Systemic & Topical
Types of fungal disease Skin infections: e.g. foot fungus (usuallysmelly but not life threatening, sometimesbecomes serious), ring worm Mucosal infections: oral or vaginal (rangefrom annoying to painful to very difficult;uncomfortable but rarely life threatening) Systemic infections: fungus in the bloodand tissues (immunocompromisedpopulation, usually life threatening)
Systemic Infection
Susceptible population: abdominal surgery,cancer chemotherapy, bone marrowtransplant, organ transplants, otherimmunotherapy, other immunecompromisingdisease High mortality: those people that getsystemic infection are already sick; currentdrugs are not effectiveFungal Infection in Humans = Mycosis
Major Types of Mycoses superficial cutaneous subcutaneous systemic opportunistic Symptoms vary from cosmetic to life threateningClassification of antifungal drugs
• Based on chemical structures: The classes includePolyene macrolides, Imidazoles, Fluorinated pyrimidines, Benzo-furans and Iodides• Based on their sites of action: Either systemic or topical antifungal drugs.• Miscellaneous classifications: Organic acids and their salts and other inorganic saltsPolyene Macrolides antifungals
• Polyene macrolides antifungals were isolated fromvarious species of Streptomyces.• Examples used in veterinary medicine include; Amphotericin B, Nystatin Pimaricin (natamycin)Mechanisms of polyene macrolides
• Polyene macrolides bind to sterols (ergosterol) in thecell membrane of susceptible fungi.• This creates a transmembrane channel, changingmembrane permeability and thus allowing leakage ofintracellular components.• In particular, amphotericin B binds to ergosterol infungal membranes disrupting its function leading to K+ ion efflux and H+ ion influx.
Consequently, internal acidification of fungal cell occursand thus stopping enzymatic functions. Sugars andamino acids also leak from an arrested cell.• For Natamycin, the binding to ergosterol in the plasmamembrane, prevents ergosterol-dependent fusion ofvacuoles, as well as membrane fusion and fission.• This differs from the mechanism of amphotericin B,which alters fungal membrane permeability.
Spectrum of activity of polyene macrolides
• They have broad antifungal activity includingfilamentous fungi, saprophytic and pathogenic fungi.• Amphotericin B is effective against Coccidiomycosis,histoplasmosis, candidiasis and blastomycosis.• Nystatin is effective against candidiasis against, otheryeasts and fungi.• Pimaricin is effective against candidiasis trichomoniasis and mycotic keratitis (dermatophytes).Indications and dose rates
• Amphotericin B is used for the treatment of systemicmycotic infections.• Nystatin is indicated for the treatment of mucocutaneousor intestinal candidiasis.• Pimaricin is used in therapeutic management of mycotickeratitis.Adverse effects, toxicity and drug interactions
• Oral administration of nystatin can lead to anorexia andGIT disturbances• Amphotericin B may cause nephrotoxicity after IVinfusion. The drug may also cause anorexia, nausea,vomiting, hypersensitivity and drug fever.• Rifampin may potentiate the amphotericin B activity.• Amphotericin B should be contraindicated duringtherapy with aminoglycosides (nephrotoxicity)The drug should not administered with digitalis drugs(increased toxicity), and neuromuscular blocking drugs.• It should be avoided when mineralocorticoids, thiazidediuretics, antineoplastic drugs, and cyclosporine havebeen used.
Imidazole antifungal drugs
• Imidazoles antifungals contains imidazole ring in theirchemical structures.• Some imidazoles also have antibacterial, antifungal,antiprotozoal, and anthelmintic activity.• Examples of imidazole derivatives used as antifungalsare; clotrimazole, miconazole, econazole, ketoconazole,itraconazole, and fluconazole.Mode of action of imidazole antifungal drugs
• Imidazoles block the synthesis of ergosterol, the primarycell sterol of fungi thereby altering the cell membranepermeability of yeasts and fungi.• They also impair enzymes required for fatty acidsynthesis and also cause toxic concentrations of hydrogenperoxide to develop intracellularly due to changes inoxidative and peroxidative enzyme activities.• This results in cell membrane and internal organelledisruption and cell death.Activity spectrum and indications of imidazole antifungals
• Miconazole has a wide antifungal spectrum against most fungi and yeasts of veterinary interest.• Ketoconazole is more effective against C immitis and some other yeasts and fungi.• Itraconazole and fluconazole are active againstdimorphic fungal organisms and dermatophytes.• Clotrimazole and econazole are used for superficialmycoses (dermatophytosis and candidiasis);
Adverse effects, toxicity and drug interactions
• Ketoconazole given orally may result in nausea,vomiting, and hepatic dysfunction, as well as altered testosterone and cortisol metabolism.• Reproductive disorders related to ketoconazoleadministration may be seen in dogs.• Voriconazole is associated with a number of adverse effects in humans, including vision disturbances.The imidazoles may be used concurrently withamphotericin B or 5-flucytosine to potentiate itsantifungal activity.• The absorption of the imidazoles, (except for that of fluconazole), is inhibited by concurrent administration of cimetidine, ranitidine, anticholinergic agents, or gastric antacids.Fluorinated pyrimidine derivatives
• This antifungal drug includes fluorinated pyrimidinecytosine analog that is related to fluorouracil.• Example includes flucytosine (5-fluorocytosine)• The drug was initially developed as an antineoplasticagent.Mode of action of flucytosine
• Flucytosine is converted by cytosine deaminase in fungalcells to fluorouracil, which interferes with RNA andprotein synthesis.• Fluorouracil is metabolized to 5-fluorodeoxyuridylicacid, which inhibits thymidylate synthetase required forDNA synthesis.• These effects eventually inhibits DNA synthesis and maycause fungal cell deaths.Spectrum of activity, indications and dose rates
• Flucytosine is effective against Cryptococcusneoformans, Candida albicans, Phialophora andCladosporium spps.• The common indications for flucytosine are cryptococcal meningitis, used together with amphotericin B.• General dosages are 25–50 mg/kg and 30–40 mg/kg,orally 4 times a day in dogs and cats, respectively.Adverse effects, toxicity and interactions
• Flucytosine is toxic at high doses and leads to nausea,vomiting, and diarrhea.• It causes reversible increased liver enzymes, anemia,neutropenia, thrombocytopenia).• The renal effects of amphotericin B prolong eliminationof flucytosine.• If flucytosine is combined with immunosuppressivedrugs, depression of bone marrow function is possible.23Benzofurans Derivatives
• Benzofuran derivative includes Griseofulvin which isfungistatic but is fungicidal for young active cells.• Griseofulvin accumulates in the stratum corneum and ishighly effective against the dermatophytes.• Dermatophytes are resistant to griseofulvin in vitro.Mode of action of griseofulvin
• Griseofulvin disrupts the mitotic spindle by interactingwith the polymerized microtubules in susceptible dermatophytes.• This results in the production of multinucleate fungalcells. The drug also acts by inhibiting nucleic acidsynthesis and forms hyphal cell wall material.• This results in distortion, irregular swelling, and spiral curling of the hyphae.
Spectrum of activity, indications and dose rates
• Griseofulvin is active against Microsporum,Epidermophyton, and Trichophyton spp.• Indicated for infections in dogs, cats, calves, horses, andother domestic and exotic animal species.• Dogs and cats the dose rate is 10-30 or 130mg/Kg orallysingle dose or divided twice or three times per day.• Horses and cattle the dose rate is 5-10 mg/Kg orally.Adverse effects, toxicity and drug interactions
• Adverse effects induced by griseofulvin but nausea, vomiting, diarrhea and hepatotoxicity may be seen.• Griseofulvin is contraindicated in pregnant mares and queens because it is teratogenic.• Lipids increase the GI absorption of griseofulvin.Barbiturates decrease absorption and antifungalactivity of Griseofulvin.• Griseofulvin is a microsomal enzyme inducer and promotes the biotransformation of concurrentlyadministered drugs.• The combined use of ketoconazole and griseofulvin may lead to hepatotoxicity