Fmoc-Freidinger s lactam

Background: Prompt initiation of antibiotic therapy improves the survival of patients with bloodstream infections (BSIs). We sought to determine if the sequence of administration of the first dose of antibiotic therapy (ie, β-lactam or vancomycin, if both are deemed necessary and cannot be administered simultaneously) impacts early mortality for patients with BSI. Methods: We conducted a multicenter, observational study of patients ≥13 years with BSIs to evaluate the association of the sequence of antibiotic administration with 7-day mortality using inverse probability of treatment weighting (IPTW) incorporating propensity scores. Propensity scores were generated based on demographics, Pitt bacteremia score, intensive care unit status, highest lactate, highest white blood cell count, Charlson comorbidity index, severe immunocompromise, administration of active empiric therapy, combination therapy, and time from emergency department arrival to first antibiotic dose. Results: Of 3376 eligible patients, 2685 (79.5%) received a β-lactam and 691 (20.5%) received vancomycin as their initial antibiotic. In the IPTW cohort, exposed and unexposed patients were similar on all baseline variables. Administration of a β-lactam agent prior to vancomycin protected against 7-day mortality (adjusted odds ratio [aOR], 0.48 [95% confidence interval {CI}, .33-.69]). Similar results were observed when evaluating 48-hour mortality (aOR, 0.45 [95% CI, .24-.83]). Administration of vancomycin prior to a β-lactam was not associated with improved survival in the subgroup of 524 patients with methicillin-resistant Staphylococcus aureus BSI (aOR, 0.93 [95% CI, .33-2.63]). Conclusions: For ill-appearing patients likely to be experiencing a BSI, prioritizing administration of a β-lactam over vancomycin may reduce early mortality, underscoring the significant impact of a relatively simple practice change on improving patient survival.

Antimicrobials are among the most important and commonly prescribed drugs in the management of critically ill patients and beta-lactams are the most common antibiotic class used. Critically ill patient's pathophysiological factors lead to altered pharmacokinetics and pharmacodynamics of beta-lactams.A comprehensive bibliographic search in PubMed database of all English language articles published from January 2000 to December 2017 was performed, allowing the selection of articles addressing the pharmacokinetics or pharmacodynamics of beta-lactam antibiotics in critically ill patients.In critically ill patients, several factors may increase volume of distribution and enhance renal clearance, inducing high intra- and inter-patient variability in beta-lactam concentration and promoting the risk of antibiotic underdosing. The duration of infusion of beta-lactams has been shown to influence the fT > minimal inhibitory concentration and an improved beta-lactam pharmacodynamics profile may be obtained by longer exposure with more frequent dosing, extended infusions, or continuous infusions.The use of extracorporeal support techniques in the critically ill may further contribute to this problem and we recommend not reducing standard antibiotic dosage since no drug accumulation was found in the available literature and to maintain continuous or prolonged infusion, especially for the treatment of infections caused by multidrug-resistant bacteria.Prediction of outcome based on concentrations in plasma results in overestimation of antimicrobial activity at the site of infection, namely in cerebrospinal fluid and the lung. Therefore, although no studies have assessed clinical outcome, we recommend using higher than standard dosing, preferably with continuous or prolonged infusions, especially when treating less susceptible bacterial strains at these sites, as the pharmacodynamics profile may improve with no apparent increase in toxicity.A therapeutic drug monitoring-guided approach could be particularly useful in critically ill patients in whom achieving target concentrations is more difficult, such as obese patients, immunocompromised patients, those infected by highly resistant bacterial strains, patients with augmented renal clearance, and those undergoing extracorporeal support techniques.

The use of α-amino-γ lactam of Freidinger (Agl) may serve as an impressive method to increase the biological stability of peptides and an appropriate tool to elucidate their structure-activity relationships. The endomorphin-2 (EM-2) and [D-Ala2, des-Leu5] enkephalin amide (DAPEA) are two linear opioid tetrapeptides agonists of MOR and MOR/DOR respectively. Herein, we investigated the influence of the incorporation of (R/S)-Agl in position 2 and 3 on the biological profile of the aforementioned products in vitro and in vivo. Receptor radiolabeled displacement and functional assays were used to measure in vitro the binding affinity and receptors activation of the novel analogues. The mouse tail flick and formalin tests allowed to observe their antinociceptive effect in vivo. Data revealed that peptide A2D was able to selectively bind and activate MOR with a potent antinociceptive effect after intracerebroventricular (i.c.v.) administration, performing better than the parent compounds EM-2 and DAPEA. Molecular docking calculations helped us to understand the key role exerted by the Freidinger Agl moiety in A2D for the interaction with the MOR binding pocket.