RESUMO
The pharmacokinetic (PK)/pharmacodynamic (PD) approach has been widely used in clinical practice to optimize antimicrobial treatment. To promote the appropriate use of antimicrobial agents, it is important to consider certain factors, such as patient (e.g., age, physique, medical history, comorbidities, and organ dysfunction), site of infection (the target site where many causative bacteria are present), and microorganism (causative bacteria and susceptibility), and the dosing regimen should be selected based on the PK/PD approach. However, for renally excreted antibiotics, dosing regimens based on only renal function, such as creatinine clearance, are mainly used. Therefore, other factors such as patient pathological factors, antibiotic penetration of target sites, susceptibility of the causative bacteria to antibiotic, and clinical evaluation (efficacy and toxicity) should be considered simultaneously. These studies aimed to tailor the dosing of antimicrobial agents to individual patients by considering these factors. Multifaceted PK/PD evaluation may improve antimicrobial efficacy and safety, thereby contributing to the successful treatment of infectious diseases. Furthermore, improved treatment success rates may help manage the prevalence of antimicrobial-resistant bacteria, which is expected to become a significant problem in the future.
Assuntos
Medicina de Precisão , Humanos , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Farmacorresistência Bacteriana , Infecções Bacterianas/tratamento farmacológico , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/administração & dosagem , Bactérias/efeitos dos fármacos , Fatores EtáriosRESUMO
OBJECTIVES: To investigate which independent factor(s) have an impact on the pharmacokinetics of vancomycin in critically ill children, develop an equation to predict the 24-hour area under the concentration-time curve from a trough concentration, and evaluate dosing regimens likely to achieve a 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio (AUC24/MIC) greater than or equal to 400. DESIGN: Prospective population pharmacokinetic study of vancomycin. SETTING: Critically ill patients in quaternary care PICUs. PATIENTS: Children 90 days old or older to younger than 18 years who received IV vancomycin treatment, irrespective of the indication for use, in the ICUs at the University of Maryland Children's Hospital and Texas Children's Hospital were enrolled. INTERVENTIONS: Vancomycin was prescribed at doses and intervals chosen by the treating clinicians. MEASUREMENTS AND MAIN RESULTS: A median of four serum levels of vancomycin per patient were collected along with other variables for up to 7 days following the first administration. These data were used to characterize vancomycin pharmacokinetics and evaluate the factors affecting the variability in achieving AUC24/MIC ratio greater than or equal to 400 in PICU patients who are not on extracorporeal therapy. A total of 302 children with a median age of 6.0 years were enrolled. A two-compartment model described the pharmacokinetics of vancomycin with the clearance of 2.76 L/hr for a typical patient weighing 20 kg. The glomerular filtration rate estimated using either the bedside Schwartz equation or the chronic kidney disease in children equation was the only statistically significant predictor of clearance among the variables evaluated, exhibiting equal predictive performance. The trough levels achieving AUC24/MIC = 400 were 5.6-10.0 µg/mL when MIC = 1 µg/mL. The target of AUC24/MIC greater than or equal to 400 was achieved in 60.4% and 36.5% with the typical dosing regimens of 15 mg/kg every 6 and 8 hours (q6h and q8h), respectively. CONCLUSIONS: The pharmacokinetics of vancomycin in critically ill children were dependent on the estimated glomerular filtration rate only. Trough concentrations accurately predict AUC24. Typical pediatric vancomycin dosing regimens of 15 mg/kg q6h and q8h will often lead to AUC24/MIC under 400.
Assuntos
Antibacterianos , Área Sob a Curva , Estado Terminal , Unidades de Terapia Intensiva Pediátrica , Testes de Sensibilidade Microbiana , Vancomicina , Humanos , Vancomicina/farmacocinética , Vancomicina/administração & dosagem , Pré-Escolar , Criança , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Lactente , Masculino , Feminino , Estudos Prospectivos , Adolescente , Estado Terminal/terapiaRESUMO
Bacterial keratitis (BK) is an infection that causes inflammation of the cornea and, if severe, can result in blindness. Topical fluoroquinolones combined with corticosteroids have been shown to be useful in the treatment of BK. A rapid, selective, and sensitive bioanalytical method for simultaneous quantification of Gatifloxacin (GAT) and Dexamethasone (DEX) has been developed and validated using tandem mass spectrometry (LC-MS/MS). Optimal separation was accomplished in under 5 min using an Agilent Zorbax C18 column (100 mm × 4.6 mm, 3.5 µm). The mobile phase was composed of a blend of 0.2% formic acid in triple distilled water and methanol with a flow rate of 0.65 mL/min in isocratic mode. GAT and DEX were detected in positive electrospray ionization multiple reaction monitoring mode (MRM), and the retention time was found to be at 1.64 and 2.93 min, respectively. The linearity of GAT and DEX was found to be in the range of 1.56-400 ng mL-1 with good precision and accuracy. The method was validated according to USFDA regulatory guidelines. The validated method was effectively utilized for preclinical pharmacokinetic analysis of GAT and DEX in rabbit tear fluid following the topical application of a commercial formulation.
Assuntos
Dexametasona , Gatifloxacina , Espectrometria de Massas em Tandem , Lágrimas , Animais , Coelhos , Espectrometria de Massas em Tandem/métodos , Gatifloxacina/farmacocinética , Gatifloxacina/química , Dexametasona/farmacocinética , Dexametasona/análise , Lágrimas/química , Reprodutibilidade dos Testes , Limite de Detecção , Cromatografia Líquida/métodos , Masculino , Modelos Lineares , Antibacterianos/farmacocinética , Antibacterianos/análise , Antibacterianos/sangue , Fluoroquinolonas/farmacocinética , Fluoroquinolonas/análise , Fluoroquinolonas/sangue , Soluções Oftálmicas/farmacocinética , Soluções Oftálmicas/química , Espectrometria de Massa com Cromatografia LíquidaRESUMO
Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic (PK/PD) parameters is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised paediatric host. In neonates and children, infections account for a high percentage of hospital admissions, and anti-infectives are the most used drugs. However, paediatric PK/PD studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals-usually used off-label in paediatrics-to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the PK parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, paediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring. The aim of this document, developed jointly by the Spanish Society of Hospital Pharmacy and the Spanish Society of Paediatric Infectious Diseases, is to describe the available evidence on the indications for therapeutic drug monitoring (TDM) of antibiotics and antifungals in newborn and paediatric patients, and to provide practical recommendations for TDM in routine clinical practice to optimise their dosing, efficacy and safety. Of antibiotics and antifungals in the paediatric population.
Assuntos
Antibacterianos , Antifúngicos , Monitoramento de Medicamentos , Humanos , Recém-Nascido , Antibacterianos/uso terapêutico , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antifúngicos/uso terapêutico , Antifúngicos/farmacocinética , Antifúngicos/efeitos adversos , Antifúngicos/administração & dosagem , Criança , Lactente , Pré-Escolar , Espanha , Serviço de Farmácia HospitalarRESUMO
Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic parameters, is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised host. In neonates and children, infections account for a high percentage of hospital admissions and anti-infectives are the most used drugs. However, pediatric pharmacokinetic and pharmacodynamic studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals -usually used off-label in pediatrics- to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the pharmacokinetic parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, pediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring. The aim of this document, developed jointly between the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Pediatric Infectious Diseases (SEIP), is to describe the available evidence on the indications for therapeutic drug monitoring of antibiotics and antifungals in newborn and pediatric patients and to provide practical recommendations for therapeutic drug monitoring in routine clinical practice to optimize pharmacokinetic and pharmacodynamic parameters, efficacy and safety of antibiotics and antifungals in the pediatric population.
Assuntos
Antibacterianos , Antifúngicos , Monitoramento de Medicamentos , Humanos , Antifúngicos/uso terapêutico , Antifúngicos/farmacocinética , Antifúngicos/efeitos adversos , Recém-Nascido , Antibacterianos/uso terapêutico , Antibacterianos/farmacocinética , Criança , Lactente , Espanha , Pré-Escolar , Serviço de Farmácia Hospitalar , Sociedades Médicas , PediatriaRESUMO
The prevalence of infections by methicillin-resistant Staphylococcus aureus (MRSA) has led to dramatically increased mortality and threated the public health worldwide. Pleuromutilin compound 14-O-[(4-(pyrrolidine-1-yl)-6-methylpyrimidine-2-yl) thioacetyl] mutilin (PMTM) is a new antibacterial agent with excellent antibacterial efficacy against Gram positive bacteria. For further developing PMTM as a potential drug against MRSA infections, the in vitro antibacterial efficacy and preclinical safety were explored in this study. The results revealed that PMTM presented the higher anti-MRSA activity, increasing post-antibiotic effect (PAE) and limited potential to develop resistance. In safety evaluation, PMTM demonstrated low cytotoxicity, poor hemolytic activity, tolerable oral acute toxic effects in rats, devoid of mutagenic response and weak inhibitory potential on CYP3A4, but displayed moderate potential hERG K+ channel inhibition. Furthermore, two salts of PMTM with sulfuric acid and hydrochloric acid were prepared and confirmed. The sulfate salt of PMTM exhibited the highest solubility based on powder dissolution experiments and was chosen to evaluate pharmacokinetics properties, in which it displayed improved mouse pharmacokinetics parameters and oral bioavailability. The present study successfully provides a good foundation of PMTM for new antibacterial drug development.
Assuntos
Antibacterianos , Diterpenos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Pleuromutilinas , Compostos Policíclicos , Ratos Sprague-Dawley , Animais , Compostos Policíclicos/farmacocinética , Compostos Policíclicos/farmacologia , Diterpenos/farmacocinética , Diterpenos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Masculino , Camundongos , Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Antibacterianos/toxicidade , Antibacterianos/administração & dosagem , Humanos , Ratos , FemininoRESUMO
The aim of the experiment was to investigate the pharmacokinetics of oxytetracycline dihydrate after a single oral administration of 80 mg kg-1 day-1 in rainbow trout and assess its biosafety at concentration of 80, 240, 400, and 800 mg kg-1 day-1 over 30 days, focusing on various aspects such as effective feed consumption, physiological responses, drug tolerance, and detection of low drug concentrations in rainbow trout. The pharmacokinetics study spanned a duration of 5 days, while the assessment of biosafety extended for a 30-day safety margin, followed by a subsequent 10-day residual analysis. Pharmacokinetic analysis revealed slow absorption with low-rate constant in tissues. Absorption rates vary among tissues, with the gill showing the highest rate (0.011 h-1) and plasma exhibiting the slowest (0.0002 h-1). According to pharmacokinetic analysis, the highest concentration, Cmax (µg kg-1) was observed in the kidney (9380 µg kg-1) and gill (8710 µg kg-1), and lowest in muscle (2460 µg kg-1). The time (Tmax) to reach peak concentration (Cmax) varied among tissues, ranging from 3 h in the gill to 32 h in the muscle, with 24 h in plasma, 32 h in the kidney, and 16 h in both the liver and skin. The liver and kidney had the highest area under the concentration-time curve (AUC(0-128)), indicating widespread drug distribution. Prolonged elimination occurred at varying rates across tissues, with the gill showing the highest rate. The study found that OTC concentrations exceeded the LOD and LOQ values. Biosafety evaluation showed effective feed consumption, physiological responses, and low drug concentrations in muscle at the recommended dosage of 80 mg kg-1 fish day-1.
Assuntos
Oncorhynchus mykiss , Oxitetraciclina , Animais , Oncorhynchus mykiss/metabolismo , Oxitetraciclina/farmacocinética , Oxitetraciclina/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Administração Oral , Distribuição Tecidual , Brânquias/metabolismoRESUMO
Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic (PK/PD) parameters is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised paediatric host. In neonates and children, infections account for a high percentage of hospital admissions, and anti-infectives are the most used drugs. However, paediatric PK/PD studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals-usually used off-label in paediatrics-to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the PK parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, paediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring. The aim of this document, developed jointly by the Spanish Society of Hospital Pharmacy and the Spanish Society of Paediatric Infectious Diseases, is to describe the available evidence on the indications for therapeutic drug monitoring (TDM) of antibiotics and antifungals in newborn and paediatric patients, and to provide practical recommendations for TDM in routine clinical practice to optimise their dosing, efficacy and safety. Of antibiotics and antifungals in the paediatric population.
Assuntos
Antibacterianos , Antifúngicos , Monitoramento de Medicamentos , Humanos , Recém-Nascido , Monitoramento de Medicamentos/métodos , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Criança , Antifúngicos/farmacocinética , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Lactente , Pré-EscolarRESUMO
BACKGROUND AND PURPOSE: The duration of antibiotic coverage in hand tissues during surgery is unknown. We investigated the time the free concentration of cefuroxime was above the minimal inhibitory concentration (fT>MIC) of 4 µg/mL in hand tissues after single and repeated administration. METHODS: In a prospective, unblinded randomized study 16 patients (13 female, age range 51-80 years) underwent trapeziectomy. Microdialysis catheters were placed in the metacarpal bone (primary effect parameter), synovial sheath, and subcutaneous tissue. Patients were randomized to postoperative administration of either intravenous single administration of cefuroxime (1,500 mg) (Group 1, n = 8) or repeated dosing (2 x 1,500 mg) with a 4 h interval (Group 2, n = 8). Samples were taken over 8 h. RESULTS: The fT>MIC of 4 µg/mL was found to be significantly longer in the metacarpal bone in Group 2 compared with Group 1 with a mean difference of 199 min (95% confidence interval 158-239). The same trend was evident in the remaining compartments. A concentration of 4 µg/mL was reached in all compartments in both groups within a mean time of 6 min (range 0-27 min). In Group 1, the mean concentrations decreased below 4 µg/mL between 3 h 59 min and 5 h 38 min. CONCLUSION: The fT>MIC was longer after repeated administration compared with single administration in all compartments. A single administration of cefuroxime 1,500 mg provided antimicrobial hand tissue coverage for a minimum of 3 h 59 min. Cefuroxime administration in hand surgeries should be done minimum 27 min prior to incision to achieve sufficient coverage in all individuals. Cefuroxime readministration should be considered in hand surgeries lasting longer than 4 h from time of administration.
Assuntos
Antibacterianos , Cefuroxima , Trapézio , Humanos , Cefuroxima/administração & dosagem , Cefuroxima/farmacocinética , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Estudos Prospectivos , Idoso de 80 Anos ou mais , Trapézio/cirurgia , Mãos/cirurgia , Ossos Metacarpais/cirurgia , Esquema de MedicaçãoRESUMO
BACKGROUND: Pathophysiological changes post-liver transplantation impact the pharmacokinetics and pharmacodynamics of antibiotics. Piperacillin, often used in combination with tazobactam, is a key antibiotic after transplantation to its broad-spectrum activity, but there is a lack of specific pharmacokinetic data in this population. This study aims to describe the pharmacokinetic parameters and target attainment of piperacillin in pediatric liver transplant recipients. METHODS: Patients with preserved renal function (estimated glomerular filtration rate > 50 mL/min/1.73 m2) receiving intravenous piperacillin-tazobactam at 112.5 mg/kg every 8 h (100 mg piperacillin/12.5 mg tazobactam), with a rapid infusion (0.5-1 h), were included. Two blood samples per child were collected during the same interval within 48 h of starting therapy. A Bayesian approach was applied to estimate individual pharmacokinetic parameters and perform dosing recommendations against Enterococcus spp., Enterobacterales and Pseudomonas aeruginosa. RESULTS: Eight patients with median age of 8 months were included. Median piperacillin clearance and central volume of distribution for the cohort were 11.11 L/h/70 kg and 9.80 L/70 kg, respectively. Seven patients (87.5%) presented with concentrations below the target of 100% fT > MIC. Simulations suggested that these patients required more frequent dosing and extended duration of infusion to ensure target attainment. One patient (12.5%) had trough concentrations that exceed 16 mg/L and could receive a lower daily dose. CONCLUSIONS: This case series highlights the importance of personalized therapy in pediatric liver transplant recipients due to the unpredictable and highly variable piperacillin pharmacokinetics in this population.
Assuntos
Antibacterianos , Transplante de Fígado , Combinação Piperacilina e Tazobactam , Piperacilina , Humanos , Masculino , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Feminino , Lactente , Piperacilina/administração & dosagem , Piperacilina/farmacocinética , Piperacilina/uso terapêutico , Combinação Piperacilina e Tazobactam/administração & dosagem , Combinação Piperacilina e Tazobactam/uso terapêutico , Combinação Piperacilina e Tazobactam/farmacocinética , Pré-Escolar , Teorema de Bayes , CriançaRESUMO
Cefpodoxime proxetil is commonly used to treat cetacean patients with suspected or confirmed bacterial infections; however, pharmacokinetic data are needed to guide proper dosing in these species. Cefpodoxime proxetil is a time-dependent, semisynthetic, third-generation cephalosporin, appropriate for once-daily dosing and U.S. Food and Drug Administration-approved for use in dogs with a broad spectrum of activity including gram-positive and gram-negative species. The objective of this study was to evaluate the population pharmacokinetics of cefpodoxime in bottlenose dolphins (Tursiops truncatus). A sparse-sampling design was used, with serum from dolphins receiving cefpodoxime proxetil at 10 mg/kg orally every 24 h to treat suspected or confirmed bacterial infections. Serum samples (n = 57) from 24 dolphins were analyzed at 12 time points from 0 to 96 h postdose. Serum samples were analyzed using liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment linear models with first order absorption were tested. Covariates including weight, age, and sex were considered for inclusion in the model, and between-subject variability was incorporated. A two-compartment model performed best, where following an oral dose of 10 mg/kg, serum concentration reached a mean maximum concentration of 23.0 µg/ml, mean time to maximum concentration of 5.0 h, and mean half-life of 11.4 h. With daily dosing, accumulation was approximately 18% and steady state was reached by the second dose. Serum protein binding was 82.8% as determined by equilibrium dialysis, similar to plasma protein binding reported in dogs. Based on the population pharmacokinetic model, once-daily oral dosing was systemically absorbed and quickly reached maximum concentrations. The half-life in dolphins appears to be longer than other species studied to date. Given the paucity of antimicrobial pharmacokinetic studies in dolphins, and limited once-daily oral antibiotic options for this species, these data are helpful for clinicians to make informed antimicrobial choices.
Assuntos
Antibacterianos , Golfinho Nariz-de-Garrafa , Animais , Golfinho Nariz-de-Garrafa/sangue , Feminino , Antibacterianos/farmacocinética , Antibacterianos/sangue , Antibacterianos/administração & dosagem , Masculino , Meia-Vida , Ceftizoxima/farmacocinética , Ceftizoxima/análogos & derivados , Ceftizoxima/administração & dosagem , Ceftizoxima/sangue , Cefpodoxima , Área Sob a CurvaRESUMO
Objective: The aim of this study was to determine the plasma pharmacokinetics of oxytetracycline (OTC) in rainbow trout (Oncorhynchus mykiss) of different body sizes. Methods: The research was carried out on three groups as small (30-50 g), medium (90-110 g) and large (185-215 g) body sizes at 8 ± 0.5 °C. OTC was administered orally at a dose of 60 mg/kg to all groups. Blood samples were taken at 19 different sampling times until the 384 h after oxytetracycline administration. The plasma concentrations of OTC were measured using high pressure liquid chromatography-ultraviolet and pharmacokinetic parameters were evaluated using non-compartmental analysis. Results: OTC was detected in small-body sized fish until the 336 h and in medium and large-body sized fish until the 384 h. The elimination half-life of OTC was 85.46, 87.24 and 86.98 h in the small, medium and large body size groups, respectively. The peak plasma concentration increased from 0.66 to 1.11 µg/mL, and the area under the plasma concentration-versus time curve from zero (0) h to infinity (∞) increased from 87.86 to 151.52 h*µg/mL, in tandem with the increase in fish body size. As fish body size increased, volume of distribution and total body clearance decreased. Conclusion: These results show that the pharmacokinetics of OTC vary depending on fish size. Therefore, there is a need to reveal the pharmacodynamic activity of OTC in rainbow trout of different body sizes.
Assuntos
Antibacterianos , Tamanho Corporal , Oncorhynchus mykiss , Oxitetraciclina , Animais , Oncorhynchus mykiss/metabolismo , Oxitetraciclina/farmacocinética , Oxitetraciclina/sangue , Oxitetraciclina/administração & dosagem , Administração Oral , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Meia-Vida , Cromatografia Líquida de Alta PressãoRESUMO
Orally administered amoxicillin is recommended as the first-line treatment of acute bacterial rhinosinusitis (ABR) and given in a high-dose regimen. However, the risk of various systemic adverse reactions and low oral bioavailability are unbearable, increasing the threat of antibiotic resistance. Therefore, nasal delivery of amoxicillin can be a potential approach for effectively treating ABR locally, as well as overcoming those drawbacks. In a way to guarantee the effectiveness for local therapy in nasal cavity, the permeation and retention properties are of significant importance considerations. Accordingly, the present work aimed to investigate the characteristics with respect to the nasal applicability of the in situ gelling amoxicillin trihydrate (AMT) and further evaluate its permeability and retention properties through human nasal mucosa. The lyophilized formulations were characterized utilizing the Differential Scanning Calorimetry (DSC) and X-ray Powder Diffraction (XRPD), and also evaluated for its polarity, reconstitution time, droplet size distribution, mucoadhesive properties, and ex vivo permeability and retention studies. The results confirmed that the in situ gelling AMT formulations possess adequate mucoadhesive behavior, especially the formulation containing 0.3 % of gellan gum. Substantially, the in situ gelling AMT formulations were able to retain the drug on the surface of nasal mucosa instead of permeating across the membrane; thus, suitable for treating nasal infections locally. Altogether, the in situ gelling systems demonstrates promising abilities as a delivery platform to enhance local application of AMT within the nasal cavity.
Assuntos
Adesividade , Administração Intranasal , Amoxicilina , Antibacterianos , Géis , Mucosa Nasal , Permeabilidade , Mucosa Nasal/metabolismo , Amoxicilina/administração & dosagem , Amoxicilina/química , Amoxicilina/farmacocinética , Géis/química , Humanos , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/química , Sistemas de Liberação de Medicamentos/métodos , Polissacarídeos BacterianosRESUMO
Introduction: Resistance of intracellular pathogens is a challenge in microbial therapy. Methicillin-resistant Staphylococcus aureus (MRSA), which is able to persist inside the cells of infected tissues, is protected from attack by the immune system and many antimicrobial agents. To overcome these limitations, nano-delivery systems can be used for targeted therapy of intracellular MRSA. Methods: Hyaluronic acid-modified azithromycin/quercetin micelles (HA-AZI/Qe-M) were synthesized by thin film hydration. The micelles were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR), and the drug loading (DL) and encapsulation efficiency (EE) were detected by high performance liquid chromatography (HPLC). The uptake ability of RAW264.7 cells was investigated, and its distribution in mice was evaluated by in vivo imaging. The inhibitory effect of the micelles against MRSA in vitro and its ability to eliminate intracellular bacteria were evaluated. Bacterial muscle-infected mice were constructed to evaluate the therapeutic effect of the micelles on bacterial infections in vivo and the biocompatibility of the micelles was investigated. Results: HA-AZI/Qe-M had suitable physical and chemical properties and characterization. In vitro antibacterial experiments showed that HA-AZI/Qe-M could effectively inhibit the growth of MRSA, inhibit and eliminate the biofilm formed by MRSA, and have an excellent therapeutic effect on intracellular bacterial infection. The results of RAW264.7 cells uptake and in vivo imaging showed that HA-AZI/Qe-M could increase the cellular uptake, target the infection site, and prolong the treatment time. The results of in vivo antibacterial infection experiments showed that HA-AZI/Qe-M was able to ameliorate the extent of thigh muscle infections in mice and reduce the expression of inflammatory factors. Conclusion: HA-AZI/Qe-M is a novel and effective nano-drug delivery system that can target intracellular bacterial infection, and it is expected to be safely used for the treatment of MRSA infection.
Assuntos
Antibacterianos , Azitromicina , Ácido Hialurônico , Staphylococcus aureus Resistente à Meticilina , Micelas , Quercetina , Infecções Estafilocócicas , Animais , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Quercetina/farmacologia , Quercetina/química , Quercetina/farmacocinética , Quercetina/administração & dosagem , Células RAW 264.7 , Infecções Estafilocócicas/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Azitromicina/química , Azitromicina/farmacologia , Azitromicina/farmacocinética , Azitromicina/administração & dosagem , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Portadores de Fármacos/química , Testes de Sensibilidade MicrobianaRESUMO
Drug-resin complexes usually form in the aqueous phase. For poorly water-soluble drugs, low drug loading limits the use of resin in drug formulation. In this study, we used a new method to prepare azithromycin resinates, improving the drug loading rate, shortening the preparation time and simplifying the process. We used hydro-alcoholic solution as the drug loading solvent and the ion exchange resin as the carrier, and this method enabled the resin to adsorb both the retardant and the drug. The sustained release effect of retardant Eudragit RL, RS100 was analyzed. Drug loading efficiency, release profiles, morphology, physicochemical characterization and pharmacokinetic study were assessed. Preparation of drug resinate by batch method resulted in 14% higher drug loading of azithromycin and 3.5 h shorter loading time as compared to pure water for hydroalcoholic solution as drug loading solvent. Raman mappings demonstrated that the retardant with higher molecular weight was more likely to adsorb to the outer layer of the resin compared to the drug. The in vitro release and in vivo pharmacokinetic study of azithromycin resinates showed a sustained release profile with few gastrointestinal adverse effects. Therefore, the addition of ethanol not only improved the efficiency of drug loading but also showed sustained-release effect with one-pot preparation of azithromycin resinates.
Assuntos
Azitromicina , Preparações de Ação Retardada , Solubilidade , Azitromicina/farmacocinética , Azitromicina/administração & dosagem , Azitromicina/química , Preparações de Ação Retardada/farmacocinética , Animais , Liberação Controlada de Fármacos , Solventes/química , Portadores de Fármacos/química , Troca Iônica , Química Farmacêutica/métodos , Masculino , Composição de Medicamentos/métodos , Resinas de Troca Iônica/química , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/química , Resinas Acrílicas/químicaRESUMO
OBJECTIVES: To define the in vitro pharmacodynamics of taniborbactam against Enterobacterales with CTXM-15, KPC, AmpC, and OXA-48 ß-lactamases. METHODS: An in vitro pharmacokinetic model was used to simulate serum concentrations associated with cefepime 2G by 1 h infusion 8 h. Taniborbactam was given in exposure ranging and fractionation simulations. Reduction in viable count at 24 h (Δ 24) was the primary end point and four strains were used: Escherichia coli expressing CTXM-15 or AmpC and Klebsiella pneumoniae expressing KPC or OXA-48 enzymes. RESULTS: Taniborbactam was administered as continuous infusions; ≥4 log kill was attained with taniborbactam concentrations of ≥0.01 mg/L against CTXM-15 E. coli, ≥0.5 mg/L against KPC- and OXA-48 K. pneumoniae, and ≥4 mg/L against AmpC E. coli. Analyses were conducted to determine the pharmacokinetic/dynamic driver for each strain. For E. coli (CTXM-15) and E. coli (AmpC), area under the concentration-time curve (AUC) was best related to change in viable count (R20.74 and 0.72, respectively). For K. pneumoniae (KPC) AUC and T > 0.25 mg/L were equally related to bacterial clearance (R20.72 for both), and for K. pneumoniae (OXA-48) T > 0.25 mg/L was the best predictor (R20.94). The taniborbactam AUC range to produce a 1-log10 reduction in viable count was 4.4-11.2 mg·h/L. Analysis of data from all strains indicated T > MIC divided by 4 was best related to change in viable count; however, curve fit was poor R2 < 0.49. CONCLUSIONS: Taniborbactam was effective in combination with cefepime in producing bacterial clearance for B lactam resistant Enterobacterales. The primary pharmacodynamic driver was AUC or time > threshold, both being closely related to antibacterial effect.
Assuntos
Antibacterianos , Cefepima , Cefalosporinas , Escherichia coli , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , beta-Lactamases , Cefepima/farmacologia , Cefepima/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , beta-Lactamases/metabolismo , Humanos , Cefalosporinas/farmacocinética , Cefalosporinas/farmacologia , Lactamas/farmacocinética , Lactamas/farmacologia , Ácidos Borínicos , Ácidos CarboxílicosRESUMO
BACKGROUND AND OBJECTIVE: Dalbavancin is increasingly used for the long-term treatment of chronic osteoarticular infections. A population pharmacokinetic/pharmacodynamic (PK/PD) analysis for assessing the relationship between dalbavancin exposure and C-reactive protein (C-RP) over time was conducted. METHODS: Non-linear mixed-effect modeling was fitted to dalbavancin and C-RP concentrations. Monte Carlo simulations assessed the weekly percentage of C-RP reduction associated with different dosing regimens, starting from baseline to < 1 mg/dL. RESULTS: A total of 45 patients were retrospectively included in the analysis. The PK of dalbavancin was described by a two-compartment model, and the PD of C-RP was described by an indirect turnover maximum inhibition model. The total dalbavancin concentration model estimate producing 50% of maximum C-RP production inhibition (IC50) was 0.70 mg/L. Monte Carlo simulations showed that in patients with staphylococcal osteoarticular infections targeting total dalbavancin concentrations at > 14.5 mg/L at any time point may achieve C-RP production inhibition over time in > 95% of patients. Based on this, the findings showed that a cumulative dose of 3000 mg administered in the first 3 weeks may lead to a > 90% C-RP decrease versus baseline in approximately 5-6 weeks. In patients needing treatment prolongation, an additional 1500 mg dose after this period may maintain C-RP concentrations < 1 mg/dL for other 3 weeks. CONCLUSIONS: A decrease in C-RP is related to dalbavancin exposure in osteoarticular infections. Targeting dalbavancin plasma concentrations above the efficacy threshold may be associated with effective treatment.
Assuntos
Antibacterianos , Proteína C-Reativa , Método de Monte Carlo , Infecções Estafilocócicas , Teicoplanina , Humanos , Teicoplanina/análogos & derivados , Teicoplanina/farmacocinética , Teicoplanina/administração & dosagem , Teicoplanina/sangue , Teicoplanina/farmacologia , Masculino , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Feminino , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Pessoa de Meia-Idade , Idoso , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Estudos Retrospectivos , Adulto , Modelos Biológicos , Idoso de 80 Anos ou maisRESUMO
This study concerns the synthesis of the florfenicol (FF) metabolites florfenicol amine (FFA), florfenicol alcohol (FFOH), and monochloroflorfenicol (FFCl), for their subsequent use as reference standards in On-line solid-phase extraction-ultra high-performance liquid chromatography-tandem mass spectrometry (SPE-UHPLC-MS/MS) analysis. The metabolites were characterized using 1H and 13C NMR, as well as HRMS, and their purities were confirmed by quantitative NMR to ensure analytical reliability. Validation of the developed analytical method showed that it presented acceptable performance, with linearity >0.99 for all the target analytes, accuracies within ±10 % of nominal concentrations, and intra- and inter-day precisions within 15 %. Application of this method to fillets from fish that had been treated with florfenicol (dose of 10 mg/kg bw daily) demonstrated its effectiveness in consistently detecting FF and its metabolites throughout the treatment. The results emphasized the utility of the method for enhancing pharmacokinetic and residue depletion research. The ability to precisely monitor the drug and its metabolites in treated fish provides important insights into florfenicol metabolism, laying the groundwork for further comprehensive profiling studies of metabolites in fish tissue.
Assuntos
Extração em Fase Sólida , Espectrometria de Massas em Tandem , Tianfenicol , Tianfenicol/análogos & derivados , Tianfenicol/análise , Tianfenicol/metabolismo , Tianfenicol/farmacocinética , Tianfenicol/química , Animais , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Extração em Fase Sólida/métodos , Reprodutibilidade dos Testes , Modelos Lineares , Limite de Detecção , Ciclídeos/metabolismo , Resíduos de Drogas/análise , Resíduos de Drogas/metabolismo , Antibacterianos/análise , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/metabolismo , Alimentos Marinhos/análiseRESUMO
INTRODUCTION: Older adults face a higher risk of vancomycin-related toxicity given their (patho)-physiological changes, making early management of supratherapeutic exposure crucial. Yet, data on vancomycin exposure in older adults is scarce. This study aims to compare vancomycin concentrations between older and younger patients, emphasizing supratherapeutic concentrations and the effect of patient characteristics. METHODS: This observational retrospective study was conducted in the University Hospital of Leuven (EC Research S65213). We analyzed early (first) vancomycin concentrations between older (≥ 75 years) and younger patients. Multivariable analyses were conducted to evaluate the association between baseline patient characteristics with supratherapeutic exposure (logistic regression), and dose-normalized concentrations (linear regression). RESULTS: We included 449 patients aged ≥ 75 years (median 80) and 1609 aged < 75 years (median 61). In univariable analysis, the first-measured vancomycin concentrations were significantly higher in older adults (p < 0.001), who more frequently reached supratherapeutic concentrations (30.7% versus 21%; p < 0.001). In multivariable analysis, factors associated with supratherapeutic concentrations were decreased the estimated glomerular filtration rate calculated by using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) [odds ratio (OR) of 0.98, confidence interval (CI) 0.97-0.98]. Supratherapeutic concentrations had inverse association with giving lower loading dose (OR of 0.59, CI 0.39-0.90), and lower maintenance dose (OR of 0.45, CI 0.26-0.77). Factors that predicted increased dose-normalized concentrations included decreased eGFRCKD-EPI (coefficient of -0.05, CI -0.06 to -0.04), lower body weight (coefficient of -0.04, CI -0.05 to -0.03), increased blood urea nitrogen (coefficient of 0.02, CI 0.01-0.03), and delayed time to therapeutic drug monitoring (TDM) sampling (coefficient of 0.08, CI 0.06-0.09). CONCLUSIONS: The absence of age as a significant factor in the multivariable analysis suggests that eGFRCKD-EPI mediated the relationship between age and vancomycin exposure. Older adults may benefit more from vancomycin TDM.
Assuntos
Antibacterianos , Taxa de Filtração Glomerular , Vancomicina , Humanos , Vancomicina/efeitos adversos , Vancomicina/farmacocinética , Vancomicina/administração & dosagem , Vancomicina/sangue , Idoso , Masculino , Feminino , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Taxa de Filtração Glomerular/efeitos dos fármacos , Pessoa de Meia-Idade , Rim/efeitos dos fármacos , Rim/metabolismoRESUMO
Sulfonamides (S) are old bacteriostatic antibiotics which are widely prescribed in combination with trimethoprim (TMP) for the treatment of various diseases in food-producing animals such as poultry. Nowadays, the 1:5 dose ratio of TMP/S used in broilers is a direct transposition of the ratio determined in Human decades ago for TMP/sulfamethoxazole (SMX), aiming to obtain a supposed synergistic plasma concentration ratio of 1:19. However, major pharmacokinetics (PK) differences exist according to the sulfonamide used in the combination. Here, we generated new PK data in broilers after a cross-over design with IV and the oral administration of 2 major sulfonamides, sulfadiazine (SDZ) and SMX, in combination with TMP, and analyzed the data via a population pharmacokinetic (popPK) modeling approach. Results showed that TMP has a greater plasma to tissue distribution than both sulfonamides with a higher volume of distribution (0.51 L/kg for SDZ, 0.62 L/kg for SMX and 3.14 L/kg for TMP). SMX has the highest elimination half-life (2.83 h) followed by SDZ and TMP (2.01 h and 1.49 h, respectively). The oral bioavailability of the 3 molecules was approximately 100%. Bodyweight could explain some of the inter-individual variability in the volume of distribution of SDZ and SMX and the clearance of SDZ and TMP, as heavier broilers have higher typical values. Monte Carlo simulations of a large virtual broiler population (n = 1,000) showed that the targeted plasma ratio of TMP:S of 1:19 was rarely or never reached at the individual level for both combinations at the marketed doses and greatly varies over time and between individuals, questioning the relevance of the 1:5 dose ratio for current formulations of TMP/S.