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

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. The pharmacodynamics of polymyxin B together with doripenem were evaluated in time-kill experiments over 48 h against 10(8) 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 10(9) cfu/mL of ATCC 19606. 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 log(10) reduction by 48 h. The polymyxin B 'front-loaded' combination resulted in more rapid and extensive initial killing (> 8 log(10)) 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. Early aggressive dosing regimens for polymyxin combinations demonstrate promise for treatment of heteroresistant A. baumannii infections.