Vol. VI, No. IV
July/August 2003
Jennifer Long,
Pharm.D., BCPS
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Pharmacotherapy
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New Antifungal Agents
Additions to the Existing Armamentarium
(Part 2)
Introduction:
Invasive fungal infections are an important cause of morbidity and
mortality, and the number of these cases has been increasing. For
example, Candida is now the fourth leading cause of nosocomial
infections. This rise may be partially due to medical advances that
have enabled the survival of critically ill patients (e.g., intravascular
catheters, total parenteral nutrition (TPN), broad spectrum antimicrobials,
and dialysis). In addition, the profile of patients at risk for
infection with opportunistic fungi, such as Aspergillus,
is expanding (e.g., solid organ and bone marrow transplants, acquired
immune deficiency syndrome (AIDS), and intensive chemotherapy regimens).
It is therefore imperative that the armamentarium of antifungals
expands to treat these infections. The ideal antifungal agent would
1) be fungicidal, 2) have a novel mechanism of action, 3) have a
broad spectrum of activity, including resistant strains, and 4)
be well tolerated. Recently, the Food and Drug Administration (FDA)
approved two new antifungals, which may benefit patients with invasive
fungal infections. Part I of this article discussed the echinocandins,
focusing on caspofungin. Part II of this article will discuss the
new azole antifungal, voriconazole.
Voriconazole:
In the next few years, several new azole antifungals will be available.
These newer agents were developed to expand the spectrum of activity
of current azoles and alleviate certain bioavailability issues.
The first of the new azole agents approved by the FDA is voriconazole
(Vfend®). It is structurally related to fluconazole (Diflucan®);
however, an expanded spectrum of activity results from the replacement
of one of the triazole rings with a fluorinated pyrimidine as well
as the addition of an α-methyl group. Another new azole, posaconazole,
is structurally related to itraconazole (Sporanox®). Like voriconazole,
several changes to the chemical structure of posaconazole have expanded
the spectrum of activity. The new azoles and their current status
can be located in Table 2.
The remainder of this discussion will focus on voriconazole.
Mechanism
of Action:
The azole antifungals inhibit the cytochrome P450 (CYP)-dependent
enzyme, 14-α-demethylase. This inhibition disrupts membrane
synthesis resulting in depletion of ergosterol and leads to accumulation
of toxic sterol precursors. Voriconazole appears to have a stronger
affinity for 14-α-demethylase compared to fluconazole.
Also, it inhibits the enzyme, 24-methylene dihydrolanasterol demethylase.
These two features may explain the increased activity of voriconazole
against certain moulds compared to other azole antifungals.
Azole resistance
has been documented in several species of Candida. The proposed
mechanisms include alteration of 14-α-demethylase and upregulation
of genes that encode for efflux pumps. Voriconazole susceptibilities
also appear to be influenced by these mechanisms. Certain efflux
pumps that affect fluconazole will also affect voriconazole. This
explains the increased minimum inhibitory concentrations (MICs)
for voriconazole noted in some fluconazole-resistant Candida.
Spectrum of Activity:
The National Committee for Clinical Laboratory Standards (NCCLS)
has established breakpoints for fluconazole and itraconazole activity
for C. albicans. Although NCCLS does not have official breakpoints
for non-albicans isolates, the breakpoints for C. albicans
are usually adopted for these other species. At this time, the NCCLS
has not set breakpoints for voriconazole. Most in-vitro studies
demonstrate voriconazole to be fungistatic against yeasts. However,
a few in-vitro studies have shown fungicidal activity of
voriconazole against certain filamentous fungi.
Yeasts.
Voriconazole is active against a majority of Candida species.
Voriconazole has activity against C. krusei and C. glabrata
which are often times inherently resistant to fluconazole. Fluconazole-resistant
C. albicans are usually susceptible to voriconazole, although
the MICs are usually higher than those noted for fluconazole-susceptible
strains. This may suggest the possibility of cross-resistance. The
voriconazole MIC for C. krusei and C. glabrata tend
to be higher than C. albicans but are still in the presumed
susceptible range. In addition, voriconazole is active against other
yeasts such as Cryptococcus, Trichosporon beigelii,
and Saccharomyces cerevisiae.
Filamentous
fungi. Voriconazole, like itraconazole, has activity against
certain filamentous fungi. It is active against Aspergillus fumigatus,
Aspergillus flavus, and Aspergillus terreus.
The fungicidal activity of voriconazole against Aspergillus
does not appear to be as great as amphotericin B but is still better
than itraconazole. Voriconazole has also demonstrated in-vitro
activity against the following opportunistic dematiaceous and hyaline
moulds: Fusarium spp., Penicillium marneffei, Pseudallescheria
boydii (Scedosporium apiospermum), and Scedosporium prolifcans.
The zygomycetes, including Rhizopus spp. and Mucor
spp. are not susceptible to voriconazole.
Dimorphic
fungi. Voriconazole has shown in-vitro activity against
the endemic fungi, Histoplasma capsulatum, Blastomyces dermatitidis,
and Coccidioides immitis.
Pharmacokinetics:
The pharmacokinetic properties of azole antifungals are summarized
in Table 3. Voriconazole is well
absorbed and has excellent bioavailability. Unlike itraconazole,
gastric acid is not needed for absorption of voriconazole. After
a loading dose is administered, steady-state concentrations are
reached within 1 day, or, if there is no loading dose, steady-state
concentrations may not be reached for 5 to 6 days. In adults, voriconazole
exhibits non-linear kinetics due to saturable metabolism. The wide
intersubject variability noted with voriconazole levels may also
be in part to its hepatic metabolism. Voriconazole is metabolized
by the CYP450 system including 2C9, 3A4, and 2C19. The CYP2C19 is
the major metabolic pathway and is highly subject to genetic polymorphism.
Low levels of CYP2C19 may lead to voriconazole levels up to four
times higher than those who metabolize voriconazole more extensively.
The major metabolite is voriconazole N-oxide, which has minimal
antifungal activity. Eight other non-active metabolites have been
identified and all are excreted in the urine. Dose adjustments are
necessary for patients with mild-to-moderate hepatic impairment
(See Indications and Dosage section). No studies have evaluated
the use of voriconazole in patients with severe hepatic insufficiency.
Renal dose adjustments are not necessary; however, the intravenous
formulation is solubilized in sulfobutyl ether ß-cyclodextrin
sodium (SBECD) which may accumulate in patients with renal insufficiency.
Therefore, intravenous voriconazole should be avoided in patients
with a creatinine clearance < 50 mL/min.
Drug
Interactions:
Voriconazole is a substrate and inhibitor of CYP2C9, 3A4, and 2C19
and has a drug-drug interaction profile similar to itraconazole.
Agents metabolized via these pathways are likely to have interactions
and require potential dosage adjustments. Tables
4 and 5 summarize select drug interactions
with voriconazole. Please note these tables are not all inclusive
and other agents metabolized via these pathways may be affected
by voriconazole.
Adverse
Effects:
Voriconazole is associated with similar adverse effects when compared
to other azole antifungals (e.g., hepatotoxicity). In addition,
there are other effects not previously noted with the class. The
potential adverse effects associated with voriconazole are summarized
in this section, although the true incidence in clinical practice
is unknown. Voriconazole is teratogenic in animals and may cause
harm when administered during pregnancy. It is listed as a pregnancy-risk
category D and patients should be informed of the potential hazards
to the fetus.
Ocular.
The most common side effect with voriconazole is a reversible disturbance
of vision. The reaction has been reported as increased brightness,
blurred vision, altered visual perception, photophobia, altered
color perception, and ocular discomfort. The incidence in healthy
volunteers and in clinical studies was approximately 30%, with only
1% of volunteers discontinuing therapy secondary to visual effects.
The reaction usually occurred approximately 30 minutes after a dose,
persisted for 30 minutes, and was most common during the first week
of therapy. The exact mechanism is unknown; however, the abnormalities
were consistent with drug effect on the rods and cones. The effects
on ocular function are not known when voriconazole therapy extends
beyond 28 days or when patients require retreatment.
Skin Effects.
Skin rashes appear to be the second most common adverse effect of
voriconazole. In some clinical trials, the incidence has been reported
as high as 18%. Most rashes were mild-to-moderate but severe rashes,
including Stevens-Johnson Syndrome and toxic epidermal necrolysis,
have been reported. Photosensitivity reactions are also common and
patients should avoid direct sunlight.
Hepatic Effects.
Increased AST, ALT, and alkaline phosphatase levels have been reported
in clinical trials in-volving voriconazole. Patients at risk for
abnormal liver function tests (LFTs) appear to have high voriconazole
plasma concentrations and receive a longer duration of therapy (i.e.,
e" 7 days). The majority of these patients remain asymptomatic,
although severe life-threatening hepatitis has been described. Other
effects include increased liver weight, centrilobular hypertrophy,
hepatocellular fatty change, single cell necrosis, and subcapsular
necrosis. According to the product labeling, LFTs should be performed
prior to therapy, within the first 2 weeks of initiation, and every
2 to 4 weeks during therapy.
It is too early to determine if the risk of hepatotoxicity is greater
with voriconazole when compared to other azole antifungals.
Infusion-Related Reactions. In healthy subjects, the product
labeling states that during infusion anaphylactoid-type reactions
(e.g., flushing, fever, sweating, tachycardia, chest tightness,
dyspnea, faintness, nausea, pruritus, and rash) have occurred immediately
upon initiation.
Cardiac Effects.
In animal models, high doses of voriconazole have been associated
with arrhythmias, in-cluding prolongation of the QTc interval. The
plasma concentrations of voriconazole ranged from 24 to 56 mcg/mL
in these studies. The product labeling states that during clinical
development and post-marketing surveillance, rare cases of torsade
de pointes have been reported. All patients had confounding factors
that made it difficult to assess the contribution of voriconazole.
Therefore, in patients receiving voriconazole, it is recommended
to maintain normal levels of potassium, mag-nesium, and calcium.
Clinical
Trials:
The major trials involving voriconazole are summarized below. Please
note that there are major caveats and questions regarding design
and statistical methods for these trials that are beyond the scope
of this article. The highlights of the trials are mentioned.
Aspergillosis.
Voriconazole was approved for this indication based upon a noncomparative
trial and a randomized trial comparing voriconazole to conventional
amphotericin B (CAB).
The noncomparative
trial had 116 evaluable patients, 70% of which had pulmonary invasive
aspergillosis (IA). Patients could receive voriconazole as primary
therapy or salvage therapy. Fourteen percent (16/116) had a complete
response, however, 2 of these patients died. Thirty-four percent
(40/116) had a partial response but 16 of these patients died. Response
rates were better in patients receiving voriconazole as primary
therapy than salvage therapy. Twenty patients in this trial were
noted to have increased liver function tests and one case of liver
failure is mentioned. Overall it is difficult to ascertain the role
of voriconazole from this trial due to the uncontrolled design.
The subsequent
large randomized trial compared voriconazole to CAB for primary
IA. The primary objective of the study was non-inferiority at week
12. An expert panel blinded to therapy determined outcomes of patients.
Overall, 144 patients were randomized to receive voriconazole and
133 patients were randomized to CAB. Complete or partial responses
at week 12 were found in 53% of voriconazole patients compared to
32% of CAB patients (difference 21%; 95% CI, 10.4%-32.9%). While
results point to the fact that voriconazole may be more effective
than CAB there are several points to keep in mind. First, physicians
were permitted to switch patients' therapy to another drug if they
were failing to respond or experiencing side effects, and these
were not classified as failures. Approximately 25% of patients in
the CAB group were changed to itraconazole and approximately 25%
in the voriconazole group were changed to an amphotericin product.
In addition, the median duration of therapy was much longer for
voriconazole than CAB (median of 77 days for voriconazole compared
to 10 days for CAB). This trial demonstrates voriconazole can be
an effective therapy but some debate exists regarding if it is truly
superior to amphotericin from the design of this trial.
Pseudoallescheria/Scedoporium/Fusarium.
These fungi have emerged as significant pathogens in immunocompromised
hosts. In-vitro data shows voriconazole to be active against
these difficult to treat pathogens. In addition, small case series
have shown voriconazole to be promising in the treatment of these
infections in both adults and children.
Candidiasis.
Voriconazole is not approved for the treatment of candidal infections.
A randomized, double-dummy trial to compare the efficacy and safety
of voriconazole versus fluconazole in 391 immuno-compromised patients
with esophageal candidias was performed. Patients received either
fluconazole 200 mg/day or voriconazole 200 mg BID for at least seven
days. There was no difference between the groups in respect to cure,
determined by esophagoscopy. A trial comparing voriconazole to CAB
followed by fluconazole is currently ongoing.
Febrile Neutropenia.
Voriconazole was compared to liposomal amphotericin B (LAMB) for
empiric therapy of febrile neutropenia in an open-label prospective
trial. The results of this trial which enrolled 412 patients in
the voriconazole group and 422 patients in the LAMB group have been
controversial. The voriconazole group did not meet the predefined
primary endpoint for non-inferiority compared to LAMB. The trial
did show a trend towards less breakthrough fungal infections in
the voriconazole group. However, based upon this trial the FDA voted
voriconazole would not be indicated for the empiric treatment of
febrile neutropenia.
Indications and Dosage. Voriconazole is FDA-approved for the
following indications:
Treatment of invasive aspergillosis (both primary and salvage therapy)
Treatment of serious fungal infections due to Fusarium and Scedosporium
spp in patients refractory or intolerant to other therapy
The recommended
dosing per Cleveland Clinic Foundation Antimicrobial Guidelines
differs from the package insert (See Tables
6a and 6b). The rationale is based
on clinical trials using this dosing scheme and the excellent bioavailability
of oral voriconazole.
Restrictions.
Voriconazole is restricted at CCF to the Department of Infectious
Diseases for the following: 1) Treatment of presumed or documented
invasive fungal infections; or
2) Monotherapy or combination therapy with amphotericin/caspofungin
for presumed or documented invasive mould infections; or
3) Second-line therapy for Candida infections in patients
intolerant or failed amphotericin/azole therapy; and
4) The intravenous formulation is restricted to patients who are
unable to take oral medications.
Cost Comparison.
See Table 7.
Conclusion.
As the rates of invasive fungal infections increase, it is important
to have new agents effective against these pathogens. Caspofungin
appears to be very good for Candida infections and effective
in salvage therapy for aspergillosis. It appears to be well tolerated
and has limited drug interactions. Voriconazole, while having many
drug interactions and some potential concerning side effects, has
added greatly to the armamentarium of agents active against Aspergillus
and emerging moulds. The role of combination therapy with azoles,
amphotericin, and echinocandins is being investigated in in-vitro
models and a few case reports have been published. While this
practice needs further study before definitive recommendations can
be made, it may hold promise for the treatment of serious and life-threatening
invasive fungal infections.
References Available Upon Request
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