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

Abstract

The multidrug resistance profiles of carbapenemase (KPC) producers have led to increased clinical polymyxin use. Combination therapy with polymyxins may improve treatment outcomes, but it is uncertain which combinations are most effective. Clinical successes with intravenous minocycline-based combination treatments have been reported for infections caused by carbapenemase-producing bacteria. The objective of this study was to evaluate the activity of polymyxin B and minocycline combination therapy against six KPC-2-producing isolates (minocycline MIC range, 2 to 32 mg/liter). Polymyxin B monotherapy (0.5, 1, 2, 4, and 16 mg/liter) resulted in a rapid reduction of up to 6 log in bactericidal activity followed by regrowth by 24 h. Minocycline monotherapy (1, 2, 4, 8, and 16 mg/liter) showed no reduction of activity of>1.34 log against all isolates, although concentrations of 8 and 16 mg/liter prolonged the time to regrowth. When the therapies were used in combination, rapid bactericidal activity was followed by slower regrowth, with synergy (60 of 120 combinations at 24 h, 19 of 120 combinations at 48 h) and additivity (43 of 120 combinations at 24 h, 44 of 120 combinations at 48 h) against all isolates. The extent of killing was greatest against the more susceptible polymyxin B isolates (MICs of ≤0.5 mg/liter) regardless of the minocycline MIC. The pharmacodynamic activity of combined polymyxin B-minocycline therapy against KPC-producing is dependent on polymyxin B susceptibility. Further and animal studies must be performed to fully evaluate the efficacy of this drug combination.

Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa

“…Repurposing veterinary medicines for human use has gained signif- icant interest recently, and several potential polymyxin combinations have been identified (40,41). To date, the majority of synergistic polymyxin combinations identified involve carbapenems, rifampin, and penicillin against P. aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, and a few studies reported synergetic combinations with fluoroquinolones against K. pneumoniae (24,25,28,29,31,42,43).…”

“…Two models have been proposed to explain the enhanced antibacterial activity achieved with the polymyxin combination therapy (24,(28)(29)(30)(31). Subpopulation synergy involves the killing of a subpopulation resistant to polymyxins by the second antibiotic and vice versa.…”

“…The same dosage regimens were simulated for the combination therapy. Serial samples were taken from the cartridges for viable counting at 0, 1,2,4,6,23,25,26,28,47,49,50,52,71,73,74,76,95,97,98, 100, and 120 h. At 23, 47, 71, 95, and 120 h, PAPs were carried out on polymyxin B-containing plates at 0.5, 1, 2, 4, and/or 8 mg/liter to detect the emergence of polymyxin resistance (42,63).…”

“…Combination therapy has been proposed as a novel strategy to maximize the antimicrobial efficacy against XDR pathogens and suppress the spread of resistance (24,(27)(28)(29)(30)(31)(32). Enrofloxacin is a fluoroquinolone with broad-spectrum activity against Grampositive and Gram-negative bacteria, and it was originally developed for veterinary use (33)(34)(35)(36).…”

Intravenous minocycline in multidrug-resistant infections: a profile of its use in the USA with a focus on Acinetobacter infections

“…colistin [29]. The combination of polymyxin B and minocycline also shown bactericidal efficacy against Klebsiella pneumoniae carbapenemase-producing K. pneumonia in a preliminary in vitro study [30].…”