Photodynamic Therapy for the Treatment of Fungal Infections

Figures & data

Figure 1 Mechanisms of action of photodynamic therapy. Following light absorption, excited state ³PS* reacts with O₂ to produce ROS and ¹O₂ (type I and II reactions). Type III PSs combine properties leading to the generation of ¹O₂ and reduction of native free radicals in target cells. Type IV mechanism involves a structural change from excited state ¹PS* by photoisomerization to enable molecular target binding of the activated PS* to its cellular target site. (* represents the excited state).

Abbreviations: PS, photosensitizer; ¹PS, singlet photosensitizer; ³PS, triplet photosensitizer; ROS, reactive oxygen species; ¹O₂, singlet oxygen; O₂, oxygen.

Table 1 Overview of the Treatment Regimen, Outcome, and Side Effects for PDT Treatment of Fungal Infections Articles Cited in This Review

References	Study Type	Case Number	Fungal Species	PS	Light Source	Light Wavelength (nm)	Light Dose (J/cm^2)	Treating Sessions (Interval Time)	Combination Treatment	Outcome	Follow Up	Adverse Effects
Onychomycosis
de Oliveira GB et al^Citation18	Clinical trial	7	T. rubrum (n=6); Epidermophyton floccosum (n=1)	16% MAL	LED	NA	NA	2 sessions (60-day intervals)	Fractional CO2 laser 10.600 nm	1-year follow-up: MC 100%; ClC 79% (15/19) (nail four quadrants count) 43% (entire nail plate) No relapse.	30 days; 1 year	NA
Morgado LF et al^Citation28	Clinical trial	20 included (16 finished)	NA	AlClPc (entrapped in nanoemulsions)	LED (red light)	660	30.9	4.45±1.76 sessions (15-days interval)	No	MC 40% ClC 60%	1 month	Pain (VAS 2.76±1.87)
Tawfik AA et al^Citation29	In vivo experience (rabbit)	80	T. mentagrophytes	3 groups: MB; Gold nanoparticles; MB + gold nanoparticles	LED (red and green light)	Red (650); Green (530)	80; 100	4 sessions (48-hours intervals)	No	CC: MB 40%; Gold nanoparticles 96%; MB + gold nanoparticles 34%	48 hours after the 4th session	NA
Cronin L et al^Citation32	In vitro study	Spore suspension (A300=0.6)	T. rubrum	Rose Bengal	Laser (green)	532	68; 133; 228	NA	No	Percentage growth inhibition 15–51%	NA	NA
Fekrazad R et al^Citation33	In vitro study	Suspensions (10^6 cells/ mL)	C.albicans; T.rubrum	Citrus EO; Indocyanine green	Infrared (IR) laser; Natural and tungsten lights	810±10 (IR laser)	55 (IR laser)	NA	No	Cell reduction rates: Citrus EO + natural and tungsten light: 99.99% (C.albicans and T.rubrum); Indocyanine green + IR laser: 91.67% (C.albicans) 74.5% (T.rubrum); Fluconazole + IR laser: 38.5% (T.rubrum)	NA	NA
Smijs TG et al^Citation26	In vitro study	Suspension and spore solution	T. rubrum	Sylsens B; DP mme	Red light	600	108	NA	No	Inhibition rates: Suspension cultures: Sylsens B (10μM-50μM): 100% DP mme (30μM): 95%; Microconidia: Sylsens B (1–5μM): 100% DP mme (4–5μM): 80–90%	2 days; 7 days; 3 months	NA
Tinea pedis (interdigital type)
Sotiriou E et al^Citation35	Clinical trial	10	T. rubrum (n=4); T. mentagrophytes (n=6)	20% 5-ALA	Red light	570–670	50	1 or 3 sessions (2-week intervals)	No	CC after 3 treatments: 60% (6/10) CC at the end of follow-up: 30% (3/10)	2 months	Burning sensation during irradiation, erythema up to 1 week after therapy.
Calzavara-Pinton PG et al^Citation36	Clinical trial	9	T. mentagrophytes (n=4); T. rubrum (n=2); C. albicans (n=3)	20% 5-ALA	Broadband red light	575–700	75	1 or 4 sessions (1-week interval)	No	CC after 1 or 4 treatments: 67% (6/9) CC at the end of follow-up: 22% (2/9)	4 weeks	Localized erythema and edema during and soon after exposure; pain; desquamation after 3–5 days.
Tinea cruris
Sotiriou E et al^Citation40	Clinical trial	10	T. rubrum	20% 5-aminolevulinic acid (ALA)	Red light	570–670	50	1–2 sessions (2-week intervals)	No	MC after 1–2 treatments: 80% (8/10) MC at the end of follow-up: 40% (4/10)	8 weeks	Mild burning and stinging during the exposure; erythema and edema up to 3–4 days after therapy.
Tinea Capitis
Lu J et al^Citation42	Case report	1	NA	20% 5- ALA	LED	630	80	3 sessions (1-week interval)	Itraconazole 100 mg/day	CC 1/1 No recurrence.	3 months	Burning sensation during irradiation; temporary edema, erythema, itch, and stinging up to 1 week after therapy.
Pityriasis versicolor (PV)
Alberdi E et al^Citation43	Pilot trial	5	Malassezia spp.	2% MB	Red LED lamp	630±5	37	6 sessions (2-week intervals)	No	CC: 5/5 No relapse.	4 weeks; 22 weeks	Hypopigmentation, no other side effects or pain.
Oral candidiasis
Freire F et al^Citation47	In vitro study; in vivo study in a murine model	10^7 CFU/mL of suspension (OD570); 15 BALB/c mice	C. albicans	Methylene blue (MB); new methylene blue (NMB)	Red diode laser	660	10; 20; 40; 60 J	5 days of daily treatment	Potassium iodide (KI)	Log reduction of CFU/mL: MB+KI (40 J): 2.31 log NMB (60 J): 1.77 log Reduction of mice bioluminescent photon flux (log10): MB+KI (40J): 2 log NMB (60 J): 1 log	NA	NA
Campos L et al^Citation48	Case report	1	Candida spp.	0.01% MB	Laser	660	178	1 session	No	ClC: 1/1	72 hours	NA
Chibebe JJ et al^Citation49	In vivo experiment in Galleria mellonella model	16/group	C. albicans Can14 (wild-type); Can37 (fluconazole-resistant)	MB (1 mM)	Red light	660±15	0.9	1 time	Fluconazole (14 mg/kg)	Can14: MB-PDT prolonged suivival. Can37: MB-PDT reduced fungal burden by 0.2 log; MB-PDT+fluconazole prolonged suivival.	100 hours - 150 hours	NA
Esophageal candidiasis (EC)
Qiu H et al^Citation51	Clinical study	2	Candida spp.	Photocarcinorin (PSD-007)	Semiconductor laser	630	135; 270	1–3 sessions (1-month and 6-month intervals)	No	Case 1: CC 2/2 EC lesions Case 2: CC 1/1 EC lesions No recurrence in two cases.	14 months; 24 months	Substernal pain within 5–7 days after PDT. (both cases) A low-grade fever lasted for 5 days post PDT. (case 1)
Vulvovaginal candidiasis (VVC)
de Santi M et al^Citation55	In vivo study in a murine model	37	C. albicans	MB (100 μM); PpNetNI (10 μM)	Laser (MB); LED (PpNetNI)	660 nm (laser); 630 nm (LED)	6048 (laser); 85 (LED)	1 time	No	Reduction of fungal CFUs: 1 order of magnitude (both PSs)	7 days	No
Machado-de-Sena RM et al^Citation56	In vivo study in a murine model	77	C. albicans	MB (1 mM)	Red laser	660	18 J; 36 J	1 or 2 sessions (24-hour intervals)	No	Reduction of fungal CFUs: 1session: 1.62 log (after 24 h) 1.16 log (after 96 h); 2 sessions: 1.66 log (after 24 h)	24 hours; 96 hours	NA
Chromoblastomycosis (CBM)
Hu Y et al^Citation58	Case report; in vitro study	1 case; 0.5–2.5×10^3 conidia/mL (in vitro)	F. monophora	20% 5-ALA	LED	635	10 J	Case: 2 sessions (each including 9 times, 1-week interval)	Case: Terbinafine (250 mg/day) In vitro study: No combination.	Case: Mycological cure and clinical greatly improvement. In vitro study: Reduce fungal CFUs by 2–4 log.	Case: 1 year; In vitro study: 7 days	Hypopigmentation
Lyon JP et al^Citation59	In vitro study	Suspension of 1–5×10^6 CFU/mL	F. pedrosoi; Cladophialophora carrionii	MB (16 μg/mL; 32 μg/mL; 64 μg/mL)	LED	NA	200 mW/cm^2	1 time	No	Reduction of fungal CFUs: 4 log approximately (32 μg/mL achieved better result)	7–10 days	NA
Huang X et al^Citation60	In vivo study in Galleria mellonella model	No specific description	F. monophora	5- ALA	Laser (red light)	NA	NA	1 session	No	Extend median survival by 2.5 days. Increase hemocyte density by 1.34×10^3 cells/μL 4h after PDT.	10 days	No
Hu Y et al^Citation9	Case series; in vitro study	5 cases; Suspension: 0.5–2.5×10^3 conidia/mL	F. nubica (n=1); F. pedrosoi (n=2); F. monophora (n=2)	20% 5- ALA	LED (white light)	635	36.8 mW/cm^2 (10 J)	Cases: 4–9 sessions (1- or 2-week intervals)	Cases: Oral itraconazole 400 mg/day; oral terbinafine 250 mg/day In vitro study: Itraconazole 1μg/mL	Cases: MC: 3/5 CC: 2/5 Clinical improvement: 3/5 No new lesions. In vitro study: Reduced approximately 2×10^3 CFUs of F. monophora.	Cases:6 months - 2 years	Hypopigmentation (n=2)
Yang W et al^Citation61	Case report	1	F. monophora	20% 5-ALA	LED (red light)	630	90	3 sessions (10-day intervals)	Itraconazole 400 mg/day	CC: 1/1 No relapse.	3 months	Pain and burning sensation during irradiation; Mild pain, swelling, and exudation whining 3–5 days after PDT.
Huang X et al^Citation62	Case report	1	F. pedrosoi	10% ALA	Red light	633±10	80–100 mW/cm^2	6 sessions (1-week interval)	No	CC: 1/1 No recurrence.	6 months	NA
Lan Y et al^Citation63	Case report	1	F. monophora	20% ALA	Red light	633±10	96	4 sessions (1-week interval)	Isotretinoin 20 mg/day; Oral terbinafine 250 mg/day, itraconazole 400 mg/day; CO2 laser.	MC: 1/1 Clinical improvement.	4 months	No
Sporotrichosis
Gilaberte Y et al^Citation66	Case report and in vitro study	1 case; Suspension optical density McFarland values 0.5.	Sporothrix schenkii	Case:1% MB; In vitro study: MAL (0–6 M); MB (1 μM); NMB (1.25 μM); DMMB (1.5 μM)	LED	635 nm (case); 639.8±10 nm (in vitro study)	37	Case: 3 and 5 sessions (2-week intervals)	No	Case: Clinical improvement; In vitro study: Reduce fungal cells by 6 log10 CFUs (MB, NMB, DMMB), No change of CFU (MAL).	NA	Pain during irradiation (score 4 on a VAS)
Phaeohyphomycosis
Liu H et al^Citation68	Case report	1	Exophiala spinifera	20% ALA	Red light	633	120 mW/cm^2	3 sessions (1-week interval)	Oral terbinafine 250 mg/day, itraconazole 200 mg/day	MC: 1/1 Clinical improved greatly.	3 months	Mild burning and temporary pain during irradiation; hyperpigmentation.
Majocchi’s granuloma (MG)
Shi L et al^Citation12	Case report; in vitro study; in vivo study in guinea pig model	1 case; In vitro study: suspension 1–5×10^5 CFU/mL	T. tonsurans	Case: 10% ALA; In vitro study: 5 mM ALA; In vivo study: 10% ALA	LED	Case: 635 In vitro and in vivo study: 633	Case:120; In vitro study: 50, 100, 150, 175, 200; In vivo study: 90.	Case: 3 sessions (3- or 4-week intervals)	No	Case: CC 1/1; no recurrence. In vitro study: Reduced approximately 4×10^5 CFU/mL of fungal concentrations. (175 and 200 J/cm^2) In vivo study: Reduced the clinical lesions scoring by 6.	Case: 3 months; In vitro study: 7 days; In vivo study: 14 days	Case: Inflammatory exudation after 1st PDT. In vivo study: Erythema and exudation 24–48 hours after PDT. Scabs formed on the 8th day.
Mucormycosis
Liu Z et al^Citation11	In vitro study	6 strains; Conidia concentra- tion of 1–3×10^6 CFU/mL	R. oryzae	MB (8, 16, and 32 μg/mL)	LED	635±10	12	1 time	No	CFU reductions: 1.1 log10 (8 μg/mL MB); 2.2 log10 (16 μg/mL MB); 4.3 log10 (32 μg/mL MB).	24 hours	NA

Abbreviations: PS, photosensitizer; PDT, photodynamic therapy; ALA, aminolevulinic acid; MAL, methyl aminolevulinate; MB, methylene blue; NMB, new methylene blue; DMMB, 1.9-dimethylmethylene blue; DP mme, deuteroporphyrin monomethylester; Citrus EO, citrus aurantifolia essential oil; AlClPc, aluminium-phthalocyanine chloride; PpNetNI, Protoporphyrin IX; LED, Light-Emitting Diode; CO₂, carbon dioxide; MC, mycological cure; ClC, clinical cure; CC, complete cure; CFU, colony forming unit; VAS, visual analogue scale; NA, not available; T., Trichophyton; C., Candida; F., Foncecaea; R., Rhizopus.

de Oliveira GB, Antonio JR, Antonio CR, et al. The association of fractional CO2 laser 10.600nm and photodynamic therapy in the treatment of onychomycosis. An Bras Dermatol. 2015;90(4):468–471. doi:10.1590/abd1806-4841.20153588

 PubMed Web of Science ®Google Scholar

Morgado LF, Trávolo A, Muehlmann LA, et al. Photodynamic Therapy treatment of onychomycosis with aluminium-phthalocyanine chloride nanoemulsions: a proof of concept clinical trial. J Photochem Photobiol B. 2017;173:266–270. doi:10.1016/j.jphotobiol.2017.06.010

 Web of Science ®Google Scholar

Tawfik AA, Noaman I, El-Elsayyad H, et al. A study of the treatment of cutaneous fungal infection in animal model using photoactivated composite of methylene blue and gold nanoparticle. Photodiagnosis Photodyn Ther. 2016;15:59–69. doi:10.1016/j.pdpdt.2016.05.010

 Web of Science ®Google Scholar

Cronin L, Moffitt M, Mawad D, et al. An in vitro study of the photodynamic effect of rose bengal on trichophyton rubrum. J Biophotonics. 2014;7(6):410–417. doi:10.1002/jbio.201200168

 Web of Science ®Google Scholar

Fekrazad R, Poorsattar BMA, Ghasemi BV, et al. Eradication of C. albicans and T. rubrum with photoactivated indocyanine green, Citrus aurantifolia essential oil and fluconazole. Photodiagnosis Photodyn Ther. 2015;12(2):289–297. doi:10.1016/j.pdpdt.2014.12.009

 PubMed Web of Science ®Google Scholar

Smijs TG, van der Haas RN, Lugtenburg J, et al. Photodynamic treatment of the dermatophyte trichophyton rubrum and its microconidia with porphyrin photosensitizers. Photochem Photobiol. 2004;80(2):197–202. doi:10.1562/2004-04-22-RA-146.1

 PubMed Web of Science ®Google Scholar

Sotiriou E, Koussidou T, Patsatsi A, et al. 5-Aminolevulinic acid-photodynamic treatment for dermatophytic tinea pedis of interdigital type: a small clinical study. J Eur Acad Dermatol Venereol. 2009;23(2):203–204. doi:10.1111/j.1468-3083.2008.02783.x

 Web of Science ®Google Scholar

Calzavara-Pinton PG, Venturini M, Capezzera R, et al. Photodynamic therapy of interdigital mycoses of the feet with topical application of 5-aminolevulinic acid. Photodermatol Photoimmunol Photomed. 2004;20(3):144–147. doi:10.1111/j.1600-0781.2004.00095.x

 PubMed Web of Science ®Google Scholar

Sotiriou E, Panagiotidou D, Ioannides D. 5-Aminolevulininic acid photodynamic therapy treatment for tinea cruris caused by Trichophyton rubrum: report of 10 cases. J Eur Acad Dermatol Venereol. 2009;23(3):341–342. doi:10.1111/j.1468-3083.2008.02880.x

 Web of Science ®Google Scholar

Lu J, Li W, Zheng W, et al. Successful treatment of kerion with itraconazole and ALA-PDT: a case report. Photodiagnosis Photodyn Ther. 2019;27:385–387. doi:10.1016/j.pdpdt.2019.07.007

 Web of Science ®Google Scholar

Alberdi E, Gómez C. Successful treatment of Pityriasis Versicolor by photodynamic therapy mediated by methylene blue. Photodermatol Photoimmunol Photomed. 2020;36(4):308–312. doi:10.1111/phpp.12555

 Web of Science ®Google Scholar

Freire F, Ferraresi C, Jorge AO, et al. Photodynamic therapy of oral Candida infection in a mouse model. J Photochem Photobiol B. 2016;159:161–168. doi:10.1016/j.jphotobiol.2016.03.049

 Web of Science ®Google Scholar

Campos L, Rezende SB, Palma LF, et al. Antimicrobial photodynamic therapy to oral candidiasis not responsive to micafungin in a patient undergoing hematopoietic cell transplantation. Photodiagnosis Photodyn Ther. 2021;34:102296. doi:10.1016/j.pdpdt.2021.102296

 Web of Science ®Google Scholar

Chibebe JJ, Sabino CP, Tan X, et al. Selective photoinactivation of Candida albicans in the non-vertebrate host infection model Galleria mellonella. BMC Microbiol. 2013;13:217. doi:10.1186/1471-2180-13-217

 Web of Science ®Google Scholar

Qiu H, Mao Y, Gu Y, et al. The potential of photodynamic therapy to treat esophageal candidiasis coexisting with esophageal cancer. J Photochem Photobiol B. 2014;130:305–309. doi:10.1016/j.jphotobiol.2013.11.028

 Web of Science ®Google Scholar

de Santi M, Prates RA, França CM, et al. Antimicrobial photodynamic therapy as a new approach for the treatment of vulvovaginal candidiasis: preliminary results. Lasers Med Sci. 2018;33(9):1925–1931. doi:10.1007/s10103-018-2557-y

 Web of Science ®Google Scholar

Machado-de-Sena RM, Corrêa L, Kato IT, et al. Photodynamic therapy has antifungal effect and reduces inflammatory signals in Candida albicans-induced murine vaginitis. Photodiagnosis Photodyn Ther. 2014;11(3):275–282. doi:10.1016/j.pdpdt.2014.03.013

 Web of Science ®Google Scholar

Hu Y, Huang X, Lu S, et al. Photodynamic therapy combined with terbinafine against chromoblastomycosis and the effect of PDT on Fonsecaea monophora in vitro. Mycopathologia. 2015;179(1–2):103–109. doi:10.1007/s11046-014-9828-3

 Web of Science ®Google Scholar

Lyon JP, Moreira LM, de Carvalho VS, et al. In vitro photodynamic therapy against fonsecaea pedrosoi and cladophialophora carrionii. Mycoses. 2013;56(2):157–161. doi:10.1111/j.1439-0507.2012.02226.x

 Web of Science ®Google Scholar

Huang X, Xu M, Pan W, et al. Antimicrobial and immunomodulatory responses of photodynamic therapy in Galleria mellonella model. BMC Microbiol. 2020;20(1):196. doi:10.1186/s12866-020-01882-9

 Web of Science ®Google Scholar

Hu Y, Qi X, Sun H, et al. Photodynamic therapy combined with antifungal drugs against chromoblastomycosis and the effect of ALA-PDT on Fonsecaea in vitro. PLoS Negl Trop Dis. 2019;13(10):e7849. doi:10.1371/journal.pntd.0007849

 Web of Science ®Google Scholar

Yang W, Zhang W, Luo J, et al. 5-aminolevulinic acid-based photodynamic therapy associated with Itraconazole successfully treated a case of chromoblastomycosis. Photodiagnosis Photodyn Ther. 2020;29:101589. doi:10.1016/j.pdpdt.2019.101589

 Web of Science ®Google Scholar

Huang X, Han K, Wang L, et al. Successful treatment of chromoblastomycosis using ALA-PDT in a patient with leukopenia. Photodiagnosis Photodyn Ther. 2019;26:13–14. doi:10.1016/j.pdpdt.2019.02.013

 Web of Science ®Google Scholar

Lan Y, Lu S, Zhang J. Retinoid combined with photodynamic therapy against hyperkeratotic chromoblastomycosis: a case report and literature review. Mycoses. 2021;64(1):18–23. doi:10.1111/myc.13190

 Web of Science ®Google Scholar

Gilaberte Y, Aspiroz C, Alejandre MC, et al. Cutaneous sporotrichosis treated with photodynamic therapy: an in vitro and in vivo study. Photomed Laser Surg. 2014;32(1):54–57. doi:10.1089/pho.2013.3590

 Web of Science ®Google Scholar

Liu H, Zhang J, Chen Y, et al. Phaeohyphomycosis due to exophiala spinifera greatly improved by ALA-PDT: a case report. Photodiagnosis Photodyn Ther. 2019;28:297–299. doi:10.1016/j.pdpdt.2019.10.002

 Web of Science ®Google Scholar

Shi L, Wu Q, Yang J, et al. ALA-PDT successfully treated Majocchi’s granuloma by directly killing Trichophyton tonsurans and recruiting T lymphocytes. Photodiagnosis Photodyn Ther. 2021;35:102328. doi:10.1016/j.pdpdt.2021.102328

 PubMed Web of Science ®Google Scholar

Liu Z, Tang J, Sun Y, et al. Effects of photodynamic inactivation on the growth and antifungal susceptibility of rhizopus oryzae. Mycopathologia. 2019;184(2):315–319. doi:10.1007/s11046-019-00321-2

 Web of Science ®Google Scholar