Experimental study of cerebrospinal fluid tumor necrosis factor-alpha release in penicillin- and cephalosporin-resistant pneumococcal meningitis treated with different antibiotic schedules

Background/Purpose: To measure the inflammatory response in terms of tumor necrosis factor-alpha (TNF-α) levels in cerebrospinal fluid (CSF), using bacteriolytic versus nonbacteriolytic antibiotic therapy and adjunctive treatment with dexamethasone in an experimental rabbit model of pneumococcal meningitis. Methods: In a rabbit model of pneumococcal meningitis, we tested CSF TNF-α levels in several samples from rabbits infected with the HUB 2349 strain and treated with ceftriaxone 100 mg/kg/d, ceftriaxone plus vancomycin 30 mg/kg/d, or daptomycin at 15 mg/kg or 25 mg/kg. Daptomycin schedules were compared with the same doses in combination with dexamethasone at 0.125 mg/kg every 12 hours over a 26-hour period. Results: The ceftriaxone group had the highest levels of TNF-α. TNF-α levels were significantly higher after ceftriaxone administration than in both daptomycin groups. The high-dose daptomycin group presented the lowest inflammatory levels in CSF samples. Adjunctive treatment with dexamethasone in this group modulated the inflammatory response, bringing down CSF TNF-α levels. Conclusion: CSF TNF-α levels were significantly lower in rabbits treated with daptomycin than in rabbits treated with ceftriaxone. Daptomycin avoided the inflammatory peak after administration observed in ceftriaxone-treated rabbits. The use of daptomycin plus dexamethasone achieved a significantly larger reduction in CSF TNF-α levels

Measurement uncertainty of β-lactam antibiotics results: estimation and clinical impact on therapeutic drug monitoring

Background: Despite that measurement uncertainty data should facilitate an appropriate interpretation of measured values, there are actually few reported by clinical laboratories. We aimed to estimate the measurement uncertainty of some β-lactam antibiotics (β-LA), and to evaluate the impact of reporting the measurement uncertainty on clinicians' decisions while guiding antibiotic therapy. Methods: Measurement uncertainty of β-LA (aztreonam [ATM], cefepime [FEP], ceftazidime [CAZ], and piperacillin [PIP]) values, obtained by an UHPLC-MS/MS based-method, was estimated using the top-down approach called the single laboratory validation approach (EUROLAB guidelines). Main uncertainty sources considered were related to calibrators' assigned values, the intermediate precision, and the bias. As part of an institutional program, patients with osteoarticular infections are treated with β-LA in continuous infusion and monitored to assure values at least 4 times over the minimal inhibitory concentration (4×MIC). We retrospectively evaluated the impact of two scenarios of laboratory reports on clinicians' expected decisions while monitoring the treatment: reports containing only the β-LA values, or including the β-LA coverage intervals (β-LA values and their expanded measurement uncertainties). Results The relative expanded uncertainties for ATM, FEP, CAZ and PIP were lower than 26.7%, 26.4%, 28.8%, and 25.5%, respectively. Reporting the measurement uncertainty, we identified that clinicians may modify their decision especially in cases where 4×MIC values were within the β-LA coverage intervals. Conclusions: This study provides a simple method to estimate the measurement uncertainty of β-LA values that can be easily applied in clinical laboratories. Further studies should confirm the potential impact of reporting measurement uncertainty on clinicians' decision-making while guiding antibiotic therapy

Estudios de eficacia antimicrobiana frente a la infección de cuerpo extraño por Staphylococcus aureus: aplicación de un modelo in vivo y un modelo dinámico in vitro

[spa] Las infecciones de prótesis articulares causadas por S. aureus son difíciles de curar, y con los tratamientos actuales recomendados siguen habiendo fallos tanto microbiológicos como clínicos. Asimismo, no se han estudiado de forma exhaustiva las posibles alternativas terapéuticas en caso de no poder administrar por alergia o intolerancia a alguno de los antibióticos considerados de elección. Actualmente se están investigando nuevas terapias terapéuticas ya sea con antibióticos de reciente aparición, como es daptomicina, o a partir de terapias anti-biofilm. Daptomicina es un lipopéptido cíclico que ha demostrado tener actividad bactericida frente a bacterias en fase planctónica y en fase estacionaria, y se ha visto que tiene una alta eficacia en combinación con otros antimicrobianos frente a la infección de cuerpo extraño por S. aureus resistente a meticilina (SARM). Por otro lado, la escasa información existente sobre la terapia anti-biofilm con macrólidos frente a S. aureus es contradictoria; si bien algunos estudios defienden que posee una actividad contra el biofilm, otros observaron poca o ninguna actividad. Como se ha comentado, las consideradas como alternativas terapéuticas en la infección por S. aureus (ej., cotrimoxazol y ácido fusídico) no se han estudiado en profundidad y la información que se tiene de estos antibióticos es de hace algunas décadas. El objetivo de esta tesis fue por un lado estandarizar dos modelos, uno in vitro en el CDC biofilm reactor y otro in vivo de infección de cuerpo extraño con cepas S. aureus sensibles a meticilina (SASM) y SARM, para poder evaluar (i) la eficacia de las combinaciones de daptomicina frente a SASM; (ii) el potencial efecto anti-biofilm de claritromicina; y (iii) la actividad de cotrimoxazol, ácido fusídico y las combinaciones de rifampicina con cotrimoxazol y linezolid como posibles alternativas terapéuticas al tratamiento estándar para S. aureus. Los principales hallazgos son: - El modelo in vivo estandarizado con una infección de 3 y 7 días, como modelo de infección aguda de cuerpo extraño, se muestra válido para la evaluación de la eficacia antimicrobiana - El modelo in vitro dinámico de CDC biofilm reactor permite la formación de biofilm de S.aureus, su mantenimiento en el tiempo, así como el estudio de la eficacia de las diferentes pautas terapéuticas. - Daptomicina-cloxacilina ha demostrado tener una actividad similar a cloxacilina- rifampicina (tratamiento estándar) y podría utilizarse como alternativa terapéutica en fase precoz del tratamiento de infecciones de prótesis por SASM - Daptomicina-rifampicina fue el tratamiento más eficaz en la infección in vivo de cuerpo extraño por SASM, incluso tuvo más actividad que el tratamiento estándar levofloxacino- rifampicina. Estos resultados sugieren que daptomicina-rifampicina podría utilizarse como alternativa terapéutica en los casos que no pudiera utilizarse las fluoroquinolonas. - Claritromicina no tuvo actividad anti-biofilm relevante frente a las infecciones por SASM y SARM - Cotrimoxazol fue ineficaz frente a la infección por SASM y SARM en la rata. Los resultados observados sugieren que una de las causas de su inactividad podría ser la interacción con la timidina (que se encuentra en altas concentraciones de forma inherente en la rata, y en infecciones purulentas) . - Ácido fusídico presentó resultados microbiológicos prometedores (aumento de actividad de daptomicina, y protección frente la aparición total o parcialmente). Sin embargo no se pudo estudiar en el modelo in vivo debido a la toxicidad que presentó en los animales. - En el modelo in vitro dinámico del reactor para SASM observamos que la combinación de levofloxacino con rifampicina fue el tratamiento más eficaz, mientras que cotrimoxazol- rifampicina y linezolid-rifampicina no mostraron diferencias significativas entre ellos en términos de eficacia. Sin embargo, linezolid fue capaz de proteger frente a la aparición de resistencias a rifampicina, mientras que cotrimoxazol no lo hizo. En el modelo para SARM, linezolid-rifampicina se presentó como la terapia más eficaz y protegió frente a la aparición de cepas resistentes. De nuevo, la combinación de cotrimoxazol-rifampicina no protegió frente a la aparición de resistencias a rifampicina, que aparecieron de forma sistemática a las 8 horas de iniciar el tratamiento.[eng] Despite optimal therapeutic management for acute prosthetic joint infections (PJI) caused by Staphylocococcus aureus, some clinical and microbiological failures occur, especially when implant retention is attempted. Moreover, occasions arise when drugs often cannot be administered owing to intolerance or allergy, and no adequately evaluated alternatives exist. In response to these difficulties, alternative therapies and other therapeutic approaches to bacterial biofilm are been investigated. Daptomycin combinations had a high efficacy against foreign-body infection by methicillin- resistant S. aureus (MRSA). On the other hand, the information about the potential anti-biofilm effect of macrolides against S. aureus is scarce and controversial. Additionally, the alternative therapies for S.aureus infections (ie cotrimoxazole and fusidic acid) have not been accurately evaluated. The aims of this project was standardize an dynamic in vitro model (CDC biofilm reactor) and an in vivo foreign-body infection (FBI) by methicillin-susceptible S. aureus (SASM) and MRSA strains, in order to evaluate (i) The efficacy of daptomycin and its combinations against SASM; (ii) the potential anti-biofilm effect of clarithromycin; and (iii) the activity of cotrimoxazole, fusidic acid and rifampicin combinations with cotrimoxazole and linezolid as possible therapeutic alternatives to the standard treatment for S. aureus. The main results were: - The In vivo model with a period of infection of 3 and 7 days, as an acute FBI model, and the dynamic in vitro model of CDC biofilm reactor were suitable to study the efficacy of different therapies. -Daptomycin-Cloxacillin therapy was as effective as cloxacillin-rifampicin (standard treatment) and can be considered as alternative anti-MSSA therapy for FBI. -Daptomycin-Rifampicin was the most effective combination, providing higher efficacy than levofloxacin-rifampicin. These results suggest that daptomycin-rifampicin may be useful as a first-line therapy against MSSA PJI. -Clarithromycin did not show anti-biofilm activity against MSSA and MRSA infections. -Cotrimoxazole was ineffective against S.aureus in animal model. The results observed suggest that the lack of activity could be due in part to its inactivation by thymidine. -Fusidic acid had promising microbiological results. However, it was not possible to perform the in vivo studies due to the animal intolerance to antibiotic. - In CDC biofilm reactor, levofloxacin-rifampicin was the most effective treatment against MSSA. Rifampicin combinations with cotrimoxazole and linezolid had similar activity. Against MRSA, linezolid-rifampicin combination was the most effective treatment. In both strains, the cotrimoxazole-rifampicin combination did not protect against rifampicin resistant strains

Pancreatic surgery outcomes: multicentre prospective snapshot study in 67 countries

Background: Pancreatic surgery remains associated with high morbidity rates. Although postoperative mortality appears to have improved with specialization, the outcomes reported in the literature reflect the activity of highly specialized centres. The aim of this study was to evaluate the outcomes following pancreatic surgery worldwide.Methods: This was an international, prospective, multicentre, cross-sectional snapshot study of consecutive patients undergoing pancreatic operations worldwide in a 3-month interval in 2021. The primary outcome was postoperative mortality within 90 days of surgery. Multivariable logistic regression was used to explore relationships with Human Development Index (HDI) and other parameters.Results: A total of 4223 patients from 67 countries were analysed. A complication of any severity was detected in 68.7 percent of patients (2901 of 4223). Major complication rates (Clavien-Dindo grade at least IIIa) were 24, 18, and 27 percent, and mortality rates were 10, 5, and 5 per cent in low-to-middle-, high-, and very high-HDI countries respectively. The 90-day postoperative mortality rate was 5.4 per cent (229 of 4223) overall, but was significantly higher in the low-to-middle-HDI group (adjusted OR 2.88, 95 per cent c.i. 1.80 to 4.48). The overall failure-to-rescue rate was 21 percent; however, it was 41 per cent in low-to-middle-compared with 19 per cent in very high-HDI countries.Conclusion: Excess mortality in low-to-middle-HDI countries could be attributable to failure to rescue of patients from severe complications. The authors call for a collaborative response from international and regional associations of pancreatic surgeons to address management related to death from postoperative complications to tackle the global disparities in the outcomes of pancreatic surgery (NCT04652271; ISRCTN95140761)