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ZYGOMYCOSIS: AN UPDATE
ON TREATMENT OPTIONS

Erin Brady, Pharm.D. Candidate


Zygomycosis, also referred to as Mucormycosis,
is a rare angioinvasive fungal infection caused by a
class of fungi called Zygomycetes. The class is com-
prised of orders Mucorales, Mortierellales, and Ento-
mophthorales. Infection with zygomycetes pro-
gresses rapidly, frequently resulting in fatality in pa-
tients with underlying illnesses. Zygomycetes are
commonly found in the environment, mostly on soil
and decaying vegetation; these fungi reproduce rap-
idly and release airborne spores which are frequently
inhaled. Zygomycete spores are inhaled frequently,
yet rarely cause infection, supporting the knowledge
that some predisposing factor usually exists in pa-
tients who develop zygomycosis. It is estimated that
there are approximately 1.7 cases per million people
per year, or 500 cases per year in the United States.5
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 Rhizopus, Mucor,
and Cunnighamella, while the genera Rhizomucor,
Saksenaea, and Apophysomyces are implicated in
fewer infections. There are several sites within the
body where infection may arise: rhino-orbital-
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-


halation of zygomycete spores. In normal individu-
als, these spores will be transported via cilia to the
pharynx and eliminated from the body through the
gastrointestinal tract. In susceptible individuals, the
fungus begins growing in the nasal turbinates or al-
veoli of the lungs.1 The present article will discuss
the pathophysiology of zygomycosis, with a focus on
reviewing current treatment options and medical lit-
erature.

RISK FACTORS
Individuals who are immunocompromised, either
from hematologic disease, diabetes, or solid organ or
hematopoetic cell transplant, are the most likely to
develop zygomycosis. A review of 929 cases of zy-
gomycosis found diabetes to be the most common
risk factor (36%), followed by hematologic malig-
nancies (17%), and solid organ or hematopoietic
stem cell transplantation (12%).1u2 Predisposing fac-
tors to infection are also related to the site of infec-
tion. The majority of infections in diabetics occur in
the rhino-orbital-cerebral area whereas many infec-
tions in patients with hematologic malignancies oc-
cur in the lungs. Other underlying factors that may
impart risk for infection are metabolic acidosis, de-
feroxamine therapy, iron overload, glucocorticoids,
HIV/AIDS, intravenous drug use, and malnutrition.




INSIDE THIS ISSUE:
ZYGOMYCOSIS: AN UPDATE ON TREATMENT
OPTIONS


mm


PharmaNote


VOLUME 24, ISSUE 4 JANUARY 2009
i ^ ^ ^ ^^ ^ ^ ^ ^ ^^ ^ ^ ^ ^^ ^ ^ ^i^^ ^ ^ ^ j


PharmaNote


Volume 24, Issue 4 January 2009







Table 1. Comparison of Antifungal Drug Therapy Options


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


MECHANISM
OF ACTION





DOSE







KINETICS








ADVERSE
EFFECTS


. Binds ergosterol in fungal cell
membrane, altering cellular per-
meability, causing leakage of cellu-
lar components

. Deoxycholate: 1-1.5 mg/kg/d IV
infusion
. Lipid Formulations: Initially 5 mg/
kg/d IV infusion
. Max: 15 mg/kg/d IV


. Metabolism unknown
. Slowly excreted by the kidneys
Dosage Adjustments:
. Use cautiously in renal impair-
ment; may extend dosing interval
to 24-36 h


. Infusion-related reactions
. Nephrotoxicity
. Normochromic, normocytic ane-
mia
. Electrolyte abnormalities
. GI toxicity
. Increased LFTs
. Neurologic effects


. Inhibits fungal cell membrane syn-
thesis via fungal CYP inhibition


. Available as suspension only
. Dose: 800 mg/d in 2-4 divided
doses
. Must be administered with a full
meal



. Substrate of p-gp
. Metabolized by glucuronidation
. t/2 = 35h
. >98% bound to albumin







. >10%: Fever, headache, N/V/D


AmB deoxvcholate:
. $17/day @ lmg/kg/d
ABLC:
. $805/day @ 5mg/kg/d
AmBi:
. $1,316/day @ 5mg/kg/d
ABCD:
. $448/day @ 4mg/kg/d14


~$190/day


$411.80/day1


P-gp = p-glycoprotein; T1/2 = 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
risk for infection due to elevated blood glucose and
metabolic acidosis. Rhizopus organisms contain an
enzyme, ketone reductase, that allows survival in an
acidic environment with high glucose content. Ke-
tone reductase places both uncontrolled type I and
type II diabetics at a high risk for zygomycosis infec-
tions, especially if in diabetic ketoacidosis.
Deferoxamine is an iron and aluminum chelator
used to treat iron and/or aluminum toxicity or


chronic overload conditions. Individuals with renal
insufficiency or individuals requiring frequent blood
transfusions are generally the population of patients
prescribed this medication. Deferoxamine can in-
crease not only growth of the fungus, but also patho-
genicity; many patients infected with zygomycosis
with concomitant use of deferoxamine will develop
generalized disseminated infection associated with
an extremely high mortality rate.


PharmaNote Volume 24, Issue 4 January 2009


. Inhibits synthesis of beta (1,3)-D-
glucan, a major fungal cell wall
component



. Not established for zygomycosis
. 70 mg IV infusion on day (loading
dose), followed by 50 mg IV



. Metabolized by hydrolysis and N-
acetylation
. Small amount (1%) excreted un-
changed in urine
. Active metabolites cleared through
biliary system


. Well-tolerated
. Occasional: Histamine-related re-
actions
. Rare:
Fever
Phlebitis
N/V
Headache


COST


PharmaNote


Volume 24, Issue 4 January 2009







Posaconazole (Noxafil) is a new triazole anti-
fungal with a broad spectrum of activity. The fol-
lowing organisms are generally considered suscepti-
ble to posaconazole: Aspergillus sp, Candida sp,
Coccidioides immitis, Cryptococcus neoformans,
Fusarium sp, Mucor sp, Rhizopus sp, and Scedospo-
rium sp. Posaconazole is available only as an oral
suspension, and must be administered with full meals
in 2 to 4 divided doses daily. The Cmax and AUC are
approximately 3 times higher when posaconazole is
given with a full meal; Cmax and AUC are approxi-
mately 4 times higher when administered with a high
-fat meal, relative to the fasting state.12 Posaconazole
possesses a 35 hour half-life, thus it takes approxi-
mately 5-7 days to reach steady state levels. This is
not an ideal kinetic profile for use as monotherapy in
initial treatment of zygomycosis. Zygomycosis is not
currently an FDA-approved indication for posacona-
zole but has been shown in two compassionate trials
to be effective as salvage therapy for refractory in-
fection.6,7
Van Burik and colleagues conducted a retrospec-
tive study in 91 patients with either refractory zygo-
mycosis or intolerance to amphotericin B treatment.
Most subjects were initially treated with lipid formu-
lations of AmB with 26% of subjects receiving con-
ventional AmB. Subjects were given posaconazole
800 mg/d in divided doses with meals or enteral
feedings to optimize drug exposure. Overall success,
defined as complete or partial response 12 weeks af-
ter initiation of posaconazole, was achieved in 60%
of the study subjects. Complete response was defined
as resolution of infection, while partial response was
defined as a clinically meaningful improvement.
Fourteen percent of patients had a complete re-
sponse, 46% had a partial response, 21% had stable
disease, 17% experienced treatment failure, and 2%
had an undetermined outcome. Most participants
(80%) were given posaconazole for at least 30 days,
with the longest course of therapy lasting 1,005 days.
Thirty-five patients (38%) died while receiving posa-
conazole or within one month of follow-up. Fifteen
of 35 patients died due to zygomycosis; most of them
received less than 30 days of treatment, reflecting the
aggressive nature of the infection. Importantly noted,
approximately one half of the participants received
antifungal prophylaxis with azoles (voriconazole,
fluconazole, or itraconazole) prior to the develop-
ment of zygomycosis. This supports findings of in-
creased numbers of zygomycosis cases in patients


receiving immunosuppressive therapy coupled with
the use of antifungal therapies that do not have activ-
ity against zygomycetes.7
In a study by Greenberg et al., data of 24 partici-
pants from two open-label, nonrandomized, multi-
center compassionate trials were analyzed. Posa-
conazole was administered at 800 mg/day in divided
doses to 19 patients refractory to standard zygomy-
cosis treatment and 5 patients intolerant to standard
therapy. The mean and median duration of treatment
with posaconazole was 292 and 182 days respec-
tively with a 79% treatment success rate (complete
and partial responses). Seventy-nine percent (19 of
24 enrollees) survived the infection; none of the
treatment failures received greater than 31 days of
treatment, with most investigators reporting evidence
of improvement within 2 weeks of initiating posa-
conazole.6
Alexander and colleagues reported the findings
of a post-hoc analysis from an open-label, multicen-
ter study in which posaconazole was administered as
salvage therapy to 23 solid organ transplant patients
with proven or probable invasive fungal infections
(IFIs).16 Primary causative pathogens were: Aspergil-
lus (n = 12), Candida (n = 3), Fusarium (n = 2),
Cryptococcus (n = 1), Zygomycetes (n = 2), and oth-
ers (n = 4). Participants with zygomycosis were con-
sidered refractory to standard therapy if they showed
disease progression or no clinical improvement after
7 days of treatment. Intolerance to standard therapy
was classified as renal impairment, severe infusion-
related toxicity, or high-risk for toxicity based on
underlying conditions or medications. The primary
endpoint was response at the end of treatment with
complete and partial responses defined as success,
and stable disease or failure defined as non-success.
Posaconazole was administered as 800mg per day in
divided doses with food; most patient received posa-
conazole for at least 30 days. Overall, 13 of 23
(57%) patients had a complete or partial response. Of
the 2 patients with zygomycosis, 1 had a successful
response but the other failed treatment. Treatment-
related adverse events were reported in 12 of 23 par-
ticipants and included: nausea (4), vomiting (2), ele-
vated LFTs (2), and increased levels of cyclosporine
and/or tacrolimus (3).

NEW TREATMENT OPTIONS
With increasing incidence of mucormycosis and
its high mortality rate, the development of new anti-


PharmaNote Volume 24, Issue 4 January 2009


PharmaNote


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 Prr (complete or partial response)
Posaconazole Primary: Response
Greenberg R, et al open-label, nonran- 800mg/da in (complete, partial,
800mg/day in (complete, partial,
(2006)6 domized, multi- di d d s Mean and median treatment dura-
divided doses failure)
centered, compas- tion was 292 and 182 days, respec-
sionate trials tively


Posaconazole Overall suc- Overall success (complete and par-
Van Burik J, et al Retrospective case 8 y in cess (complete, partial, t w 6 a
,...,7' .800mg/day in tial) was 60% after 12 weeks of
(2006)7 series data d d 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.
(2008)16 from an open-label, 800mg/day in treatment (complete, One of two participants with zgo-
(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-
Polye 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 fr icaspofungin had superior success
(2008)1 cerebral zygomyco- (100% vs 45%, p = 0.02) and im-
sis cases AmB 0.3-1.5mg/kg : K proved Kaplan-Meier survival time
ABLC5-10mg/kg; Secondary: Kaplan-
AB5-10mg/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.1 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 Rhizopus oryzae, 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 valuable pa-


PharmaNote Volume 24, Issue 4 January 2009







tients were treated up-front with a combination of
polyene (mostly ABLC) and caspofungin therapy.
Patients treated with polyene-caspofungin combina-
tion therapy initially had superior success (100% vs.
45%; p = 0.02) and Kaplan-Meier survival time (p
= .02) compared to patients treated with any AmB
formulation as monotherapy. Combination therapy of
AmB-caspofungin appears to be a promising thera-
peutic option for zygomycosis based on these results.
The limitation of this study however, was that the
majority of participants were non-neutropenic and
diabetic. Therefore, these findings may not be gener-
alizable to immunocompromised patients with neu-
tropenia.

SUMMARY
Zygomycosis is a rare, angioinvasive fungal in-
fection most commonly found in immunocompro-
mised patients or individuals with predisposing fac-
tors such as: diabetes mellitus, immunosuppressive
drug therapy, deferoxamine drug therapy and IVDU.
Zygomycosis is associated with a poor prognosis evi-
denced by an overall survival rate (with treatment) of
only 40-50%. Successful treatment relies on early
diagnosis, removal of predisposing factors, surgical
debridement of infected tissue, and aggressive anti-
fungal drug therapy. A lipid formulation of ampho-
tericin B remains the drug of choice for treatment of
zygomycosis and many other fungal infections be-
cause of its broad spectrum of activity and few in-
stances of antifungal resistance. Posaconazole has
been shown in 2 retrospective studies to be effective
as salvage therapy for patients refractory or intoler-
ant to AmB. Echinocandins initially were thought to
be ineffective against zygomycetes in vitro and in
vivo. However, recent evidence suggests that
Rhizopus sp express the target enzyme of the echino-
candins. Combination polyene-caspofungin therapy
has been shown to be a promising option for treat-
ment of rhino-orbital-cerebral zygomycosis in dia-
betics in both murine models and humans.


REFERENCES
1. Cox GM, et al. Zygomycosis (Mucormycosis).
UpToDate, 2008.
2. Roden MM, et al. Epidemiology and outcome of
zygomycosis: a review of 929 reported cases.
Clinical Infectious Diseases 2005; 41:634.
3. Clinical Pharmacology Online. Accessed No-


vember 2, 2008.
4. Boelaert JR, Van Cutsem J, et al. Deferoxamine
augments growth and pathogenicity of Rhizopus,
while hydroxypyridinone chelators have no ef-
fects. Kidney Int 1994; 45:667.
5. Spellberg B, Edwards J, et al. Novel perspectives
on mucormycosis: Pathophysiology, presentation,
and management. Clinical Microbiology Reviews
2005; 18:3.
6. Greenberg RN, Mullane K, et al. Posaconazole as
Salvage Therapy for Zygomycosis. Antimicrobial
Agents and Chemotherapy 2006; 50:1.
7. van Burik J, Hare R, et al. Posaconazole Is Effec-
tive as Salvage Therapy in Zygomycosis: A Ret-
rospective Summary of 91 Cases. Clinical Infec-
tious Diseases 2006; 42.
8. Adler-Moore JP, Proffitt RT. Amphotericin B
lipid preparations: what are the differences? Clin
Microbiol Infect 2008; 14 (Suppl. 4):25-36.
9. Lantemier F, Lortholary O. Liposomal ampho-
tericin B: what is its role in 2008?. Clin Micro-
biol Infect 2008;14 (Suppl. 4):71-83.
10. Walsh TJ, Kontoyiannis DP. What is the Role of
Combination Therapy in Management of Zygo-
mycosis?. Clinical Infectious Diseases
2008;47:372-4.
11. Reed C, Bryant R, et al. Combination Polyene-
Caspofungin Treatment of Rhino-Orbital-
Cerebral Mucormycosis. Clinical Infectious Dis-
eases 2008; 47:364-71.
12. Noxafil [package insert]. Kenilworth, NJ: Scher-
ing Corporation; 2008.
13. Caspofungin acetate. Johns Hopkins ABX Guide,
2008. antibiotics/antifungal/caspofungin acetate.html?
contentInstanceld=254891>. Accessed December
3, 2008.
14. Antifungal Therapy Cost Analysis. Doctor Fun-
gus, 2008. thedrugs/costl.htm>. Accessed December 5,
2008.
15. Petrikkos G, Skiada A. Recent advances in anti-
fungal chemotherapy. International Journal of
Antimicrobial Agents 2007; 30:108-117.
16. Alexander BD, Perfect JR, et al. Posaconazole as
Salvage therapy in Patients with Invasive Fungal
Infections After Solid Organ Transplant. Trans-
plantation 2008;86:791-6.


PharmaNote Volume 24, Issue 4 January 2009


PharmaNote


Volume 24, Issue 4 January 2009







DRUG UPDATE


k Fenofibric Acid (TriLipix)) Abbott Pharmaceu-
ticals

S In December 2008, the FDA approved the use
Sof fenofibric acid, the active metabolite of fenofi-
brate. Like the other 'fibrates,' fenofibric acid is
most effective at treating lipid disorders associated
with high levels of serum triglycerides. It is the
Only fibrate currently approved for combination use
with stations in the management of mixed dyslipide-
mia. In clinical trials, patients taking fenofibric
acid monotherapy experienced myalgias at a rate
Similar to those taking combination therapy with
stations (3.3% vs. 3.1-3.5%). However, caution
Should still be exercised before initiating dual ther-
Sapy, particularly in patients with renal failure.
TriLipix is available as 45 mg or 135 mg delayed
-release capsules. Starting dose for adults is 45 to
S135 mg once daily with dose titration after 4 to 8
Weeks as needed. Maximum daily dose is 135 mg
l dal\ Fenofibric acid ma\ be administered \ uthotut
SreCiard to meals The most common ac\ erse effects C
Snclde headache IleA and uastiroIntestinal effects
/


% Zoledrollic Acid (Reclsl"s) Av ii'
S1 l'hu InaIeuiakl, /

The FDA recently approved injectable
Szoledronic acid for the treatment of osteoporosis in
men. It is the first of the bisphosphonates to
receive an indication for the treatment of both
sexes. Zoledronic acid is one of only a handful oft
bisphosphonates with data supporting a reduced
incidence of vertebral, nonvertebral and hip
fractures. However, FDA approval for the
treatment in men was based on a two year
Srandomized, active control, non-inferiority trial
Comparing changes in bone mineral density among
participants taking zoledronic acid once yearly and
alendronate 70mg once weekly for 2 years.
Approved dose in men is a 5 mg infusion over 15
minutes once yearly. Administration of zoledronic
Said is considered a medical procedure covered by
Medicare Part B. Most Medicare Part B carriers
Should no\\ co\ er Reclast' infusions' for men
%/


MEDICAL NEWS


Influenza Updaile

Preliminary surveillance data from the Centers
for Disease Control (CDC) suggests high levels of
Circulating influenza A virus, predominantly the
H1N1 subtype. Of the 88 preliminary samples
Tested nationally, 86 (98%) are resistant to osel-
tamivir (Tamiflu"), the most widely prescribed an-
tiviral worldwide. These samples have shown no
Z resistance to zanamivir (Relenza) or the older ada-
mantane antivirals, amantadine or rimantidine.
SHowever, some strains of influenza A (H3N2) and
all strains of influenza B virus remain resistant to
the adamantanes.
S The CDC recommends the use of zanamivir
alone or oseltamivir and rimantidine combination
Z therapy over oseltamivir therapy alone for the treat-
ment of influenza infection during the current sea-
i son. Influenza testing can help determine which
strain is present and may help streamline antiviral
Choice. Influenza infection rates are expected to
. rise throughout the remainder of the flu season, so
Influenza vaccination should continue to be recom-
I mended.




The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida



John G. Gums Editor
Pharm.D., FCCP

R. Whit Curry, M.D. Associate Editor

Steven M. Smith Assistant Editor
Pharm.D.


% Vmay


PharmaNote


Volume 24, Issue 4 January 2009




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