Archive for January 27, 2018

Population Pharmacokinetic Analysis of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Healthy Subjects, Subjects with Various Degrees of Renal Function, and Patients with Complicated Urinary Tract Infection or Acute Uncomplicated Pyelonephritis

Agents and Chemotherapy February 2018 V.62 N.2

Nao Kawaguchi, Takayuki Katsube, Roger Echols and Toshihiro Wajima

aProject Management Department, Shionogi & Co., Ltd., Osaka, Japan

bInfectious Disease Drug Development Consulting, LLC, Easton, Connecticut, USA

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains.

The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens and to calculate the fraction of the time during the dosing interval where the free drug concentration in plasma exceeds the MIC (fTMIC).

Population PK models were developed with three renal function markers, body surface area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance, on the basis of 2,571 plasma concentrations from 91 subjects without infection and 238 patients with infection.

The population PK models with each renal function marker adequately described the plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed.

Body weight and disease status (with or without infection) were also significant covariates. The CL in patients with infection was 26% higher than that in subjects without infection.

The fTMIC values were more than 75% in all patients (and were 100% in most patients), suggesting that a sufficient exposure to cefiderocol was provided by the tested dose regimens (2 g every 8 h as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens.




January 27, 2018 at 3:12 pm

Host-Pathogen-Treatment Triad: Host Factors Matter Most in Methicillin-Resistant Staphylococcus aureus Bacteremia Outcomes

Agents and Chemotherapy February 2018 V.62 N.2

Cristina Vazquez Guillamet, Rodrigo Vazquez, Benjamin Deaton, Jenny Shroba, Laia Vazquez and Renee-Claude Mercier

aDivision of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA

bDivision of Internal Medicine, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA

cCollege of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA

dDepartment of Internal Medicine, Bridgeport Hospital-Yale University School of Medicine, Bridgeport, Connecticut, USA

Previous studies have separately emphasized the importance of host, pathogen, and treatment characteristics in determining short-term or in-hospital mortality rates for patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections.

Less is known about the relative importance of these factors and their interactions in determining short-, medium-, and long-term mortality rates.

This is an observational cohort study in which data for all patients admitted to the University of New Mexico (UNM) Health Sciences Center (HSC) between July 2002 and August 2013 with MRSA-positive blood cultures were recorded.

We collected patients’ demographics and treatment data, as well as data on genetic markers of the MRSA isolates.

Outcomes of interest were determinants of short-term (within 30 days), medium-term (30 to 90 days), and long-term (>90 days) mortality rates.

This study included 273 patients with MRSA bacteremia. Short-, medium-, and long-term mortality rates were 18.7%, 26.4%, and 48%, respectively. Thirty-day mortality rates were influenced by host variables and host-pathogen interaction characteristics.

Pitt bacteremia scores, malignancy, and health care exposure contributed to 30- to 90-day mortality rates, while treatment duration of >4 weeks had a protective effect.

Age remained a significant risk factor for death at >90 days, while admission leukocytosis was protective. Infection represented the most frequent cause of death for all three time frames; rates varied from 72.6% in the first 30 days and 60% for 30 to 90 days to 35.7% for >90 days (P = 0.003).

Host characteristics affect short-, medium-, and long-term mortality rates for MRSA bloodstream infections more than do pathogen genetic markers and treatment factors.




January 27, 2018 at 3:10 pm

In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, against Carbapenem-Nonsusceptible and Multidrug-Resistant Isolates of Gram-Negative Bacilli Collected Worldwide in 2014 to 2016

Agents and Chemotherapy February 2018 V.62 N.2

Meredith A. Hackel, Masakatsu Tsuji, Yoshinori Yamano, Roger Echols, James A. Karlowsky and Daniel F. Sahm

aInternational Health Management Associates, Inc., Schaumburg, Illinois, USA

bDrug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan

cPharmaceutical Research Division, Shionogi & Co., Ltd., Osaka, Japan

dClinical Development and Medical Affairs, ID3C, LLC, Easton, Connecticut, USA

eDepartment of Medical Microbiology, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

The in vitro activity of the investigational siderophore cephalosporin, cefiderocol (formerly S-649266), was determined against a 2014–2016, 52-country, worldwide collection of clinical isolates of carbapenem-nonsusceptible Enterobacteriaceae (n = 1,022), multidrug-resistant (MDR) Acinetobacter baumannii (n = 368), MDR Pseudomonas aeruginosa (n = 262), Stenotrophomonas maltophilia (n = 217), and Burkholderia cepacia (n = 4) using the Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution method.

Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB), prepared according to a recently approved (2017), but not yet published, CLSI protocol, was used to test cefiderocol; all other antimicrobial agents were tested using CAMHB.

The concentration of cefiderocol inhibiting 90% (MIC90) of isolates of carbapenem-nonsusceptible Enterobacteriaceae was 4 μg/ml; cefiderocol MICs ranged from 0.004 to 32 μg/ml, and 97.0% (991/1,022) of isolates demonstrated cefiderocol MICs of ≤4 μg/ml.

The MIC90s for cefiderocol for MDR A. baumannii, MDR P. aeruginosa, and S. maltophilia were 8, 1, and 0.25 μg/ml, respectively, with 89.7% (330/368), 99.2% (260/262), and 100% (217/217) of isolates demonstrating cefiderocol MICs of ≤4 μg/ml. Cefiderocol MICs for B. cepacia ranged from 0.004 to 8 μg/ml.

We conclude that cefiderocol demonstrated potent in vitro activity against a 2014–2016, worldwide collection of clinical isolates of carbapenem-nonsusceptible Enterobacteriaceae, MDR A. baumannii, MDR P. aeruginosa, S. maltophilia, and B. cepacia isolates as 96.2% of all (1,801/1,873) isolates tested had cefiderocol MICs of ≤4 μg/ml.




January 27, 2018 at 3:08 pm


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