Dr Khulood Alsaraf

Fungal infection
are termed mycosis & in general can be divided into:

Superficial infection [ affecting skin, nails, scalp or mucus memb.] Systemic infection [ affecting deeper tissues & organs ]

Fungal infection are :

- More difficult to treat than bacterial infection - fungal organisms grow slowly & they have rigid cell wall containing chitin as well as poly saccharides & a well memb. Composed of ergosterol - thus resistance to antibiotics - requires prolonged treatment - disseminated fungal infections caused by dimorphic fungi, the yeasts Cryptococcus neoformans, & various Candida spp. respond to limited no. of systemic agents - A growing no. of topical & systemic agents are available for the treatment of these infections

1- Drugs for subcutanous & systemic mycotic infection

-A polyene antifungal drug produced by Streptomyces nodosus. - Bind to the fungal cell memb. component ergosterol, leading to increased fungal cell memb. Permeability & the loss of intracellular constituents. - It is effective against wide range of fungi, like: Candida albicans, histoplasma capsulatum, cryptococcus neoformans & many strains of

A- Amphotericin B

aspergillus.

- The development of resistance is rare.

Most commonly used to treat serious disseminated yeast and dimorphic fungal infections in immunocompromised patients. For the unstable neutropenic patient with candida albicans fungemia, Amph. Is the drug of choice. For the AIDS patient with moderate to sever cryptoccocal meningitis (for the initiation of treatment). For the AIDS patient with disseminated histoplasmosis (for the initiation of treatment). Amph. remains the drug of choice in the treatment of invasive aspergillosis and many disseminated fungal infections occurring in immunocompromised patients.

Amphotericin B with low therapeutic index, it may cause : -Renal toxicity -Anemia -Impaired hepatic function -Thrombocytopenia -Anaphylactic reaction -Chills, fever, tinnitus & headache -Neurotoxicity

Caspofungin, Anidulafungin, and Micafungin

Caspofungin
-Inhibit Fungal cell wall synthesis. -Not effective orally. -This drugs spectrum limited to Aspergillus and Candida. -May cause fever, rash, nausea, and flushing. -Second line antifungal for those who cannot tolerate Amphotericin B and Azol.

B- Candins

Andulafungin and Micafungin

-Not effective orally. -Both of them have similar efficacy against Candida. -May cause Histamine mediated side effects. -Do not have any associated drug interactions.

-Is a fluorinated pyrimidine analogue of cytocine -5-FC is converted to 5-fluorouracil inside the cell by the fungal enzyme cytocine deaminase -5-FC metabolites interfere with fungal DNA synthesis by inhibiting thymidylate synthetase -Incorporation of these metabolites into fungal RNA and inhibit protein synthesis -Not used as a single antimycotic agent because of resistance

C- Flucytocine

-It has singnificant antifungal activity against C.albicans, other Candida spp. & Cryptococcal.neoformans. -Its a part of combination therapy for systemic candidiasis & Cryptococcal meningitis -It combined with Amph.B for the treatment of Cryptococcal meningitis & disseminated candida infections. Adverse effects
1-anemia 2-neutropenia & thrombocytopenia 3-alopecia

D-Azole
1-Triazoles
-Are synthetic compounds with broad-spectrum antifungal activity. -All triazole exert antifungal activity by binding to cytochrome P450 enzymes responsible for the demethylation of Lanosterol to Ergosterol -Reduced fungal memb. Ergosterol conc. result in damaged, leaky cell memb. -The toxicity of these drugs depends on their relative affinities for mammalian & fungal cytochrome P450 enzymes.

Azoles used in treatment of systemic fungal infection are:-

Fluconazole, Posaconazole, Ketoconazole, Itraconazole, and Voriconazol.

-It is drug of first choice for most types of fungal meningitis bec. Cerebrospinal fluid levels are 60-80% of serum levels. -It is very effective in the treatment of infection with candida spp. -It may be an acceptable alternative to Amph.B in the initial treatment of mild Cryptococcal meningitis . -It is taken prophylactically by end-stage AIDS patients can reduce the incidence of Cryptococcal meningitis , esophageal candidiasis & superficial fungal infection . -Orally absorbed. -Less adverse effects than others, causes GI disturbances.

Fluconazole

-Drug of choice in treatment of blastomycosis, sporotrichosis, and histoplasmosis. -Main adverse effects include: -GI disturbances -Hypertension and hypokalemia -Drug-Drug interactions.

Itraconazole

Posaconazole
-Used to prevent Candida and Aspergillus infections in severely immunocompromised patients and for oropharyngeal candiasis treatment. The common side effects are:-GI disturbances -Elevation of liver enzymes -Drug-Drug interactions, increase the toxicity of cyclosporin, tacrolimus, and sirolumus.

Voriconazole
-Broad spectrum antifungal agent. -IV and oral administration. -Replaced Amphotericin B in treatment of invasive Aspergillosis. -Penetrates CNS tissues -Have side effects like other Azol, but it also cause transient visual disturbances.

Ketoconazole
-Effective in treatment of cutaneous & mucus memb. Dermatophyte &
yeast infection. -Effective in treatment of histoplasmosis, Blastomycosis & sporotrichosis as alternative to Itraconazole. -Orally absorbed, widely distributed through out the tissue & CNS. The common side effects are:1- GI disturbances 2- Liver toxicity 3-Endocrine effects result from blocking of androgen & adrenal steroid syn.: [ gynecomastia, decreased libido, impotance & menstrual irregulation ]. 4-Drug interaction : by inhibiting cytochrome P450, it can potentiate the toxicity of cyclosporine, phenytoin & increased the level of warfarin, rifampin, cyclosporin and phenytoin.

2- Drugs for Superficial mycotic infection

A-Azole
Imidazoles
Clotrimazole
-Is a broad-spectrum fungistatic imidazole drug used in the topical treatment of oral skin & vaginal infections with C.albicans. -It is also employed in the treatment of infections with cutaneous dermatophytes.

Miconazole

- Is a broad-spectrum imidazole agent used in the topical treatment of cutaneous dermatophytes infections & mucus memb. Candida infections such as vaginitis.

B-Griseofulvin
-Is an oral fungistatic agent used in the long-term treatment of dermatophyte infections caused by Epidermophyton, Microsporum, & Trichophyton spp. -It inhibit fungal growth by binding to the microtubules responsible for mitotic spindle formation, leading to defective cell wall development. -It binds to keratin precursor cells & newly synthesized keratin in the stratum corneum of the skin, hair, & nail, stopping the progression of dermatophyte infection. -It potently induce cytochrome P450 enzyme & causes several drug interaction.

-It

usually well tolerated 1-headache is common 2- hepatotoxicity

C- Nystatin
-Is a polyene antifungal drug with a ring structure similar to that of Amph.B & mechanism of action identical to that of Amph.B . -Too toxic for systemic use. -It is limited to the topical treatment of superficial infections caused by C.albicans . -Infections commonly treated by this drug include oral candidiasis [ thrush], mild esophageal candidiasis & vaginitis.

Is a synthetic allylamine Orally effective Usefull in treatment of dermatophytoses especially onychomycosis It is fungicidal Like azole, it interferes with ergosterol biosynthesis, but rather than interacting with the P450 system. It inhibits the fungal enzyme squalene epoxide, this lead to the accumulation of the sterol squalene, which is toxic to the organism. It is more effective than Griseofulvin or Itraconazole in treatment of onychomycosis Adverse effect are rare, including GIT upset and headache.

E- Terbinafine