Pogue: Antimicrobials III Flashcards
Which of the following drugs would not be
expected to have activity versus e.faecalis.
– A) piperacillin
– B) ampicillin
– C) ceftazadime
– D) ampicillin/sulbactam
C.
A patient has pneumonia with P.aeruginosa.
Which antibiotic would never be appropriate
– A) Ertapenem
– B) Doripenem
– C) Piperacillin
– D) Cefepime
A.
Which cephalosporin would you expect to have the best Gram‐negative activity – A) Cefuroxime – B) Cephalexin – C) Ceftriaxone
C.
Which of the following MRSA agents also has broad spectrum Gram (‐) activity? – Vancomycin – Tigecycline – Daptomycin – Linezolid
Tigecycline
If a patient was placed on tigecycline, which of the following would be the major adverse event of concern? – Hepatotoxicity – Rhabdomyolysis – Thrombocytopenia – Nausea/vomiting
Nausea/Vomiting
Hepatotoxicity = Rifampin Rhabdomyolysis = Daptomycin Thrombocytopenia = Linezolid
If you had a patient on linezolid, which of the
following agents would you be concerned for
a potential drug interaction with?
– A) rifampin
– B) multivitamins
– C) paroxetine
– D) triamterene
C. SSRI, Linezolid is an MAOI
Fungi to know (of clinical
relevance/importance)
• Dermatophytes • Candida spp. – C.albicans vs. C.glabrata vs. others • “Endemic fungi” – Histoplasmosis, Blastomycosis, Coccidiomycoses • Aspergillus spp. • Mucormycoses • Cryptococcus neoformans
General classes of antifungals (4)
Azoles
Polyene
Echinocandins (newest)
Misc.
Antifungals
Azoles (4)
– Fluconazole
– Itraconazole
– Voriconazole
– Posaconazole
Antifungals
Polyene (2)
– Amphotericin B
– Nystatin
Antifungals
Echinocandins (3)
– Caspofungin
– Micafungin
– Anidulafungin
Antifungals
Miscellaneous (3)
– Flucytosine
– Griseofulvin
– Terbinafine
What is first line against C.Albicans, C.Tropicalis, C.parapsilosis?
Fluconazole
What is first line against C.krusei, C.glabrata?
Echinocandins
What is first line against Endemic mycoses?
Itraconazole, Amphtericin B
What is first line against aspergillus?
Voriconazole
What is first line against mucor?
Amphotericin B
AZOLES:
MOA:
What is inhibited?
What enzyme inhibits?
Inhibit production of ergosterol, which is a key component of the fungal cell membrane
Enzyme that inhibits is a fungal CYP450 enzyme (making it more specific for fungus, but can also inhibit your P450 enzymes)
AZOLES
Pharmacokinetics:
Absorption:
Bioavailability
What needs a high fatty meal for absorption?
Metabolism
Excretion
Absorption:
o Highly bioavailable (IV dose=PO dose), but variable among patients
o Therapeutic drug monitoring (dose adjustment)
o Posaconazole needs a high fatty meal for absorption
Metabolism: by CYP450 system (drug interactions)
Excretion: only fluconazole needs to be renally dosed
AZOLES
Spectrum of activity (6):
All have excellent coverage of: All endemic fungi except: Some: What is voriconazole first line against? Which drugs can be used against mucomycoses?
- Candida spp: all have excellent coverage for albicans; variable coverage for glabrata
- Cryptococcus neoformans
- Endemic fungi: all except fluconazole
- Some dermatophytes: but not mainstay of therapy
- Aspergillus: voriconazole is first line; itraconazole and posaconazole can also be used
- Mucormycoses: posaconazole only
AZOLES
Clinical uses
Fluconazole:
Itraconazole:
Voriconazole:
Posaconazole:
Fluconazole: empiric antifungal treatment; candida infections
Itraconazole: DOC for non-life threatening cases of endemic mycoses
Voriconazole: DOC for aspergillus
Posaconazole: mucormycoses and in some prophylaxis regimens
AZOLES
Side effects:
Main issue for the class:
DDI: (KNOW!)
Worst with:
Notable interactions (4):
Side Effects:
- Hepatotoxicity: main issue for this class; must monitor LFTs*
- Nephrotoxiticy: IV voriconazole only
- Visual Disturbances: voriconazole only (related to concentration)
Drug Interactions: LOTS
- Worst with voriconazole and itraconazole
- Keep MOA in mind
- Always check concomitant drugs
Notable Interactions: o HIV medications o Calcineurin inhibitors (cyclosporine, tacroliumus) o Anticonvulsants o Rifampin
AMPHOTERICIN B:
MOA:
Binds to ergosterol in fungal cell membrane, and forms pores that allow molecules to leak in/out of the cell, resulting in cell death
AMPHOTERICIN B:
Spectrum of Activity (5)
For Candida:
First line against:
Candida spp: broad spectrum, including glabrata (but not lusitaniae- does not cause a lot of infections)
Cryptococcus neoformans: first line
Endemic fungi: first line for life-threatening illnesses
Aspergillus: second line
Mucormycoses
AMPHOTERICIN B:
Clinical Applications:
What is almost exclusively used?
DOC for?
Use against:
Lipid formulation almost exclusively used now: higher doses and somewhat decreased toxicity
Broadest spectrum antifungal: DOC for cryptococcus and endemic mycoses (life-threatening)
Use against “oddball” fungi
AMPHOTERICIN B (3):
Side Effects:
What occurs in over 20% of pts?
Results in:
What is thought to be less toxic? Why
Premedicate with what to decrease symptoms?
(Ampho-terrible)
Nephrotoxicity: can also “punch holes” into renal cell walls; occurs in over 20% of patients
o Dose dependent and usually reversible
o Results in electrolyte abnormalities (K, Mg); consider sodium loading
o Renal tubular acidosis
o Lipid base formulations thought to be less toxic: no deoxycholate (may be the cause); but still high rates
Infusion Reactions: fevers, chills, rigors, hypotension; can premedicate to decrease symptoms (antipyretics, antihistamines, corticosteroids)
Hepatotoxicity
ECHINOCANDINS:
MOA Pharmacokinetics: Spectrum of activity (2): DOC for: What is the 'Achilles-heel'?
MOA: inhibit production of 1-3-B-D-glucan (key component of SOME fungal cell walls) by inhibiting 1-3-B-D glucan synthase enzyme
Pharmacokinetics:
- IV formulations only
- Not renally eliminated: avoid for UTIs!
Spectrum of Activity:
- Candida spp: albicans and DOC for glabrata (does not cover C.parapsilosis)
- C.parapsilosis is the ‘Achilles-heel’
- Aspergillus: generally not first line, but can be used in combination therapy
ECHINOCANDINS
Clinical use:
DOC for:
Side Effects:
Clinical Use:
DOC for C.glabrata: used as both definitive and empiric treatment
- Aspergillus: rarely as monotherapy (unless patient cannot tolerate voriconazole or amphotericin); can be used as prophylaxis in some patients
Side Effects: VERY WELL TOLERATED
- Hepatotoxicity: rare
Dealing with Yeast in the Blood (Algorithm):
3 Steps:
- Make sure patient not at risk for Cryptococcus (HIV, immunosuppressed) –> if it is Cryptococcus, treat with amphotericin B
- If not Cryptococcus, most likely a candida spp. (albicans or glabrata)
- Decide if the patient is at risk for a fluconazole-resistant organism (recent azole exposure or known colonizer with glabrata?)
o If yes –> treat with echinocandin
o If no –> treat with fluconazole
.
FLUCYTOSINE (5-FC):
MOA:
Spectrum of Action (3):
MOA: converted by fungal cells to 5-FU (chemotherapeutic agent) and then to other products to inhibit DNA/RNA synthesis
Spectrum of Action:
- Candida
- Aspergillus
- Cryptococcus
- Not used as monotherapy (equate to aminoglycosides)
FLUCYTOSINE (5-FC):
Clinical Use:
Clinical Use:
- Never as monotherapy**
- Synergy with amphotericin B for severe infections:
o Candida endocarditis
o Cryptococcus neoformans CNS infections
FLUCYTOSINE (5-FC):
Side effects (KNOW!)
• Side Effects:
- Bone marrow suppression: dose-dependent; use therapeutic drug monitoring to avoid (levels <100)
- Hepatotoxicity
Antifungals for Dermatophytes
Terbinafine
Griseofulvin
TERBINAFINE:
MOA:
Adverse Effects:
MOA: blocks ergosterol production by inhibiting squalene epoxidase production
Adverse Effects: hepatotoxicity
GRISEOFULVIN:
MOA:
Adverse Effects:
MOA: prevents infections of new skin structures; eventually the infected ones die and get replaced
Adverse Effects: allergic reactions and hepatotoxicity
Antifungal pharmacology goodies What causes hepatotoxicity? Nephrotoxicity? What penetrates the urine? What causes bone marrow suppression?
• All cause hepatotoxicity
– Most associated with azoles
• Nephrotoxicity and amphotericin
• Penetrating the urine
– Fluconazole, amphotericin
• Azoles and drug interactions
• Flucytosine synergy and bone marrow
suppression
Common Viral Infections (4):
Herpes simplex virus (HSV) 1 and 2
Varicella-Zoster virus (VZV)
o Varicella: chicken pox
o Zoster: shingles
Cytomegalovirus (CMV)
Influenza A and B
ACYCLOVIR: MOA: Modified by: Where? What does it act as in growing DNA? Competitively inhibits :
– Inactive entity
– Modified by viral enzyme (thymidine kinase)
intracellularly into a monophosphate derivative
– Then host enzymes convert it into a tri‐phosphate
– This active moiety acts as a chain terminator in
growing DNA
• Also competitively inhibits viral DNA polymerase
ACYCLOVIR
Pharmacokinetics:
Not well absorbed orally (requires higher dosing- not often used orally for this reason)
Requires IV dosing for severe infections
ACYCLOVIR
Spectrum of Activity:
HSV:
VZV:
CMV:
Influenza A and B:
- HSV: active against both 1 and 2
- VZV: active, but requires higher doses
- CMV: no
- Influenza A and B: no
ACYCLOVIR Adverse Effects (3):
Headaches
Crystallization in urine: IV formulation in high doses (avoid by hydration)
Neurotoxicity: IV formulation in high doses (rare)
VALCYCLOVIR (VALTREX):
MOA
Pharmacokinetics
Everything else
MOA: oral prodrug of acyclovir (same MOA)
Pharmacokinetics:
- Well absorbed, and then converted to acyclovir
- Still need to use IV acyclovir for severe infections
Everything Else: same as acyclovir
What is the DOC for CMV?
Ganciclovir
GANCICLOVIR:
MOA:
Activated by:
HSV and VZV: similar to acyclovir (thymidine kinase activation)
CMV: inactive drug that is activated by kinase phosphotransferase that is present in CMV; then follows the same host mediated phosphorylations as acyclovir
o Note: does not act as a true host terminator, but forms smaller, ineffective DNA fragments
GANCICLOVIR
Spectrum of Activity (4):
HSV 1 and 2
VZV:
CMV:
Influenza:
Side Effects:
Spectrum of Action:
- HSV 1 and 2: less than acyclovir
- VZV: less than acyclovir
- CMV: DOC*
- Influenza: no
Side Effects:
- Bone Marrow Suppression: happens A LOT; especially when used with other suppressing agents (CMV common in immunosuppressed patients)
- CNS Side Effects: headache –> coma (5-15%)
VALGANCICLOVIR
MOA:
MOA: oral produg of gangciclovir (allows for better absorption)
EQUIVALENT OF VALCYCLOVIR FOR ACYCLOVIR
Ganciclovir and Valganciclovir
Side effects
BONE MARROW SUPPRESSION
• Happens a lot!
• Especially with other suppressing agents
– Extremely common in the patient population that needs these
drugs (immunosuppressants)
CNS side effects
• Range from headache to coma (5‐15%)
CIDOFOVIR:
MOA:
Spectrum of activity:
Clinical use:
Side Effects (2):
MOA: cytosine nucleotide (like the others above), but does NOT require viral activation
Spectrum of Activity:
- HSV, VZV and CMZ
- Some oddball viruses
Clinical Use:
- CMV resistant to others (ganciclovir/foscarnet) or if patients cannot tolerate these agents
Side Effects:
- Nephrotoxicity: 20-30%
- Neutropenia: ~25%
FOSCARNET:
MOA:
SE (3):
MOA: inorganic pyrophosphate compound that inhibits DNA polymerase, RNA polymerase and HIV reverse transcriptase
Spectrum of Acitivity:
- HSV, VZV, CMV (major)
- Some oddball viruses
- HIV (in vitro- not clinically used)
Side Effects:
- Nephrotoxicity: 33%
- Headache and Seizures
- Chelator of divalent cations in the blood: hypokalemia, hypocalcemia, hypomagnesmia
ANTIVIRALS FOR INFLUENZA:
When does treatment need to be commenced?
What is key?
Only have a modest effect in the treatment of influenza
Treatment needs to be commenced within 48 hours of symptom onset
VACCINATION IS KEY
ADAMANTANES
MOA:
Agents:
Spectrum of Activity:
Side Effects:
MOA: prevents viral uncoding of influenza A only (blocks penetration into the host)
Agents:
- Amantadine
- Rimantadine
Spectrum of Action:
- Influenza A (more recently, high levels of resistance)
- Also used in Parkinson’s Disease (DA reuptake)
Side Effects:
- CNS Effects: nervousness, lightheadedness, inability to concentration (due to DA reuptake)
NEURAMINIDASE INHIBITORS:
MOA:
Agents:
Spectrum of Action:
Side Effects:
MOA: inhibits viral neuraminidase, which is necessary for viral replication and release from host
Agents:
- Zanamivir
- Oseltamivir
Spectrum of Action:
- Influenza A and B (effective against H1N1)
Side Effects:
- Zanamivir (Inhalation): can exacerbate COPD
