1. MOST COMMONLY PRESCRIBED ANTIFUNGAL AND ANTIVIRAL MEDICATIONS
Talk about drugs more globally, not specific details. That’s what you will get out of your drug cards
Anneliese Bodding-Long
University of Washington
Doctor of Pharmacy Candidate, 2012

2. OBJECTIVES
Identify the commonly prescribed antifungal and antiviral medications, their mechanism of action, and what they are commonly prescribed for
Explain common counseling points for each class
Identify the specific counseling points, side effects, and toxicities of these medications

3. ANTIVIRALS Influenza: Oseltamivir Herpes Simplex/ Herpes Zoster:
Acyclovir
Valacyclovir
Famciclovir

4. VIRAL UPPER RESPIRATORY INFECTIONS OR “THE COMMON COLD”
Caused by more than 200 viruses
Rhinovirus, influenza, coronavirus, respiratory syncytial virus, etc.
Virus replicates and “sheds”
Symptoms and shedding usually last 3-7 days
Most contagious the day before fever begins through 24 hours after fever ends
Symptoms
Nasal congestion, non-productive cough,
fever, muscle aches, sore throat
Virus replicates in upper respiratory epithelium, sloughs of superficial cells which leads to virus shedding

5. WHEN TO TREAT THE COMMON COLD?
Empiric use of antibiotics
More harm than good? Unnecessary adverse effects? Increase bacterial resistance?
“My snot’s yellowish-green, not clear. Is it bacterial?”
Should we culture, and is it an infection or normal colonization?
Cultures may take a few days to return from lab, pt often already has begun antibiotic treatment
Rapid tests for influenza- results in 1 hr
Can’t use if symptoms > 3 days, or recent LAIV
False negatives and low sensitivity
Expensive
Antibiotic therapy does help those infections with a positive culture for the “big three” bacterial suspects
H. influenzae, M. catarrhalis, or S. pneumoniae
Antibiotics are important to prevent secondary infections
Pneumonia, otitis media, bronchitis, sinusitis
LAIV nasal vs. IM
Most viral infections have a resolution of symptoms in 3-7 days and fully clear within 1-2 weeks. Bacterial infections can clear as well but may require antibiotics if they do not appear to be clearing on their own, are associated with too many symptoms, or are in an individual with many comorbid conditions.
colored nasal discharge is a normal self-limited phase of the uncomplicated common cold. Treating with antibiotics in clinical trials does reduce the risk of persistent purulent discharge but adverse effects of antibiotics outweighed benefit of treatment.
Some of us are natural colonizers of the big three bugs that cause complications of the common cold: H. influenzae, M. catarrhalis, or S. pneumoniae. So is it a positive culture or was always there? There is still controversy regarding whether diagnostic tests and treatment for influenza are cost-effective in healthy individuals who will likely resolve anyways. Diagnostic tests are expensive and many patients present after the time period If we take a culture and send the patient home on antibiotics then it comes back viral what do we do? Tell them to stop antibiotics, unforeseen risks of developing resistance either way?
Each situation must be weighed individually for risk vs. benefit. Generally all treatment should be symptomatic (fluids, APAP for fever, etc) unless a secondary bacterial infection is suspected.

6. WHEN TO PROPHYLAX/TREAT INFLUENZA WITH AN ANTIVIRAL?
High risk populations:
≥65 years old
Pregnant women
Chronic medical conditions
Diabetes, asthma, COPD, cardiovascular disease, etc
Asplenic patients
Influenza requiring hospitalization
Prevent outbreak
Nursing homes, long-term care facilities, correctional facilities
Influenza A gains resistance very quickly, don’t want to use in everyone
Defined by CDC as high risk populations, more at risk from complications of influenza
Pregnancy category C
No spleen, can’t remove capsulated bacteria- risk for secondary bacterial infection
Empirically-without laboratory confirmation

7. ANTIVIRALS FOR INFLUENZA
Oseltamivir (Tamiflu®)
Oral capsule
Oral suspension

8. MECHANISM OF ACTION
Oseltamivir: inhibits influenza virus neuraminidase which stops viral particle release
LAYMEN’s terms: prevents the infected host cell from releasing new virus
Reduces replication of virus

9. OSELTAMIVIR INDICATIONS
Prophylaxis
Treatment
Influenza A & B
H1N1
Avian (H5N1)
Prophylaxis should begin hr after exposure for best effect
Continue for 10 days
QD therapy
Prophylaxis is NOT replacement for vaccine
Influenza A & B
H1N1
Avian (H5N1)
Treatment should begin ASAP, or hr after onset of symptoms
Continue for 5 days
BID therapy
Oseltamivir resistance?
Zanamivir
Prophylaxis can continue for longer than 10 days in immunocompromised individuals or in H1N1 if they have continued exposure. (Continue 10 days past last exposure)
There are oseltamivir resistant influenza strains particularly with Influenza A strain. Pandemic H1N1 less resistant than seasonal H1N1 There is another neuraminidase inhibitor Zanamivir (nasal inhalation) that can be used and has shown less resistance. There is also a class of antivirals called adamantanes which includes amantadine and rimantadine but they are only effective against Influenza A.

10. OSELTAMIVIR PATIENT INFORMATION
Administration:
Take with or without food
Food may decrease GI upset
Suspension:
Shake well
Store in fridge
Contraindications
No live vaccines w/in 2 weeks before or 48 hours after
What to expect:
Improvement of symptoms
May shorten duration of flu symptoms by 1-3 days
May decrease risk of transmission to others
Reduction in secondary antibiotic use
Lasts 10 days at room temperature, 17 days in fridge
Live attenuated influenza vaccine; vaccine requires immune response and replicating virus to establish immunity, obviously this would lead to diminished efficacy of the vaccine
How do you know if it’s working, should see improvement, if get worse see PCP

11. HERPES INFECTIONS HSV1 HSV2 Herpes Zoster
Herpes labialis or “cold sores”, fever blisters
HSV2
Genital herpes
Acquired through sexual contact, lifelong recurrent infection
Can by asymptomatic, still transmissible
Herpes Zoster
Varicella zoster virus
Causes chicken pox in children, shingles, and postherpetic neuralgia
HSV1- what learned from OTC
Postherpetic neuralgia is pain after shingles

12. ANTIVIRALS FOR HERPES INFECTIONS
Acyclovir (Zovirax®)
Oral capsule, tablet, and IV
Oral suspension
Topical cream, ointment
Valacyclovir (Valtrex®)
Oral tablet
Famciclovir (Famvir®)
When would you use topical for what indication
Acyclovir is only one available topically. Topical use should only be for Shingles or cold sores. CDC discourages topical acyclovir use for genital herpes except in immunocompromised individuals

13. MECHANISM OF ACTION
Acyclovir: acts as a purine nucleotide analog to interfere with herpes viral DNA polymerase
Valacylovir: Prodrug converted to acyclovir
Famciclovir: Prodrug converted to penciclovir (acts similarly to acyclovir)
LAYMEN’s terms: interferes with viral DNA replication by terminating the DNA chain
Prodrug- administered in inactive form and is activated in the body by metabolism or some other metabolic process to the active drug

14. INDICATIONS Acyclovir Valacyclovir Famciclovir
Herpes Labialis (topical)
Genital Herpes
Initial, Recurrent, Chronic Suppression
Herpes Zoster (shingles)
Varicella-zoster (chicken-pox)
Valacyclovir
Herpes Labialis
Genital Herpes
Initial, Recurrent, Reduction of Transmission, Chronic Suppression
Herpes Zoster
Varicella-zoster
Famciclovir
Initial, Recurrent, Chronic Suppression
Note that Famciclovir is not approved to be used in chickenpox in children

15. COMMON COUNSELING POINTS
Take with or without food
Take with extra fluids
Tell patients to drink enough to urinate every few hours
Topical application:
Use gloves, wash hands
Cover lesion, rub on gently
Adverse Effects with oral medication:
Headache, fatigue
N/V/D/constipation
More SE with Herpes Zoster treatment (increased dose)
Shingles lesions or genital lesions
Eliminated completely by kidneys, will prevent kidney problems
TOPICAL?

16. COMMON COUNSELING POINTS, CONT
If taking chronically, explain importance of adherence to prevent outbreaks
Cost of therapy? Covered by insurance?
Reduction of stressors (may increase risk of outbreak)
Pts concerned should know toxicity of long-term therapy is minimal
Explain that this is not a cure, give realistic expectations
If taking medication episodically for genital herpes, take within 24 hours of outbreak symptoms (tingling) to suppress or reduce duration and severity
Reduces pain, length of time to healing, viral shedding
Practice SAFE SEX
Chronic therapy does reduce transmission risk
Use condom, avoid sex during outbreak
Quality of life higher in patients undergoing suppressive therapy versus episodic therapy (who just treat based on outbreaks). Recommended to use chronic therapy if have 6+ outbreaks per year. Some patients may be very asymptomatic and may not require antivirals. Stress, get more sleep.
Though most studies only followed for 1 year. Reoccurrences decrease over time. Patients should be re-evaluated to determine if they can go off chronic therapy

17. SPECIFIC PATIENT INFORMATION
Valacyclovir and famciclovir have longer half- lives than acyclovir, take less frequently
Example: Acyclovir 5 times a day x 5 days
Valacyclovir 2 times a day x 3 days
May increase patient adherence to chronic med
Acyclovir and valacyclovir
Drug-Drug Interaction with probenicid
May increase levels of these antivirals, increase side effects
Put in dosing schedule, don’t use acyclovir as much. This example shows recurrence
Acyclovir needs to be taken much more frequently depending on the infection, anywhere from four to 5 times a day for shingles and chickenpox, 2-5 times a day for suppressive therapy in genital herpes depending on the strength. Valacyclovir and famciclovir are max bid in genital herpes.
Probenecid: used in gout and some STD treatments. This population likely has higher risk of STD’s so just be aware

18. ANTIFUNGALS

19. FUNGAL INFECTIONS Superficial Infections
Tinea (dermatophyte) infections
Named for site of infection
Tinea pedis, corporis, cruris, capitus, etc
Onychomycosis
Infection of finger/toenails by dermatophytes
Sebborrheic dermatitis
Vaginal candidiasis (yeast infection)
Most common species is C. albicans, though other spp are on the rise
Antibiotic treatment can lead to overgrowth
OTC treatment possible if uncomplicated
Superficial involves the skin, hair and nails. Does anyone remember another name for onychomycosis? (tinea unguium) All tinea infections can be treated topically except….. Capitus and onychomycosis
Subcutaneous is confined to the dermis or adjacent structures, very rare unless in tropical or exotic locations
Sebborrheic dermatitis: inflammatory condition, overproduction of cells and sebum, overgrowth of normal skin fungus (yeast). Dandruff is a symptom of sebborrheic dermatitis but not all dandruff is caused by fungal overgrowth. Dandruff is always confined to scalp, whereas s.d. can be around nose and eyebrows as well.
Do you remember some OTC treatments: clotrimazole cream and tablet, miconazole. When would someone have complicated yeast infection? Diabetes (high blood sugar, yeast may flourished), immunocompromised, pregnancy, recurrent infx.
Oral and topical treatment are therapeutically equivalent, oral preferred due to convenience

20. FUNGAL INFECTIONS, CONT.
Oropharyngeal (thrush) and Esophageal candidiasis
Infection can spread from oral mucosa into esophagus
Risk factors include antibiotics, inhaled steroids, dentures, smoking, immunocompromised patients
Systemic and Opportunistic Infections
Can gain entry through GI, lungs, or IV
Systemic candidiasis
Can include peritonitis, pneumonia, and others
Individuals can be carriers of Candida, and these risk factors give the yeast an opportunity to flourish
Systemic is an infection involving the whole body, blood and internal organs. Opportunistic is an infection only occurring in immunocompromised individuals such as HIV infected individuals
Peritonitis is inflammation of the peritoneum, which is the tissue that covers the abdominal organs. There are quite a few other systemic infections that are caused by other strains of fungi, such as invasive aspergillosis but I won’t be discussion anything other than candidia which is a yeast.

21. ANTIFUNGAL MEDICATIONS
Azoles
Imidazoles: ketoconazole
Triazoles: fluconazole, itraconazole, voriconazole
Terbinafine
Nystatin
Imidazoles: ketoconazole, Triazoles: fluconazole, itraconazole, voriconazole, posaconazole

22. MECHANISM OF ACTION
Triazoles: inhibition of CYP450 enzyme dependent ergosterol synthesis
Ketoconazole and Terbinafine: interfere with fungal ergosterol biosynthesis
Nystatin: binds to sterols in cell membrane and changes permeability
LAYMEN’s terms: prevents proper production of fungal cell membrane resulting in cell death
Ergosterol is main sterol component of fungal cell membranes, inhibiting production of this allows increased permeability and leakage
Disruptions in the biosynthesis of ergosterol cause significant damage to the cell membrane by increasing its permeability, resulting in cell lysis and death. Despite this mechanism of action, the triazoles are generally considered fungistatic against Candida species.

23. AZOLES Ketoconazole (Nizoral®) Fluconazole (Diflucan®)
Oral tablet & topicals: cream, gel, shampoo, foam
Fluconazole (Diflucan®)
Oral tablet and IV
Itraconazole (Sporanox®)
Oral capsule
Voriconazole (VFEND®)
Fun fact: fluconazole oral dose is equivalent to the IV dose, makes it easy to convert someone to PO

24. OTHER ANTIFUNGALS Terbinafine (Lamisil®) Nystatin (Nystat- RX®)
Oral tablets
Topicals: cream, gel, solution
Nystatin (Nystat- RX®)
Oral tablets
Oral suspension
Vaginal tablets
Topical powder
Lamisil also OTC for treatment of athletes foot (tinea pedis) or jock itch and ring worm (tinea corporis, tinea cruris)
There are multiple brand names for Nystatin. This is just one of them

25. MOST COMMON INDICATIONS
Tinea Infections (1-4 wks)
Ketoconazole
Terbinafine
Onychomycosis (6wks-1yr)
Itraconazole
Vaginal Candidiasis (1d- 2wks)
Fluconazole
Nystatin
Oropharyngeal Candidiasis (7-14d)
Fluconazole
Itraconazole
Nystatin
Esophageal Candidiasis
(14-21d)
Voriconazole
Systemic Infections
By no means ALL of the indications that they can be used for. Additionally, in each case the provider must have an understanding that the fungi they are treating will be susceptible to the drug, otherwise resistance will prevent treatment. Resistance will likely lead to reoccurrence and treatment failure.
Ketoconazole is not often used systemically because the other azoles because have less drug interactions, higher safety profiles, and higher efficacy for invasive infections
Formulations used differently:

26. PATIENT INFORMATION FOR ALL ANTIFUNGALS
Administration
Superficial fungal infections may take a LONG time to effectively treat (weeks to months)
Exception-Fluconazole for vaginal yeast infection
Important to counsel on adherence and time to effect
Onychomycosis
Side Effects
Oral: Headache, dizziness, changes in taste
GI upset: N/V/D
Can take with food to prevent
Exception- take voriconazole 1-2 hrs before meal
Topical: Irritation, burning, and dryness
Reminder to wash hands after administration
Counseling is crucial for fungal infections because patient adherence is directly linked to therapeutic outcome. If the patient has realistic goals initially, that there will be slow improvement over time, they are more likely to follow-through with therapy than give up after a week with no change. In onychomycosis which takes months to treat due to slow growing toenails, let the patient know that sometimes the nail will not return to normal appearance even when the fungus has been eradicated.
Fluconazole for vaginal yeast infection is a one time dose, flu has half-life of 30 hours, vaginal concentrations are roughly equivalent to plasma. Symptoms begin to improve in 24 hours
Itraconazole capsules should be taken with food to increase absorption
Voriconazole should be taken 1-2 hours before food to maximize absorption

27. SPECIFIC PATIENT INFO Contraindications
Azoles and Terbinafine can lead to liver toxicity so liver function should be closely monitored
[US Black Box Warning]
Azoles (especially triazoles) have drug interactions since MOA involves P450 enzymes
Inhibit CYP3A4, 2C9, 2C19 (warfarin, phenytoin, benzodiazepines…)
Terbinafine also exhibits drug interactions
inhibits CYP2D6 (antidepressants, codeine…)
Ketoconazole and Itraconazole : separate from antacids by 2 to 4 hours.
Why?
Voriconazole: may cause visual disturbances, photophobia
Itraconazole: take with food to increase absorption
Liver functions is often tested before long-term therapy and every 6 weeks thereafter.
Black Box warning is something the FDA attaches to a drug or drug class so that practitioners are aware of a specific side effect or interaction
Itraconazole is a good choice for onychomycosis if the patient is on CYP2D6 drugs because Terbinifine inhibits CYP2D6
Oral ketoconazole/itraconazole absorption is pH dependent, so it is is decreased by antacids. Be aware if pt is on H2 antagonists and PPI they will likely have reduced absorption due to increased gastric pH
What’s an example of a PPI
CYP issues:
Ketoconazole: CYP3A4 substrate, inhibits 2C9 and 3A4
Fluconazole: inhibits all three
Itraconazole: CYP3A4 substrate, inhibits 2C and 3A4
Voriconazole: CYP2C19 substrate, inhibits all three

28. QUESTIONS?

29. QUIZ NEXT WEEK:
Know COMMON counseling points about the classes of antifungals and antivirals
Know the drugs in each class and their mechanisms of action (Laymen’s terms ok)
Know some SPECIFIC counseling points, side effects, and toxicities for these medications
*Hint* look at items in bold or all caps 

30. FEEDBACK!
Please take out a ½ sheet of paper and respond to these questions:
1) What was the most useful information you learned today?
2) What questions remain about the lecture material?
3) What constructive feedback to you have?
THANK YOU!