Activity of Polymyxin B and the Novel Polymyxin Analogue CB-182,804 Against Contemporary Gram-Negative Pathogens in New York City

Abstract

Multidrug-resistant Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa have become common in many regions, often requiring therapy with colistin or polymyxin B. An increase in resistance to these agents would render many infections untreatable. We tested the activity of polymyxin B and the novel polymyxin analogue CB-182,804 against over 5,000 recent Gram-negative clinical isolates from New York City, a region with a high prevalence of multiresistant strains. Over 96% of Escherichia coli, K. pneumoniae, A. baumannii, and P. aeruginosa were susceptible to polymyxin B; only 76% of Enterobacter spp. was susceptible. The MICs of CB-182,804 were generally two-fold higher than polymyxin B and cross-resistance was observed. The addition of rifampin resulted in synergistic inhibition and bactericidal activity in time kill studies, and restored activity against all polymyxin-resistant strains. The synergistic effect of the combination with rifampin was most pronounced against A. baumannii strains, and was slightly greater with CB-182,804 than with polymyxin B against K. pneumoniae and Enterobacter spp. Despite considerable usage of polymyxin B and colistin in this region, polymyxin B retains excellent activity against most Gram-negative isolates. CB-182,804 shows similar activity, particularly when combined with rifampin. The clinical utility of CB-182,804 remains to be determined.

Pharmacology of Polymyxins: New Insights into an ‘Old‘ Class of Antibiotics

“…The availability of large quantities of polymyxin B/colistin and ease of semisynthesis has meant that most medicinal chemistry programs have focused on generating N-terminal analogs of the polymyxin molecule [56–62]. The available SAR data indicate that a hydrophobic substituent at the N-terminus of the polymyxin molecule is indispensable for antimicrobial activity.…”

“…However, the LPS-binding affinity of the polymyxin molecule appears to correlate with the hydrophobicity of the N-terminal substituent [58,63]. Interestingly, the Cubist Pharmaceuticals polymyxin clinical candidate CB-182,804 contained a shorter N-terminal 2-chlorophenyl carbamate group, yet had comparable in vitro and in vivo antibacterial activity with polymyxin B and colistin [62]. Furthermore, there has been a recent report describing des-fatty acyl polymyxin analogs that display selective antimicrobial activity against P. aeruginosa [64].…”

New antibiotics for bad bugs: where are we?

“…CB-182,804 has showed high activity against colistin-susceptible and -resistant isolates. Colistin-resistant strains that are resistant to all available antibiotics are found to be susceptible, even if a cross resistance with colistin has been observed [98]. Currently the drug is in Phase I clinical stage.…”

Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections

“…The activity of CB-182 804 was explored against a wide range of clinical isolates and this compound was shown to have MIC 50 and MIC 90 values approximately one dilution (2 × ) less potent than PMB. 67 Efficacy was determined in thigh and lung infection models and was generally similar to PMB and colistin. 68 CB-182 804 had an EC 50 against the rat renal proximal tubule cell line LLC-PK1 of 41000 μg ml − 1 compared with 318 μg ml − 1 for PMB.…”