GUIDELINES FOR TREATMENT OF INVASIVE ASPERGILLOSIS AND MUCORMYCOSIS IN PATIENTS ON PEDIATRIC SERVICES Clinical Setting Therapy Comments Invasive Infectious Disease Consult is STRONGLY Dosing Aspergillosis (IA) recommended if Aspergillosis is suspected Please discuss dosing adjustments with a Clinical (i.e., positive biomarker or culture, radiologic Pharmacy Specialist prior to changes in doses. Categories (see findings) Weight-based dosing recommendations for adult footnote for host and obese patients for voriconazole and Liposomal radiology criteria): Preferred - voriconazole: amphotericin B are available <16 years: Proven IA: Voriconazole 9 mg/kg IV/PO q12h Duration histopathology 16-17 years: Minimum of 6-12 weeks, typically months, demonstrating Voriconazole 6 mg/kg IV/PO q12h determined by clinical response, radiological invasive disease or ≥18 years: response, and patient’s underlying disease or culture of a sterile Voriconazole 6 mg/kg IV/PO q12h x2 doses, immune status, in discussion with Pediatric site then 4 mg/kg IV/PO q12h Infectious Diseases. Probable IA: Therapeutic Drug Monitoring a susceptible host Preferred alternative in patients intolerant to Therapeutic drug monitoring is recommended for with suggestive voriconazole or with refractory or isavuconazole, posaconazole, and voriconazole. radiology and a breakthrough disease on voriconazole (see Please see Recommendations for Therapeutic Drug positive culture, comments): Monitoring of Antifungal Agents cytopathology/sme ≥16 years AND ≥50 kg: ar, or serum/BAL Isavuconazole 372 mg IV/PO q8h x6 doses, Drug Interactions galactomannan. then 372 mg IV/PO daily Numerous significant drug interactions occur with <16 years OR <50 kg OR unable to tolerate azole antifungals. A comprehensive review of the A positive β-D- azoles: patient profile should be undertaken when these Glucan test is LAmB (liposomal amphotericin B) 5 mg/kg agents are initiated and discontinued (see footnote supportive of, but IV daily for specific notes). not specific for a diagnosis of Preferred alternative in patients intolerant to Adverse Reactions probable IA azoles or with refractory or breakthrough Posaconazole and voriconazole have been disease on an azole (see comments): associated with QTc prolongation. Patients with a Possible IA: LAmB (liposomal amphotericin B) 5 mg/kg prolonged QTc or on certain anti-arrythmics should Negative IV daily avoid voriconazole/posaconazole or perform EKG microbiology monitoring due to an increased risk of QTc- (culture, Options for salvage therapy or in patients prolongation or torsades. pathology, or intolerant to above therapies (see comments): Isavuconazole is associated with dose-dependent galactomannan Micafungin decreases in QTc interval. As such, isavuconazole assay), but OR may be preferred in some patients experiencing radiographically Posaconazole issues with QTc prolongation. suggestive in a Unlike posaconazole and voriconazole, susceptible host isavuconazole is water-soluble and thus does not require solubilization by cyclodextrin for an Micafungin Dosing: intravenous formulation. There are potential Monotherapy with micafungin should only be nephrotoxicity concerns with cyclodextrin in considered in possible disease if above options patients with pre-existing renal impairment. are not feasible. Use is not recommended as However, there is no strong clinical evidence monotherapy for primary treatment. suggesting an increased risk of worsening renal Micafungin 5 mg/kg IV daily (max: 150 function with IV voriconazole use, so use of IV mg/dose) voriconazole may be considered, at the shortest duration possible, if deemed clinically appropriate. Posaconazole Dosing: Visual hallucinations with voriconazole are usually Delayed-release tablets are preferred over oral transient (associated with loading dose) and/or suspension due to better absorption. Tablets associated with supra-therapeutic levels (>5.5 cannot be crushed or divided. ug/mL). Visual disturbances, such as photopsia, are <13 years: not dose dependent, may continue to occur, but Posaconazole delayed-release tablets 4 have no long-term consequences. mg/kg (rounded to the nearest 100 mg) Isavuconazole and posaconazole are associated with PO BID on Day 1 then 4 mg/kg (rounded significantly less visual disturbances, hallucinations, to the nearest 100 mg) PO daily starting and photosensitivity compared to voriconazole. on Day 2 (initial max: 300 mg/dose) Isavuconazole may be an option in patients ≥13 years: intolerant to voriconazole. Posaconazole delayed-release tablets Isavuconazole was associated with fewer 300 mg PO BID on Day 1 then 300 mg hepatobiliary adverse effects than voriconazole (9% PO daily starting on Day 2 vs. 16%, respectively) in a trial of aspergillosis. However, hepatic adverse effects with voriconazole In patients unable to tolerate whole tablets are generally both reversible and do not require (oral suspension should be given with fatty discontinuation in clinical trials. As such, pre-existing meals and acidic carbonated beverages to hepatic impairment is not a contraindication to ensure adequate levels. Use of acid voriconazole and mild elevations during therapy are suppression should be avoided): often multi-factorial and do not necessarily mandate <13 years: a change in therapy. Posaconazole oral suspension 4 mg/kg PO QID (initial max: 200 mg/dose) Breakthrough Infection and Salvage Treatment ≥13 years: Patients with breakthrough infection on Posaconazole oral suspension 200 mg voriconazole/posaconazole prophylaxis may be at PO QID risk for azole resistance. If an isolate is available, susceptibilities should be performed. In patients unable to tolerate oral medications: Current and prior azole concentrations during <18 years: prophylaxis/treatment should be reviewed when Posaconazole intravenous solution 4 assessing potential breakthrough infection or need mg/kg IV q12h on Day 1; 4 mg/kg IV for salvage therapy. q24h starting on Day 2 (initial max: 300 mg) Miscellaneous ≥18 years: In patients with central nervous system Posaconazole intravenous solution 300 involvement, voriconazole therapy is preferred. mg IV q12h on Day 1; 300 mg IV q24h Liposomal Amphotericin B therapy is appropriate starting on Day 2 for patients intolerant or refractory to voriconazole. There is insufficient data regarding preference of Initial combination therapy (addition of other alternatives, and such decisions should be micafungin to voriconazole X 2 weeks) may be made on a case-by-case basis. considered in patients with PROVEN or In patients with endophthalmitis, voriconazole PROBABLE disease who meet ANY of the (concomitant systemic and intravitreal) therapy is following criteria: preferred. Have extensive multi-lobar involvement or disseminated infection Have increasing oxygen requirements or respiratory distress with impending respiratory failure. Expected long duration of neutropenia (>10 days) or extensive GVHD. Page 2 of 3 Clinical Setting Therapy Comments Proven or Probable Infectious Disease Consult is STRONGLY Please note that voriconazole IS NOT ACTIVE against Mucormycosis recommended if Mucormycosis is suspected mucormycosis (e.g., Rhizopus spp., Mucor spp., Primary Duration Rhizomucor spp., Surgical debridement is generally necessary Generally prolonged (months). Until resolution of others) clinical signs and symptoms or treatment limiting LAmB adverse effects 5 mg/kg IV daily with consideration of escalation to a maximum of 10 mg/kg daily Therapeutic Drug Monitoring in patients with progressive or extensive Therapeutic drug monitoring is recommended for disease or possible CNS disease isavuconazole and posaconazole. Please see Recommendations for Therapeutic Drug Monitoring Combination therapy should be discussed with of Antifungal Agents ID Consultant Options for step-down therapy, salvage therapy, or in patients unable to take LAmB include isavuconazole or posaconazole (see Invasive Aspergillosis section for dosing recommendations). Specific Recommendations Regarding Drug Interactions with Azoles: • Sirolimus, tacrolimus, and cyclosporine levels increase. Drug levels and dose adjustment may be necessary in consultation with transplant pharmacy • Concomitant use of azoles with certain chemotherapeutic agents (vincristine, tyrosine-kinase inhibitors (e.g., imatinib, dasatinib, nilotinib, bosutinib, ponatinib), sorafenib, clofarabine, doxorubicin, or if mandated by clinical trial protocol (e.g., quizartinib) is not recommended and an alternative antifungal should be used (discuss with hematology) • P-450 inducers (e.g., rifampin, phenobarbital, carbamazepine, St. John’s wort) may result in subtherapeutic azole levels • Complex drug interactions with antiretroviral agents exist and may alter serum azole and/or antiretroviral levels Host and Radiologic Criteria for the Diagnosis of Invasive Fungal Infection (De Pauw B et al. Clin Infect Dis 2008;46:1813-21) • Host factors: • Recent history of neutropenia (<500 neutrophils/mm3 for >10 days) temporally related to the onset of fungal disease • Receipt of an allogeneic stem cell transplant • Prolonged use of corticosteroids (excluding among patients with allergic bronchopulmonary aspergillosis) at a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for >3 weeks • Treatment with other recognized T cell immunosuppressants, such as cyclosporine, TNF-a blockers, specific monoclonal antibodies (such as alemtuzumab), or nucleoside analogues during the past 90 days • Inherited severe immunodeficiency (such as