Pharmacokinetics/pharmacodynamics and therapeutic drug monitoring of ceftazidime/avibactam administered by continuous infusion in patients with MDR Gram-negative bacterial infections.

BACKGROUND: Therapeutic drug monitoring (TDM) of ß-lactams in critically ill patients has been correlated with better clinical outcomes. Evidence on TDM of newer ß-lactams such as ceftazidime/avibactam administered by continuous infusion (CI) is very limited. OBJECTIVES: To describe our experience with TDM of ceftazidime/avibactam and pharmacokinetic/pharmacodynamic (PK/PD) target attainment in patients with MDR bacterial infections. Clinical outcomes of ceftazidime/avibactam administered by CI were also assessed. METHODS: Patients treated with ceftazidime/avibactam administered by CI and undergoing TDM of ceftazidime plasma concentrations were included. Blood samples were obtained as part of the TDM program. The PK/PD therapeutic target of ceftazidime/avibactam was defined as 100%fT > 4 × MIC of the causative pathogen, and 100%fT > 10 × MIC was considered overexposure. Dose changes were made according to the TDM results. RESULTS: Thirty-one patients were included. Ceftazidime/avibactam total daily doses ranged from 1 g/0.25 g to 6 g/1.5 g. Twenty-six patients (83.9%) achieved a 100%fT > 4 × MIC, 15 (48.4%) of which were overexposed (100%fT > 10 × MIC). Dose reduction was suggested in 16/28 (57.1%) patients and dose maintenance in 12/28 (42.9%). Overall clinical cure was observed in 21 (67.7%) patients, and 18 of these (85.7%) achieved a 100%fT > 4 × MIC. CONCLUSIONS: Administering ceftazidime/avibactam by CI enabled the desired PK/PD target to be achieved in a large proportion of patients, even at lower doses than those recommended for a 2 h extended infusion. We suggest that the use of CI with TDM may be a useful tool for reducing initial doses, which could help to reduce antimicrobial-related adverse effects and treatment costs.

Drug-related problems in patients admitted for SARS-CoV-2 infection during the COVID-19 pandemic.

Introduction: Drug-related problems (DRP) are events or circumstances in which drug therapy does or could interfere with desired health outcomes. In December 2019, a new coronavirus, SARS-CoV-2, appeared. Little knowledge about this type of infection resulted in the administration of various drugs with limited use in other pathologies. Evidence about DRP in patients with COVID-19 is lacking. Objective: The aim of the present study is to describe identified cases of DRP and those drugs involved in the first wave of patients with COVID-19, and evaluate associated risk factors. Material and methods: Observational, retrospective study performed in a tertiary university hospital between 14th March 2020 and 31 May 2020 (corresponding to the first COVID-19 wave). We recruited patients admitted during the study period. Exclusion criteria included age < 18 years; admission to critically ill units; and care received either in the emergency room, at-home hospitalization or a healthcare center. Results: A total of 817 patients were included. The mean age was 62.5 years (SD 16.4) (range 18-97), and 453 (55.4%) were male. A total of 516 DRP were detected. Among the patients, 271 (33.2%) presented at least one DRP. The mean DRP per patient with an identified case was 1.9. The prevailing DRPs among those observed were: incorrect dosage (over or underdosage) in 145 patients (28.2%); wrong drug combination in 131 (25.5%); prescriptions not in adherence to the then COVID-19 treatment protocol in 73 (14.1%); prescription errors due to the wrong use of the computerized physician order entry in 47 (9.2%); and incorrect dosage due to renal function in 36 (7%). The logistic regression analysis showed that patients who received only prescriptions of antibacterials for systemic use (J01 ATC group) faced a higher likelihood of experiencing a DRP (OR 2.408 (1.071-5.411), p = 0.033). Conclusion: We identified several factors associated with an increased risk of DRPs, similar to those reported in other pre-pandemic studies, including a prolonged length of stay, higher number of prescribed drugs and antimicrobial administration. The relevance of pharmacists and tools like pharmacy warning systems can help prevent, identify and resolve DRP efficiently.

Impact of the COVID-19 pandemic: Community and hospital shared pharmaceutical care model. Satisfaction and acceptability of patients with HIV infection on antiretroviral treatment.

OBJECTIVE: The health crisis due to the COVID-19 pandemic is a challenge in the dispensing of outpatient hospital medication (OHM). Models of Antiretroviral Therapy (ART) based on community pharmacy support (ARTCP) have proven to be successful. The aim was to evaluate the degree of satisfaction, acceptability and limitations of the implementation of ARTCP, in the context of a pandemic, in our environment. METHODS: Descriptive cross-sectional study carried out in a Barcelona hospital, during the months of July-November 2020. A telephone survey was carried out via a questionnaire on the quality dimensions of the model (degree of satisfaction, acceptability) and associated inconveniences. Data collected: demographics, antiretroviral treatment (ART), concomitant medication, drug interactions (DDIs), CD4 lymphocyte count and plasma viraemia. Data analysis included descriptive statistics. RESULTS: A total of 533 (78.0%) HIV patients receiving ART were included. 71.9% (383/533) of these patients were very satisfied and 76.2% preferred attending the community pharmacy rather than the hospital. The mean satisfaction rating was 9.3 (DS: 1.4). The benefits reported were: 1) proximity to home (406: 76.1%); 2) lower risk of contagion of COVID-19 (318: 59.7%); 3) shorter waiting time (201: 37.1%); 4) time flexibility (104: 19.5%); 5) reduction of financial expenses (35: 6.57%). A total of 11 (2%) patients reported no benefit. Only 22.9% reported disadvantages associated with ARTCP: 1) lack of privacy (65: 12.2%); 2) lack of coordinationorganization (57: 10.7%). CONCLUSIONS: The COVID-19 pandemic has had an impact on the provision of pharmaceutical care for HIV patients. The ARTPC model has proved efficient, with patients reporting a high degree of satisfaction.

Dosage Individualization of Linezolid: Precision Dosing of Linezolid To Optimize Efficacy and Minimize Toxicity.

The high interindividual variability in the pharmacokinetics (PK) of linezolid has been described, which results in an unacceptably high proportion of patients with either suboptimal or potentially toxic concentrations following the administration of a fixed regimen. The aim of this study was to develop a population pharmacokinetic model of linezolid and use this to build and validate alogorithms for individualized dosing. A retrospective pharmacokinetic analysis was performed using data from 338 hospitalized patients (65.4% male, 65.5 [±14.6] years) who underwent routine therapeutic drug monitoring for linezolid. Linezolid concentrations were analyzed by using high-performance liquid chromatography. Population pharmacokinetic modeling was performed using a nonparametric methodology with Pmetrics, and Monte Carlo simulations were employed to calculate the 100% time >MIC after the administration of a fixed regimen of 600 mg administered every 12 h (q12h) intravenously (i.v.). The dose of linezolid needed to achieve a PTA ≥ 90% for all susceptible isolates classified according to EUCAST was estimated to be as high as 2,400 mg q12h, which is 4 times higher than the maximum licensed linezolid dose. The final PK model was then used to construct software for dosage individualization, and the performance of the software was assessed using 10 new patients not used to construct the original population PK model. A three-compartment model with an absorptive compartment with zero-order i.v. input and first-order clearance from the central compartment best described the data. The dose optimization software tracked patients with a high degree of accuracy. The software may be a clinically useful tool to adjust linezolid dosages in real time to achieve prespecified drug exposure targets. A further prospective study is needed to examine the potential clinical utility of individualized therapy.

Cáncer de mama triple negativo: terapias sistémicas actuales y experiencia local / Triple negative breast cancer: current systemic therapy and local experience

Resumen El cáncer de mama (CM) es la principal causa de muerte por cáncer en mujeres chilenas. Es una enfermedad heterogénea, en la cual se han identificado cuatro subtipos básicos, determinados según características clínicas, histológicas y moleculares, los que se relacionan a estrategias terapéuticas. El CM triple negativo (CMTN) se caracteriza por su agresividad, recaída temprana y mayor tendencia a presentarse en etapas avanzadas. Frecuentemente afecta a mujeres jóvenes o con antecedentes familiares de CM u ovario. La única terapia sistémica aprobada para el CMTN es la quimioterapia; sin embargo, recientemente terapias moleculares con inhibidores de puntos de control inmune e inhibidores de la poli-adenosina difosfato ribosa polimerasa, han mostrado eficacia en pacientes seleccionados, y se han agregado al arsenal terapéutico para CMTN. Dada la aparición de estas nuevas estrategias, parece relevante entender la heterogeneidad de esta enfermedad, los mecanismos de acción de las nuevas terapias, resultados clínicos y criterios de selección de pacientes para terapias moleculares. Presentamos una revisión de la terapia sistémica actual del CMTN.

Breast cancer is the leading cause of cancer death in Chilean women and worldwide. It is a heterogeneous disease and four different subtypes have been identified based on clinical, histological and molecular features, which correlate with different treatment tumor sensitivity. Triple negative breast cancer is characterized by its aggressiveness, early relapse, and a greater tendency to present in advanced stages. It frequently affects young women, with cancer family history, especially breast or ovarian cancer. The approved systemic therapy for triple negative breast cancer is chemotherapy; however, recently, targeted therapies with checkpoint inhibitors and polyadenosine diphosphate ribose polymerase inhibitors have been shown to be effective in selected patients and have been added to the therapeutic arsenal for triple negative breast cancer. Given the appearance of these new strategies, it seems relevant to understand the heterogeneity of this disease, the mechanisms of action behind new therapies, clinical results, and the criteria to select patients for molecular therapies. We present a review of the current systemic therapy of this breast cancer subtype.

Combined moxidectin-levamisole treatment against multidrug-resistant gastrointestinal nematodes: A four-year efficacy monitoring in lambs.

Nematicide combinations may be a valid strategy to achieve effective nematode control in the presence of drug resistance. The goal of the current trial was to evaluate the pharmaco-parasitological performance of the moxidectin (MOX) and levamisole (LEV) combination after four years of continuous use in lambs naturally parasitized with multi-resistant gastrointestinal nematodes. At the beginning of the trial, 40 lambs were divided into four groups (n = 10), which were untreated (control) or subcutaneously treated with MOX (0.2 mg/kg), LEV (8 mg/kg) or with the combination MOX + LEV (administered separately at 0.2 and 8 mg/kg, respectively). Blood samples were collected at different times post-treatment and LEV and MOX plasma concentrations were measured by HPLC. The clinical efficacy of the continuous use of MOX + LEV combination was assessed with the controlled efficacy test (CET), performed at the beginning and end of the study, and with the faecal egg count reduction (FECR) test, performed over the four-year study period. No significant adverse pharmacokinetic changes were observed either for MOX or LEV after their co-administration to infected lambs. The CET (first year) showed efficacies of 84.3 % (Haemonchus contortus), 100 % (Teladorsagia circumcincta and Trichostrongylus axei), and 97.4 % (T. colubriformis). After the repetitive use of the combined treatment for four years, those efficacies remained high (100 %) and only decreased to 58 % against T. colubriformis. The evaluation of the FECR over the study period showed fluctuations in the performance of the combined administration. The initial FECR (2014) was 99 % (MOX), 85 % (LEV) and 100 % (MOX + LEV). The co-administration of MOX + LEV during the four-year experimental period resulted in a significantly higher anthelmintic effect (87 %) than that of MOX (42 %) or LEV (69 %) given alone. The combined use of MOX + LEV to control resistant gastrointestinal nematodes appears to be a valid strategy under specific management conditions. A high initial therapeutic response to the combination would be a relevant feature for the success of this tool.

Administración de radioyodo en cáncer diferenciado de tiroides bajo régimen hospitalario: a propósito de la implementación del aislamiento de radioyodoterapia en un hospital regional / Administration of radioiodine in differentiated thyroid cancer under a hospital regime: about the implementation of radioiodotherapy isolation in a regional hospital

Resumen Introducción El cáncer diferenciado de tiroides (CDT) presenta un aumento a nivel mundial. El uso selectivo de terapia con radioyodo (RAI) es un pilar de su tratamiento. Su efecto terapéutico se debe a la radiación beta, mientras que la gamma hace que sea necesaria la hospitalización para limitar la exposición de terceros. Objetivo Describir la seguridad de la administración de altas dosis de RAI en pacientes con CDT. Materiales y Método Estudio retrospectivo descriptivo. Se incluyó a todos los pacientes con diagnóstico de CDT que requirieron hospitalización para administración de RAI ≥ 30 mCi en el Hospital Regional de Talca (HRT) entre agosto-diciembre de 2018. Resultados Durante el período descrito 10 pacientes recibieron RAI bajo régimen hospitalario. La mediana de dosis de RAI administrada fue de 100 mCi (rango: 50-150 mCi). Todos los pacientes fueron manejados con asilamiento estricto. El promedio de hospitalización fue 28 horas, siendo dados de alta al reportar una tasa de dosis absorbida < 70 µSv/h a 1 metro. Se entregaron instrucciones al alta para minimizar el riesgo de irradiación o contaminación a terceras personas. Conclusiones Nuestro protocolo de administración de RAI permite tratar de manera segura a pacientes con CDT disminuyendo la exposición a radiación de terceros. Las salas de asilamiento de radioyodoterapia, podrían dar cobertura al 100% de la demanda de terapia con RAI en CDT a nivel local.

Introduction Differentiated thyroid cancer (CDT) presents an increase in global levels. The selective use of radioiodine therapy (RAI) is a pillar of its treatment. Its therapeutic effect is due to beta radiation, while gamma makes hospitalization necessary to limit exposure. Aim To describe the safety treated with RAI inpatients and the functioning of the radioactive isolation rooms of our center. Materials and Method Retrospective descriptive study. All patients diagnosed with CDT who required RAI therapy under a hospital regimen at the Regional Hospital of Talca (HRT) between August-December 2018 were included. Results During the period described, 10 patients were treated. The median dose of RAI administered was 100 mCi (range: 50-150 mCi). The average of hospitalization was 28 hours, being discharged when reporting an absorbed dose rate < 70 μSv/h at 1 meter, giving the patient instructions, so that they follow to minimize the risk of irradiation or contamination of people in their environment. Conclusions Our RAI administration protocol allows patients with CDT to be treated safely. The radioactive isolation rooms could cover 100% of the demand for RAI therapy in CDT at the local level.

Plant-Derived Compounds as a Tool for the Control of Gastrointestinal Nematodes: Modulation of Abamectin Pharmacological Action by Carvone.

The combination of synthetic anthelmintics and bioactive phytochemicals may be a pharmacological tool for improving nematode control in livestock. Carvone (R-CNE) has shown in vitro activity against gastrointestinal nematodes; however, the anthelmintic effect of bioactive phytochemicals either alone or combined with synthetic drugs has been little explored in vivo. Here, the pharmacological interaction of abamectin (ABM) and R-CNE was assessed in vitro and in vivo. The efficacy of this combination was evaluated in lambs naturally infected with resistant gastrointestinal nematodes. Additionally, the ligand and molecular docking of both molecules to P-glycoprotein (P-gp) was studied in silico. The presence of R-CNE produced a significant (p < 0.05) increase of Rho123 and ABM accumulation in the intestinal explants. After 60 min of incubation, Rho123 incubated with R-CNE had a 67 ± 21% higher concentration (p < 0.01) than when it was incubated alone. In the case of ABM, a significant increase in the intestinal concentrations was observed at 15 and 30 min after incubation with R-CNE. In the in vivo assay, no undesirable effects were observed after the oral administration of R-CNE. The coadministration of the natural compound prolonged ABM absorption in lambs. ABM T ½ absorption was 1.57-fold longer (p < 0.05) in the coadministered group. Concentrations of R-CNE between 420 and 2,593 ng/mL were detected in the bloodstream between 1 and 48 h posttreatment. The in vivo efficacy of ABM against gastrointestinal nematodes increased from 94.9 to 99.8% in the presence of R-CNE, with the lower confidence interval limit being >90%. In vitro/in vivo pharmacoparasitological studies are relevant for the knowledge of the interactions and the efficacy of bioactive natural products combined with synthetic anthelmintics. While ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions and the molecular docking study showed a good interaction between ABM and P-gp, R-CNE does not appear to modulate this efflux protein. Therefore, the pharmacokinetic-pharmacodynamic effect of R-CNE on ABM should be attributed to its effect on membrane permeability. The development of pharmacology-based information is critical for the design of successful strategies for the parasite control.

Pharmacologic interaction between oxfendazole and triclabendazole: In vitro biotransformation and systemic exposure in sheep.

The aim of the current work was to evaluate a potential pharmacokinetic interaction between the flukicide triclabendazole (TCBZ) and the broad-spectrum benzimidazole (BZD) anthelmintic oxfendazole (OFZ) in sheep. To this end, both an in vitro assay in microsomal fractions and an in vivo trial in lambs parasitized with Haemonchus contortus resistant to OFZ and its reduced derivative fenbendazole (FBZ) were carried out. Sheep microsomal fractions were incubated together with OFZ, FBZ, TCBZ, or a combination of either FBZ and TCBZ or OFZ and TCBZ. OFZ production was significantly diminished upon coincubation of FBZ and TCBZ, whereas neither FBZ nor OFZ affected the S-oxidation of TCBZ towards its sulfoxide and sulfone metabolites. For the in vivo trial, lambs were treated with OFZ (Vermox® oral drench at a single dose of 5 mg/kg PO), TCBZ (Fasinex® oral drench at a single dose of 12 mg/kg PO) or both compounds at a single dose of 5 (Vermox®) and 12 mg/kg (Fasinex®) PO. Blood samples were taken to quantify drug and metabolite concentrations, and pharmacokinetic parameters were calculated by means of non-compartmental analysis. Results showed that the pharmacokinetic parameters of active molecules and metabolites were not significantly altered upon coadministration. The sole exception was the increase in the mean residence time (MRT) of OFZ and FBZ sulfone upon coadministration, with no significant changes in the remaining pharmacokinetic parameters. This research is a further contribution to the study of metabolic drug-drug interactions that may affect anthelmintic efficacies in ruminants.

Population Pharmacokinetics of Anidulafungin in Critically Ill Patients.

A two-compartment pharmacokinetic (PK) population model of anidulafungin was fitted to PK data from 23 critically ill patients (age, 65 years [range, 28 to 81 years]; total body weight [TBW], 75 kg [range, 54 to 168 kg]). TBW was associated with clearance and incorporated into a final population PK model. Simulations suggested that patients with higher TBWs had less-extensive MIC coverage. Dosage escalation may be warranted in patients with high TBWs to ensure optimal drug exposures for treatment of Candida albicans and Candida glabrata infections.

Resultados funcionales de pacientes tratados con faringolaringectomía y reconstrucción faríngea con colgajo pediculado / Functional Outcomes using pedicle flap reconstruction approach after pharyngolaryngectomy in laryngeal carcinoma patients

INTRODUCCIÓN: La laringectomía total es el tratamiento de elección del cáncer de laringe avanzado, requiriendo en ocasiones asociar una resección parcial o total de la faringe para su manejo. El defecto faríngeo, puede repararse con colgajos libres o pediculados, teniendo estos últimos la ventaja de ser simples, confiables y resistentes a la radioterapia. OBJETIVO: Presentar los resultados funcionales de una serie de pacientes tratados con faringolaringectomía y reconstrucción faríngea con colgajo pediculado. MATERIAL Y MÉTODO: Se revisaron registros de pacientes con laringectomía total más faringectomía parcial y reconstrucción con colgajo pediculado en el Hospital Regional de Talca entre 2009 y 2017, encontrando 6 casos de los cuales 4 se encontraron vivos al momento de iniciar el estudio. Se realizó videofluoroscopía para evaluar deglución, presencia de estenosis y/o fístulas, además, de evaluación nutricional y encuesta de calidad de vida. RESULTADOS: En el estudio de la deglución por fluoroscopía, todos los pacientes presentaron escasa retención del material de contraste en la hipofaringe y esófago cervical, lo cual está en relación con cambios morfológicos posquirúrgicos, sin afectar significativamente el mecanismo deglutorio. Todos los pacientes se encontraron eutróficos en su evaluación nutricional y sin evidencias de alteración de su calidad de vida secundaria a la deglución. CONCLUSIONES: La reconstrucción faríngea parcial con colgajo pediculado en pacientes con laringectomías totales asociadas a faringectomía parcial permite una deglución adecuada y sin disfagia, con un estado nutricional eutrófico.

INTRODUCTION: Total laryngectomy is the treatment of choice for advanced laryngeal cancer and after radiotherapy failure. In patients with pharyngeal invasion, it is associated with total or partial pharyngectomy, wich defect can be repaired with free or pedicle flaps. AIM: To present a brief series of pedicle flap reconstruction approach after pharyngolaryngectomy in laryngeal carcinoma patients and functional outcomes MATERIALS AND METHOD: We looked at laryngeal cancer patient records who were treated with total laryngectomy with partial pharyngectomy and pharyngeal reconstruction with pedicle flap at "Hospital Regional de Talca" between the years 2009 and 2017, finding 6 cases, 4 of which were alive at the beginning of the study. We analized videoflourocopy swallow studies to assess mechanisms of deglutition, and presence of stenosis or fistulas. We also performed a nutritional state assessment and a quality of life questionnaire. RESULTS: During videodeglutition study, the 4 patients showed minimal contrast swallow delay at hypopharynx and cervical esophagus. All the patients were found eutrophic in their nutritional assessment and with no significant evidence of quality of life disturbances secondary to deglutition state. CONCLUSIONS: Partial pharyngeal reconstruction using pedicle flaps in patients who underwent total laryngectomy with partial pharyngectomy allows to maintain an adequate deglutition without dysphagia, as well as a good nutritional state.

Frequency and severity of potential drug interactions in a cohort of HIV-infected patients Identified through a Multidisciplinary team.

OBJECTIVES: Interactions between antiretroviral treatment (ART) and comedications are a concern in HIV-infected patients. This study aimed to determine the frequency and severity of potential drug-drug interactions (PDDIs) with ART in our setting. METHODS: Observational study by a multidisciplinary team in 1259 consecutive HIV patients (March 2015-September 2016). Data on demographics, toxic habits, comorbidities, and current ART were collected. A structured questionnaire recorded concomitant medications (including occasional and over-the-counter drugs). PDDIs were classified into four categories: (1) no interactions, (2) mild (clinically non-significant), (3) moderate (requiring close monitoring or drug modification/dose adjustment), and (4) severe (contraindicated). STATISTICAL ANALYSIS: chi-square test, logistic regression analysis. RESULTS: In total, 881 (70%) patients took comedication, and 563 (44.7%) had ≥ PDDI. Forty-one comedicated patients (4.6%) had severe and 522 (59.2%) moderate PDDIs. Moderate PDDIs mainly involved cardiovascular (53.8%) and central nervous system (40.2%) drugs. Independent risk factors for PDDIs were ART containing a boosted protease inhibitor (odds ratio [OR]=9.11, 95% confidence interval [CI] 5.15-16.11; p = 0.0001) and/or non-nucleoside reverse transcriptase (NNRTI) (OR = 4.34, 95%CI 2.49-7.55; p = 0.0001), HCV co-infection (OR = 3.26, 95%CI 2.15-4.93; p = 0.0001), and use of two or more comedications (OR = 3.36, 95%CI 2.27-4.97; p = 0.0001). Adherence and effectiveness of ART were similar in patients with and without PDDIs. The team made 133 recommendations related to comedications (drug change or dose adjustment) or ART (drug switch or change in administration schedule). CONCLUSIONS: Systematic evaluation detected a significant percentage of PDDIs requiring an intervention in HIV patients on ART. Monitoring and advice about drug-drug interactions should be part of routine practice.

Successful treatment of Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus pneumonia with high doses of linezolid administered in continuous infusion / Tratamiento eficaz de una neumonia comunitaria producida por un Staphylococcus aureus resitente a meticilina leucocidina Panton-Valantin con altas dosis de linezolid en perfusión continua

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Five Years of Multidisciplinary Care in Hereditary Cancer: Our Experience in a Spanish University Hospital.

OBJECTIVE: To analyse the evolution of a multidisciplinary heredofamilial cancer unit (HFCU) in a university hospital. METHODS: This was a retrospective analysis of the activity of our HFCU in its first 5 years of existence. RESULTS: Between July 2010 and July 2015, 1,518 patients from 1,318 families attended our HFCU. Genetic testing was offered to 862 patients. Of those, 833 (96.6%) accepted testing, with available results for 636 (76.4%). Pathogenic mutations in BRCA1 and BRCA2 were found in 175 patients. Lynch syndrome and adenomatous polyposis were the most frequent syndromes diagnosed (151/175, 86.3%) among 17 different syndromes studied. Of the 404 patients without a previous genetic diagnosis in the family, 62 (15.3%) were found to have mutations in disease-causing genes. Prophylactic surgery and follow-up (33.7%) or follow-up only (66.3%) was proposed for mutation carriers according to international guidelines and patients' preferences. CONCLUSION: We have a high mutation detection rate, genetic test acceptance, and compliance with risk reduction strategies. However, there is room for improvement, especially in genetic testing timing, considering that an increase in the indications for genetic testing is expected.

Comparative Population Plasma and Tissue Pharmacokinetics of Micafungin in Critically Ill Patients with Severe Burn Injuries and Patients with Complicated Intra-Abdominal Infection.

Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of micafungin in the plasma and burn eschar of severely burned patients with those of micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 ± 0.47 versus 0.15 ± 0.06 h(-1), respectively; P < 0.05). Most patients would achieve plasma PK/pharmacodynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of ≤0.008 mg/liter and ≤0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively.

Urinary micafungin levels are sufficient to treat urinary tract infections caused by Candida spp.

Six cases of patients diagnosed with urinary tract infection (UTI) successfully treated with micafungin are reported. Four were infected with fluconazole-resistant Candida spp. and two (with hepatic injury) were infected with fluconazole-sensitive Candida spp. Traditionally, echinocandins have not been considered for the treatment of UTIs. However, despite its low urinary excretion rate, therapeutic drug monitoring of micafungin urinary levels could be helpful in order to achieve optimal pharmacokinetic/pharmacodynamic (PK/PD) indices for treating UTIs caused by Candida spp. resistant to fluconazole.

Plasma and peritoneal fluid population pharmacokinetics of micafungin in post-surgical patients with severe peritonitis.

OBJECTIVES: Limited information about the pharmacokinetics of micafungin in the peritoneal cavity is available. The aim of this study was to explore the pharmacokinetics/pharmacodynamics of micafungin in plasma and peritoneal fluid in post-surgical critically ill patients with proven or suspected intra-abdominal fungal infection. METHODS: Patients were administered 100 mg/day micafungin. Serial blood and peritoneal fluid samples were collected on day 1 and day 3 (steady-state) of treatment. Concentrations were determined by validated chromatography and were subject to a population pharmacokinetic analysis with Pmetrics(®). Monte Carlo simulations were performed for AUC0-24/MIC ratios in plasma. The PTA was calculated using AUC0-24/MIC cut-offs: 285 for Candida parapsilosis and 3000 for non-parapsilosis Candida spp. RESULTS: Ten patients were included; six were male. The median (range) age, APACHE II score and Mannheim peritonitis index were 72 (43-85) years, 15 (11-36) and 26 (8-37), respectively. On day 1, median (SD) penetration of micafungin into the peritoneal cavity was 30% (30%-40%). A three-compartment model adequately described the data. The mean (SD) estimates for clearance and volume of distribution of the central compartment were 1.27 (0.75) L/h and 9.26 (1.11) L, respectively. In most patients, the PTA in plasma was ≥ 90% for MICs of 0.008-0.016 mg/L for Candida spp. and 0.125-0.25 mg/L for C. parapsilosis. CONCLUSIONS: After the first dose, micafungin at 100 mg/day achieves pharmacokinetic/pharmacodynamic targets in plasma for Candida spp. and C. parapsilosis MICs of 0.008-0.016 and 0.125-0.25 mg/L, respectively.

Comparative pharmacokinetic and pharmacodynamic response of single and double intraruminal doses of ivermectin and moxidectin in nematode-infected lambs.

AIMS: To compare the pharmacokinetics, distribution and efficacy (pharmacodynamic response) of intraruminal ivermectin (IVM) and moxidectin (MXD) administered at 0.2 and 0.4 mg/kg to naturally nematode-infected lambs, and to determine the ex vivo accumulation of these anthelmintics by Haemonchus contortus. METHODS: Romney Marsh lambs, naturally infected with IVM-resistant H. contortus, were allocated to treatment groups based on faecal nematode egg counts. They received 0.2 or 0.4 mg/kg IVM or MXD (n=10 per group), or no treatment (Control; n=6), on Day 0. Samples from four animals from each treatment group, including abomasal parasites, were obtained on Day 1. Plasma samples were also collected from Day 0 to 14, and a faecal egg count reduction test (FECRT) and a controlled efficacy trial were carried out on Day 14. Concentrations of IVM and MXD in plasma, in abomasal and intestinal tissues and in H. contortus were evaluated by high-performance liquid chromatography. Additionally, the ex vivo drug accumulation of IVM and MXD by H. contortus was determined. RESULTS: Peak plasma concentrations and the area under the concentration vs. time curve for both IVM and MXD were higher for 0.4 than 0.2 mg/kg treatments (p<0.05), but there were no differences for other parameters. Concentrations of IVM and MXD in the gastrointestinal target tissues and in H. contortus were higher compared to those measured in plasma. Concentrations of both drugs in H. contortus were correlated with those observed in the abomasal content (r=0.86; p<0.0001). The exposure of H. contortus to IVM and MXD was related to the administered dose. Mean FECRT and efficacy for removal of adult H. contortus was 0% for IVM at 0.2 and 0.4 mg/kg. For MXD, FECRT were >95% for both treatments, and efficacy against H. contortus was 85.1% and 98.1% for 0.2 and 0.4 mg/kg, respectively. The ex vivo accumulation of IVM and MXD in H. contortus was directly related to the drug concentration present in the environment and was influenced by the duration of exposure. CONCLUSION: Administration of IVM and MXD at 0.4 compared with 0.2 mg/kg accounted for enhanced drug exposure in the target tissues, as well as higher drug concentrations within resistant nematodes. The current work is a further contribution to the evaluation of the relationship between drug efficacy and basic pharmacological issues in the presence of resistant parasite populations.