Antimycobacterial and Antifungal therapy Flashcards
Resistance to any agent is present in ____ bacteria
1 x 10-5 to 1 x 10-8
Clinical rule for tuberculosis therapy (3)
- multiple drug therapy required
- start therapy with 3 or 4 drugs
- never change a single drug at a time
First line of therapy for tuberculosis: list the drug, it’s action, resistance if any, and adverse effects
“RIPE”
- Rifampin (rifabutin)
- inhibts DNA-dependent RNA polymerase, prevention of chain initiation
- drug turns bodily fluids red-orange tine
- potent inducer of all CYP450 isoenzymes
- heptatisis
- Izoniazid
- inhibits mycolic acid biosynthesis
- resistance in 1 x 10-6
- hepatitis, peripheral neuropathy
-
Pyrazinamide
* mechanism unknown! - Ethambutol
- inhibits enzymes needed for cell wall synthesis
- retrobulbar neuritis
- Streptomycin
- an aminoglycoside
- nephrotoxicity, neural toxicity
What additional vitamin is necessary to administer during first line TB therapy and why?
VB6, isoniazid can cause peripheral neuropathy
What is the standard active TB regimen?
INH + Vit B6, RIF, PZA, EMB x 2 months
then:
INH +Vit B6, RIF x 4
6 months total (4 for 2, 2 for 4!)
Resistance to one or more agents for TB therapy is common. What is the following resistances?
MDR = ?
XDR = ?
MDR = INH + Rifampin (1.5%)
XDR = INH + Rifampin + FQ and injectable agents
(^high mortality rate, very limited options for therapy)
Antimicrobial drugs for Hansen’s Disease
- Rifampin
- Dapson
- Clofazamine
- occasionally ofloxacin or MInocycline
What are the two antiinflammatory durgs for Hansen’s disease?
- Thalidomide
- Steroids
What are the 6 classes of antifungals?
- Polyenes
- Anti-metabolites
- Azoles
- Echinocandins
- Allylamines
- Others
List the steps to make ergosterol and the important enzymes involved. Which antifungal treatments block which steps?
- Mevalonic Acid –> Squalene
- Squalene –> Lanosterol (squalene epoxidase)
- Lanosterol –> Eergosterol (14 alpha demethylase)
- allylamines block squalene epoxidase
- echinocandins block 14 alpha demethylase
- polyenes block ergosterol
List the two important Polyenes and their activity
- Amphotericin B
- Nystatin
- most fungal pathogens
- systemic candida
- cryptococcal meningitis (with Flucytosine)
- Severe pneumonia and extrapulmonary Balstomycosis, Histoplasmosis, and Coccidioiomycosis
- Invasive Aspergillosis
- Invasive Sportrichosis
- Murcormycosis
What are adverse reactions to Polyenes?
“Amphoterrible, awfultericin”
- febrile reactions (shake and bake)
- Tubular nephrotoxicity (K, Mg+, and bicarbonate wasting)
- glomerular nephrotocitity (increased creatinine)
“Nasty nystatin”
- only effective against yeast
- too toxic to take as iv, topical use only; not absorbed from GI so treats oral and esophageal infections
What are the two types of azoles?
Imidazoles and Triazoles
Imidazoles
- ketoconazole
- miconazole
- clotrimazole
Triazoles
- fluconazole
- itraconazole
- voriconazole
- posaconazole
- ravuconazole
Ketoconazole:
- activity
- characteristics
- clinical considerations
- Candida, Tinea
- Oldest, cheapest
- absoprtion highly gastric pH dependent– administer with food or cola; many cytochrome P450 effects, interacts with many meds
Clotrimazole:
- activity
- characteristic
- effective against yeasts and molds, skin and mucous membranes
- topical use only – cream, lotion, powder, solution; available OTC
Itraconazole:
- Activity
- clinical considerations
- histoplasmosis, Coccidiomycosis, Aspergillosis, Onychomycosis
- absorption highly gastric pH dependent–administer with food or cola
Fluconazole:
- Activity
- Clinical considerations
- drug of choice for cryptococcus neoformans; effective against Candida
- Modest cytochrome effect
What exception to the Candida specias is resistant to Fluconazole? What does Fluconazole also have little effect on?
- candida glabrata
- against filamentous fungi (aspergillus, zygomycetes/mucor)
Voricanazole
- Activity
- Clinical considerations
- first line therapy for Aspergillosis, candida that is resistant to other triazoles
- unique toxicity: visual disturbance (30%), metabolized via cytochrome P450-multiple drug interactions
Posiconazole:
- Activity
- Characteristic
- treats candida or aspergillus, prophylazie of fungal infections in cancer patients, improved activity against more resistant fungi (zygomycetes)
- oral formulation only
Echinocandins irreversibly inhibits _____, which are responsible for _______
Beta-1,3-D glucan synthase; making glucan polymers, which provide cell wall rigidity
Echinocandins:
- 3 main types
- activity
- characteristics
- Caspfungin, Micafungin, Anadulifungin
- Candida, Aspergillus (invasive), other unusual fungi (trichosporin, fusarium)
- iv therapy, generally well tolerated
What is the one anti-metabolie?
- action
- activity
- clinical consideration
`
Flucytosine (5FC)
- interferes with DNA, RNA, and protein synthesis
- used in combo with other meds, especially cryptococcal meningitis
- bone marrow toxic
Griseofulvan
- action
- activity
“greasy fulcrum”
- prevents cell division via funal cell mitotic spindles disruption
- levels dermatophyte plaques off skin; not used in USA due to high incidence of adverse reactions
