Despite concerns of nephrotoxicity, polymyxin antibiotics often remain the only susceptible agents for multidrug-resistant (MDR) Gram-negative bacteria. Colistin has been more commonly used clinically due to a perceived safety benefit. We compared the nephrotoxicity of colistin to polymyxin B. The in vitro cytotoxicity of colistin was compared to polymyxin B in two mammalian renal cell lines. To validate the clinical relevance of the findings, we evaluated adult patients with normal renal function who received a minimum of 72 h of polymyxin therapy in a multicenter study. The primary outcome was the prevalence of nephrotoxicity, as defined by the RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria. Colistin exhibited an in vitro cytotoxicity profile similar to polymyxin B. A total of 225 patients (121 receiving colistimethate, 104 receiving polymyxin B) were evaluated. Independent risk factors for colistimethate-associated nephrotoxicity included age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.00 to 1.07; P ‫؍‬ 0.03), duration of therapy (OR 1.08; 95% CI, 1.02 to 1.15; P ‫؍‬ 0.02), and daily dose by ideal body weight (OR 1.40; 95% CI, 1.05 to 1.88; P ‫؍‬ 0.02). In contrast, cystic fibrosis was found to be a protective factor in patients who received colistimethate (OR, 0.03; 95% CI, 0.001 to 0.79; P ‫؍‬ 0.04). In a matched analysis based on the risk factors identified (n ‫؍‬ 76), the prevalence of nephrotoxicity was higher with colistimethate than with polymyxin B (55.3% versus 21.1%; P ‫؍‬ 0.004). Polymyxin B was not found to be more nephrotoxic than colistin and may be the preferred polymyxin for MDR infections. A prospective study comparing the two polymyxins directly is warranted.

CYP3A5 expressors had faster atazanavir CL/F and lower C(min) than non-expressors. The effect was most pronounced in non-African-American men. Ritonavir lessened CYP3A5 expressor effects. The wild-type ABCB1 CGC haplotype was associated with slower CL/F and the UGT1A1 *28 genotype was associated with increased bilirubin. Thus, CYP3A5, ABCB1 and UGT1A1 polymorphisms are associated with atazanavir pharmacokinetics and pharmacodynamics in vivo.

Carbapenem-resistant Enterobacterales (CRE) are considered urgent antimicrobial resistance (AMR) threats. The vast majority of CRE research has focused on carbapenemase-producing Enterobacterales (CPE) even though noncarbapenemase-producing CRE (non-CP-CRE) comprise 50% or more of isolates in some surveillance studies.

To address the increase of drug-resistant bacteria and widespread inappropriate use of antimicrobials, many healthcare institutions have implemented antimicrobial stewardship programs to promote appropriate use of antimicrobials and optimize patient outcomes. However, a consensus definition of appropriate use is lacking. We conducted a multicenter observational study to compare 4 definitions of appropriateness--a study site-specific definition, use supported by susceptibility data, use supported by electronic drug information resources (Clinical Pharmacology/Micromedex), or study site principal investigator (PI) opinion-among patients receiving 1 or more of 13 identified antimicrobials. Data were collected for 262 patients. Overall, appropriateness with the 4 definitions ranged from 79% based on PI opinion to 94% based on susceptibility data. No single definition resulted in consistently high appropriate use for all target antimicrobials. For individual antimicrobials, the definitions with the highest rate of appropriate use were Clinical Pharmacology/Micromedex support (6 of 7 antimicrobials) and susceptibility data (5 of 7 antimicrobials). For specific indications, support from susceptibility data resulted in the highest rate of appropriate use (4 of 7 indications). Overall comparisons showed that appropriateness assessed by PI opinion differed significantly compared with other definitions when stratified by either target antimicrobial or indication. The significant variability in the rate of appropriate use highlights the difficulty in developing a standardized definition that can be used to benchmark judicious antimicrobial use.