Polymyxins are an important class of antibiotics for the treatment of bacterial infections due to multidrug resistant Gram-negative pathogens. However, their clinical utility is limited by nephrotoxicity. Here, we report a series of promising next generation polymyxin nonapeptides identified on the basis of our understanding of the relationship of structure with activity, cytotoxicity, and kidney compartment accumulation. We demonstrate that nonapeptides with an amine-containing N-terminal moiety of specific regio- and stereochemistry possess superior in vitro activity, together with lower cytotoxicity compared to polymyxin B. We further demonstrate that compounds with a β-branched aminobutyrate N-terminus with an aryl substituent offer a promising combination of low cytotoxicity and kidney exposure, leading to low toxicity in the mouse. From this series, SPR206 has been selected as a development candidate.
SPR741 is a novel polymyxin B derivative, with minimal intrinsic antibacterial activity and reduced nonclinical nephrotoxicity compared to levels with polymyxin B, that interacts with the outer membrane of Gram-negative bacteria, enhancing penetration of coadministered antibiotics. The safety, tolerability, and pharmacokinetics (PK) of SPR741 were evaluated in two studies, after single and multiple intravenous (i.v.) doses in healthy adult subjects and after coadministration with partner antibiotics. In the single and multiple ascending-dose study, SPR741 or placebo was administered as a 1-h infusion at single doses of 5 to 800 mg and in multiple doses of 50 to 600 mg every 8 h (q8h) for 14 days. In the drug-drug interaction study, a single 400-mg i.v. dose of SPR741 was administered alone and in combination with piperacillin-tazobactam, ceftazidime, and aztreonam. PK parameters for SPR741 and partner antibiotics were determined using noncompartmental analysis. After single doses, a dose-linear and proportional increase in mean maximum concentration in plasma (Cmax) and area under the concentration-time curve (AUC) was observed. At doses of 100 to 800 mg, >50% of the dose was excreted in the urine in the first 4 h postdose. After multiple doses, the mean half-life was 2.2 h on day 1 and up to 14.0 h on day 14, with no evidence of accumulation after 14 days of dosing up to 400 mg. The PK profile of SPR741 and partner antibiotics was unchanged with coadministration. SPR741 was generally well tolerated at doses up to 1,800 mg/day. These data support further clinical development of SPR741 for treating serious infections due to resistant bacteria. (These studies have been registered at ClinicalTrials.gov under identifiers NCT03022175 and NCT03376529.)
Daptomycin is a lipopeptide antibiotic with strong bactericidal effects against Gram-positive bacteria and minor side effects on skeletal muscles. The type and magnitude of the early effect of daptomycin on skeletal muscles of rats was quantified by histopathology, examination of contractile properties, Evans Blue Dye uptake, and effect on the patch repair process. A single dose of daptomycin of up to 200 mg/kg had no effect on muscle fibers. A dose of 150 mg/kg of daptomycin, twice per day for 3 days, produced a small number of myofibers (
Purpose of Review Enhanced recovery after surgery (ERAS) has become a widespread topic in perioperative medicine over the past 20 years. The goals of ERAS are to improve patient outcomes and perioperative experience, reduce length of hospital stay, minimize complications, and reduce cost. Interventions and factors before, during, and after surgery all potentially play a role with the cumulative effect being superior quality of patient care. Recent Findings Preoperatively, patient and family education, optimization of nutritional status, and antibiotic prophylaxis all improve outcomes. Recovery is also expedited by the use of multimodal analgesia, regional anesthesia, and opioid reducing approaches. Intraoperatively, the anesthesiologist can have an impact by using less-invasive monitors appropriately to guide fluid and hemodynamic management as well as maintaining normothermia. Postoperatively, early enteral feeding, mobilization, and removal of invasive lines support patient recovery. Implementation of ERAS protocol in cardiac surgery faces challenges by some unique perioperative perspectives in cardiac surgery, such as systemic anticoagulation, use of cardiopulmonary bypass, significantly more hemodynamic variations, larger volume replacement, postoperative intubation and mechanical ventilation and associated sedation, and potentially significantly more coexisting morbidities than other surgical procedures. Summary ERAS in cardiac surgery may benefit patients more related to its high risk and high cost nature. This manuscript specifically reviews the unique aspects of enhanced recovery in cardiac surgery.
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