Ampicillin and Ceftriaxone Solution Stability at Different Temperatures in Outpatient Parenteral Antimicrobial Therapy.

The inclusion of ampicillin-containing regimens in outpatient parenteral antimicrobial therapy programs (OPAT) depends upon solution stability under conditions similar to those experienced in these programs. Lack of this information could hinder the inclusion in OPAT of patients suffering from Enterococcus faecalis infective endocarditis treated with ampicillin plus ceftriaxone. The purpose of this study is to determine the stability of ampicillin and ampicillin plus ceftriaxone solutions in a simulated outpatient setting conditions. Solutions of ampicillin 24 g/liter and ampicillin 24 g/liter combined with ceftriaxone 8 g/liter were stored at 25°C ± 2°C, 30°C ± 2°C and 37°C ± 2°C for 48 h. Chemical and physical stability were evaluated at 20, 24, 30, and 48 h after manufacturing. The solutions were considered stable if the percentage of intact drug was ≥90% and color and clearness remained unchanged. After 24 h of storage at a controlled temperature, ampicillin solution in 0.9% sodium chloride was found to be stable for 30 h at 25 and 30°C and for 24 h at 37°C. In the ampicillin plus ceftriaxone combined solution, both antibiotics were found to be stable after 30 h of storage at 25 and 30°C, but at 37°C, the stability criterion was not met at any time point. Our study offers solid evidence demonstrating that the concentrations of both drugs at two of the tested temperatures (25°C and 30°C) were stable for up to 30 h. Therefore, both ampicillin alone and ampicillin plus ceftriaxone solutions would be appropriate candidates for inclusion in OPAT programs.

How the environment shapes animal signals: a test of the acoustic adaptation hypothesis in frogs.

Long-distance acoustic signals are widely used in animal communication systems and, in many cases, are essential for reproduction. The acoustic adaptation hypothesis (AAH) implies that acoustic signals should be selected for further transmission and better content integrity under the acoustic constraints of the habitat in which they are produced. In this study, we test predictions derived from the AAH in frogs. Specifically, we focus on the difference between torrent frogs and frogs calling in less noisy habitats. Torrents produce sounds that can mask frog vocalizations and constitute a major acoustic constraint on call evolution. We combine data collected in the field, material from scientific collections and the literature for a total of 79 primarily Asian species, of the families Ranidae, Rhacophoridae, Dicroglossidae and Microhylidae. Using phylogenetic comparative methods and including morphological and environmental potential confounding factors, we investigate putatively adaptive call features in torrent frogs. We use broad habitat categories as well as fine-scale habitat measurements and test their correlation with six call characteristics. We find mixed support for the AAH. Spectral features of torrent frog calls are different from those of frogs calling in other habitats and are related to ambient noise levels, as predicted by the AAH. However, temporal call features do not seem to be shaped by the frogs' calling habitats. Our results underline both the complexity of call evolution and the need to consider multiple factors when investigating this issue.

Outpatient parenteral antimicrobial therapy in Enterococcus faecalis infective endocarditis.

WHAT IS KNOWN AND OBJECTIVE: Enterococcus faecalis is the third most common causal agent of infective endocarditis. Currently, the treatment recommended is a combination of ampicillin (2 g/4 h) plus ceftriaxone (2 g/12 h), so patients must remain hospitalized for almost 6 weeks to receive the treatment. They are not generally included in outpatient parenteral antimicrobial therapy programs because 2 different electronic pumps are required to administer these 2 antibiotics. To enable the treatment of patients with E. faecalis IE at home, we designed a continuation combination regimen of ceftriaxone 4 g once daily in a short infusion plus ampicillin 2 g/4 h using a programmable pump. METHODS: We analyzed a cohort of patients attended in an outpatient parenteral antimicrobial therapy program that has been working since 2012 in 2 tertiary hospitals. We selected patients attended in this program for E. faecalis IE treated with a continuation regimen of ampicillin 12 g daily (2 g/4 h) and ceftriaxone 4 g every 24 hours between July 2012 and March 2017. RESULTS AND DISCUSSION: Of the 720 patients included in the outpatient parenteral antimicrobial therapy program, 42 had infective endocarditis, and 4 (9.52%) were treated using the combination regimen described above. All patients were men, and all had left-sided native-valve infective endocarditis. All 4 patients received ampicillin 2 g every 4 hours and ceftriaxone 2 g every 12 hours in hospital, for a median duration of 25 days (IQR 15-32). Thereafter, in the program, they received the following regimen: a 30-minute infusion of ceftriaxone 4 g in 250 mL of saline solution, followed by ampicillin 12 g daily in 500 mL of saline solution delivered by a pump programmed to administer 2 g every 4 hours. Patients received this treatment at home for a median of 22.5 days (IQR 13-32). All patients achieved clinical and microbiological cure with no recurrences or complications after a lengthy follow-up period (median 365 days, IQR 221-406). No drug-related adverse events or problems with the pump system were reported. WHAT IS NEW AND CONCLUSIONS: Use of ceftriaxone 4 g in a single dose yields a mean plasma concentration of 30 µg/mL. Ceftriaxone also has a high plasma protein binding capability, and once this binding is saturated, there is no reason to administer higher doses. Therefore, it seems reasonable to use a dose of 4 g of ceftriaxone once daily to have a synergist effect with ampicillin within the vegetation, and enable the treatment of patients with E. faecalis infective endocarditis at home. In conclusion, the administration of ampicillin (2 g/4 h) plus ceftriaxone (4 g/24 h) as a continuation regimen in an outpatient parenteral antimicrobial therapy program may be as effective and safe as the usual lengthy in-hospital regimen (ampicillin 2 g/4 h and ceftriaxone 2 g/12 h) in patients with E. faecalis infective endocarditis.

[Diagnosis and management in pediatric patients with ovarian masses]. / Diagnóstico y manejo de masas ováricas en pacientes pediátricas.

OBJECTIVE: Review of the diagnosis and management of ovarian masses in children, through the identification of preoperative risk factors of malignancy, the evaluation of surgical management and its results. METHODS: Retrospective study in pediatric patients under 18 years old, managed surgically by ovarian masses. Analyzed data were symptoms, imagining, tumor markers, treatment, outcomes and pathology. The primary endpoint was ovarian malignancy. RESULTS: We identified 54 patients with ovarian masses between 2014 and 2017, of which 49 were benign and 5 malignant; The malignant ovarian masses were significantly larger than the benign, with an average of 19.4 cm vs 6.49 cm (p = 0.0001); had greater solid component in the imaging and positive tumor markers (p = 0.001) and were treated with oophorectomy plus tumor staging surgery. Forty-three patients with benign tumors underwent ovarian preservation surgery. The postoperative follow-up of all the patients was on average 3.4 months (1-25 months) and 20.3% presented pelvic pain associated with alterations of the menstrual cycle in their postoperative control. There are no reports of recurrence or contralateral ovarian tumor. CONCLUSIONS: Large masses with solid components and positive tumor markers were significant predictors of malignancy. Minimally invasive ovarian preserving surgery should be considered as the first treatment option in masses with low risk of malignancy. On the other hand, oophorectomy plus tumor staging surgery should be considered for ovarian tumors with a high risk of malignancy.

OBJETIVO: Revisión del diagnóstico y manejo de las masas ováricas en población infantil, mediante la identificación de factores de riesgo preoperatorios de malignidad, la evaluación del manejo quirúrgico y sus resultados. METODOS: Estudio retrospectivo en pacientes pediátricas menores de 18 años, intervenidas quirúrgicamente por masas ováricas. Se analizaron datos como síntomas, imágenes diagnósticas, marcadores tumorales, tratamiento, resultados y patología. La variable principal fue malignidad ovárica. RESULTADOS: Se identificaron 54 pacientes con masas ováricas entre el año 2014 a 2017, de las cuales 49 fueron benignas y 5 malignas. Las masas ováricas malignas fueron significativamente más grandes que las benignas, con media de 19,4 cm vs 6,49 cm (p = 0,0001); tuvieron mayor componente sólido en los hallazgos imagenológicos y marcadores tumorales positivos (p = 0,001) y fueron tratadas con ooforectomía más cirugía de estadificación tumoral. A 43 pacientes con tumores benignos se les realizó cirugía preservadora de ovario. El seguimiento postoperatorio de todas las pacientes fue en promedio de 3,4 meses (1-25 meses) y el 20,3% presentaron dolor pélvico asociado a alteraciones del ciclo menstrual en su control postoperatorio. No hay reportes de recidiva ni tumor de ovario contralateral. CONCLUSIONES: Masas grandes, con componentes sólidos y marcadores tumorales positivos fueron predictores significativos de malignidad. La cirugía preservadora de ovario por vía mínimamente invasiva debe ser considerada como primera opción de tratamiento en masas con bajo riesgo de malignidad; Por otra parte, la ooforectomía más cirugía de estadificación tumoral, debe ser considerada para los tumores ováricos con alto riesgo de malignidad.

Advanced stage yolk sac ovarian tumour: clinical approach with cytoreductive surgery upfront.

The authors report the case of a 21-year-old woman that presented a Pseudo Meigs' syndrome, secondary to a pure endodermal sinus tumour (yolk sac tumour). Fine needle aspiration biopsy was compatible with high-grade carcinoma and the alpha fetoprotein (αFP) was at 13,185 U/ml. Cytoreductive surgery was performed, followed by bleomycin, etoposide, and cisplatin (BEP) chemotherapy.

Use of bevacizumab as a first-line treatment for metastatic breast cancer.

OBJECTIVE: During clinical practice, it can be challenging, given the lack of response biomarkers, to identify the patients with metastatic breast cancer (mbca) who would benefit most from the addition of bevacizumab to first-line standard chemotherapy. The aim of the present review was to summarize the relevant scientific evidence and to discuss the experience of a group of experts in using bevacizumab to treat mbca. METHODS: A panel of 17 Spanish oncology experts met to discuss the literature and their experience in the use of bevacizumab as first-line treatment for mbca. During the meeting, discussions focused on three main issues: the profile of the patients who could benefit most from bevacizumab, the optimal bevacizumab treatment duration, and the safety profile of bevacizumab. RESULTS: The subset of mbca patients who would benefit the most from the addition of bevacizumab to first-line standard chemotherapy are those with clinically defined aggressive disease. Treatment with bevacizumab should be maintained until disease progression or the appearance of unacceptable toxicity. In the mbca setting, the toxicity profile of bevacizumab is well known and can be managed in clinical practice after adequate training. CONCLUSIONS: This expert group recommends administering bevacizumab as first-line treatment in patients with clinically aggressive disease.

Phase I clinical trial of nintedanib plus paclitaxel in early HER-2-negative breast cancer (CNIO-BR-01-2010/GEICAM-2010-10 study).

INTRODUCTION: Previous small-molecule antiangiogenics have compromised chemotherapy dose intensity in breast cancer. We present a phase I trial of a novel selective agent, nintedanib, plus standard chemotherapy in early breast cancer. METHODS: Her-2-negative breast cancer patients with tumours larger than 2 cm were eligible for dose-escalation trial (classic 3+3 method). RESULTS: The recommended phase II dose (RP2D) was 150 mg BID of nintedanib combined with standard dose of weekly paclitaxel followed by adriamycin plus cyclophosphamide. The dose-limiting toxicity was transaminase elevation. At the RP2D, the dose intensity was ∼100%. The pathologic complete response was 50%. CONCLUSIONS: The combination allows the delivery of full-dose intensity, while efficacy seems promising.

Propagation of natural toad calls in a Mediterranean terrestrial environment.

Propagation patterns of animal acoustic signals provide insights into the evolution of signal design to convey signaler's information to potential recipients. However, propagation properties of vertebrate calls have been rarely studied using natural calls from individuals; instead playback calls broadcast through loudspeakers have been used extensively, a procedure that may involve acoustical and physical features differing from natural sounds. Measurements of the transmission characteristics of natural advertisement calls, which are simple tonal sounds, of the Iberian midwife toad, Alytes cisternasii, were carried out, and the results were compared with previously published results broadcasting recorded calls of the same species. Measurements of sound pressure level (SPL) of calls from individual male A. cisternasii revealed that the call amplitude decreases at distances of 1-8 m from the source at rates averaging 1-5 dB above spherical transmission loss in an omni-directional pattern. A comparison between SPLs of natural calls in the current study and of playback calls from a previous study showed that patterns of propagation did not differ in average values, but variance was significantly higher for natural calls. Results suggest that using broadcast signals for transmission experiments may result in a simplification of the conditions in which actual animals communicate in nature.

ERK5 signalling in prostate cancer promotes an invasive phenotype.

BACKGROUND: Aberrant mitogen/extracellular signal-regulated kinase 5 (MEK5)-extracellular signal-regulated protein kinase 5 (ERK5)-mediated signalling has been implicated in a number of tumour types including prostate cancer (PCa). The molecular basis of ERK5-driven carcinogenesis and its clinical relevance remain to be fully characterised. METHODS: Modulation of ERK5 expression or function in human PCa PC3 and PC3-ERK5 (stably transfected with ERK5) cells was performed using siRNA-mediated knockdown or the MEK inhibitor PD18435 respectively. In vitro significance of ERK5 signalling was assessed by assays for proliferation, motility, invasion and invadopodia. Expression of matrix metalloproteinases/tissue inhibitors of metalloproteases was determined by Q-RT-PCR. Extracellular signal-regulated protein kinase 5 expression in primary and metastatic PCa was examined using immunohistochemistry. RESULTS: Reduction of ERK5 expression or signalling significantly inhibited the motility and invasive capability of PC3 cells. Extracellular signal-regulated protein kinase 5-mediated signalling significantly promoted formation of in vivo metastasis in an orthotopic PCa model (P<0.05). Invadopodia formation was also enhanced by forced ERK5 expression in PC3 cells. Furthermore, in metastatic PCa, nuclear ERK5 immunoreactivity was significantly upregulated when compared with benign prostatic hyperplasia and primary PCa (P=0.013 and P<0.0001, respectively). CONCLUSION: Our in vitro, in vivo and clinical data support an important role for the MEK5-ERK5 signalling pathway in invasive PCa, which represents a potential target for therapy in primary and metastatic PCa.

Cholelithiasis and associated complications in pediatric patients. / Colelitiasis y complicaciones asociadas en pacientes pediátricos.

OBJECTIVE: To review the clinical characteristics and complications associated with cholelithiasis in pediatric patients by identifying risk factors and assessing surgical management and results. METHODS: Retrospective study in patients under 18 years of age undergoing cholelithiasis surgery. The following data were analyzed: age, sex, body mass index (BMI), associated comorbidities, clinical presentation, symptom duration, surgical treatment, pathological report, postoperative complications, and hospital stay. RESULTS: 135 cholelithiasis patients underwent surgery from 2013 to 2018, with an increasing trend in the annual number of cholecystectomies. Most patients were adolescents (86.7%) and female (72.6%), and they had cholesterol gallstones (86.6%) and >85 BMI (33%). Mean symptom duration was 85 days (SD: 148). Symptomatic cholelithiasis was present in 131 cases (97%). CL associated complications were recorded in 64.4% of patients, with cholecystitis, pancreatitis, and choledocholithiasis being the most frequent ones. All patients underwent laparoscopic cholecystectomy; 4 (2.9%) required conversion to open surgery, and 6 (4.4%) had postoperative complications. Mean hospital stay and postoperative follow-up were 5.7 days (SD: 4) and 2.3 months (SD: 1.9), respectively. CONCLUSIONS: Non-hemolytic cholelithiasis in the pediatric population is more frequent in female overweight and obese adolescents. Symptomatic cholelithiasis is associated with higher risk of complications such as cholecystitis, pancreatitis, or choledocholithiasis, which supports early surgical management.

OBJETIVO: Revisión de las características clínicas y complicaciones asociadas de los pacientes pediátricos con colelitiasis, mediante la identificación de factores de riesgo, la evaluación del manejo quirúrgico y sus resultados. METODOS: Estudio retrospectivo en pacientes menores de 18 años, intervenidos quirúrgicamente por colelitiasis. Se analizaron datos como edad, género, índice de masa corporal (IMC), comorbilidades asociadas, presentación clínica, tiempo de los síntomas, tratamiento quirúrgico, reporte de patología, complicaciones posoperatorias y estancia hospitalaria. RESULTADOS: Se intervinieron quirúrgicamente 135 pacientes con colelitiasis entre los años 2013 a 2018, con una tendencia ascendente en el número de colecistectomías realizadas anualmente. La mayoría fueron pacientes adolescentes (86,7%), con cálculos de colesterol (86,6%), de género femenino (72,6%) y con IMC > 85 (33%). El tiempo de los síntomas en promedio fue de 85 días (DE 148). Colelitiasis sintomática se presentó en 131 casos (97%). Complicaciones asociadas a CL se registraron en 64,4% pacientes, siendo las más frecuentes colecistitis, pancreatitis y coledocolitiasis. En todos los pacientes se realizó colecistectomía laparoscópica, 4 (2,9%) requirieron conversión a cirugía abierta y 6 (4,4%) presentaron complicaciones postoperatorias. La estancia hospitalaria y el seguimiento posoperatorio fueron en promedio 5,7 días (DE 4) y 2,3 meses (DE 1,9), respectivamentea. CONCLUSIONES: La colelitiasis no hemolítica en la población pediátrica, es más frecuente en pacientes adolescentes de género femenino con sobrepeso u obesidad. La colelitiasis sintomática está asociada con mayor riesgo de complicaciones como colecistitis, pancreatitis o coledocolitiasis, en consecuencia, se justifica una intervención quirúrgica temprana.

Ceftriaxone pharmacokinetics by a sensitive and simple LC-MS/MS method: Development and application.

Ceftriaxone is a third-generation cephalosporin, worldwide use as a first-line treatment for several infections, including life-threatening infections as meningitis or endocarditis. Nowadays, ceftriaxone use is changing, embracing high-dose schemes, new populations treated and requirement of dose individualization and optimization. These reasons warranted the development of new sensitive assays. This study aimed to develop and validate a fast and handy bioanalytical method for the quantification of ceftriaxone in human plasma covering a broad range of concentrations. The analysis was performed using high-performance liquid chromatography coupled to tandem mass spectrometry. Sample preparation was based on protein precipitation with acetonitrile followed by centrifugation. Chromatography separation was performed on Phenomenex Luna C18 column (5 µm, 150 × 2.0 mm) and a mobile phase consisting of 70 % of mobile phase A (10 mM of ammonium acetate and 1% formic acid in purified water) and 30 % mobile phase B (0.1 % formic acid in acetonitrile) at a flow rate of 500 µl/min on an isocratic program. Both the analyte and the internal standard were quantified using the positive electrospray ionization (ESI) mode within a single runtime of 5.00 min. The method was validated following the U.S. Food and Drug Administration guidelines over the concentration range of 3-1000 µg/mL. The within-run and between-run precision and accuracy were <15 %, and therefore met the standard regulatory acceptance criterion. In conclusion, a sensitive and robust LC-MS/MS method was developed for a fast quantitation of ceftriaxone concentrations in plasma samples with multiples applications in research and clinical therapeutic drug monitoring.

[Pulmonary infiltrates and fever in a HIV infected patient after Pneumocystis jirovecii pneumonia]. / Infiltrado pulmonar y fiebre tras la resolución de neumonía por Pneumocystis jirovecii en un paciente con infección por el VIH.

In HIV-infected patients, cytomegalovirus (CMV) disease diagnosis is usually difficult and disease results from reactivation of latent infection or reinfection in the context of severe immunosupression. Although the introduction of highly active antiretroviral therapy (HAART) has resulted in a important decline of CMV disease, it has considerable morbidity and mortality rate. We present a case of a patient who presented fever, pulmonary infiltrates and abdominal pain after P.jirovecii pneumonia, with isolated of CMV (positive shell-vial) from LBA and gastric biopsy. We propose a possible diagnosis of digestive and pulmonary CMV disease and we initiated treatment for this with clinical response. It results surprising the rapid progression to SIDA of the patient and we can suggest that a co-infection HIV-CMV could be the cause for the rapid immunological damage.