03 Pharmacology/PK/Therapeutic Use of Antifungal Agents Cupo Flashcards
1
Q
What are the general characteristics of Amphotericin B?
A
Broad spectrum, fungicidal, rare resistance. Polyene antibiotic. Binds ergosterol in fungal cell membrane. Creates transmembrane channel and electrolyte leakage
2
Q
What is Amphotericin B NOT active against?
A
Candida lusitaniae, Aspergillus terreus, Scedosporium spp.
3
Q
What is the PK of Amphotericin B (Fungizone) like?
A
Low BA, IV only. 24-48 hr initial t1/2 w/ terminal t1/2 15 days. High protein binding (90%)
4
Q
What is the distribution of Amphotericin B (Fungizone) like?
A
High in kidney, liver, spleen. Very good in lung, heart, skeletal muscle. POOR: Brain, Bone, CSF, Eye
5
Q
What is the dosage of Amphotericin B (deoxycholate) like?
A
Dose range: 0.25-1mg/kg/day. Treatment duration: total dose ~1-2 grams. Dosages are not altered with renal or hepatic dysfunction
6
Q
What is the Tolerability to Amphotericin B like?
A
Infusion-related: fever, chills, N/V, HA, myalgias, arthralgias, rigors. Anemia, rare thrombocytopenia. Phlebitis. Maculopapular rash. Hepatotoxicity (rare)
7
Q
What are the current recommendations for testing Amphotericin B tolerability?
A
Start with ~30% target dose on day 1, infuse slowly for first 15 min, monitor for ADRs. Rapidly escalate to full dose w/in 24 hrs
8
Q
What is renal insufficiency like for Amphotericin B?
A
Decrease in renal blood flow leads to decreased GFR, increased BUN. Distal tubular ischemia - wasting of potassium, sodium, and magnesium. Enhanced in patients who are volume depleted or who are on concomitant nephrotoxic agents
9
Q
How can renal insufficiency be reduced with Amphotericin B?
A
Sodium loading - administer 500-1000 ml NS prior to administration of AMB
10
Q
What are the drug interactions associated with AMB?
A
Avoid concomitant use with nephrotoxic agents (aminoglycosides, foscarnet, cyclosporine, tacrolimus)
11
Q
What is the dosing of Abelcet like?
A
5mg/kg/day (can push it to 10mg/kg/day at times)
12
Q
What is the dosing of Amphotec like?
A
3-4mg/kg/day
13
Q
What is the dosing of Ambisome like?
A
3-5mg/kg/day (can push it to 10mg/kg/day, mainly 3mg/kg/day used)
14
Q
What is a general summary for the Non-Conventional Amphotericin B formulations?
A
All have different phospholipid:molar ratios. Cleared by RES; highest distribution to liver and spleen w/ less to kidneys. All have propensity for infusion-related effects ABCD (Amphotec)»_space; ABLC (Abelcet)»_space; L-AMB (AmBisome)
15
Q
What are the subclasses of Azole Antifungals?
A
Imidazole. Triazoles. 2nd gen Triazole
16
Q
What drug falls under Imidazole (type of Azole)?
A
Ketoconazole (Nizoral)
17
Q
What drugs fall under Triazoles (type of Azole)?
A
Itraconazole (Sporanox). Fluconazole (Diflucan)
18
Q
What drug falls under 2nd Generation Triazole (type of Azole)?
A
Voriconazole (Vfend)
19
Q
What is the MOA of Azoles?
A
Bind to CYP P450 enzyme lanosterol 14-a demethylase. Inhibits formation of ergosterol. Sterol biosynthesis is halted
20
Q
What are the pharmacodynamics of Azoles?
A
Concentration-dependent fungistatic agents (dosage escalation may be necessary when faced with more resistant fungal species). Goal of dosing is to maintain AUC: MIC > 50 (i.e. maintain concentrations 1-2x MIC for the entire dosing interval)
21
Q
What is the spectrum of coverage from Ketoconazole?
A
Candida spp., B. dermatidis, C. immitis, H. capsulatum
22
Q
What is the PK of Ketoconazole?
A
BA 75%. T1/2 8 hrs. Highly protein bound 99%. Extensive metabolism (O-dealkylation, oxidation). Biliary and renal elimination
23
Q
What is the tolerability of Ketoconazole like?
A
Gastrointestinal (N/V, dose-dependent). Hepatotoxicity (<10%), increased LFTs, hepatitis. Gynecomastia, oligosperima, decreased libido. Adrenal insufficiency
24
Q
What is a unique ADR associated with Ketoconazole and why does it occur?
A
Gynecomastia, Oligospermia, decreased libido, and adrenal insufficiency all occur d/t Ketoconazole inhibiting testosterone and cortisol synthesis
25
What are the drug interactions with Ketoconazole?
CYP 3A4 mediated (potent inhibitor). Increases cyclosporine, tacrolimus, sirolimus, WARFARIN levels. Decreased ketoconazole levels when taken with Rifampin, phenytoin. Altered absorption w/ increased gastric pH (antacids, PPIs, H2-antagonists, sucralfate)
26
What is the dosing of Ketoconazole like?
Serious infections: 800mg PO QD. Other: 200-400mg PO QD
27
What is the spectrum of activity from Fluconazole?
Candida albicans, Cryptococcus neoformans, Candida parapsilosis
28
What does Fluconazole NOT very active against?
C. krusei, +/- C. glabrata (S-DD), Aspergillus spp.
29
What is the PK of Fluconazole like?
Available as both IV and PO. BA > 90%. T1/2 ~24h. Low protein binding. Low metabolism. High elimination unchanged through kidney
30
What is the distribution of Fluconazole like?
Well distributed to most tissues; CSF:Plasma (0.5-0.8)
31
What dosages does Fluconazole come in?
100, 150, 200mg tablets; 200, 400mg IV
32
How is Fluconazole dosed for Vulvovaginal candidiasis?
150mg x1
33
How is Fluconazole dosed for Mucosal candidiasis?
100-200mg/day
34
How is Fluconazole dosed for a systemic infection?
400-800mg/day. >800mg/day if unstable, S-DD isolate or non-albicans spp (e.g. 12mg/kg/day)
35
How is Fluconazole dosed for maintenance for cryptococcal meningitis?
200-400mg/day
36
What are the ADRs associated with Fluconazole?
N/V. Rash. Asymptomatic increase in LFTs. No endocrine effect
37
What are the drug interactions associated with Fluconazole?
Main increase phenytoin, cyclosporine, tacrolimus, sirolimus, warfarin concentrations. Rifampin may decrease Fluconazole levels by half
38
What is the PK of Itraconazole?
Variable BA: 25% (capsule) to 60% (liquid). T1/2 24-30 hrs. High protein binding 99%
39
What is the distribution of Itraconazole like?
Liver, Kidney, Skin (2-20 fold > than plasma). NO CSF
40
What is the dosing/administration like for Itraconazole?
Available as 100mg caps, oral solution. Dosage variable, depends on onchomycosis (200mg daily), aspergillosis (200mg Q12h)
41
What is the tolerability of Itraconazole like?
CNS (HA, Dizziness, Fatigue, Somnolence in 2%). GI (N/V/D). Hepatotoxicity. Warning: re-CHF (negative inotropic effects)
42
What is the spectrum of activity for Voriconazole (Vfend)?
Candida. Aspergillus. Fusarium. Scedosporium
43
What does Voriconazole NOT cover?
Zygomycoses
44
What is the PK of Voriconazole?
BA >90%. T1/2 6 hrs. Protein binding 58%. Metabolized (N-Oxide 72%) 2C19 > 2C9 > 3A4
45
What are the serum levels like with Voriconazole?
High interpatient variability. Non-linear: saturable metabolism. Genetic polymorphism CYP 2C19
46
What is the normal dosing like for Voriconazole?
6mg/kg IV Q12h load x 2 doses, decrease to 4mg/kg Q12h. 200mg PO Q12h
47
What is the dosage adjustment like for Voriconazole?
Hepatic: normal load, decreased maintenance dose by 50% for Child-Pugh A, B. Renal: Avoid in CrCl < 40-50ml/min (avoid the IV preparation)
48
What is the tolerability of Voriconazole?
Visual disturbances (20%). Transaminases (13%). Nausea. Rash. Fever. Chills. HA. Hallucinations. Photophobia
49
What drugs is Voriconazole contraindicated with?
Rifampin (large decrease in Voriconazole concentrations), Carbamazepine, Long-acting Barb. Sirolimus
50
What should be done when Voriconazole is taken with Phenytoin?
Lower Voriconazole concentration. Increase Voriconazole from 4mg/kg IV Q12h to 5mg/kg OR from 200mg to 400mg
51
What should be done when Voriconazole is taken with Warfarin?
Increases INR 2-fold. Monitor INR closely
52
What is the trough level target range for Voriconazole?
2-6 micrograms/mL
53
Which Triazoles have excellent CSF penetration?
Fluconazole and Voriconazole. NOT Itraconazole
54
Which Triazole is primarily renally cleared?
Fluconazole
55
Which Which Triazoles are strong CYP3A4 inhibitors?
Voriconazole. Itraconazole
56
What is the Spectrum of activity for Posaconazole (Noxafil)?
Candida. Aspergillus. Fusarium. Scedosporium. AND Zygomycoses
57
What is the PK of Posaconazole?
PO only (BA increased with food). T1/2 19-30 hrs. High protein binding 99%. Metabolized by liver, 77% biliary elimination
58
What are the ADRs associated with Posaconazole?
CNS (fatigue, HA, somnolence, dizziness ~10%). GI (constipation, diarrhea, abdominal pain, N/V). LFTs. Rash. Musculoskeletal pain
59
What is the dosing of Posaconazole like?
800mg/day (in 2-4 divided doses)
60
What is the clinical role of Posaconazole?
Paucity of data. Limited role as salvage therapy
61
What is the PK of Flucytosine (Ancobon)?
High BA 70-90%. T1/2 ~6 hrs. Small Vd. Low protein binding. 80-90% unchanged drug eliminated by glomerular filtration
62
What is the distribution of Flucytosine like?
Liver, Kidney, Spleen, Heart, Bronchial secretions, CSF:Plasma (0.6-1:1), Urine:Plasma (10-100:1)
63
What is the dosing of Flucytosine like?
50-150mk/kg/d (4 divided doses)
64
When is the Flucytosine dose adjusted?
CrCl 40ml/min (t1/2 doubled). CrCl 10ml/min (t1/2 quadrupled); dose adjust accordingly
65
What is the tolerability of Flucytosine like?
Hematologic (dose-dependent bone marrow suppression). Hepatotoxicity (asymptomatic increase in LFTs). Dermatologic (rash, itching). GI (N/V/D, abdominal pain). CNS (HA, dizziness, confusion)
66
What are the drug interactions for Flucytosine?
Concominant hematologic toxicity w/ other myelosuppressive agents
67
What is the clinical use of Flucytosine?
Combination w/ AMB or Fluconazole vs. Candida spp or Cryptococcus. Limited monotherapy d/t rapid development of resistance
68
What are the Echinocandins?
Cyclic lipopeptides that non-competitively inhibit 1,3-B-D Glucan Synthase. Three echinocandins: Cancidas (caspofungin), Mycamine (Micafungin), Eraxis (Anidulafungin)
69
What is the spectrum of activity for Echinocandins?
Candida spp (less potent vs. C. parapsilosis). Aspergillus spp
70
What do Echinocandins NOT cover?
C. neoformans, H. capsulatum, B. dermatitidis, Scedosporium spp., Zygomycetes spp
71
What is the PK of Caspofungin (Cancidas)?
Very low BA. T1/2 9-11 hrs. High protein binding 97%
72
What is the distribution of Caspofungin (Cancidas)?
Liver (16:1). Kidney (3:1). Lung, Spleen (1:1). <1:1 for Heart, Brain
73
What is the metabolism/elimination of Caspofungin (Cancidas)?
Metabolism: N-acetylation, hydrolysis, no Cyto P450 metabolism. Elimination: About 1-10% unchanged drug renally (not used for urinary infections)
74
What is the dosage/administration of Caspofungin (Cancidas)?
70mg x1 LD, 50mg IVPB QD. With moderate hepatic insufficiency: lower dose to 35mg QD
75
What are the drug interactions with Caspofungin (Cancidas)?
Increase AUC for cyclosporine (monitor LFTs). Decrease tacrolimus levels by 20%. Not inhibitor, inducer of CYP P450. Substrate (may be affected by enzyme inducers) - e.g. Rifampin, Phenytoin, Dexamethasone, CBZ: Increase dose of Caspofungin
76
What is the Tolerability of Caspofungin (Cancidas)?
Hepatic (Increased: LFTs, Alk Phos, Bili). CNS (HA, paresthesias). Renal (increased BUN and SCr). Hematologic (Decrease H/H and Neutrophils). Dermatologic (Facial flush, erythema, pruritis, rash). Thrombophlebitis. GI (N/V/D, abdominal pain)
77
What is the PK of Micafungin (Mycamine)?
T1/2 15 hrs. High protein binding 99%. Small Vd
78
What is the metabolism/elimination of Micafungin (Mycamine)?
Metabolism: Non-oxidative metabolism. Elimination: < 15% renal, remainder hepatic
79
What is the dosage/administration for Micafungin (Mycamine) when treating Candidial prophylaxis (stem cell tx)?
50mg/day
80
What is the dosage/administration for Micafungin (Mycamine) when treating Esophageal Candidiasis?
150mg/day
81
What is the dosage/administration for Micafungin (Mycamine) when treating Candidemia?
100mg/day
82
What is the dosage adjustment for Micafungin (Mycamine)?
No adjustment for renal or hepatic dysfunction
83
What is the tolerability for Micafungin (Mycamine)?
Hepatic (Increased LFTs and Bili). CNS (HA, Dizziness, Somnolence). Hematologic (Decreased: H/H, Neutrophils, Platelets). Dermatologic (Facial flush, pruritus, rash). Thrombophlebitis
84
What are the DDIs with Micafungin (Mycamine)?
May increase levels of Sirolimus, Nifedipine
85
What is the PK of Anidulafungin (Eraxis)?
Very low BA. T1/2 26 hrs. High protein binding 84%. Low Vd
86
What is the metabolism/elimination of Anidulafungin (Eraxis)?
Metabolism: Chemical degradation to inactive metabolite. Elimination: < 1% renal, nearly 100% biliary
87
How is Anidulafungin (Eraxis) dosed for Esophageal Candidiasis?
100mg x1, then 50mg QD
88
How is Anidulafungin (Eraxis) dosed for Invasive Candidiasis?
200mg x1, then 100mg QD
89
What is the administration of Anidulafungin (Eraxis) like?
Diluent (20% w/w dehydrated alcohol). Volume 100mg (MD) & 250ml (LD), 200mg (500ml). Rate 100mg over 90min, 200mg over 3 hrs
90
What is the dosage adjustment like for Anidulafungin (Eraxis)?
No adjustment for renal or hepatic dysfunction
91
What is the tolerability of Anidulafungin (Eraxis)?
GI (N/V/D). Hepatic (Increased: ALT, AST, Alk Phos). Dermatologic (rash). Other: Histamine related rash, uritcaria, flushing, dyspnea, hypotension (infuse at 1.1mg/min to avoid)
92
What are the DDIs with Anidulafungin (Eraxis)?
Slight SS increased AUC for Anidulafungin with concomitant CsA
93
What are the risk factors for getting systemic fungal infections?
Diseases/Underlying Conditions (AIDS, DM, Hodgkin's Disease/other lymphomas, Leukemia, Kidney failure). Immunosuppressive therapy (chemotherapy, corticosteroids, other immunomodulators)
94
What are the most common Systemic Fungal Infections?
Candidiasis. Aspergillosis
95
What are the less common systemic fungal infections?
Cryptococcosis. Coccidiomycosis. Histoplasmosis. Zygomycosis. Sportichosis
96
What are the two most common Candida causing systemic infections?
C. albicans and C. glabrata
97
What are the sites of involvement for Nosocomial Candida Infections?
Blood. Urine. Kidney. Heart. Eye. CNS. Hepatosplenic. Peritonitis
98
What is the treatment outline for Nosocomial Candida Infections?
Correction of underlying risk factor. Echinocandins. Systemic Azoles (e.g. high dose Fluconazole or Voriconazole). AMB (total dose depends; may be as low as 0.5-1g)
99
What are the risk factors for Candidemia?
Immunosuppression (Corticosteroids, chemotherapy, age, malignancy, neutropenia w/ ANC < 500, malnutrition, renal failure). Site for infection (mechanical ventilation, hemodialysis access site, GI surgery, TPN, indwelling central catheters). Promote fungal colonization (prior broad spectrum antimicrobial therapy). ICU stay (exposure to pathogens)
100
What is the Candidemia Treatment (Non-Neutropenic) before exact species is identified?
Fluconazole 800mg x1, then 400mg QD OR Echinocandin (either Caspo, Mica, or Anidula). Echinocandin favored if moderate to severe illness or if recent azole exposure. Fluconazole favored if less critically ill and no history of recent azole exposure
101
For Candidemia Treatment (Non-Neutropenic), what is done if species is identified to be C. albicans or C. parapsilosis and if they are clinically stable/improved?
Change Echinocandin to Fluconazole
102
For Candidemia Treatment (Non-Neutropenic), what is done if species is identified to be C. glabrata?
Echinocandin is preferred. May transition to Fluconazole/Vori if susceptibility testing is done
103
What is the empiric therapy for Suspected Candidemia in Neutropenics?
Echinocandin (Mica 100mg/day, Caspo 70mg x1 and then 50mg QD, Anidulafungin 200mg x1 and then 100mg QD). L-AMB at 3mg/kg/day. Voriconazole in situations where additional mold coverage is warranted. No fluconazole used here
104
What are the QA Issues with Candidemia?
Fundoscopic exam for all patients w/ culture-confirmed Invasive Candidiasis (IC) to rule out opthamologic dissemination. Discontinue central lines, devices. Start antifungals w/in 24 hrs of positive blood culture. Follow up blood culture to document eradication
105
What are the future roles of diagnostic testing?
Currently, no susceptibility breakpoints for Echinocandins (do increased MICs for C. parapsilosis really matter?). Rapid diagnostic testing/identification either thru PNA Fish, etc. (helps to speciate Candida rapidly and help direct therapy regarding Echinocandin vs. Fluconazole)
106
Which types of transplants have the highest risks of invasive Aspergillosis?
Heart > Lung > Liver > Renal
107
What is the Aspergillus susceptibility like for the different species and AMB?
All susceptible except A. terreus
108
What are clues for early diagnosis of Aspergillosis?
Patients in high risk groups. Febrile neutropenia, refractory to abx. Clinical presentation usually includes acute pneumonia picture. Diagnosis: Isolation from BAL; best is bronch w/ biopsy. Surrogate markers: Galactomannan assay or B-Glucan assay. Radiologic: CT-scan halo sign
109
What are some general characteristics of Aspergillosis?
Most common cause of mortality in BMT and Leukemia patients. Prevention, prompt empiric tx are key to decreasing mortality; still mortality approaches 30-40%
110
What are the drug choices for Aspergillosis?
Voriconazole (pulm I-A, extra pulm B-III). Other agents: L-AMB, Echinocandins
111
What are some general characteristics of Coccidiomycosis?
Pulmonary cocci (> 6 weeks) as persistent pneumonia with hemoptysis, pulmonary scarring, cavitary lesions, or bronchopleural fistulas. Dissemination < 1%. Sites of dissemination: meninges, skin, skeletal system. In AIDS, usually reactivation of previous infection
112
What is the treatment like for Coccidiomycosis?
Pulmonary nodule, asymptomatic - no antifungal needed. Pulmonary cavitation: close f/u if asymptomatic, symptomatic (e.g. hemoptysis) - oral azole, Ruptured lesion - lobectomy + antifungals
113
What is the treatment like for Chronic Progressive Fibrocavitary Pneumonia caused by Coccidiomycosis?
Severe, primary pulmonary infection. Immunocompromised patients. Rising IgG antibody titers. Pulmonary infection > 6 weeks. Therapy w/ ORAL AZOLE x1 year
114
How is Amphotericin B (conventional) dosed for Coccidiomycosis?
0.6 - 1mg/kg/day until total dose of 2-3 grams is reached (~4 weeks). AMB has been used to treat dissemination to all sites
115
What is used to treat Meningitis caused by Coccidiomycosis?
High dose fluconazole. Intrathecal AMB (0.1 - 1.5mg/dose)
116
What are the general characteristics of Cryptococcosis?
Infection via inhalation. Major virulence factor - capsular polysaccharide. Primary Crypto: affects lungs w/ subclinical presentation. Most common manifestation --> CNS
117
What is the diagnosis like for Cryptococcosis?
CSF india ink prep shows oval yeast cells. (+) capsular antigen via latex agglutination. CSF findings: Increased ICP, CSF pleocytosis w/ lymphocytosis
118
What is used as treatment for Cryptococcosis (HIV infected individuals - Meningoencephalitis)?
3 phase treatment. 1) Induction: AMB 0.7-1.0mg/kg/day plus 5-FC 100mg/kg/day in divided doses for 2 weeks. 2) Consolidation: Fluconazole 800mg QD x 4 weeks. 3) Maintenance (suppressive) therapy fluconazole 200mg QD x1 year
119
What is used as treatment for Cryptococcosis (Organ transplants - Meningoencephalitis)?
3 phase treatment: 1) Induction: L-AMB 3-4 mg/kg/day plus 5-FC 100mg/kg/day in 4 divided doses for 2 weeks. 2) Consolidation: Fluconazole 400-800mg QD x8 weeks. 3) Maintenance (suppressive) therapy Fluconazole 200-400mg QD x6monts to 1 year
120
What is used as treatment for Cryptococcosis (Non-HIV, Non-Transplant - Meningoencephalitis)?
3 phase treatment. 1) Induction: AMB 0.7-1mg/kg/day plus 5-FC 100mg/kg/day in 4 divided doses for 2 weeks. 2) Consolidation: Fluconazole 400-800mg/day x8 weeks. 3) Maintenance: Fluconazole 200mg QD x6 months to 1 year
121
What is the treatment for mild to moderate pulmonary disease caused by Cryptococcosis?
Fluconazole 400mg/day x 6-12 months. Patients w/ severe pulmonary disease - same as CNS (duration = 12 months). Patients with cryptococcemia - same as CNS (12 months)
122
What are some beneficial (PK) antifungal combinations?
AMB + 5-FC. AMB + FLU. Echinocandin + Newer triazole
