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1.
Ecotoxicol Environ Saf ; 191: 110186, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954922

RESUMO

A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established based on molecular structures and docking scores (representing the biodegradability); the scores were obtained for 23 fluoroquinolones (FQs) and the oxidoreductase (PDB ID: 1YZP) of Phanerochaete chrysosporium in the aerobic process of municipal wastewater treatment plants. In the Comparative Molecular Field Analysis (CoMFA) model, q2 was 0.516 and r2pred was 0.727, which showed that the model was reliable and robust. The modification information obtained by the contour maps showed that introducing electronegative, bulky or electropositive groups at different active sites could increase the biodegradability of fluoroquinolone derivatives. Using levofloxacin (LEV) as a modified molecule, 35 fluoroquinolone derivatives with higher biodegradability than LEV were designed. After the evaluation of genotoxicity, bioconcentration and photodegradation, Derivative-15, with higher biodegradability (increased by 27.85%), higher genotoxicity, higher photodegradation and lower bioconcentration, was identified as the most environmentally friendly fluoroquinolone derivative. The 2D-QSAR model of FQ biodegradability was established through the quantization parameters, and q+ was identified as the main parameter affecting the biodegradability of FQs through sensitivity analysis. In addition, the docking results of LEV and Derivative-15 with the oxidoreductase in P. chrysosporium showed that the electrostatic field force between Derivative-15 and the amino acid residues promoted the binding of the donor to the receptor protein, thereby increasing the biodegradability of Derivative-15. Additionally, molecular dynamics simulations revealed that the enhancement of the electrostatic field force with Derivative-15 could promote the binding of the ligand to the receptor, which was basically consistent with the conclusion of molecular docking. Finally, the three microbial degradation pathways of LEV and Derivative-15 were also proposed. The total energy barrier value of the pathway with the lowest total energy barrier of biodegradation was reduced by 32.07%, which was basically consistent with the enhancement of biodegradability of Derivative-15.


Assuntos
Fluoroquinolonas/química , Modelos Moleculares , Poluentes Químicos da Água/química , Basidiomycota/enzimologia , Biodegradação Ambiental , Fluoroquinolonas/farmacocinética , Fluoroquinolonas/toxicidade , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Oxirredutases/química , Relação Quantitativa Estrutura-Atividade , Poluentes Químicos da Água/farmacocinética , Poluentes Químicos da Água/toxicidade
2.
BMC Infect Dis ; 20(1): 57, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31952493

RESUMO

BACKGROUND: Critically ill patients undergo extensive physiological alterations that will have impact on antibiotic pharmacokinetics. Up to 60% of intensive care unit (ICU) patients meet the pharmacodynamic targets of beta-lactam antibiotics, with only 30% in fluoroquinolones. Not reaching these targets might increase the chance of therapeutic failure, resulting in increased mortality and morbidity, and antibiotic resistance. The DOLPHIN trial was designed to demonstrate the added value of therapeutic drug monitoring (TDM) of beta-lactam and fluoroquinolones in critically ill patients in the ICU. METHODS: A multi-centre, randomised controlled trial (RCT) was designed to assess the efficacy and cost-effectiveness of model-based TDM of beta-lactam and fluoroquinolones. Four hundred fifty patients will be included within 24 months after start of inclusion. Eligible patients will be randomly allocated to either study group: the intervention group (active TDM) or the control group (non-TDM). In the intervention group dose adjustment of the study antibiotics (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, amoxicillin, amoxicillin with clavulanic acid, flucloxacillin, piperacillin with tazobactam, meropenem, and ciprofloxacin) on day 1, 3, and 5 is performed based upon TDM with a Bayesian model. The primary outcome will be ICU length of stay. Other outcomes amongst all survival, disease severity, safety, quality of life after ICU discharge, and cost effectiveness will be included. DISCUSSION: No trial has investigated the effect of early TDM of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients. The findings from the DOLPHIN trial will possibly lead to new insights in clinical management of critically ill patients receiving antibiotics. In short, to TDM or not to TDM? TRIAL REGISTRATION: EudraCT number: 2017-004677-14. Sponsor protocol name: DOLPHIN. Registered 6 March 2018 . Protocol Version 6, Protocol date: 27 November 2019.


Assuntos
Antibacterianos/farmacocinética , Monitoramento de Medicamentos , Fluoroquinolonas/farmacocinética , beta-Lactamas/farmacocinética , Adulto , Antibacterianos/sangue , Antibacterianos/uso terapêutico , Teorema de Bayes , Estado Terminal/terapia , Fluoroquinolonas/sangue , Fluoroquinolonas/uso terapêutico , Humanos , Unidades de Terapia Intensiva , Tempo de Internação , Qualidade de Vida , beta-Lactamas/sangue , beta-Lactamas/uso terapêutico
3.
N Z Vet J ; 68(1): 31-37, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31437418

RESUMO

Aims: To determine the pharmacokinetics and tissue depletion of 2 mg/kg marbofloxacin (MBX) in Bilgorajska geese (Anser anser domesticus) after I/V and oral administration, to calculate the daily dose from experimental data and to compare it with that calculated by allometric scaling.Methods: Eight clinically normal female Bilgorajska geese were used in a three-phase study with a 3-week wash-out period between phases. In the first phase birds received I/V administration of 2 mg/kg MBX; the same dose was given orally in the second and third phases. Blood samples were collected between 0 minutes and 48 hours in the first and second phases, and samples of liver, kidney, lung, muscle and heart were collected following slaughter of birds between 6 and 48 hours in the third phase. Concentrations of MBX in plasma and tissues were analysed using HPLC. Two additional birds served as controls. The optimal dose was calculated based on a minimal inhibitory concentration (MIC) of 0.125 µg/mL using the observed clearance, or using clearance calculated by allometric scaling.Results: Concentrations of MBX in plasma were detectable up to 24 hours following both I/V and oral administration. Mean oral bioavailability was 26.5 (SD 7.7)%. Concentrations of MBX in all tissues were highest at 6 hours and decreased constantly up to 34 hours. The mean optimal daily dose for oral administration of MBX, calculated using the observed clearance was 10.36 (SD 2.18) mg/kg, and using predicted clearance was 5.54 (SD 0.14) mg/kg. The preliminary withdrawal time for a maximum residue limit of 0.15 mg/kg calculated for muscle was 38.4 hours, heart 33.6 hours, kidney 48.3 hours, lung 47.7 hours and liver 49.3 hours.Conclusion and Clinical Relevance: There was insufficient evidence to recommend MBX orally administered to geese at a daily dose of 2 mg/kg for treatment of bacteria with an MIC of 0.125 µg/mL. Further pharmacokinetic/pharmacodynamic studies in geese are recommended to determine the MBX dose regimen and its clinical efficacy in geese.


Assuntos
Anseriformes/sangue , Antibacterianos/farmacocinética , Fluoroquinolonas/farmacocinética , Administração Intravenosa/veterinária , Administração Oral , Animais , Antibacterianos/administração & dosagem , Antibacterianos/metabolismo , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Resíduos de Drogas , Escherichia coli/efeitos dos fármacos , Feminino , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/metabolismo , Rim/química , Fígado/química , Pulmão/química , Músculo Esquelético/química , Miocárdio/química , Consumo de Álcool por Menores
4.
J Vet Pharmacol Ther ; 42(5): 556-563, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31424100

RESUMO

Avian pathogenic Escherichia coli could cause localized and systemic infection in the poultry, and danofloxacin is usually used to treat avian colibacillosis through oral administration. To promote prudent use of danofloxacin and reduce the emergence of drug-resistant E. coli strains, it is necessary to understand the population pharmacokinetics (PopPK) of danofloxacin in chicken intestines. In this study, reversed-phase high performance liquid chromatography (HPLC) with fluorescence detection was used to detect the concentrations of danofloxacin in the contents of duodenum, jejunum, and ileum of the healthy and infected chickens after single oral administration (5 mg/kg body weight). Then, the PopPK of danofloxacin in intestines were analyzed using NONMEM software. As a result, a two-compartment PK model best described the time-concentration profile of duodenal, jejunal, and ileal contents. Interestingly, absorption rate (Ka ), distribution volume (V), and clearance (CL) for danofloxacin from duodenal, jejunal to ileal contents were sequentially decreased in the healthy chickens. However, the trend of Ka , V, and CL of danofloxacin was changed dramatically in the intestine of infected chickens. Ka and V of danofloxacin in the jejunum were higher than in the ileum and duodenum. Compared with healthy chickens, Ka and V of danofloxacin in the duodenum decreased significantly, while increased in jejunum, respectively. It has been noted that Ka decreased and V increased in the ileum of infected chickens. Besides, CL in the duodenum, jejunum, and ileum of infected chickens was, respectively, lower than those of healthy chickens. Interestingly, the relative bioavailability (F) of danofloxacin in the ileum was relatively higher in both healthy and infected chickens. In addition, F in the duodenal, jejunal, and ileal contents of infected chickens was respectively higher than healthy chickens. In summary, the PopPK for danofloxacin in infected chicken intestines was quite different from healthy chickens. The absorption, distribution, and clearance of danofloxacin in healthy chickens decreased from duodenum to jejunum and to ileum. Moreover, the pharmacokinetic characteristics in the intestine of infected chickens changed significantly, and the pharmacokinetic characteristics in the ileum can be used as a representative of all intestinal segments.


Assuntos
Galinhas , Infecções por Escherichia coli/veterinária , Fluoroquinolonas/farmacocinética , Conteúdo Gastrointestinal/química , Doenças das Aves Domésticas/microbiologia , Animais , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Infecções por Escherichia coli/tratamento farmacológico , Fluoroquinolonas/uso terapêutico , Modelos Biológicos , Doenças das Aves Domésticas/tratamento farmacológico
5.
Trop Anim Health Prod ; 51(8): 2603-2610, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31230255

RESUMO

The study aimed to define the effects of M. haemolytica and a single oral dose of albendazole on the single-dose pharmacokinetics of marbofloxacin in lambs. The pharmacokinetic-pharmacodynamic integration of marbofloxacin was applied to describe a 3 mg/kg intramuscular dose in lambs. The 6 healthy and 12 naturally infected with M. haemolytica lambs (Akkaraman, males weighing 10-15 kg and aged 2-3 months) were used in this study. In the marbofloxacin group, 6 healthy lambs received marbofloxacin. In the albendazole group after 2 weeks washout period, the same animals received marbofloxacin on 1 h after albendazole. In the diseased marbofloxacin group, 6 lambs naturally infected with M. haemolytica received marbofloxacin. In the diseased albendazole group, 6 lambs naturally infected with M. haemolytica received marbofloxacin on 1 h after albendazole. The marbofloxacin and albendazole were administered each as a single dose of 3 mg/kg intramuscular and 7.5 mg/kg oral, respectively, in the respective groups. Plasma concentration of marbofloxacin was measured with HPLC-UV and pharmacokinetic parameters were analyzed by non-compartmental model. Albendazole did not change the pharmacokinetic profiles of marbofloxacin in healthy and diseased lambs. However, M. haemolytica affected the pharmacokinetics of marbofloxacin in diseased lambs, AUC0-24/MIC90 ratio was not found to be higher than 125, but Cmax/MIC90 ratios was found to be higher than 10 for an MIC value of 0.25 µg/mL in all groups. The marbofloxacin dose described in this study may not be effective for the treatment of infections due to M. haemolytica in lambs, with MIC ≤ 0.25 µg/mL.


Assuntos
Albendazol/farmacologia , Anti-Helmínticos/farmacologia , Antibacterianos/farmacocinética , Fluoroquinolonas/farmacocinética , Mannheimia haemolytica/fisiologia , Pasteurelose Pneumônica/tratamento farmacológico , Doenças dos Ovinos/tratamento farmacológico , Animais , Injeções Intramusculares/veterinária , Masculino , Pasteurelose Pneumônica/microbiologia , Ovinos , Doenças dos Ovinos/microbiologia , Turquia
6.
PLoS One ; 14(6): e0218864, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31233558

RESUMO

Pneumonia is one of the most economically important respiratory diseases of calves and knowledge of the impact of clinical disease on pharmacokinetics (PK) in young calves is limited. This study was undertaken to investigate the efficacy and PK of two antibiotics, tulathromycin and danofloxacin, in two age groups of calves experimentally infected with Pasteurella multocida. Both danofloxacin, a fluoroquinolone antibiotic, and tulathromycin, a macrolide antibiotic is approved for the treatment of bovine respiratory disease (BRD). To evaluate potential influences of age and disease on drug distribution and elimination in calves, plasma, interstitial fluid (ISF), and pulmonary epithelial lining fluid (PELF) were analyzed for drug concentrations. Concentrations for both drugs in the PELF were estimated by a urea dilution assay of the collected bronchoalveolar lavage fluids. Age was determined to be a significant covariate for calves administered danofloxacin and tulathromycin for plasma PK parameters. For calves administered danofloxacin, the area under the curve (AUC) in the plasma was lower in 6-month old calves (18.9 ± 12.6 hr* µg/mL) vs. 3-week old calves (32.0 ± 8.2 hr* µg/mL). Clearance (CL/F) of danofloxacin was higher in 6-month old calves. In contrast, tulathromycin plasma concentrations were higher in 6 month old calves and CL/F was higher in 3-week old calves. Age did not significantly influence the ISF concentrations of danofloxacin or tulathromycin in calves with respiratory disease, unlike previous studies which reported higher ISF concentrations of danofloxacin and tulathromycin in 6-month old calves when compared to younger calves. PELF concentrations were higher than plasma and ISF for both danofloxacin and tulathromycin, but did not differ between age groups. Potential reasons for age-related differences on plasma concentration-time profiles and the impact of disease on the partitioning of the drug from the blood to the lungs and ISF as a function of age are explored.


Assuntos
Doenças dos Bovinos/tratamento farmacológico , Dissacarídeos/farmacocinética , Fluoroquinolonas/farmacocinética , Compostos Heterocíclicos/farmacocinética , Infecções por Pasteurella/veterinária , Transtornos Respiratórios/veterinária , Fatores Etários , Animais , Área Sob a Curva , Líquido da Lavagem Broncoalveolar/química , Bovinos , Dissacarídeos/administração & dosagem , Líquido Extracelular/química , Feminino , Fluoroquinolonas/administração & dosagem , Compostos Heterocíclicos/administração & dosagem , Infecções por Pasteurella/tratamento farmacológico , Pasteurella multocida/patogenicidade , Transtornos Respiratórios/tratamento farmacológico
7.
J Vet Pharmacol Ther ; 42(4): 430-439, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31102281

RESUMO

The pharmacokinetics (PK) and pharmacodynamics (PD) of marbofloxacin (MBF) were determined in six healthy female goats of age 1.00-1.25 years after repeated administration of MBF. The MBF was administered intramuscularly (IM) at 2 mg kg-1  day-1 for 5 days. Plasma concentrations of MBF were determined by high-performance liquid chromatography, and PK parameters were obtained using noncompartmental analysis. The MBF concentrations peaked at 1 hr, and peak concentration (Cmax ) was 1.760 µg/ml on day 1 and 1.817 µg/ml on day 5. Repeated dosing of MBF caused no significant change in PK parameters except area under curve (AUC) between day 1 (AUC0-∞ D1 = 7.67 ± 0.719 µg × hr/ml) and day 5 (AUC0-∞ D5 = 8.70 ± 0.857 µg × hr/ml). A slight difference in mean residence time between 1st and 5th day of administration and accumulation index (AI = 1.13 ± 0.017) suggested lack of drug accumulation following repeated IM administration up to 5 days. Minimum inhibitory concentration (MIC) demonstrated that Escherichia coli (MIC = 0.04 µg/ml) and Pasturella multocida (MIC = 0.05 µg/ml) were highly sensitive to MBF. Time-kill kinetics demonstrated rapid and concentration-dependent activity of MBF against these pathogens. PK/PD integration of data for E. coli and P. multocida, using efficacy indices: Cmax /MIC and AUC0-24hr /MIC, suggested that IM administration of MBF at a dose of 2 mg kg-1  day-1 is appropriate to treat infections caused by E. coli. However, a dose of 5 mg kg-1  day-1 is recommended to treat pneumonia caused by P. multocida in goats. The study indicated that MBF can be used repeatedly at dosage of 2 mg/kg in goats without risk of drug accumulation up to 5 days.


Assuntos
Escherichia coli/efeitos dos fármacos , Fluoroquinolonas/farmacocinética , Cabras/sangue , Pasteurella multocida/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Área Sob a Curva , Esquema de Medicação , Farmacorresistência Bacteriana , Feminino , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/farmacologia , Meia-Vida , Injeções Intramusculares , Testes de Sensibilidade Microbiana
8.
Ecotoxicol Environ Saf ; 180: 202-207, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31096125

RESUMO

Fluoroquinolones (FQs) are extensively used in humans and animals, which have aroused wide attention due to the emergence of FQ resistant bacteria and frequent detection in water, sediment and organism. However, little information is available about the bioconcentration and tissue distribution of FQs in fish. In the present study, we investigated the uptake and depuration of eight FQs (balofloxacin (BAL), enoxacin (ENO), enrofloxacin (ENR), fleroxacin (FLE), lomefloxacin (LOM), moxifloxacin (MOX), ofloxacin (OFL), sparfloxacin (SPA)) in common carp under controlled laboratory conditions. The results showed that all target FQs could accumulate in fish tissues, and had a similar tendency over time during the whole uptake and depuration periods. The uptake rate constant (k1), depuration rate constant (k2) and half-lives (t1/2) were in the ranges of 0.007-3.599 L/(kg·d), 0.051-0.283 d-1 and 2.4-10.7 d, respectively. The ranges of bioconcentration factors (BCFs) were 0.24-39.55 L/kg, 0.21-24.97 L/kg and 0.04-1.07 L/kg in liver, kidney and muscle, respectively. BCFs of eight FQs decreased in the order: MOX > ENR > ENO ≈ BAL ≈ FLE ≈ OFL ≈ LOM ≈ SPA, which may be correlated with the substituents at positions 7 and 8 of the basic quinolone nucleus and the metabolic capacity. Besides, BCFs were relative with pH-adjusted distribution coefficient (log D), suggesting that molecular status of ionizable compounds strongly influenced the bioconcentration processes. The present study provides important insights for understanding the bioconcentration and tissues distribution of FQs.


Assuntos
Antibacterianos/farmacocinética , Carpas/metabolismo , Fluoroquinolonas/farmacocinética , Animais , Distribuição Tecidual
9.
J Vet Med Sci ; 81(5): 730-733, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-30918227

RESUMO

The purpose of this study was to clarify the distribution of marbofloxacin (MBFX) within the bronchoalveolar region of calves. Four clinically healthy calves were intramuscularly injected with a single dose of MBFX (2 mg/kg). Samples of plasma and bronchoalveolar lavage fluid (BALF) were obtained for each calf at 0 (before administration), 1, 2, 6 and 24 hr after injection of MBFX. The injections and series of sample collections were conducted and repeated again after two weeks. The results show that the MBFX concentrations in the pulmonary epithelial lining fluid (ELF) were significantly higher than that in plasma and in alveolar cells at 2 hr after injection (P<0.05). For concentrations of MBFX within the ELF, the mean area under the MBFX concentration curve calculated during the 0 to 24 hr timeframe (AUC0-24) was significantly higher than the mean determined from samples collected from the plasma (P<0.05). These results suggest that intramuscularly injected MBFX was well distributed in the bronchoalveolar region.


Assuntos
Antibacterianos/farmacocinética , Líquido da Lavagem Broncoalveolar/química , Bovinos/metabolismo , Fluoroquinolonas/farmacocinética , Células Epiteliais Alveolares/metabolismo , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/sangue , Injeções Intramusculares/veterinária , Masculino
10.
J Vet Med Sci ; 81(5): 753-757, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-30853667

RESUMO

This study aimed to investigate the pharmacokinetics of danofloxacin in red-eared slider turtle (Trachemys scripta elegans) following a single intravenous (IV) and intramuscular (IM) administrations of 6 mg/kg, using a two-way crossover study with 30-day washout period. Eight clinically healthy red-eared slider turtle weighing 410-600 g (mean 490 g) were used for the study. Danofloxacin concentrations were measured using the reversed-phase high-performance liquid chromatography. The plasma concentration-time data were evaluated by a non-compartmental method. After IV administration, the elimination half-life (t1/2ʎz), mean residence time (MRT0-∞), area under the concentration-time curve (AUC0-∞), volume of distribution at steady state and total body clearance in plasma were 24.17 hr, 30.64 hr, 143.31 hr·µg/ml, 1.29 l/kg and 0.04 l/hr/kg, respectively. Following IM administration, t1/2ʎz, MRT0-∞, AUC0-∞, peak concentration (Cmax), time to reach Cmax, and bioavailability in plasma were 32.00 hr, 41.15 hr, 198.23 hr·µg/ml, 8.75 µg/ml, 1.5 hr and 139.89%, respectively. Danofloxacin has clinically superior pharmacokinetic properties, including the complete IM absorption, slow elimination and wide volume of distribution in red-eared slider turtles. However, further pharmacokinetics/pharmacodynamics studies are necessary for the treatment of diseases caused by susceptible bacteria with known minimum inhibitory concentration values in red-eared slider turtles.


Assuntos
Anti-Infecciosos/farmacocinética , Fluoroquinolonas/farmacocinética , Tartarugas , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/sangue , Disponibilidade Biológica , Estudos Cross-Over , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/sangue , Injeções Intramusculares/veterinária , Injeções Intravenosas/veterinária
11.
Biomed Chromatogr ; 33(7): e4532, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30861568

RESUMO

WCK 771 is an l-arginine salt of levonadifloxacin (LND) being developed in intravenous dosage form and has recently completed a phase III trial in India. The pharmacokinetics of WCK 771, a novel anti-MRSA fluoroquinolone, were examined in mice, rats, rabbits, dogs, monkeys and humans after systemic administration during pre-clinical and clinical investigations. Urine and serum were evaluated for identification of metabolites. It was observed that LND mainly follows phase II biotransformation pathways. All of the species showed a different array of metabolites. In mice, rabbit and dog, the drug was mainly excreted in the form of O-glucuronide (M7) and acyl glucuronide (M8) conjugates, whereas in rat and human major metabolite was sulfate conjugate (M6). Monkeys exhibited equal distribution of sulfate (M6) and glucuronide conjugates (M7, M8). In addition to these three major phase II metabolites; five phase I oxidative metabolites (M1, M2, M3, M4 and M5) were identified using liquid chromatography tandem mass spectrometry. Out of these eight metabolites M2, M3, M5, M7 and M8 are reported for the first time.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fluoroquinolonas/farmacocinética , Fluoroquinolonas/urina , Espectrometria de Massas em Tandem/métodos , Animais , Cães , Fluoroquinolonas/química , Fluoroquinolonas/farmacologia , Haplorrinos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Coelhos , Ratos
12.
BMC Vet Res ; 15(1): 51, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30717803

RESUMO

BACKGROUND: Improper use of antimicrobials results in poor treatment and severe bacterial resistance. Breakpoints are routinely used in the clinical laboratory setting to guide clinical decision making. Therefore, the objective of this study was to establish antimicrobial susceptibility breakpoints for danofloxacin against Escherichia coli (E.coli), which is an important pathogen of digestive tract infections. RESULTS: The minimum inhibitory concentrations (MICs) of 1233 E. coli isolates were determined by the microdilution broth method in accordance with the guidelines in Clinical and Laboratory Standards Institute (CLSI) document M07-A9. The wild type (WT) distribution or epidemiologic cutoff value (ECV) was set at 8 µg/mL with statistical analysis. Plasma drug concentration data were used to establish pharmacokinetic (PK) model in swine. The in vitro time kill test in our study demonstrated that danofloxacin have concentration dependent activity against E.coli. The PK data indicated that danofloxacin concentration in plasma was rapidly increased to peak levels at 0.97 h and remained detectable until 48 h after drug administration. The pharmacodynamic cutoff (COPD) was determined as 0.03 µg/mL using Monte Carlo simulation. To the best of our knowledge, this is the first study to establish the ECV and COPD of danofloxacin against E.coli with statistical method. CONCLUSIONS: Compared to the COPD of danofloxacin against E.coli (0.03 µg/mL), the ECV for E.coli seemed reasonable to be used as the final breakpoint of danofloxacin against E.coli in pigs. Therefore, the ECV (MIC ≤8 µg/mL) was finally selected as the optimum danofloxacin susceptibility breakpoint for swine E.coli. In summary, this study provides a criterion for susceptibility testing and improves prudent use of danofloxacin for protecting public health.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Escherichia coli/veterinária , Escherichia coli/efeitos dos fármacos , Fluoroquinolonas/uso terapêutico , Doenças dos Suínos/tratamento farmacológico , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Antibacterianos/farmacocinética , Infecções por Escherichia coli/tratamento farmacológico , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/sangue , Fluoroquinolonas/farmacocinética , Testes de Sensibilidade Microbiana/veterinária , Método de Monte Carlo , Suínos , Doenças dos Suínos/microbiologia
13.
Eur J Pharm Sci ; 131: 230-242, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30811969

RESUMO

Antibacterial drugs, including fluoroquinolones, can exert their therapeutic action only with adequate penetration at the infection site. Multiple factors, such as rate of protein binding, drug liposolubility and organ blood-flow all influence ability of antibiotics to penetrate target tissues. Microdialysis is an in vivo sampling technique that has been successfully applied to measure the distribution of fluoroquinolones in the interstitial fluid of different tissues both in animal studies and clinical setting. Tissue concentrations need to be interpreted within the context of the pathogenesis and causative agents implicated in infections. Integration of microdialysis -derived tissue pharmacokinetics with pharmacodynamic data offers crucial information for correlating exposure with antibacterial effect. This review explores these concepts and provides an overview of tissue concentrations of fluoroquinolones derived from microdialysis studies and explores the therapeutic implications of fluoroquinolone distribution at various target tissues.


Assuntos
Antibacterianos/farmacocinética , Fluoroquinolonas/farmacocinética , Microdiálise , Animais , Antibacterianos/farmacologia , Fluoroquinolonas/farmacologia , Humanos
14.
J Vet Pharmacol Ther ; 42(2): 207-213, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30474236

RESUMO

The aim of the present study was to determine the pharmacokinetics (PKs) and bioavailability of danofloxacin in chukar partridge (Alectoris chukar) following intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations at a dose of 10 mg/kg. A total of eight clinically healthy chukar partridges weighing 480 ± 45 g were used for the investigation. The study was performed in a crossover design (2 × 2 × 2 × 2) with a 15-day washout period between two administrations in four periods. The plasma concentrations of danofloxacin were determined using reversed-phase high-performance liquid chromatography. Noncompartmental PK parameters were also estimated. No local or systemic adverse drug effects were observed in any of the chukar partridges. The mean elimination half-life ranged between 8.18 and 12.08 hr and differed statistically among administration routes. The mean peak plasma concentrations of danofloxacin following IM, SC, and PO administrations were 8.05, 9.58, and 3.39 µg/ml at 0.5, 1, and 4 hr, respectively. Following IM, SC, and PO administrations, the mean bioavailability was 86.33%, 134.40%, and 47.62%, respectively. The mean total clearance and volume of distribution at steady-state following IV administration were 0.13 L hr-1  kg-1 and 0.96 L/kg, respectively. These data, including favorable PKs and the absence of adverse drug effects, suggest that danofloxacin is a useful antibiotic in chukar partridges.


Assuntos
Antibacterianos/farmacocinética , Fluoroquinolonas/farmacocinética , Galliformes/metabolismo , Administração Oral , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/veterinária , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/sangue , Galliformes/sangue , Meia-Vida , Injeções Intramusculares/veterinária , Injeções Intravenosas/veterinária , Injeções Subcutâneas/veterinária
15.
Res Vet Sci ; 122: 36-39, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30453178

RESUMO

Pharmacokinetics of difloxacin (DF), a fluoroquinolone antibiotic, were investigated in Japanese quails (Coturnix japonica) after a single intravenous (IV) and oral (PO) administration of 10 mg/kg bodyweight. Plasma concentration profiles of DF were analyzed by a compartmental pharmacokinetic method. Following IV injection, the plasma concentration vs time profile was best described by a two-compartment open model. Elimination half-life (t1/2ß), total body clearance (Cltot), volume of distribution at steady state (Vdss) and mean residence time (MRT) of DF were 5.45 ±â€¯0.14 h, 0.22 ±â€¯0.01 L/kg/h, 1.54 ±â€¯0.06 L/kg and 6.92 ±â€¯0.19 h, respectively. Following PO administration, DF was rapidly absorbed, with peak plasma concentration (Cmax) of 3.67 µg/mL attained at 1.90 h (Tmax) after administration. Absorption half-life (t1/2ab), elimination half-life (t1/2el), mean absorption time (MAT) were 0.5 h, 5.26 h and 1.11 h, respectively. The bioavailability (F) following PO administration of DF was high (84.40%). For a successful clinical effect of DF in quails, a multiple dosage regimen of 10 mg/kg bodyweight, administered orally every 24 h is recommended to maintain effective plasma concentrations with bacterial infections, in which MIC90 is <0.2 µg/mL.


Assuntos
Ciprofloxacino/análogos & derivados , Coturnix/sangue , Fluoroquinolonas/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Ciprofloxacino/administração & dosagem , Ciprofloxacino/farmacocinética , Coturnix/metabolismo , Fluoroquinolonas/administração & dosagem , Meia-Vida , Injeções Intramusculares , Injeções Intravenosas
16.
Eur J Drug Metab Pharmacokinet ; 44(3): 305-317, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30324277

RESUMO

Delafloxacin has recently received approval by the US Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections. This article provides a balanced and comprehensive systematic critique of the literature in order to provide an up-to-date summary of its clinical pharmacology. Oral delafloxacin is rapidly absorbed and exhibits comparable exposure characteristics (300 mg intravenous versus 450 mg oral) between the two formulations, allowing easy transition from intravenous to oral therapy. The bioavailability is high (60-70%) and absorption is not affected by food intake, although further studies are required under clinically relevant conditions. Delafloxacin is primarily excreted renally (thus requiring renal dose adjustment in the setting of renal dysfunction), but also undergoes metabolism by uridine diphosphate-glucuronosyltransferase enzymes in the formation of a conjugated metabolite. Few drug-drug interaction studies have been identified, although more systematic characterizations in vitro and in vivo are warranted. Delafloxacin is a concentration-dependent bactericidal agent that has in vitro susceptibility for gram-positive (notably potent activity against methicillin-resistant Staphylococcus aureus), gram-negative, and anaerobic organisms. In addition to acute bacterial skin and skin structure infections, the clinical utility of delafloxacin has also been studied in community-acquired pneumonia, acute exacerbation of chronic bronchitis, and gonorrhea, with potentially promising findings. Given its mild side effect profile, including an apparent lack of association with clinically important QTc prolongation, delafloxacin is generally well tolerated.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Fluoroquinolonas/farmacologia , Fluoroquinolonas/farmacocinética , Administração Intravenosa , Administração Oral , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Dermatopatias Bacterianas/tratamento farmacológico , Dermatopatias Bacterianas/microbiologia
17.
J Pediatric Infect Dis Soc ; 8(1): 69-72, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29309672

RESUMO

Concomitant administration of enteral fluoroquinolones (FQs) with divalent or trivalent cation-containing compounds results in a reduction in FQ bioavailability. A review of enteral FQ administration with regards to the timing of divalent or trivalent cation-containing compounds in pediatric patients revealed a high number of inappropriately administered FQs. Suggestions for reducing the number of inappropriately timed FQ administrations are presented here.


Assuntos
Antibacterianos/administração & dosagem , Fluoroquinolonas/administração & dosagem , Alimentos Formulados , Interações Alimento-Droga , Administração Oral , Adolescente , Antibacterianos/farmacocinética , Cátions , Criança , Pré-Escolar , Nutrição Enteral , Fluoroquinolonas/farmacocinética , Humanos , Prescrição Inadequada , Estudos Retrospectivos
18.
Drugs Today (Barc) ; 54(11): 657-666, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30539165

RESUMO

Delafloxacin meglumine (Baxdela, WQ-3034, ABT-492, RX-3341; Melinta Therapeutics) was approved by the U.S. Food and Drug Administration (FDA) in June 2017 for the treatment of acute bacterial skin and skin structure infections on the basis of data from two phase III trials. Delafloxacin is a broad-spectrum anionic fluoroquinolone and its distinct chemical structure increases its potency in acidic environments. It is known to inhibit DNA replication and repair by targeting DNA gyrase and topoisomerase IV. Delafloxacin is administered via both oral and parenteral routes. It has potent activity against methicillin-resistant Staphylococcus aureus and Streptococci, and is also effective against Enterobacteriaceae and Pseudomonas aeruginosa. Delafloxacin is currently in phase III evaluation for treatment of community-acquired pneumonia and was classified as a qualified infectious disease product by the U.S. FDA in its approval.


Assuntos
Antibacterianos/administração & dosagem , Fluoroquinolonas/administração & dosagem , Dermatopatias Bacterianas/tratamento farmacológico , Doença Aguda , Animais , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Interações Medicamentosas , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/farmacocinética , Humanos , Dermatopatias Bacterianas/diagnóstico , Dermatopatias Bacterianas/microbiologia , Resultado do Tratamento
19.
Am J Vet Res ; 79(12): 1268-1276, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30457901

RESUMO

OBJECTIVE To determine whether target values for pharmacokinetic-pharmacodynamic (PK-PD) indices against selected canine pathogens were achievable for pradofloxacin in various canine fluids and leukocytes. ANIMALS 8 healthy adult hounds (experiments 1 and 2) and 6 healthy adult dogs (experiment 3). PROCEDURES In 3 experiments, pradofloxacin (3, 6, or 12 mg/kg) and enrofloxacin (5 or 10 mg/kg) were orally administered once a day for 5 days, and blood, interstitial fluid (ISF), and other fluid samples were collected at various points. Sample drug concentrations were measured, and noncompartmental pharmacokinetic analysis was performed; then, PK-PD indices (ratios between maximum observed concentration [Cmax] and minimum inhibitory or mutant prevention concentrations) were determined for 7 bacterial species. RESULTS PK-PD values for pradofloxacin at 3 mg/kg were approximately 5 times as high in leukocyte versus plasma and were lowest in CSF, synovial fluid, and aqueous humor. No significant differences were noted between serum and ISF. Value ratios for serum versus other body fluids were numerically higher for pradofloxacin (vs enrofloxacin) for all fluid types except CSF and aqueous humor. Target PK-PD values were exceeded for pradofloxacin against all 7 bacterial species in leukocytes and against all species except Bacteroides spp in serum and ISF. Enrofloxacin achieved the target Cmax-to-minimum inhibitory concentration ratio against Pasteurella multocida in serum, ISF, and leukocytes and for Staphylococcus pseudintermedius in serum and leukocytes. A Cmax-to-mutant prevention concentration ratio ≥ 1 against Eschericha coli was achieved for pradofloxacin at 6 mg/kg. CONCLUSIONS AND CLINICAL RELEVANCE These findings supported once-daily oral administration of pradofloxacin to dogs at the currently recommended dose (7.5 mg/kg).


Assuntos
Antibacterianos/farmacocinética , Cães/metabolismo , Fluoroquinolonas/farmacocinética , Administração Oral , Animais , Antibacterianos/administração & dosagem , Área Sob a Curva , Feminino , Masculino , Testes de Sensibilidade Microbiana , Pasteurella multocida/efeitos dos fármacos , Staphylococcus/efeitos dos fármacos
20.
Elife ; 72018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30427309

RESUMO

Understanding the distribution patterns of antibiotics at the site of infection is paramount to selecting adequate drug regimens and developing new antibiotics. Tuberculosis (TB) lung lesions are made of various immune cell types, some of which harbor persistent forms of the pathogen, Mycobacterium tuberculosis. By combining high resolution MALDI MSI with histology staining and quantitative image analysis in rabbits with active TB, we have mapped the distribution of a fluoroquinolone at high resolution, and identified the immune-pathological factors driving its heterogeneous penetration within TB lesions, in relation to where bacteria reside. We find that macrophage content, distance from lesion border and extent of necrosis drive the uneven fluoroquinolone penetration. Preferential uptake in macrophages and foamy macrophages, where persistent bacilli reside, compared to other immune cells present in TB granulomas, was recapitulated in vitro using primary human cells. A nonlinear modeling approach was developed to help predict the observed drug behavior in TB lesions. This work constitutes a methodological advance for the co-localization of drugs and infectious agents at high spatial resolution in diseased tissues, which can be applied to other diseases with complex immunopathology.


Assuntos
Antituberculosos/farmacocinética , Fluoroquinolonas/farmacocinética , Tuberculose/tratamento farmacológico , Tuberculose/patologia , Animais , Antituberculosos/administração & dosagem , Antituberculosos/análise , Modelos Animais de Doenças , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/análise , Histocitoquímica , Macrófagos/química , Macrófagos/microbiologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Coelhos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
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