Pharmacokinetic/pharmacodynamic analysis of ceftazidime/avibactam and fosfomycin combinations in an in vitro hollow fiber infection model against multidrug-resistant Escherichia coli

Abstract

ABSTRACT Rational combination therapy offers a valuable option to increase efficacy and prevent emergence of resistance. Therefore, this study provides a translational pharmacokinetic/pharmacodynamic analysis of the synergy of /avibactam and fosfomycin in a clinical Escherichia coli strain expressing extended spectrum beta-lactamase (CTX-M-15 and TEM-4) and carbapenemase (OXA-244) genes. Detailed static time-kill experiments primed dynamic hollow fiber studies mimicking mono- and combination therapies with doses of ceftazidime/avibactam ranging from 0.06/0.015 to 2/0.5 g every 8 h (q8h) and doses of fosfomycin ranging from 0.125 to 6 g q8h. The drug effects and interactions were quantitatively evaluated by pharmacokinetic/pharmacodynamic modeling using semi-mechanistic and subpopulation synergy. A pharmacokinetic/pharmacodynamic model describing the effects of ceftazidime, avibactam, and fosfomycin and their synergy was developed from the static time-kill experiments and hollow fiber studies. Simulations revealed that combined doses as low as 0.5-g q8h fosfomycin and 0.25-/0.06-g q8h ceftazidime/avibactam lead to suppression of the bacterial count. Conversely, in monotherapy, substantially higher doses by a factor of 12 for fosfomycin (6 g q8h) or by a factor of 6 for ceftazidime/avibactam (1.5/0.375 g q8h) were needed to achieve a comparable killing over 72 h. The combination of ceftazidime/avibactam and fosfomycin was therefore shown to be highly synergistic and suppressed the emergence of resistances. Clinical evaluations of potential dose reductions or the possibility to treat strains with high-level resistance with this combination are warranted. IMPORTANCE Mechanistic understanding of pharmacodynamic interactions is key for the development of rational antibiotic combination therapies to increase efficacy and suppress the development of resistances. Potent tools to provide those insights into pharmacodynamic drug interactions are semi-mechanistic modeling and simulation techniques. This study uses those techniques to provide a detailed understanding with regard to the direction and strength of the synergy of ceftazidime-avibactam and ceftazidime-fosfomycin in a clinical Escherichia coli isolate expressing extended spectrum beta-lactamase (CTX-M-15 and TEM-4) and carbapenemase (OXA-244) genes. Enhanced killing effects in combination were identified as a driver of the synergy and were translated from static time-kill experiments into the dynamic hollow fiber infection model. These findings in combination with a suppression of the emergence of resistance in combination emphasize a potential clinical benefit with regard to increased efficacy or to allow for dose reductions with maintained effect sizes to avoid toxicity.

Keywords

• PK/PD
• drug interactions
• ceftazidime/avibactam
• fosfomycin
• synergy
• hollow fiber infection model