RESUMEN
Background: Aspergillus flavus is one of the most common agents of invasive aspergillosis and is associated with high mortality. The orotomides are a new class of antifungal agents with a novel mechanism of action. An understanding of the pharmacodynamics (PD) of the lead compound F901318 is required to plan safe and effective regimens for clinical use. Methods: The pharmacokinetics (PK) and PD of F901318 were evaluated by developing new in vitro and in vivo models of invasive fungal sinusitis. Galactomannan was used as a pharmacodynamic endpoint in all models. Mathematical PK-PD models were used to describe dose-exposure-response relationships. Results: F901318 minimum inhibitory concentrations (MICs) ranged from 0.015 to 0.06 mg/L. F901318 induced a concentration-dependent decline in galactomannan. In the in vitro model, a minimum concentration:MIC of 10 resulted in suppression of galactomannan; however, values of approximately 10 and 9-19 when assessed by survival of mice or the decline in galactomannan, respectively, were equivalent or exceeded the effect induced by posaconazole. There was histological clearance of lung tissue that was consistent with the effects of F901318 on galactomannan. Conclusions: F901318 is a potential new agent for the treatment of invasive infections caused by A flavus with PDs that are comparable with other first-line triazole agents.
Asunto(s)
Acetamidas/farmacocinética , Acetamidas/uso terapéutico , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Aspergillus flavus/efectos de los fármacos , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Pirroles/farmacocinética , Pirroles/uso terapéutico , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Aspergilosis Pulmonar Invasiva/microbiología , Aspergilosis Pulmonar Invasiva/patología , Ratones , Triazoles/farmacocinética , Triazoles/uso terapéutico , Voriconazol/farmacocinética , Voriconazol/uso terapéuticoRESUMEN
BACKGROUND: Operative intervention to correct incisional hernia affects 150,000 patients annually, with 1 in 3 repairs recurring within 9 years. The aim of this study was to compare the incidence of incisional hernia and postoperative complications in elective midline laparotomy patients after the use of prophylactic mesh placement and primary suture closure. METHODS: A systematic review was performed to identify studies comparing prophylactic mesh placement to primary suture closure in elective, midline laparotomy at index abdominal aponeurosis closure. The primary outcome was incisional hernia. Secondary outcomes included postoperative complications. RESULTS: Fourteen studies were included (2,114 patients), with 1,152 receiving prophylactic mesh placement. Prophylactic mesh placement decreased the risk of incisional hernia overall when compared to primary suture closure (relative risk = 0.15; P < .00001) and in trials using only polypropylene mesh versus 4:1 primary suture closure (relative risk = 0.15; P = .003). Prophylactic mesh placement reduced the risk of incisional hernia regardless of mesh location or composition: onlay (relative risk = 0.07; P < .0001), retrorectus (relative risk = 0.04; P = .002), and preperitoneal (relative risk = 0.18; P = .02). Prophylactic mesh placement increased risk of seroma overall (relative risk = 1.95; P < .0001), onlay (relative risk = 2.43; P = .01) and preperitoneal (relative risk = 1.47; P = .01) but not retrorectus plane (relative risk = 1.55; P = .26). Polypropylene mesh increased seroma risk only in the onlay position (relative risk = 2.77; P = .04). Prophylactic mesh placement patients are at increased risk for chronic wound pain compared to primary suture closure (relative risk = 1.70; P = .03). CONCLUSION: Prophylactic mesh placement is associated with an 85% postoperative incisional hernia risk reduction when compared to primary suture closure in at-risk patients undergoing elective, midline laparotomy closure. This technique appears to be safe with comparable complication profiles, barring an increased risk of seroma, especially with the onlay technique, and the possibility for an increased risk of chronic pain. Despite this verification, evidence from large domestic trials that sufficiently addresses major knowledge gaps is simply lacking.