Antimycotics in Dentistry Antimycotics for Infection Control and Prevention in Dentistry MSc. Carlos Daniel Ferreira Fonseca 29.11.2024 1 Before we start… Palmer, N. (Ed). Antimicrobial Prescribing in Dentistry: Good Practice Guidelines. 3rd Edition. London, UK: Faculty of General Dental Practice (UK) and Faculty of Dental Surgery; 2020. 2 Polyenes • Local nystatin • Polyene macrolide • Parenteral administration is very toxic • Mechanism of action: selective binding to fungi membrane → pore → altering cellular permeability avidity for ergosterol • Adverse effects: nausea, vomiting and diarrhoea • Modes of administration: P.O, topical • Limited to topical treatment of cutaneous and mucosal candida infections • Absorption from GIT is negligible • Use of nystatin oral suspension in the mouth for several minutes four times daily before swallowing • Other example of local administered polyene: natamycin 5 Polyenes • Systemic amphotericin B • prepared as a colloidal suspension • broadest spectrum of action → including mucormycosis • Oral amphotericin B → effective only on fungi in the GIT • Use in systemic infections → IV administration (slow infusion) • Nowadays there is one azole (posaconazole) with less side effects and activity against mucor • amphipathic characteristic facilitates pore formation • Mechanism of action: selective binding to fungi membrane → pore → altering cellular permeability - avidity for ergosterol 6 Polyenes • Systemic amphotericin B • Can be used topically for treatment of keratitis and mycotic corneal ulcers • Adverse effects • Infusion-Related Toxicity (Phlebitis): fever, chills, muscle spasms, vomiting, headache, and hypotension • Ameliorated with administer normal saline infusions with the daily doses of amphotericin B • Cumulative Toxicity: Renal toxicity → renal tubular acidosis, hypokalaemia and hypomagnesemia → Torsade de points • Modes of administration: P.O, IV, IT (Intrathecal), topical • Hepatic elimination 7 Azoles • Local • clotrimazole • econazole • miconazole • Systemic • fluconazole • itraconazole • voriconazole • posaconazole Mechanism of action: inhibition of fungal cytochrome P450 enzymes (14-α-demethylase) Inhibition of conversion of lanosterol to ergosterol Interfering with fungi cell membrane Inhibition of fungal growth 8 Azoles • Broad spectrum of action • Candida • Cryptococcus neoformans • Endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis) • Dermatophytes (ringworm) → Trichophyton fungus • Trichophyton causes athlete's foot • 2 big families: imidazoles and triazoles • Imidazole: clotrimazole, miconazole, and ketoconazole (less potent) • Triazole: fluconazole, itraconazole and voriconazole (more potent) • Inhibition of human cytochrome P450 • Mainly topical use • Safe use → biggest risk is skin irritation 9 ringworm Azoles • Peroral and IV administration → Systemic fungal infections • Oral or vaginal → Candidiasis Imidazole → ↓ selectivity and ↑ drug interactions and side effects than triazoles • Used topically to treat skin infections • clotrimazole used as a lozenge for oropharyngeal candidiasis • miconazole or clotrimazole for vulvovaginal candidiasis • miconazole or clotrimazole for dermatophyte infections (Tinea) Triazoles • fluconazole → Candidosis + Cryptococcus neoformans (drug of choice for treatment and prophylaxis) • PO and IV administration • oral bioavailability is high, wide therapeutic index, high CSF penetration • Resistance • Side effects: GIT disturbances and interference with hepatic enzymes (less than with other azoles) • CYP2C9 (drug interaction with warfarin) and CYP3A4 inhibitor (interactions with statins, cyclosporine, tacrolimus) 10 2nd or 3rd Line after amphotericin B Azoles Triazoles • itraconazole → Candidosis + Cryptococcus neoformans + Histoplasma + Coccidioides + Blastomyces • voriconazole → Candidosis + Cryptococcus neoformans + Histoplasma + Coccidioides + Aspergillus • PO and IV administration • Oral bioavailability is high • CYP3A4 inhibitor (known interactions with statins, cyclosporine, tacrolimus) • Side effects: rash and elevated hepatic enzymes and visual disturbances (blurring and photosensitivity) 11 Echinocandins (-fungin) • Newest class of antifungal agents • caspofungin • micafungin • anidulafungin • Spectrum of action: Candida and Aspergillus (only with fungus that have β(1–3)-glucan • Mode of administration: IV (now well absorbed GIT) • Treatment of disseminated and mucocutaneous candidal infections → 1st line on serious systemic infections • (1st choice over amphotericin B) • Mechanism of action: echinocandins → fungal cell wall by inhibiting the synthesis of β(1–3)-glucan • This results in disruption of the fungal cell wall and cell death • Side effects: hepatoxicity (↑ liver enzymes), GIT problems, rash, facial flushing (histamine release) 12 Terbinafine • Synthetic allylamine → it is lipophilic and keratophilic → accumulates in adipose tissue and in keratin • Mode of administration: PO, topical (1 % cream) • Treatment of dermatophytosis (specially onychomycosis) • 6 weeks for fingernail infections • 12 weeks for toenail infections • relapse is extremely common • CYP2D6 inhibitor • Mechanism of action: inhibiting squalene epoxidase • accumulation of squalene → fungicidal action • Side effects: gastrointestinal problems, headache, hepatotoxicity, dysgeusia (loss of taste) 13 Griseofulvin • Derived from a species of penicillium and is also keratophilic • Mode of administration: PO • Only used in the treatment of dermatophytosis • treating tinea infections of the scalp and glabrous (nonhairy) skin • Mechanism of action: interference with microtubules → interfering with mitosis • Side effects: serum sickness, serious skin reactions, a lupus-like syndrome, hepatotoxicity • Should not be used in pregnant women (teratogenic) • CYP3A4 inducer (e.g interaction with warfarin) • Largely a 2nd or 3rd line medication after Terbinafine or Itraconazole 14 Flucytosin (or 5-FU) • Potent antifungal agent • Mode of administration: PO, IV • Only used in the treatment of systemic infections • candidiasis, cryptococcal meningitis, and chromoblastomycosis • used in combination with amphotericin-B (increased penetration in the cell) and azoles • Mechanism of action: converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis • Side effects: Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia • Should not be used in pregnant women (teratogenic) • Spectrum of action is much narrower than that of amphotericin B 15 Candidosis • Yeast • C. albicans → most common cause of infection • C.glabrata, C.tropicalis, C.krusei, C.auris • Common cause of infection in the immunocompromised (opportunistic) • Antibiotic therapy, chemotherapy, diabetes, HIV • People with braces also have an unfavourable growth of Candida • Present on skin and mucous membranes 16 C. albicans Candidosis • Present on skin and mucous membranes • Pseudomembranous candidosis (or Thrush) • Stratified squamous epithelium layer → accumulation of the destroyed cells and the keratin protein • Common in young infants and the elderly → weak immune system • Raw bleeding mucosa → after scrape • Erythematous candidosis • Appearance of red lesions • Involves the same the risk factors as the previous • May result from loss of the pseudomembrane in pseudomembranous candidosis 17 Candidosis • Another types of lesions • Esophagus • Esophagitis → individuals that suffer from HIV • With or without thrush • Vulvovaginitis → mainly by C.albicans • Discharge • Pain while urinating • Invasive Candidosis → Tropism towards different organs → Brain, Liver, Spleen • Serious • In immunocompromised patients • Can result from a formed biofilm in prosthetic devices (catheter) • Complications: septic shock, meningoencephalitis and pyelonephritis 18 Candidosis • Pseudomembranous candidosis (and also Erythematous candidosis) • Combination of antifungal medication + local measures • nystatin • Polyene macrolide • Parenteral administration is very toxic • Use of nystatin oral suspension in the mouth for several minutes four times daily before swallowing • Mechanism of action: selective binding to fungi membrane → pore → altering cellular permeability • avidity for ergosterol – the same for the drug amphotericin B (polyene) • Adverse effects: nausea, vomiting and diarrhoea • Modes of administration: P.O • Limited to topical treatment of cutaneous and mucosal candida infections • Absorption from GIT is negligible 19 Candidosis • Pseudomembranous candidosis • Combination of antifungal medication + local measures • miconazole or fluconazole • Part of the azole class • miconazole as an oral gel • 2.5ml of oral gel to the affected area four times a day after food and retain near the lesion before swallowing. Use for at least seven days, after lesions have healed or symptoms have cleared • fluconazole as a tablet or suspension (children) → Widest therapeutic index from the azoles • 50 mg orally once a day for 7-14 days (maximum 14 days unless severely immunocompromised); Increased to 100 mg a day for unusually difficult infections • Mechanism of action: inhibition of fungal cytochrome P450 enzymes (14-α-demethylase) • Inhibition of conversion of lanosterol to ergosterol • Interfering with fungi cell membrane • Inhibition of fungal growth 20 Candidosis • amphotericin B • prepared as a colloidal suspension • broadest spectrum of action → including mucormycosis • Oral amphotericin B → effective only on fungi in the GIT • Use in systemic infections → IV administration (slow infusion) • Nowadays there is one azole (posaconazole) with less side effects and activity against mucor • amphipathic characteristic facilitates pore formation • Mechanism of action: selective binding to fungi membrane → pore → altering cellular permeability • avidity for ergosterol 21 Candidosis • amphotericin B • Can be used topically for treatment of keratitis and mycotic corneal ulcers • Adverse effects • Infusion-Related Toxicity: fever, chills, muscle spasms, vomiting, headache, and hypotension • Ameliorated with administer normal saline infusions with the daily doses of amphotericin B • Cumulative Toxicity: Renal toxicity → renal tubular acidosis, hypokalaemia and hypomagnesemia • Modes of administration: P.O, IV, IT (Intrathecal), topical • Hepatic elimination 22