Treatment with the soluble guanylate cyclase activator BAY 60-2770 normalizes bladder function in an in vivo rat model of chronic prostatitis.

BACKGROUND AND PURPOSE: Chronic pelvic pain syndrome (CPPS) is a common and bothersome condition for which no pharmacological treatment options with acceptable efficacy exist. The aim of this study was to investigate the effects of the soluble guanylate cyclase (sGC) activator BAY 60-2770 and the COX-2 inhibitor celecoxib on bladder function in a rat model of CPPS. EXPERIMENTAL APPROACH: Forty-eight male Sprague-Dawley rats were intraprostatically injected with either saline, serving as control, or zymosan, to induce prostatitis. On days 8-20, the rats were treated with either dimethylsulphoxide (DMSO; vehicle), celecoxib, BAY 60-2770 or a combination of celecoxib and BAY 60-2770. Thereafter, micturition parameters were assessed in a metabolic cage and urine samples were collected. The following day, cystometry was performed. Subsequently, the urinary bladder and prostate were removed and examined histopathologically. KEY RESULTS: Induction of prostatitis led to a significant increase of micturition frequency and corresponding decrease of volume per micturition. These alterations were ameliorated by celecoxib, and completely normalized by BAY 60-2770. Induction of prostatitis led to a significantly increased number of non-voiding contractions, decreased bladder compliance and increased voiding time. These parameters were normalized by treatment with BAY 60-2770, either alone or in combination with celecoxib. The immunohistochemical analysis showed signs of prostate inflammation, but not bladder inflammation. CONCLUSION AND IMPLICATIONS: Induction of prostatitis led to significant impairment in bladder function. These alterations could be prevented by BAY 60-2770, alone or in combination with celecoxib. This is the first study to show that sGC activators could be a promising option for the treatment of CPPS.

3D-printed electrochemical pestle and mortar for identification of falsified pharmaceutical tablets.

Falsified medicines and healthcare supplements provide a major risk to public health and thus early identification is critical. Although a host of analytical approaches have been used to date, they are limited, as they require extensive sample preparation, are semi-quantitative and/or are inaccessible to low- and middle-income countries. Therefore, for the first time, we report a simple total analysis system which can rapidly and accurately detect falsified medicines and healthcare supplements. We fabricated a poly-lactic acid (PLA) pestle and mortar and using a commercial 3D printer, then made carbon black/PLA (CB/PLA) electrodes in the base of the mortar using a 3D printing pen to make an electrochemical cell. The pestle and mortar were able to crush and grind the tablets into a fine powder to the same consistency as a standard laboratory pestle and mortar. Using melatonin tablets to characterise the device, the 3D-printed pestle and mortar was able to detect the concentration of melatonin in the presence of insoluble excipients. The calibration plot showed a linear response from 37.5 to 300 µg/mL, where the limit of detection was 7 µg/mL. Electrochemical treatment was able to regenerate the CB/PLA working electrode allowing for repeated use of the device. In a blinded study, the device was able to accurately determine falsified melatonin tablets with recovery percentages between 101% and 105%. This was comparable to HPLC measurements. Overall, these findings highlight that our 3D-printed electrochemical pestle and mortar is an accessible and effective total analysis system that can have the ability to identify falsified medicines and healthcare supplements in remote locations.

Role of inorganic phosphate concentrations in in vitro activity of fosfomycin.

OBJECTIVES: The objective of this study was to evaluate the in vitro activity of fosfomycin under different physiological concentrations of inorganic phosphate (Pi). METHODS: The wild-type BW25113 strain, four isogenic mutants (ΔglpT, ΔuhpT, ΔglpT-uhpT, and ΔphoB) and six clinical isolates of Escherichia coli with different fosfomycin susceptibilities were used. EUCAST breakpoints were used. Susceptibility was evaluated by agar dilution using standard Mueller-Hinton agar (Pi concentration of 1 mM similar to human plasma concentration) and supplemented with Pi (13 and 42 mM, minimum and maximum urinary Pi concentrations) and/or glucose-6-phosphate (25 mg/L). Fosfomycin transporter promoter activity was assayed using PglpT::gfpmut2 or PuhpT::gfpmut2 promoter fusions in standard Mueller-Hinton Broth (MHB), supplemented with Pi (13 or 42 mM) ± glucose-6-phosphate. Fosfomycin activity was quantified, estimating fosfomycin EC50 under different Pi concentrations (1, 13 and 42 mM + glucose-6-phosphate) and in time-kill assays using fosfomycin concentrations of 307 (maximum plasma concentration (Cmax)), 1053 and 4415 mg/L (urine Cmax range), using MHB with 28 mM Pi (mean urine Pi concentration) + 25 mg/L glucose-6-phosphate. RESULTS: All the strains showed decreased susceptibility to fosfomycin linked to increased Pi concentrations: 1-4 log2 dilution differences from 1 to 13 mM, and 1-8 log2 dilution differences at 42 mM Pi. Changes in phosphate concentration did not affect the expression of fosfomycin transporters. By increasing Pi concentrations higher fosfomycin EC50 bacterial viability was observed, except against ΔglpT-uhpT. The increase in Pi reduced the bactericidal effect of fosfomycin. DISCUSSION: Pi variations in physiological fluids may reduce fosfomycin activity against E. coli. Elevated Pi concentrations in urine may explain oral fosfomycin failure in non-wild-type but fosfomycin-susceptible E. coli strains.

Amikacin Combined with Fosfomycin for Treatment of Neonatal Sepsis in the Setting of Highly Prevalent Antimicrobial Resistance.

Antimicrobial resistance (particularly through extended-spectrum ß-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16-arm dose-ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented the emergence of resistance, compared to monotherapy with either antibiotic. Modeling of the experimental quantitative outputs and data from checkerboard assays indicated synergy. We further assessed the combination regimen at clinically relevant doses in the HFIM with nine Enterobacterales strains with high fosfomycin and amikacin MICs and demonstrated successful kill to sterilization for 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales strains, i.e., MICF × MICA < 256 (where MICF and MICA are the fosfomycin and amikacin MICs, respectively). Monte Carlo simulations predict that a standard fosfomycin-amikacin neonatal regimen would achieve >99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empirical treatment of neonatal sepsis and is suitable for further clinical assessment in a randomized controlled trial.

[Effectiveness of a nursing program of self-care and Mindfulness, in the approach to the common mental disorder in primary care]. / Efectividad de un programa de enfermería en autocuidados y mindfulness, para el abordaje del trastorno mental común, en atención primaria.

OBJECTIVE: To evaluate the effectiveness of the implementation of a mindfulness and self-care program to treat common mental health disorders in primary care. DESIGN: Quasi-experimental non-controlled, non-randomised study, with repeated measurements. SETTING: Seven health centres, in area v of the Principality of Asturias, between 2014 and 2018. PARTICIPANTS: Subjects between 18-65 years with mixed anxiety, depressive, and adaptive disorders, with no serious mental disease. Non-probabilistic convenience sampling was used. INTERVENTION: A group intervention was made, consisting of 9 weekly sessions of 90min, daily practice, and reinforcement sessions at one month, 3, 6, and 12 months. MAIN MEASUREMENTS: Pre-post measurements using validated and self-administered questionnaires; medium-term (3-6 months) and long-term (>12 months) of the variables: trait anxiety/state anxiety (Status-Trait Anxiety Questionnaire -STAI-); anxiety/depression (Goldberg Anxiety and Depression Scale -GHQ28-), mindfulness (Five Facet Mindfulness Questionnaire -FFMQ-), reduction of pharmacological treatment (open questions). RESULTS: The study included a final sample of 314 subjects. A statistically significant difference in means was found in the 3 follow-up periods as regards the baseline values for all the scales/subscales. There was a reduction of 54.3% in the taking of anxiolytic/antidepressant baseline medication in the long-term follow-up (P<.001). CONCLUSIONS: A moderate reduction of the symptoms, together with the reduction of the medication, indicate that the intervention of mindfulness supervised by the primary care nurse can be a treatment option for the mental disorders common in this level of care.

Crecimiento de cuyes (Cavia porcellus) con alimento para conejos y suplementación de vitamina C / Growth of Guinea pigs (Cavia porcellus) with feed for rabbits and supplementation of vitamin C

RESUMEN Objetivo. Evaluar el consumo, la digestibilidad y el crecimiento de cuyes alimentados con dos alimentos (A y K) formulados para esta especie y un alimento para conejos en crecimiento con suplementación de vitamina C (AC+VC). Materiales y métodos. Dieciocho cuyes (Cavia porcellus) de 248±38 g de peso vivo inicial se distribuyeron en un diseño completamente al azar con un arreglo factorial 3 × 2 (tipo de alimento y género). La ingesta de alimento, fibra detergente neutro, el aumento de peso, la conversión alimenticia, y los cambios en las variables morfométricas se midieron diariamente, mientras que la digestibilidad de la MS y FDN se determinaron al final del periodo. Resultados. No hubo diferencias en el consumo de MS (p=0.88); sin embargo, la digestibilidad de la MS fue mayor (p<0.01) en los alimentos para cuyes e inferior en AC+VC. El consumo y digestibilidad de FDN fueron mayores en AC+VC (p<0.01). La ganancia diaria fue similar entre los tratamientos (p>0.05). No hubo diferencias (p>0.01) en las variables morfométricas entre los alimentos, pero los machos fueron más grandes que las hembras (p<0.01). Conclusiones. Los cuyes pueden ser alimentados con alimento de conejo suplementado con vitamina C.

ABSTRACT Objective. An experiment was conducted to evaluate the feed intake, digestibility and growth of pigs fed with two feeds (A and K) specially formulated for this species and a commercial feed for growing rabbits with supplementation of vitamin C (RF+VC). Materials and methods. Eighteen Guinea pigs of 248±38 g initial body weight were distributed in a completely randomized design with factorial arrangement 3×2 (dietary treatments and sex). Feed and neutral detergent fiber intake, weight gain, feed/gain, and morphometric variables were measured individually for 30 days. Dry matter and neutral detergent fiber digestibility were measured during the last seven days of the experiment. Results. There were no differences on feed intake (p=0.88); however, the dry matter digestibility was higher (p<0.01) in feeds formulated for Guinea pigs (A and K) and lower in the rabbit feed plus vitamin C. The intake and digestibility of NDF were higher in the RF+VC and lower in feeds for Guinea pigs (p< 0.01). The average daily gain was similar among the treatments (p>0.05). There were no differences (p>0.01) in the morphometric variables among dietary treatments, but there were sex differences as the males were bigger than the females (p<0.01). Conclusions. The results indicate that Guinea pigs can be fed with rabbit feed supplemented with vitamin C.

Titanium - castor oil based polyurethane composite foams for bone tissue engineering.

Polyurethanes (PU) foams with titanium particles (Ti) were prepared with castor oil (CO) and isophorone diisocyanate (IPDI) as polymeric matrix, and 1, 3 and 5 wt.% of Ti. Composites were physicochemically and mechanically characterized and their biocompatibility assessed using human dental pulp stem cells (HDPSC). PU synthesis was confirmed by FTIR, but the presence of Ti was detected by RAMAN, X-ray diffraction (peak at 2θ = 40.2°) and by EDX-mapping. Materials showed three decomposition temperatures between 300 °C and 500 °C and their decomposition were not catalyzed by Ti particles. Compressive modulus (164-846 kPa), compressive strength (12.9-116.7 kPa) and density (128-240 kg/m3) tend to increase with Ti concentration but porosity was reduced (87% to 80%). Composites' foams were fully degraded in acid and oxidative media while remained stable in distilled water. HDPSC viability on all composites was higher than 80% up to 14 days while proliferation dropped up to 60% at 21 days. Overall, these results suggest that these foams can be used as scaffolds for bone tissue regeneration.

Building an integrated infrastructure for exploring biodiversity: field collections and archives of mammals and parasites.

Museum specimens play an increasingly important role in predicting the outcomes and revealing the consequences of anthropogenically driven disruption of the biosphere. As ecological communities respond to ongoing environmental change, host-parasite interactions are also altered. This shifting landscape of host-parasite associations creates opportunities for colonization of different hosts and emergence of new pathogens, with implications for wildlife conservation and management, public health, and other societal concerns. Integrated archives that document and preserve mammal specimens along with their communities of associated parasites and ancillary data provide a powerful resource for investigating, anticipating, and mitigating the epidemiological, ecological, and evolutionary impacts of environmental perturbation. Mammalogists who collect and archive mammal specimens have a unique opportunity to expand the scope and impact of their field work by collecting the parasites that are associated with their study organisms. We encourage mammalogists to embrace an integrated and holistic sampling paradigm and advocate for this to become standard practice for museum-based collecting. To this end, we provide a detailed, field-tested protocol to give mammalogists the tools to collect and preserve host and parasite materials that are of high quality and suitable for a range of potential downstream analyses (e.g., genetic, morphological). Finally, we also encourage increased global cooperation across taxonomic disciplines to build an integrated series of baselines and snapshots of the changing biosphere. Los especímenes de museo desempeñan un papel cada vez más importante tanto en la descripción de los resultados de la alteración antropogénica de la biosfera como en la predicción de sus consecuencias. Dado que las comunidades ecológicas responden al cambio ambiental, también se alteran las interacciones hospedador-parásito. Este panorama cambiante de asociaciones hospedador-parásito crea oportunidades para la colonización de diferentes hospedadores y para la aparición de nuevos patógenos, con implicancias en la conservación y manejo de la vida silvestre, la salud pública y otras preocupaciones de importancia para la sociedad. Archivos integrados que documentan y preservan especímenes de mamíferos junto con sus comunidades de parásitos y datos asociados, proporcionan un fuerte recurso para investigar, anticipar y mitigar los impactos epidemiológicos, ecológicos y evolutivos de las perturbaciones ambientales. Los mastozoólogos que recolectan y archivan muestras de mamíferos, tienen una oportunidad única de ampliar el alcance e impacto de su trabajo de campo mediante la recolección de los parásitos que están asociados con los organismos que estudian. Alentamos a los mastozoólogos a adoptar un paradigma de muestreo integrado y holístico y abogamos para que esto se convierta en una práctica estándarizada de la obtención de muestras para museos. Con este objetivo, proporcionamos un protocolo detallado y probado en el campo para brindar a los mastozoólogos las herramientas para recolectar y preservar materiales de parásitos y hospedadores de alta calidad y adecuados para una gran variedad de análisis subsecuentes (e.g., genéticos, morfológicos, etc.). Finalmente, también abogamos por una mayor cooperación global entre las diversas disciplinas taxonómicas para construir una serie integrada de líneas de base y registros actuales de nuestra cambiante biosfera.

Freeze-dried bioadhesive vaginal bigels for controlled release of Tenofovir.

Nowadays, million women live with the human immunodeficiency virus (HIV) worldwide and many of them are dying per year, particularly in Sub-Saharan Africa. The development of systems that can be accessed by this population group to prevent the sexual transmission of the virus is therefore necessary. The aim of this work was the formulation of freeze-dried bioadhesive vaginal bigels releasing Tenofovir in a controlled manner. Systems containing three different proportions of guar gum hydrogel and sesame oil were prepared, adding Span®60 or Span®60 and Tween®60 as surfactants. Drug and excipients were evaluated by cytotoxicity assays, showing no toxicity at the concentrations tested neither for the drug nor any of the excipients. Fresh formulations were characterised through texture analyses and confocal laser microcopy. The system with the lowest guar gum hydrogel/sesame oil proportion and containing Span®60 and Tween®60 (batch ST1) had the highest consistency and adhesion capacity according to texture analyses. Furthermore, a genuine bigel microstructure was observed. After freeze-drying, swelling, bioadhesion and drug release tests were performed on the resulting systems. ST1 showed the longest bioadhesion time and the most controlled release, as well as a low swelling grade, becoming an interesting option for preventing HIV sexual transmission in women.

Cirugía de second look más HIPEC en pacientes sin evidencia de recidiva con alto riesgo de desarrollar carcinomatosis tras resección de cáncer colorrectal / Systematic Second-look Surgery Plus HIPEC in Patients Without Evidence of Recurrence, at High Risk of Carcinomatosis After Colorectal Cancer Resection

Introducción: Analizar el impacto de la cirugía de second look (CSL) combinada con quimioterapia intraperitoneal hipertérmica (HIPEC) realizada un año después de la cirugía del tumor primario en pacientes asintomáticos con alto riesgo de desarrollar carcinomatosis peritoneal (CP) tras resección de cáncer colorrectal. Métodos: Entre febrero 2012 y febrero 2016, 33 pacientes con alto riesgo de recidiva peritoneal, sin signos de recurrencia en pruebas de imagen fueron prospectivamente incluidos en el estudio y sometidos a CSL con el objetivo de tratar posibles recidivas peritoneales precozmente. Los pacientes fueron seleccionados por 5 criterios: pT4 (n = 15), citología peritoneal positiva por cáncer (n = 2), tumor perforado (n = 4), enfermedad peritoneal sincrónica resecada (n = 10), metástasis ováricas sincrónicas resecadas (n = 2). Resultados: Se detectó carcinomatosis peritoneal (CP) en 10 de los 33 pacientes (30,3%) (CP+), en los cuales se realizó citorreducción completa más HIPEC. En el subgrupo de los pacientes pT4 (n = 15) se detectó CP solo en 2 casos (13,3%). El resto de los pacientes (CP-) fueron sometidos a HIPEC profiláctica. La mediana de seguimiento después de CSL ha sido de 14,5 meses. La tasa de morbilidad postoperatoria grave (Clavien-Dindo III-V) fue del 15,2% (5/33) y la mortalidad del 3,0% (1 paciente al 55.° día postoperatorio). La supervivencia global a 3 años fue del 93% y la supervivencia libre de enfermedad del 33%. Tras CSL + HIPEC, 4/33 pacientes (12,1%) recidivaron en el peritoneo, 2 CP + (20%) y 2 CP - (8,7%) (p = 0,04). Conclusiones: La realización de CSL + HIPEC en nuestra serie de pacientes con alto riesgo de desarrollar CP permite su detección temprana y su tratamiento en el 30,3% de los casos, con una tasa muy baja de recurrencia peritoneal posterior. Es importante continuar evaluando los resultados para aumentar la precisión de los criterios de inclusión, especialmente del criterio pT4, que en esta serie tiene un bajo poder predictivo para la aparición de CP (AU)

Introduction: To analyze the impact of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) performed 1 year after resection of the primary tumor, in asymptomatic patients at high risk of developing peritoneal carcinomatosis (PC). Methods: Between 2012-2016, 33 patients without any sign of peritoneal recurrence on imaging studies were prospectively included in the study and underwent second-look surgery aimed at treating limited PC earlier and were prospectively recorded. They were selected based on 5 primary tumor-associated criteria: resected minimal synchronous macroscopic PC (n = 10), synchronous ovarian metastases (n = 2), positive peritoneal cytology (n = 2), pT4 primary tumors (n = 15) and perforation (n = 4). Results: PC was found and treated by cytoreduction plus HIPEC in 10 of the 33 (30.3%) patients, although it was detected in only 2/15 patients of the pT4 subgroup (13.3%). The patients without PC underwent complete abdominal exploration plus HIPEC. Median follow-up was 14.5 months. One patient died postoperatively at day 55. Severe morbidity rate (Clavien-Dindo III-V) was low (15.2%). The 3-year overall survival rate was 93% and the 3-year disease-free survival rate was 33%. Peritoneal recurrences occurred in 4 patients (12.1%), 2 of whom had macroscopic PC discovered at the second-look (20%), while the other 2 patients had no macroscopic PC (8.7%) (P = .04). Conclusions: The second look + HIPEC strategy in our series of patients at high risk of developing PC, allows its early detection and its treatment in 30.3% of cases, with a very low rate of peritoneal recurrence. It is important to continue evaluating the results to increase the accuracy of the inclusion criteria, especially the pT4 criterion that in this series has a low predictive power for the occurrence of PC (AU)

Systematic Second-look Surgery Plus HIPEC in Patients Without Evidence of Recurrence, at High Risk of Carcinomatosis After Colorectal Cancer Resection. / Cirugía de second look más HIPEC en pacientes sin evidencia de recidiva con alto riesgo de desarrollar carcinomatosis tras resección de cáncer colorrectal.

INTRODUCTION: To analyze the impact of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) performed 1 year after resection of the primary tumor, in asymptomatic patients at high risk of developing peritoneal carcinomatosis (PC). METHODS: Between 2012-2016, 33 patients without any sign of peritoneal recurrence on imaging studies were prospectively included in the study and underwent second-look surgery aimed at treating limited PC earlier and were prospectively recorded. They were selected based on 5 primary tumor-associated criteria: resected minimal synchronous macroscopic PC (n = 10), synchronous ovarian metastases (n = 2), positive peritoneal cytology (n = 2), pT4 primary tumors (n = 15) and perforation (n = 4). RESULTS: PC was found and treated by cytoreduction plus HIPEC in 10 of the 33 (30.3%) patients, although it was detected in only 2/15 patients of the pT4 subgroup (13.3%). The patients without PC underwent complete abdominal exploration plus HIPEC. Median follow-up was 14.5 months. One patient died postoperatively at day 55. Severe morbidity rate (Clavien-Dindo III-V) was low (15.2%). The 3-year overall survival rate was 93% and the 3-year disease-free survival rate was 33%. Peritoneal recurrences occurred in 4 patients (12.1%), 2 of whom had macroscopic PC discovered at the second-look (20%), while the other 2 patients had no macroscopic PC (8.7%) (P = .04). CONCLUSIONS: The second look + HIPEC strategy in our series of patients at high risk of developing PC, allows its early detection and its treatment in 30.3% of cases, with a very low rate of peritoneal recurrence. It is important to continue evaluating the results to increase the accuracy of the inclusion criteria, especially the pT4 criterion that in this series has a low predictive power for the occurrence of PC.

Prevalence of musculoskeletal disorders and rheumatic disease in the Warao, Kari'ña, and Chaima indigenous populations of Monagas State, Venezuela.

This study aimed to estimate the prevalence of musculoskeletal disorders and rheumatic diseases in the Warao, Kari'ña, and Chaima indigenous populations of Monagas State, Venezuela. A cross-sectional, analytical, community-based study was conducted in 1537 indigenous subjects ≥18 years old (38.6 % male, mean age 41.4 ± 17.5 years). The cross-culturally validated Community Oriented Program for the Control of Rheumatic Diseases (COPCORD) diagnostic questionnaire was applied. Subjects with a positive COPCORD diagnosis (either historic or current pain) were evaluated by primary care physicians and rheumatologists. A descriptive analysis was performed and comparisons made using analysis of variance and the chi-square test. Pain in the last 7 days was reported by 32.9 %, with pain intensity, according to a Likert-type scale [no pain, 195 (38.5 %); minimal pain, 231 (45.6 %); strong pain, 68 (13.4 %); intense pain, 5 (0.9 %)], 38.0 % reported historical pain, and 641 (41.7 %) had either historic or current pain. Of the COPCORD-positive subjects, pain most frequently occurred in the knee, back, and hands. Musculoskeletal and rheumatic diseases included osteoarthritis (14.1 %), back pain (12.4 %), rheumatic regional pain syndromes (RRPS) (9.7 %), undifferentiated arthritis (1.5 %), rheumatoid arthritis (1.1 %), and fibromyalgia (0.5 %). Chaima (18.3 %) and Kari'ña (15.6 %) subjects had a high prevalence of osteoarthritis, and Warao subjects had a high prevalence of low back pain (13.8 %). The prevalence of RRPS was high in all three ethnic groups. The Chaima group had the highest prevalence of rheumatic diseases, with 2.0 % having rheumatoid arthritis. This study provides useful information for health care policy-making in indigenous communities.

Pharmacodynamics of Voriconazole in Children: Further Steps along the Path to True Individualized Therapy.

Voriconazole is the agent of choice for the treatment of invasive aspergillosis in children at least 2 years of age. The galactomannan index is a routinely used diagnostic marker for invasive aspergillosis and can be useful for following the clinical response to antifungal treatment. The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) mathematical model that links the pharmacokinetics of voriconazole with the galactomannan readout in children. Twelve children receiving voriconazole for treatment of proven, probable, and possible invasive fungal infections were studied. A previously published population PK model was used as the Bayesian prior. The PK-PD model was used to estimate the average area under the concentration-time curve (AUC) in each patient and the resultant galactomannan-time profile. The relationship between the ratio of the AUC to the concentration of voriconazole that induced half maximal killing (AUC/EC50) and the terminal galactomannan level was determined. The voriconazole concentration-time and galactomannan-time profiles were both highly variable. Despite this variability, the fit of the PK-PD model was good, enabling both the pharmacokinetics and pharmacodynamics to be described in individual children. (AUC/EC50)/15.4 predicted terminal galactomannan (P= 0.003), and a ratio of >6 suggested a lower terminal galactomannan level (P= 0.07). The construction of linked PK-PD models is the first step in developing control software that enables not only individualized voriconazole dosages but also individualized concentration targets to achieve suppression of galactomannan levels in a timely and optimally precise manner. Controlling galactomannan levels is a first critical step to maximizing clinical response and survival.

Effect of lysine addition on growth of black iguana (Ctenosaura pectinata).

The effects of the addition of lysine to commercial feed given to captive black iguana (Ctenosaura pectinata) were evaluated in terms of growth and feed digestibility. Twenty-eight-day-old black iguana with an initial weight of 5.5 ± 0.3 g were housed individually in cages measuring 45 × 45 × 45 cm. The experiment lasted 150 days. The ambient temperature ranged from 28 to 35°C with a relative humidity of 60 to 95%. Treatments consisted of the addition of different percentages of lysine to the feed (0.0, 0.1, 0.2, and 0.3%, dry matter [DM] base). There was a linear response (P < 0.01) in daily gain (68, 112, 118, and 151 mg/d) and daily intake (251, 289, 297, and 337 mg/d) for levels from 0 to 0.3%, respectively, as well in the growth in head size, snout-vent length, and total length. The digestibility of DM, neutral detergent fiber, and acid detergent fiber were reduced linearly (P < 0.01) as lysine levels increased. Intake and digestibility were negatively correlated (r = -0.74; P < 0.001). It is concluded that the addition of lysine to the black iguana diet in the first months of life is important to stimulate growth and intake.

Efficacies of colistin and tigecycline in mice with experimental pneumonia due to NDM-1-producing strains of Klebsiella pneumoniae and Escherichia coli.

New Delhi metallo-ß-lactamase-1 (NDM-1)-producing Enterobacteriaceae have emerged as a global threat. The aim of this study was to assess the efficacies of colistin and tigecycline in an experimental model of pneumonia caused by NDM-1-producing Escherichia coli and Klebsiella pneumoniae. The susceptibilities of K. pneumoniae NDM, E. coli NDM and K. pneumoniae ATCC 29665 were determined using the broth microdilution technique. The pharmacokinetics of colistin and tigecycline in an experimental model of pneumonia were performed using immunocompetent C57BL/6 mice. Mice were treated with colistin (60 mg/kg/day) or tigecycline (10 mg/kg/day). Mortality, bacteraemia and lung bacterial concentrations were recorded. The strains were susceptible to colistin and tigecycline. The ratio of area under the concentration-time curve/minimum inhibitory concentration (AUC/MIC) for colistin was 158.5 (all three strains) and that for tigecycline was 18.5 (K. pneumoniae NDM) and 37 (K. pneumoniae ATCC 29665 and E. coli NDM). In vivo, colistin decreased bacterial lung concentrations of K. pneumoniae NDM and K. pneumoniae ATCC 29665 by 1.16 log colony-forming units (CFU)/g and 2.23 logCFU/g, respectively, compared with controls (not significant). Tigecycline reduced K. pneumoniae NDM and K. pneumoniae ATCC 29665 load by 2.67 logCFU/g and 4.62 logCFU/g (P<0.05). Colistin and tigecycline decreased lung concentrations of E. coli NDM by 2.27 logCFU/g and 4.15 logCFU/g (P<0.05), respectively, compared with controls, and was more active than colistin (P<0.05). In conclusion, these results suggest that colistin is inappropriate for treating pneumonia due to NDM-1-producing K. pneumoniae and its efficacy was suboptimal against NDM-1-producing E. coli. A high tigecycline dose was efficacious for treating experimental pneumonia due to NDM-1-producing E. coli and K. pneumoniae.

Efficacy of beta-lactams against experimental pneumococcal endocarditis caused by strains with different susceptibilities to penicillin.

OBJECTIVES: To compare the in vitro and in vivo activity of penicillin, cefotaxime and ceftriaxone, using three strains of Streptococcus pneumoniae with different susceptibilities to penicillin (MICs of 0.015, 0.25 and 2 mg/L, respectively). METHODS: Time-kill curves and an experimental model of endocarditis in rabbits. RESULTS: Penicillin was efficacious in clearing bacteria from vegetations and blood irrespective of whether infections were caused by penicillin-susceptible or penicillin-resistant strains (P < 0.01 with respect to control groups). The same efficacy was shown with cefotaxime and ceftriaxone. Comparing the results of the in vivo model with those obtained in time-kill curves, penicillin showed the best results. CONCLUSIONS: These results confirm that penicillin is efficacious in the treatment of pneumococcal infections, including those produced by strains with MICs < or = 2 mg/L (with the exception of pneumococcal meningitis). These results also suggest that the breakpoints to define susceptibility and resistance of S. pneumoniae to penicillin must be reviewed, as has been done with amoxicillin and third-generation cephalosporins.