Anthelmintic closantel enhances bacterial killing of polymyxin B against multidrug-resistant Acinetobacter baumannii

Abstract

Polymyxins, an old class of antibiotics, are currently used as the last resort for the treatment of multidrug-resistant (MDR) Acinetobacter baumannii. However, recent pharmacokinetic and pharmacodynamic data indicate that monotherapy can lead to the development of resistance. Novel approaches are urgently needed to preserve and improve the efficacy of this last-line class of antibiotics. This study examined the antimicrobial activity of novel combination of polymyxin B with anthelmintic closantel against A. baumannii. Closantel monotherapy (16 mg/L) was ineffective against most tested A. baumannii isolates. However, closantel at 4-16 mg/L with a clinically achievable concentration of polymyxin B (2 mg/L) successfully inhibited the development of polymyxin resistance in polymyxin-susceptible isolates, and provided synergistic killing against polymyxin-resistant isolates (MIC ≥4 mg/L). Our findings suggest that the combination of polymyxin B with closantel could be potentially useful for the treatment of MDR, including polymyxin-resistant, A. baumannii infections. The re-positioning of non-antibiotic drugs to treat bacterial infections may significantly expedite discovery of new treatment options for bacterial 'superbugs'.

Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet?

“…However, despite rapid initial killing, re-growth often occurs quickly (as early as within 2 h of the initial exposure). PMB displays very similar pharmacodynamics to that of colistin, with similar rapid killing against A. baumannii , K. pneumoniae and P. aeruginosa in vitro, followed by rapid re-growth [35–37]. In polymyxin-heteroresistant strains, amplification of polymyxin-resistant subpopulations has been shown to play an important role in the rapid emergence of resistance [38–40].…”

Novel Polymyxin Combination with the Antiretroviral Zidovudine Exerts Synergistic Killing against NDM-Producing Multidrug-Resistant Klebsiella pneumoniae

“…The use of synergistic combinations of antibiotics with FDA-approved nonantibiotics has been proposed as a promising alternative to improve the clinical efficacy of polymyxins against these problematic MDR Gram-negative pathogens (13,(15)(16)(17)(18)(19). To date, a number of studies have shown that polymyxin B in combination with FDA-approved nonantibiotics drugs (e.g., ascorbic acid [20], benserazide [20], chloroxine [20], closantel [16], loperamide [21], tamoxifen [17], tegaserod [20], mitomycin C [20], mitotane [19], ivacaftor [15], and silver nanoparticles [18]) display synergistic killing activity against MDR Pseudomonas aeruginosa and Acinetobacter baumannii. However, only several studies investigated the efficacy of polymyxin combinations with nonantibiotic drugs against NDM-producing MDR K. pneumoniae (13,17,18).…”

The in vitro antibacterial activity of the anthelmintic drug oxyclozanide against common small animal bacterial pathogens

“…Although oxyclozanide has displayed poor activity against Gram‐negative bacterial pathogens in this study, it could conceivably have a role as an adjuvant. A previous study found that the salicylanilide closantel enhanced the bacterial killing of polymyxin B against MDR Acinetobacter baumanni , including polymyxin B‐resistant strains . For clinical application and safety, identifying the topical dermal irritant threshold concentration of oxyclozanide also is recommended.…”