In Vitro Spectrum of Pexiganan Activity When Tested against Pathogens from Diabetic Foot Infections and with Selected Resistance Mechanisms

Abstract

Pexiganan, a 22-amino-acid synthetic cationic peptide, is currently in phase 3 clinical trials as a topical antimicrobial agent for the treatment of mild infections associated with diabetic foot ulcers. Bacterial isolates from the 2013 SENTRY Antimicrobial Surveillance Program designated as pathogens from diabetic foot infections (DFI) and Gram-negative and -positive pathogens from various infection types that harbored selected resistance mechanisms/phenotypes were tested against pexiganan in reference cation-adjusted Mueller-Hinton broth. The MIC 50 and MIC 90 against all organisms tested from DFI were 16 and 32 g/ml, respectively. Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter cloacae, Acinetobacter species, and Pseudomonas aeruginosa MIC values ranged from 8 to 16 g/ml. Pexiganan MIC values among Staphylococcus aureus (methicillinresistant S. aureus [MRSA] and methicillin-susceptible S. aureus [MSSA]), beta-hemolytic streptococci, and Enterococcus faecium ranged from 8 to 32 g/ml. Pexiganan activity was not adversely affected for members of the family Enterobacteriaceae or P. aeruginosa that produced ␤-lactamases or resistance mechanisms to other commonly used antimicrobial agents. Decreased susceptibility to vancomycin did not affect pexiganan activity against S. aureus or E. faecium. Enterococcus faecalis appears to be intrinsically less susceptible to pexiganan (MIC, 32 to 256 g/ml). The "all organism" MIC 90 of 32 g/ml for pexiganan in this study was >250-fold below the pexiganan concentration in the cream/delivery vehicle being developed for topical use. Magainans are broad-spectrum antimicrobial agents found in animals that provide innate immunity to defend against microbes in the environment (1-3). These cationic peptides selectively damage bacterial membranes through mechanisms that make the development of resistance to these agents by bacteria extremely difficult (1, 2). Many antimicrobial peptides exist in nature; protegrins and defensins are examples (3-5). Pexiganan is a 22-amino-acid synthetic analogue of peptide magainin II undergoing phase 3 development as a topical agent (pexiganan cream 0.8% [8,000 g/ml pexiganan free base]) for treatment of mild infections of diabetic foot ulcers (ClinicalTrials.gov registration numbers NCT01594762 and NCT01590758).Common bacterial pathogens associated with mild (usually treated with oral agents) diabetic foot infections (DFI) include Staphylococcus aureus and Streptococcus spp. (6). In moderate to severe infections, S. aureus, Streptococcus spp., members of the family Enterobacteriaceae, and obligate anaerobes are the common bacterial pathogens (6). In a prospective randomized clinical trial of severe DFI, enterococci and Pseudomonas aeruginosa occurred in approximately 10 and 20% of patients, respectively (7). Pexiganan has been shown to have activity against many of the abovementioned pathogens (8-10).The available susceptibility profiles for pexiganan were published in the late 1990s (8-10). To determine whether the current sus...

In vitro spectrum of pexiganan activity; bactericidal action and resistance selection tested against pathogens with elevated MIC values to topical agents

“…Pexiganan has been shown previously to exhibit broad-spectrum activity (Flamm et al, 2015;Fuchs et al, 1998;Ge et al, 1999b;Ge et al, 1999a) (Ge et al, 1999b). When isolates from patiets with diabetic foot infections from two clinical trials were tested, MIC results were similar to those above (Ge et al, 1999a).…”

“…Those diabetic foot isolates were not selected for any particular resistance pattern. In that study (Flamm et al, 2015), there were several Enterobacteriaceae isolates with MIC values >256 µg/mL for pexiganan, and in this study there were three gram-negative isolates with PMB MIC values of >4 µg/mL which also had elevated pexiganan MIC results (≥1024 µg/mL). Further study of pexiganan activity against PMB-resistant bacteria will be necessary to determine how frequently elevated MIC values to both these agents would occur together among Gram-negative bacteria.…”

“…For S. aureus, this was shown as pexiganan MIC values (4-32 µg/mL) were similar for the subsets of isolates with elevated MIC values to the various topical antimicrobials. The pexiganan MIC values for this collection of non-WT isolates were identical to the mode and MIC 50 value exhibited when pexiganan was tested against 20 S. aureus isolates selected from diabetic foot infections (Flamm et al, 2015). Those diabetic foot isolates were not selected for any particular resistance pattern.…”

Current and Emerging Topical Antibacterials and Antiseptics: Agents, Action, and Resistance Patterns

“…As topical antimicrobial agents, both ebselen and PXL150 are still in preclinical development. However, another emerging topical antimicrobial agent is pexiganan, a cationic peptide that is in phase 3 clinical development for topical use (190,191). Clinically, pexiganan has been evaluated against systemic ofloxacin for the treatment of mildly infected diabetic foot ulcers, and it demonstrated clinical and microbiological equivalence in one study involving 835 patients (192).…”

“…Pexiganan has a broad spectrum of activity against Gram-positive and Gram-negative pathogens (193), and it is thought to act by interacting with the negatively charged lipid bilayer, inducing toroid-like pore formation and subsequent disruption of the bacterial membrane (194). In vitro studies have shown good activity against S. aureus, CoNS, and S. pyogenes, with minimal development of resistance on serial passage at sub-MIC concentrations and no apparent cross-resistance to other commonly used topical agents, such as mupirocin and fusidic acid (190,191).…”