos , Nanopartículas Metálicas/administração & dosagem , Prata/farmacocinética , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Materiais Biocompatíveis/química , Técnicas Eletroquímicas , Transportador de Glucose Tipo 1/genética , Fatores Imunológicos/imunologia , Masculino , Nanopartículas Metálicas/química , Camundongos , Nanotubos/química , Osseointegração/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Próteses e Implantes , Células RAW 264.7 , Ratos Sprague-Dawley , Prata/química , Tíbia/diagnóstico por imagem , Tíbia/cirurgia , Titânio/química , Cicatrização/efeitos dos fármacos
12.
Ecotoxicol Environ Saf ; 196: 110549, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32251953

RESUMO

Chemicals used to assure agricultural production and the feasibility of planting sites often end up in bodies of water used for crop irrigation. In a pot study, we investigated the consequences associated with the irrigation of maize with water contaminated by ciprofloxacin (Cipro; 0, 0.2, 0.8, 1.4 and 2.0 µg l-1) and/or glyphosate (0, 5, 25 and 50 mg l-1) on yields and food safety. Glyphosate in concentrations ≥25 mg l-1 prevented plant establishment, regardless of Cipro presence. Evaluations made at the V5 stage of plants reveal that Cipro concentrations ≥0.8 µg l-1 and glyphosate decreased photosynthesis and induced changes in leaf anatomy and stem biophysical properties that may contribute to decreased kernel yields. When those chemicals were applied together, kernel yield reductions were accentuated, evidencing their interactive effects. Irrigation with contaminated water resulted in accumulations of Cipro and glyphosate (as well as its metabolite, aminomethylphosphonic acid) in plant tissues. Accumulation of these chemicals in plant tissues such as leaves and kernels is a problem, since they are used to feed animals and humans. Moreover, these chemicals are of potential toxicological concern, principally due to residue accumulations in the food chain. Specially, the antibiotic residue accumulations in maize tissues can assist the induction of antibiotic resistance in dangerous bacteria. Therefore, we point out the urgency of monitoring the quality of water used for crop irrigation to avoid economic and food-quality losses.


Assuntos
Antibacterianos/toxicidade , Ciprofloxacino/toxicidade , Glicina/análogos & derivados , Poluentes Químicos da Água/toxicidade , Zea mays/efeitos dos fármacos , Irrigação Agrícola , Animais , Antibacterianos/farmacocinética , Ciprofloxacino/farmacocinética , Produtos Agrícolas/anatomia & histologia , Produtos Agrícolas/efeitos dos fármacos , Produtos Agrícolas/economia , Inocuidade dos Alimentos , Glicina/farmacocinética , Glicina/toxicidade , Humanos , Fotossíntese/efeitos dos fármacos , Folhas de Planta/anatomia & histologia , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Poluentes Químicos da Água/farmacocinética , Zea mays/anatomia & histologia , Zea mays/metabolismo
14.
Int J Infect Dis ; 96: 105-111, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32251797

RESUMO

BACKGROUND: Significant alterations in the pharmacokinetic characteristics of linezolid are often seen in sepsis patients. The study aimed to identify a target pharmacokinetics/pharmacodynamics (PK/PD) index of the efficacy of linezolid treatment, and to estimate the optimum dosage regimen of linezolid in sepsis patients. METHODS: The PK data were modeled using the one-compartment model, which determined the target PK/PD index for successful treatment by logistic regression. The probability of thrombocytopenia was identified by establishing a logistic model. Different dosing regimens were evaluated using Monte Carlo simulation. RESULTS: Reaching 80% bacterial eradication required an AUC24/MIC of 100, which defined the therapeutic target. The proposed regimen to attain a cumulative fraction of response ≥80% was 800 mg/12 h (safety probability 66.8%) for sepsis patients with normal renal function or mild kidney damage. By contrast, the target cumulative fraction of response was attained with a standard dosing regimen in sepsis patients on continuous renal replacement therapy [600 mg/12 h (safety probability 49.7%)]. CONCLUSIONS: This study identified different dosing strategies to achieve target linezolid PK/PD values according to whether sepsis patients were treated with continuous renal replacement therapy. Due to the high incidence of thrombocytopenia in sepsis patients on continuous renal replacement therapy, therapeutic drug monitoring should be encouraged for optimizing linezolid exposure in sepsis patients.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Linezolida/administração & dosagem , Linezolida/efeitos adversos , Sepse/tratamento farmacológico , Adulto , Idoso , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Feminino , Humanos , Linezolida/farmacocinética , Linezolida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Medição de Risco , Sepse/complicações , Sepse/metabolismo , Trombocitopenia/epidemiologia , Trombocitopenia/etiologia
16.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(1): 50-55, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32148231

RESUMO

OBJECTIVE: To estimate the predictive performance of the population pharmacokinetics software JPKD-vancomycin on predicting the vancomycin steady-state trough concentration, and to analyze the related factors affecting the predictive performance. METHODS: The clinical data of patients who were treated with vancomycin and received therapeutic drug monitoring (TDM) admitted to Suzhou Hospital Affiliated to Nanjing Medical University from July 2013 to December 2018 were enrolled. All patients were designed an empirical vancomycin regimen (initial regimen) according to vancomycin medication guidelines. Steady-state trough concentrations of vancomycin were determined at 48 hours after the first dose and 0.5 hour before the next dose. Dosage regimen was adjusted when steady-state trough concentration was not in 10-20 mg/L (adjustment regimen), and then the steady-state trough concentration was determined again 48 hours after adjustment. First, the JPKD-vancomycin software was used to calculate the initial regimen and predict the steady-state trough concentration according to the results calculated by classic pharmacokinetic software Vancomycin Calculator. Second, the JPKD-vancomycin software was used to adjust the vancomycin dosage regime and predict the steady-state trough concentration of adjustment regimen. The weight residual (WRES) between the predicted steady-state trough concentration (Cpre) and the measured steady-state trough concentration (Creal) was used to evaluate the ability of the JPKD-vancomycin software for predicting the vancomycin steady-state trough concentration. The TDM results of initial regimen were divided into accurate prediction group (WRES < 30%) and the inaccurate prediction group (WRES ≥ 30%) according to the WRES value. Patient and disease characteristics including gender, age, weight, height, the length of hospital stay, comorbidities, vasoactive agent, mechanical ventilation, smoking history, postoperative, obstetric patients, trauma, laboratory indicators, vancomycin therapy and TDM results were collected from electronic medical records. Univariate and multivariate Logistic regression analysis was used to screen the related factors that influence the predictive performance of JPKD-vancomycin software, and the receiver operating characteristic (ROC) curve was drawn to evaluate its predictive value. RESULTS: A total of 310 patients were enrolled, and 467 steady-state trough concentrations of vancomycin were collected, including 310 concentrations of initial regimen and 157 concentrations of adjustment regimen. Compared with the initial regimen, the WRES of adjusted regimen was significantly reduced [14.84 (6.05,22.89)% vs. 20.41 (11.06,45.76)%, P < 0.01], and the proportion of WRES < 30% increased significantly [82.80% (130/157) vs. 63.87% (198/310), P < 0.01]. These results indicated that JPKD-vancomycin software had a better accuracy prediction for steady-state trough concentration of the adjusted regimen than the initial regimen. There were 198 concentrations in the accurate prediction group and 112 in the inaccurate prediction group. Univariate Logistic regression analysis showed that women [odds ratio (OR) = 0.466, 95% confidence interval (95%CI) was 0.290-0.746, P = 0.002], low body weight (OR = 0.974, 95%CI was 0.953-0.996, P = 0.022), short height (OR = 0.963, 95%CI was 0.935-0.992, P = 0.014), low vancomycin clearance (CLVan; OR < 0.001, 95%CI was 0.000-0.231, P = 0.023) and postoperative patients (OR = 1.695, 95%CI was 1.063-2.702, P = 0.027) were related factors affecting the predictive performance of JPKD-vancomycin software. Multivariate Logistic regression analysis indicated that women (OR = 0.449, 95%CI was 0.205-0.986, P = 0.046), low CLVan (OR < 0.001, 95%CI was 0.000-0.081, P = 0.015) and postoperative patients (OR = 2.493, 95%CI was 1.455-4.272, P = 0.001) were independent risk factors for inaccurate prediction of JPKD-vancomycin software. The ROC analysis indicated that the area under ROC curve (AUC) of the CLVan for evaluating the accuracy of JPKD-vancomycin software in predicting vancomycin steady-state trough concentration was 0.571, the sensitivity was 56.3%, and the specificity was 57.1%. The predictive performance of JPKD-vancomycin software was decreased when CLVan was lower than 0.065 L×h-1×kg-1. CONCLUSIONS: JPKD-vancomycin software had a better predictive performance for the vancomycin steady-state trough concentrations of adjustment regimen than initial regimen. JPKD-vancomycin software had a poor predictive performance when the patient was female, having low CLVan, and was postoperative. The predictive performance of JPKD-vancomycin software was decreased when CLVan was lower than 0.065 L×h-1×kg-1.


Assuntos
Antibacterianos/farmacocinética , Monitoramento de Medicamentos , Software , Vancomicina/farmacocinética , Feminino , Humanos , Masculino , Estudos Retrospectivos
17.
Dis Mon ; 66(6): 100971, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32201008

RESUMO

Antimicrobial agents play a key role in controlling and curing infectious disease. Soon after the discovery of the first antibiotic, the challenge of antibiotic resistance commenced. Antimicrobial agents use different mechanisms against bacteria to prevent their pathogenesis and they can be classified as bactericidal or bacteriostatic. Antibiotics are one of the antimicrobial agents which has several classes, each with different targets. Consequently, bacteria are endlessly using methods to overcome the effectivity of the antibiotics by using distinct types of mechanisms. Comprehending the mechanisms of resistance is vital for better understanding and to continue use of current antibiotics. Which also helps to formulate synthetic antimicrobials to overcome the current mechanism of resistance. Also, encourage in prudent use and misuse of antimicrobial agents. Thus, decline in treatment costs and in the rate of morbidity and mortality. This review will be concentrating on the mechanism of actions of several antibiotics and how bacteria develop resistance to them, as well as the method of acquiring the resistance in several bacteria and how can a strain be resistant to several types of antibiotics. This review also analyzes the prevalence, major clinical implications, clinical causes of antibiotic resistance. Further, it evaluates the global burden of antimicrobial resistance, identifies various challenges and strategies in addressing the issue. Finally, put forward certain recommendations to prevent the spread and reduce the rate of resistance growth.


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Farmacorresistência Bacteriana , Humanos
18.
Int J Infect Dis ; 93: 329-338, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32112965

RESUMO

OBJECTIVES: The aim of this study was to assess the influence of renal function, in particular the presence of augmented renal clearance (ARC), on the pharmacokinetics of linezolid in critically ill patients. The effect of continuous infusion on the probability of therapeutic success from a pharmacokinetic/pharmacodynamic (PK/PD) perspective was also evaluated. METHODS: Seventeen patients received linezolid (600 mg every 12 h) as a 30-min infusion and 26 as a continuous infusion (50 mg/h). The PK parameters were calculated and the probability of PK/PD target attainment (PTA) was estimated by Monte Carlo simulation (MCS) for different doses administered by intermittent (600 mg every 12 h or 600 mg every 8 h) or continuous infusion (50 mg/h or 75 mg/h). RESULTS: In patients without ARC, the standard dose was adequate to attain the PK/PD target. However, linezolid clearance was significantly higher in ARC patients, leading to sub-therapeutic concentrations. Continuous infusion (50 mg/h) provided concentrations ≥2 mg/l in 70% of the ARC patients. MCS revealed that concentrations ≥2 mg/l would be reached in >90% of patients receiving 75 mg/h. CONCLUSIONS: ARC increases linezolid clearance and leads to a high risk of underexposure with the standard dose. Continuous infusion increases the PTA, but an infusion rate of 75 mg/h should be considered to ensure concentrations ≥2 mg/ml.


Assuntos
Antibacterianos/farmacocinética , Estado Terminal , Rim/metabolismo , Linezolida/farmacocinética , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Estado Terminal/terapia , Feminino , Humanos , Testes de Função Renal , Linezolida/administração & dosagem , Linezolida/uso terapêutico , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Método de Monte Carlo
19.
Yakugaku Zasshi ; 140(3): 345-354, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115551

RESUMO

This study was designed to clarify the intrapulmonary pharmacokinetics and distribution characteristics of drugs in order to develop better therapies for respiratory diseases, including respiratory infections and pulmonary fibrosis. The distribution characteristics of three macrolide antimicrobial agents-clarithromycin, azithromycin, and telithromycin-in plasma, lung epithelial lining fluid (ELF), and alveolar macrophages (AMs), were examined for the optimization of antimicrobial therapy. The time course of the uptake of these agents in ELF and AMs, following oral administration to rats, resulted in markedly higher concentrations than that in plasma. The high concentration of the agents in AMs was due to their sustained distribution to ELF via multidrug resistance protein 1 and to high uptake by AMs themselves via active transport mechanisms and trapping and/or binding in acidic organelles. The intrapulmonary pharmacokinetics of aerosolized model compounds administered to animals with bleomycin-induced pulmonary fibrosis via aerosol formulations of model compounds (MicroSprayer) were then evaluated. The concentrations of these compounds in the plasma of pulmonary fibrotic rats were markedly higher than in that of control rats. The expression of epithelial tight junctions decreased in pulmonary fibrotic lesions. The accumulation of extracellular matrix inhibited the intrapulmonary distribution of aerosolized model compounds, indicating that aerosolized drugs are easily absorbed after leakage through damaged alveolar epithelia, but cannot become widely distributed in the lungs because of interruption by the extracellular matrix. This review provides useful findings for the development of therapies for respiratory infections and pulmonary fibrosis.


Assuntos
Antibacterianos/farmacocinética , Pulmão/metabolismo , Macrolídeos/farmacocinética , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/metabolismo , Administração Oral , Animais , Antibacterianos/administração & dosagem , Injeções Intralesionais , Macrolídeos/administração & dosagem , Macrófagos Alveolares/metabolismo , Camundongos , Ratos , Distribuição Tecidual
20.
Int J Nanomedicine ; 15: 913-925, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32103946

RESUMO

Introduction: Masquelet proposed a new solution for the healing of segmental bone defects, thus minimizing the disadvantages associated with traditional bone grafting. However, a major factor leading to the failure of this technique pertains to be the residual infection. Accordingly, we developed an antibiotic- and osteo-inductive agent-loaded composite scaffold to solve this problem. Methods: A mesh-like polycaprolactone scaffold was prepared using a lab-exploited solution-type three-dimensional printer, and hybrid sheath-core structured poly(lactic-co-glycolic-acid) nanofibers were fabricated using co-axial electrospinning technology. Vancomycin, ceftazidime, and bone morphological protein (BMP)-2 were employed. The in vitro and in vivo (rabbit fracture model) release patterns of applied agents from the composite scaffold were investigated. Results: The results revealed that the drug-eluting composite scaffold enabled the sustainable release of the medications for at least 30 days in vitro. Animal tests demonstrated that a high concentration of medications was maintained. Abundant growth factors were induced within the bioactive membrane stimulated by the applied scaffold. Finally, satisfactory bone healing potential was observed on radiological examination and biomechanical evaluation. Discussion: The developed composite scaffold may facilitate bone healing by inducing bioactive membrane formation and yielding high concentrations of antibiotics and BMP-2 during the Masquelet procedure.


Assuntos
Antibacterianos/administração & dosagem , Regeneração Óssea/fisiologia , Fêmur/cirurgia , Nanofibras/química , Procedimentos Cirúrgicos Reconstrutivos/métodos , Animais , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Ceftazidima/química , Ceftazidima/farmacologia , Nanofibras/administração & dosagem , Nanofibras/uso terapêutico , Osteotomia/métodos , Poliésteres/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Impressão Tridimensional , Coelhos , Procedimentos Cirúrgicos Reconstrutivos/efeitos adversos , Infecção da Ferida Cirúrgica/prevenção & controle , Tecidos Suporte , Vancomicina/química , Vancomicina/farmacologia
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