2-4 Anti- mycobacterial, protozoal, helminthic and fungal Flashcards

Question

What is trypanosomiasis infection?

Answer 1

_Trypanosomiasis:_ * There are three main pathogenic species leading to different diseases o * ***T. brucei:*** * T. brucei parasites live and grow in the blood before they invade tissues and the CNS, causing inflammation of the brain and spinal cord that produce the characteristic lethargy and eventually continuous sleep * Clinical: Sleeping sickness * Symptoms manifest after 1 week * Stage: * Primer chancre * Lymphadenopathy * Encephalopathy * **T. brucei gambiens** is prevalent in West-Africa causing sleeping sickness (African trypanosomiasis) * Slow onset chronic trypanosomiasis * It often ends fatally, with CNS involvement * **T. brucei rhodesiense** is prevalent in East-Africa and causes more virulent sleeping sickness (African trypanosomiasis) * Causes fast onset acute trypanosomiasis * ***T. cruzi*** is prevalent in South-America and leads to Chagas-disease (American trypanosomiasis) * Chagas disease has two forms, a trypomastigote found in human blood and an amastigote found in tissue * The acute form usually goes unnoticed and may manifest itself as a localized swelling at the site of entry, a chagoma – Romaña’s sign * Fever, myalgia and edema may also occur

Answer 2

_Helminths:_ * Worms: * Nematodes – roundworms * Trematodes - flukes * Cestodes – tapeworms * They usually enter the human body through the mouth, bite of insect vector or penetration * They are localized in the internal organs, dermal and lymphatic tissues and blood vessels * Characteristic laboratory findings: eosinophilia and elevated IgE titer _Possible drug targets of helminths:_ * Neuromuscular coordination * Carbohydrate metabolism * Microtubule integration (lie eggs, shooting, larval development, glucose transport, enzyme function)

Answer 3

* *_Yeasts:_* * Candida albicans * Cryptococcus neoformans * *_Dimorphic:_* * Histoplasma capsulatum * Blastomyces dermatitidis * Coccidioides immitis * *_Molds:_* * Aspergillus fumigatus * Mucor species * *_Dermatophytes:_* * Trychophytons * Epidermophytons * Microsporon * Malassezia furfur _Systemic fungal infections:_ * Systemic candidiasis: RTI * Cryptococcal meningitis, endocarditis * Rhinocerebral mucormycosis (rare) * Pulmonary aspergillosis * Blastomycosis (pneumonia) * Histoplasmosis (cough, fever, multiple pneumonic infiltrates) * Coccidiodomycosis * Pneumocystis carinii pneumonia

Answer 4

_Based on mechanism of action:_ * Fungal cell wall synthesis inhibition: *Echinocandins* * Bind to fungal cell membrane ergosterol: *Amphotericin–B*, *Nystatin* * Inhibition of ergosterol + lanosterol synthesis: *Terbinafine*, *Naftifine* * Inhibition of ergosterol synthesis: *Azoles* * Inhibition of nucleic acid synthesis: *5–Flucytosine* * Disruption of mitotic spindle and inhibition of fungal mitosis: *Griseofulvin* * Miscellaneous: *Ciclopirox* _Based on structure:_ *_Antibiotics:_* * ***Polyene****:* *amphotericin, nystatin* * ***Heterocyclic benzofurane:*** *griseofulvin* *_Antimetabolites:_* * *Flucytosine* *_Azoles:_* * ***Imidazoles:*** *ketoconazole, clotrimazole, oxiconazole, miconazole* * ***Triazoles:*** *fluconazole, itraconazole, voriconazole, posaconazole* *_Allylamines:_* * *Terbinafine* * *Naftifine* *_Echinocandins:_* * *Caspofungin* * *Anidulafungin* * *Micafungin*

Answer 5

_Polyenes (macrolide antibiotics):_ *_Drugs:_* * *Amphotericin B* * *Liposomal amphotericin B* *_Mechanism of action:_* * It can differentiate between fungal and mammalian cell membranes so it can be used systemically (binds with higher affinity to the ergosterol type membranes) * Binds to ergosterol and alters the permeability of the cell by forming pores in the cell membrane ==\> cell content leaks out ==\> death * Fungicide *_Spectrum:_* * Broadest spectrum of action * Aspergillus * Blastomyces dermatitidis * Candida sp. * Cryptococcus neoformans * Coccidioides immitis * Histoplasma capsulatum * Mucor spp. * Leishmaniae and acanthamoeba * No effect on dermatophytes *_Pharmacokinetics:_* * Parenteral administration * Good distribution, but not CNS entry * Long elimination half-life * Liposomal form: * Better effect * Less side effects * Slow elimination through kidney * No dose adjustment is necessary at hepatic or kidney impairment *_Clinical use_* * Useful drug in nearly all life threatening mycotic infections: mycosis of the organs, sepsis * Coccidio- or candida meningitis * Intrathecal administration * Topically applied for ocular or bladder infections * Effective in leishmaniasis *_Adverse effects:_* * Fever * GI disturbances (infusion-related toxicity) * Cumulative toxicity: * Nephrotoxicity (monitorization) * Impaired liver functions * Bone marrow suppression * ***Liposomal amphotericin B:*** * Less nephrotoxic and bone marrow suppression * Higher doses can be used

Answer 6

*_Drugs:_* * *5-flucytosine* *_Mechanism of action:_* * 5-FU is formed from it in the fungal cells, incorporates into RNA, inhibits protein synthesis *_Pharmacokinetics:_* * Well absorbed orally * Good distribution, enters CNS * Short half-life * Renal elimination *_Clinical use_* * Combination with *amphotericin B* ==\> synergistic effect: * Increased entry of 5-flucytosine * Reduced toxicity * Reduced duration of therapy * Reduced resistance * Effective against Cryptococcus neoformans and candida species *_Adverse effects:_* * Bone marrow and liver toxicity * GI disturbances * Toxic enterocolitis (rare, at high serum level)

Answer 7

*_Drugs:_* * ***Imidazoles:*** * *Clotrimazole* * *Ketoconazole* (not used systematically) * ***Triazoles:*** * 1^st generation: *Fluconazole, itraconazole* * 2^nd generation: *voriconazole, posaconazole* *_Mechanism of action:_* * Inhibit the ergosterol synthesis by binding to the cytochrome P-450 enzyme system * High selectivity, greater affinity for the fungal enzyme system *_Pharmacokinetics:_* * Well absorbed orally * *Itraconazole*: poorly enters CNS, eliminated mainly through the GI tract * *Fluconazole* and *voriconazole*: enter CNS, excreted mainly by the urine * *Itraconazole* and *fluconazole*: accumulate in the nails and skin *_Clinical use_* * Broad spectrum: * Candida spp * Cryptococcus * Blastomycosis * Coccidioidomycosis * Histoplasmosis * Dermatophytons * *Itraconazole* and *voriconazole*: effective in Aspergillus infections too * *Itraconazole*, *fluconazole*: in dermato- and onychomycosis * *Fluconazole*: Cryptococcus meningitis * *Fluconazole*, *voriconazole*: often used at ICU for the treatment of sepsis, ex. Candida sepsis * *Posaconazole*: the newest, indicated in invasive aspergillosis. Significant effect in mucormycosis. * Ketoconazole is used only locally *_Adverse effects:_* * Relatively non-toxic * Mainly GI * Liver enzyme elevation * Rarely hepatitis * *Ketoconazole* – gynaecomastia, oligospermia, impotence (inhibits testosterone synthesis)

Answer 8

* Newest class of antifungal agents *_Drugs:_* * *Capsofungin* * *Micafungin* * *Anidulafungin* *_Mechanism of action:_* * Inhibit b-glucan synthesis ==\> disruption of fungal cell wall *_Pharmacokinetics:_* * Only IV administration *_Clinical use_* * Candida species * Aspergillus niger * Sepsis * Multiresistant infections *_Adverse effects:_* * Well tolerated but: * Fever * GI disturbances * Flush * Increased liver enzymes * *Micafungin*: Increased risk of liver tumors and suppresses bone marrow

Answer 9

**_Terbinafine_**_:_ *_Mechanism of action:_* * Inhibit the fungal enzyme squalene epoxidase ==\> accumulation of squalene * Toxic effect and lack of ergosterol * Fungicide *_Pharmacokinetics:_* * Good oral absorption * Accumulates in skin, hair and nails *_Clinical use_* * Broad spectrum * Local and systemic treatment of onicho- and dematomycosis (dermatophytons) * Some candida infections *_Adverse effects:_* * GI disturbances * Skin reactions (rarely, Stevens-Johnson syndrome) * Increased liver enzymes **_Griseofulvin_**_:_ *_Mechanism of action:_* * Unclear * Inhibits mitosis * Fungistatic * Effective mainly against dermatophytons *_Pharmacokinetics:_* * Good oral absorption * Accumulates in hair, skin and nails * ***Interactions:*** * Enzyme inducer *_Clinical use_* * Microsporia capitis of the scalp *_Adverse effects:_* * GI disturbances * Increased liver enzymes, hepatotoxicity

Answer 10

**_Nystatin_** _(polyene macrolide antibiotic):_ *_Mechanism of action:_* * Compound similar to amphotericin B *_Pharmacokinetics:_* * Not absorbable orally as it has local effects in the GIT * Poor absorption from the skin and mucosal membranes *_Clinical use_* * Candidiasis of oral cavity and of esophagus * Infections of the gastrointestinal tract * Superficial infections of skin and mucosas *_Adverse effects:_* * Nausea, vomiting * Diarrhea * Exanthema _Others:_ *_Allylamines:_* * ***Terbinafine:*** * Fungicide cream, spray, gel * ***Naftitin:*** * Fungicide cream and solution *_Amorolfine:_* * Fungicide * Nail polish *_Ciclopirox:_* * Broad spectrum antifungal drug * Antibacterial and anti-inflammatory effect * Onychomycosis, dermatomycosis * Cream, nail polish, solution *_Azoles:_* * *Clotrimazole* * *Bifonazole* * *Econazole* * *Flutrimazole* * *Ketoconazole* * *Omoconazole*