New Synergistic Combination Therapy of Mupirocin and α-Pinene Against Multidrug-Resistant Clinical Strains of Methicillin-Resistant Staphylococcus aureus.

OBJECTIVE: Increased mupirocin use leads to mupirocin resistance and is associated with persistence of methicillin-resistant Staphylococcus aureus (MRSA) carriers, prolonged hospitalization, and significant economic burdens for health systems. The study aimed to investigate the antimicrobial activity of compounds of Salvia rosmarinus L. ("rosemary", formerly Rosmarinus officinalis), alone or in combination with mupirocin, against multidrug resistant MRSA using isolates obtained from pediatric patients. METHODS: The in vitro antibacterial activity of the monoterpene α-pinene (α-Pi), a rosemary essential oil constituent, alone and in combination with mupirocin, was evaluated by determining the minimum inhibitory concentrations and minimum bactericidal concentrations (MBCs) and the fractional inhibitory concentration indices (FICIs) and fractional bactericidal concentration indices against multidrug-resistant clinical MRSA strains. The in vivo efficacy of α-Pi, alone and in combination with mupirocin, to eradicate MRSA infection was determined using an optimized mouse model of MRSA-infected wounds. Mouse skin samples (obtained via biopsy) were assessed for toxicity, and rabbit skin samples for irritation. RESULTS: Both in vitro and in vivo, α-Pi was active against MRSA strains and acted synergistically with mupirocin against MRSA strains. Mupirocin-monoterpene combinations exhibited FICI values of 0.2 to 0.4, reducing the MBC of topical mupirocin 33-fold. A topical formulation containing α-Pi and mupirocin enhanced the efficacy of mupirocin in an in vivo MRSA-infected mouse skin model without significantly harming the skin of mice and rabbits. CONCLUSIONS: A topical formulation combining mupirocin and α-Pi may aid in the development of innovative agents for treating MRSA infections.

Integrative oncology: Addressing the global challenges of cancer prevention and treatment.

The increase in cancer incidence and mortality is challenging current cancer care delivery globally, disproportionally affecting low- and middle-income countries (LMICs) when it comes to receiving evidence-based cancer prevention, treatment, and palliative and survivorship care. Patients in LMICs often rely on traditional, complementary, and integrative medicine (TCIM) that is more familiar, less costly, and widely available. However, spheres of influence and tensions between conventional medicine and TCIM can further disrupt efforts in evidence-based cancer care. Integrative oncology provides a framework to research and integrate safe, effective TCIM alongside conventional cancer treatment and can help bridge health care gaps in delivering evidence-informed, patient-centered care. This growing field uses lifestyle modifications, mind and body therapies (eg, acupuncture, massage, meditation, and yoga), and natural products to improve symptom management and quality of life among patients with cancer. On the basis of this review of the global challenges of cancer control and the current status of integrative oncology, the authors recommend: 1) educating and integrating TCIM providers into the cancer control workforce to promote risk reduction and culturally salient healthy life styles; 2) developing and testing TCIM interventions to address cancer symptoms or treatment-related adverse effects (eg, pain, insomnia, fatigue); and 3) disseminating and implementing evidence-based TCIM interventions as part of comprehensive palliative and survivorship care so patients from all cultures can live with or beyond cancer with respect, dignity, and vitality. With conventional medicine and TCIM united under a cohesive framework, integrative oncology may provide citizens of the world with access to safe, effective, evidence-informed, and culturally sensitive cancer care.

Intensive Safety Monitoring of Rituximab (Biosimilar Novex® and the Innovator) in Pediatric Patients With Complex Diseases.

Although rituximab is widely used off-label for complex pediatric diseases, safety reports are limited. We aimed to report evidence of its use in clinical practice, to describe the incidence of adverse drug reactions (ADR) to rituximab biosimilar Novex® and innovator, and to identify risk factors for the development of ADR in a real-life follow-up cohort of pediatric patients with complex diseases. We conducted a prospective, longitudinal, observational, single-centre study in patients that received rituximab for any complex disease, and as part of an intensive pharmacovigilance program. Demographic, pharmacological, clinical, and drug-related data were collected for all patients. ADR-free survival, including infusion-related reactions (IRR) and delayed ADR (dADR), was estimated using Kaplan-Meier curves. Risk factors were evaluated by multivariable Cox regression models. In total, 77 patients (<19 y.o.) received 187 infusions of rituximab Novex® (n = 155) or innovator rituximab (n = 32) for neurologic (Neu), immune-hematologic-rheumatic (IHR), oncologic (O) diseases, and hematopoietic stem-cell transplantation (HSCT) or solid-organ transplantation (SOT). We recorded 29 IRR and 58 dADR that occurred in 27 (35.1%) and 29 (37.7%) patients, respectively. The respiratory tract was the most affected during IRR (29.6%) and hypogammaglobulinemia (37.9 %) was the most frequent dADR. First versus subsequent infusions (HR 5.4, CI95% 2.4-12.1, p<0.05), sex (boys vs. girls, HR 0.3, CI95% 0.1-0.8, and p<0.05), and diagnosis (Neu-IHR diseases vs. O-HSCT-SOT, HR 2.3, CI95% 1.02-5.4, and p < 0.05) were significantly associated with the development of IRR. For dADR, risk factors were diagnosis (Neu-IHR diseases vs. O-HSCT-SOT, HR 0.4, CI95% 0.2-0.9, and p < 0.05) and cumulative body surface area-normalized dosage (HR 1.0003, CI95% 1.0001-1.0006, and p < 0.05). The present is the largest real-world safety assessment of rituximab in Latin-American children with complex diseases supporting its use based on the overall acceptable safety. Identification of risk factors may contribute to optimization of off-label rituximab treatment in pediatrics.

Medicina Integrativa en Pediatría y Neonatología en Argentina / Integrative Medicine in Pediatrics and Neonatology in Argentina

Transcurrimos un tiempo en el que están cambiando muchos paradigmas, con lo que se abre la perspectiva de un universo holístico e interconectado. Estos paradigmas están transformando también la medicina, proporcionando la comprensión y el respeto entre diferentes filosofías y sus correspondientes prácticas. Los niños son el futuro y la esperanza para el mundo; la Pediatría es la disciplina más importante para el cuidado de su salud, desde la concepción hasta el final de la adolescencia. La Pediatría debe ocuparse no solo de los individuos y sus organismos, sino también de influencias ambientales, culturales y sociales, que tienen impacto considerable sobre la salud física, emocional y mental de los niños y sus familias.

Principios de estadística Bayesiana y su relación con la farmacocinética aplicada / Principles of Bayesian statistics and its relationship with applied pharmacokinetics

La metodología estadística Bayesiana permite, si se conoce la probabilidad poblacional de que un suceso ocurra, modificar su valor cuando se dispone de nueva información individual. Aunque las metodologías Bayesiana y frecuentista (clásica) tienen idénticos campos de aplicación, la primera se aplica cada vez más en investigación científica y análisis de big data. En la farmacoterapia moderna, la farmacocinética clínica ha sido responsable de la expansión de la monitorización, facilitada por desarrollos técnico-analíticos y matemático-estadísticos. La farmacocinética poblacional ha permitido identificar y cuantificar las características fisiopatológicas y de tratamiento en una población de pacientes determinada, en particular en pediatría y neonatología, y otros grupos vulnerables, explicando la variabilidad farmacocinética interindividual. Asimismo, la estimación Bayesiana resulta importante como herramienta estadística aplicada en programas informáticos de optimización farmacoterapéutica cuando la monitorización farmacológica se basa en la interpretación farmacocinética clínica. Aunque con ventajas y limitaciones, la optimización farmacoterapéutica basada en la estimación Bayesiana es cada vez más usada en la actualidad, siendo el método de referencia. Esto es particularmente conveniente para la práctica clínica de rutina debido al limitado número de muestras requeridas por parte del paciente, y a la flexibilidad en cuanto a los tiempos de muestreo de sangre para cuantificación de fármacos. Así, la aplicación de los principios Bayesianos a la práctica de la farmacocinética clínica resulta en la mejora de la atención farmacoterapéutica.

If one knows the probability of an event occurring in a population, Bayesian statistics allows mo difying its value when there is new individual information available. Although the Bayesian and frequentist (classical) methodologies have identical fields of application, the first one is increasin gly applied in scientific research and big data analysis. In modern pharmacotherapy, clinical phar macokinetics has been used for the expansion of monitoring, facilitated by technical-analytical and mathematical-statistical developments. Population pharmacokinetics has allowed the identification and quantification of pathophysiological and treatment characteristics in a specific patient popu lation, especially in the pediatric and neonatal population and other vulnerable groups, explaining interindividual variability. Likewise, Bayesian estimation is important as a statistical tool applied in pharmacotherapy optimization software when pharmacological monitoring is based on clinical phar macokinetic interpretation. With its advantages and despite its limitations, pharmacotherapeutic op timization based on Bayesian estimation is increasingly used, becoming the reference method today. This characteristic is particularly convenient for routine clinical practice due to the limited number of samples required from the patient and the flexibility it shows regarding blood sampling times for drug quantification. Therefore, the application of Bayesian principles to the practice of clinical phar macokinetics has led to the improvement of pharmacotherapeutic care.

Medicinal cannabis in Latin America: History, current state of regulation, and the role of the pharmacist in a new clinical experience with cannabidiol oil.

OBJECTIVE: Cannabis sativa was introduced in Latin America in the 16th century. Nevertheless, many years have elapsed, and scientific progress and the medicinal use of C sativa have been restricted by the national laws of the countries in the region. SUMMARY: In Argentina, the first law on medical cannabis, approved in 2017 (#17,350), establishes a regulatory framework for the medical use and scientific research of this plant and its derivatives. In 2018, the first clinical research protocol in Latin America was approved at Hospital de Pediatria Garrahan (Buenos Aires, Argentina) to evaluate the efficacy and safety of cannabidiol (CBD) oil for the treatment of pediatric patients with refractory epilepsy. In this context, the role of pharmacists in the health care system related to the study protocol and the medicinal use of CBD has evolved from dispensing to active participation in clinical follow-up and research protocols. CONCLUSION: Considering this experience, here we discuss the active role of the clinical pharmacist in the use of medicinal cannabis. Medicinal cannabis should be controlled in a legal framework based on clinical evidence, and the participation of the pharmacist in research and clinical protocols, as well as the dispensing and provision of information on the medicinal products should be emphasized in the clinical setting.

Population pharmacokinetics of amikacin in patients with pediatric cystic fibrosis.

INTRODUCTION: Amikacin is commonly used in patients with pediatric cystic fibrosis (CF) for the treatment of pulmonary exacerbations. Amikacin efficacy is related to maximum plasma concentration/minimum inhibitory concentration (Cmax/MIC) ratio >8. Pharmacokinetic data in patients with pediatric CF are scarce. The aim of this study was to develop a population pharmacokinetic (PopPK) model describing amikacin disposition in patients with pediatric CF. METHODS: CF patients under 18 years of age with pulmonary exacerbation who received amikacin were enrolled. Patients received different amikacin regimens (30 mg-1 kg-1 day-1 every 8, 12, or 24 hours) depending on the patient's status and hospital protocols. Amikacin serum levels were obtained for therapeutic drug monitoring. PopPK model was developed using MONOLIX Suite-2018R1 (Lixoft). RESULTS: A total of 39 patients (114 amikacin concentrations) were included in this study. Population estimates for the elimination rate constant (k) and the volume of distribution (V) were 0.541 hours-1 and 0.451 L/kg, respectively. Between-subject and between-occasion variability were 53% and 16.5% for k and 31% and 22% for V, respectively. Bodyweight was a significant covariate associated with V. Based on simulations, almost 70% of the patients receiving 30 mg-1 kg-1 day-1 every 24 hours would achieve a Cmax/MIC ratio >8 which is an appropriate therapeutic goal while no patient in the other two groups (Q8 and Q12) would achieve that objective. CONCLUSIONS: The regimen of 30 mg-1 kg-1 day-1 every 24 hours more adequately fulfilled the therapeutic target for amikacin. Although all our patients had good clinical results and a good adverse-events profile, further studies are necessary to redefine the optimal treatment strategy.

Resistencia emergente a la mupirocina en aislados de Staphylococcus aureus resistente a meticilina en un hospital pediátrico terciario en la Argentina / Emerging mupirocin resistance in methicillin-resistant Staphylococcus aureus isolates at a tertiary care children's hospital in Argentina

En América Latina, existen escasos estudios sobre la resistencia a mupirocina y producción de biofilm en Staphylococcus aureus resistente a la meticilina (SARM). En este trabajo, se investigó la resistencia a mupirocina en SARM aislados de pacientes pediátricos con bacteremia y su capacidad para producir biofilm. Se estudió la resistencia a antibióticos por Kirby-Bauer y microdilución en caldo. Se cuantificó el biofilm bacteriano por ensayo de cristal violeta. El 2,3 % (5/217) de los aislados de SARM presentaron un alto nivel de resistencia a mupirocina con una concentración inhibitoria mínima de >512 μ/ml, además de resistencia cruzada con clindamicina, eritromicina, gentamicina y ciprofloxacina. Notablemente, dichos aislados formaron biofilm en un nivel moderado-alto. Este primer reporte en Argentina de aislados clínicos de SARM resistentes a la mupirocina es clave para seguir su evolución en el tiempo a nivel local y en la región de América Latina.

In Latin America, few studies have been done in mupirocin resistance and biofilm formation in methicillin-resistant Staphylococcus aureus (MRSA). This study investigated mupirocin-resistance in MRSA isolates from pediatric patients with bacteremia and their ability to form biofilm. Antibiotic resistance was analyzed with the Kirby-Bauer test and the broth microdilution method. Bacterial biofilm formation was measured using the crystal violet assay. Among MRSA isolates, 2.3 % (5/217) exhibited a high level of mupirocin-resistance with a minimum inhibitory concentration of > 512 μg/mL, in addition to cross-resistance with clindamycin, erythromycin, gentamicin, and ciprofloxacin. Remarkably, biofilm formation in such isolates was moderate to high. This is the first report published in Argentina on clinical isolates of mupirocin-resistant MRSA and it is critical for following its evolution over time at a local level and in the Latin American region.

Survival Time to Biopsy-Proven Acute Rejection and Tacrolimus Adverse Drug Reactions in Pediatric Liver Transplantation.

BACKGROUND: Despite advances in surgical procedures and the optimization of immunosuppressive therapies in pediatric liver transplantation, acute rejection (AR) and serious adverse drug reaction (ADR) to tacrolimus still contribute to morbidity and mortality. Identifying risk factors of safety and efficacy parameters may help in optimizing individual immunosuppressive therapies. This study aimed to identify peritransplant predictors of AR and factors related to the risk of ADR to tacrolimus in a large Latin American cohort of pediatric liver transplant patients. METHODS: We performed a retrospective cohort study in a pediatric liver transplant population (n = 72). Peritransplant variables were collected retrospectively including demographic, clinical, laboratory parameters, genomic (CYP3A5 donor and recipients polymorphism), and tacrolimus trough concentrations (C0) over a 2-year follow-up period. Variability in tacrolimus C0 was calculated using percent coefficient of variation and tortuosity. ADR- and AR-free survival rates were calculated using the Kaplan-Meier method, and risk factors were identified by multivariate Cox regression models. RESULTS: Cox-proportional hazard models identified that high tortuosity in tacrolimus C0 was associated with an 80% increased risk of AR [hazard ratio (HR), 1.80; 95% confidence interval (CI), 1.01-3.22; P < 0.05], whereas steroid in maintenance doses decreased this risk (HR, 0.56; 95% CI, 0.31-0.99; P < 0.05). Forty-six patients experienced at least one ADR including hypomagnesemia, nephrotoxicity, hypertension, malignancies, and tremor as a first event. Multivariate analysis showed that C0 values 10 days before the event (HR, 1.25; 95% CI, 1.21-1.39; P < 0.0001) and CYP3A5 expresser recipients (HR, 2.05; 95% CI, 1.03-4.06; P < 0.05) were independent predictors of ADR. CONCLUSIONS: Tacrolimus C0 values, its variability, and CYP3A5 polymorphisms were identified as risk factors of AR and tacrolimus ADR. This knowledge may help to control and reduce their incidence in pediatric liver transplant patients. Prospective studies are important to validate these results.

Espacios verdes en un hospital pediátrico de alta complejidad: beneficios, evaluación taxonómica y perspectiva / Green spaces in a tertiary care children's hospital: Benefits, taxonomic survey, and perspective

El contacto del ser humano con espacios verdes naturales tiene un efecto físico, mental y social beneficioso. Con el primer objetivo de conocer las especies vegetales de los jardines del Hospital de Pediatría Garrahan (Ciudad de Buenos Aires), se realizó un relevamiento taxonómico entre diciembre de 2013 y noviembre de 2016. Otro objetivo fue revisar el estado del conocimiento sobre cómo los espacios verdes naturales influían en la salud de los pacientes internados. Existen sesenta y nueve especies de plantas que abarcan cuarenta y siete familias botánicas; de ellas, solo el ocho por ciento son nativas. Se sugiere incrementar las especies autóctonas y coordinar aspectos relacionados con su preservación. Este relevamiento, como parte de un plan que incluirá la divulgación del conocimiento, comprensión y concientización sobre espacios verdes y salud, y la cuantificación de esos efectos concretos en este Hospital, profundizará y fomentará la interacción de los pacientes, los familiares y los profesionales con los espacios verdes naturales.

Humans coming in contact with natural green spaces experience beneficial physical, mental, and social effects. For the primary purpose of describing plant species found in the gardens of Hospital de Pediatría "Prof. Dr. Juan P. Garrahan" (Autonomous City of Buenos Aires), a taxonomic survey was carried out between December 2013 and November 2016. A secondary objective was to review the extent of knowledge on how natural green spaces affect the health of hospitalized patients. There are 69 plant species from 47 botanical families; of these, only 8% are native. The recommendation is to increase the number of native species and coordinate those aspects related to their preservation. This survey, which is part of a plan that will include the dissemination of knowledge, understanding and awareness of green spaces and health, and the quantification of such specific effects in this hospital, will deepen and promote the interaction of patients, families, and health care providers with natural green spaces.

Therapeutic monitoring of pediatric transplant patients with conversion to generic tacrolimus.

OBJECTIVE: Therapeutic monitoring during interchange of tacrolimus commercial formulations is essential to ensure similar exposure in transplant patients. However, there are limited data in the pediatric transplant population. This study aims to evaluate exposure, safety and efficacy in maintenance pediatric transplant patients under generic tacrolimus substitution. METHOD: Pediatric patients who underwent interchange of tacrolimus formulations were detected by the Service of Pharmacy and included in this study. Tacrolimus trough levels (C0), laboratory parameters and clinical characteristics were recorded before and after the switch. Statistical analysis was performed using Wilcoxon matched pair t-test. RESULTS: In total, 10 patients with kidney, liver, heart and hematopoietic stem cell transplantation received the innovator and switched to the generic product. The median (range) of the C0 normalized by the dose before and after switch was 74.8 [(ng/ml)/(mg/kg)] (13.8-518.4) and 65.1 [(ng/ml)/(mg/kg)] (13.5-723.5), respectively (p>0.05). Tacrolimus dose was 0.070(mg/kg) (0.024-0.461) and 0.069(mg/kg) (0.017- 0.571) for the innovator and generic formulation, respectively, with no difference when comparing both values (p>0.05). Laboratory parameters did not change after conversion (p>0.05). Adverse events, acute rejection, death and graft loss were not observed. CONCLUSION: In our study population, no significant differences in terms of laboratory parameters, drug exposure and dose were observed. We emphasize the need of close monitoring to ensure a safe interchange, especially in vulnerable populations such as the pediatric.

Objetivo: La monitorización terapéutica durante el intercambio de marcas comerciales de inmunosupresores es esencial para mantener una similar exposición al fármaco en pacientes trasplantados. Sin embargo, la información disponible en trasplante pediátrico es limitada. El objetivo del trabajo fue evaluar la exposición, seguridad y eficacia en pacientes pediátricos trasplantados en etapa de mantenimiento, sujetos a intercambio entre el producto innovador y el genérico de tacrolimus. Método: El Área de Farmacia del hospital detectó aquellos pacientes sujetos a intercambio de formulaciones según la disponibilidad de medicamentos. Se obtuvieron las concentraciones de tacrolimus en el valle (C0), parámetros de laboratorio y características clínicas antes y después del intercambio. El análisis estadístico se realizó mediante el test de muestras pareadas de Wilcoxon. Resultados: Se incluyeron 10 pacientes con trasplante renal, hepático, cardíaco y de células hematopoyéticas. La mediana (rango) del C0 normalizado por la dosis pre y post intercambio fue 74,8[(ng/ml)/(mg/kg)](13,8-518,4) y 65,1[(ng/ml)/(mg/kg)] (13,5-723,5), respectivamente (p>0,05). La dosis de tacrolimus fue 0,070(mg/kg) (0,024-0,461) y 0,069(mg/kg) (0,017-0,571) para el innovador y el genérico, respectivamente (p>0,05). Los parámetros de laboratorio de funcionalidad renal y hepática no cambiaron con la conversión de marcas (p>0,05). No se observaron eventos adversos, rechazo agudo, muerte o pérdida del injerto durante el periodo analizado. Conclusiones: En la población estudiada, no se observaron diferencias significativas en los parámetros de laboratorio, exposición al tacrolimus o dosis en el intercambio de marcas comerciales. Destacamos el rol de la monitorización terapéutica a la hora de garantizar una sustitución segura, especialmente en poblaciones vulnerables.