Download Optimizing antifungal choice and administration

Current Medical Research & Opinion
0300-7995
doi:10.1185/03007995.2012.761135
Vol. 29, Supplement 4, 2013, 13–18
Article FT-0389.R1/761135
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Abstract
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Address for correspondence:
David Andes MD, University of Wisconsin, MFCB,
Room 5211, 1685 Highland Ave, Madison, WI 537052281, USA.
Tel.: þ1 608 263 1545; Fax: þ1 608 263 4464;
[email protected]
Keywords:
Antifungal – Aspergillus – Candida – Echinocandins –
Fungicidal – Polyenes – Spectrum of activity –
Therapeutic drug monitoring – Triazoles
Accepted: 11 December 2012; published online: 11 January 2013
Citation: Curr Med Res Opin 2013; 29:13–18
Background:
The antifungal armamentarium includes a number of drug classes and agents within each class. Successful
IFI management depends on optimal matching of drug choice with the individual patient and causative
pathogen, and maximizing effectiveness of the selected drug through appropriate dosing and toxicity
management.
,
University of Wisconsin School of Medicine and Public
Health, Madison, WI, USA
se oa
d
David Andes
Co
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Review
Optimizing antifungal choice and administration
Objective:
This review is intended to provide a brief overview of key factors involved in optimizing antifungal choice and
administration for patients with invasive fungal infections (IFIs).
Findings:
Antifungals differ in spectrum of activity, and these differences are critical when selecting the antifungal
most likely to provide success for a patient with an IFI. When the species has not yet been identified, an
analysis of regional epidemiology and risk factors can provide clues as to the most likely pathogen. For
severely immunocompromised patients, a fungicidal agent may be preferred over a fungistatic agent,
although more research is needed in this area. Triazoles, particularly itraconazole and posaconazole,
exhibit great interpatient pharmacokinetic variability related to absorption. Steps can be taken to
maximize absorption when using these agents. Voriconazole concentration is affected by polymorphisms
in the major metabolic enzyme, cytochrome P450 2C19. Triazoles, and to a lesser extent other antifungals,
are also subject to drug–drug interactions, which needs to be considered when selecting a particular
antifungal agent for use in a severely ill patient on polypharmacy. Therapeutic drug monitoring may be a
useful adjunct for patients receiving itraconazole, voriconazole, or posaconazole. When the IFI involves a
pharmacologically protected site, such as the central nervous system (CNS) or eye, 5-fluorocytosine,
fluconazole, or voriconazole are generally preferred. Echinocandin penetration is typically inadequate for
IFIs of the CNS or eye. Antifungal agents also differ in their toxicity profiles, and these issues also need to be
considered and managed when making an antifungal choice.
Conclusion:
Successful management of IFIs relies in part on the accurate selection of an antifungal agent for the
infection. Drug characteristics can help in the selection of drug therapy. These characteristics include
the drug’s spectrum of activity, pharmacokinetics, pharmacodynamics, toxicity profile, and distribution to
the infection site. Matching the drug profile to the patient and fungal species contribute to optimal
management of infection.
Introduction
Clinicians now have multiple drugs from several antifungal drug classes for the
management of invasive fungal infections (IFIs). These include four drugs of the
polyene class (amphotericin B [AmB] deoxycholate and three lipid-based
amphotericin B formulations: amphotericin B colloidal dispersion [ABCD],
amphotericin B lipid complex [ABLC], and liposomal AmB [L-AMB]); four
triazole drugs (itraconazole, fluconazole, voriconazole, and posaconazole);
three echinocandins (caspofungin, micafungin, and anidulafungin), and
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Optimizing antifungal choice and administration Andes
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Volume 29, Supplement 4
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Table 1. Antifungal spectrum of activity against more common invasive fungal pathogens (data from Lewis, 20111; Denning and Hope, 20105; Dodds Ashley
et al., 20067; and Pfaller and Diekema, 20108).
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Polyenesa
Candida spp.
C. albicans
C. glabrata
C. tropicalis
C. parapsilosis
C. krusei
C. lusitaniae
C. guilliermondii
Aspergillus spp.
A. fumigatus
A. flavus
A. terreus
A. niger
A. nidulans
Cryptococcus neoformans
Fusarium spp.
Scedosporium prolificans
Scedosporium apiospermum
Mucorales
Blastomyces spp.
Histoplasma spp.
Coccidioides spp.
Triazoles
Echinocandins
Fluconazole
Itraconazole
Voriconazole
Posaconazole
Caspofungin
Micafungin
Anidulafungin
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Plus signs (þ) indicate the antifungal agent has activity against the specified organism; plus/minus signs () indicate the agent has variable or slight activity
against the specified organism; and minus signs () indicate the agent does not have activity against the specified organism.
a
Includes amphotericin B deoxycholate (AmB) and lipid amphotericin B formulations.
b
Variable echinocandin activity against dimorphic fungi has been described in vitro, depending on whether they are in mycelial or yeast-like form.
5-fluorocytosine (5FC, also known as flucytosine), a
pyrimidine analog1,2. Additional agents are in
development3,4.
The azoles are available as either intravenous (IV) or
oral formulations (with the exception of posaconazole,
which does not currently have an IV formulation, and
itraconazole, which has an IV formulation in Europe but
not the United States); the polyenes and echinocandins
can only be administered parenterally; and 5FC is only
available in an oral preparation5. Besides route of administration, other variables differentiate antifungal agents,
and can be important when selecting the most suitable
agent.
This review examines how to utilize these differentiating characteristics to optimize antifungal choice and
administration for patients. Ideally, data from randomized
controlled, head-to-head clinical trials would be available
when selecting an agent (e.g., Herbrecht et al., comparing
voriconazole and AmB for invasive aspergillosis [IA]6), but
often these data are not available. Hence, an understanding of drug characteristics assumes greater importance for
drug selection.
Spectrum of activity
A critically important consideration is the agent’s spectrum of activity. Antifungal classes, and even agents
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Optimizing antifungal choice and administration Andes
within the same class, often exhibit differential activity
against particular fungal pathogens (Table 11,5,7,8). For
example, different antifungals show variable activity
against different Candida spp. C. albicans and C. tropicalis
are susceptible to all agents, but triazoles show minimal or
variable activity against C. glabrata, and echinocandins
exhibit the greatest activity1,5,7,8. Both polyenes and (particularly) echinocandins are active against C. krusei,
while only voriconazole and to a lesser extent posaconazole exhibit reasonable activity1,5,7–9. Polyenes and triazoles demonstrate good activity for C. parapsilosis, while
echinocandins are less active against this pathogen.
Polyenes are not effective for C. lusitaniae. The echinocandins exhibit reduced activity against C. parapsilosis and
C. guilliermondii.
Although important, identification at the species level
is often not available in most microbiology laboratories
until several days into the course of treatment; delayed
or inadequate initial antifungal therapy has been linked
with poorer outcomes10–14. Hence, ‘hitting the target right
the first time’ requires an understanding of local epidemiology patterns, and using this in conjunction with antifungal spectrum of activity to guide initial drug selection.
Candida spp. distribution and patterns of resistance can
vary not only by clinical service8 but also globally and by
geographic regions15–20. In the United States, the most
recent survey has demonstrated the continuing emergence
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of C. glabrata and corresponding decline in C. albicans in
invasive candidiasis (IC)21. Therefore, at my institution,
the University of Wisconsin Hospital in Madison, echinocandins are first-line therapy for IC while waiting for
species identification.
Species identification has also become important for
Aspergillus and other pathogenic molds. A. fumigatus –
the most common cause of invasive aspergillosis (IA) –
is susceptible to polyenes, echinocandins, and all triazoles
except fluconazole, while A. terreus and A. nidulans are
susceptible to triazoles (except fluconazole) and echinocandins but not polyenes5,7,8,22–24. Most Mucor spp.
or Zygomycetes are susceptible to posaconazole, but
not to echinocandins, voriconazole, or other azoles;
polyenes exhibit variable activity against these pathogens1,5,7,8,25. For Fusarium spp. and Scedosporium spp.,
only voriconazole and posaconazole exhibit relatively
consistent activity against these pathogens, with polyenes exhibiting more variable activity for Fusarium but
limited activity for Scedosporium spp. Neither echinocandins nor other triazoles are active against any of these
species5,7,8.
Cryptococcus neoformans is susceptible to polyenes, 5FC,
all the triazoles, but not echinocandins1,5,7,8,24,26. The
fungi that cause histoplasmosis, blastomycosis, and coccidioidomycosis exhibit in vitro susceptibility to polyenes and
all triazoles1,7,8.
Pharmacokinetics (PK) and therapeutic
drug monitoring (TDM)
PK issues are also important considerations for drug selection and when trying to optimize drug levels for maximal
benefit and minimal risk. PK variability is a particular concern with triazole therapy, where various factors affect
absorption and bioavailability and where genetic polymorphisms of cytochrome P450 (CYP) 2C19 can alter
voriconazole plasma levels. Drug–drug interactions and
comorbidities (renal or hepatic insufficiency) can also
have important PK effects.
Oral itraconazole and posaconazole show greater variability in absorption than oral fluconazole or voriconazole. The capsular form of itraconazole is associated
with wide variability27–29, with markedly lower absorption and plasma concentrations when administered
under fasting versus fed conditions30,31. Itraconazole
solution demonstrates more predictable absorption and
higher plasma concentrations compared to the itraconazole capsule formulation, particularly under fasting
conditions32,33. Administration of itraconazole capsules
with an acidic beverage has been shown to enhance
absorption. Food also increases the bioavailability of
the capsule form34. Wide interpatient pharmacokinetic
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variability has also been observed with posaconazole35,
and similar to itraconazole, absorption and bioavailability of posaconazole is markedly increased when administered with food or a nutritional supplement versus when
fasting36–39. Gastric acidity is also important for posaconazole absorption40. Finally, posaconazole absorption
is saturable, thus despite a long elimination half life,
exposure is increased when administered as divided
doses of 200 mg four times daily versus as a single
800 mg daily dose41,42. Interpatient variability with voriconazole is primarily due to differences in metabolism
related to CYP2C19 polymorphisms, rather than absorption issues, although voriconazole absorption is modestly
reduced by administration with food43. CYP2C19 is
the major determinant of voriconazole metabolism and
clearance, and patients who are homozygous extensive
CYP2C19 metabolizers have markedly lower plasma
concentrations than homozygous poor metabolizers or
heterozygous extensive metabolizers44,45. Fluconazole
demonstrates predictable, linear PK that is unaffected
by food or gastric acidity46–48.
TDM has been proposed as a potential tool for optimizing therapy with itraconazole, voriconazole, and posaconazole35,49–52. Each of these drugs meet widely accepted
criteria for TDM: unpredictable population PK, a relatively narrow therapeutic window, and a fairly well defined
clinical therapeutic range49,51. TDM recommended trough
concentrations for voriconazole and posaconazole efficacy
are each approximately 41 mg/mL50,51,53–57. A recommended trough 55 mg/mL has been recommended to
limit the likelihood of voriconazole toxicity; a toxicity
trough associated with posaconazole has not been
defined51.
Comorbid organ dysfunction, specifically renal or hepatic insufficiency, alters the PK of certain antifungals and
impacts either drug selection or the dosing regimen design.
Dose reductions of fluconazole or 5FC are recommended
for patients with renal sufficiency. No dosing adjustments
for any of the polyene formulations, oral voriconazole,
posaconazole, or any of the echinocandins are required
in patients with renal dysfunction7. However, caution
should be exercised when IV voriconazole is used in
patients with a creatinine clearance (CrCl) 550 mL/min
or with IV itraconazole in patients with CrCl 530 mL/
min7. This is because the cyclodextrin component of
these parenteral formulations can accumulate in patients
with renal disease, and some animal studies suggest very
high cyclodextrin may be associated with renal toxicity58.
Voriconazole dose reduction is recommendations for
patients with mild-to-moderate hepatic dysfunction59.
Similarly caspofungin dose should be halved in patients
with moderate hepatic insufficiency60. No dosing adjustments are needed based on hepatic insufficiency for any
other antifungal7.
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Drug interactions and toxicity
The likelihood for drug–drug interactions is greater with
triazoles than other major antifungal classes. All the triazoles are substrates for one or more CYP450 enzymes,
which creates the potential for bidirectional drug–drug
interactions when these drugs are used concomitantly
with other drugs that are also substrates for these enzymes.
All triazoles are either moderate or strong inhibitors of
CYP3A4, while fluconazole, and voriconazole also inhibit
CYP2C91. Voriconazole is also a strong inhibitor of
CYP2C191. Because of this, clinically relevant potential
drug–drug interactions can occur when particular triazoles
are coadministered with drugs that either induce or inhibit
CYP450 isoenzymes or that are substrates for them. A large
list of significant drug–drug interactions have been noted
with triazoles (although less with posaconazole)61,62.
Drug–drug interactions need to be considered not only
when initiating antifungal therapy, but also when discontinuing it. One will often need to adjust the dose of the
remaining non-antifungal drug. Interestingly, at our institution, we sometimes use the voriconazole-elevating
effects of coadministered omeprazole63 to increase voriconazole exposure in situations where simple dosage
increases have minimal impact.
Drug–drug interactions involving other (non-triazole)
antifungals have been reviewed elsewhere7,64–66.
Echinocandins are not appreciable substrates, inducers,
or inhibitors of CYP450 isoenzymes, and exhibit few clinically relevant drug–drug interactions. Clinically relevant
polyene drug–drug interactions are not associated with
drug exposure per se, but rather with their polyene nephrotoxicity, additive nephrotoxic effects when coadministered with other nephrotoxic agents, and altered renal
elimination or electrolyte imbalances due to these renal
effects.
Toxicities associated with antifungal agents can also
impact drug choice and monitoring1,2,5,7,64,67. Toxicity
associated with 5FC includes hepatitis and myelosuppression, especially at serum concentrations 4100 mg/mL.
Polyene antifungals exhibit dose-related nephrotoxicity
which is reduced with newer lipid formulations of AmB
compared to conventional AmB deoxycholate2,68.
Polyenes have also been linked with common infusionrelated reactions and less frequently anemia.
Furthermore, polyene-related nephrotoxicity increases
the risk of serious 5FC-related adverse events such as
bone marrow suppression when polyenes are coadministered with this 5FC69,70. Triazoles are generally safe and
well tolerated2,68. The most common side effects are gastrointestinal. One important consideration with the triazole class is modest QTc prolongation. This is not typically
important unless they are combined with other pharmacologic agents with similar conduction properties. Among
the class, voriconazole is associated with greater but still
16
Optimizing antifungal choice and administration Andes
low incidence of hepatotoxicity and also exhibits several
unique side effects including visual disturbances and photosensitivity71. Very high concentrations of voriconazole
have also been associated with reversible neurologic toxicity, with 31% (5/16) of patients with trough levels
45.5 mg/L experiencing encephalopathy as a serious
adverse event in one study, and none of 30 patients with
trough levels 5.5 mg/L53. Onset of encephalopathy
ranged from 5 to 30 days following start of voriconazole
therapy. Fluconazole is a well tolerated antifungal without
significant toxicity. All triazoles are also teratogenic.
Echinocandins are generally well tolerated and exhibit
few toxicities, the most common being occasional mild
infusion-related reactions.
Distribution to infection sites
Distribution to the site of infection is another PK variable
of potential importance when individualizing antifungal
therapy. A number of pathogenic fungi have a propensity
to disseminate to pharmacologically protected body sites –
particularly the central nervous system (CNS) or eye, or
urine with Candida spp. – and antifungals differ in their
ability to penetrate these tissues72. Of the triazoles, only
fluconazole and voriconazole penetrate to any measurable
degree into the CSF or intra-ocular compartments, while
the echinocandins typically lack penetration or achieve
very low levels in these tissues73,74. 5FC exhibits excellent
penetration to all common infection sites, while polyenes
show only modest penetration into the CSF. Fluconazole
and 5FC are the only antifungals that demonstrate any
appreciable excretion into the urine for patients with
asymptomatic Candida urinary tract infections75.
Conclusions
Optimal IFI management depends on multiple factors,
including rapid and accurate diagnosis and early treatment
with an antifungal agent or antifungal combination best
suited for the individual patient and causative pathogen.
Once a suitable antifungal is selected, it is important to
maximize effectiveness by managing its administration and
taking the appropriate steps to maximize efficacy and
reduce toxicity. Under certain circumstances, TDM may
be useful.
Knowledge of the agent’s spectrum of activity is essential, particularly when the species has been identified, but
epidemiology patterns and risk factor evaluation are
important guides when species identification is not available. Certain antifungals and dosages are better than
others when the IFI involves a pharmacologically protected site. When selecting certain triazoles, an understanding of factors affecting absorption and ways to
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optimize exposure is essential, including an understanding
of drug–drug interactions. Toxicity monitoring is important when using polyenes and 5FC, and to a lesser extent
with certain triazoles. Risk of nephrotoxicity is a concern
when considering polyene selection. Knowledge of all
these factors contributes to an optimal therapy regimen
for patients with an IFI.
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Transparency
Declaration of funding
This review was funded by an educational grant from Merck &
Co. Inc.
Declaration of financial/other relationships
D.A. has disclosed that he has been a consultant to Astellas
and Merck.
CMRO peer reviewers on this manuscript have received honoraria for their review work, but have no other relevant financial
relationships to disclose.
Acknowledgment
The authors of this supplement thank Global Education
Exchange Inc. for editorial support.
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