1.  Increased use of antibiotics (broad-spectrum)

2.  Advances in surgery

3.  HIV epidemic

Amphotericin B

1.  Produced by:

2.  Water soluble?

3.  Two types of preparations

4.  Static or cidal?

1.  Streptomyces nodosus

2.  Practially insoluble

3.  A)  colloidal susp with sodium desoxycholate for IV

     B)  Lipid-associated delivery system (LFAmB)

4.  Cidal

Amphotericin B

1.  MOA

2.  Potential reason for toxicity

1.  Binds ergosterol in fungal membranes

    Multiple amphotericin B molecules form a pore leading to cell lysis

2.  Binding to human sterols

Amphotericin B ADME

1.  GI absorption?

2.  Why take the oral form?

3.  What route for systemic infection?

4.  % protein binding

5.  % CSF penetration

1.  No

2.  Funal infection in lumen of GI tract

3.  IV prep

4.  90%

5.  2-3% of serum level reached in CSF:  intrathecal administration may be required

Amphotericin B:  Clinical Use

1.  Narrow or broad spectrum?

2.  Species effected

1.  Broad

2.  Candida albicans;  Cryptococcus neoformans;  Histoplasma capsulatum;  Blastomyces dermatitids;  Coccidioides immitis;  Aspergillus fumigatus;  Mucor spp

Amphotericin B:  ADEs

1.  Infusion related (immediate reactions) (6)

2.  2 ways to prevent #1

3.  Slow reactions (4)

1.  Nearly universal reactions; fever/chills; muscle spasms; vomiting; HA; hypotension

2.  Slow rate or lower dose; Administer:  antipyretics, antihistamines, corticosteriods, or meperidine before use

3.  Renal damage in nearly everybody (50% ARF)

-Occassional increase in liver enzymes

-Anemia

-Intrathecal can lead to seizures or CNS dysfunction

Flucytosine

1.  Type of analog

2.  Spectrum of activity compared with amphotericin B

3.  MOA

1.  Water-soluble pyrimidine related to 5-FU

2.  Narrower

3.  Converted to components that inhibit DNA and RNA synthesis

-Parent drug cannot be converted by human cells

Flucytosine:  ADME

1.  Dosage route

2.  Protein bound?

3.  Distribution

4.  Excretion

1.  Only Oral:  well-absorbed

2.  Not extensively

3.  Penetrates all bodily fluides, including CSF

4.  Excreted in urine so renal insufficiency may lead to toxicity

Flucytosine

1.  Used to treat 

2.  Used as a single agent?

3.  Exhibits synergy with other antifungals (2 listed, name the othe rdrugs and what it treats)

1.  Cryptococcus neoformans; candida; dermatiaceous molds causing chromoblastomycosis

2.  No, resistance occurs if used as a single agent

3.  Amp B + Flucytosine:  Cryptococcus meningitis

-Itraconazole + Flucytosine:  Chromoblastomycosis 

Flucytosine:  ADEs:  Narrow therapeutic index

1.  Metabolized to what by gut flora

2.  ADEs (3)

1.  5-fluorouracil

2.  -Bone marrow toxicity:  anemia, leukopenia, thrombocytopenia

-May affect liver enzymes

-Toxic enterocolitis

Azoles

1.  Difference between imidazoles and triazoles

2.  Imidazoles (3)

3.  Triazoles (4)

1.  Imidazoles:  2 nitrogens in azole ring; Triazoles:  3 nitrogens in azole ring

2.  Ketoconazole, miconazole, clotrimazole

3.  Itraconazole, fluconazole, voriconazole, posaconazole

Azoles

1.  MOA

2.  Which ar eless epecific with higher DDIs and S/E

1.  Reduction of ergosterol synthesis by inhibition of fungal P450s

2.  Imidazoles

*  Resistance increasing

Azoles

1.  Broad or narrow spectrum?

2.  Species used against

1.  Broad

2.  Candida spp;  Cryptococcus neoformans;  dermatophyts; organisms resistant to Amp B

Azoles:  ADEs, overall relatively nontoxic

List the 3

1.  Minor GI upset

2.  Increase in liver enzymes

3.  Drug interactions due to inhibition of P450s

*Varies with each azole, so check drug for specific S/E

Ketoconazole

1.  Route of admin

2.  Replaced by what unless cost is an issue

1.  Oral

2.  Itraconazole

Itraconazole

1.  Routes of administration (2)

2.  CYP for which it is a substrate and inhibitor

3.  % protein bound

4.  Type of excretion

5.  Contraindicated in?

1.  Oral and IV

2.  CYP3A4

3.  99%

4.  Renal

5.  Pregnancy

*Few DDIs

Fluconazole

1.  Where absorbed?

2.  % bioavailability

3.  Altered by food or gastric acid?

4.  Excretion

5.  Protein bound?

6.  Inhibitor of which 2 CYPs

7.  Used to Tx

8.  ADEs (4)

1.  GI

2.  100%

3.  No

4.  Renal

5.  No

6.  CYP3A4 and CYP2C9

7. Candida spp., cryptococcosis, other mycoses

8.  ADEs:  N/V; HA; Rash; abdominal pain

Voriconazole

1.  What is the slite difference from fluconazole?

2.  Routes of admin

3.  % protein bound

4.  Metabolized by what cyps

5.  Inhibits what cyps

6.  Usage

7.  Contraindicated in

8.  What to monitor

9.  Tell pts to watch for

1.  Broader activity and poorly water soluble

2.  Oral or IV (good oral bioavailability)

3.  50%

4.  2C9 and 2C19

5.  2C9, 2C19, and 3A4

6.  Invasive aspergillosis, esophageal candidiasis, salvage therapy:  Pseudalleceria boydii and Fusarium 

7.  Pregnancy

8.  LFTs

9.  Possible vision problems

Posaconazole

1.  When must it be given?

2.  Strong inhibitor of what CYP

3.  Approved as a ___ agent

1.  During or within 20 minutes following a full meal or liquid nutritional supplement; OR, with an acidic carbonated beverage (ginger ale)...without this, limited absorption and potential treatment failure

2.  CYP3A4

3.  Prophylactic agent in immunocompromised patients

Echinocandins

1.  Drugs included in class (3)

2.  Route of admin

3.  MOA

1.  Caspofungin, micofungin, andulafungin

2.  IV

3.  Inhibit synthesis of fungal cell wall component Beta (1-3) glucan

Candida

Aspergillus when Amp B fails or during febrile neutropenia

Esophageal candidiasis

Candiada prophylaxis:  hematopoietic stem cell transplant

Candidemia

Acute disseminated candidiasis

Other Candida infectinos (peritonitis and abcesses)

1.  Minor GI S/E

2.  Flushing

3.  Some DDIs, but fewer than azoles

Griseofulvin

1.  Cidal or static?

2.  What improves absorption

3.  Only clinical use

4.  MOA

5.  ADEs

6.  What 2 drugs have replaced it?

1.  Static

2.  Fatty foods taken concurrently with medication

3.  Dermatophytosis

4.  Binds keratin to protect skin from new infection

5.  Allergic syndrome similar to serum sickness; hepatitis; DDI with warfarin and phenobarb

6.  Itraconazole and terbinafine

Terbinafine

1.  Route

2.  Cidal or static

3.  Used to tx

4.  MOA

5.  ADEs:  rare

6.  Topical varient brand name

1.  Oral

2.  Cidal

3.  Dermatophytosis

4.  Binds keratin, interferes with ergosterol synthesis, but interacts with a different fungal enzyme:  squalene epoxidase

5.  GI and HA

6.  Lamisil AT

Nystatin

1.  Similar in structure to?

2.  Only route of administration

3.  Spp treated

1.  Amp B

2.  Topical:  too toxic systemically

3.  Candida:  thrush and vaginal candidiasis

Topical Azoles

1.  Drugs (2)

2.  Use

1.  Clotrimazole and miconazole

2.  Vulvovaginal candidiasis or oral thrush (clotrimazole troches); tinea corporis, tinea pedia, tinea cruris

1.  Mycolic acid 

2.  Enzymes that play a role int the processes essential to organisms life

3.  enzymes that are unique to the bacteria

1.  Isoniazid

2.  Rifampin (and related drugs)

3.  Ethambutol

4.  Pyrazinamide

Second-Line TB Therapy

Reasons used:  5

1.  Microbial resistance

2.  Cases not responding to conventional therapy

3.  ADEs

4.  Expert guidance is available to deal with toxicity

5.  May initiate Tx with 5-6 drugs

1.  Sterptomycin

2.  Moxiflox or gatiflox

3.  Ethionamide

4.  Aminosalicylic acid

5.  Cycloserine

6.  Amikacin

7.  Kanamycin

8.  Capreomycin

9.  Linezolid

Isoniazid:  Primary drug for TB treatment

1.  Static or cidal?

2.  Highly selective for

3.  Can penetrate what?

1.  Static for resting bacilli

2.  Cidal for rapidly dividing microorganisms

3.  Macrophages

Isoniazid

1.  MOA

1.  Prodrug:  converted to active metabolite by mycobacterial catalase-peroxidase 

-Inhibits synthesis of mycolic acid

-Drug target appears to be inhA gene product (inhA codes for enzyme that converts unsaturated FAs to sturated FAs in mycolic acid biosynthesis)

Isoniazid

1.  Resistance

2.  # of bacteria resistant

1.  Maps to at least 5 different genes; codes for catalase-peroxidase enzyme that activates isoniazid

2. 1 in a million

Isoniazid:  ADME

1.  Routes of admin

2.  Distribution

3.  Excretion

4.  Metabolism

5.  What prolongs half-life

1.  Oral or parenteral

2.  All body fluids and cells

3.  Renal

4.  Acetylation and hydrolysis

5.  Hepatic insufficiency (anywhere from 1-5 hrs)

Isoniazid:  Genetic differences in metabolism

1.  What gene altered which does what

2.  Slow is ___ recessive

3.  Fast is ____ dominant

1.  NAT2: acetylation

2.  Autosomal

3.  Autosomal

Isoniazid and pyridoxine (B6)

1.  Why given together?

2.  What patients is it indicated for?

1.  To minimize risk of peripheral neuropathy and CNS toxicity

2.  Malnourish pts; those predisposed to nerupoathy (elderly, pregnant, HIV +, diabetics, alcoholics, anemia, uremia, slow acetylators)

Isoniazid ADEs

1.  Common (3)

2.  Rare

1.  Drug induced hepatitis:  N/V, jaundice, RUQ pain

2.  Inc LFTs

3.  Peripheral neuropathy

Rare:  Fever, skin rash, drug-induced SLE, hematologic abnormalities, Tinnitus, GI discomfort, Reduces metabolism of phenytoin, CNS toxicity