Miconazole Induces Fungistasis and Increases Killing of Candida albicans Subjected to Photodynamic Therapy

Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.
Photochemistry and Photobiology (Impact Factor: 2.27). 11/2011; 88(3):596-603. DOI: 10.1111/j.1751-1097.2011.01039.x
Source: PubMed


Cutaneous and mucocutaneous Candida infections are considered to be important targets for antimicrobial photodynamic therapy (PDT). Clinical application of antimicrobial PDT will require strategies that enhance microbial killing while minimizing damage to host tissue. Increasing the sensitivity of infectious agents to PDT will help achieve this goal. Our previous studies demonstrated that raising the level of oxidative stress in Candida by interfering with fungal respiration increased the efficiency of PDT. Therefore, we sought to identify compounds in clinical use that would augment the oxidative stress caused by PDT by contributing to reactive oxygen species (ROS) formation themselves. Based on the ability of the antifungal miconazole to induce ROS in Candida, we tested several azole antifungals for their ability to augment PDT in vitro. Although miconazole and ketoconazole both stimulated ROS production in Candida albicans, only miconazole enhanced the killing of C. albicans and induced prolonged fungistasis in organisms that survived PDT using the porphyrin TMP-1363 and the phenothiazine methylene blue as photosensitizers. The data suggest that miconazole could be used to increase the efficacy of PDT against C. albicans, and its mechanism of action is likely to be multifactorial.

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    • "The increased numbers of fungal infections and the subsequent need for high-cost and time-consuming development of new antimicrobial strategies and anti-infectives has emerged as a major problem among infectious diseases researchers and clinicians [6,26]. Antimicrobial PDT is one of the most promising alternative countermeasures for cutaneous or mucosal infections, caused by either bacteria or fungi [6,26]. "
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    ABSTRACT: Candida spp. are recognized as a primary agent of severe fungal infection in immunocompromised patients, and are the fourth most common cause of bloodstream infections. Our study explores treatment with photodynamic therapy (PDT) as an innovative antimicrobial technology that employs a nontoxic dye, termed a photosensitizer (PS), followed by irradiation with harmless visible light. After photoactivation, the PS produces either singlet oxygen or other reactive oxygen species (ROS) that primarily react with the pathogen cell wall, promoting permeabilization of the membrane and cell death. The emergence of antifungal-resistant Candida strains has motivated the study of antimicrobial PDT (aPDT) as an alternative treatment of these infections. We employed the invertebrate wax moth Galleria mellonella as an in vivo model to study the effects of aPDT against C. albicans infection. The effects of aPDT combined with conventional antifungal drugs were also evaluated in G. mellonella. We verified that methylene blue-mediated aPDT prolonged the survival of C. albicans infected G. mellonella larvae. The fungal burden of G. mellonella hemolymph was reduced after aPDT in infected larvae. A fluconazole-resistant C. albicans strain was used to test the combination of aPDT and fluconazole. Administration of fluconazole either before or after exposing the larvae to aPDT significantly prolonged the survival of the larvae compared to either treatment alone. G. mellonella is a useful in vivo model to evaluate aPDT as a treatment regimen for Candida infections. The data suggests that combined aPDT and antifungal therapy could be an alternative approach to antifungal-resistant Candida strains.
    Full-text · Article · Oct 2013 · BMC Microbiology
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    • "Conventional antimicrobial therapy could be combined with aPDT as an adjunct therapy [58]. The combination of PDT with antimicrobials has been used with success when compared to either approach [23], [63]. "
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    ABSTRACT: has emerged as one of the most important pathogens in healthcare-associated infections worldwide due to its intrinsic and acquired resistance to many antibiotics, including vancomycin. Antimicrobial photodynamic therapy (aPDT) is an alternative therapeutic platform that is currently under investigation for the control and treatment of infections. PDT is based on the use of photoactive dye molecules, widely known as photosensitizer (PS). PS, upon irradiation with visible light, produces reactive oxygen species that can destroy lipids and proteins causing cell death. We employed (the greater wax moth) caterpillar fatally infected with to develop an invertebrate host model system that can be used to study the antimicrobial PDT (alone or combined with antibiotics). In the establishment of infection by in , we found that the death rate was dependent on the number of bacterial cells injected into the insect hemocoel and all strains tested were capable of infecting and killing . Antibiotic treatment with ampicillin, gentamicin or the combination of ampicillin and gentamicin prolonged caterpillar survival infected by ( = 0.0003, = 0.0001 and = 0.0001, respectively). In the study of antimicrobial PDT, we verified that methylene blue (MB) injected into the insect followed by whole body illumination prolonged the caterpillar survival ( = 0.0192). Interestingly, combination therapy of larvae infected with vancomycin-resistant , with antimicrobial PDT followed by vancomycin, significantly prolonged the survival of the caterpillars when compared to either antimicrobial PDT ( = 0.0095) or vancomycin treatment alone ( = 0.0025), suggesting that the aPDT made the vancomycin resistant strain more susceptible to vancomycin action. In summary, provides an invertebrate model host to study the antimicrobial PDT and to explore combinatorial aPDT-based treatments.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "This persister phenotype hypothesis has been proven for C. albicans biofilms using amphotericin B and chlorhexidine (Lafleur et al., 2006) as well as in patients with long-term oral carriage harbor high-persister mutants (Lafleur et al., 2010). This concept may explain partially the mechanism of action in the success of miconazole to augment PDI-mediated by the porphyrin TMP-1363 and MB in C. albicans (Snell et al., 2011). In this study, a list of antifungals were tested, miconazole and ketoconazole both stimulated ROS production in C. albicans, but only miconazole enhanced the killing of C. albicans and induced prolonged fungistasis in organisms that survived PDI. "
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    ABSTRACT: Opportunistic fungal pathogens may cause superficial or serious invasive infections, especially in immunocompromised and debilitated patients. Invasive mycoses represent an exponentially growing threat for human health due to a combination of slow diagnosis and the existence of relatively few classes of available and effective antifungal drugs. Therefore systemic fungal infections result in high attributable mortality. There is an urgent need to pursue and deploy novel and effective alternative antifungal countermeasures. Photodynamic therapy (PDT) was established as a successful modality for malignancies and age-related macular degeneration but photodynamic inactivation has only recently been intensively investigated as an alternative antimicrobial discovery and development platform. The concept of photodynamic inactivation requires microbial exposure to either exogenous or endogenous photosensitizer molecules, followed by visible light energy, typically wavelengths in the red/near infrared region that cause the excitation of the photosensitizers resulting in the production of singlet oxygen and other reactive oxygen species that react with intracellular components, and consequently produce cell inactivation and death. Antifungal PDT is an area of increasing interest, as research is advancing (i) to identify the photochemical and photophysical mechanisms involved in photoinactivation; (ii) to develop potent and clinically compatible photosensitizers; (iii) to understand how photoinactivation is affected by key microbial phenotypic elements multidrug resistance and efflux, virulence and pathogenesis determinants, and formation of biofilms; (iv) to explore novel photosensitizer delivery platforms; and (v) to identify photoinactivation applications beyond the clinical setting such as environmental disinfectants.
    Full-text · Article · Apr 2012 · Frontiers in Microbiology
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