Fungal Resistance, Biofilm, and Its Impact In the Management of Nail Infection

Faculty

Raza Aly, PhD, MPHProfessor Emeritus

University of California Medical Center (MSSF)

Professor, Dermatology

Faculty – MCSF

San Francisco, California

Faculty Disclosures

Dr. Aly has disclosed no relevant financial relationships with any commercial interests.

Learning Objectives

1) Recognize dermatophytoma (biofilm) in order to customize the approach to more specific treatment

2) Explain how biofilm research (an under-recognized condition) could lead to finding new targets for antifungal therapy

3) Emphasize the role of KOH and culture in identifying infection between dermatophytes and non-dermatophytes

4) Discuss latest topical treatments available

Onychomycosis

Onychomycosis (cont)

Genetic Susceptibility

• Zaias N,etal.examined2000patientswithdistalsubungualonychomycosisfora20-yearperiod

• TheconclusionwasthatcertainpatientsmayinheritsusceptibilitytoTrichophytonrubrum infectioninanautosomal-dominantpattern

Zaias N, et al. J Am Acad Derm. 1996;34:302.

Onychomycosis: Potential Pathogens

Gupta AK, et al. Dermatol Clin. 2003;21(2):257-268.

Specimen Collection

The Nail Culture

Comparing PAS Histologic Examination with KOH

• 1146nailclippingscomparingPASwithKOHandculture

• PASwasmostsensitive(82%sensitivitycomparedwith53%forcultureand48%forKOH)

PAS = periodic-acid Schiff; KOH = potassium hydroxide.Wilsmann-Theis D, et al. J Eur Acad Dermatol Venereol. 2011;25:235-237.

Scopulariopsis brevicaulis

KOHINFECTEDNAIL

Non-Dermatophyte (KOH)

Aspergillus Onychomycosis

KOHINFECTEDNAIL

• Psoriasiscommonlymisdiagnosedasonychomycosis

• Bothdiseasesmaycoexist• Symptoms:Pitting,onycholysis,

subungualthickening,nailplatealterations

• Psoriasisdistinguishedbysharplydefinedpittingofnailplatesurface

Differential Diagnosis

Dermatophytoma

Roberts DT, et al. Br J Dermatol. 1998;138:189-190.

• Abiofilmisanygroupoforganismsinwhichcellssticktoeachotherandoftenadheretoasurface

• Theadherentcellsproduceextracellularpolysaccharidematrix,adheringtoeachotherand/ortoasurface

• Biofilminfection:Pneumonia,cysticfibrosis,chronicwounds,implants,andcatheters– Affectsmillionsofpeople– Also,dentalplaque

TheRoleofBiofilmsinOnychomycosis

Gupta AK, et al. J Am Acad Derm. 2016; 74(6):1241-1246.

The Role of Biofilmsin Onychomycosis (cont)

• Biofilm research could lead to new approaches for antifungal therapies

• Studies are needed to understand the micro-environment of biofilm in dermatophyte infection… biological, chemical, and physical factors involved in this complex relationship– To alternate or stop bacterial or fungal ability to synthesize

the extracellular polysaccharide

– Drugs that will penetrate the biofilms to kill the fungi or bacteria in this complex relationship

Burkhart CN, et al. J Am Acad Dermatol. 2002;47:629-631.

Chilling Out

Current Treatments

Agent Dose DurationTerbinafine 250 mg Daily for 12 weeks

Itraconazole 200 mg Daily, 12 weeks, 200 mg bid for 1 week/month,3 pulses

Fluconazole(not approved bythe FDA)

300-450 mg Weekly for 9 to12 months

Ciclopirox 8% Remove lacquer/week, 48 weeks

Effinaconazole 10% Applied o/d for48 weeks

Tavaborole 5% Applied o/d for48 weeks

US Food and Drug Administration (FDA). Drugs. https://www.fda.gov/Drugs/. Last updated June 29, 2017. Accessed June 29, 2017.

Non-Dermatophyte Treatment

• Aspergillus species onychomycosis can be treated with oral terbinafine (250 mg/d for 2-3 months) or itraconazole (400 mg/d in 2-3 pulses)

• Onychomycosis caused by Acremonium species, Scopulariopsis brevicaulis, and Fusarium species is more difficult to cure

• The combination of topical with systemic increases the percentage of cure

• Onychomycosis caused by Scytalidium species does not respond to systemic treatment

• A case of complete cure of Scytalidium hyalinumfingernail onychomycosis using amorolfine nail lacquer was reported

Down AM. Br J Dermatol. 1999;140(3):555.

TreatmentofCandida SpeciesNailInfectionwithTerbinafine

• Twenty patients were treated with terbinafine (250 mg/d) for 16 weeks• 60% of target nails were cured clinically and

mycologically• Two patients showed mild, reversible elevation of

liver enzymes• Most nails were infected by Candida parapsilosis• Only two patients were infected with

Candida albicans

Segal R, et al. J Am Acad Dermatol. 1996;35(6):958-961.

Non-Dermatophyte Molds

• Clinical studies have shown that terbinafine is more efficacious than itraconazole, although itraconazole has broader antimicrobial coverage for non-dermatophytes

• Generally, Aspergillus species and Scopulaciopsisspecies are more susceptible than other non-dermatophytes

• For the more difficult-to-treat non-dermatophytes,a combination of oral antifungals with topical agents is recommended

• Surgical or chemical evulsion or debridement may be the best option in certain cases

Ameen A, et al. Br J Dermatol. 2014:171(5):937-958.

Are Lasers More Effective than Traditional Treatments?

• Evidence-based support for the use of laseris lacking

• Double-blind studies comparing lasers to placebo are lacking

• Laser treatment probably is safe, but its efficacy remains to be proven

• Cost-wise, it is unlikely that laser will be less expensive than the traditional treatments

Bristow IR. J Foot Ankle Res. 2014;7:34.

Hepatotoxicity of AntifungalsEstimated Symptomatic Risk

De Doncker P. 1998. Canadian monograph. Hall, 1997. Hay, 1993.

Poor Prognostic Factors

1. Extentofnailinvolvement>50%2. Significantlateraldisease3. Subungualhyperkeratosis4. White/yellowororange/brownstreaksinthenail

(includesdermatophytoma)5. Totaldystrophiconychomycosis(withmatrixinvolvement)6. Nonresponsiveorganisms(eg,Scytalidiummold)7. Patientswithimmunosuppression8. Diminishedperipheralcirculation9. Chronicplantartineapedis

Scher RK, et al. J Am Acad Dermatol. 2007;56(6):939-944.

Onychomycosis: Booster Therapy

De Doncker P, et al. Poster Presentation. AAD. 1998. Del Rosso JQ, et al. Poster Presentation, AAD. 1998.Gupta AK, et al. Cutis. 1998;61:339-342.

How to Improve Cure Rate for the Management of Onychomycosis

• Correctdiagnosis:Notalldystrophicnailsareonychomycotic;KOH,culture,histopathology

• Bioavailability:Oralbioavailabilityofitraconazoleismaximalafterameal

• Poorpatientcompliance:Drugregimenmaybemonitored• Maximizingefficacyofantifungals,longertreatment• Combinationtherapy:Withoralortopicalagent• Mechanicaltherapy:Mechanicaldebridementorpartialavulsionofthenail(eg,dermatophytoma[spike])

• Preventingrelapsesandrecurrences

Toenail-fungus.org [Web site]. http://toenail-fungus.org/. Accessed June 28, 2017.

Antifungal: Relapse Rates

Tosti A, et al. Dermatology. 1998;197:162-166.

Recalcitrant Infections

Aly R. Anacor Pharmaceutical Company. Phase III studies. In press. 2017.

The End