Background: 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.Results: 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.Conclusions: 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.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Science and Technology Planning Project of Guangdong Province, P.R. ChinaFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)NIHUS Air Force MFEL ProgramUniv Estadual Paulista UNESP, Dept Biosci & Oral Diag, BR-12245000 Sao Jose Dos Campos, SP, BrazilMassachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USAFac Pindamonhangaba, Dept Restorat Dent, BR-12422970 Pindamonhangaba, SP, BrazilMassachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USANucl & Energy Res Inst, Ctr Lasers & Applicat, BR-05508000 Sao Paulo, BrazilSouthern Med Univ, Huiqiao Dept, Nanfang Hosp, Guangzhou 510515, Guangdong, Peoples R ChinaSecond Mil Med Univ, Sch Pharm, Shanghai 200433, Peoples R ChinaUniv New Mexico, Dept Pathol, Albuquerque, NM 87131 USAUniv New Mexico, Ctr Mol Discovery, Albuquerque, NM 87131 USAHarvard Univ, Sch Med, Dept Dermatol, Boston, MA 02114 USAMIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USABrown Univ, Warren Alpert Med Sch, Rhode Isl Hosp, Providence, RI 02903 USABrown Univ, Warren Alpert Med Sch, Miriam Hosp, Providence, RI 02903 USAUniv Estadual Paulista UNESP, Dept Biosci & Oral Diag, BR-12245000 Sao Jose Dos Campos, SP, BrazilCAPES: PDEE 2507-11-0Science and Technology Planning Project of Guangdong Province, P.R. China2011B080701091FAPESP: 12/19915-6NIHRO1 AI050875NIH5U54MH084690-02US Air Force MFEL ProgramFA9550-04-1-0079