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1.
PLoS One ; 15(6): e0234211, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497083

RESUMO

Fluoroquinolone resistance in Salmonella Typhimurium is becoming a major concern. Hence, an intervention to limit the growth in resistance is inevitable. One way to combat this challenge is through combination therapy. The combination of antibiotics with phytochemicals has become an ideal means of preventing antimicrobial resistance. Recently, in an in vitro study, the combination of methyl gallate (MG) with marbofloxacin (MAR) has shown to prevent Salmonella Typhimurium invasion. It is also worth to study the effects of plant extracts on the pharmacokinetics of antibiotics. Hence, the objective of this study was to determine the effect of MG on the pharmacokinetics of MAR and pharmacokinetics/pharmacodynamics integration of MG and MAR. The micro-broth dilution method was used to obtain the minimum inhibitory concentration (MIC), and fractional inhibitory concentration (FIC) of MAR and MG. Whereas, the pharmacokinetic was conducted in rats by administering either MAR alone or combined with MG through oral and/or intravenous routes. The results indicated that the MIC of MAR and MG against standard strain Salmonella Typhimurium (ATCC 14028) was 0.031 and 500 µg/mL, respectively. The FICindex of the combination of MAR and MG was 0.5. For orally administered drugs, the Cmax and AUC24h of MAR were 1.04 and 0.78 µg/mL and 5.98 and 6.11 h.µg/mL when MAR was given alone and in combination with MG, respectively. The intravenous administration of MAR showed a half-life of 3.8 and 3.9 h; a clearance rate of 1.1 and 0.73 L/h/kg and a volume of distribution of 5.98 and 4.13 L/kg for MAR alone and in combination with MG, respectively. The AUC24/MIC for MAR alone and in combination with MG was 192.8 and 381.9 h, respectively. In conclusion, MG has shown to increase the antimicrobial activity of MAR in vitro and ex vivo experiments without affecting the pharmacokinetics of MAR in rats.


Assuntos
Fluoroquinolonas/farmacologia , Fluoroquinolonas/farmacocinética , Ácido Gálico/análogos & derivados , Salmonella typhimurium/efeitos dos fármacos , Animais , Interações Medicamentosas , Ácido Gálico/farmacocinética , Ácido Gálico/farmacologia , Masculino , Testes de Sensibilidade Microbiana , Ratos , Ratos Sprague-Dawley
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.
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
4.
Arch Environ Contam Toxicol ; 78(2): 310-328, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31605151

RESUMO

Fluoroquinolone (FQ) derivatives with environmental friendliness regarding photodegradation, bioconcentration, and genotoxicity were selected from our previous works so that their transformation pathways of biological metabolism, photodegradation, microbial degradation, and chlorination disinfection could be studied. The pathways of these molecules and their derivatives were simulated to investigate the genotoxicity of their transformation products. The results showed that the genotoxicity of the biological metabolites, photodegradation products, and microbial degradation products of the maternal FQ derivatives partially increased, whereas the disinfection by-products exhibited lower genotoxicity than their precursors. Some designed FQ molecular derivatives still had potential environmental risks in biological metabolism, photodegradation, and microbial degradation. This study demonstrated that it is necessary to take into account the potential environmental risks of the transformed products of the modified FQs molecules during biometabolism, photodegradation, microbial degradation, and chlorination processes when designing novel FQ molecules. In future studies, assessing the potential environmental risks during various artificial or natural processes can be applied to screen environmentally friendly novel FQ molecules to avoid and or reduce their threat to environmental and human health.


Assuntos
Antibacterianos/toxicidade , Poluentes Ambientais/toxicidade , Fluoroquinolonas/toxicidade , Relação Quantitativa Estrutura-Atividade , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Biotransformação , Poluentes Ambientais/química , Poluentes Ambientais/farmacocinética , Fluoroquinolonas/química , Fluoroquinolonas/farmacocinética , Humanos , Testes de Mutagenicidade , Fotólise
5.
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
6.
Acta Vet Hung ; 67(4): 602-609, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842594

RESUMO

The plasma pharmacokinetics of danofloxacin was studied in healthy African catfish (Clarias gariepinus) following a single intravenous (IV) and intramuscular (IM) administration of 10 mg/kg at 22 °C. Catfish were divided into two groups (each group containing 78 fish), then danofloxacin mesylate (10 mg/kg) was administered IV (into the caudal vein) in Group 1 and IM (into the right epaxial muscle) in Group 2, and blood was obtained from the caudal vein before (0 h) and after (0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 72 and 96 h) of drug administration. High-performance liquid chromatography was used for the determination of plasma concentration, and a non-compartmental model was used for the analysis of pharmacokinetic parameters. After IV administration, elimination half-life (t1/2λz, 24.49 h), mean residence time (MRT, 30.14 h), volume of distribution at steady state (Vdss, 1.07 L/kg) and total body clearance (CLT, 0.035 L/h/kg) were determined. After IM administration, t1/2λz, MRT, peak concentration (Cmax), time to reach Cmax and bioavailability were 47.64 h, 61.06 h, 5.22 µg/mL, 1 h and 67.12%, respectively. After IM administration, danofloxacin showed good bioavailability and long t1/2λz. The favourable pharmacokinetic characteristics after IM administration support the use of danofloxacin for the treatment of susceptible bacterial infections in catfish.


Assuntos
Antibacterianos/farmacocinética , Peixes-Gato/metabolismo , Fluoroquinolonas/farmacocinética , Animais , Injeções Intramusculares/veterinária , Injeções Intravenosas/veterinária , Masculino
7.
J Avian Med Surg ; 33(4): 361-368, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31833304

RESUMO

The pharmacokinetics of danofloxacin was investigated in rehabilitated California brown pelicans (Pelecanus occidentalis californicus) after a single intramuscular injection at a dose of 15 mg/kg body weight. The concentration of the drug in plasma was assayed by high-pressure liquid chromatography. A sparse-sampling design was used to reduce the number of samples (1-4 venipunctures) obtained from 24 brown pelicans. A population pharmacokinetic analysis with nonlinear mixed-effects modeling was used to accommodate the sparse-sampling strategy. The nonlinear mixed-effects modeling approach measured both fixed effects (typical values for the population) and random effects (between-subject variability) for this population. A 1-compartment model best represented the concentration-versus-time data after injection. After injection, the elimination half-life, peak concentration, area under the curve, and volume of distribution were 2.76 hours, 2.5 µg/mL, 13.75 µg/h/mL, and 4.35 L/kg, respectively. Rate of absorption was highly variable among the birds. The intramuscular injection of danofloxacin in pelicans at this dose produced plasma concentrations that meet therapeutic targets for bacteria with a minimum inhibitory concentration of ≤0.25 µg/mL. This dose can be used for future studies to evaluate the efficacy of danofloxacin for treating susceptible bacteria.


Assuntos
Anti-Infecciosos/farmacocinética , Aves/metabolismo , Fluoroquinolonas/farmacocinética , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/sangue , Área Sob a Curva , Cromatografia Líquida de Alta Pressão/veterinária , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/sangue , Meia-Vida , Injeções Intramusculares/veterinária , Absorção Intramuscular , Testes de Sensibilidade Microbiana/veterinária , Dinâmica não Linear , Músculos Peitorais/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-31611354

RESUMO

Clinical studies of new antitubercular drugs are costly and time-consuming. Owing to the extensive tuberculosis (TB) treatment periods, the ability to identify drug candidates based on their predicted clinical efficacy is vital to accelerate the pipeline of new therapies. Recent failures of preclinical models in predicting the activity of fluoroquinolones underline the importance of developing new and more robust predictive tools that will optimize the design of future trials. Here, we used high-content imaging screening and pharmacodynamic intracellular (PDi) modeling to identify and prioritize fluoroquinolones for TB treatment. In a set of studies designed to validate this approach, we show moxifloxacin to be the most effective fluoroquinolone, and PDi modeling-based Monte Carlo simulations accurately predict negative culture conversion (sputum sterilization) rates compared to eight independent clinical trials. In addition, PDi-based simulations were used to predict the risk of relapse. Our analyses show that the duration of treatment following culture conversion can be used to predict the relapse rate. These data further support that PDi-based modeling offers a much-needed decision-making tool for the TB drug development pipeline.


Assuntos
Antituberculosos/farmacologia , Antituberculosos/farmacocinética , Fluoroquinolonas/farmacologia , Fluoroquinolonas/farmacocinética , Modelos Biológicos , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/metabolismo , Linhagem Celular , Simulação por Computador , Técnicas de Apoio para a Decisão , Desenvolvimento de Medicamentos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Método de Monte Carlo , Moxifloxacina/farmacocinética , Moxifloxacina/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Células THP-1 , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/metabolismo
9.
Artigo em Inglês | MEDLINE | ID: mdl-31636067

RESUMO

Fluoroquinolone treatments induce dysbiosis of the intestinal microbiota, resulting in loss of resistance to colonization by exogenous bacteria such as Clostridioides difficile that may cause severe diarrhea in humans and lethal infection in hamsters. We show here that DAV131A, a charcoal-based adsorbent, decreases the intestinal levels of the fluoroquinolone antibiotics levofloxacin and ciprofloxacin in hamsters, protects their intestinal microbiota, and prevents lethal infection by C. difficile.


Assuntos
Carvão Vegetal/administração & dosagem , Infecções por Clostridium/prevenção & controle , Administração Oral , Adsorção , Animais , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Ciprofloxacino/efeitos adversos , Ciprofloxacino/farmacocinética , Modelos Animais de Doenças , Disbiose/induzido quimicamente , Disbiose/metabolismo , Disbiose/prevenção & controle , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/farmacocinética , Microbioma Gastrointestinal/efeitos dos fármacos , Levofloxacino/efeitos adversos , Levofloxacino/farmacocinética , Masculino , Mesocricetus
10.
Artigo em Inglês | MEDLINE | ID: mdl-31405868

RESUMO

Sitafloxacin showed potent activity against various respiratory pathogens. Blood and bronchoalveolar lavage (BAL) fluid samples were obtained from 12 subjects after a single oral dose of sitafloxacin 200 mg. The mean ± SD (median) maximum ratio of epithelial lining fluid (ELF) to unbound plasma concentration was 1.02 ± 0.58 (1.33). The penetration ratios based on the mean and median area under the curve from 0 to 8 h (AUC0-8) were 0.85 and 0.79 µg · h/ml, respectively. Sitafloxacin penetrates well into ELF in critically ill Thai patients with pneumonia. (This study has been registered in the Thai Clinical Trials Registry [TCTR] under registration no. TCTR20170222001.).


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Fluoroquinolonas/farmacocinética , Fluoroquinolonas/uso terapêutico , Macrófagos Alveolares/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Mucosa Respiratória/efeitos dos fármacos , Adulto , Idoso , Lavagem Broncoalveolar/métodos , Líquido da Lavagem Broncoalveolar , Estado Terminal , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Macrófagos Alveolares/metabolismo , Masculino , Pessoa de Meia-Idade , Pneumonia/metabolismo , Mucosa Respiratória/microbiologia , Tailândia
11.
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
12.
Enferm. infecc. microbiol. clín. (Ed. impr.) ; 37(6): 394-397, jun.-jul. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-189346

RESUMO

INTRODUCCIÓN: El objetivo de este trabajo fue analizar la susceptibilidad de Mycoplasma genitalium a macrólidos y fluoroquinolonas mediante técnicas moleculares. MÉTODOS: La susceptibilidad a macrólidos se analizó (Gipuzkoa, 2014-2017) mediante PCR en tiempo real con sondas (gen 23S ARNr) y a fluoroquinolonas mediante secuenciación tras PCR convencionales (genes parC/gyrA). RESULTADOS: Se detectaron mutaciones asociadas con resistencia a macrólidos en 43/263 (16,3%) casos y con posible resistencia a fluoroquinolonas en 21/267 (7,9%). La resistencia a macrólidos fue más frecuente tras tratamiento previo con azitromicina (76,5 vs. 7,4%; p < 0,001) y con la pauta única de 1 g (31,3 vs. 7% pauta ampliada, p < 0,001). Se detectaron 5/245 (2%) casos con mutaciones de posible resistencia para ambos antibióticos. CONCLUSIONES: La técnica empleada para el estudio de la susceptibilidad de Mycoplasma genitalium a la azitromicina permitió una respuesta rápida con un tratamiento antibiótico dirigido. Moxifloxacino puede ser una buena alternativa en casos con resistencia a macrólidos


INTRODUCTION: The objective of this study was to analyse the susceptibility of Mycoplasma genitalium to macrolides and fluoroquinolones using molecular techniques. METHODS: Susceptibility to macrolides was tested (Gipuzkoa, 2014-2017) by a rapid probe-based real-time polymerase chain reaction assay (23S rRNA gene) and to fluoroquinolones by sequencing the parC and gyrA genes. RESULTS: Mutations associated with macrolide resistance were detected in 43/263 (16.3%) cases and potential fluoroquinolone resistance in 21/267 (7.9%). Macrolide resistance was more frequent in patients previously treated with azithromycin (76.5% vs 7.4%, P < .001) as well as in those treated with a single 1g dose (31.3%) vs the extended regimen (7%, P < .001). There were 5/245 (2%) cases with mutations probably associated with resistance to both antibiotics. CONCLUSIONS: The technique used for testing Mycoplasma genitalium susceptibility to azithromycin allowed the rapid implementation of resistance-guided antibiotic therapy. Moxifloxacin could be a good option in cases of macrolide resistance


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Fluoroquinolonas/farmacocinética , Macrolídeos/farmacologia , Mycoplasma genitalium/isolamento & purificação , Infecções por Mycoplasma/tratamento farmacológico , Mutação , Antibacterianos/uso terapêutico , Macrolídeos/uso terapêutico , Mycoplasma genitalium/efeitos dos fármacos , Azitromicina/administração & dosagem , Terapia de Alvo Molecular/métodos , Técnicas Microbiológicas/métodos , Espanha/epidemiologia , Infecções por Mycoplasma/epidemiologia
13.
J Vet Pharmacol Ther ; 42(6): 624-631, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31190327

RESUMO

The aim of this study was to determine the pharmacokinetics/pharmacodynamics of enrofloxacin (ENR) and danofloxacin (DNX) following intravenous (IV) and intramuscular (IM) administrations in premature calves. The study was performed on twenty-four calves that were determined to be premature by anamnesis and general clinical examination. Premature calves were randomly divided into four groups (six premature calves/group) according to a parallel pharmacokinetic (PK) design as follows: ENR-IV (10 mg/kg, IV), ENR-IM (10 mg/kg, IM), DNX-IV (8 mg/kg, IV), and DNX-IM (8 mg/kg, IM). Plasma samples were collected for the determination of tested drugs by high-pressure liquid chromatography with UV detector and analyzed by noncompartmental methods. Mean PK parameters of ENR and DNX following IV administration were as follows: elimination half-life (t1/2λz ) 11.16 and 17.47 hr, area under the plasma concentration-time curve (AUC0-48 ) 139.75 and 38.90 hr*µg/ml, and volume of distribution at steady-state 1.06 and 4.45 L/kg, respectively. Total body clearance of ENR and DNX was 0.07 and 0.18 L hr-1  kg-1 , respectively. The PK parameters of ENR and DNX following IM injection were t1/2λz 21.10 and 28.41 hr, AUC0-48 164.34 and 48.32 hr*µg/ml, respectively. The bioavailability (F) of ENR and DNX was determined to be 118% and 124%, respectively. The mean AUC0-48CPR /AUC0-48ENR ratio was 0.20 and 0.16 after IV and IM administration, respectively, in premature calves. The results showed that ENR (10 mg/kg) and DNX (8 mg/kg) following IV and IM administration produced sufficient plasma concentration for AUC0-24 /minimum inhibitory concentration (MIC) and maximum concentration (Cmax )/MIC ratios for susceptible bacteria, with the MIC90 of 0.5 and 0.03 µg/ml, respectively. These findings may be helpful in planning the dosage regimen for ENR and DNX, but there is a need for further study in naturally infected premature calves.


Assuntos
Animais Recém-Nascidos , Antibacterianos/farmacocinética , Bovinos/sangue , Enrofloxacina/farmacocinética , Fluoroquinolonas/farmacocinética , Nascimento Prematuro , Animais , Antibacterianos/sangue , Área Sob a Curva , Bactérias/efeitos dos fármacos , Bovinos/metabolismo , Enrofloxacina/sangue , Fluoroquinolonas/sangue , Meia-Vida , Testes de Sensibilidade Microbiana
14.
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
15.
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
16.
J Clin Microbiol ; 57(7)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31043468

RESUMO

Fluoroquinolones remain some of the more commonly prescribed antimicrobial agents in the United States, despite the wide array of reported side effects that are associated with their use. In 2019, the Clinical and Laboratory Standards Institute revised the fluoroquinolone antimicrobial susceptibility testing breakpoints for both Enterobacteriaceae and Pseudomonas aeruginosa This breakpoint revision was deemed necessary on the basis of pharmacokinetic and pharmacodynamic analyses suggesting that the previous breakpoints were too high, in addition to the inability of the previous breakpoints to detect low-level resistance to this antibiotic class. In this minireview, we review the published data in support of this revision, as well as the potential challenges that these breakpoint revisions are likely to pose for clinical laboratories.


Assuntos
Antibacterianos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Testes de Sensibilidade Microbiana/normas , Pseudomonas aeruginosa/efeitos dos fármacos , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Serviços de Laboratório Clínico/organização & administração , Serviços de Laboratório Clínico/normas , Enterobacteriaceae/isolamento & purificação , Fluoroquinolonas/farmacocinética , Fluoroquinolonas/uso terapêutico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Guias de Prática Clínica como Assunto , Pseudomonas aeruginosa/isolamento & purificação , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia
17.
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
18.
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
19.
Artigo em Inglês | MEDLINE | ID: mdl-31061152

RESUMO

Fluoroquinolones are group A drugs in tuberculosis guidelines. We aim to compare the culture conversion between new-generation (levofloxacin and moxifloxacin) and old-generation (ciprofloxacin and ofloxacin) fluoroquinolones, develop pharmacokinetic models, and calculate target attainment for levofloxacin and moxifloxacin. We included three U.S. tuberculosis centers. Patients admitted between 1984 and 2015, infected with drug-resistant tuberculosis, and who had received fluoroquinolones for ≥28 days were included. Demographics, sputum cultures and susceptibility, treatment regimens, and serum concentrations were collected. A time-to-event analysis was conducted, and Cox proportional hazards model was used to compare the time to culture conversion. Using additional data from ongoing studies, pharmacokinetic modelling and Monte Carlo simulations were performed to assess target attainment for different doses. Overall, 124 patients received fluoroquinolones. The median age was 40 years, and the median weight was 60 kg. Fifty-six patients (45%) received old-generation fluoroquinolones. New-generation fluoroquinolones showed a faster time to culture conversion (median 16 versus 40 weeks, P = 0.012). After adjusting for isoniazid and clofazimine treatment, patients treated with new-generation fluoroquinolones were more likely to have culture conversion (adjusted hazards ratio, 2.16 [95% confidence interval, 1.28 to 3.64]). We included 178 patients in the pharmacokinetic models. Levofloxacin and moxifloxacin were best described by a one-compartment model with first-order absorption and elimination. At least 1,500 to 1,750 mg levofloxacin and 800 mg moxifloxacin may be needed for maximum kill at the current epidemiologic cutoff values. In summary, new-generation fluoroquinolones showed faster time to culture conversion compared to the old generation. For optimal target attainment at the current MIC values, higher doses of levofloxacin and moxifloxacin may be needed.


Assuntos
Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Fluoroquinolonas/farmacocinética , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciprofloxacino/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Fluoroquinolonas/administração & dosagem , Humanos , Levofloxacino/administração & dosagem , Levofloxacino/farmacocinética , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Modelos Biológicos , Moxifloxacina/administração & dosagem , Moxifloxacina/farmacocinética , Ofloxacino/farmacocinética , Estudos Retrospectivos , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Adulto Jovem
20.
Clin Infect Dis ; 68(Suppl 3): S213-S222, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30957164

RESUMO

Fluoroquinolones have been in clinical use for over 50 years with significant efficacy. However, increasing resistance and emergence of some marked adverse events have limited their usage. The most recently approved class member, delafloxacin, is the only available anionic (non-zwitterionic) fluoroquinolone. Its unique molecular structure provides improved in vitro activity against most Gram-positive pathogens, including quinolone-resistant strains, which is further enhanced at acid pH. Delafloxacin shows favorable pharmacological properties, with about 60% bioavailability after oral administration, only mild inhibition of cytochrome P450 3A, and no evidence of cardiac- or phototoxicity in healthy volunteers (tested against positive controls). Its twice daily dosing, suitability for intravenous, oral, or switch dosing, the lack of many clinically significant drug-drug interactions, and acceptable adverse event profile in registration clinical trials supports its use in the treatment of acute bacterial skin and skin structure infections, and potentially in other infections, where resistance to other agents, safety, and/or the need for early discharge is of concern.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Fluoroquinolonas/química , Fluoroquinolonas/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Monitoramento de Medicamentos , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/farmacocinética , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
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