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

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.