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

<span class="paragraphSection"><div class="boxTitle">Objectives</div>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 <span style="font-style:italic;">Acinetobacter baumannii</span>.<div class="boxTitle">Methods</div>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 <span style="font-style:italic;">A. baumannii</span> 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.<div class="boxTitle">Results</div>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.<div class="boxTitle">Conclusions</div>Early aggressive dosing regimens for polymyxin combinations demonstrate promise for treatment of heteroresistant <span style="font-style:italic;">A. baumannii</span> infections.</span>

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