JAC Advance Access originally published online on February 29, 2008
Journal of Antimicrobial Chemotherapy 2008 61(5):1092-1098; doi:10.1093/jac/dkn074
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Original research |
Antimicrobial activity of omiganan pentahydrochloride tested against contemporary bacterial pathogens commonly responsible for catheter-associated infections
1 JMI Laboratories, North Liberty, IA 52317, USA 2 Universidade Federal de Sao Paulo, Sao Paulo, Brazil 3 Tufts University School of Medicine, Boston, MA, USA
* Corresponding author. Tel: +1-319-665-3370; Fax: +1-319-655-3371; E-mail: thomas-fritsche{at}jmilabs.com
Received 14 November 2007; returned 29 December 2007; revised 17 January 2008; accepted 31 January 2008
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Abstract |
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Objectives: Omiganan pentahydrochloride is a cidal cationic peptide with a broad antimicrobial spectrum, including yeast, currently in development as a topical agent for the prevention of catheter-associated infections. We evaluated the spectrum and potency of omiganan against pathogens commonly associated with such infections.
Methods: A recent (2005–06) collection of bacterial isolates originating from patients with bloodstream, respiratory tract, and skin and skin structure infections in US medical centres was evaluated by reference broth microdilution methods against omiganan and comparator agents.
Results: All tested Gram-positive (390) and -negative (167) isolates were inhibited by 
128 and 1024 mg/L, respectively, of omiganan. The agent was the most active against coagulase-negative staphylococci (range 1–8 mg/L; MIC50/90, 4 mg/L) and inhibited all Staphylococcus aureus at 32 mg/L (MIC50/90, 16 mg/L). Omiganan was 16-fold more active against Enterococcus faecium than Enterococcus faecalis (MIC50/90 results, 4/8 versus 64/128 mg/L, respectively). MIC ranges and MIC50 potencies were unaffected by methicillin resistance in staphylococci, vancomycin resistance in enterococci, and penicillin resistance in streptococci. Omiganan potency was also unaffected by extended-spectrum β-lactamase (ESBL) production in Escherichia coli when compared with wild-type strains (MIC50 values 32 mg/L), although a 4-fold increase was noted among ESBL-positive Klebsiella spp. (128 versus 32 mg/L, respectively). Wild-type Enterobacter spp. displayed higher omiganan MIC50/90 results (64/512 mg/L) compared with AmpC-hyperproducing strains (32/64 mg/L). Carbapenem-susceptible and -resistant P. aeruginosa strains exhibited omiganan MIC50/90 values of 128/256 mg/L.
Conclusions: At a 1% (10 000 mg/L) topical gel formulation, omiganan can be expected to inhibit all clinically relevant bacterial species producing catheter-associated infections (all MIC values, 1024 mg/L), including those with antimicrobial-resistant phenotypes.
Keywords: cationic peptides , topical antimicrobials , resistance , bloodstream infections
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Introduction |
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Central venous catheters, among venous access devices, are a major source of preventable bloodstream infections with an estimated 250 000 cases occurring annually in the USA.1,2 Non-tunnelled central venous catheter infections are thought to arise primarily from colonization of the extraluminal surfaces with skin microbiota following placement and secondarily from colonization of the catheter hub and catheter lumen. Given the excess length of hospital stay, additional costs, and attributable morbidity and mortality patients may experience from catheter-related bloodstream infections, prevention of local catheter site infections is one critical component in controlling the incidence of nosocomial infections and improving patient outcomes.1,2
The use of the antiseptics povidine-iodine, isopropyl alcohol and/or chlorhexidine gluconate, including use of a chlorhexidine-impregnated dressing patch, is among the more common skin decontamination techniques currently recommended.1 Rigorous attention to daily catheter insertion-site assessment and dressing care are also important preventative components of an infection reduction programme. The larger list of antimicrobial agents used topically for wound care, but not for catheter care, includes mupirocin, fusidic acid, triple-antibiotic ointment (TAO) and the recently approved pleuromutilin compound, retapamulin.3 All these are used for infections presumably caused by bacteria, as they are generally narrow spectrum and are inactive against fungi. Among novel agents in development, cationic peptides and the related cationic steroid antimicrobials that mimic naturally occurring antimicrobial peptides are other classes with broad potential for topical decontamination.4 One of these agents, omiganan pentahydrochloride, is a novel peptide analogue of indolicidin that has a broad spectrum of rapidly cidal activity including Gram-positive and -negative bacterial species and, importantly, yeast, and is known to significantly reduce normal skin flora counts following topical applications.5,6 This agent is being developed as a topical antimicrobial, targeting the prevention of local catheter-site infections and, secondarily, catheter-related bloodstream infections, and is currently in a Phase III USA and European clinical trial for the prevention of catheter-associated infections.7
The purpose of this study was to update and expand the analysis of omiganan activity against prevalent Gram-positive and -negative pathogens [coagulase-negative staphylococci (CoNS), Staphylococcus aureus, Pseudomonas spp., Enterobacteriaceae and Enterococcus spp.], including strains with emerging resistance phenotypes, to better characterize the compound's breadth of spectrum and potency against those species most commonly associated with catheter-associated infections.1
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Materials and methods |
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Organism collection
Omiganan activity was determined against contemporary (2005–06 USA isolates) bacterial pathogens originating from bloodstream, respiratory tract, or skin and skin structure infections. Organisms examined (557 isolates; resistant phenotypes over-represented) included S. aureus [110; oxacillin-susceptible (MSSA; 49), oxacillin-resistant (MRSA; 30) and community-associated (CA)-MRSA (USA300 strains; 31)]; CoNS [104; oxacillin-susceptible (43) and oxacillin-resistant (61)]; Enterococcus faecalis [44; vancomycin-susceptible (24) and vancomycin-resistant (20)]; Enterococcus faecium [67; vancomycin-susceptible (31) and vancomycin-resistant (36)]; β-haemolytic-streptococci (30); viridans group streptococci [35; penicillin-susceptible (15), penicillin-intermediate (5) and penicillin-resistant (15)]; Escherichia coli [43; wild-type (32) and extended-spectrum β-lactamase (ESBL)-producers (11)]; Klebsiella spp. [41; wild-type (30) and ESBL-producers (11)]; Enterobacter spp. [42; wild-type (30) and derepressed AmpC-hyperproducing mutants (12)]; and P. aeruginosa [41; carbapenem-susceptible (30), carbapenem-intermediate (1) and carbapenem-resistant (10)].
Broth microdilution MIC testing was performed according to CLSI methods [documents M7-A7 (2006) and M100-S17 (2007)].8,9 Panels were produced by JMI Laboratories (North Liberty, IA, USA) using cation-adjusted Mueller–Hinton broth (with the addition of 2% to 5% lysed horse blood supplement for the testing of fastidious streptococci). Omiganan (supplied by Cadence Pharmaceuticals, San Diego, USA) was tested from 0.5 to 1024 mg/L. Quality control (QC) was performed per M7-A7 (2006) and M100-S17 (2007) recommendations and guidelines (omiganan QC ranges are as specified by Anderegg et al.10) using the following strains: S. aureus ATCC 29213, Streptococcus pneumoniae ATCC 49619, E. faecalis ATCC 29212, E. coli ATCC 25922 and P. aeruginosa ATCC 27853. All routine QC results for omiganan and comparison antimicrobial agents were within the control ranges as specified.10
Interpretive criteria for comparator agents, where available, were those as published by CLSI.9 Other breakpoints utilized were: mupirocin at 8 mg/L (susceptible; low-level) and high-level resistance at >256 mg/L; neomycin at 10 mg/L (susceptible); bacitracin at 3.12 mg/L (susceptible); and fusidic acid at <2 mg/L (susceptible). The TAO breakpoint used was that of the most active component (neomycin, polymyxin B or bacitracin) as suggested earlier by our group.3
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Results |
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All tested Gram-positive isolates were inhibited by
128 mg/L of omiganan (Table 1), with CoNS displaying the lowest MIC values (1 mg/L), and enterococci and viridians group streptococci the highest (128 mg/L). Omiganan was 4-fold more active against CoNS (MIC50/90, 4 mg/L) than against S. aureus (MIC50/90, 16 mg/L), although all isolates, including CA-MRSA, were inhibited by 32 mg/L (Table 2).
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Omiganan was consistently more active against E. faecium (MIC50/90, 4/8 mg/L) than against E. faecalis (64/128 mg/L; 16-fold higher; Tables 1 and 2). Omiganan was slightly more active against β-haemolytic streptococci than against viridans group streptococci (MIC90, 32 and 128 mg/L, respectively). The presence of commonly occurring resistance mechanisms (oxacillin resistance in staphylococci, vancomycin resistance in enterococci and penicillin resistance in streptococci) had no adverse effect on MIC50 potency measurements of omiganan (Tables 1 and 2).
Among comparator agents targeting staphylococci, fusidic acid (MIC50, 0.12 mg/L), mupirocin (MIC50, 4 mg/L) and vancomycin (MIC50, 1 and 2 mg/L) remained active. Notably, 1.8% to 4.8% of these species displayed MICs of mupirocin that were >256 mg/L (high-level resistance). Although TAO remained active against most CoNS, susceptibilities varied from 83.7% for MSSA to 16.7% for MRSA (data not shown).
Omiganan activity (MIC50, mg/L) against Gram-negative pathogens in decreasing order was: E. coli = Klebsiella spp. (32), Enterobacter spp. (64) and P. aeruginosa (128; Table 2). Highest MIC results were observed among Enterobacter spp. (1024 mg/L) and Klebsiella spp. (512 mg/L) isolates (Tables 1 and 2). Omiganan potency was unaffected by ESBL production in E. coli when compared with wild-type strains (MIC50 values 32 mg/L), although a 4-fold increase was noted among ESBL-positive Klebsiella spp. (128 versus 32 mg/L, respectively) (Table 1). AmpC-hyperproducing Enterobacter spp. showed lower omiganan MIC50/90 results (32/64 mg/L) than did wild-type strains (64/512 mg/L; Table 1), although the reason remains unclear. Carbapenem-susceptible and -resistant P. aeruginosa strains exhibited omiganan MIC50/90 values of 128/256 mg/L (Table 1).
Although TAO and its active components neomycin and polymyxin-B inhibited E. coli (100%), Klebsiella spp. (97.6%), Enterobacter spp. (97.6%) and P. aeruginosa (100.0%; Table 2), they were less active against ESBL-positive Klebsiella spp. (90.9%), unlike omiganan (data not shown). Although a breakpoint for omiganan has not been established, MICs above 1024 mg/L have not been described here or elsewhere, and the omiganan MIC population appears unimodal (exclusively wild-type; Table 1).
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Discussion |
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Suppression of cutaneous colonization and ingress of pathogens along the subcutaneous catheter tract are approaches aimed at decreasing the incidence of catheter-associated infections. The use of chlorhexidine gluconate as part of skin decontamination and placement of a chlorhexidine-impregnated ‘patch’ at the site of catheter insertion have been shown to be efficacious in reducing catheter colonization, although actual reductions in bloodstream infection rates have been less clear.1 The use of catheters that are impregnated with silver sulfadiazine, chlorhexidine or antimicrobials has also been shown to decrease nosocomial bloodstream infection rates, but are recommended interventions only when other preventive strategies do not achieve proscribed benchmark values.2
As a topical agent, omiganan is being developed for application at the catheter insertion site following placement and at each dressing change to prevent catheter-associated infections and, secondarily, catheter-related bloodstream infections.6,7 In an initial study of the spectrum of omiganan, the agent was shown to be broadly active against a variety of Gram-positive and -negative pathogens and yeast (Candida spp.) encountered in catheter-related bloodstream infections (MIC90 ranges, 4–256, 32–256 and 32–512 mg/L, respectively).5 Preliminary results from the analysis of more than 1600 clinical trial isolates demonstrated that all bacterial and fungal isolates were inhibited by 512 mg/L of omiganan.7
In this in vitro survey, we found that omiganan was active against all commonly isolated Gram-positive pathogens known to produce catheter-associated infections: staphylococci, including MRSA and CA-MRSA strains (all inhibited by 32 mg/L); enterococci, including vancomycin-resistant strains (128 mg/L); and streptococci, including penicillin-resistant strains (128 mg/L). Among Enterobacteriaceae, E. coli, Klebsiella spp. and Enterobacter spp. were all inhibited by 64, 512 and 1024 mg/L, respectively, with no differences observed among strains resistant to advanced-generation cephalosporins (ESBL-producing and AmpC-hyperproducing strains). Likewise, carbapenem-susceptible and -resistant P. aeruginosa showed no differences in omiganan susceptibilities (all 256 mg/L).
None of the topically utilized comparator agents tested retains an antibacterial spectrum that compares with that of omiganan, which when coupled with this compound's recognized activity against Candida spp. represents a ‘first-in-class’ agent that displays antimicrobial inhibition of all major pathogens responsible for local catheter site and catheter-related bloodstream infections.5,7 Given the lack of described bacterial or fungal resistance to omiganan, the current 1% clinical formulation concentration (topical gel, 10 000 mg/L) can be expected to cover the pathogens implicated in intravascular catheter-associated infections. Ongoing surveillance of susceptibility of bacterial and yeast pathogens causing such infections is warranted to recognize resistance trends, especially to newer agents in development or recently released novel compounds for which resistance has yet to be described.
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Funding |
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This study was funded by an educational/research grant from Cadence Pharmaceuticals.
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T. R. F., H. S. S. and R. N. J. have received research/education grants in the last 3 years from Cadence Pharmaceuticals. P. R. R.: none to declare.
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Acknowledgements |
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This material was presented in part at the Forty-seventh Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.
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References |
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1 Viale P, Stefani S. Vascular catheter-associated infections: a microbiological and therapeutic update. J Chemother (2006) 18:235–49.[Web of Science][Medline]
2 Schuerer DJ, Zack JE, Thomas J, et al. Effect of chlorhexidine/silver sulfadiazine-impregnated central venous catheters in an intensive care unit with a low blood stream infection rate after implementation of an educational program: a before–after trial. Surg Infect (Larchmt) (2007) 8:445–54.[CrossRef][Medline]
3 Jones RN, Li Q, Kohut B, et al. Contemporary antimicrobial activity of triple antibiotic ointment: a multiphased study of recent clinical isolates in the United States and Australia. Diagn Microbiol Infect Dis (2006) 54:63–71.[CrossRef][Web of Science][Medline]
4 Gordon YJ, Romanowski EG, McDermott AM. A review of antimicrobial peptides and their therapeutic potential as anti-infective drugs. Curr Eye Res (2005) 30:505–15.[CrossRef][Web of Science][Medline]
5
Sader HS, Fedler KA, Rennie RP, et al. Omiganan pentahydrochloride (MBI 226), a topical 12-amino-acid cationic peptide: spectrum of antimicrobial activity and measurements of bactericidal activity. Antimicrob Agents Chemother (2004) 48:3112–8.
6 Isaacson RE. MBI-226. Micrologix/Fujisawa. Curr Opin Investig Drugs (2003) 4:999–1003.[Medline]
7 Ross JE, Jones RN, Rhomberg PR, et al. In vitro activity of omiganan pentahydrochloride against >1,600 clinical trial isolates. (2007) Abstracts of the Forty-fifth IDSA Annual Meeting: San Diego, CA. Arlington, VA, USA: Infectious Diseases Society of America. 139. Abstract 433.
8 Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Seventh Edition: Approved Standard M7-A7. (2006) Wayne, PA, USA: CLSI.
9 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Seventeenth Informational Supplement M100-S17. (2007) Wayne, PA, USA: CLSI.
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Anderegg TR, Fritsche TR, Jones RN. Quality control guidelines for MIC susceptibility testing of omiganan pentahydrochloride (MBI 226), a novel antimicrobial peptide. J Clin Microbiol (2004) 42:1386–7.
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