Abstract
Omiganan, a bactericidal and fungicidal cationic peptide being developed as a topical gel for prevention of catheter-associated infections, inhibited commonly occurring fungal pathogens including Candida spp. (106 isolates) at ≤256 μg/ml and molds (including 10 Aspergillus isolates) at ≤1,024 μg/ml. All fungi were inhibited by omiganan at concentrations well below the 1% (10,000 μg/ml) clinical formulation, including species with reduced susceptibility to azoles and echinocandins.
Indwelling venous access devices, especially central venous catheters, are a primary source of nosocomial bloodstream infections, accounting for an estimated 250,000 cases annually in the United States (15). While staphylococci and enterococci produce most bloodstream infections, data from the National Nosocomial Infections Surveillance system and other published sources has consistently shown that approximately 8 to 10% are produced by Candida spp. (1, 14, 15). Given the importance of fungi as pathogens in compromised hosts and difficulty in medical management of these infections, prevention of their occurrence can be expected to have a significant impact on overall patient morbidity and mortality and related health care expenditures (1, 4, 5, 16). The emergence of resistance among fungal pathogens, either appearing de novo or through selection of species with intrinsic resistance mechanisms (e.g., fluconazole resistance in Candida krusei), further confounds this problem and poses special challenges in patient management (3, 11).
Prevention of local catheter site infections by both bacterial and fungal pathogens is an important component in controlling nosocomial bloodstream infections and improving patient outcomes (15, 19). Efforts to decrease infection rates have included education on proper catheter insertion techniques and care, use of sterile barrier precautions, and appropriate skin decontamination given many such infections follow from invasion of the transcutaneous catheter tract (15). The usual skin decontamination protocols have utilized povidone-iodine, isopropyl alcohol, and/or chlorhexidine gluconate, including the use of a chlorhexidine-impregnated dressing (7). The recent description of human antimicrobial peptides such as defensins and cathelicidins as possible effector molecules in prevention of infection is another novel therapeutic approach based upon the antimicrobial properties of naturally occurring compounds found in leukocytes and epithelial secretions of vertebrates (8). One such agent is omiganan, a rapidly bactericidal and fungicidal cationic peptide analog of indolicidin that is known to significantly reduce normal skin flora counts following topical applications (18). This agent is being developed as a topical antimicrobial agent and is currently in a phase III U.S. and European clinical trial for prevention of catheter-associated infections and in preclinical development for other indications (8-10, 17, 18).
The purpose of this study was to update and expand the analysis of omiganan activity against prevalent fungal pathogens, to better characterize the compound's breadth of spectrum and potency against species commonly encountered in catheter colonization and catheter-associated bloodstream infections, and also to establish the level of activity against prevalent mold species. (This material was presented in part at the 47th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy held in Chicago, IL, 11 to 20 September 2007.)
Test organisms originated from sterile site infections (126 isolates; bloodstream, respiratory tract, and deep tissues recovered during 2005 and 2006) and included Candida albicans (52 isolates), Candida glabrata (22 isolates), Candida tropicalis (11 isolates), Candida parapsilosis (11 isolates), C. krusei (10 isolates), Aspergillus spp. (10 isolates), and other mold species (10 isolates).
Broth microdilution MIC testing was performed according to CLSI methods (documents M27-A2, M27-S2, and M38-A; 2002) (6, 12, 13). Omiganan standard powder was solubilized in sterile distilled water; other agents were handled as recommended by CLSI (12, 13). Panels were produced by JMI Laboratories (North Liberty, IA) using RPMI-1640 broth supplemented with morpholinepropanesulfonic acid buffer; results were recorded at 48 h as specified, and interpretive criteria, where available, were those published in M27-S2 (12). Quality control (QC) was performed as recommended in M27-A2 and M38-A (12, 13) using the following QC strains: C. parapsilosis ATCC 22019 and C. krusei ATCC 6258. Omiganan QC ranges utilized were those of Anderegg et al. (2), and all QC results for omiganan and comparator antifungal agents were within the specified control ranges.
Omiganan inhibited all Candida sp. isolates within a 4-log2 dilution range (16 to 256 μg/ml), being most active against C. tropicalis, C. albicans, and C. krusei (concentration at which 50% or 90% of organisms are inhibited [MIC50/MIC90], 32 to 64/32 to 128 μg/ml) and least active against C. glabrata and C. parapsilosis (MIC50/MIC90, 128 to 256/256 μg/ml [Table 1]). Similar antifungal activity (MIC50, 64 μg/ml) was evident against C. krusei with intrinsic resistance to fluconazole (MIC50, 32 μg/ml) compared with that of C. albicans (MIC50, 1 μg/ml [Table 2]). While all mold isolates were inhibited by ≤1,024 μg/ml of omiganan, MIC90s for non-Aspergillus spp. were generally fourfold lower than those for Aspergillus spp. (Tables 1 and 2).
TABLE 1.
Cumulative percent inhibited at omiganan MICs tested against six groups of yeasts and molds (126 isolates)
| Organism group (no. of isolates tested) | Cumulative % organisms inhibited at MIC (μg/ml) ofa:
|
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.5 | 1 | 2 | 4 | 8 | 16 | 32 | 64 | 128 | 256 | 512 | 1,024 | |
| Candida spp. (106) | 0 | 0 | 0 | 0 | 0 | 4 | 14 | 51 | 81 | 100 | ||
| C. albicans (52) | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 65 | 100 | |||
| C. glabrata (22) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 18 | 100 | ||
| C. krusei (10) | 0 | 0 | 0 | 0 | 0 | 0 | 20 | 70 | 100 | |||
| C. parapsilosis (11) | 0 | 0 | 0 | 0 | 0 | 0 | 9 | 18 | 82 | 100 | ||
| C. tropicalis (11) | 0 | 0 | 0 | 0 | 0 | 36 | 100 | |||||
| Molds (20) | 0 | 5 | 5 | 5 | 15 | 20 | 25 | 45 | 60 | 80 | 80 | 100 |
| Aspergillus spp. (10) | 0 | 0 | 0 | 0 | 0 | 10 | 20 | 30 | 50 | 60 | 60 | 100 |
| Non-Aspergillus (10)b | 9 | 10 | 10 | 10 | 30 | 30 | 30 | 60 | 70 | 100 | ||
Omiganan clinical formulation concentration = 10,000 μg/ml.
Curvularia spp. (2 isolates), Fusarium spp. (2 isolates), Paecilomyces variotii (1 isolate), Penicillium marneffei (1 isolate), and Penicillium spp. (4 isolates).
TABLE 2.
Activities of omiganan and comparator antifungal agents tested against yeast and mold pathogens (126 isolates)
| Organism (no. of isolates tested) or antimicrobial agent | MIC (μg/ml)
|
% Organisms susceptible/ resistanta | ||
|---|---|---|---|---|
| 50% | 90% | Range | ||
| Candida albicans (52) | ||||
| Omiganan | 64 | 128 | 32-128 | —/— |
| Amphotericin B | 1 | 1 | 0.5-1 | —/— |
| Fluconazole | 1 | >64 | 0.12->64 | 67.3/30.8 |
| 5-Flucytosine | 0.12 | 1 | ≤0.03-2 | 100.0/0.0 |
| Itraconazole | 0.12 | 16 | ≤0.008-16 | 50.0/48.1 |
| Nystatin | 8 | 8 | 8 | —/— |
| Voriconazole | 0.03 | >16 | ≤0.008-16 | 75.0/25.0 |
| Candida glabrata (22) | ||||
| Omiganan | 256 | 256 | 128-256 | —/— |
| Amphotericin B | 1 | 1 | 0.5-1 | —/— |
| Fluconazole | 4 | >64 | 1->64 | 77.3/18.2 |
| 5-Flucytosine | 0.06 | 0.06 | ≤0.03-0.06 | 100.0/0.0 |
| Itraconazole | 0.12 | 0.5 | 0.03-1 | 72.7/4.6 |
| Nystatin | 8 | 8 | 8 | —/— |
| Voriconazole | 0.06 | 2 | 0.03-2 | 86.4/0.0 |
| Candida krusei (10) | ||||
| Omiganan | 64 | 128 | 32-128 | —/— |
| Amphotericin B | 1 | 2 | 0.5-2 | —/— |
| Fluconazole | 32 | 64 | 32-64 | 0.0/100.0 |
| 5-Flucytosine | 16 | 32 | 8-32 | 0.0/30.0 |
| Itraconazole | 0.5 | 0.5 | 0.12-0.5 | 10.0/0.0 |
| Nystatin | 8 | 8 | 8 | —/— |
| Voriconazole | 0.25 | 0.5 | 0.12-0.5 | 100.0/0.0 |
| Candida parapsilosis (11) | ||||
| Omiganan | 128 | 256 | 32-256 | —/— |
| Amphotericin B | 1 | 1 | 1 | —/— |
| Fluconazole | 0.5 | 16 | 0.5-16 | 81.8/0.0 |
| 5-Flucytosine | 0.12 | 0.12 | 0.06-0.12 | 100.0/0.0 |
| Itraconazole | 0.06 | 0.25 | 0.015-0.25 | 63.6/0.0 |
| Nystatin | 8 | 8 | 8 | —/— |
| Voriconazole | 0.015 | 0.12 | ≤0.008-0.12 | 100.0/0.0 |
| Candida tropicalis (11) | ||||
| Omiganan | 32 | 32 | 16-32 | —/— |
| Amphotericin B | 1 | 1 | 0.5-1 | —/— |
| Fluconazole | 0.25 | >64 | 0.12->64 | 81.8/18.2 |
| 5-Flucytosine | 0.06 | 0.12 | 0.06-0.12 | 100.0/0.0 |
| Itraconazole | 0.03 | 0.12 | 0.015-0.12 | 100.0/0.0 |
| Nystatin | 8 | 8 | 8 | —/— |
| Voriconazole | 0.015 | 16 | 0.015-16 | 72.7/27.3 |
| Aspergillus spp. (10) | ||||
| Omiganan | 128 | 1024 | 16-1024 | —/— |
| Amphotericin B | 0.5 | 1 | 0.12-1 | —/— |
| Fluconazole | >64 | >64 | 32->64 | —/— |
| 5-Flucytosine | >64 | >64 | 1->64 | —/— |
| Itraconazole | 0.03 | 0.06 | ≤0.008-0.12 | —/— |
| Nystatin | 16 | 16 | 2-32 | —/— |
| Voriconazole | 0.25 | 0.25 | 0.06-0.25 | —/— |
| Non-Aspergillus sp. molds (10) | ||||
| Omiganan | 64 | 256 | 1-256 | —/— |
| Amphotericin B | 0.25 | 0.5 | 0.015-1 | —/— |
| Fluconazole | >64 | >64 | 1->64 | —/— |
| 5-Flucytosine | >64 | >64 | 0.25->64 | —/— |
| Itraconazole | 0.06 | >16 | ≤0.008->16 | —/— |
| Nystatin | 8 | 16 | 0.5-16 | —/— |
| Voriconazole | 0.25 | 2 | ≤0.008->16 | —/— |
Criteria as published by the CLSI (2005); —, no breakpoint available.
Among comparator antifungal agents, results were highly variable and species dependent, with C. krusei being the most resistant to all agents except voriconazole (Table 2). Only amphotericin B and omiganan (MIC90, 1 to 2 and 32 to 256 μg/ml, respectively) displayed consistent activity against all yeast and mold species.
In the current clinical gel formulation of 1% gel (topical concentration, 10,000 μg/ml), omiganan was active against all commonly isolated yeast and mold pathogens (highest documented MICs, 256 and 1,024 μg/ml, respectively) associated with catheter-related or sterile site infection, including those species with intrinsically reduced susceptibilities to other antifungal agents (Table 2).
This cationic peptide (omiganan) represents a “first-in-class” topical agent that displays broad antifungal and antibacterial coverage of all major pathogens responsible for local catheter site and catheter-associated bloodstream infections; none of the currently marketed topical antimicrobials (mupirocin, triple antibiotic ointment, or retapamulin) demonstrates a spectrum that has comparable breadth. Given the availability of standardized antifungal susceptibility test methods (12, 13), ongoing surveillance of fungal pathogens implicated in catheter-associated infections will be an important management tool to anticipate changes in species composition, infection rates, and trends of resistance to the applied topical agents, including omiganan.
Acknowledgments
This study was funded by an educational/research grant from Cadence Pharmaceuticals.
We express our appreciation to the following individuals for assistance with technical support, manuscript preparation, and editorial processing: J. Streit, M. Janechek, M. Stilwell, and N. O'Mara-Morrissey.
Footnotes
Published ahead of print on 7 January 2008.
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