Towards precision medicine of long-acting aripiprazole through population pharmacokinetic modelling.

Population pharmacokinetic (popPK) models constitute a valuable tool for characterizing the pharmacokinetic properties of once-monthly long-acting injectable aripiprazole (LAI aripiprazole) and quantifying the sources of variability in drug exposure. Our aim is to develop a popPK model of both aripiprazole and its metabolite dehydro-aripiprazole in patients treated with LAI aripiprazole, and to personalize the dosing regimen of aripiprazole across different sub-groups of patients. This is a prospective study investigating the pharmacokinetics of LAI aripiprazole. A total of 93 patients were included, 21 for model development and 71 for external model evaluation. A one-compartment model with linear absorption and elimination adequately described both aripiprazole and dehydro-aripiprazole concentrations. The weight of the patients has been shown to be the factor that most influences the absorption. However, the metabolizing phenotype for CYP2D6 and the concomitant treatment with strong inhibitors of this cytochrome have been shown to be the covariates that most influence total drug exposure. This is the first popPK model developed for LAI aripiprazole that includes aripiprazole and its main active metabolite, dehydroaripiprazole. It provides a personalized dosage recommendation that maximizes the probability of achieving optimal therapeutic concentrations and minimizes the difficulties associated with trial-and-error therapeutic strategies carried out in clinical practice.

Real-world data of the use and experience of caplacizumab for the treatment of acquired thrombotic thrombocytopenic purpura: Case series.

PURPOSE: Caplacizumab was licensed for acquired thrombotic thrombocytopenic purpura (aTTP) based on prospective controlled trials. Real-world evidence is crucial in rare diseases. We aim to describe a patient population with aTTP, receiving caplacizumab in a real-world setting, reporting their outcomes, including safety and tolerability, and contrasting them with a historical cohort from our center. METHODS: We describe data collected retrospectively from 2012 to 2022 for 16 patients with aTTP (8 received caplacizumab and 8 the historical standard-of-care). Patients' characteristics and outcomes were compared between groups. RESULTS: Patients' demographic and baseline characteristics were similar in both groups. Caplacizumab led to a rapid normalization of the platelet count of 3.5 (IQR, 2-6) versus 16 (IQR, 9.5-23.5) days in the historical cohort: (p = .002). The median number of plasma exchanges and the length of days requiring them, between the caplacizumab group versus the historical cohort, was 6 (IQR, 6-10) versus 19.5 (IQR, 12.5-29.5) plasma exchanges (p = .006); and 9 (IQR, 8.5-13.5) versus 22 (15-31) days (p = .049), respectively. There were no refractory cases in the caplacizumab group in comparison with 37.5 % in the historical cohort. None of patients treated with caplacizumab experienced a recurrence after 1081 (IQR, 511-3125) days of follow-up. Safety was in line with data reported in clinical trials, with mild adverse events (mostly grade≤2). CONCLUSION: We provided real-world evidence in the treatment of aTTP, confirming the results obtained in clinical trials. Caplacizumab reduced the time to platelet count recovery and the number and length of plasma exchanges.

Real-Life Data on the Effectiveness and Safety of Cefiderocol in Severely Infected Patients: A Case Series.

INTRODUCTION: Real-life data about cefiderocol use to treat extensively drug-resistant bacteria are scarce. We aim to report our early experience in patients with difficult-to-treat infections and limited therapeutic options. METHODS: Patients treated with cefiderocol from March 2018 to April 2022 in a tertiary-care hospital in Spain were included. Demographic, clinical, and microbiological data were collected up to 90 days after the end of treatment or until death. Survival status was recorded at 30 and 90 days. RESULTS: Ten patients were included, seven of them critically ill. Ventilator-associated pneumonia (40%) and bacteremia (40%) were the main infections. Multidrug-resistant or extensively drug-resistant P. aeruginosa was the most frequently isolated pathogen (70%, of which six patients were infected with bacteria with difficult-to-treat resistance), followed by A. baumannii, E. coli, and A. xylosoxidans (10% each). Seven patients received combination therapy. Clinical and microbiological cures were achieved in 90% and 80% of patients, respectively. Two previously susceptible strains (20%) developed resistance to cefiderocol. Overall, 30-day and 90-day mortality rates were 10% and 50%, respectively, although two out of five patients died due to the infection. No serious adverse events were reported, except for one patient who developed thrombocytopenia. CONCLUSION: Cefiderocol seems to be an effective and safe rescue therapy for patients infected with difficult-to-treat pathogens, although there is a definite risk of the emergence of resistance.

Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age.

In 2010, the WHO recommended an increase in the daily doses of first-line anti-tuberculosis medicines in children. We aim to characterize the pharmacokinetics of the once-daily isoniazid (INH) dose at 10 mg/kg of body weight in infants <6 months of age. We performed a multicenter pharmacokinetic study in Spain. The N-acetyltransferase 2 gene was analyzed to determine the acetylation status. Samples were analyzed using a validated UPLC-UV assay. A non-compartmental pharmacokinetic analysis was performed. Twenty-three pharmacokinetic profiles were performed in 20 infants (8 females) at a median (IQR) age of 19.0 (12.6-23.3) weeks. The acetylator statuses were homozygous fast (n = 1), heterozygous intermediate (n = 12), and homozygous slow (n = 7). INH median (IQR) Cmax and AUC0-24h values were 4.8 (3.7-6.7) mg/L and 23.5 (13.4-36.7) h*mg/L and the adult targets (>3 mg/L and 11.6-26.3 h*mg/L) were not reached in three and five cases, respectively. The age at assessment or acetylator status had no impact on Cmax values, but a larger INH AUC0-24h (p = 0.025) and trends towards a longer half-life (p = 0.055) and slower clearance (p = 0.070) were observed in homozygous slow acetylators. Treatment was well tolerated; mildly elevated alanine aminotransferase levels were observed in three cases. In our series of young infants receiving isoniazid, no major safety concerns were raised, and the target adult levels were reached in most patients.

Drug-drug interactions of ritonavir-boosted SARS-CoV-2 protease inhibitors in solid organ transplant recipients: experience from the initial use of lopinavir-ritonavir.

OBJECTIVES: To review the drug-drug interactions between tacrolimus and lopinavir/ritonavir in 23 patients who received solid organ transplant during the first wave of COVID-19 and to determine the efficacy as well as safety of prednisone monotherapy. METHODS: Observational study performed between March and June 2020 in solid organ transplant recipients admitted with an established diagnosis of SARS-CoV-2 infection who received lopinavir/ritonavir (≥2 doses). Once lopinavir/ritonavir therapy was initiated, calcineurin inhibitor treatment was temporarily switched to prednisone monotherapy (15-20 mg/d) to avoid drug-drug interactions and toxicity. After lopinavir/ritonavir treatment completion, immunosuppressive treatment was restarted with reduced doses of prednisone-tacrolimus (target minimum blood concentration -C0- approximately 5 ng/mL). Patients were observed for 3 months to confirm the absence of rejection. RESULTS: The median time from discontinuation of tacrolimus to initiation of lopinavir/ritonavir was 14 hours (interquartile range [IQR], 12-15) and from discontinuation of lopinavir/ritonavir to resumption of tacrolimus 58 hours (IQR, 47-81). The duration of lopinavir/ritonavir treatment was 7 days (IQR, 5-7). Nine of the 21 (42.8%) patients on tacrolimus treatment had C0 above the cutoff point after lopinavir/ritonavir initiation, despite having been substituted with prednisone before lopinavir/ritonavir initiation. Three patients had very high concentrations (>40 ng/mL) and developed toxicity. No episodes of acute rejection were diagnosed. DISCUSSION: We did not observe toxicity in patients for whom tacrolimus was discontinued 24 hours before starting lopinavir/ritonavir and reintroduced at half dose 48 to 72 hours after lopinavir/ritonavir discontinuation. Prednisone monotherapy during lopinavir/ritonavir therapy was safe with no episodes of acute rejection. Experience with lopinavir/ritonavir may be applicable to the use of nirmatrelvir/ritonavir, but larger multicentre studies are needed to confirm these findings.

Tigecycline population pharmacokinetics in critically ill patients with decompensated cirrhosis and severe infections.

OBJECTIVES: Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. METHODS: Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate tigecycline exposure to assess the PTA. RESULTS: Twenty critically ill patients were enrolled in the study. Data were best described by a two-compartment linear model. Mean ± SD parameter estimates for clearance (CL), intercompartmental clearance (Q), central and peripheral volumes of distribution (V1 and V2) were 14.8 ± 11 L/h, 38.4 ± 24 L/h, 63.7 ± 14 L and 233 ± 30 L, respectively. MELD score significantly influenced tigecycline CL, and total serum proteins significantly affected V1. Monte Carlo simulations showed that tigecycline elimination is hampered as MELD score values increase, consequently requiring lower drug doses. Patients with hypoproteinaemia would have lower peak tigecycline concentrations but similar steady-state concentrations compared with patients with normoproteinaemia. CONCLUSIONS: Our study confirms that tigecycline dose adjustment is needed in severe hepatic dysfunction and suggests using the MELD score for dose optimization since it is identified as a covariate that significantly influences tigecycline CL. Dosing regimens are recommended to reach several PK/PD targets considering this clinical variable and any MIC within the susceptibility range.

Case Report: A Case Study Documenting the Activity of Atezolizumab in a PD-L1-Negative Triple-Negative Breast Cancer.

The immune checkpoint inhibitor atezolizumab is approved for PD-L1-positive triple-negative breast cancer (TNBC). However, no activity of atezolizumab in PD-L1-negative TNBC has been reported to date. Here, we present the case study of a woman with TNBC with low tumor infiltrating lymphocytes and PD-L1-negative disease, which achieved a significant response to atezolizumab monotherapy and durable response after the combination of atezolizumab and nab-paclitaxel. The comprehensive genomic analysis that we performed in her tumor and plasma samples revealed high tumor mutational burden (TMB), presence of the APOBEC genetic signatures, high expression of the tumor inflammation signature, and a HER2-enriched subtype by the PAM50 assay. Some of these biomarkers have been shown to independently predict response to immunotherapy in other tumors and may explain the durable response in our patient. Our work warrants further translational studies to identify biomarkers of response to immune checkpoint inhibitors in TNBC beyond PD-L1 expression and to better select patients that will benefit from immunotherapy.

Neonatal Feeding Trajectories in Mothers With Bipolar Disorder Taking Lithium: Pharmacokinetic Data.

Purpose: Women who take lithium during pregnancy and continue after delivery may choose to breastfeed, formula feed, or mix these options. The aim of the study was to evaluate the neonatal lithium serum concentrations based on these three feeding trajectories. Methods: We followed 24 women with bipolar disorder treated with lithium monotherapy during late pregnancy and postpartum (8 per trajectory). Lithium serum concentrations were determined by an AVL 9180 electrolyte analyser with a 0.10 mEq/L detection limit and a 0.20 mEq/L limit of quantification (LoQ). Results: There was complete lithium placental passage at delivery, with a mean ratio of lithium concentration in the umbilical cord to maternal serum of 1.12 ± 0.17. The median times to LoQ were 6-8, 7-8, and 53-60 days for formula, mixed, and exclusive breastfeeding respectively. The generalized log-rank testing indicated that the median times to LoQ differ according to feeding trajectory (p = 0.037). According to the multivariate analysis-adjusted lithium serum concentrations at birth, times to LoQ are, on average, longer under exclusive breastfeeding (formula, p = 0.015; mixed, p = 0.012). No lithium accumulation was observed in infants under either exclusive or mixed breastfeeding. During the lactation follow-up, there was no acute growth or developmental delays in any neonate or infant. Indeed, lithium concentrations in the three trajectories declined in all cases. However, the time needed to reach the LoQ was much longer for those breastfeeding exclusively. Conclusions: In breastfeed infant no sustained accumulation of lithium and no adverse effects on development or growth were observed.

Evaluación de las concentraciones plasmáticas de voriconazol en práctica clínica / Assessment of plasma voriconazole concentrations in clinical practice

Introducción: Voriconazol presenta una alta variabilidad interindividual en sus concentraciones plasmáticas (Cp). Los objetivos son: (i) describir sus Cp en una cohorte adulta, (ii) estudiar sus potenciales causas de variabilidad y (iii) relacionarlas con las recomendaciones de monitorización farmacocinética actuales. Método: Estudio observacional retrospectivo, incluyendo pacientes con ≥1 determinación de Cp mínima (Cmin) de voriconazol durante 2017. Resultados: Se analizaron 165 Cmin correspondientes a 51 pacientes. La mediana de Cmin fue de 2,4µg/mL (IQR:1,4-3,6), siendo <1µg/mL en 26 casos y >4µg/mL en 34. Se observaron Cmin significativamente superiores en >65 años (p=0,006) y en pacientes con albúmina <27g/L (p<0,001). Siguiendo las recomendaciones de monitorización de las Cp de voriconazol según la guía ESCMID-ECMM-ERS, se detectarían el 91,1% de Cmin que resultaron fuera de intervalo. Conclusiones: Observamos un 36,4% de las Cmin de voriconazol fuera del intervalo óptimo. Identificamos la edad y la concentración de albúmina como factores que influencian las Cp. (AU)

Introduction: Voriconazole presents a high interindividual variability in plasma concentrations. We aimed to: (i) describe plasma voriconazole concentrations (PVC) of an adult cohort, (ii) identify potential causes of variability and (iii) relate them with current pharmacokinetic monitoring recommendations. Method: Observational retrospective study. All patients with at least one determination of PVC during 2017 were included. Results: A total of 165 trough concentrations (Ctrough) were analyzed from 51 patients. The median Ctrough was 2.4μg/mL (IQR:1.4-3.6). Ctrough were <1μg/mL in 26 cases and >4 μg/mL in 34. Significantly higher concentrations were ob-served in patients older than 65 years (p=0.006) and in patients with albumin levels <27g/L (p<0.001). Following PVC’s monitoring recommendation from ESCMID-ECMM-ERS’s guideline, we would detect the 91.1% of Ctrough out of the interval. Conclusions: We observed 36.4% of PVC outside of its optimal range. We identified age and albumin concentration as factors that influence PVC (AU)

Case Report: Clinical and Pharmacokinetic Profile of Lithium Monotherapy in Exclusive Breastfeeding. A Follow-Up Case Series.

Background: Most guidelines advise that women taking lithium should not breastfeed. The variation in transfer is just one reason behind this advice. Objectives: To present clinical and pharmacokinetic data of nine mother-infant pairs exposed to lithium monotherapy during late pregnancy and exclusive breastfeeding at the Perinatal Psychiatric Unit (2006-2018). Methods: We obtained sociodemographic data, medical risk factors, obstetric variables, and family and personal psychiatric history by semi-structured interview, and assessed maternal psychopathology with the Hamilton Depression Rating Scale and Young Mania Rating Scale. A senior neonatologist reviewed neonatal outcomes at birth using the Peripartum Events Scale. Paired maternal and cord blood and infant venous blood samples were collected. During the breastfeeding period, we monitored serum lithium and creatinine concentrations in mother-infant pairs at delivery, and at days 1-5, 7-11, 30, and 60 postpartum, and monthly until 6-months. Results: Lithium equilibrated completely across the placenta [1.13 (0.10), range (1.02-1.30)]. No women presented symptoms of postpartum lithium intoxication, two of the neonates presented transient hypotonia (22%). Lithium exposure was significantly less during breastfeeding than during late pregnancy, and serum lithium concentrations decreased up to 44% overtime from delivery to the first-month, and up to 60% to the third-month postpartum. There was no growth or developmental delay in the follow-up period. One woman had a manic episode with psychotic features at 45 days postpartum. Conclusions: In carefully selected women with bipolar disorder, lithium therapy when breastfeeding can be an appropriate option if coupled with close monitoring of the mother-infant pair.

Effectiveness of vancomycin plus cloxacillin compared with vancomycin, cloxacillin and daptomycin single therapies in the treatment of methicillin-resistant and methicillin-susceptible Staphylococcus aureus in a rabbit model of experimental endocarditis.

OBJECTIVES: To investigate if the addition of cloxacillin to vancomycin enhances the activity of both monotherapies for treating MSSA and MRSA experimental endocarditis (EE) in rabbits. METHODS: Vancomycin plus cloxacillin was compared with the respective monotherapies and daptomycin. In vitro time-kill studies were performed using standard (105 cfu) and high (108 cfu) inocula of five MRSA, one glycopeptide-intermediate (GISA) and five MSSA strains. One MSSA (MSSA-678) and one MRSA (MRSA-277) strain were selected to be used in the in vivo model. A human-like pharmacokinetics model was applied and the equivalents of cloxacillin 2 g/4 h IV and daptomycin 6 mg/kg/day IV were administered. To optimize vancomycin activity, dosage was adjusted to achieve an AUC/MIC ≥400. RESULTS: Daptomycin sterilized significantly more vegetations than cloxacillin (13/13, 100% versus 9/15, 60%; P = 0.02) and showed a trend of better activity than vancomycin (10/14, 71%; P = 0.09) and vancomycin plus cloxacillin (10/14, 71%; P = 0.09) against MSSA-678. Addition of cloxacillin to vancomycin (13/15, 87%) was significantly more effective than vancomycin (8/16, 50%; P = 0.05) and showed similar activity to daptomycin (13/18, 72%; P = 0.6) against MRSA-277. In all treatment arms, the bacterial isolates recovered from vegetations were re-tested and showed the same daptomycin susceptibility as the original strains. CONCLUSIONS: Vancomycin plus cloxacillin proved synergistic and bactericidal activity against MRSA. Daptomycin was the most efficacious option against MSSA and similar to vancomycin plus cloxacillin against MRSA. In settings with high MRSA prevalence, vancomycin plus cloxacillin might be a good alternative for empirical therapy of S. aureus IE.

Once-daily 1 g ceftriaxone optimizes exposure in patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration.

PURPOSE: Ceftriaxone total and unbound pharmacokinetics (PK) can be altered in critically ill patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration (CVVHDF). The objective of this study was to determine the dosing strategy of ceftriaxone that maximizes the probability of maintaining the concentration above the MIC of the susceptible bacteria (≤2 mg/L by the EUCAST) for a 100% of the dosing interval (100% ƒuT>MIC). METHODS: In a prospective PK study in the intensive care units of two tertiary Spanish hospitals, six timed blood samples were collected per patient; for each sample, ceftriaxone total and unbound concentrations were measured using a liquid chromatography coupled to tandem mass spectrometry method. Population PK analysis and Monte-Carlo simulations were performed using NONMEMv.7.3®. RESULTS: We enrolled 8 critically ill patients that met the inclusion criteria (47 blood samples). Median age (range) was 70 years (47-85), weight 72.5 kg (40-95), albumin concentration 24.2 g/L (22-34), APACHE II score at admission 26 (17-36), and SOFA score on the day of study 12 (9-15). The unbound fraction (ƒu) of ceftriaxone was 44%, and total CL was 1.27 L/h, 25-30% higher than the CL reported in septic critically ill patients not receiving renal replacement therapies, and dependent on albumin concentration and weight. Despite this increment in ƒu and CL, Monte-Carlo simulations showed that a dose of 1 g once-daily ceftriaxone is sufficient to achieve a 100% ƒuT>MIC for MICs ≤2 mg/L for any range of weight and albumin concentration. CONCLUSION: Once-daily 1 g ceftriaxone provides optimal exposure in critically ill patients with septic shock and hypoalbuminemia receiving CVVHDF.

Personalized antimicrobial therapy in critical and elderly patients.

OBJECTIVE: Personalized therapy in the treatment of infections is essential to  ensure optimization of antimicrobial drug levels. This strategy, together with an  understanding of the activity of these drugs, decreases the risk of bacterial  resistance and improves the drugs' safety profile. Alternative  outes of administration, such as inhalation, and the information provided by  pharmacokinetic models, are essential given the limitation of antimicrobial  activity allowed by the new antimicrobials. METHOD: A non-systematic review of the literature is presented as a way of  tackling and finding solutions to the problem. A search for high-quality articles  on the research topic was conducted. Results: A total of 370 articles were  detected, which were subjected to a further selection to discard low quality  papers by a team of five clinical pharmacists and an intensivist. Finally, 153  articles were included in the review. CONCLUSIONS: The geriatric and the critical care patient population require the  administration of antimicrobials with close monitoring. The routes of  administration recommended for the first group are discouraged for the  second. The inhaled route often results in high plasma concentrations in  patients with respiratory infections. Pharmacokinetic models are a valuable tool  in the treatment of geriatric patients, who are often excluded  from clinical trials.

OBJETIVO: La terapia personalizada en el tratamiento de las infecciones es esencial para garantizar la optimización de los niveles de fármaco  lcanzados en el paciente tratado. Adicionalmente, esta estrategia, juntamente  con el conocimiento de la actividad antimicrobiana de estos fármacos,  isminuye la posibilidad de desarrollar resistencias bacterianas y mejora el perfil  de seguridad de estos fármacos. Las terapias por vías alternativas, como  la inhalada, y el soporte de la información facilitada por modelos  farmacocinéticos son esenciales debido a la limitación de la actividad aportada  por los nuevos antimicrobianos.Método: Se presenta una revisión no sistemática de la literatura como medida  de orientación de la problemática y soluciones a lo expuesto  anteriormente. Se ha efectuado una búsqueda de artículos de alta calidad  sobre el tópico planteado. RESULTADOS: Se detectaron 231 artículos que sufrieron una selección posterior,  en base a la calidad de los trabajos valorada por un equipo de cinco farmacéuticos clínicos y un médico intensivista. Finalmente, se incluyeron 153 artículos que soportan la revisión que se ha desarrollado. CONCLUSIONES: La población geriátrica y la integrada por pacientes críticos presenta la necesidad de utilización de los antimicrobianos con una  estrecha monitorización. Vías de administración recomendadas en la primera,  están desaconsejadas en la segunda. La vía inhalada es una vía que suele  relacionarse con elevadas concentraciones en pacientes con infecciones  respiratorias. Los modelos farmacocinéticos son un soporte de gran valor para poblaciones como la geriátrica debido a que es mayoritariamente excluida de los ensayos clínicos.

New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia.

INTRODUCTION: Chagas disease (CD) affects ~7 million people worldwide. Benznidazole (BZN) and nifurtimox (NFX) are the only approved drugs for CD chemotherapy. Although both drugs are highly effective in acute and paediatric infections, their efficacy in adults with chronic CD (CCD) is lower and variable. Moreover, the high incidence of adverse events (AEs) with both drugs has hampered their widespread use. Trials in CCD adults showed that quantitative PCR (qPCR) assays remain negative for 12 months after standard-of-care (SoC) BZN treatment in ~80% patients. BZN pharmacokinetic data and the nonsynchronous nature of the proliferative mammal-dwelling parasite stage suggested that a lower BZN/NFX dosing frequency, combined with standard or extended treatment duration, might have the same or better efficacy than either drug SoC, with fewer AEs. METHODS AND ANALYSIS: New ThErapies and Biomarkers for ChagaS infEctiOn (TESEO) is an open-label, randomised, prospective, phase-2 clinical trial, with six treatment arms (75 patients/arm, 450 patients). Primary objectives are to compare the safety and efficacy of two new proposed chemotherapy regimens of BZN and NFX in adults with CCD with the current SoC for BZN and NFX, evaluated by qPCR and biomarkers for 36 months posttreatment and correlated with CD conventional serology. Recruitment of patients was initiated on 18 December 2019 and on 20 May 2021, 450 patients (study goal) were randomised among the six treatment arms. The treatment phase was finalised on 18 August 2021. Secondary objectives include evaluation of population pharmacokinetics of both drugs in all treatment arms, the incidence of AEs, and parasite genotyping. ETHICS AND DISSEMINATION: The TESEO study was approved by the National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), federal regulatory agency of the Plurinational State of Bolivia and the Ethics Committees of the participating institutions. The results will be disseminated via publications in peer-reviewed journals, conferences and reports to the NIH, FDA and participating institutions. TRIAL REGISTRATION NUMBER: NCT03981523.

Terapia antimicrobiana personalizada en pacientes críticos y en edad avanzada / Personalized antimicrobial therapy in critical and elderly patients

Objetivo: La terapia personalizada en el tratamiento de las infecciones esesencial para garantizar la optimización de los niveles de fármaco alcanzadosen el paciente tratado. Adicionalmente, esta estrategia, juntamente con el conocimiento de la actividad antimicrobiana de estos fármacos, disminuye la posibilidad de desarrollar resistencias bacterianas y mejora el perfil de seguridad deestos fármacos. Las terapias por vías alternativas, como la inhalada, y el soportede la información facilitada por modelos farmacocinéticos son esencialesdebido a la limitación de la actividad aportada por los nuevos antimicrobianos.Método: Se presenta una revisión no sistemática de la literatura comomedida de orientación de la problemática y soluciones a lo expuesto anteriormente. Se ha efectuado una búsqueda de artículos de alta calidadsobre el tópico planteado.Resultados: Se detectaron 231 artículos que sufrieron una selecciónposterior, en base a la calidad de los trabajos valorada por un equipode cinco farmacéuticos clínicos y un médico intensivista. Finalmente, seincluyeron 153 artículos que soportan la revisión que se ha desarrollado.Conclusiones: La población geriátrica y la integrada por pacientes críticospresenta la necesidad de utilización de los antimicrobianos con una estrechamonitorización. Vías de administración recomendadas en la primera, estándesaconsejadas en la segunda. La vía inhalada es una vía que suele relacionarse con elevadas concentraciones en pacientes con infecciones respiratorias. Los modelos farmacocinéticos son un soporte de gran valor parapoblaciones como la geriátrica debido a que es mayoritariamente excluidade los ensayos clínicos. (AU)

Objective: Personalized therapy in the treatment of infections is essentialto ensure optimization of antimicrobial drug levels. This strategy, togetherwith an understanding of the activity of these drugs, decreases the risk ofbacterial resistance and improves the drugs’ safety profile. Alternative routes of administration, such as inhalation, and the information provided bypharmacokinetic models, are essential given the limitation of antimicrobialactivity allowed by the new antimicrobials.Method: A non-systematic review of the literature is presented as a wayof tackling and finding solutions to the problem. A search for high-qualityarticles on the research topic was conducted.Results: A total of 370 articles were detected, which were subjected toa further selection to discard low quality papers by a team of five clinicalpharmacists and an intensivist. Finally, 153 articles were included in thereview.Conclusions: The geriatric and the critical care patient populationrequire the administration of antimicrobials with close monitoring. The routes of administration recommended for the first group are discouraged forthe second. The inhaled route often results in high plasma concentrationsin patients with respiratory infections. Pharmacokinetic models are a valuable tool in the treatment of geriatric patients, who are often excluded fromclinical trials. (AU)

Meropenem population pharmacokinetics in patients with decompensated cirrhosis and severe infections.

OBJECTIVES: Meropenem pharmacokinetics (PK) may be altered in patients with cirrhosis, hampering target attainment. We aimed to describe meropenem PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. METHODS: Serum concentrations and covariates were obtained from patients with severe infections under meropenem treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate meropenem exposure to assess the PTA. RESULTS: Fifty-four patients were enrolled in the study. Data were best described by a one-compartment linear model. The estimated typical mean value for clearance (CL) was 8.35 L/h and the estimated volume of distribution (V) was 28.2 L. Creatinine clearance (CLCR) and MELD score significantly influenced meropenem CL, and acute-on-chronic liver failure (ACLF) significantly affected V. Monte Carlo simulations showed that a lower meropenem dose would be needed as CLCR decreases and as the MELD score increases. Patients with ACLF would have lower peak meropenem concentrations but similar steady-state concentrations compared with patients with no ACLF. CONCLUSIONS: Our study identified two new covariates that influence meropenem PK in patients with decompensated cirrhosis in addition to CLCR: MELD score and ACLF. Dosing regimens are recommended to reach several PK/PD targets considering these clinical variables and any MIC within the susceptibility range.

Cloxacillin or fosfomycin plus daptomycin combinations are more active than cloxacillin monotherapy or combined with gentamicin against MSSA in a rabbit model of experimental endocarditis.

BACKGROUND: In vitro and in vivo activity of daptomycin alone or plus either cloxacillin or fosfomycin compared with cloxacillin alone and cloxacillin plus gentamicin were evaluated in a rabbit model of MSSA experimental endocarditis (EE). METHODS: Five MSSA strains were used in the in vitro time-kill studies at standard (105-106 cfu/mL) and high (108 cfu/mL) inocula. In the in vivo EE model, the following antibiotic combinations were evaluated: cloxacillin (2 g/4 h) alone or combined with gentamicin (1 mg/kg/8 h) or daptomycin (6 mg/kg once daily); and daptomycin (6 mg/kg/day) alone or combined with fosfomycin (2 g/6 h). RESULTS: At standard and high inocula, daptomycin plus fosfomycin or cloxacillin were bactericidal against 4/5 and 5/5 strains, respectively, while cloxacillin plus gentamicin was bactericidal against 3/5 strains at standard inocula but against none at high inocula. Fosfomycin, cloxacillin, gentamicin and daptomycin MIC/MBCs of the MSSA-678 strain used in the EE model were: 8/64, 0.25/0.5, 0.25/0.5 and 1/8 mg/L, respectively. Adding gentamicin to cloxacillin significantly reduced bacterial density in vegetations compared with cloxacillin monotherapy (P = 0.026). Adding fosfomycin or cloxacillin to daptomycin [10/11 (93%) and 8/11 (73%), respectively] significantly improved the efficacy of daptomycin in sterilizing vegetations [0/11 (0%), P < 0.001 for both combinations] and showed better activity than cloxacillin alone [0/10 (0%), P < 0.001 for both combinations] and cloxacillin plus gentamicin [3/10 (30%), P = 0.086 for cloxacillin plus daptomycin and P = 0.008 for fosfomycin plus daptomycin]. No recovered isolates showed increased daptomycin MIC. CONCLUSIONS: The addition of cloxacillin or fosfomycin to daptomycin is synergistic and rapidly bactericidal, showing better activity than cloxacillin plus gentamicin for treating MSSA EE, supporting their clinical use.

ERBB2 mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer.

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High ERBB2 mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. ERBB2 expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20-8.41% of tumors across 15 cancer types as ERBB2-high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high ERBB2 mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by ERBB2 levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.

Evaluation of dose-tapering strategies for intravenous tocilizumab in rheumatoid arthritis patients using model-based pharmacokinetic/pharmacodynamic simulations.

PURPOSE: Tocilizumab is a humanized monoclonal antibody approved for rheumatoid arthritis treatment. In clinical practice, empirical dose-tapering strategies are implemented in patients showing sustained remission or low disease activity (LDA) to avoid overtreatment and reduce costs. Since rational adaptive-dosing algorithms taking the full pharmacokinetic (PK)/pharmacodynamic (PD) characteristics into account are currently lacking, we aimed to develop novel tapering strategies and compare them with currently used empirical ones. METHODS: Four strategies were simulated on a virtual population. In all of them, the same initial dose was administered every 28 days for six consecutive months. Then, different strategies were considered: (1) label-dosing; (2) mild empirical dose-tapering; (3) intense empirical dose-tapering; (4) therapeutic drug monitoring (TDM)-guided dose-tapering. The different strategies were evaluated on the proportion of patients who maintain remission/LDA 1 year after the intervention. Cost-savings of direct drug costs were also estimated as relative dose intensity. RESULTS: The overall proportion of simulated patients in remission/LDA after 1 year of the intervention was comparable between the mild empirical and the TDM-guided dose-tapering strategies, and much lower for the intense empirical dose-tapering strategy (80.3%, 78.2%, and 69.0%, respectively). Likewise, 1-year flare rates were lower for the mild empirical and TDM-guided tapering strategies. The relative dose intensity was lowest for the intense empirical dose-tapering, followed by the TDM-guided and the mild empirical dose-tapering approaches (61.2%, 71.0%, and 80.4%, respectively). CONCLUSION: We demonstrated that the TDM-guided strategy using model-based algorithms performed similarly to mild empirical dose-tapering strategies in overall remission/LDA rates but is superior in cost-savings.

Anticholinergic Burden and Safety Outcomes in Older Patients with Chronic Hepatitis C: A Retrospective Cohort Study.

AIM: Older patients with chronic hepatitis C infection starting direct-acting antivirals (DAAs) are frequently prescribed multiple medications that may be categorized as inappropriate. Anticholinergic burden has been shown to be a predictor of adverse health and functional outcomes. Different scales are available to calculate anticholinergic burden. The aim of this study was to determine the prevalence of anticholinergic medication among older patients treated with DAAs and the risk factors associated using the Anticholinergic Cognitive Burden (ACB) scale, the Anticholinergic Risk Scale (ARS) and the Anticholinergic Drug Scale (ADS) and analyze the resulting safety consequences. METHODS: Observational, retrospective cohort study of consecutive patients ≥65 years old receiving DAAs and taking concomitant medication. This study was conducted in accordance with the Strengthening the Reporting of observational studies in Epidemiology Statement. RESULTS: 236 patients were included. The average age was 71.7 years, 73.3% cirrhotic, and 47% patients took ≥5 medicines. According to the ACB, ARS and ADS scales, 35.2% (n = 83), 10.6% (n = 25) and 34.3% (n = 81) of the patients were treated with anticholinergic medication. Two hundred-and-six (86%) patients presented any adverse events (AEs) during therapy. ARS scale showed a significant relationship between presence of anticholinergic medication and AEs. A large number of patients suffered anticholinergic events, with more events per patient in patients taking anticholinergic drugs. CONCLUSIONS: Older hepatitis C chronic patients are exposed to potentially inappropriate polypharmacy and anticholinergic risk, according to the ACB, ARS and ADS scales. The three scales showed different results. Only the ARS scale was associated with AEs, but the rate of anticholinergic effects per patient was significantly higher in patients with anticholinergic drugs, regardless of the scale used. Consider quality of pharmacotherapy when starting DAA with a multidisciplinary approach could improve health outcomes.