Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii: pharmacodynamics of new dosing strategies

Gauri G. Rao, Neang S. Ly, Jurgen B. Bulitta, Rachel L. Soon, Marie D. San Roman, Patricia N. Holden, Cornelia B. Landersdorfer, Roger L. Nation, Jian Li, Alan Forrest, Brian T. Tsuji

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

Abstract

Objectives: Polymyxin B is being increasingly utilized as a last resort against resistant Gram-negative bacteria. We examined the pharmacodynamics of novel dosing strategies for polymyxin B combinations to maximize efficacy and minimize the emergence of resistance and drug exposure against Acinetobacter baumannii. Methods: The pharmacodynamics of polymyxin B together with doripenem were evaluated in time-kill experiments over 48 h against 108 cfu/mL of two polymyxin-heteroresistant A. baumannii isolates (ATCC 19606 and N16870). Pharmacokinetic/pharmacodynamic relationships were mathematically modelled using S-ADAPT. A hollow-fibre infection model (HFIM) was also used to simulate clinically relevant polymyxin B dosing strategies (traditional, augmented 'front-loaded' and 'burst' regimens), together with doripenem, against an initial inoculum of 109 cfu/mL of ATCC 19606. Results: In static time-kill studies, polymyxin B concentrations >4 mg/L in combination with doripenem 25 mg/L resulted in rapid bactericidal activity against both strains with undetectable bacterial counts by 24 h. The mathematical model described the rapid, concentration-dependent killing as subpopulation and mechanistic synergy. In the HFIM, the traditional polymyxin B combination regimen was synergistic, with a >7.5 log10 reduction by 48 h. The polymyxin B 'front-loaded' combination resulted in more rapid and extensive initial killing (>8 log10) within 24 h, which was sustained over 10 days. With only 25% of the cumulative drug exposure, the polymyxin B 'burst' combination demonstrated antibacterial activity similar to traditional and 'front-loaded' combination strategies. The polymyxin B 'front-loaded' and 'burst' combination regimens suppressed the emergence of resistance. Conclusions: Early aggressive dosing regimens for polymyxin combinations demonstrate promise for treatment of heteroresistant A. baumannii infections.

Original languageEnglish
Pages (from-to)3148-3156
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume71
Issue number11
DOIs
Publication statusPublished - 1 Nov 2016

Cite this