Archive for August 25, 2019

In vitro pharmacokinetics/pharmacodynamics of the combination of avibactam and aztreonam against MDR organisms.

J Antimicrob Chemother. July 2016 V.71 N.7 P.1866-80.

Sy SK1, Beaudoin ME2, Zhuang L1, Löblein KI1, Lux C1, Kissel M1, Tremmel R1, Frank C1, Strasser S1, Heuberger JA1, Mulder MB1, Schuck VJ2, Derendorf H3.

Author information

1 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

2 AstraZeneca, Waltham, MA, USA.

3 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA hartmut@cop.ufl.edu.

Abstract

OBJECTIVES:

The combination of aztreonam and avibactam has been proposed for the treatment of infections caused by metallo-β-lactamase-producing Gram-negative organisms, given the stability of aztreonam against metallo-β-lactamases plus the broad coverage of avibactam against AmpC β-lactamases and ESBLs. This study aimed to evaluate the efficacy of the combination against four clinical isolates with defined but diverse β-lactamase profiles.

METHODS:

The MICs of aztreonam were determined without and with avibactam (1, 2, 4, 8 and 16 mg/L). Using the MIC values, the static time-kill kinetic studies were designed to encompass aztreonam concentrations of 0.25, 0.5, 1, 2 and 4 times the MIC at the respective avibactam concentrations from 0 to 8 mg/L. Aztreonam and avibactam concentrations were determined by LC-MS/MS during the course of the time-kill kinetic studies to evaluate whether avibactam protects aztreonam from degradation.

RESULTS:

Three of the four isolates had aztreonam MICs ≥128 mg/L in monotherapy. Dramatically increasing susceptibility associated with a decrease in aztreonam MIC was observed with increasing avibactam concentration. Against all isolates, the combinations resulted in greater killing with a much lower dose requirement for aztreonam. The resulting changes in base-10 logarithm of cfu/mL at both the 10 h and 24 h references (versus 0 h) were synergistic. In contrast, a significantly higher concentration of aztreonam in the monotherapy was required to produce the same kill as that in the combination therapy, due to rapid aztreonam degradation in two isolates.

CONCLUSIONS:

The aztreonam/avibactam combination protects aztreonam from hydrolysis and provides synergy in antimicrobial activity against multiple β-lactamase-expressing strains with a wide MIC range.

abstract

https://academic.oup.com/jac/article/71/7/1866/1751177

PDF (CLIC en PDF)

August 25, 2019 at 11:36 am


Calendar

August 2019
M T W T F S S
 1234
567891011
12131415161718
19202122232425
262728293031  

Posts by Month

Posts by Category