RESUMEN

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.

Asunto(s)

Antibacterianos , Cefuroxima , Hueso Trapecio , Humanos , Cefuroxima/administración & dosificación , Cefuroxima/farmacocinética , Femenino , Persona de Mediana Edad , Anciano , Masculino , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Estudios Prospectivos , Anciano de 80 o más Años , Hueso Trapecio/cirugía , Mano/cirugía , Huesos del Metacarpo/cirugía , Esquema de Medicación

RESUMEN

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.

Asunto(s)

Antibacterianos , Tamaño Corporal , Oncorhynchus mykiss , Oxitetraciclina , Animales , Oncorhynchus mykiss/metabolismo , Oxitetraciclina/farmacocinética , Oxitetraciclina/sangre , Oxitetraciclina/administración & dosificación , Administración Oral , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Semivida , Cromatografía Líquida de Alta Presión

RESUMEN

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.

Asunto(s)

Antibacterianos , Antifúngicos , Monitoreo de Drogas , Humanos , Recién Nacido , Antibacterianos/uso terapéutico , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antifúngicos/uso terapéutico , Antifúngicos/farmacocinética , Antifúngicos/efectos adversos , Antifúngicos/administración & dosificación , Niño , Lactante , Preescolar , España , Servicio de Farmacia en Hospital

RESUMEN

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.

Asunto(s)

Antibacterianos , Antifúngicos , Monitoreo de Drogas , Humanos , Antifúngicos/uso terapéutico , Antifúngicos/farmacocinética , Antifúngicos/efectos adversos , Recién Nacido , Antibacterianos/uso terapéutico , Antibacterianos/farmacocinética , Niño , Lactante , España , Preescolar , Servicio de Farmacia en Hospital , Sociedades Médicas , Pediatría

RESUMEN

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.

Asunto(s)

Antibacterianos , Delfín Mular , Animales , Delfín Mular/sangre , Femenino , Antibacterianos/farmacocinética , Antibacterianos/sangre , Antibacterianos/administración & dosificación , Masculino , Semivida , Ceftizoxima/farmacocinética , Ceftizoxima/análogos & derivados , Ceftizoxima/administración & dosificación , Ceftizoxima/sangre , Cefpodoxima , Área Bajo la Curva

RESUMEN

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.

Asunto(s)

Antibacterianos , Antifúngicos , Monitoreo de Drogas , Humanos , Recién Nacido , Monitoreo de Drogas/métodos , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Niño , Antifúngicos/farmacocinética , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Lactante , Preescolar

RESUMEN

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by an excessive host response to infection, manifested by elevated levels of inflammatory cytokines. At present, the use of hemoperfusion to remove inflammatory cytokines from the bloodstream has been expanding. Meanwhile, the pharmacokinetics and pharmacodynamics characteristics of antibiotics in critically ill patients may be impacted by hemoperfusion. CASE PRESENTATION: The patient was a 69-year-old male with poorly controlled type 2 diabetes. When admitted to the ICU, Multiple Organ Dysfunction Syndrome (MODS) appeared within 48 h, and he was suspected of septic shock due to acute granulocytopenia and significantly increased procalcitonin. Broad-spectrum antibiotics imipenem was administered according to Sepsis 3.0 bundle and hemoperfusion lasting 4 h with a neutron-macroporous resin device (HA-380, Jafron, China) five times was conducted to lower the extremely high value of serum inflammatory factors. Blood samples were collected to measure imipenem plasma concentration to investigate the effect of hemoperfusion quantitatively. This study showed that 4 h of hemoperfusion had a good adsorption ability on inflammatory factors and could remove about 75.2% of imipenem. CONCLUSIONS: This case demonstrated the high adsorption capacity of hemoperfusion on imipenem in critically ill patients. It implies a timely imipenem supplement is required, especially before hemoperfusion.

Asunto(s)

Antibacterianos , Enfermedad Crítica , Hemoperfusión , Imipenem , Choque Séptico , Humanos , Masculino , Imipenem/uso terapéutico , Imipenem/administración & dosificación , Imipenem/farmacocinética , Anciano , Choque Séptico/tratamiento farmacológico , Choque Séptico/terapia , Hemoperfusión/métodos , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Adsorción

RESUMEN

Clarithromycin extended-release (CLA-ER) was used as companion drug to rifampicin (RIF) for Mycobacterium ulcerans infection in the intervention arm of a WHO drug trial. RIF enhances CYP3A4 metabolism, thereby reducing CLA serum concentrations, and RIF concentrations might be increased by CLA co-administration. We studied the pharmacokinetics of CLA-ER at a daily dose of 15 mg/kg combined with RIF at a dose of 10 mg/kg in a subset of trial participants, and compared these to previously obtained pharmacokinetic data. Serial dried blood spot samples were obtained over a period of ten hours, and analyzed by LC-MS/MS in 30 study participants-20 in the RIF-CLA study arm, and 10 in the RIF-streptomycin study arm. Median CLA Cmax was 0.4 mg/L-and median AUC 3.9 mg*h/L, following 15 mg/kg CLA-ER. Compared to standard CLA dosed at 7.5 mg/kg previously, CLA-ER resulted in a non-significant 58% decrease in Cmax and a non-significant 30% increase in AUC. CLA co-administration did not alter RIF Cmax or AUC. Treatment was successful in all study participants. No effect of CLA co-administration on RIF pharmacokinetics was observed. Based on our serum concentration studies, the benefits CLA-ER over CLA immediate release are unclear.

Asunto(s)

Úlcera de Buruli , Claritromicina , Preparaciones de Acción Retardada , Mycobacterium ulcerans , Rifampin , Humanos , Claritromicina/farmacocinética , Claritromicina/administración & dosificación , Masculino , Femenino , Adulto , Rifampin/farmacocinética , Rifampin/administración & dosificación , Rifampin/uso terapéutico , Persona de Mediana Edad , Úlcera de Buruli/tratamiento farmacológico , Úlcera de Buruli/microbiología , Mycobacterium ulcerans/efectos de los fármacos , Preparaciones de Acción Retardada/farmacocinética , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Anciano , Adulto Joven , Área Bajo la Curva , Espectrometría de Masas en Tándem

RESUMEN

Importance: Prophylactic administration of antibiotics before skin incision is an important component in the prevention of periprosthetic joint infection in arthroplasty surgery. For antibiotics to be effective, the local tissue concentration (LTC) must exceed the minimum inhibitory concentration of typical infecting organisms; however, the LTC of cefazolin during arthroplasty is poorly understood. Objective: To compare the systemic concentration of cefazolin in serum with the LTC in fat, synovium, and bone during primary total knee arthroplasty (TKA) while assessing the effect of tourniquet inflation. Design, Setting, and Participants: This prospective randomized clinical trial was conducted from March 1, 2022, to June 30, 2023, in patients undergoing TKA at a single academic center. Intervention: Total knee arthroplasty with or without a limb tourniquet. Main Outcomes and Measures: Systemic blood and local tissues from the surgical site (fat, synovium, and bone) were harvested at regular intervals during the surgery. The primary outcome was the LTC of cefazolin, quantified using the liquid chromatography-tandem mass spectrometry technique. Results: A total of 59 patients were included in the study, with 29 in the tourniquet group (mean [SD] age, 69.3 [9.6] years; 23 [79.3%] female) and 30 in the no tourniquet group (mean [SD] age, 69.9 [9.7] years; 21 [70.0%] female). In patients undergoing TKA without a tourniquet, the mean concentration of cefazolin in serum was 71.9 µg/mL (95% CI, 66.4-77.5 µg/mL), whereas the mean LTCs were 13.9 µg/g (95% CI, 12.1-15.7 µg/g) in fat, 27.7 µg/g (95% CI, 24.3-31.0 µg/g) in synovium, and 17.7 µg/g (95% CI, 14.8-20.5 µg/g) in bone. For patients undergoing TKA with a tourniquet, the mean concentration of cefazolin in serum was 72.0 µg/mL (95% CI, 66.3-77.7 µg/mL), and the mean LTCs were 9.9 µg/g (95% CI, 8.7-11.1 µg/g) in fat, 21.8 µg/g (95% CI, 18.7-25.0 µg/g) in synovium, and 13.0 µg/g (95% CI, 10.8-15.2 µg/g) in bone. The use of a tourniquet resulted in significantly lower mean LTCs by 60 minutes after cefazolin infusion (10.8 µg/g [95% CI, 9.1-12.4 µg/g] vs 16.9 µg/g [95% CI, 14.1-19.6 µg/g], P = .001 in fat; 18.9 µg/g [95% CI, 14.1-23.6 µg/g] vs 25.8 µg/g [95% CI, 21.4-30.3 µg/g], P = .03 in synovium; and 11.8 µg/g [95% CI, 9.3-14.2 µg/g] vs 19.4 µg/g [95% CI, 14.5-24.4 µg/g], P = .007 in bone). Conclusions and Relevance: In this randomized clinical trial, the concentration of cefazolin was lower in local tissues (fat, synovium, and bone) than in systemic blood, and the use of a limb tourniquet further significantly reduced these concentrations. Although the current prophylactic dosing regimen for cefazolin provides sufficient serum concentrations, the levels in the periarticular tissue during TKA may be insufficient to prevent periprosthetic joint infection. Trial Registration: ClinicalTrials.gov Identifier: NCT05604157.

Asunto(s)

Antibacterianos , Artroplastia de Reemplazo de Rodilla , Cefazolina , Torniquetes , Humanos , Cefazolina/farmacocinética , Cefazolina/administración & dosificación , Cefazolina/sangre , Femenino , Masculino , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/análisis , Antibacterianos/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Infecciones Relacionadas con Prótesis/prevención & control , Profilaxis Antibiótica/métodos , Infección de la Herida Quirúrgica/prevención & control

RESUMEN

The formulation and delivery of macromolecules through the oral route pose considerable challenges due to factors such as large molecular weight, pH sensitivity, and limited formulation approaches. This challenge is compounded if the drug is poorly permeable, necessitating innovative drug delivery strategies. Vancomycin, a widely prescribed glycopeptide antibiotic, has an oral bioavailability of less than 10%, leading to predominantly intravenous administration and potential patient discomfort. This study explores the potential of the buccal route as a non-invasive, highly vascularised alternative route of administration, offering a rapid onset of action while bypassing the first-pass metabolism. In this study, vancomycin was coated with L-glutamic acid using an isothermal dry particle coater to modulate permeation through the buccal cell line, TR146. Results confirm significant impact of both amino acid concentration and dry particle coating on the rate and extent of drug permeability. With the introduction of L-glutamic acid and utilisation of the isothermal dry particle coater, vancomycin's permeation profile increased six-fold compared to the control due to the formation of drug ion-pair complex. Imaging studies showed the presence of layered micronized glutamic acid particles on the surface of dry coated vancomycin particles which confirms the role of dry coating and amino acid concentration in modulating drug permeation. Microbiology experiments in Staphylococcus aureus, minimum inhibitory concentration and biofilm disruption studies, provided confirmatory evidence of antimicrobial activity of dry coated glutamic acid-vancomycin ion pair particulate structure. This study demonstrates, for the first-time, buccal delivery of dry coated large molecule drug, vancomycin, through controlled deposition of amino acid using innovative particle coating strategy.

Asunto(s)

Antibacterianos , Vancomicina , Vancomicina/administración & dosificación , Vancomicina/farmacocinética , Humanos , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/farmacocinética , Aminoácidos/química , Aminoácidos/metabolismo , Staphylococcus aureus/efectos de los fármacos , Mucosa Bucal/metabolismo , Permeabilidad/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Línea Celular , Ácido Glutámico/metabolismo

RESUMEN

Knowledge of amoxicillin (AMX) pharmacokinetics (PK) and tissue residues in fish, which is necessary for prudent drug use, remains limited. The study aimed to explore the PK characteristics of AMX in Nile tilapia (Oreochromis niloticus) reared at 25 and 30 °C as well as to determine optimal dosages and drug withdrawal time (WDT). In the PK investigation, the fish received a single dose of 40 mg/kg AMX via oral gavage, and the optimal dosage was determined by the pharmacokinetic-pharmacodynamic approach. In the tissue residue study, the fish were orally gavaged with 40 mg/kg/day AMX once daily for 5 days and the WDT was established by the linear regression analysis. The results revealed the temperature-dependent drug elimination; the clearance relative to bioavailability (CL/F) and elimination half-life at 30 °C (0.180 L/kg/h and 6.06 h, respectively) were about twice those at 25 °C (0.090 L/kg/h and 10.49 h, respectively). The optimal dosages at the minimum inhibitory concentration (MIC) of 2 µg/mL were 10.97 (25 °C) and 41.03 (30 °C) mg/kg/day, respectively. Finally, following the multiple oral administration, the muscle/skin residue of AMX on day 1 after the last dosing at 25 and 30 °C were 548 and 264 ng/g, respectively. The average tissue residues were depleted below the maximum residue limits (MRL) of 50 µg/kg on day 5 (25 °C) and 3 (30 °C), respectively, and the WDT were 6 and 4 days when rearing at 25 and 30 °C, respectively. This knowledge serves as a practical guideline for responsible use of AMX in treating bacterial diseases in Nile tilapia aquaculture.

Asunto(s)

Amoxicilina , Antibacterianos , Cíclidos , Temperatura , Animales , Amoxicilina/farmacocinética , Amoxicilina/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Residuos de Medicamentos , Pruebas de Sensibilidad Microbiana , Semivida , Relación Dosis-Respuesta a Droga

RESUMEN

Vancomycin, a first-line drug for treating methicillin-resistant Staphylococcus aureus infections, is associated with acute kidney injury (AKI). This study involved an evaluation of biomarkers for AKI detection and their comparison with traditional serum creatinine (SCr). We prospectively enrolled patients scheduled to receive intravenous vancomycin for methicillin-resistant S aureus infection. Blood samples for pharmacokinetic assessment and SCr and cystatin C (CysC) measurements were collected at baseline and on days 3, 7, and 10 from the initiation of vancomycin administration (day 1). Urinary biomarkers, including kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin, and clusterin, were collected from days 1 to 7 and adjusted for urinary creatinine levels. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Of the 42 patients, 6 experienced vancomycin-induced AKI. On day 7, the change from baseline eGFR using CysC (ΔeGFRCysC) showed a stronger correlation with vancomycin area under the curve (r = -0.634, P < .001) than that using SCr (ΔeGFRSCr; r = -0.437, P = .020). ΔeGFRSCr showed no significant correlation with vancomycin pharmacokinetic in patients with body mass index ≥23. The median (interquartile range) level of KIM-1 (µg/mg) was significantly higher in the AKI group (0.006 [0.005-0.008]) than in the non-AKI group (0.004 [0.001-0.005]) (P = .039, Mann-Whitney U test), with area under the receiver operating characteristic curve (95% confidence interval) of 0.788 (0.587-0.990). Serum CysC, particularly in overweight individuals or those with obesity, along with urinary KIM-1 are important predictors of vancomycin-induced AKI. These results may aid in selecting better biomarkers than traditional SCr for detecting vancomycin-induced AKI.

Asunto(s)

Lesión Renal Aguda , Antibacterianos , Biomarcadores , Creatinina , Cistatina C , Receptor Celular 1 del Virus de la Hepatitis A , Vancomicina , Humanos , Vancomicina/efectos adversos , Vancomicina/farmacocinética , Vancomicina/administración & dosificación , Vancomicina/sangre , Biomarcadores/orina , Biomarcadores/sangre , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/orina , Lesión Renal Aguda/sangre , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Anciano , Receptor Celular 1 del Virus de la Hepatitis A/análisis , Cistatina C/sangre , Cistatina C/orina , Creatinina/sangre , Creatinina/orina , Tasa de Filtración Glomerular , Lipocalina 2/orina , Lipocalina 2/sangre , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus Resistente a Meticilina , Clusterina/orina , Clusterina/sangre

RESUMEN

Tylosin, an antibiotic with a long history in treating respiratory bacterial infections, has unknown effects on the gut microbiota of healthy and infected pigs. The study aimed to investigate the effect of a therapeutic dose of tylosin on swine gut microbiota and explored the relationship between this effect and tylosin pharmacokinetics (PK). We also assessed whether changes in gut microbiota after tylosin administration differ between healthy animals (n = 7) and animals intranasally co-infected (n = 7) with Actinobacillus pleuropneumoniae and Pasteurella multocida. Both groups were intramuscularly administered with tylosin (20 mg/kg). The 16S rRNA gene analyses revealed a significantly lower species richness and diversity, after tylosin treatment, in the infected than the healthy pigs, with infected pigs having lower levels of Bacteroidetes and Firmicutes and higher levels of Proteobacteria. Greater tylosin exposure (greater area under curve (AUC) and maximum plasma concentration (Cmax), and slower elimination (longer terminal half-life, T1/2) were observed in healthy than infected pigs. Relative abundance of Lactobacillus, Oscillibacter, Prevotella, and Sporobacter was positively and significantly correlated with AUC and Cmax, whereas the abundance of Acinetobacter, Alishewanella, and Pseudomonas was positively and significantly correlated with T1/2 and mean residence time (MRT) of tylosin. Our findings, for the first time, demonstrated significant changes in swine gut microbiota after a single therapeutic dose of tylosin was administered, whereas the effect of these changes on tylosin PK was not evident.

Asunto(s)

Antibacterianos , Microbioma Gastrointestinal , Tilosina , Animales , Tilosina/farmacocinética , Tilosina/administración & dosificación , Microbioma Gastrointestinal/efectos de los fármacos , Porcinos , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Enfermedades de los Porcinos/microbiología , Enfermedades de los Porcinos/tratamiento farmacológico , ARN Ribosómico 16S/genética , Pasteurella multocida/efectos de los fármacos , Actinobacillus pleuropneumoniae/efectos de los fármacos

RESUMEN

This study aimed to prepare and assess active microneedle (MN) patches based on a novel biomaterial and their effective coupled (physical and electrical) transdermal delivery of a model drug (Linezoid). Modified MN patches (e.g. fabricated from Linezoid, boronated chitosan, polyvinyl alcohol and D-sorbitol) were engineered using a vacuum micromoulding method. Physicochemical, FTIR (Fourier transform infrared), in-silico, structural and thermal analysis of prepared formulations were conducted to ascertain MN quality, composition and integrity. In-vitro mechanical tests, membrane toxicity, drug release, antibiofilm, ex-vivo mucoadhesion, insertion and in-vivo antibiofilm studies were performed to further validate viability of the coupled system. Optimized MN patch formulation (CSHP3 - comprising of 3 % w/v boronated chitosan, 3.5 % w/v PVA and 10 % w/w D-sorbitol) exhibited sharp-tipped, equi-distant and uniform-surfaced micron-scaled projections with conforming physicochemical features. FTIR analysis confirmed modification (i.e., boronation) of chitosan and compatibility as well as interaction between CSHP3 constituents. In-silico analysis indicated non-covalent interactions between all formulation constituents. Moreover, boronated chitosan-mucin glycoprotein complex showed a stronger bonding (∼1.86 times higher CScore) as compared to linezolid-mucin counterpart. Thermal analysis indicated amorphous nature of CSHP3. A âˆ¼ 1.42 times higher tensile strength was displayed by CSHP3 as compared to control (i.e., pure chitosan, polyvinyl alcohol and D-sorbitol-based MN patch). Membrane toxicity study indicated non-toxic and physiological compatible nature of CSHP3. Within 90 min, 91.99 ± 2.3 % linezolid was released from CSHP3. During release study on agarose gel, CSHP3-iontophoresis treatment resulted in a âˆ¼ 1.78 and âˆ¼ 1.20 times higher methylene blue-covered area and optical density, respectively, within 60 min as compared to CSHP3 treatment alone. Staphylococcus aureus biofilms treated with CSHP3 exhibited 65 ± 4.2 % reduction in their mass. CSHP3 MN patches remained adhered to the rabbit oral mucosa for 6 ± 0.15 h. Mucosa treated with CSHP3 and CSHP3-iontophoresis combination showed a generation of pathways in the epithelium layers without any damage to the underlying lamina propria. Eradication of Staphylococcus aureus from oral mucosal wounds and complete tissue regeneration was recorded following 7-day treatment using CSHP3-iontophoresis coupled approach.

Asunto(s)

Biopelículas , Quitosano , Linezolid , Agujas , Quitosano/química , Quitosano/administración & dosificación , Biopelículas/efectos de los fármacos , Animales , Linezolid/administración & dosificación , Linezolid/farmacocinética , Linezolid/farmacología , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/farmacocinética , Staphylococcus aureus/efectos de los fármacos , Liberación de Fármacos , Boca/microbiología , Sistemas de Liberación de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/instrumentación

RESUMEN

Polymyxin B (PB) and Polymyxin E (PE, also called colistin) are used as the last treatment resort for multidrug-resistant Gram-negative bacterial infections. The nephrotoxicity and neurotoxicity of polymyxins limit their clinical use, and guidelines recommend therapeutic drug monitoring (TDM) to optimize efficacy and reduce toxicity. However, there are limited analytical methods available for the determination of PB and PE. This study aimed to develop a simple and robust liquid chromatography with tandem mass spectrometry (LC-MS/MS) analytical method for determining the main compounds of PB and PE, namely PB1, PB2, ile-PB1, PE1, and PE2, in human plasma and to investigate of their pharmacokinetics in critically ill patients with the use of PB and PE, respectively. Plasma PB1, PB2, ile-PB1, PE1, and PE2 were chromatographically separated on a Welch LP-C18 column and detected using electrospray ionization mode coupled with multiple reaction monitoring. The calibration curve showed acceptable linearity over 20-10,000 ng/mL for PB1, PE1, and PE2 and 10-5000 ng/mL for PB2 and ile-PB1 in the plasma, respectively. After validation following approved guidelines, this method was successfully applied for PB and PE pharmacokinetic analysis and TDM in critically ill patients. Additionally, the composition of PB1, PB2, ile-PB1, PE1, and PE2 remains unchanged from 0 to 12 h after entering the patient's body.

Asunto(s)

Antibacterianos , Monitoreo de Drogas , Polimixina B , Espectrometría de Masas en Tándem , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antibacterianos/farmacocinética , Antibacterianos/sangre , Calibración , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodos , Colistina/farmacocinética , Colistina/sangre , Colistina/análogos & derivados , Enfermedad Crítica , Monitoreo de Drogas/métodos , Límite de Detección , Polimixina B/farmacocinética , Polimixina B/sangre , Polimixinas/farmacocinética , Polimixinas/sangre , Polimixinas/análogos & derivados , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodos

RESUMEN

Nanocellulose is a potential material utilized in numerous biomedical applications. However, its hydrophilic characteristic and uncontrolled encapsulated drug release hinders nanocellulose uses in oral drug administration. Thus, this work developed novel nanocellulose/alginate composite (CNC/Alg) beads for oral delivery and bioavailability enhancement of a model drug, Ciprofloxacin (CIP). CNC was green synthesized employing electrolysis process from sugarcane bagasse. CNC/Alg beads were formulated by dropwise adding CNC-Alg mixture in CaCl2 solution at room temperature. CIP was incorporated into CNC/Alg beads by adsorption technique. X-ray diffractometry and Fourier-transform infrared spectra images showed that the beads were effectively produced with high crystallinity of 75.5 %, and the typical bond of cellulose and alginate. Within 4 h of adsorption, CIP loading efficiency reached 45.27 %, with 87.2 % molecules in the zwitterionic state. The adsorption followed Elovich and pseudo-second-order models, indicating a multi-mechanism including both physical and chemical adsorptions. Importantly, in gastrointestinal tract, the beads could protect CIP from acidic stomach environment while releasing it sustainably in simulated intestinal condition (75.05 %). The beads also showed strong antibacterial activity against both Gram(-) and Gram(+) bacteria, as evidenced by low IC50 and minimum inhibitory concentration values. Finally, CNC/Alg beads could improve CIP bioavailability for effective oral drug delivery route.

Asunto(s)

Alginatos , Antibacterianos , Disponibilidad Biológica , Celulosa , Ciprofloxacina , Ciprofloxacina/química , Ciprofloxacina/farmacología , Ciprofloxacina/farmacocinética , Ciprofloxacina/administración & dosificación , Celulosa/química , Alginatos/química , Antibacterianos/química , Antibacterianos/farmacología , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Liberación de Fármacos , Portadores de Fármacos/química , Adsorción , Pruebas de Sensibilidad Microbiana

RESUMEN

BACKGROUND AND OBJECTIVE: Renal replacement therapy (RRT) plays a critical role in antimicrobial removal, particularly for low-molecular-weight drugs with low plasma protein binding, low distribution volume and hydrophilicity. Medium cut-off (MCO) membranes represent a new generation in dialysis technology, enhancing diffusive modality efficacy and increasing the cut-off from 30 to 45 kDa, crucial for middle molecule removal. This monocentric randomized crossover pilot study aimed to evaluate the impact of continuous haemodialysis with MCO membrane (MCO-CVVHD) on the removal of piperacillin, tazobactam and meropenem compared with continuous veno-venous hemodiafiltration with standard high-flux membrane (HFM-CVVHDF). METHODS: Twenty patients were randomized to undergo MCO-CVVHD followed by HFM-CVVHDF or vice versa. Extraction ratio (ER), effluent clearance (Cleff) and treatment efficiency were assessed at various intervals. Antibiotic nadir plasma levels were measured for both treatment days. RESULTS: HFM-CVVHDF showed greater ER compared with MCO-CVVHD for meropenem (ß = - 8.90 (95% CI - 12.9 to - 4.87), p < 0.001) and tazobactam (ß = - 8.29 (95% CI - 13.5 to - 3.08), p = 0.002) and Cleff for each antibiotic (meropenem ß = - 10,206 (95% CI - 14,787 to - 5787), p = 0.001); tazobactam (ß = - 4551 (95% CI - 7781 to - 1322), p = 0.012); piperacillin (ß = - 3913 (95% CI - 6388 to - 1437), p = 0.002), even if the carryover effect influenced the Cleff for meropenem and tazobactam. No difference was observed in nadir plasma concentrations or efficiency for any antibiotic. Piperacillin (ß = - 38.1 (95% CI - 47.9 to - 28.3), p < 0.001) and tazobactam (ß = - 4.45 (95% CI - 6.17 to - 2.72), p < 0.001) showed lower nadir plasma concentrations the second day compared with the first day, regardless the filter type. CONCLUSION: MCO demonstrated comparable in vivo removal of piperacillin, tazobactam and meropenem to HFM.

Asunto(s)

Antibacterianos , Terapia de Reemplazo Renal Continuo , Estudios Cruzados , Meropenem , Diálisis Renal , Choque Séptico , Humanos , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Antibacterianos/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Choque Séptico/terapia , Choque Séptico/tratamiento farmacológico , Choque Séptico/sangre , Proyectos Piloto , Terapia de Reemplazo Renal Continuo/métodos , Diálisis Renal/métodos , Meropenem/uso terapéutico , Meropenem/administración & dosificación , Meropenem/farmacocinética , Tazobactam/uso terapéutico , Tazobactam/farmacocinética , Piperacilina/farmacocinética , Piperacilina/uso terapéutico , Piperacilina/administración & dosificación , Hemodiafiltración/métodos

RESUMEN

Drug-resistant gonorrhea is caused by the bacterial pathogen Neisseria gonorrhoeae, for which there is no recommended oral treatment. We have demonstrated that the FDA-approved human carbonic anhydrase inhibitor ethoxzolamide potently inhibits N. gonorrhoeae; however, is not effective at reducing N. gonorrhoeae bioburden in a mouse model. Thus, we sought to optimize the pharmacokinetic properties of the ethoxzolamide scaffold. These efforts resulted in analogs with improved activity against N. gonorrhoeae, increased metabolic stability in mouse liver microsomes, and improved Caco-2 permeability compared to ethoxzolamide. Improvement in these properties resulted in increased plasma exposure in vivo after oral dosing. Top compounds were investigated for in vivo efficacy in a vaginal mouse model of gonococcal genital tract infection, and they significantly decreased the gonococcal burden compared to vehicle and ethoxzolamide controls. Altogether, results from this study provide evidence that ethoxzolamide-based compounds have the potential to be effective oral therapeutics against gonococcal infection.

Asunto(s)

Antibacterianos , Etoxzolamida , Neisseria gonorrhoeae , Neisseria gonorrhoeae/efectos de los fármacos , Animales , Humanos , Ratones , Células CACO-2 , Femenino , Etoxzolamida/farmacología , Etoxzolamida/farmacocinética , Etoxzolamida/síntesis química , Etoxzolamida/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/uso terapéutico , Microsomas Hepáticos/metabolismo , Gonorrea/tratamiento farmacológico , Relación Estructura-Actividad , Pruebas de Sensibilidad Microbiana , Inhibidores de Anhidrasa Carbónica/farmacocinética , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/uso terapéutico

RESUMEN

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.

Asunto(s)

Extracción en Fase Sólida , Espectrometría de Masas en Tándem , Tianfenicol , Tianfenicol/análogos & derivados , Tianfenicol/análisis , Tianfenicol/metabolismo , Tianfenicol/farmacocinética , Tianfenicol/química , Animales , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Extracción en Fase Sólida/métodos , Reproducibilidad de los Resultados , Modelos Lineales , Límite de Detección , Cíclidos/metabolismo , Residuos de Medicamentos/análisis , Residuos de Medicamentos/metabolismo , Antibacterianos/análisis , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/metabolismo , Alimentos Marinos/análisis

RESUMEN

Background and Objectives: The predicted serum concentrations of vancomycin are determined using population pharmacokinetic parameters. However, the accuracy of predicting vancomycin serum concentrations in the older population remains unclear. Therefore, this study aimed to investigate the accuracy of predicting vancomycin serum concentrations and identifying elements that diminish the prediction accuracy in older people. Materials and Methods: A total of 144 patients aged 75 years or older were included. The serum vancomycin concentrations in the patients were predicted based on population pharmacokinetic parameters common in Japan. We examined the accuracy of serum vancomycin concentration prediction in elderly individuals by comparing the predicted and measured serum vancomycin concentrations in each patient. The prediction accuracy was evaluated using the mean prediction error (ME) and mean absolute error of prediction (MAE) calculated from the measured and predicted serum vancomycin concentrations in each patient. Results: The ME for all patients was 0.27, and the 95% CI included 0, indicating that the predicted values were not significantly biased compared to the measured values. However, the predicted serum concentrations in the <50 kg body weight and serum creatinine (Scr) < 0.6 mg/dL groups were significantly biased compared to the measured values. The group with a history of intensive care unit (ICU) admission showed the largest values for the ME and MAE. Conclusions: Our prediction accuracy was satisfactory but tended to be lower in underweight patients, those with low creatinine levels, and patients admitted to the ICU. Patients with multiple of these factors may experience a greater degree of decreased predictive accuracy.

Asunto(s)

Antibacterianos , Vancomicina , Humanos , Anciano , Vancomicina/farmacocinética , Vancomicina/sangre , Vancomicina/uso terapéutico , Femenino , Masculino , Anciano de 80 o más Años , Estudios Retrospectivos , Antibacterianos/farmacocinética , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Japón , Creatinina/sangre