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Infectious Diseases II (c) Rifampin 600 mg daily plus isoniazid 300 mg daily for 3 months (d) Isoniazid 300 mg daily or 900 mg twice weekly for 6–9 months (9 months preferred, especially for children and pregnant women) ii. Patients who are coinfected with HIV (a) Rifapent...

Infectious Diseases II (c) Rifampin 600 mg daily plus isoniazid 300 mg daily for 3 months (d) Isoniazid 300 mg daily or 900 mg twice weekly for 6–9 months (9 months preferred, especially for children and pregnant women) ii. Patients who are coinfected with HIV (a) Rifapentine 900 mg orally plus isoniazid 15 mg/kg orally (900 mg maximum) plus pyridoxine 50 mg orally, all once weekly for 12 weeks (b) Isoniazid 300 mg orally plus rifampin 600 mg orally plus pyridoxine 25–50 mg orally, all daily for 3 months (watch for drug interactions with rifampin) (c) Alternatives: isoniazid 300 mg orally plus pyridoxine 25–50 mg orally daily for 6-9 months (especially if rifamycin drug interactions are a concern); rifampin 600 mg orally daily for 4 months; isoniazid 300 mg orally plus rifapentine orally plus pyridoxine 25–50 mg orally, all daily for 4 weeks iii. Areas with multidrug-resistant isolates: Two drugs with activity against the isolate for 6–12 months Patient Case 9. R.J. is a 32-year-old HIV-positive man who presents to the clinic with increased weight loss, night sweats, and a cough productive of sputum. He is currently receiving darunavir/ritonavir 800 mg/100 mg daily, tenofovir disoproxil fumarate 300 mg daily, emtricitabine 200 mg daily, fluconazole 200 mg/day orally, and trimethoprim/sulfamethoxazole double strength daily. A sputum sample is positive for acid-fast bacillus. R.J. lives in an area with a low incidence of multidrug-resistant TB. Which is the best initial treatment? A. Initiate isoniazid, rifampin, and pyrazinamide with no change in HIV medications. B. Initiate isoniazid, rifampin, and pyrazinamide; increase the dosage of darunavir/ritonavir; and use a higher dosage of rifampin. C. Initiate isoniazid, rifabutin, pyrazinamide, and ethambutol, with a lower dosage of rifabutin. D. Initiate isoniazid, rifabutin, pyrazinamide, and ethambutol, and decrease the dosage of darunavir/ ritonavir. 2. Treatment of active TB infection (Tables 10 and 11) a. Principles of treatment i. Regimens must contain many drugs to which the organisms are susceptible. ii. Drug therapy must continue for a sufficient period. Table 10. Pharmacotherapeutic Agents in the Treatment of Tuberculosis First-Line Agents Isoniazid Rifampin Pyrazinamide Ethambutol Second-Line Agents Amikacin/kanamycin Bedaquiline Capreomycin Cycloserine Ethionamide Fluoroquinolones Para-aminosalicylic acid Pretomanid Rifabutin Rifapentine Streptomycin ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-273 Infectious Diseases II b. Therapeutic options for treating active TB (Note: Any regimen administered two, three, or five times/week should be done by directly observed therapy.) Table 11. Treatment of Tuberculosis Recommended Patients without HIV Antibiotic Regimen Antibiotic Patients with HIV Regimen Intensive Phasea Isoniazidb Rifampin Pyrazinamide Ethambutol Treat for 2 months (daily or five times weekly) Isoniazid Rifampin or rifabutin Pyrazinamide Ethambutol Treat for 2 months (daily or five times weekly) Continuation Phase Isoniazid Rifampin Treat for 4 monthsc (daily or five times weekly) Isoniazid Rifampin or rifabutin Antibiotic Treat for 4 monthsd (daily or five times weekly) Optional (less efficacy)e Antibiotic Regimen Intensive Phasea Isoniazid Rifampin Pyrazinamide Ethambutol Treat for 2 months (three times weekly or daily for two weeks followed by two times weekly) N/A N/A Continuation Phase Isoniazid Rifampin Treat for 4 months (three times weekly or twice weekly) N/A N/A Regimen If TB isolate is susceptible to both INH and RIF, then ethambutol can be dropped from the intensive phase. Pyridoxine should be given to all those receiving isoniazid and at increased risk of neuropathy (e.g., pregnant women, breastfeeding infants, HIV infected persons, patients with diabetes, alcoholism, malnutrition, or chronic renal failure, persons of advanced age). c Extend to 7 months if cavitary lesions on chest x-ray and positive sputum culture after intensive phase. d Extend to 7 months if patient not receiving ART. e Efficacy diminishes as the number of weekly doses decreases. a b c. Concurrent therapy in patients with HIV i. For ART-naive patients, ART should be initiated within 2 weeks when the CD4 count is less than 50 cells/mm3 and by 8–12 weeks for all others. ii. PIs and NNRTIs (except for efavirenz or nevirapine) should not be administered concurrently with rifampin; INSTIs can be administered with rifampin (except elvitegravir, bictegravir, and cabotegravir), but doses need to be adjusted; NRTIs can be administered with rifampin, except for tenofovir alafenamide. iii. A washout period of 1–2 weeks may be necessary once rifampin is discontinued before PIs, elvitegravir, or NNRTIs are initiated. iv. Rifabutin can be substituted for rifampin; patients may take NRTIs and NNRTIs with rifabutin except for tenofovir alafenamide, but rifabutin doses may need to be increased to 450–600 mg daily (see HIV guidelines). v. Patients may take PIs with rifabutin unless the PI is boosted with cobicistat; if the PI is boosted with ritonavir, the rifabutin dose should be decreased to 150 mg every day. vi. Elvitegravir and bictegravir should not be used with rifabutin. vii. Patients taking rifabutin and PIs, INSTIs, or NNRTIs should have HIV RNA and rifabutin concentrations performed periodically. viii. Rifapentine should only be given to patients receiving an efavirenz-, dolutegravir- or raltegravirbased regimen. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-274 Infectious Diseases II d. Known drug resistance to isoniazid: Administer rifampin, pyrazinamide, ethambutol, and moxifloxacin or levofloxacin for 2 months; rifabutin may be substituted for rifampin in patients with HIV. Continuation phase should be completed with rifampin (or rifabutin) plus ethambutol plus moxifloxacin (or levofloxacin) for 7 months. e. Known drug resistance to rifampin: Administer isoniazid, pyrazinamide, and ethambutol for 9–12 months; streptomycin may be added for the first 2 months to shorten the total treatment time to 9 months. f. Total duration of therapy should be based on number of doses received, not on calendar time. i. Pulmonary TB: 6 months ii. Pulmonary TB and culture positive after 2 months of TB treatment: 9 months iii. Extrapulmonary TB with central nervous system (CNS) infection: 9–12 months iv. Extrapulmonary TB with bone or joint involvement: 6–9 months v. Extrapulmonary TB in other sites: 6 months Patient Cases 10. Which represents the best follow-up for R.J. (from Patient Case 9)? A. Treatment with the initial drugs should continue for 6 months. B. Treatment can be decreased to isoniazid and a rifamycin after 2 months for a total treatment of 18–24 months. C. Treatment can be decreased to isoniazid and a rifamycin after 2 months for a total treatment of 6 months; HIV RNA concentrations should be observed closely during therapy. D. Treatment can be decreased to isoniazid, a rifamycin, and either pyrazinamide or ethambutol after 2 months for a total treatment of 6 months; HIV RNA concentrations should be observed closely during therapy. 11. L.F. is a 55-year-old man (73 kg) who was involved in a motor vehicle accident with subsequent rib fractures and bilateral pneumothoraces. He is admitted to the ICU and mechanically ventilated. He is started on levofloxacin which after 3 days is switched to piperacillin/tazobactam and vancomycin. After 5 days of broad spectrum antibiotics his temperature continues to spike. A blood culture is positive for Candida krusei. What is the best treatment for L.F.? A. Fluconazole 400 mg IV daily for 7 days following the first negative blood culture. B. Micafungin 100 mg IV daily for 14 days following the first negative blood culture. C. Amphotericin B lipid formulation 3 mg/kg/day for 14 days following the first negative blood culture. D. Voriconazole 200 mg IV twice daily for 7 days following the first negative blood culture. IV. FUNGAL PHARMACOTHERAPY A. Candida 1. Background a. C. albicans, C. krusei, C. parapsilosis, C. tropicalis, C. glabrata, C. auris b. Risk factors: i. Broad spectrum antibiotics ii. Central catheters, urinary catheters, etc. (remove if found to be the source of infection) iii. Prosthetic devices iv. Immunocompromised (chemotherapy, radiation, corticosteroid, HIV, etc.) 2. Therapy a. Oral/esophageal candidiasis (see II. Opportunistic Infections: Patients With HIV, C. Candida Infections) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-275 Infectious Diseases II b. c. Candidemia i. Echinocandin (caspofungin, anidulafungin, or micafungin) ii. Fluconazole: only use if known or suspected fluconazole-sensitive organism (400 mg/day) iii. Amphotericin B lipid formulation – for resistance or intolerance to other antifungals iv. Treat for 14 days after first negative blood culture Endocarditis i. Amphotericin B lipid formulation ± flucytosine or high dose echinocandin ii. Fluconazole (or voriconazole or posaconazole) can be used as step down therapy for sensitive isolates iii. Replace the valve and treat for 6 weeks iv. Consider chronic suppressive therapy with fluconazole for prosthetic valve endocarditis d. Osteomyelitis/Septic arthritis i. Fluconazole for 6-12 months ii. Echinocandin for 2 weeks followed by fluconazole for 6-12 months iii. Amphotericin B lipid formulation for 2 weeks followed by fluconazole for 6-12 months iv. Same recommendations for septic arthritis except total therapy is only 6 weeks e. Urinary tract infections i. Remove indwelling catheters, nephrostomy tubes, stents, etc. ii. Asymptomatic: treat only if patient is neutropenic or undergoing urologic manipulation associated with mucosal trauma or bleeding (see guidelines at Clin Infect Dis 2019;68:e83-e110) iii. Symptomatic (a) Fluconazole for 2 weeks (b) Amphotericin B deoxycholate (not liposomal preparations) (1-7 days) or flucytosine (7-10 days) for fluconazole resistant organisms (c) Other azoles and echinocandins do not achieve adequate urinary concentrations f. Invasive Candidiasis in the Intensive Care Unit i. Empiric treatment (a) Use for patients with unexplained fever and risk factors: Candida colonization, severe illness, broad spectrum antibiotics, recent abdominal surgery, necrotizing pancreatitis, dialysis, total parenteral nutrition, corticosteroids, central venous catheter (b) Echinocandin therapy recommended (c) Fluconazole use only in patients without recent azole use or colonization with azoleresistant organisms (d) Amphotericin B lipid formulation if patient intolerant to other antifungals (e) Duration: 2 weeks if patient responds or 4-5 days with no response ii. Prophylaxis (a) Fluconazole 400 mg daily in ICUs where invasive candidiasis occurs in more than 5% of patients (b) Echinocandins can be used alternatively B. Histoplasmosis 1. Background a. Histoplasma capsulatum b. Endemic regions: lower Mississippi and Ohio valleys c. Organisms in excrement are aerosolized and inhaled d. Signs and symptoms: lymphadenopathy, splenomegaly, fever, weight loss, headache, chills, cough, chest pain, myalgias, fatigue ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-276 Infectious Diseases II 2. Therapy a. 50% mortality even with therapy – relapses are frequent b. Moderate to severe illness: Lipid formulation amphotericin B (3–5 mg/kg/day) for at least 1-2 weeks followed by itraconazole to complete 12 weeks of therapy c. Mild illness: itraconazole 200 mg three times daily for 3 days and then twice daily for 12 weeks (may need to extend to 12-24 months in patients with chronic or disseminated disease) C. Coccidioidomycosis 1. Background a. Coccidioides immitis b. Endemic regions: California, Arizona, Nevada, New Mexico, Utah, Texas c. Organisms in soil are aerosolized and inhaled d. Signs and symptoms: cough, sputum production, chest pain, malaise, fever, chills, night sweats, anorexia, weakness, arthralgias 2. Therapy a. Consider not treating in immunocompetent host b. Fluconazole 400 mg daily or itraconazole 400 mg daily for 3-6 months c.  Severe/diffuse/disseminated disease: amphotericin B lipid formulation (5 mg/kg/day) until improvement then fluconazole or itraconazole for at least a year D. Blastomycosis 1. Background a. Blastomyces dermatitidis b. Endemic regions: Southeastern states, Ohio and Mississippi river basins, and Great Lakes region including the St. Lawrence seaway c. Sources: soil – organisms in soil are aerosolized and inhaled d. Signs and symptoms: cough, sputum production, chest pain, malaise, fever, chills, weakness, arthralgias e. Cutaneous manifestations (occurs in 40-80% of patients): small papulopustular lesions that spread to form a crusted, heaped-up lesion or an ulcerative pustular lesion 2. Therapy a. Itraconazole 200 mg three times daily for 3 days and then twice daily for 24 weeks b. Severe/life threatening disease: amphotericin B lipid formulation (5 mg/kg/day) until improvement then itraconazole for 6-12 months E. Aspergillosis 1. Background a. Aspergillus fumigatus b. Ubiquitous in the environment c. Sources: grows in stored hay/grain, decaying vegetation, soil, compost piles, and manure – common during hospital renovation / construction, in potted plants, and air conditioner filters – organisms are aerosolized and inhaled d. Allergic bronchopulmonary aspergillosis – in asthma patients, aspergillosis causes hypersensitivity reaction and granuloma formation (treat with prednisone) e. Pneumonia – secondary to prolonged neutropenia; high fever and dense pulmonary infiltrates – rapidly progressing and universally fatal in bone marrow transplant patients 2. Therapy a. Voriconazole 6 mg/kg intravenously twice daily for two doses and then 4 mg/kg intravenously twice daily or 200-300 mg orally twice daily ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-277 Infectious Diseases II b. Alternatives: isavuconazole 200 mg every 8 hours for six doses and then 200 mg daily or amphotericin B lipid formulation (3-5 mg/kg/day) c. Echinocandins only if azoles and amphotericin are contraindicated d. Treat for 6-12 weeks 3. Prophylaxis a.  Recommended for at-risk patients with prolonged neutropenia, graft-versus-host disease or lung transplant b. Voriconazole or posaconazole or micafungin (use voriconazole, itraconazole, or inhaled amphotericin for 3-4 months after lung transplant) F. Mucormycosis 1. Background a. Rhizopus spp. and Mucor spp. b. Ubiquitous in the environment c. Sources: decaying organic matter – organisms are aerosolized and inhaled d. Signs and symptoms: fever, cough, shortness of breath (pulmonary); can also cause sinusitis with associated symptoms or cutaneous infections 2. Therapy a. Amphotericin B lipid formulation (5 mg/kg/day) until improvement then isavuconazole or posaconazole b. Treat until resolution of infection (usually months) Patient Case 12. A.B. is a 55-year-old woman who presents to your clinic with toenail discoloration with a few of her toenails separating from the nail bed. She is diagnosed with onychomycosis. What is the best treatment for A.B.? A. Fluconazole 200 mg orally daily for 14 days. B. Itraconazole 200 mg orally daily for 28 days. C. Miconazole cream applied twice daily to toenails for 2 months. D. Terbinafine 250 mg orally daily for 3 months. G. Superficial fungal infections 1. Background a. Caused by dermatophytes (Microsporum, Trichophyton, Epidermophyton) b. More common in males than females c. More common in tropical, humid climates d. Transmitted person to person, via soil contact and via animal contact 2. Tinea capitis – infection of the scalp a. Peak incidence of 3-9 years of age, more common in nonwhites b. Spores invade the hair shaft leading to hair loss without inflammation or spores spread beyond the hair shaft leading to inflammation c. Therapy: i. Griseofulvin (preferable for Microsporum) 10–15 mg/kg/day for 6–8 weeks ii. Terbinafine (preferable for Trichophyton): Weight less than 10 kg: 62.5 mg; 10–20 kg: 125 mg; greater than 20 kg: 250 mg daily for 4 weeks iii. Itraconazole, fluconazole – alternatives; treat for 4–6 weeks iv. Selenium sulfide 2.5% shampoo (reduces spread of infection and reinfection) 3. Tinea pedis – infection of the foot a. Increase in frequency with age; more common in men than women, and in those who wear shoes b. Moccasin like distribution (difficult to treat) or intertrigenous involvement which may lead to secondary bacterial infection ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-278 Infectious Diseases II c. Therapy: i. Topical antifungal agent twice daily until clear ii. Terbinafine, itraconazole, or fluconazole for severe or resistant cases 4. Tinea cruris – infection of the groin and thigh a. More common in males than females b. Predisposing factors include obesity, tight-fitting clothes, wet swimsuits, etc. c. Therapy: i. Topical antifungals twice daily for 3-4 weeks ii. Loose-fitting cotton underwear and good hygiene 5. Tinea corporis – “ringworm” a. Common in hot, humid climates – transmitted person to person b. Asymptomatic or pruritic annular plaque – scaling, crusting, vesicle formation and papules on nonhairy skin c. Therapy: i. Topical antifungal twice daily for 2-4 weeks ii. Terbinafine or itraconazole for extensive skin involvement 6. Onychomycosis – nail infection a. Increases with age – affects 5% of the population b. Predisposing factors include superficial fungal infection of feet or hands, repeated minor trauma with heat and moisture c. Nail discoloration, subungual hyperkeratosis, separation of nail from bed d. Therapy: i. Terbinafine ii. Itraconazole (pulse or continuous therapy) iii. Onychomycosis specific topical agents: efinaconazole, tavaborole, or ciclopirox iv. Duration: fingernails: 6 weeks; toenails: 12 weeks (longer if using topical agents) Patient Case 13. C.A. is a 66-year-old man with a history of advanced non–small cell lung cancer. After his most recent chemotherapy, he became severely neutropenic and received a diagnosis of Aspergillus pneumonia. C.A. has acute renal failure related to his chemotherapy and is receiving warfarin, diltiazem, dronedarone, atorvastatin, pantoprazole, and carbamazepine. Which antifungal would be the best therapy for C.A.? A. Lipid amphotericin. B. Micafungin. C. Fluconazole. D. Voriconazole. V. ANTIFUNGAL AGENTS A. Amphotericin B (Fungizone, Abelcet, Amphotec, AmBisome) 1. Mechanism of action: Binds to ergosterol in the fungal cell membrane, altering membrane permeability and causing cell lysis 2. Spectrum of activity a.  Candida, Blastomyces dermatitidis, Coccidioides immitis, C. neoformans, Paracoccidioides, Histoplasma capsulatum, Sporothrix, Aspergillus, mucormycoses ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-279 Infectious Diseases II b. Clinical use i. Cryptococcal meningitis ii. Systemic fungal infections caused by sensitive fungi iii. Limited use clinically with newer antifungals 3. Adverse effects (less common with lipid formulations) a. Renal toxicity (glomerular and tubular) i. Glomerular filtration rate decreases by about 40% within 2 weeks and usually stabilizes at 20%–60% of normal. ii. In general, reversible unless total dose is more than 4–5 g iii. Manifestations: Renal tubular acidosis, urine casts, azotemia, oliguria, magnesium, and potassium wasting iv. Prevention (a) Correct salt depletion: 3 L normal saline for 24 hours or 500 mL of normal saline before and after amphotericin dose (b) Avoid diuretics and liberalize salt intake; risk-benefit with other disease states b. Thrombophlebitis prevention (deoxycholate formulation only) i. Dilute to 0.1 mg/mL and infuse for at least 4 hours; a faster infusion (i.e., 45 minutes to 2 hours) may be tolerated. ii. Use a central site. iii. Adding heparin may decrease phlebitis. c. Anemia d. Fever and chills i. Mechanism: Amphotericin B induces prostaglandin synthesis. ii. Premedications (a) Hydrocortisone: 25 mg intravenously before the dose or in the bottle decreases fever and chills (higher doses are not significantly better) (b) Ibuprofen (10 mg/kg up to 600 mg 30 minutes before infusion): Significantly more fever and chills in placebo (87%) than in ibuprofen group (48%) (c) Acetylsalicylic acid, acetaminophen, diphenhydramine: Never shown to be effective (but not specifically studied) e. Rigors treatment i. Meperidine 50 mg: Stops reaction within 30 minutes (mean, 10.8 minutes) ii. If the patient consistently needs meperidine, then prophylactic doses may be appropriate. 4. Dosing a. Start therapy with 0.25 mg/kg (some suggest 5–10 mg) administered for 4–6 hours. b. Increase gradually to desired milligram per kilogram concentration (i.e., 5- to 10-mg increments). c. May increase rapidly in fulminant infections or immunocompromised patients d. Amphotericin can be given on alternate days by doubling the daily dose to a maximum of 1.5 mg/kg. 5. Lipid amphotericin formulations (liposome, lipid complex, and colloidal dispersion; Table 12) a. Lipid formulations are designed to maintain therapeutic efficacy, but they diminish renal and infusion-related toxicity. b. Mainly taken up by macrophages in the lung, liver, spleen, bone marrow, and circulating monocytes c. Liposomes target fungal cell membranes much more than human cell membranes. d. Amphotericin dissociates from the liposome over time, decreasing its toxicity (only free drug is toxic). e. Primary use in patients with aspergillosis and cryptococcal meningitis who cannot tolerate amphotericin B deoxycholate f. Potential use for invasive candidiasis ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-280 Infectious Diseases II B. Azole Antifungals 1. Mechanism of action: Inhibits the synthesis of ergosterol, a component of the fungal cell membrane, vital for normal growth 2. Fluconazole (Diflucan) a. Spectrum of activity i.  Candida spp. (poor activity against C. glabrata and no activity against C. krusei), Cryptococcus, Blastomyces, Histoplasma, dermatophytes ii. Clinical use (a) Candida infections (primarily C. albicans and C. parapsilosis) (b) Cryptococcal meningitis Table 12. Amphotericin Formulations Amphotericin B Deoxycholate Lipid type Abelcet Amphotec AmBisome Multilamellar vesicle with ribbonlike structure (lipid complex) Colloidal dispersion in aqueous solution (disk-shaped bilayer) Unilamellar liposome Dose 0.7–1 mg/kg/day 5 mg/kg/day for 2 hours 3–4 mg/kg/day for 3–4 hours 3–5 mg/kg/day Test dose Yes None Yes None Chills or rigors (%) 54–56 18 77 18 Fever (%) 44–47 14 55 17 Nephrotoxicity (%) 34–47 28 8 19 Hypokalemia (%) 12–29 5 26 7 N/A 6 20 Hypomagnesemia (%) 11–26 b. Pharmacokinetics i. Well absorbed orally (bioavailability 100%); also available intravenously ii. Half-life is about 30 hours; primarily eliminated unchanged in the urine c. Adverse effects i. Nausea, abdominal pain, headache, reversible alopecia ii. Elevated liver function tests d. Drug interactions (CYP3A4 inhibitor at more than 400 mg/day and CYP2C9 inhibitor at lower doses) i. Cyclosporine ii. Phenytoin iii. Warfarin e. Dosing i. Oral candidiasis: 100–200 mg/day ii. Esophageal candidiasis: 200–400 mg/day iii. Invasive candidiasis: 400–800 mg/day iv. Acute cryptococcal meningitis: 400–800 mg/day v. Cryptococcal meningitis prophylaxis: 200 mg/day 3. Itraconazole (Sporanox) a. Spectrum of activity i.  Candida spp. (usually just C. albicans), Cryptococcus, Aspergillus, Blastomyces, Histoplasma, dermatophytes ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-281 Infectious Diseases II ii. Clinical use (a) Onychomycosis (b) Histoplasmosis (c) Aspergillosis (d) Blastomycosis b. Pharmacokinetics i. Capsule absorption improves with food; solution should be taken on an empty stomach. ii. Half-life is about 20 hours; extensively metabolized; hydroxy itraconazole is active. c. Adverse effects i. Nausea, abdominal pain, headache, rash ii. Elevated liver function tests, potential fulminant hepatitis iii. Caution in heart failure (avoid doses of 400 mg/day or greater; do not use for treatment of onychomycosis if heart failure) d. Drug interactions (CYP2C9, CYP2C19 and CYP3A4 inhibitor) i. Antacids, H2-blockers, proton pump inhibitors, didanosine (GI absorption) ii. Cyclosporine iii. Digoxin (decreases digoxin volume of distribution) iv. Phenytoin v. Warfarin vi. PIs vii. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors e. Dosing: 200 mg three times daily for 3 days and then 100–200 mg/day. Oral capsules with food; oral solution without food f. Therapeutic Drug Monitoring (TDM) i. TDM appropriate for most patients receiving itraconazole ii. Trough concentrations taken 7-14 days after starting therapy or making dose adjustments. iii. Target concentrations > 0.5 mg/L for prophylaxis and > 1 mg/L for treatment. 4. Voriconazole (Vfend) a. Spectrum of activity i. Candida spp., Aspergillus, Fusarium, Scedosporium, Histoplasma, Cryptococcus ii. Clinical use (a) Resistant Candida infections (especially C. glabrata and C. krusei) (b) Aspergillosis (c) Histoplasmosis b. Pharmacokinetics i. Oral absorption about 95%; also available intravenously ii. Half-life is about 6 hours; extensively metabolized; CYP2C9, CYP3A4, CYP2C19 c. Adverse effects i. Abnormal vision 30% (abnormal vision, color changes, photophobia). Short-term (20–30 minutes) effects on retina. Dose related. Not studied for more than 28 days of therapy ii. Elevated liver function tests, rash, nausea, corrected QT interval (QTc) prolongation, alkaline phosphatase elevations, skin cancers d. Drug interactions (CYP3A4 and CYP2C9 inhibitor and substrate; see Table 13) e. Dosing i. Aspergillosis: Loading dose, 6 mg/kg every 12 hours for 2 doses intravenously (infuse for 2 hours); maintenance dose, 4 mg/kg every 12 hours intravenously (infuse for 2 hours) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-282 Infectious Diseases II ii. Candidiasis and candidemia: 400 mg orally or intravenously every 12 hours for two doses, then 200 mg every 12 hours (a) For patients who are receiving phenytoin, increase dose to 5 mg/kg every 12 hours intravenously or 200–400 mg every 12 hours orally. (b) Dose reduction for moderate or severe cirrhosis: After loading dose, decrease dose by 50% in Child-Pugh class A/B. No information for patients in Child-Pugh class C (c) No adjustment of the oral dose for renal insufficiency; patients with CrCl less than 50 mL/ minute/1.73 m2 should not receive the intravenous product because of accumulation of the intravenous vehicle sulfobutyl ether-β-cyclodextrin (d) Therapeutic drug monitoring indicated because of polymorphism in CYP2C19 metabolism f. Therapeutic Drug Monitoring (TDM) i. TDM appropriate for most patients receiving voriconazole (esp. pediatrics, patients with toxicity, and patients receiving interacting drugs). ii. Consider monitoring when transitioning from IV to oral (esp. in obesity) iii. Trough concentrations taken 4-5 days after starting therapy or making dose adjustments. iv. Target concentrations > 0.5 mg/L for prophylaxis and > 1-2 mg/L for treatment. Table 13. Drug Interactions Reported with Voriconazole Drug Rifampin (CYP inducer) Rifabutin (CYP inducer) Carbamazepine (CYP inducer) Barbiturates, long acting (CYP inducers) Ergot alkaloids Sirolimus (CYP3A4 substrate) Cyclosporine (CYP3A4 substrate) Effect ↓ Voriconazole ↓ Voriconazole ↑ Rifabutin ↓ Voriconazole ↓ Voriconazole Recommendation Coadministration contraindicated Coadministration contraindicated ↑ Ergot alkaloids ↑ Risk ergotism ↑ Sirolimus Coadministration contraindicated ↑ Cyclosporine Coadministration contraindicated Coadministration contraindicated Coadministration contraindicated Tacrolimus (CYP3A4 substrate) ↑ Tacrolimus Omeprazole (CYP2C19 inhibitor, CYP2C19 and CYP3A4 substrate) Warfarin (CYP2C9 substrate) ↑ Voriconazole ↑ Omeprazole Reduce cyclosporine dose by half when initiating voriconazole Monitor levels closely Increase cyclosporine dose as necessary when voriconazole is discontinued Reduce tacrolimus dose to one-third of initial dose when initiating voriconazole Monitor levels closely Increase tacrolimus dose as necessary when voriconazole is discontinued In patients receiving omeprazole doses ≥ 40 mg, reduce omeprazole dose by half ↑ Warfarin ↑ PT Closely monitor PT/INR and adjust warfarin dose as needed INR = international normalized ratio; PT = prothrombin time. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-283 Infectious Diseases II 5. Posaconazole (Noxafil) a. Spectrum of activity i. Candida spp., Cryptococcus, Trichosporon, Aspergillus, Fusarium, Zygomycetes ii. Clinical use (a) Candida infections (b) Aspergillosis (c) Zygomycoses (d) Fusariosis b. Pharmacokinetics i. Oral absorption of suspension increased by a high-fat meal ii. Oral tablet formulation: Food has less impact on absorption. iii. Half-life is about 24–30 hours; primarily eliminated unchanged in the feces c. Adverse effects i. Nausea, vomiting, diarrhea ii. Elevated liver function tests, rash, hypokalemia, thrombocytopenia iii. QTc prolongation d. Drug interactions: CYP3A4 inhibitor; decreased posaconazole suspension absorption with proton pump inhibitors and H2-blockers e. Dosing: Oropharyngeal candidiasis, 100 mg daily suspension; refractory oropharyngeal candidiasis, 400 mg twice daily suspension; prophylaxis of invasive fungal infections in neutropenic and patients with graft-versus-host disease, 200 mg three times daily (suspension), 300 mg daily (tablet or intravenous) 6. Isavuconazonium (Cresemba) a. Spectrum of activity i. Candida spp., Cryptococcus, Aspergillus, Mucorales, Fusarium, Histoplasma, Blastomyces ii. Clinical use (a) Aspergillosis (b) Mucormycosis b. Pharmacokinetics i. Prodrug that is rapidly hydrolyzed in the blood to isavuconazole ii. Oral absorption is complete (take with or without food) and protein binding is greater than 99%. iii. Half-life is about 130 hours; metabolized primarily by CYP3A4 c. Adverse effects i. Nausea, vomiting, diarrhea ii. Elevated liver function tests, hypokalemia, cough, peripheral edema, back pain d.  Drug interactions: CYP3A4 substrate and moderate inhibitor; P-glycoprotein mild inhibitor; increased isavuconazole with PIs; decreased isavuconazole with rifampin e. Dosing: 372 mg (200 mg isavuconazole) every 8 hours for six doses (loading dose) followed by 372 mg (200 mg isavuconazole) daily (maintenance dose) C. Echinocandins 1. Mechanism of action: Inhibits synthesis of 1,3-β-d-glucan, an essential component of the fungal cell wall 2. Caspofungin (Cancidas), micafungin (Mycamine), anidulafungin (Eraxis) a. Spectrum of activity i. Candida spp. (weak against C. parapsilosis), Aspergillus ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-284