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 boddia@uw.edu

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

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

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

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.

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

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

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

OSELTAMIVIR INDICATIONS Prophylaxis Treatment Influenza A & B H1N1 Avian (H5N1) Prophylaxis should begin 24- 48hr 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 12-48 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.

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

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

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

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

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

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?

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

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

ANTIFUNGALS

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

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.

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

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.

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

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

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:

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

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

QUESTIONS?

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 

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!