Polymyxin B in Combination with Rifampin and Meropenem against Polymyxin B-Resistant KPC-Producing Klebsiella pneumoniae

• Published in: Antimicrobial agents and chemotherapy Vol. 61; no. 2
• Main Authors: Diep, John K, Jacobs, David M, Sharma, Rajnikant, Covelli, Jenna, Bowers, Dana R, Russo, Thomas A, Rao, Gauri G
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.02.2017
• Subjects: Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; beta-Lactamases; beta-Lactamases - genetics; beta-Lactamases - metabolism; Klebsiella pneumoniae; Klebsiella pneumoniae - drug effects; Klebsiella pneumoniae - enzymology; Klebsiella pneumoniae - genetics; Microbial Sensitivity Tests; Pharmacology; Polymyxin B; Polymyxin B - pharmacology; Rifampin; Rifampin - pharmacology; Thienamycins; Thienamycins - pharmacology; carbapenemase; triple combination; pharmacodynamics; polymyxin B; Klebsiella pneumoniae
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02121-16

Safe and effective therapies are urgently needed to treat polymyxin-resistant KPC-producing Klebsiella pneumoniae infections and suppress the emergence of resistance. We investigated the pharmacodynamics of polymyxin B, rifampin, and meropenem alone and as polymyxin B-based double and triple combinations against KPC-producing K. pneumoniae isolates. The rates and extents of killing with polymyxin B (1 to 128 mg/liter), rifampin (2 to 16 mg/liter), and meropenem (10 to 120 mg/liter) were evaluated against polymyxin B-susceptible (PB ) and polymyxin B-resistant (PB ) clinical isolates using 48-h static time-kill studies. Additionally, humanized triple-drug regimens of polymyxin B (concentration at steady state [C ] values of 0.5, 1, and 2 mg/liter), 600 mg rifampin every 12 or 8 h, and 1 or 2 g meropenem every 8 h dosed as an extended 3-h infusion were simulated over 48 h by using a one-compartment in vitro dynamic infection model. Serial bacterial counts were performed to quantify the pharmacodynamic effect. Population analysis profiles (PAPs) were used to assess the emergence of polymyxin B resistance. Monotherapy was ineffective against both isolates. Polymyxin B with rifampin demonstrated early bactericidal activity against the PB isolate, followed by regrowth by 48 h. Bactericidal activity was sustained at all polymyxin B concentrations of ≥2 mg/liter in combination with meropenem. No two-drug combinations were effective against the PB isolate, but all simulated triple-drug regimens showed early bactericidal activity against both strains by 8 h that was sustained over 48 h. PAPs did not reveal the emergence of resistant subpopulations. The triple-drug combination of polymyxin B, rifampin, and meropenem may be a viable consideration for the treatment of PB KPC-producing K. pneumoniae infections. Further investigation is warranted to optimize triple-combination therapy.