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Volume 24, Issue 4 January 2009

halation of zygomycete spores. In normal individu- als, these spores will be transported via cilia to the and eliminated from the body through the ZYGOMYCOSIS: AN UPDATE . In susceptible individuals, the ON TREATMENT OPTIONS begins growing in the nasal turbinates or al- 1 veoli of the lungs. The present article will discuss Erin Brady, Pharm.D. Candidate the pathophysiology of zygomycosis, with a focus on reviewing current treatment options and medical lit- erature.

RISK FACTORS Zygomycosis, also referred to as , Individuals who are immunocompromised, either is a rare angioinvasive fungal infection caused by a from hematologic disease, diabetes, or solid organ or class of fungi called Zygomycetes. The class is com- hematopoetic cell transplant, are the most likely to prised of orders , Mortierellales, and Ento- develop zygomycosis. A review of 929 cases of zy- mophthorales. Infection with zygomycetes pro- gomycosis found diabetes to be the most common gresses rapidly, frequently resulting in fatality in pa- risk factor (36%), followed by hematologic malig- tients with underlying illnesses. Zygomycetes are nancies (17%), and solid organ or hematopoietic commonly found in the environment, mostly on soil stem cell transplantation (12%). 1,2 Predisposing fac- and decaying vegetation; these fungi reproduce rap- tors to infection are also related to the site of infec- idly and release airborne spores which are frequently tion. The majority of infections in diabetics occur in inhaled. Zygomycete spores are inhaled frequently, the rhino-orbital-cerebral area whereas many infec- yet rarely cause infection, supporting the knowledge tions in patients with hematologic malignancies oc- that some predisposing factor usually exists in pa- cur in the lungs. 2 Other underlying factors that may tients who develop zygomycosis. It is estimated that impart risk for infection are metabolic acidosis, de- there are approximately 1.7 cases per million people feroxamine therapy, iron overload, , per year, or 500 cases per year in the United States. 5 HIV/AIDS, intravenous drug use, and malnutrition. Almost all human infections caused by zygomycetes have some underlying compromising condition. 1 The most common organisms within the zygomy- cetes class causing infection are , , and Cunnighamella , while the genera Rhizomucor , INSIDE THIS ISSUE : , and are implicated in fewer infections. There are several sites within the ZYGOMYCOSIS : A N UPDATE ON TREATMENT body where infection may arise: rhino-orbital- OPTIONS cerebral sites, pulmonary, renal, gastrointestinal, and cutaneous. Rhino-orbital-cerebral and pulmonary infections are the most common. Rhino-orbital- cerebral and pulmonary infections are caused by in-

PharmaNote 1 Volume 24, Issue 4 January 2009 Table 1. Comparison of Drug Therapy Options

Amphotericin B (Fungizone®) Posaconazole (Noxafil®) Caspofungin (Cancidas®)

• Binds ergosterol in fungal cell • Inhibits synthesis of beta (1,3)-D- MECHANISM membrane, altering cellular per- • Inhibits fungal cell membrane syn- glucan, a major fungal cell wall meability, causing leakage of cellu- thesis via fungal CYP inhibition OF ACTION component lar components

• Deoxycholate: 1-1.5 mg/kg/d IV • Available as suspension only infusion • Dose: 800 mg/d in 2-4 divided • Not established for zygomycosis DOSE • Lipid Formulations: Initially 5 mg/ doses • 70 mg IV infusion on day (loading kg/d IV infusion • Must be administered with a full dose), followed by 50 mg IV • Max: 15 mg/kg/d IV meal

• Metabolism unknown • Metabolized by hydrolysis and N- • Slowly excreted by the kidneys • Substrate of p-gp acetylation Dosage Adjustments : • Metabolized by glucuronidation • Small amount (1%) excreted un- KINETICS • Use cautiously in renal impair- • t1/2 = 35h changed in urine ment; may extend dosing interval • >98% bound to albumin • Active metabolites cleared through to 24-36 h biliary system

• Infusion-related reactions • Well-tolerated • Nephrotoxicity • Occasional : Histamine-related re- • Normochromic, normocytic ane- actions ADVERSE mia • Rare : • >10%: Fever, headache, N/V/D EFFECTS • Electrolyte abnormalities • Fever • GI toxicity • Phlebitis • Increased LFTs • N/V • Neurologic effects • Headache

AmB deoxycholate : • $17/day @ 1mg/kg/d ABLC : • $805/day @ 5mg/kg/d ~$190/day $411.80/day 13 COST AmBi : • $1,316/day @ 5mg/kg/d ABCD : 14 • $448/day @ 4mg/kg/d

P-gp = p-glycoprotein; T 1/2 = elimination half-life; LFT = liver function test; IV = intravenous; GI = gastrointestinal; N/V/D = nau- sea/vomiting/diarrhea; CYP = cytochrome P450 enzyme system

Patients in diabetic ketoacidosis (DKA) are at highest chronic overload conditions. Individuals with renal risk for infection due to elevated blood glucose and insufficiency or individuals requiring frequent blood metabolic acidosis. Rhizopus organisms contain an transfusions are generally the population of patients enzyme, ketone reductase, that allows survival in an prescribed this medication. Deferoxamine can in- acidic environment with high glucose content. Ke- crease not only growth of the fungus, but also patho- tone reductase places both uncontrolled type I and genicity; many patients infected with zygomycosis type II diabetics at a high risk for zygomycosis infec- with concomitant use of deferoxamine will develop tions, especially if in diabetic ketoacidosis. generalized disseminated infection associated with Deferoxamine is an iron and aluminum chelator an extremely high mortality rate. used to treat iron and/or aluminum toxicity or

PharmaNote 2 Volume 24, Issue 4 January 2009 Posaconazole (Noxafil®) is a new triazole anti- receiving immunosuppressive therapy coupled with fungal with a broad spectrum of activity. The fol- the use of antifungal therapies that do not have activ- lowing organisms are generally considered suscepti- ity against zygomycetes. 7 ble to posaconazole: sp, Candida sp, In a study by Greenberg et al., data of 24 partici- immitis, , pants from two open-label, nonrandomized, multi- sp, Mucor sp, Rhizopus sp, and Scedospo- center compassionate trials were analyzed. Posa- rium sp . Posaconazole is available only as an oral conazole was administered at 800 mg/day in divided suspension, and must be administered with full meals doses to 19 patients refractory to standard zygomy- in 2 to 4 divided doses daily. The C max and AUC are cosis treatment and 5 patients intolerant to standard approximately 3 times higher when posaconazole is therapy. The mean and median duration of treatment given with a full meal; C max and AUC are approxi- with posaconazole was 292 and 182 days respec- mately 4 times higher when administered with a high tively with a 79% treatment success rate (complete -fat meal, relative to the fasting state. 12 Posaconazole and partial responses). Seventy-nine percent (19 of possesses a 35 hour half-life, thus it takes approxi- 24 enrollees) survived the infection; none of the mately 5-7 days to reach steady state levels. This is treatment failures received greater than 31 days of not an ideal kinetic profile for use as monotherapy in treatment, with most investigators reporting evidence initial treatment of zygomycosis. Zygomycosis is not of improvement within 2 weeks of initiating posa- currently an FDA-approved indication for posacona- conazole. 6 zole but has been shown in two compassionate trials Alexander and colleagues reported the findings to be effective as salvage therapy for refractory in- of a post-hoc analysis from an open-label, multicen- fection. 6,7 ter study in which posaconazole was administered as Van Burik and colleagues conducted a retrospec- salvage therapy to 23 solid organ transplant patients tive study in 91 patients with either refractory zygo- with proven or probable invasive fungal infections or intolerance to treatment. (IFIs). 16 Primary causative pathogens were: Aspergil- Most subjects were initially treated with lipid formu- lus (n = 12), Candida (n = 3), Fusarium (n = 2), lations of AmB with 26% of subjects receiving con- Cryptococcus (n = 1), Zygomycetes (n = 2), and oth- ventional AmB. Subjects were given posaconazole ers (n = 4). Participants with zygomycosis were con- 800 mg/d in divided doses with meals or enteral sidered refractory to standard therapy if they showed feedings to optimize drug exposure. Overall success, disease progression or no clinical improvement after defined as complete or partial response 12 weeks af- 7 days of treatment. Intolerance to standard therapy ter initiation of posaconazole, was achieved in 60% was classified as renal impairment, severe infusion- of the study subjects. Complete response was defined related toxicity, or high-risk for toxicity based on as resolution of infection, while partial response was underlying conditions or medications. The primary defined as a clinically meaningful improvement. endpoint was response at the end of treatment with Fourteen percent of patients had a complete re- complete and partial responses defined as success, sponse, 46% had a partial response, 21% had stable and stable disease or failure defined as non-success. disease, 17% experienced treatment failure, and 2% Posaconazole was administered as 800mg per day in had an undetermined outcome. Most participants divided doses with food; most patient received posa- (80%) were given posaconazole for at least 30 days, conazole for at least 30 days. Overall, 13 of 23 with the longest course of therapy lasting 1,005 days. (57%) patients had a complete or partial response. Of Thirty-five patients (38%) died while receiving posa- the 2 patients with zygomycosis, 1 had a successful conazole or within one month of follow-up. Fifteen response but the other failed treatment. Treatment- of 35 patients died due to zygomycosis; most of them related adverse events were reported in 12 of 23 par- received less than 30 days of treatment, reflecting the ticipants and included: nausea (4), vomiting (2), ele- aggressive nature of the infection. Importantly noted, vated LFTs (2), and increased levels of cyclosporine approximately one half of the participants received and/or tacrolimus (3). antifungal prophylaxis with azoles (voriconazole, fluconazole, or itraconazole) prior to the develop- NEW TREATMENT OPTIONS ment of zygomycosis. This supports findings of in- With increasing incidence of mucormycosis and creased numbers of zygomycosis cases in patients its high mortality rate, the development of new anti-

PharmaNote 3 Volume 24, Issue 4 January 2009 Table 2. Summary of Clinical Trials for Treatment of Zygomycosis

AUTHORS STUDY DESIGN DRUG ENDPOINTS RESULTS

Retrospective data 79% survived the infection collected from two (complete or partial response) Posaconazole Primary: Response Greenberg R, et al open-label, nonran- 800mg/day in (complete, partial, (2006) 6 domized, multi- Mean and median treatment dura- divided doses failure) centered, compas- tion was 292 and 182 days, respec- sionate trials tively

Primary: Overall suc- Posaconazole Overall success (complete and par- Van Burik J, et al Retrospective case cess (complete, partial, 800mg/day in tial) was 60% after 12 weeks of (2006) 7 series data stable disease, treat- divided doses posaconazole therapy ment failure)

Overall success (complete and par- Primary: Global re- tial responses) documented in 13 of Retrospective data Posaconazole sponse at the end of Alexander B, et al 23 patients. from an open-label, 800mg/day in treatment (complete, (2008) 16 One of two participants with zygo- multicenter trial divided doses partial responses, sta- mycosis experienced treatment suc- ble disease, failure) cess.

Polyene mono- Primary: Success (alive therapy vs. combi- and not needing hos- Retrospective review nation polyene & Participants treated with polyene- pice care) at 30 days Reed C, et al of rhino-orbital- caspofungin caspofungin had superior success after discharge (2008) 11 cerebral zygomyco- (100% vs 45%, p = 0.02) and im-

sis cases AmB 0.3-1.5mg/kg proved Kaplan-Meier survival time Secondary: Kaplan- ABLC 5-10mg/kg; Meier survival time LAmB 5-10mg/kg

AmB = Conventional amphotericin B; ABLC = amphotericin B lipid complex; LAmB = Liposomal amphotericin B fungal drug therapies for treatment of zygomycosis is (10.8%), reversible elevation of hepatic enzymes, important. 11 The echinocandins are a class of antifun- and injection-site reactions (1.5-12%). 3 Caspofungin gal medications with activity against synthesis of also has few significant drug interactions because it beta (1,3)-D-glucan, a major fungal cell wall compo- is neither a substrate nor inhibitor of cytochrome nent. Traditionally echinocandins were thought to P450. 15 have no in vitro activity against zygomycetes, but A retrospective review of 41 patients with rhino- recent data has shown that , the most orbital-cerebral zygomycosis treated with either common zygomycete to cause zygomycosis, ex- AmB or AmB plus caspofungin from 1994 through presses the target enzyme of the echinocandins. 2006 was conducted by Reed et al. 11 Patients were Caspofungin (Cancidas®) is effective in combination predominantly Hispanic males with diabetes (83%), with AmB for the treatment of zygomycosis in mur- and all participants had predisposing factors for rhino ine models. 10 Caspofungin has a favorable side effect -orbital-cerebral zygomycosis: cancer (34%), active profile because the target enzyme of the drug is not corticosteroid therapy (46%), neutropenia (12%), or present in mammalian cells. Common adverse reac- transplantation (10%). Patients were treated with tions consist of: histamine-related reactions (1-4%), ABLC (n = 20), AmB (n = 15), or liposomal AmB (n fever (3-26%), nausea/ vomiting (3.8-7.2%), head- = 4) at average doses of 5 mg/kg/day, 1 mg/kg/day, ache (6-11%), reduction in serum potassium levels and 5 mg/kg/day, respectively. Six evaluable pa-

PharmaNote 4 Volume 24, Issue 4 January 2009 tients were treated up-front with a combination of vember 2, 2008. polyene (mostly ABLC) and caspofungin therapy. 4. Boelaert JR, Van Cutsem J, et al. Deferoxamine Patients treated with polyene-caspofungin combina- augments growth and pathogenicity of Rhizopus, tion therapy initially had superior success (100% vs. while hydroxypyridinone chelators have no ef- 45%; p = 0.02) and Kaplan-Meier survival time ( p fects. Kidney Int 1994; 45:667. = .02) compared to patients treated with any AmB 5. Spellberg B, Edwards J, et al. Novel perspectives formulation as monotherapy. Combination therapy of on mucormycosis: Pathophysiology, presentation, AmB-caspofungin appears to be a promising thera- and management. Clinical Microbiology Reviews peutic option for zygomycosis based on these results. 2005; 18:3. The limitation of this study however, was that the 6. Greenberg RN, Mullane K, et al. Posaconazole as majority of participants were non-neutropenic and Salvage Therapy for Zygomycosis. Antimicrobial diabetic. Therefore, these findings may not be gener- Agents and Chemotherapy 2006; 50:1. alizable to immunocompromised patients with neu- 7. van Burik J, Hare R, et al. Posaconazole Is Effec- tropenia. tive as Salvage Therapy in Zygomycosis: A Ret- rospective Summary of 91 Cases. Clinical Infec- SUMMARY tious Diseases 2006; 42. Zygomycosis is a rare, angioinvasive fungal in- 8. Adler-Moore JP, Proffitt RT. Amphotericin B fection most commonly found in immunocompro- lipid preparations: what are the differences? Clin mised patients or individuals with predisposing fac- Microbiol Infect 2008; 14 (Suppl. 4):25-36. tors such as: diabetes mellitus, immunosuppressive 9. Lanternier F, Lortholary O. Liposomal ampho- drug therapy, deferoxamine drug therapy and IVDU. tericin B: what is its role in 2008?. Clin Micro- Zygomycosis is associated with a poor prognosis evi- biol Infect 2008;14 (Suppl. 4):71-83. denced by an overall survival rate (with treatment) of 10. Walsh TJ, Kontoyiannis DP. What is the Role of only 40-50%. Successful treatment relies on early Combination Therapy in Management of Zygo- diagnosis, removal of predisposing factors, surgical mycosis?. Clinical Infectious Diseases debridement of infected tissue, and aggressive anti- 2008;47:372-4. fungal drug therapy. A lipid formulation of ampho- 11. Reed C, Bryant R, et al. Combination Polyene- tericin B remains the drug of choice for treatment of Caspofungin Treatment of Rhino-Orbital- zygomycosis and many other fungal infections be- Cerebral Mucormycosis. Clinical Infectious Dis- cause of its broad spectrum of activity and few in- eases 2008; 47:364-71. stances of antifungal resistance. Posaconazole has 12. Noxafil [package insert]. Kenilworth, NJ: Scher- been shown in 2 retrospective studies to be effective ing Corporation; 2008. as salvage therapy for patients refractory or intoler- 13. Caspofungin acetate. Johns Hopkins ABX Guide, ant to AmB. Echinocandins initially were thought to 2008. < http://prod.hopkins-abxguide.org/ be ineffective against zygomycetes in vitro and in antibiotics/antifungal/caspofungin_acetate.html? vivo . However, recent evidence suggests that contentInstanceId=254891 >. Accessed December Rhizopus sp express the target enzyme of the echino- 3, 2008. candins. Combination polyene-caspofungin therapy 14. Antifungal Therapy Cost Analysis. Doctor Fun- has been shown to be a promising option for treat- gus, 2008. < http://www.doctorfungus.org/ ment of rhino-orbital-cerebral zygomycosis in dia- thedrugs/cost1.htm >. Accessed December 5, betics in both murine models and humans. 2008. 15. Petrikkos G, Skiada A. Recent advances in anti- fungal chemotherapy. International Journal of REFERENCES Antimicrobial Agents 2007; 30:108-117. 1. Cox GM, et al. Zygomycosis (Mucormycosis). 16. Alexander BD, Perfect JR, et al. Posaconazole as UpToDate, 2008. Salvage therapy in Patients with Invasive Fungal 2. Roden MM, et al. Epidemiology and outcome of Infections After Solid Organ Transplant. Trans- zygomycosis: a review of 929 reported cases. plantation 2008;86:791-6. Clinical Infectious Diseases 2005; 41:634. 3. Clinical Pharmacology Online. Accessed No-

PharmaNote 5 Volume 24, Issue 4 January 2009 DDDRUG UUUPDATE MMMEDICAL NNNEWS

Fenofibric Acid (TriLipix ®) - Abbott Pharmaceu- Influenza Update ticals Preliminary surveillance data from the Centers In December 2008, the FDA approved the use for Disease Control (CDC) suggests high levels of of fenofibric acid, the active metabolite of fenofi- circulating influenza A virus, predominantly the brate. Like the other ‘fibrates,’ fenofibric acid is H1N1 subtype. Of the 88 preliminary samples most effective at treating lipid disorders associated tested nationally, 86 (98%) are resistant to osel- with high levels of serum triglycerides. It is the tamivir (Tamiflu ®), the most widely prescribed an- only fibrate currently approved for combination use tiviral worldwide. These samples have shown no with statins in the management of mixed dyslipide- resistance to zanamivir (Relenza ®) or the older ada- mia. In clinical trials, patients taking fenofibric mantane antivirals, amantadine or rimantidine. acid monotherapy experienced myalgias at a rate However, some strains of influenza A (H3N2) and similar to those taking combination therapy with all strains of influenza B virus remain resistant to statins (3.3% vs. 3.1-3.5%). However, caution the adamantanes. should still be exercised before initiating dual ther- The CDC recommends the use of zanamivir apy, particularly in patients with renal failure. alone or oseltamivir and rimantidine combination TriLipix® is available as 45 mg or 135 mg delayed therapy over oseltamivir therapy alone for the treat- -release capsules. Starting dose for adults is 45 to ment of influenza infection during the current sea- 135 mg once daily with dose titration after 4 to 8 son. Influenza testing can help determine which weeks as needed. Maximum daily dose is 135 mg strain is present and may help streamline antiviral daily. Fenofibric acid may be administered without choice. Influenza infection rates are expected to regard to meals. The most common adverse effects rise throughout the remainder of the flu season, so include headache and gastrointestinal effects. influenza vaccination should continue to be recom- mended.

Zoledronic Acid (Reclast ®) - Novartis Pharmaceuticals

The FDA recently approved injectable The PharmaNote is Published by: zoledronic acid for the treatment of osteoporosis in The Department of Pharmacy men. It is the first of the bisphosphonates to Services, UF Family Practice Medical receive an indication for the treatment of both Group, Departments of Community sexes. Zoledronic acid is one of only a handful of Health and Family Medicine and bisphosphonates with data supporting a reduced Pharmacy Practice incidence of vertebral, nonvertebral and hip University of Florida fractures. However, FDA approval for the treatment in men was based on a two year randomized, active control, non-inferiority trial comparing changes in bone mineral density among John G. Gums Editor participants taking zoledronic acid once yearly and Pharm.D., FCCP alendronate 70mg once weekly for 2 years. R. Whit Curry, M.D. Associate Editor Approved dose in men is a 5 mg infusion over 15 minutes once yearly. Administration of zoledronic Steven M. Smith Assistant Editor acid is considered a medical procedure covered by Pharm.D. Medicare Part B. Most Medicare Part B carriers ® should now cover Reclast infusions for men.

PharmaNote 6 Volume 24, Issue 4 January 2009