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Fulltext Proof-of-concept for incorporating mechanistic insights from multi-omics analyses of polymyxin B in combination with chloramphenicol against Klebsiella pneumoniae

Hanafin PO, Abdul Rahim N, Sharma R, Cess CG, Finley SD, Bergen PJ, et al.

CPT Pharmacometrics Syst Pharmacol, 2023 Mar;12(3):387-400.
PMID: 36661181 DOI: 10.1002/psp4.12923

Carbapenemase-resistant Klebsiella pneumoniae (KP) resistant to multiple antibiotic classes necessitates optimized combination therapy. Our objective is to build a workflow leveraging omics and bacterial count data to identify antibiotic mechanisms that can be used to design and optimize combination regimens. For pharmacodynamic (PD) analysis, previously published static time-kill studies (J Antimicrob Chemother 70, 2015, 2589) were used with polymyxin B (PMB) and chloramphenicol (CHL) mono and combination therapy against three KP clinical isolates over 24 h. A mechanism-based model (MBM) was developed using time-kill data in S-ADAPT describing PMB-CHL PD activity against each isolate. Previously published results of PMB (1 mg/L continuous infusion) and CHL (Cmax : 8 mg/L; bolus q6h) mono and combination regimens were evaluated using an in vitro one-compartment dynamic infection model against a KP clinical isolate (108 CFU/ml inoculum) over 24 h to obtain bacterial samples for multi-omics analyses. The differentially expressed genes and metabolites in these bacterial samples served as input to develop a partial least squares regression (PLSR) in R that links PD responses with the multi-omics responses via a multi-omics pathway analysis. PMB efficacy was increased when combined with CHL, and the MBM described the observed PD well for all strains. The PLSR consisted of 29 omics inputs and predicted MBM PD response (R2 = 0.946). Our analysis found that CHL downregulated metabolites and genes pertinent to lipid A, hence limiting the emergence of PMB resistance. Our workflow linked insights from analysis of multi-omics data with MBM to identify biological mechanisms explaining observed PD activity in combination therapy.
Fulltext "It's Valid and Reliable" Is Not Enough: Critical Appraisal of Reporting of Measures in Trials Evaluating Patient Decision Aids

Sepucha KR, Matlock DD, Wills CE, Ropka M, Joseph-Williams N, Stacey D, et al.

Med Decis Making, 2014 07;34(5):560-6.
PMID: 24713692 DOI: 10.1177/0272989X14528381

BACKGROUND: This review systematically appraises the quality of reporting of measures used in trials to evaluate the effectiveness of patient decision aids (PtDAs) and presents recommendations for minimum reporting standards.
METHODS: We reviewed measures of decision quality and decision process in 86 randomized controlled trials (RCTs) from the 2011 Cochrane Collaboration systematic review of PtDAs. Data on development of the measures, reliability, validity, responsiveness, precision, interpretability, feasibility, and acceptability were independently abstracted by 2 reviewers.
RESULTS: Information from 178 instances of use of measures was abstracted. Very few studies reported data on the performance of measures, with reliability (21%) and validity (16%) being the most common. Studies using new measures were less likely to include information about their psychometric performance. The review was limited to reporting of measures in studies included in the Cochrane review and did not consult prior publications.
CONCLUSIONS: Very little is reported about the development or performance of measures used to evaluate the effectiveness of PtDAs in published trials. Minimum reporting standards are proposed to enable authors to prepare study reports, editors and reviewers to evaluate submitted papers, and readers to appraise published studies.

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