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

Abstract

Safe and effective therapies are urgently needed to treat polymyxinresistant 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 s ) and polymyxin B-resistant (PB r ) clinical isolates using 48-h static time-kill studies. Additionally, humanized triple-drug regimens of polymyxin B (concentration at steady state [C ss ] 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 s isolate, followed by regrowth by 48 h. Bactericidal activity was sustained at all polymyxin B concentrations of Ն2 mg/liter in combination with meropenem. No two-drug combinations were effective against the PB r 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 r KPC-producing K. pneumoniae infections. Further investigation is warranted to optimize triple-combination therapy.

Synergistic Antimicrobial Activity of Colistin in Combination with Rifampin and Azithromycin against Escherichia coli Producing MCR-1

“…The increased in vitro bacterial effect of double-or triple-drug combinations of colistin or polymyxin B and various drugs, such as rifampin (6,7), meropenem (8,9), and amikacin (10,11), has been well demonstrated in many studies. Azithromycin is the most commonly prescribed antibiotic, other than for the clinical treatment of serious Gram-negative infections because of poor diffusion across the outer membrane of most Gram-negative bacteria (12).…”

In Vitro Assessment of Combined Polymyxin B and Minocycline Therapy against Klebsiella pneumoniae Carbapenemase (KPC)-Producing K. pneumoniae

“…Triple combinations, although infrequently used in the United States, may be necessary for prolonged sustained activity to treat infections due to highly resistant K. pneumoniae isolates. Previous studies have suggested a clinical and microbiological benefit to three-drug combinations (7,26). Moreover, adding an additional drug such as a carbapenem or fosfomycin to the polymyxin B and minocycline combination may increase efficacy against KPC-producing K. pneumoniae by increasing the log kill rate of polymyxin B with minocycline to theoretically slow any regrowth.…”

“…Time-kill studies. The bacterial killing activity of polymyxin B and minocycline as monotherapies and in combination was evaluated against the six isolates by performing time-kill experiments over 48 h using methods previously described (26). Polymyxin B concentrations of 0.5, 1, 2, 4, and 16 mg/liter and minocycline concentrations of 1, 2, 4, 8, and 16 mg/liter were evaluated as monotherapy.…”

Mechanism‐Based Disease Progression Model Describing Host‐Pathogen Interactions During the Pathogenesis of Acinetobacter baumannii Pneumonia

“…In vitro models of infection include static time-kill, dynamic onecompartment, and hollow-fiber systems; in vivo infection models typically utilize neutropenic mice. 3,4 However, current preclinical translational designs and models fail to take the host immune response, which is key to initiating bacterial clearance and clinical outcome, into account. The interaction between the invading bacterial pathogen and host innate immune system is the principal pathway for elimination of virulent extracellular grampositive and gram-negative pathogens from the lung, tipping the immune balance toward inflammation.…”

“…Current translational research primarily optimizes existing antibiotics against these hard‐to‐treat pathogens using in vitro and in vivo infection pharmacokinetic (PK) and pharmacodynamic (PD) models of drugs and bacteria. In vitro models of infection include static time‐kill, dynamic one‐compartment, and hollow‐fiber systems; in vivo infection models typically utilize neutropenic mice …”