479

Drugs Active against Fungi,

39  Pneumocystis, and Microsporidia
John H. Rex and David A. Stevens

SHORT VIEW SUMMARY

FUNGI
Drug Class: Polyene Antifungal
(Amphotericin B)
• Binds to ergosterol in fungal cell membrane,
increases permeability
Administration and Usage
• Usage: candidiasis, cryptococcosis,
histoplasmosis, blastomycosis, aspergillosis,
mucormycosis, coccidioidomycosis,
paracoccidioidomycosis, penicilliosis marneffei
• Amphotericin B deoxycholate: 0.7 to
1.0 mg/kg daily
• Liposomal amphotericin B: 3 to 5 mg/kg daily
(Abelcet)
• Lipid complex amphotericin B: 5 mg/kg daily
(AmBisome)
• Cholesteryl amphotericin B: 3 to 6 mg/kg daily
(Amphotec)
Drug Class: Azole Antifungals
• Binds to cytochrome P-450 enzymes and
reduces ergosterol in fungal cell membrane
Administration and Usage
• Itraconazole: 200 mg PO once or twice daily;
treatment of blastomycosis,
coccidioidomycosis, paracoccidioidomycosis,
sporotrichosis, histoplasmosis
• Fluconazole: 400 mg PO or IV; treatment of
candidiasis, cryptococcal meningitis,
coccidioidomycosis
• Voriconazole: 6 mg/kg q12h × 2 then 4 mg/kg
PO or IV q12h; treatment of aspergillosis,
candidiasis, fusariosis, pseudallescheriasis
• Posaconazole: 200 mg PO 2 to 4 times daily;
treatment of oropharyngeal candidiasis,
prophylaxis in prolonged neutropenia,
graft-versus-host disease
Drug Class: Flucytosine
• Interferes with DNA synthesis and RNA function
• Dose 100 mg/kg PO in four divided doses
Drug Class: Echinocandin Antifungals
(Caspofungin, Anidulafungin, Micafungin)
• Inhibits synthesis of 1,3-β-D-glucan in fungal
cell wall
Administration and Usage
• Intravenous (IV): in general, well tolerated;
occasional histamine-like symptoms
• Few drug-drug interactions
• Caspofungin: 75 mg, then 50 mg daily;
treatment of candidiasis, aspergillosis
• Anidulafungin: 200 mg, then 100 mg daily;
candidiasis
• Micafungin: 100 mg daily; candidiasis,
prophylaxis in hematopoietic stem cell
transplant recipients
PNEUMOCYSTIS
Treatment
• See text and Table 271-3 for details and use of
prednisone.
• Preferred: trimethoprim (TMP), 15 to 20 mg/
kg/day, and sulfamethoxazole (SMX), 75 to
100 mg/kg/day
• IV or PO (oral) divided into q6-8h doses
Treatment Alternatives (see Table 271-3)
• Moderate-to-severe infection: pentamidine
4 mg/kg IV daily
• Mild-to-moderate infection: clindamycin-
primaquine, trimethoprim-dapsone, or
atovaquone
Prophylaxis (see Table 271-4)
• Trimethoprim-sulfamethoxazole: one
double-strength tablet PO qd or 1 single-
strength tablet PO qd
• Dapsone: 100 mg PO/day in one or two doses
• Dapsone: 50 mg PO qd plus pyrimethamine
50 mg q wk plus leucovorin 25 mg q wk
• Atovaquone: 1500 mg/day in one or two doses
MICROSPORIDIA
Treatment
• See text and Table 272-3 for albendazole and
fumagillin use.

Systemic antifungal agents and their use for the therapy of invasive
mycoses, infections caused by Pneumocystis jirovecii (formerly Pneu-
mocystis carinii), and infections caused by microsporidia are discussed
in this chapter. Many of these agents can also be used to treat the muco-
cutaneous forms of candidiasis, but those usages are discussed in detail
in Chapter 258 and thus mentioned only in passing here. Likewise, the
therapy of the various forms of tinea and of onychomycosis with either
topical agents or systemic agents is discussed in Chapter 268.
AMPHOTERICIN B–BASED
PREPARATIONS
General Features
Mechanism of Action
Amphotericin B is available in a formulation with deoxycholate and in
three lipid-associated formulations. For all preparations, the active
component is amphotericin B produced by Streptomyces nodosus.
Amphotericin B is a lipophilic molecule (Fig. 39-1) that exerts its
antifungal effect by insertion into the fungal cytoplasmic membrane,
probably orienting as head-to-tail oligomers perpendicular to the
plane of the membrane.1 The drug is closely bound to sterols such as
ergosterol. Amphotericin B causes membrane permeability to increase
(Fig. 39-2). At lower drug concentrations, potassium ion (K+)-channel
activity is increased.2 At higher concentrations, pores are formed in the
membrane. Loss of intracellular potassium and other molecules
impairs fungal viability. The onset of action is rapid and unrelated to
the growth rate, consistent with the concept that the drug acts at
preformed sites and no metabolic processing is required before a target
is exposed. Amphotericin B also has effects via oxidative pathways that
may enhance antifungal activity. In addition, amphotericin B localizes
to endothelial cells and may thereby produce endothelial cell activa-
tion.3 The possible effects of amphotericin B and its lipid formulations
on the immune system have been recently reviewed.4
Spectrum of Activity and Mechanisms of
Resistance
Amphotericin B is active against most fungi, and its spectrum of activ-
ity is not influenced by the choice of formulation. Where resistance
occurs, it is generally attributed to reductions in ergosterol biosynthesis
and synthesis of alternative sterols that lessen the ability of amphoteri-
cin B to interact with the fungal membrane.5 Resistance may also
follow from increased production of reactive-oxidant scavengers.6
Primary resistance is common for Aspergillus terreus, Scedosporium
spp., and Trichosporon spp.5 Among the Candida spp., primary resis-
tance is noted at meaningful frequencies most often for Candida lusita-
niae. Development of resistance in isolates of normally susceptible
species is uncommon but has been described for essentially all common
pathogens. Although such isolates may exhibit altered growth and
reduced pathogenicity,7 invasive and lethal infections are well described.
Identification of amphotericin B–resistant isolates by standardized sus-
ceptibility testing methods is difficult, and optimal methods are as yet
undefined.8 In studies of amphotericin B deoxycholate as therapy for
candidiasis, the principal pharmacodynamic driver of in vivo response
479
 479.e1
KEYWORDS
ABLC; amphotericin B; amphotericin B lipid complex;
anidulafungin; caspofungin; colloidal amphotericin B; echinocandins;

Chapter 39  Drugs Active against Fungi, Pneumocystis, and Microsporidia

fluconazole; flucytosine; 5-fluorocytosine; fumagillin; itraconazole;
liposomal amphotericin B; micafungin; pentamidine; posaconazole;
trimethoprim-sulfamethoxazole
 480
has been ratio of the peak achieved serum concentration to the minimal the resulting cloudiness could not be perceived in the milky-looking
inhibitory concentration (MIC).9 lipid. Use of such preparations should be reserved for investigational
settings.
Available Formulations
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

There are four commercially available amphotericin B formulations. Amphotericin B Deoxycholate

Amphotericin B deoxycholate (ABD, Fungizone) was licensed in 1959
in the United States.10 Subsequently, three lipid-associated formula-
tions have been marketed: amphotericin B colloidal dispersion (ABCD,
Amphotec or Amphocil), amphotericin B lipid complex (ABLC,
Abelcet), and liposomal amphotericin B (LAMB, AmBisome).11 In
attempts to produce lower-cost lipid-associated formulations, some
reports have advocated mixing ABD with a parenteral fat emulsion at
an ABD concentration of 1 to 2 mg/mL. Although less nephrotoxicity
in adults has been suggested with this preparation, at a dose of 1 mg/
kg daily, than with infusions of ABD in 5% dextrose,12 no advantage
was found in children,13 and serum amphotericin B concentrations
were also lower with the fat emulsion, thus raising the possibility that
amphotericin B was simply aggregating in the fat emulsion, but that
Formulation.  ABD is insoluble in water at physiologic pH. The drug
is marketed for intravenous (IV) use as a powder containing ampho-
tericin B, 50 mg; sodium deoxycholate, 41 mg; and sodium phosphate
buffer, 25.2 mg. Although a clear yellow solution forms when the
powder is hydrated, the colloidal nature of ABD is easy to demonstrate.
If a filter with a 0.22-µpore diameter is placed in the infusion line,
considerable drug is removed by the filter. ABD must be prepared by
dissolving in water or dextrose in water: dissolution in electrolyte-
containing diluents (e.g., sodium chloride or sodium bicarbonate)
will aggregate the colloids, produce visible clouding, and must be
avoided. ABD is currently manufactured by a number of different
generic manufacturers, and significant differences in amphotericin A
contamination and the ability of the product to induce interleukin-1β

OH O OH OH OH OH O
HOOC NH2
O
OH N F
HO

O O N
O OH
H
5-Fluorocytosine (5-FC)
HO OH Amphotericin B
NH2

Cl
OH O
N N
Cl
N CH2 C CH2 N
N N O CH2O N N COCH3
F CH2

Fluconazole N Ketoconazole
F N

N
N
N Cl
Itraconazole
CH2 CH3
Cl
O
O O N CH CH2 CH3
CH2 O N N N
N

H2N
NH OH
O
HO O H
N
N
N H
H 2N
N N O H 3C
N CH F
3 O HN OH CH3 CH3
OH
HO NH O
F N N O H N CH3
N
OH • 2 CH3COOH
HO
OH O
F Voriconazole

Caspofungin
HO
FIGURE 39-1  Structures of the most commonly used systemic antifungal agents.
 481

H H OH O
HO OC5H11

Chapter 39  Drugs Active against Fungi, Pneumocystis, and Microsporidia

H O NH
NH
HO O
H3C H
HN CH3
H N O H
HO O H OH
H NH N
H3C H H OH
HO N
O
H H
O H
OH
H H Anidulafungin
OH

O
CH3
F F O N N N N
N OH
H 3C
O
N N
Posaconazole
N

OH
HO H O
O H OH H SO3Na
H
H 2N NH OH
H H
H O
N O O OH
H3C H
O O N H
H
HO H NH H
CH3
HN
HO H OH
O
H OH H
NH
O
H3C O N O
Micafungin

O
H2N NH
C *O (CH2)5 *O C O
HN [R] [R] NH2 OMe O
O
OH
Pentamidine O Fumagillin

FIGURE 39-1, cont’d

production have been reported and may be part of the cause of the
intersubject variation in toxicities observed with this compound.14
Pharmacology.  Concentrations of amphotericin B in biologic
fluids have usually been measured by bioassay,15 but use of high-
pressure liquid chromatography (HPLC),16,17 immunoassay,18 and
radiometric respirometry19 have been described. Despite the prolifera-
tion of methods, routine determination of amphotericin B serum,
urine, or cerebrospinal fluid (CSF) concentrations has no definite clini-
cal value. Nonetheless, amphotericin B assays have revealed some
remarkable pharmacologic properties of ABD. When colloidal ampho-
tericin B is admixed in serum, deoxycholate separates from amphoteri-
cin B, and more than 95% of the latter binds to serum proteins,
principally to β-lipoprotein. Presumably the drug is bound to the cho-
lesterol carried on this protein. Most of the drug leaves the circulation
promptly, perhaps bound to cholesterol-containing cytoplasmic mem-
branes. Amphotericin B is stored in the liver and other organs; the drug
appears to reenter the circulation slowly. Most of the drug is degraded
in situ, with only a small percentage being excreted in urine or bile.
Blood levels are uninfluenced by hepatic or renal failure. Hemodialysis
does not alter blood levels, except in an occasional patient with lipemic
plasma, who may be losing drug by adherence to the dialysis mem-
brane. Concentrations of amphotericin B in fluid from inflamed areas,
such as pleura, peritoneum, joint, vitreous humor, and aqueous humor,
are roughly two thirds of the trough serum level. Cord blood from one
infant contained an amphotericin B concentration of 0.37 µg/mL, half
the simultaneous maternal trough blood level. Amphotericin B pene-
trates poorly into CSF (whether meninges are normal or inflamed),
saliva, bronchial secretions, brain, pancreas, muscle, bone, vitreous
humor, or normal amniotic fluid. Urine concentrations are similar to
serum concentrations. Peak serum concentrations with conventional
IV doses are 0.5 to 2.0 µg/mL and rapidly fall initially to slowly
approach a plateau of 0.2 to 0.5 µg/mL.15 The initial half-life is about
24 hours; the β-phase half-life is roughly 15 days. Serum concentra-
tions can be detected for at least 7 weeks after the end of therapy,
 482
presumably reflecting release from cell membranes. The drug also has
Nuclear
DNA and complex immunomodulatory properties, potentially of clinical signifi-
membrane
RNA inside cance but presently undefined.
5-FC Nephrotoxicity.  ABD causes a dose-dependent decrease in the
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

nucleus
glomerular filtration rate. The direct vasoconstrictive effect of ampho-
5-FU tericin B on afferent renal arterioles results in reduced glomerular
and renal tubular blood flow.20 Other primary or secondary effects
5-FdUMP on the kidney include potassium, magnesium, and bicarbonate wasting
and and decreased erythropoietin production. Permanent loss of renal
5-FUTP
function is roughly related to the total dose, not the level of temporary
azotemia, and is due to destruction of renal tubular cells, disruption
5-FC: disrupts RNA
(via 5-FUTP) and of tubular basement membrane, and loss of functioning nephron units.
DNA (via 5-FdUMP) Saline loading, such as infusion of 1  L of saline before ABD, has been
Cytoplasm
synthesis associated with reduced nephrotoxicity in some studies but not
others.21 Benefits from oral salt loading have also been reported.22
Potassium wasting often requires supplemental oral or IV potassium.
Renal tubular acidosis from bicarbonate wasting rarely requires base
replacement, but other drugs and diseases that promote acidosis may
Azoles: block biosynthesis act synergistically.
Cytoplasm of ergosterol, a sterol Azotemia caused by amphotericin B is often worse in patients
needed for cell membrane taking other nephrotoxic drugs, such as cyclosporine or aminoglyco-
stability sides. Hypotension, intravascular volume depletion, renal transplanta-
Echinocandins: disrupt Lipid bilayer tion, and other preexisting renal disease all magnify the management
function of the 1,3-β-D- fungal cell problems associated with amphotericin B–induced azotemia. These
glucan synthase complex membrane toxicities are lessened by use of the lipid-associated formulations
of amphotericin B (LFAB; see “Lipid-Associated Formulations of
Amphotericin B”).
E A A E Early in a course of therapy with ABD, azotemia may increase
glucan
synthase rapidly, often falls a little, and then stabilizes after several days. Adults
with no other renal disease may develop an average serum creatinine
E A A E level of 2 to 3 mg/dL at therapeutic doses, and therapy should not be
withheld unless azotemia exceeds this level. Attempting to give ABD
to an adult without causing azotemia will usually lead to inadequate
therapy.
Amphotericin B: forms Other Chronic Toxicity.  Nausea, anorexia, and vomiting are
aggregates in cell common. Phlebitis occurs if peripheral vein catheters are used. Nor-
membrane with mocytic normochromic anemia occurs gradually and is associated
ergosterol, leading to
Fungal cell wall: with lower plasma erythropoietin levels than anticipated from the level
pores that cause
interwoven polymers leakage of cellular of anemia. The hematocrit rarely falls below 20% to 25% unless other
of glucans, chitins, and contents causes of anemia are present. Rarely, thrombocytopenia, modest leu-
various proteins kopenia, arrhythmias, coagulopathy, hemorrhagic enteritis, tinnitus,
Outside
vertigo, encephalopathy, seizures, hemolysis, or dysesthesia of the soles
FIGURE 39-2  Mechanisms of action of the antifungal agents. of the feet may be observed.
Shown are the major mechanisms and sites of action for the most com- Acute Reactions.  About 30 to 45 minutes after beginning the first
monly used and currently licensed antifungal agents. Many of the precise few ABD infusions, chills, fever, and tachypnea may occur, peak in 15
details of the physical interactions are not known, and the diagram is at to 30 minutes, and slowly abate over a period of 2 to 4 hours. A patient
best an approximation. (1) The interaction between amphotericin B (A) with underlying cardiac or pulmonary disease may have hypoxemia.
and ergosterol (E) in the fungal cell membrane is consistent with the
formation of pores with a diameter of approximately 0.8 nm.278 The struc-
These reactions are less common in young children or patients receiv-
ture of the pore is not known, but the available data suggest that ampho- ing adrenal corticosteroids. Subsequent infusions of the same dose
tericin molecules would line the inner surface of the pore.279,280 These pores cause progressively milder reactions. Premedication with acetamino-
permit leakage of intracellular contents. (2) The interaction between the phen or the addition of hydrocortisone, 25 to 50 mg, to the infusion
echinocandins and glucan synthase leads to reduced synthesis of 1,3-β-D- solution can diminish the reactions. Meperidine given early in a chill
glucan, a critical component of the interwoven glucan polymers that form shortens the rigors but may induce nausea or emesis. Concern about
the fungal cell wall.189 The site of action of the echinocandin and the this kind of reaction in an unstable patient had led some physicians to
precise molecular mechanism by which enzyme function is inhibited use a test dose of 1 mg given over a 15-minute period to assess the
remain unsettled at present. (3) The azole antifungal agents act within the subsequent reaction over 1 hour before deciding whether the next dose
cell to inhibit 14α-demethylase and thus to reduce synthesis of ergos-
terol,281 a sterol that is critical to cell membrane function. (4) Flucytosine
should be a full therapeutic dose of at least 0.5 mg/kg or an intermedi-
is (a) converted into 5-fluorouridine triphosphate (5-FUTP), incorporated ate dose. Whether or not a test dose is given, patients with rapidly
into fungal RNA, and thus becomes an inhibitor of fungal protein synthesis progressive mycoses should receive a full therapeutic dose within 24
or (b) converted into 5-fluorodeoxyuridine monophosphate (5-FdUMP),  hours, without any delay entailed by test or intermediate doses. Equally
an inhibitor of thymidylate synthetase and thus of DNA synthesis.282 important, this reaction should not be mistaken for anaphylaxis or
These compounds presumably are created in the cytoplasm with sub­ otherwise considered a contraindication to further ABD. True allergic
sequent diffusion into the nucleus. Not shown are trimethoprim- reactions are extremely rare.
sulfamethoxazole (interferes with folate metabolism), pentamidine (an Administration.  ABD is infused in 5% dextrose over a 2- to
ill-understood mechanism that involves interactions with DNA, RNA, topoi- 4-hour infusion interval. Infusion 1 hour in duration appears to gener-
somerase, and ubiquitin248), and fumagillin (acts by binding to methionine
aminopeptidase 2.260) 5-FC, 5-fluorocytosine; 5-FU, 5-fluorouracil.
ally be safe for persons who have tolerated slower infusions and may
be advantageous for outpatient therapy.23,24 Early in the course of
therapy, fever is more pronounced with infusion intervals of only 45
minutes than with infusion lasting 4 hours.25 Rapid infusion in patients
with severely compromised renal function may lead to acute, marked
hyperkalemia and ventricular fibrillation.

Once therapy is well under way, patients receiving a stable daily
dose may be changed to a double dose on alternate days to reduce the
frequency of infusion-associated toxicity, particularly anorexia, and as
a convenience for outpatient therapy. Doses greater than 1.5 mg/kg are
not generally given on this schedule because the toxicity of such infu-
sions is not well described. Amphotericin B should not be switched to
alternate-day administration at the same dose as daily therapy. This
dosage results in reduced trough serum concentrations and may lead
to serious underdosing. As another approach to reduction of toxicity,
continuous infusion of amphotericin B with doses up to 2.0 mg/kg
per 24 hours has been described based on limited data,26 but this
approach is not consistent with the observation that the principal phar-
macodynamic driver of efficacy for amphotericin B is peak drug
concentration.27,28
Dosage.  Daily ABD doses of 0.3 mg/kg often suffice for esophageal
candidiasis. A dose of 0.5 mg/kg is appropriate for blastomycosis, dis-
seminated histoplasmosis, and extracutaneous sporotrichosis. Patients
with cryptococcal meningitis are generally given doses of 0.6 to 0.8 mg/
kg; those with coccidioidomycosis may require doses of 1 mg/kg.
Patients with mucormycosis or invasive aspergillosis are given daily
doses of 1 to 1.5 mg/kg until improvement is clearly present. Doses of
0.5 to 1.0 mg/kg are often used in neutropenic patients receiving
empirical amphotericin B (see Chapter 310).29 Local instillation of
amphotericin B into cerebrospinal fluid, joints, or pleura is rarely indi-
cated. One exception is coccidioidal meningitis, which can be treated
with intrathecal amphotericin B, because it may produce superior
results, particularly in the long term, although with far greater toxicity
than seen with systemic azole therapy. Intraocular administration for
fungal endophthalmitis is occasionally used; doses of 5 to 10 µg appear
to avoid retinal toxicity. Corneal baths with 1 mg/mL in sterile water
are useful for fungal keratitis but are irritating. Bladder irrigation with
50 µg/mL in sterile water is useful for patients with Candida cystitis
and a Foley catheter, particularly as preparation for genitourinary
surgery. Equivalent results may be obtained with oral fluconazole.
Lipid-Associated Formulations of
Amphotericin B (LFABs)
General.  The three LFABs are licensed in the United States for a variety
of indications and at a range of doses. When using these agents, it is
critical to be aware of the ease with which their names can be confused.
Only one of the products (LAMB, trade name AmBisome) is a liposo-
mal formulation. The other two (ABLC, trade name Abelcet) and
ABCD (two trade names: Amphotec and Amphocil) are aggregates of
lipid and amphotericin B rather than liposomes. The problem is that the
phrase “liposomal amphotericin B” is often used mistakenly as a label
for the entire class of compounds. Thus, this chapter uses the phrase
lipid-associated formulation of amphotericin B (LFAB) as a general
label for the class. Because the tolerance to one product does not always
translate to tolerance for another, it is important that the physician use
an unambiguous name when prescribing these compounds.
ABLC is licensed in the United States for treatment of invasive
fungal infections in patients who are refractory to or intolerant of
conventional amphotericin B therapy (5 mg/kg/day).30 LAMB is
licensed for empirical therapy for presumed fungal infection in febrile,
neutropenic patients (3 mg/kg/day); treatment of cryptococcal menin-
gitis in human immunodeficiency virus (HIV)-infected patients (6 mg/
kg/day); treatment of patients with Aspergillus spp., Candida spp., and/
or Cryptococcus spp. infections refractory to amphotericin B deoxycho-
late; or in patients where renal impairment or unacceptable toxicity
precludes the use of amphotericin B deoxycholate. LAMB is also indi-
cated for treatment of visceral leishmaniasis (3 mg/kg/day for immu-
nocompetent patients, 4 mg/kg/day for immunocompromised patients;
see Chapter 277 for further details).31 ABCD is licensed for treatment
of invasive aspergillosis in patients where renal impairment or unac-
ceptable toxicity precludes the use of amphotericin B deoxycholate in
effective doses or where prior amphotericin B deoxycholate therapy
has failed (3 to 4 mg/kg/day).32 All formulations must be infused in 5%
dextrose with no electrolytes added. Infusion bottles need not be pro-
tected from light.
Pharmacology and Toxicity.  The three LFABs have quite different
pharmacokinetic patterns.10,11 When compared on the basis of equal
483
mg/kg dosages, the LFABs produce tissue amphotericin B concentra-
tions that range from 10% to 500% of those seen with ABD,10 with a
consistent relative reduction seen in the kidney concentration (80% to
90% reduction). Because the LFABs are typically given at mg/kg doses
Chapter 39  Drugs Active against Fungi, Pneumocystis, and Microsporidia
that are 3- to 12-fold higher than those used for ABD, the relevance of
these comparisons is uncertain, although it is generally clear that all
three LFABs require higher doses in experimental animals to achieve
the same therapeutic effect as ABD.
These higher but equipotent doses of the LFABs are notably better
tolerated than ABD, with reductions in both the frequency and severity
of acute infusion-related reactions and chronic nephrotoxicity.33 An
exception to this rule is ABCD, which generally shows acute infusion-
related reactions similar or worse than those with ABD.
Amphotericin B Colloidal Dispersion.  ABCD, which contains
cholesterol sulfate in equimolar amounts to amphotericin B, forms
disc-like colloidal particles about 122 ± 48 nm in diameter. Like ABD,
it forms a clear yellow solution when hydrated. A randomized prospec-
tive, double-blind comparison of ABD, 0.8 mg/kg/day, and ABCD,
4 mg/kg/day, was done in neutropenic patients whose fever had not
abated after 72 hours of antibacterial therapy.34 Efficacy was the same
in the 98 patients receiving ABCD as in the 95 receiving ABD, with
53% and 58%, respectively, becoming afebrile after 48 hours, and 14%
compared with 15% having a suspected or documented mycosis
emerge during amphotericin B therapy. Acute febrile reactions were
significantly more common with ABCD than ABD, with hypoxia
developing in 15% and 3%, respectively. The percentage of patients
having amphotericin B therapy discontinued because of some toxicity
was the same in the two arms (14% and 15%), with the ABD discon-
tinuations much more often being due to azotemia. In a randomized,
double-blind study of ABCD, 6 mg/kg/day, versus ABD, 1 to 1.5 mg/
kg/day, as therapy for invasive aspergillosis,35 response rates for the two
therapies were similar (52% vs. 51%, respectively), with reduced rates
of nephrotoxicity noted with ABCD (25% vs. 49%). However, infusion-
related chills and fever were more common with ABCD than with
ABD. The recommended dose for adults and children is 3 to 4 mg/kg
once daily infused as 0.6 mg/mL at a rate of 1 mg/kg/hr. The infusion
duration can be reduced to 2 hours for patients who tolerate the drug
well. Premedication with acetaminophen has not been studied pro-
spectively but should be considered.
Amphotericin B Lipid Complex.  ABLC is a complex of almost
equimolar concentrations of amphotericin B and lipid, the latter being
a 7 : 3 mixture of dimyristoylphosphatidylcholine and dimyristoylphos-
phatidylglycerol. The drug is shipped as a cloudy suspension with
particles 1.6 to 11 µm in diameter. Particle shape is not globular but
ribbon-like. The manufacturer provides a device for the pharmacy to
filter out aggregates larger than 5 µm before dispensing in 5% dextrose
solution. The major efficacy data are from the manufacturer’s open-
label, noncomparative studies: one of 556 adult and pediatric patients36
and another of 111 pediatric patients.37 All patients in these studies had
either failed prior ABD therapy or were intolerant of ABD therapy. Of
the enrolled patients, only 345 were considered to have a documented
mycosis and had sufficient data to evaluate the drug’s therapeutic effect.
If all the mycoses are considered together, a complete response to
ABLC was judged to have occurred in 28% and a partial response in
32%, for an overall response rate of 60%.
Liposomal Amphotericin B.  LAMB comprises a unilamellar lipo-
some about 55 to 75 nm in diameter that contains roughly one mole-
cule of amphotericin B per nine molecules of lipid. The latter is a
mixture of hydrogenated soy lecithin–cholesterol-distearoylphosphati-
dylglycerol in a 10 : 5 : 4 ratio. Unlike the other lipid-associated ampho-
tericins, serum concentrations are not lower than those obtained with
the same dose of ABD, the circulating drug is liposome-associated after
IV infusion, and the amount of unbound amphotericin is less than with
ABD. A randomized three-way trial comparing LAMB at 3 mg/kg/day,
LAMB at 6 mg/kg/day, and ABD at 0.7 mg/kg/day enrolled 267 HIV-
infected subjects with cryptococcal meningitis, and the trial reported
global response rates of 66%, 75%, and 66%, respectively.38 A random-
ized comparison of LAMB at 3 mg/kg/day versus ABD at 0.7 mg/kg/
day for histoplasmosis in HIV-infected subjects reported superior
efficacy for LAMB (89% vs. 59% response, P = .01).39 Open-label
efficacy data in patients with invasive mycoses (mostly candidiasis and
 484
aspergillosis) not responding to or intolerant of ABD have also been
reported.40-43 Of the patients in these studies with defined mycoses and
evaluable outcomes, 118 of 161 (73%) were judged to have a complete
or partial response to therapy. The European Organization for Research
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
and Treatment of Cancer conducted a prospective randomized com-
parison of 1 and 4 mg/kg LAMB in 120 patients with proven and
probable aspergillosis.44 Of the 87 evaluable patients, responses were
the same in the 41 receiving 1 mg/kg as in the 46 receiving 4 mg/kg,
although the group receiving the higher dosage did contain the greater
proportion of subjects with proven (rather than probable) aspergillosis.
In a subsequent study, the response rate for invasive aspergillosis after
2 weeks of therapy was the same at 3 mg/kg/day (50% of 107 patients)
as at 10 mg/kg/day (46% of 94 patients) but with greater nephrotoxicity
and hypokalemia at the higher dosage.45
Three prospective randomized studies, in both adults and children,
have compared LAMB with ABD in neutropenic patients with fever
not responsive to 96 hours of antibacterial antibiotics. The U.S. study
compared 343 patients receiving 1.5 to 6.0 mg/kg LAMB daily and 344
patients receiving 0.3 to 1.2 mg/kg ABD daily.46 Even though some
patients received relatively low doses of ABD, the two regimens had
identical efficacy. A subset analysis of possible and proven mycoses
emerging during therapy suggested an advantage for LAMB. A report
of two combined studies in Europe that compared ABD, 1 mg/kg, with
LAMB, 3 mg/kg, also found equal efficacy in neutropenic patients
failing 96 hours of antibacterial therapy.47 No difference was noted in
mycoses emerging during empirical therapy.
The above studies generally suggest that LAMB causes less nephro-
toxicity and less severe hypokalemia than ABD, a result supported by
a direct comparison of these two formulations.48 Infusion at 1 to 2 mg/
mL over a 2-hour period is recommended. Infusion intervals can be
shortened to 60 minutes for patients in whom the treatment is well
tolerated. A triad of infusion-related reactions (symptoms from the
categories of [1] chest pain, dyspnea, and hypoxia; [2] severe pain in
the abdomen, back, flank, or leg; and [3] flushing and urticaria) have
been reported to occur, most often within the first 5 minutes of infu-
sion and apparently unrelated to infusion speed.49 These reactions are
effectively managed by administration of diphenhydramine and brief
interruption of the LAMB infusion. LAMB is the only lipid-associated
amphotericin B formulation that does not contraindicate the use of an
in-line filter, although pore size should be at least 1.0 µm.
Comparison of Amphotericin B Deoxycholate
and the Lipid-Associated Formulations of
Amphotericin B
Randomized clinical trials comparing ABD as therapy for a defined
mycosis are limited to the demonstrations for LAMB of similar efficacy
for cryptococcal meningitis38 and greater efficacy for histoplasmosis.39
Randomized comparisons with ABD as therapy in the persistently
neutropenic and febrile cancer patient provide consistent demonstra-
tions of a generally better tolerability profile, but there are few data on
differential antifungal effect other than a subset analysis showing a
reduced rate of breakthrough infections in one study.46 Consistent with
these results, the aggregate open-label data efficacy rates for the LFABs
are similar to those for ABD.10 Although the LFABs are notably more
costly (10- to 60-fold) than ABD, the purchase cost of the compound
must be balanced against the morbidity and financial costs of monitor-
ing, treating, and managing ABD-related nephrotoxicity. Of impor-
tance, such toxicity may be well tolerated in an outpatient with few
other comorbidities or in children, whereas ABD-related nephrotoxic-
ity (50% increase in baseline creatinine to a minimum of 2 mg/dL) was
associated with a 6.6-fold increased odds of death and an absolute
increase in mortality from 16% to 54%.50 In the majority of patients,
liposomal amphotericin B or ABLC is preferred over ABD.
The lipid-associated amphotericins also remain valuable agents
when compared with the azoles and echinocandins. Although associ-
ated with more adverse events than agents from these two other classes,
ABLC and liposomal amphotericin B remain appropriate for acute
management of severe disseminated histoplasmosis, initial manage-
ment of cryptococcosis, and treatment of suspected mucormycosis.
They also provide important options for management of the persis-
tently febrile neutropenic patient (particularly when this syndrome
develops despite prophylaxis with an azole that has activity against
molds) and for treatment of selected cases of candidiasis.51 Use of
ABCD has been restricted by the high incidence of acute reactions and
the relative paucity of efficacy data.
Inhaled Amphotericin B
Inhalation of amphotericin B has been used both therapeutically and
prophylactically, but the supporting data for this practice are relatively
sparse.52 Nebulized forms of the lipid-associated amphotericins have
been better tolerated than amphotericin B deoxycholate, in part
because of the bitter taste of the bile salt. Formal studies on prophylaxis
in high-risk populations have shown encouraging results.53 An argu-
ment has been made that the aerosol might decrease Aspergillus infec-
tions in lung transplant recipients, including infections at the
bronchotracheal anastomotic site.54,55
FLUCYTOSINE
Formulation and Pharmacology.  Flucytosine (5-fluorocytosine,
Ancobon) is the fluorine analogue of a normal body constituent, cyto-
sine (see Fig. 39-1). Flucytosine is moderately soluble in water, very
stable in dry storage, and marketed as 250- and 500-mg capsules.
Absorption from the gastrointestinal tract is rapid and complete, and
approximately 90% is excreted unchanged in the urine. Protein binding
is barely measurable.56 CSF concentrations approximate 74% of simul-
taneous serum concentrations. Limited data suggest that it also pene-
trates well into aqueous humor, joints, bronchial secretions, peritoneal
fluid, brain, bile, and bone. The drug is readily cleared by hemodialy-
sis56 and peritoneal dialysis.
The half-life of the drug in the serum of patients with normal renal
function is 3 to 5 hours and higher in newborns. Abnormal hepatic
function has no influence, but decreased renal function prolongs the
half-life.
Mechanisms of Action and Resistance.  Isolates of Candida spp.
other than C. krusei are usually susceptible to flucytosine,57 as are
most isolates of Cryptococcus neoformans.58 It is often active against
isolates of Aspergillus spp. and against the melanin-pigmented molds
that cause chromoblastomycosis. The mechanism of flucytosine’s
antifungal action appears to be by deamination to 5-fluorouracil and
then conversion through several steps to 5-fluorodeoxyuridylic acid
monophosphate, a noncompetitive inhibitor of thymidylate synthetase
that interferes with DNA synthesis, or through its conversion to
5-fluorouridine triphosphate, which causes aberrant transcription (see
Fig. 39-2).5 In studies of therapy of candidiasis, the principal pharma-
codynamic driver of response was the proportion of the time the blood
level exceeded the MIC.9 Resistance may be due to loss of the cytosine
permease that permits flucytosine to cross the fungal cell membrane
or loss of any of the enzymes that lead to its conversion into the forms
that interfere with DNA or RNA synthesis. Induction of resistance
during monotherapy is sufficiently frequent and rapid that flucytosine
is essentially always used as part of combination therapy.
Administration and Dosage.  Flucytosine is usually administered
by mouth at 100 mg/kg/day in four divided doses. Patients with a
serum creatinine level of 1.7 mg/dL or greater usually require dose
reduction. As an approximation, the total daily dose should be reduced
to 75 mg/kg, with a creatinine clearance of 26 to 50 mL/min and to
37 mg/kg when the creatinine clearance is 13 to 25 mL/min.59 Ideally,
the blood level should be measured in azotemic patients 2 hours after
the last dose and immediately before the next dose. The target blood
level range has long been thought to be between 20 and 100 µg/mL,
although recent pharmacodynamic work suggests that levels of 10 to
50 µg/mL would be adequate.60,61 Patients requiring hemodialysis may
be given a single postdialysis dose of 37.5 mg/kg. Further doses are
adjusted by blood level. Reliable biologic,62 enzymatic,63 and physical64
methods are available to assay flucytosine, even in the presence of
amphotericin B.
Flucytosine given alone to patients with normal renal, hematologic,
and gastrointestinal function is associated with very infrequent adverse
effects, including rash, diarrhea, and in about 5%, hepatic dysfunction.
In the presence of azotemia—such as that caused by concomitant
amphotericin B—leukopenia, thrombocytopenia, and enterocolitis
may appear and can be fatal. These complications seem to be far more

frequent among patients whose flucytosine blood levels attain, and
especially if they exceed, 100 to 125 µg/mL.59 Patients receiving flucy-
tosine and whose renal function is changing should have their serum
flucytosine concentrations determined as often as twice per week and
the leukocyte count, platelet count, alkaline phosphatase, and amino-
transferase levels measured at a similar frequency. Patients in whom
loose stools or dull abdominal pain suddenly develops or who have
laboratory evidence consistent with flucytosine toxicity should have
their flucytosine blood levels determined and consideration given to
withholding therapy with the drug until the situation is clarified.
Patients with bone marrow and gastrointestinal toxicity from flucyto-
sine often tolerate the drug at reduced dosage. Patients with rash or
hepatotoxicity have not been rechallenged. Uncommonly, vomiting,
bowel perforation, confusion, hallucinations, headache, sedation, and
euphoria have been reported. Flucytosine is teratogenic for rats and is
contraindicated in pregnancy.
Conversion of flucytosine to 5-fluorouracil within the human body
occurs in sufficient degree to be a possible explanation for toxicity to
bone marrow and the gastrointestinal tract.65 It is likely that the drug
is secreted into the gut where flucytosine becomes deaminated by
intestinal bacteria and is reabsorbed as 5-fluorouracil.66
Flucytosine has a beneficial effect in patients with cryptococcosis,67
candidiasis, and chromoblastomycosis. It is not the drug of choice for
any infection because (1) its clinical efficacy in the first two mycoses
is inferior to that of amphotericin B, (2) primary drug resistance is not
uncommon in Candida infection, and (3) secondary drug resistance is
common in cryptococcosis and chromoblastomycosis.
Flucytosine and amphotericin B are at least additive in their effects
in vitro and in mice experimentally infected with susceptible isolates
of Candida and Cryptococcus. Flucytosine permitted a lower dose of
amphotericin B to be used to gain the same therapeutic effect, and
amphotericin B prevented the emergence of secondary drug resistance.
The same advantages have been confirmed in two large multicenter
studies of cryptococcal meningitis conducted during the pre-HIV
era.68 The current recommendation that flucytosine be added during
the first 2 weeks of IV amphotericin B therapy for patients with
acquired immunodeficiency syndrome (AIDS) and cryptococcal men-
ingitis69 was based initially on these data plus a retrospective analysis.70
Subsequently, a four-arm randomized study of 64 patients demon-
strated that the combination of amphotericin B deoxycholate, 0.7 mg/
kg/day, with flucytosine, 100 mg/kg/day, produced more rapid steril-
ization of the CSF than amphotericin B alone or in combination with
fluconazole but did not show an improvement in mortality.71 Observa-
tional data from a 208-patient experience likewise found the lowest
failure rate with this combination.72 Experience with candidiasis
remains limited.73 Finally, results with Aspergillus are contradictory,
with the combination never shown to be better than an optimum dose
of amphotericin B alone.74,75
Flucytosine is more difficult to manage in patients with diminished
bone marrow reserve. Leukopenia and diarrhea are difficult to manage
in patients with AIDS, as are leukopenia and thrombocytopenia in
patients after bone marrow transplantation or patients with leukemia
or other hematologic malignancies. Oral flucytosine may not be reli-
ably administered in patients who are confused or vomiting. IV flucy-
tosine is no longer available in the United States but is used at the same
dose as the capsule formulation. The incidence of diarrhea or leuko-
penia is not lower with IV administration.
Flucytosine resistance has occurred, albeit uncommonly, during
combination therapy. Use of the combination in such patients incurs
the risk of toxicity without evidence that flucytosine adds to the thera-
peutic effect. Whenever flucytosine is used to treat a patient who has
received that drug before, the isolate should be tested for susceptibility.
In most laboratories, an MIC of 20 µg/mL or less is considered
susceptible.
AZOLE ANTIFUNGAL AGENTS
General Features
Mechanism of Action
The imidazole ring (see Fig. 39-1) confers antifungal activity on a
variety of synthetic organic compounds. Unlike the 5-nitroimidazoles,
such as metronidazole, activity against bacteria and protozoa, although
485
measurable, has not been clinically significant. Most of the imidazoles
reaching clinical trials have had similar in vitro activity against a broad
range of superficial and deep pathogens.76 Methods for in vitro suscep-
tibility testing are increasingly available as standardized tools. Stan-
Chapter 39  Drugs Active against Fungi, Pneumocystis, and Microsporidia
dardization has facilitated the establishment of clinically predictive
interpretive breakpoints for susceptibility testing results of Candida
spp.77,78
N-substitution of imidazoles has created a family of drugs, called
triazoles, that have the same mechanism of action as imidazoles, a
similar or broader spectrum of activity, and less effect on human sterol
synthesis. Both imidazoles and triazoles inhibit C-14α demethylation
of lanosterol in fungi by binding to one of the cytochrome P-450
enzymes, which leads to the accumulation of C-14α methylsterols and
reduced concentrations of ergosterol, a sterol essential for a normal
fungal cytoplasmic membrane (see Fig. 39-2). Inhibition of cyto-
chrome P-450 also decreases the synthesis of testosterone and gluco-
corticoids in mammals, an effect seen clinically with ketoconazole but
not with later azoles. In studies of candidiasis, the principal pharma-
codynamic driver for response to the triazole antifungal agents has
been the ratio of total drug exposure (area under the curve [AUC]) to
the MIC.9 By studying cytochrome P-450 inhibition in vitro, new drugs
can be selected that have better antifungal specificity. Some azoles, in
addition to blocking ergosterol synthesis, have an immediate effect of
damaging the fungal cytoplasmic membrane.
Because of their interaction with the P-450 system (including
metabolism of the azoles by same), the azoles as a class have a sig­
nificant number of drug-drug interactions. Fluconazole and posacon-
azole have the fewest significant interactions with itraconazole and
voriconazole having many more. Key interactions are summarized in
Table 39-1.
Newer triazoles have properties that make them preferable to
ketoconazole—not only less hormonal inhibition but also both paren-
teral and oral formulations, a broader spectrum, better distribution
into body fluids, less gastrointestinal distress, and less hepatotoxicity.
For this reason, ketoconazole will not be included in the discussion
below. The reader is referred to this chapter in prior editions of this
text if further details on ketoconazole are needed. The ideal triazole
has not arrived because none has all these properties yet, and resistance
to azoles in previously susceptible species is emerging. Resistance
mechanisms include increased drug efflux and altered or increased
C-14α demethylase.5 Development of fluconazole resistance has been
documented in C. albicans, and increased resistance has been seen in
Candida glabrata. Candida krusei, C. glabrata, Candida norvegensis,
and Candida inconspicua are intrinsically more resistant to azoles.79
Increased isolation of C. glabrata and C. krusei has been observed in
patients receiving long-term azoles. Isolates resistant to fluconazole are
variably cross-resistant to other azoles.5 Because of a common muta-
tion, possibly driven by agricultural azole usage, resistance (and often,
cross-resistance) to the three azoles (itraconazole, voriconazole,
posaconazole) that have reliable mold activity toward Aspergillus spp.
has also emerged in some localities.80
Itraconazole (Sporanox)
Formulations and Pharmacology.  Itraconazole is marketed as a
100-mg capsule, as an oral suspension of 100  mg/10  mL in cyclo-
dextrin (an oligosaccharide ring), and, formerly, as a solution in
cyclodextrin for IV administration.81 The ring entraps the hydropho-
bic, water-insoluble drug. The drug is thus made soluble and is then
released either at the lipid membrane of the enterocyte after oral
administration or directly into tissues after IV administration. The
solution makes possible delivery of the drug through a nasogastric
tube in intubated patients and makes dosing of infants and small
children more convenient. Oral absorption of the capsule is signifi-
cantly enhanced by food, although absorption of the solution is best
on an empty stomach.82 Bioavailability of the capsule is 55% when
ingested after breakfast, and the area under the time-concentration
curve is increased 30% if the capsules are taken with food or if the
solution is used. Bioavailability increases 25% to 30% with the solu-
tion in a fasting state.83-86 Co-administration of a cola beverage with
itraconazole capsules almost doubled the area under the plasma
concentration-time curve.87 Peak levels with either preparation are
 486

TABLE 39-1  Azole Drug-Drug Interactions

DRUG FLUCONAZOLE VORICONAZOLE ITRACONAZOLE* POSACONAZOLE
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

A.  Azole Causes Increased Blood Levels of Other Drug

Alfentanil Yes Yes
Alprazolam Yes Yes
Astemizole Yes† Yes† Yes Yes
Calcium channel blockers Yes Yes (Nisoldipine†) Yes
Carbamazepine Yes Yes
Cisapride Yes† Yes† Yes† Yes†
Coumarin-type anticoagulants Yes Yes Yes
Cyclosporine Yes Yes Yes Yes*
Digoxin No Yes
Disopyramide Yes
Dofetilide Yes†
†
Ergot alkaloids Yes Yes† Yes†
†
HMG-CoA reductase inhibitors (“statins”) Yes Yes Yes, if CYP3A4 substrate†
Levacetylmethadol (levomethadyl) Yes†
Methadone Yes Yes Yes
Midazolam (and other short-acting benzodiazepines) Yes Yes† Yes† Yes*
Nisoldipine Yes†
Omeprazole Yes
Oral hypoglycemics (e.g., tolbutamide, glyburide, glipizide) Yes Yes Yes No for glipizide
Phenytoin Yes Yes Yes Yes
Pimozide Yes† Yes† Yes† Yes†
Quinidine Yes† Yes† Yes† Yes†
Rifabutin Yes Yes† Yes Yes
Saquinavir and other protease inhibitors Yes Yes Yes
Sirolimus Yes Yes† Yes Yes†
Tacrolimus Yes Yes Yes Yes*
Terfenadine Yes Yes† Yes Yes
Theophylline Yes
Triazolam Yes Yes Yes† Yes
Vinca alkaloids Yes Yes
B.  Azole Level is Reduced by Other Drug
DRUG FLUCONAZOLE VORICONAZOLE ITRACONAZOLE POSACONAZOLE
Antacids of any type, including proton pump inhibitors No No Yes Yes for suspension,‡ no for
tablets
Carbamazepine Yes Yes† Yes Yes
Efavirenz Yes§ Yes Yes
Fosamprenivir Yes
Isoniazid Yes
Long-acting barbiturates Yes†
Metoclopramide Yes for suspension, no for
tablets
Nevirapine Yes Yes
Phenobarbital Yes† Yes
Phenytoin Yes Yes Yes
Rifabutin Yes† Yes Yes
Rifampin Yes Yes† Yes Yes
Ritonavir Yes†
St. John’s wort Yes† Yes
*In addition, itraconazole levels are increased by clarithromycin, erythromycin, indinavir, and ritonavir.
†
Absolute contraindication.
‡
When given concomitantly with the suspension formulation, cimetidine and esomoprazole have been shown to reduce plasma posaconazole levels.
§
Concomitant usage requires unusually careful dose adjustments and monitoring.
Note: Azoles are involved in drug-drug interactions either (1) by interfering with metabolism and thus increasing the concentration of other drugs (Table 39-1A) or (2) by
having their level reduced via either induction of hepatic metabolism or reduced absorption (Table 39-1B). The principal interactions are via CYP3A4 (all azoles) plus
CYP2C9 (fluconazole, voriconazole) and CYP2C19 (fluconazole, voriconazole). Because of the differential distribution of the cytochrome P-450 enzymes in the liver and gut,
the magnitude of drug-drug interactions may be influenced by the route of drug administration.283 For example, voriconazole’s effect on tacrolimus is even more
pronounced (higher tacrolimus levels) when voriconazole is given orally rather than intravenously.284,285 Key interactions found in the U.S. prescribing information are
summarized here; more exhaustive reviews153 and discussions of management strategies286 are available in the published literature.
HMG-CoA, hydroxymethylglutaryl coenzyme A.

achieved 4 to 6 hours after a dose. Steady state is achieved only after
13 to 15 days, at which time the β-elimination half-life is about 19
to 22 hours. Absorption of the capsules in patients with AIDS is
about half that in normal volunteers.88 Absorption of the capsule is
markedly depressed in bone marrow transplant recipients, probably
because of hypochlorhydria, mucositis, and graft-versus-host intestinal
changes, but the depressed absorption can be alleviated by using the
solution.82
For deep mycoses, an initial itraconazole dose of 200 mg three
times daily is recommended for the first 3 days to give quickly high
serum and tissue levels. Hydroxyitraconazole, a metabolite of itracon-
azole, appears in blood in amounts roughly twice that of the parent
drug and has antifungal activity and pharmacokinetics similar to those
of the parent compound.89
Therapeutic blood level monitoring is useful to confirm adequate
exposure. Because the existence of the active metabolite causes bioas-
says of itraconazole to give much higher concentrations than does
HPLC (the difference follows from the susceptibility of the bioassay
organism to hydroxyitraconazole), interpretation of the results depends
on the method used. Target levels of the parent (unmetabolized) itra-
conazole molecule of 500 ng/mL, determined by HPLC, generally
appear adequate, especially for prophylactic usage. A target of 1000 ng/
mL for the parent and its bioactive metabolite by bioassay also seem
adequate. Limited data suggest that levels of 1000 ng/mL determined
by HPLC might be preferred for proven infection.60,61
Tissue, pus, and bronchial secretion concentrations of itraconazole
are generally higher than plasma concentrations, but CSF concentra-
tions are usually unmeasurable, even in patients with meningitis.
Ocular levels are low. Saliva concentrations persist for 8 hours after the
solution and provide a possible benefit in treating oral disease or eradi-
cating oral colonization. The drug is metabolized in the liver and
excreted in feces as metabolites. Fifty percent to 64% of the cyclodex-
trin liquid administered is secreted intact in feces, with most of the
remainder broken down by gut bacteria amylases; less than 0.5% is
absorbed. No significant amount of bioactive itraconazole appears in
urine. Plasma concentrations do not increase in patients with renal
insufficiency or decrease with hemodialysis. The half-life is prolonged
in those with cirrhosis. About 99% of serum itraconazole is bound to
plasma proteins.
Adverse Effects.  The most common adverse effect is dose-related
nausea and abdominal discomfort, but symptoms rarely necessitate
stopping therapy.90 Dividing the dose into twice-daily administration
improves tolerance and absorption. Hypokalemia and edema may
occur at 400 mg/day or higher doses. Allergic rash is seen occasionally.
Therapy is contraindicated during pregnancy and in nursing mothers.
Itraconazole is infrequently hepatotoxic and does not suppress adrenal
or testicular function at the dosages recommended. Flavoring in the
solution somewhat ameliorates the unpleasant taste of cyclodextrin.
Diarrhea, nausea, and other gastrointestinal complaints are more
frequent with the solution. This increased toxicity is probably due to
the osmotic effect or bile salt complexing with unmetabolized
cyclodextrin.
Interactions.  As noted in the introductory discussion of the azoles,
itraconazole has many clinically relevant drug interactions. Key inter-
actions are summarized in Table 39-1. Most notably, itraconazole is
contraindicated in combination with a range of CYP3A4-metabolized
drugs: cisapride, oral midazolam, nisoldipine, pimozide, quinidine,
dofetilide, triazolam, levacetylmethadol (levomethadol), lovastatin,
simvastatin, and the ergot alkaloids.
Uses.  Itraconazole is useful for treatment of invasive aspergillosis,91
allergic bronchopulmonary aspergillosis,92 blastomycosis,93 histoplas-
mosis,93 meningeal94 and nonmeningeal95 coccidioidomycosis, para-
coccidioidomycosis, sporotrichosis,96,97 phaeohyphomycosis, ringworm
(including onychomycosis),98 and tinea versicolor. Itraconazole is also
useful for the prevention of relapse in AIDS patients with disseminated
histoplasmosis.99 Itraconazole suspension may be useful for prophy-
laxis against fungal infections during neutropenia,100-102 and possibly
reduced the rate of invasive aspergillosis in one study.100 A comparison
of itraconazole with amphotericin B as therapy for persistent fever in
384 neutropenic patients, 56% of whom had acute myelogenous leu-
kemia and 38% of whom had received marrow transplantation, found
487
that IV itraconazole (which is no longer manufactured), followed by
oral itraconazole, was similarly effective and less toxic.103 The solution
shows promise for the treatment of oral and esophageal candidiasis
when used at 100 to 200 mg daily.104,105 Leishmania major infections
Chapter 39  Drugs Active against Fungi, Pneumocystis, and Microsporidia
respond poorly.106
Fluconazole (Diflucan)
Formulations and Pharmacology.  Fluconazole is currently available
in 50-, 100-, 150-, and 200-mg tablets, a powder for oral suspension,
and an IV formulation of either 200 or 400  mg, both as 2  mg/mL.107
Fluconazole is well absorbed from the gastrointestinal tract.108 After
ingestion of fluconazole, more than 80% of the drug can be found
in the circulation. Of the oral dose, 60% to 75% appears unchanged
in the urine, and 8% to 10% appears unchanged in the feces. Oral
absorption is not decreased in patients with AIDS or patients taking
H2 blocking agents.109 Only 11% of serum fluconazole is protein
bound.
Concentrations of fluconazole in CSF are approximately 70% of
simultaneous blood levels, whether or not the meninges are inflamed
and the drug penetrates into the brain. Penetration into saliva, sputum,
urine, and other body fluids has also been excellent.106 Local instillation
into the CSF, bladder, or another site is unnecessary because of excel-
lent penetration of the drug into body compartments.
The half-life in patients with normal renal function is 27 to 34 hours
and increases to 59 and 98 hours in groups with creatinine clearances
of 35 and 14 mL/min, respectively. According to the manufacturer, the
normal dose should be reduced to 50% when the creatinine clearance
is reduced to 50 mL/min and to 25% when creatinine clearance is less
than 20 mL/min. A loading dose of twice the daily dose is recom-
mended. Patients receiving hemodialysis should have one daily dose
after each session. A dose of 6 mg/kg every 3 days has been advocated
for premature infants in the first week of life, with dosing every 2 days
during the second week of life.110
Drug Interactions.  As noted in the introductory discussion of the
azoles, fluconazole has a moderate number of clinically relevant drug
interactions. Key interactions are summarized in Table 39-1. Most
notably, fluconazole is contraindicated in combination with CYP3A4-
metabolized drugs with the potential to prolong the QT interval (e.g.,
cisapride, astemizole, pimozide, and quinidine).
Side Effects.  Adverse effects are uncommon.111 Even with chronic
therapy, including doses exceeding 400 mg/day, headache, hair loss,
and anorexia were the most common symptoms, each occurring in 3%
of patients, whereas 10% had rises in aspartate aminotransferase levels.
Alopecia is reversible, even in some instances when the drug is con-
tinued at lower doses.112 Neurotoxicity has been described after heroic
doses of 2000 mg daily. Rarely, anaphylaxis after the first dose or
Stevens-Johnson syndrome has been observed. Fluconazole is U.S.
Food and Drug Administration (FDA) pregnancy category D, meaning
that it should be avoided during pregnancy except for single 150-mg
doses used for vulvovaginal candidiasis. This decision was based on
evidence of teratogenicity in animals and three children with similar
birth defects. However, a review of 7352 fluconazole-exposed Danish
pregnancies did not confirm the same pattern of birth defects but
found an increased prevalence of tetralogy of Fallot.113
Indications
Candidiasis.  Fluconazole, 50 to 100 mg once daily, is one of the most
effective agents for the treatment of oropharyngeal candidiasis. Daily
doses of 100 mg are effective for esophageal candidiasis.114 A single
dose of 150 mg is approximately as effective as topical treatment of
vulvovaginal candidiasis. Patients with candidemia who are not neu-
tropenic or otherwise seriously immunosuppressed respond as well to
IV fluconazole therapy as to amphotericin B, provided that they do not
have fluconazole-resistant Candida spp.115 A study comparing flucon-
azole with a combination of fluconazole plus amphotericin, as initial
therapy of candidemia, suggested that the combination might produce
more rapid clearance of the bloodstream, but this result was con-
founded by differences in severity of illness between the two study
groups.116 In a small number of patients with Candida endocarditis,
long-term fluconazole therapy has been used to prevent relapse after
amphotericin B therapy. For immunosuppressed patients and rapidly
 488
progressing or severely ill patients with deep candidiasis, amphotericin
B or caspofungin would be preferred.
Cryptococcal Meningitis.  Fluconazole has been used for the
initial treatment of AIDS patients with cryptococcal meningitis who
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
are neurologically intact and judged to have a good prognosis.117 Many
authorities recommend amphotericin B or amphotericin B plus flucy-
tosine for at least the first 2 weeks and until clinically improved.
Therapy can be changed to fluconazole, 400 mg daily for 2 months,
after the patient has remained clinically stable. The propensity of AIDS
patients to relapse has led to lifelong maintenance therapy with fluco-
nazole, 200 mg daily.118 Patients who have completed 1 to 2 years of
antifungal therapy, have achieved an increase in CD4+ count to at least
100/µL, have had an unmeasurable viral load for at least 3 months, and
have a negative or low serum cryptococcal antigen may have their
maintenance therapy discontinued. If the CD4+ count subsequently
falls below 200/µL, maintenance therapy should be resumed.119 Itra-
conazole capsules, 200 mg daily, are inferior to fluconazole, 200 mg
daily, for maintenance therapy.120 Thus far, relapse because of flucon-
azole resistance has been rare. Fluconazole is effective for the eradica-
tion of genitourinary foci. For initial treatment, fluconazole at doses of
800 mg121 or given with flucytosine122 has been advocated, but insuf-
ficient data exist to recommend these regimens (see Chapter 264). For
patients without AIDS, fluconazole is useful for those who have com-
pleted a course of amphotericin B and seem to have a high risk of
relapse. At present, there are few firm data to guide selection of either
dose or duration of fluconazole therapy for non-AIDS patients with
cryptococcosis.
Other Mycoses.  Fluconazole is useful for coccidioidal meningitis
and for disseminated nonmeningeal coccidioidomycosis,112,123 but a
direct comparison with itraconazole found a trend favoring itracon-
azole that was driven by superior efficacy of itraconazole for skeletal
infections.95 The two drugs were similarly efficacious for soft tissue and
pulmonary infection. Cutaneous sporotrichosis,112,124 ringworm, histo-
plasmosis,125 and blastomycosis may respond, but the results are infe-
rior to those with itraconazole. Fluconazole is not indicated for
aspergillosis, mucormycosis, or scedosporiosis.
Prophylaxis in Neutropenic Patients.  In a multicenter trial,
administration of fluconazole, 400 mg daily, decreased the incidence
of death from deep mycoses in bone marrow transplant recipients,
most of whom had received allogeneic transplants, from 10 per 177
placebo recipients to 1 per 179 fluconazole recipients.126 All the protec-
tion afforded seemed to be in deep candidiasis, not aspergillosis. This
result was confirmed in a similar study of bone marrow transplant
recipients.127 Fluconazole resulted in decreased use of empirical
amphotericin B in one study127 but not the other.126 Reduction in deep
mycoses has not been convincingly demonstrated in other groups,
such as patients with acute leukemia.128,129 In a long-term follow-up of
one study of the above studies, bone marrow transplant recipients who
received at least 75 days of fluconazole prophylaxis also had improved
survival.130 Use for prophylaxis may result in shifts to less susceptible
species.131,132
Prophylaxis in Patients with Acquired Immunodeficiency Syn-
drome.  Fluconazole, 200 or 400 mg once per week, has reduced the
incidence of oral and vulvovaginal candidiasis in patients with
advanced HIV infection, but this regimen has not been demonstrated
to prevent histoplasmosis, cryptococcosis, or esophageal candidiasis in
this population.133,134 Prophylaxis with 200 mg daily does reduce the
incidence of oropharyngeal and esophageal candidiasis, as well as cryp-
tococcosis in patients with a CD4 count of less than 200/mm3. Cost,
lack of effect on survival, and the possibility of azole resistance has led
the U.S. Public Health Service–Infectious Diseases Society of America
advisory committee to recommend against fluconazole prophylaxis
in AIDS patients. Fluconazole is an alternative to itraconazole for
maintenance therapy in AIDS patients with prior disseminated
histoplasmosis.135
Prophylaxis in Preterm Neonates.  Fluconazole at 3 to 6 mg/kg
(every third day for first 2 weeks of life, then every day) until day 30
of life (neonates weighing 1000 to 1500 g at birth) or day 45 (neonates
weighing <1000 g at birth) reduced the rate of invasive candidal infec-
tion from 13% (placebo) to 2.7% (6-mg group) and 3.8% (3-mg group)
in a randomized multicenter study of 322 evaluable infants.136 When
taken with prior studies,137 these data suggest that neonatal units might
consider use of fluconazole prophylaxis in additional to standard infec-
tion control procedures for very-low-birth-weight neonates.
Voriconazole (Vfend)
Formulations and Pharmacology.  Voriconazole is marketed as a
50-mg tablet, a 200-mg tablet, a powder for oral suspension at 40 mg/L,
and as a solution in sulfobutyl ether β-cyclodextrin for IV administra-
tion.138 The oral bioavailability of voriconazole is ≈96% and plasma
protein binding is ≈58%.139,140 Detailed tissue distribution data are not
available, but voriconazole’s volume of distribution (4.6 L/kg) greatly
exceeds that of water, thus suggesting extensive distribution into
tissues. Concentrations in the CSF are approximately 50% of plasma
concentrations.141 Voriconazole is cleared by hepatic metabolism with
less than 2% of the dose excreted unchanged in the urine. Hepatic
clearance is via the P-450 system. Voriconazole exhibits significantly
nonlinear pharmacokinetics because of saturation of the clearance
pathways at higher doses. The principal enzyme involved in clearance
is CYP2C19.142,143 This enzyme has significant genetic polymorphisms
that permit any given individual to be a homozygous extensive metab-
olizer, a homozygous poor metabolizer, or a heterozygous intermediate
metabolizer. A heterozygous metabolizer will have, on average, a
twofold higher total voriconazole exposure relative to a homozygous
extensive metabolizer. A homozygous poor metabolizer will have a
fourfold higher drug exposure on average. Fifteen percent to 20% of
Asians, but only 3% to 5% of whites and blacks, are homozygous poor
metabolizers. Despite these differences in metabolism, the achieved
plasma levels overlap across the three possible groups, and dose adjust-
ment based on genotype or racial group is not recommended. Usual
trough concentrations are in the range of 0.5 to 5 mg/L, with consider-
able intraindividual variation.60,144 Therapeutic drug monitoring is of
use in settings where systemic exposures are less well predicted (e.g.,
in combination with inducers of hepatic metabolism or in chil-
dren).145,146 Target exposures of greater than 0.5 mg/L are suggested for
prophylaxis and 1 to 2 mg/L for treatment, although the data are weak
61, 147,148
In a randomized trial comparing active monitoring, with a goal
of maintaining trough levels in the range 1 to 5.5 mg/L, with standard
dosing and clinical observation, active monitoring of plasma levels did
not reduce the overall frequency of adverse events but was associated
with reduced drug discontinuation for adverse events as well as a trend
toward improved response.149
Standard loading dosing regimens, followed by maintenance doses
that are 50% of normal are recommended for individuals with mild-
to-moderate hepatic cirrhosis (Child-Pugh class A and B). However,
no data are available on rates of clearance in individuals with severe
hepatic cirrhosis (Child-Pugh class C). Dosage adjustments are not
required for renal dysfunction, and voriconazole is not significantly
cleared by hemodialysis. Children aged 2 to 12 years have variably
increased metabolism and may require higher doses. In one study, a
dose of 4 mg/kg every 12 hours in the children was found to produce
systemic exposures comparable to those produced by a dose of 3 mg/
kg every 12 hours in adults. Initiation of therapy in children with 6 mg/
kg q12h times two doses has been suggested.150,151 The European pre-
scribing information for voriconazole recommends that children aged
2 to younger than 12 years should be treated twice daily IV with a
loading dose of 9 mg/kg q12h (two doses), followed by 8 mg/kg q12h.
For oral dosing, 9 mg/kg is given twice daily to a maximum of 350 mg/
day.152 Data for children younger than 2 years were inadequate to
permit dose selection.
Drug Interactions.  As noted in the introductory discussion of the
azoles, voriconazole has many clinically relevant drug interactions. Key
interactions are summarized in Table 39-1. Of particular note,
co-administration is contraindicated with terfenadine, astemizole, cis-
apride, pimozide, quinidine, sirolimus, rifampin, carbamazepine, long-
acting barbiturates, high-dose ritonavir (400 mg q12h), rifabutin, ergot
alkaloids, and St. John’s wort.
Side Effects.  Voriconazole is generally well tolerated and has a
side-effect profile that is largely similar to other triazoles,153 with an
increased frequency of adverse events at plasma concentrations greater
than 5 to 6 mg/L in some studies.61,148 The most frequently reported
adverse event is a visual disturbance that appears to be unique to

voriconazole. In the clinical studies reported to date, approximately
30% of patients reported altered or enhanced light perception, begin-
ning approximately 30 minutes after a dose and lasting for approxi-
mately 30 minutes. The visual alteration is described as blurred vision,
color vision change, and/or photophobia. The effect is mild, only rarely
results in discontinuation of therapy, and is uniformly reversible.
Despite extensive studies, the mechanism for this side effect is not
known. Although the effect is usually transient, patients should be
advised to avoid activities that require keen visual acuity while experi-
encing visual changes. Hallucinations and confusion have also been
reported; hallucinations occurred in 12 of 72 patients in one study, were
visual or auditory, and most often occurred in the first 24 hours of IV
therapy at 6 mg/kg.154 Similarly, hallucinations were reported in 16 of
25 patients treated with voriconazole in another series.141 Voriconazole
can cause severe photosensitivity,155 and observational experience sug-
gests that prolonged voriconazole usage may be a risk factor for skin
cancer in immunosuppressed patients.156,157,158 Periostitis with bone
pain, elevated alkaline phosphatase, and periosteal elevation on bone
films has been observed after months of voriconazole.159 Finally, vori-
conazole has been rarely associated with prolongation of the QT inter-
val and torsade de pointes. These events have occurred in individuals
with multiple proarrhythmic factors (e.g., cardiotoxic chemotherapy,
cardiomyopathy, hypokalemia), and caution is thus recommended
when voriconazole is given to such patients. In particular, electrolyte
disturbances, such as hypokalemia, hypomagnesemia, and hypocalce-
mia, should be corrected before initiation of voriconazole therapy.
Indications
Aspergillosis.  Voriconazole was licensed for treatment of invasive
aspergillosis on the basis of a randomized, unblinded comparative trial
in which patients with invasive aspergillosis were randomized to
receive initial therapy with either voriconazole (two IV doses of 6 mg/
kg on day 1, two IV 4-mg/kg doses daily for at least the next 7 days,
and then 200 mg PO twice daily) or ABD (1 to 1.5 mg/kg/day).160 After
initial randomization, patients could be switched to other licensed
therapies as dictated by clinical events. After 12 weeks, 53% of the
patients randomized to voriconazole, but only 32% of those random-
ized to ABD, had a successful outcome. In addition, the survival rate
of the voriconazole group was 71% versus only 58% for those random-
ized to ABD. Subsequently, the combination of voriconazole with
anidulafungin versus voriconazole alone as therapy for proven or prob-
able aspergillosis was studied in patients with hematologic malignan-
cies.161 Although the response was not significantly different between
the two arms, the combination was associated with reduced mortality
at week 6 of therapy (P = .0868). Collectively, these results clearly
demonstrate the efficacy of voriconazole for aspergillosis and its supe-
riority over ABD and are supported as well by data from open-label
studies of therapy of aspergillosis with voriconazole.162
Other Mycoses.  Voriconazole is also licensed for treatment of
invasive fusariosis and scedosporiosis, based on data submitted to the
FDA showing a 43% (9 of 21 patients) and 63% (15 of 24 patients)
response rate for these two diseases, respectively. Although not licensed
for esophageal candidiasis, voriconazole, 200 mg twice daily PO, was
at least as effective as fluconazole, 200 mg once daily, in a randomized
and blinded trial but was more often associated with adverse events.163
Based on data from a trial of voriconazole versus amphotericin B
deoxycholate as therapy for invasive candidiasis in which voriconazole
was not inferior to amphotericin B deoxycholate,164 voriconazole is
indicated for treatment of candidemia in non-neutropenic patients as
well as for other forms of deeply invasive candidiasis. Efficacy in refrac-
tory candidiasis has also been reported.165,166
Fever and Neutropenia.  Voriconazole was compared with liposo-
mal amphotericin B as empirical antifungal therapy for persistent fever
in the neutropenic cancer patient in a large open-label randomized
study.167 The results were mixed, but the most conservative analyses
found voriconazole to be possibly inferior to liposomal amphotericin
B, and the FDA did not approve voriconazole for this indication.168
Posaconazole (Noxafil)
Formulations and Pharmacology.  Posaconazole is marketed as a
40-mg/mL suspension.169 The oral bioavailability of posaconazole is
489
affected by food but not by buffering of gastric acidity: nonfat and
high-fat meals increase absorption 2.6- and 4.0-fold, respectively, and
drug administration with food or a nutritional supplement is
recommended.169-171 Although the half-life is 20 to 30 hours,169 and thus
Chapter 39  Drugs Active against Fungi, Pneumocystis, and Microsporidia
potentially consistent with daily dosing, exposure is further increased
by dividing the daily dose, with the maximum AUC being with four
divided doses, each taken with a fatty meal.172
A delayed-release 100-mg tablet of posaconazole was approved in
late 2013 in the United States.169 When dosed as three 100-mg tablets
given twice on day 1 and then once daily thereafter, the tablets produce
plasma exposures that generally exceed that of the solution dosed at
200 mg three times daily.172a,172b In phase 1 studies of dosing in human
volunteers, exposures were similar when the tablet was given with and
without food.169,172b In addition, exposures produced by the tablets are
not altered by concomitant use of agents that alter gastric pH or
motility.169,172a
Posaconazole is lipophilic, greater than 98% protein bound, and has
a volume of distribution much greater than body water (1774 L in
adults).169 These data suggest extensive distribution and penetration
into tissues. Posaconazole circulates primarily as the parent com-
pound. Clearance is primarily by fecal excretion, with only a minority
(13%) via renal clearance. Hepatic metabolism via uridine diphosphate
glucuronidation plays only a small role in clearance, and CYP450-
mediated oxidation does not occur.169 Posaconazole is a substrate for
P-glycoprotein.
Posaconazole is indicated for prophylaxis of invasive fungal infec-
tion during neutropenia or moderate-to-severe graft-versus-host
disease (GVHD).173,174 When used in this setting, posaconazole may be
dosed either as the suspension (200 mg [5 mL] three times daily) or as
the tablets (three 100-mg tablets given twice on day 1 and then once
daily thereafter). For oropharyngeal candidiasis, posaconazole suspen-
sion (the tablets are not indicated for treatment of oropharyngeal can-
didiasis) is dosed at 100 mg (2.5 mL) twice daily on day 1 and then
100 mg daily for 13 days; the dosage may be increased to 400 mg twice
daily for infections refractory to itraconazole or fluconazole. Dose
adjustment is not required for renal insufficiency; the principal concern
is that plasma exposures in this group are more variable and that
inadequate exposures might result.169 Data in hepatic insufficiency are
limited, but dose adjustment is recommended in patients with mild-
to-severe hepatic insufficiency.169,175 The dosage in pediatrics is not
known, but limited data suggest similar pharmacology in older
children.169,176
Although data on definitive target exposures have been confus-
ing,147 low or negligible levels are sufficiently common177 that monitor-
ing of posaconazole plasma concentrations appears useful. Plasma
concentrations of at least 0.5 to 0.7 mg/L at steady state (typically after
7 or more days of therapy) appear linked to greater efficacy.61,147,178
Drug Interactions.  As noted in the introductory discussion of the
azoles, posaconazole has a moderate number of clinically relevant drug
interactions. Key interactions are summarized in Table 39-1. The most
important of these is that posaconazole is contraindicated in combina-
tion with ergot alkaloids, sirolimus, CYP3A4 substrates that prolong
the QT interval (e.g., pimozide, quinidine), and hydroxymethylglutaryl–
coenzyme A reductase inhibitors primarily metabolized through
CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin).
Side Effects.  The tolerability of posaconazole is generally similar
to that of fluconazole, with gastrointestinal symptoms and headache
being the most commonly reported adverse events.175 Although all
azoles have at least some predisposition to hepatic injury, significant
hepatitis resulting from posaconazole appears to be rare. Posaconazole
did not prolong QT intervals in studies of volunteers, but caution
should still be taken (e.g., careful attention to correction of electrolyte
disturbances) when administering to patients with potentially proar-
rhythmic conditions and co-administration with proarrhythmic drugs
metabolized by CYP3A4 should be avoided.169 Plasma levels have not
been consistently linked to adverse events.
Indications
Prophylaxis of Invasive Fungal Infection during Periods of Very
High Risk.  Posaconazole decreases the incidence of fungal infections
in high-risk patients during GVHD associated with allogeneic bone
 490
marrow transplantation or the neutropenic period associated with
myelosuppressive chemotherapy for acute myelogenous leukemia or
myelodysplastic syndrome. In the study by Ullman and co-workers173
of prophylaxis during GVHD, posaconazole was similar to fluconazole
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
in the incidence of overall fungal infections, but it was superior in
prevention of aspergillosis (2.4% vs. 7.0%, respectively), and preven-
tion of breakthrough fungal infections (2.4% vs. 7.6%, respectively). In
the study by Cornely and co-workers174 of prophylaxis during chemo-
therapy, posaconazole was superior to standard regimens of either
fluconazole or itraconazole in prevention of invasive fungal infections
in general (2% vs. 8%, respectively) and aspergillosis in particular (1%
vs. 7%, respectively). In both studies, probable aspergillosis was largely
diagnosed by serum galactomannan. Adverse events resulting from
posaconazole were more common in the study by Cornely and
co-workers174 but occurred at similar rates to the comparator therapy
in the study by Ullman and co-workers.173
Oropharyngeal Candidiasis.  In a report by Vazquez and
co-workers,179 posaconazole (200 mg on day 1, 100 mg daily for 13
days thereafter) was as effective as fluconazole (same dosage regimen)
in treatment of oropharyngeal candidiasis in subjects with HIV/AIDS.
Consistent with its long half-life, post-therapy mycologic suppression
was somewhat better and clinical relapse was somewhat less frequent
in the posaconazole-treated group. Refractory cases of posaconazole
have been reported to respond effectively to extended courses (up to 3
months) of posaconazole at 400 mg twice daily.180 Extended therapy in
this setting appears well tolerated.
Therapy of Various Mold Infections.  Consistent with its in vitro
activity against a broad range of yeast and mold fungi, a variety
of observational studies have suggested utility in refractory aspergil-
losis,181 fusariosis,182 coccidioidomycosis,183 eumycetoma,184 and chro-
moblastomycosis.184 Posaconazole has also shown activity in a small
number of case reports of treatment of mucormycosis, although limited
data suggest limited penetration into the central nervous system and
thus uncertain potential for therapy at that site.185,186 Therapy has gen-
erally been with 800 mg/day in divided doses. The long-term therapy
often required in these settings appears well tolerated.183-184,187
Investigational Triazoles
Isavuconazole, albaconazole, and ravuconazole are additional triazoles
currently in the later stages of development.188 All three appear to
possess good antifungal spectra. Isavuconazole and ravuconazole have
half-lives that may permit very infrequent dosing.
ECHINOCANDIN ANTIFUNGAL
AGENTS
General Features
The echinocandin antifungal agents act by inhibiting the synthesis of
1,3-β-d-glucan. Along with 1,6-β-d-glucan, chitin (a polymer of
N-acetyl glucosamine), and cell wall proteins, 1,3-β-d-glucan is one
of the fibrillar and interwoven macromolecules that form the fungal
cell wall.189 1,3-β-d-glucans are the predominant component of the cell
wall of the ascomycetous fungi, provide much of the rigidity of the
wall, and are synthesized by a transmembrane glucan synthase complex.
Although the precise mechanism of action is unknown, the echinocan-
dins inhibit the functioning of this complex (see Fig. 39-2). Disruption
of 1,3-β-d-glucan synthesis leads to reduced wall integrity, abnormal
cell morphology, and finally cell rupture and death. To date, in studies
of echinocandins as therapy for candidiasis, the principal pharmaco-
dynamic driver of in vivo response has been the ratio of the peak
achieved concentration to the MIC.9
There are three licensed echinocandins: caspofungin, micafungin
and anidulafungin. These agents are much more similar than they are
different. All are cyclic lipopeptides (see Fig. 39-1) that must be given
intravenously, they have very few drug interactions, they have an admi-
rably low adverse event rate, and they have essentially identical anti-
fungal spectra.190,191 Selection of which echinocandin to use is based
on price and published data on efficacy. Caspofungin has the broadest
array of approved indications and the most available clinical data of
the three products.190 Micafungin has the most detailed data on use in
neonates and children. Anidulafungin appears to have somewhat fewer
drug-drug interactions and no dose adjustments for hepatic failure. In
vitro activity is generally similar for the three, especially when testing
is performed in the presence of serum.192,193 The only direct compari-
son of any of the three has been a study of micafungin versus caspo-
fungin for treatment of invasive candidiasis.194 The two drugs gave
essentially identical results. It is notable that very few patients with
neutropenia and candidemia have been included in clinical trials of
echinocandins, largely because of the infrequency of those cases.
The echinocandins are fungicidal for all Candida spp., including
isolates resistant to other agents.190,191 A paradoxical effect has been
described in which the fungicidal activity of caspofungin against some
isolates of C. albicans and C. dubliniensis disappears at higher concen-
trations. Attempts to demonstrate this effect in experimentally infected
mice has been inconclusive.195 All echinocandins have somewhat
reduced activity against isolates of C. parapsilosis and C. guilliermondii,
but this lesser activity does not appear clinically relevant in studies
reported to date. Although C. glabrata was initially routinely suscep-
tible to the echinocandins, isolates with reduced echinocandin suscep-
tibility resulting from fks1 or fks2 gene mutations have been reported
with increasing frequency with these isolates, also often exhibiting
fluconazole resistance.196
All echinocandins are active in vitro against Aspergillus spp., but
activity is limited to growing and dividing hyphal elements; resting
forms are not killed.197
The echinocandins are not active against Cryptococcus neoformans
or Trichosporon asahii, and their activity against other fungi is variable
with complete resistance noted in many cases. Thus, these agents are
presently limited to therapy of candidiasis and aspergillosis. Available
susceptibility testing methods do correlate with defined molecular
resistance mechanisms,198-199 and a consensus has emerged on detec-
tion of clinically relevant resistance.200
Caspofungin (Cancidas)
Formulations and Pharmacology.  Caspofungin is marketed in 50-
and 70-mg dose units as a powder to be reconstituted in water or saline
for IV infusion.201 In a murine study, caspofungin tissue levels were
higher than serum levels in liver and kidney; lower in the heart, brain,
and thigh; and similar in lung and spleen.202 Caspofungin is 97% bound
to serum albumin. The plasma kinetics of caspofungin are driven pri-
marily by tissue distribution; metabolism is limited, and clearance of
caspofungin occurs via a combination of spontaneous chemical deg-
radation, hydrolysis, and N-acetylation.203 Dose adjustments are not
required for renal function because caspofungin is neither excreted by
the kidney nor cleared by hemodialysis. The clearance of caspofungin
is modestly reduced in subjects with moderate hepatic insufficiency
(Child-Pugh score, 7 to 9), and a dosage reduction from the usual daily
dose of 50 mg/day to 35 mg/day is recommended. There are no data
from individuals with more advanced hepatic insufficiency. Children
aged 3 months to 17 years are given a loading dose of 70 mg/m2 body
surface area, followed by 50 mg/m2 per day, with the total daily dose
not to exceed 70 mg.201 Based on very limited data, neonates would be
treated with 1 mg/kg daily × two doses and then 2 mg/kg daily.151
Drug Interactions.  Caspofungin is not an inhibitor or inducer of
the hepatic cytochrome metabolism enzymes and has very few mean-
ingful drug interactions. Cyclosporine co-administration increases
caspofungin exposure and has been associated with increased hepatic
transaminase levels in volunteers. As a consequence, concomitant
usage of caspofungin and cyclosporine is not recommended unless the
potential benefit outweighs the potential risk to the patient. Caspofun-
gin co-administration reduces tacrolimus exposure by approximately
20%, and dosage adjustments may be required. Rifampin reduces
caspofungin blood levels by approximately 30%, and the daily dosage
of caspofungin should be increased from 50 mg to 70 mg if these drugs
are co-administered. Likewise, limited data with other inducers of drug
clearance (efavirenz, nevirapine, phenytoin, dexamethasone, and car-
bamazepine) suggest that reduced caspofungin levels are possible and
that an increase in the daily dose to 70 mg should be considered.
Side Effects.  Adverse reactions with caspofungin have overall been
infrequent and minor. Symptoms possibly related to histamine release
have been reported and infusion over 1 hour is recommended.201
Caspofungin does not appear to be significantly hepatotoxic or
nephrotoxic.

Indications
Candidiasis.  Caspofungin is indicated for the treatment of several
forms of invasive candidiasis (candidemia, intra-abdominal abscesses,
peritonitis, and pleural space infections) as well as for treatment of
esophageal candidiasis.204 This licensure was based primarily on a ran-
domized, double-blind, placebo-controlled comparison of caspofun-
gin (70 mg loading dose, followed by 50 mg daily) versus ABD (0.6 to
1.0 mg/kg/day) as therapy for invasive candidiasis in adults, with 80%
of the subjects enrolled for candidemia.205 Both study arms permitted
a switch to oral fluconazole after 10 days of IV therapy. The success
rates showed a trend favoring caspofungin (73% success) over ampho-
tericin B (62%), with far fewer adverse events noted in the caspofungin-
treated group. Responses for the two study regimens were similar for
each of the Candida spp. causing meaningful numbers of infections
(C. albicans, C. parapsilosis, C. tropicalis, and C. glabrata). The results
are entirely consistent with the efficacy and safety data shown in three
related studies of caspofungin as therapy for esophageal candidia-
sis,206-208 including disease caused by fluconazole-resistant isolates.209
Aspergillosis.  Caspofungin is also licensed as therapy for invasive
aspergillosis in patients who are refractory to or intolerant of other
therapies. The dosage is the same as for candidiasis. This indication is
based on a series of open-label cases of invasive aspergillosis.201,210,211
An overall success rate of approximately 40% was reported in a series
of patients where neutropenia, malignancy, and concomitant immu-
nosuppressive therapy were common. Subsequent reports have pro-
vided further open-label monotherapy211,212 and open-label combination
experience210,213,214 documenting response rates in the same range. In
most cases, caspofungin was used as salvage after initial therapy with
another antifungal.
Empirical Therapy of Presumed Fungal Infections in Febrile,
Neutropenic Patients.  Caspofungin was noninferior to liposomal
amphotericin B in a large comparative study of treatment of adults with
persistent fever and neutropenia.215 Caspofungin was overall better
tolerated than liposomal amphotericin B.
Mucormycosis.  In a retrospective analysis of patients with rhino-
orbital mucormycosis, 6 of 7 patients given the combination of caspo-
fungin with amphotericin B were successfully treated (4 with ABLC
and 2 with liposomal amphotericin B).216 These results were better than
7 of 22 started on ABLC alone but not better than monotherapy with
other amphotericin B formulations (P = .15). Because of the small
numbers, retrospective nature, the important but confounding role of
sinus surgery, and inconsistencies in the results, future studies are
needed to determine the usefulness of this combination.
Anidulafungin (Eraxis)
Formulations and Pharmacology.  Anidulafungin is marketed in 50-
and 100-mg dose units as a powder to be reconstituted in water.217
Anidulafungin is more than 99% bound to plasma proteins. Distribu-
tion from the circulation occurs quickly into a volume of distribution
(30 to 50 L) that is similar to total body fluid volume. Anidulafungin
is slowly degraded by chemical opening of its ring structure.218 Dose
adjustments are not required for renal insufficiency, hepatic insuffi-
ciency, age, or gender. Pediatric dosing has not been well established.
In pediatric (age 2 to 11 years) and adolescent (age 12 to 17 years)
children, doses of 0.75 mg/kg/day and 1.5 mg/kg/day, respectively,
produced blood levels similar to those achieved in adults with 50- and
100-mg/day doses.219,220
Drug Interactions.  Anidulafungin has no meaningful CYP450
enzyme interactions: it is not an inducer, inhibitor, or substrate and
has no interaction with either drugs cleared by these pathways or with
drugs that induced these pathways.217 Specifically, dose adjustments or
other special precautions are not needed during co-administration of
cyclosporine, voriconazole, tacrolimus, liposomal amphotericin B, or
rifampin.217
Side Effects.  Histamine-mediated symptoms (rash, urticaria,
flushing, pruritus, dyspnea, hypotension) have been noted on occasion
but are infrequent when the rate of infusion does not exceed 1.1 mg/
min.217 Adverse reactions with anidulafungin have otherwise overall
been infrequent, minor, and overall comparable to those observed
with fluconazole. Anidulafungin is not significantly hepatotoxic or
nephrotoxic.
491
Indications
Candidiasis.  Anidulafungin is indicated for the treatment of invasive
candidiasis and of esophageal candidiasis. In the key study of invasive
candidiasis,221 anidulafungin (200 mg on day 1, then 100 mg/day) was
Chapter 39  Drugs Active against Fungi, Pneumocystis, and Microsporidia
compared with fluconazole (800 mg on day 1, followed by 400 mg
daily). Success rates at the end of IV therapy were significantly higher
with anidulafungin than fluconazole (76% vs. 60%). The superiority of
anidulafungin was particularly marked in one center, and removing
the results from this one center removed the statistical significance of
superiority. Efficacy data were also provided from a smaller dose-
ranging study in invasive candidiasis222 and from a larger noncompara-
tive study of anidulafungin as therapy for candidemia and invasive
candidiasis in the critical care setting.223 Anidulafungin (100 mg on
day 1, then 50 mg/day) was found to be noninferior to fluconazole
(200 mg PO on day 1, then 100 mg PO per day) in esophageal candi-
diasis, with success rates greater than 97% for both arms. The safety
profile of anidulafungin was essentially the same as that of fluconazole
in the comparative studies.
Use in Other Settings.  Anidulafungin is active in vitro against
Aspergillus spp., but data on its clinical utility as monotherapy against
this fungus are limited.218, 224 Use in combination with voriconazole for
invasive aspergillosis has also been described (see “Aspergillosis” under
“Voriconazole [Vfend]”). Studies have not as yet been reported on its
use as either a prophylactic agent during periods of risk for invasive
aspergillosis or candidiasis or as empirical therapy of persistently
febrile neutropenic patients.
Micafungin (Mycamine)
Formulations and Pharmacology.  Micafungin is marketed in 50- and
100-mg unit doses for reconstitution in saline.225 Micafungin is more
than 99.5% bound to serum proteins (mostly albumin), and its volume
of distribution approximates that of body water.226 Micafungin under-
goes a small amount of metabolic transformation, but the primary
route of elimination is via fecal excretion. Dose adjustments are not
required for race, gender, renal function (any severity), or hepatic
dysfunction (mild and moderate).225 No data are available in severe
hepatic dysfunction. Appropriate pediatric dosing has not been well
established. A dose of 2 mg/kg/day in both premature infants and older
children was associated with clinical responses comparable to those for
liposomal amphotericin B (3 mg/kg).227 In children aged 2 to 8 years,
micafungin has a somewhat higher clearance and volume of distribu-
tion than in older children or adults,228,229 with dosages of 2 to 3 mg/
kg/day (children aged 9 to 17 years) and 3 to 4 mg/kg/day (children
aged 2 to 8 years) producing systemic exposures similar to those seen
in adults.220,230 Limited data suggest the possible need for doses greater
than 5 mg/kg/day in very young or premature infants.220,231
Drug Interactions.  Micafungin does not have any meaningful
interactions with the hepatic oxidative CYP450 enzymes (it does not
induce any of these enzymes, is only minimally metabolized, and is not
an inhibitor of CYP3A). Further, micafungin lacks interactions with
the P-glycoprotein transport system. Based on specific drug-drug
interactions studies conducted by the drug sponsor, no dose adjust-
ments are required when micafungin is co-administered with myco-
phenolate mofetil, cyclosporine, tacrolimus, prednisolone, fluconazole,
voriconazole, amphotericin B, ritonavir, or rifampin. As judged by
AUC, micafungin increases the systemic exposure of itraconazole,
nifedipine, and sirolimus by about 20%. Dose adjustment is not rou-
tinely recommended for these three agents, but patients should be
monitored closely for toxicity.225,226
Side Effects.  Adverse reactions with micafungin have overall been
infrequent and minor,226 even at very high doses.232,233 Histamine
release–related symptoms (pruritus, facial swelling, vasodilatation)
have been reported and are reduced when the drug is given over 1
hour.225 Phlebitis may occur, and appears more common with admin-
istration via a peripheral vein.225 Micafungin does not appear to be
significantly hepatotoxic or nephrotoxic.
Indications
Candidiasis.  Based on both randomized194,234 and open-label data,235
micafungin is indicated at 100  mg/day for the treatment of invasive
candidiasis. In the study by Kuse and co-workers,234 micafungin
 492
(100  mg/day) was noninferior to liposomal amphotericin B (3  mg/
kg/day; success rates of 90% for both arms), with fewer drug-related
adverse events seen in the micafungin arm. Similarly, a three-way
comparison of micafungin, (dose groups at 100  mg/day and 150  mg/
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
day) with caspofungin (70  mg on day 1, 50  mg/day on subsequent
days) found very similar response rates (76%, 71%, and 72%, respec-
tively) across the three arms.194 Adverse event rates were similar for
the caspofungin and micafungin arms. Finally, a comparison of
micafungin (2  mg/kg/day) with liposomal amphotericin B (3  mg/
kg/day) as treatment of invasive candidiasis in both premature infants
and older children found similar response rates of 73% and 76%,
respectively.236
Based on a pair of studies by De Wet and co-workers,237,238 mica-
fungin is also registered for treatment of esophageal candidiasis at a
dose of 150 mg/day.
Prophylaxis of Candidal Infections in Hematopoietic Stem Cell
Transplant Recipients.  Based on a study reported by Van Burik and
co-workers,239 micafungin is registered for use at 50 mg/day during the
at-risk period after hematopoietic stem cell transplantation. In this
study, micafungin was compared with fluconazole (400 mg/day). The
level of risk for infection varied substantially across the study group:
about half of the enrolled subjects had received an allogeneic trans-
plant, and half had received an autologous transplant. Subjects were
treated for a median of only 19 days, and the rate of proven fungal
infection was similar and low (2%) in both arms. Because the mycoses
were nearly all candidiasis, micafungin is approved for the prevention
of candidiasis and not aspergillosis. Adverse events were similar for the
two study groups.
Use in Other Settings.  Micafungin is active in vitro against Asper-
gillus spp., but only a small amount of open-label monotherapy data
on its clinical utility against this fungus have been reported.240,241 Simi-
larly, studies have not as yet been reported on its use as empirical
therapy of persistently febrile neutropenic patients.
Combination Antifungals
A combination of amphotericin B plus voriconazole has been used in
empirical therapy of highly immunosuppressed patients with pre-
sumed mold pneumonia that might be either aspergillosis or mucor-
mycosis. Should a diagnosis be established, therapy would continue
with a single agent. Combining voriconazole with an echinocandin for
treatment of invasive pulmonary aspergillosis appeared to have an
effect that was at least additive, if not synergistic, in animal models,
but a randomized clinical trial did not find voriconazole plus anidula-
fungin superior to voriconazole alone.161
AGENTS USED TO TREAT AND
PREVENT PNEUMOCYSTIS
JIROVECII
Trimethoprim-Sulfamethoxazole
Trimethoprim-sulfamethoxazole (TMP-SMX) has long been the stan-
dard treatment and prophylaxis for Pneumocystis infections in at-risk
individuals.242 Specific details on these two components are provided
in Chapter 33.
Treatment with TMP-SMX of adults with pneumonia caused by
P. jirovecii is given for 21 days and may be either IV or PO at a dosage
of 15 to 20 mg/kg/day (TMP) and 75 to 100 mg/kg/day (SMX), with
the total daily dosage divided into three or four doses.243-245 For further
details on treatment, including a discussion of the important role
played by concomitant corticosteroid therapy, see Chapter 271. The
standard prophylaxis regimen in at-risk HIV-infected adults is one
double-strength tablet of TMP-SMX (160 mg and 800 mg of the two
components, respectively) daily.245 Also effective, and perhaps better
tolerated, is a reduced dosage of one single-strength tablet daily or one
double-strength tablet three times weekly.245
TMP-SMX is also the standard for treatment and prevention of
Pneumocystis infection in children. Prophylaxis is given at 150 mg/m2
and 750 mg/m2 body surface area/day (TMP and SMX, respectively;
total daily dose not to exceed 320 mg and 1600 mg, respectively),
administered orally in two equally divided doses given on 3 consecu-
tive days per week.246 For treatment, children receive the same body
weight–adjusted dosage as adults (15 to 20 mg/kg/day TMP plus 75 to
100 mg/kg/day SMX), divided into three or four daily doses and given
for 21 days.246
As discussed further in Chapter 271, hypersensitivity reactions to
TMP-SMX are particularly common when treating HIV-infected sub-
jects, with hypersensitivity reactions reported in up to approximately
two thirds of subjects versus rates of less than or equal to 5% in subjects
with normal immunity or other forms of immunosuppression.247
Pentamidine
Formulations, Pharmacology, and Indications.  Pentamidine is an
aromatic diamidine used as its isethionate salt, both intravenously for
treatment and by inhalation for prophylaxis. It has also been used in
the treatment of leishmaniasis and trypanosomiasis. Pentamidine’s
mechanism of action remains ill understood but appears broad based;
it has been shown to interact with DNA, RNA, topoisomerase, and
ubiquitin.248 Pentamidine has been reported to be embryotoxic in
rats,249 and its use should be avoided in pregnancy.250
For injection, it is provided as a 300-mg unit-dose powder for
reconstitution in 5% dextrose or sterile water.250 A dosage of 4 mg/
kg/day is given in a total infusate volume of 50 to 250 mL over 1 to
2 hours. Pentamidine distributes principally to the liver and kidney
and is slowly excreted unchanged into both the urine and feces;
decreasing amounts of pentamidine are detected in the urine up to 8
weeks250 and in the plasma for up to 8 months251 after IV dosing.
When given for 21 days as treatment for Pneumocystis pneumonia,
the overall efficacy and safety of pentamidine appears similar to that
for TMP-SMX.243,244
Although often supplanted by easier oral therapies, pentamidine
can also be used for prophylaxis.245 For this indication, it is available
as a 300-mg unit-dose powder for reconstitution in 6 mL sterile
water.252 Given by nebulizer (Marquest Respirgard II [Marquest
Medical Products, Englewood, CO] nebulizer must be used for best
results), the recommended dosage is 300 mg once every 4 weeks. The
protective effect is limited to the lung. Aerosol pentamidine should not
be used for treatment: plasma levels are negligible, efficacy is limited
to the lung, and relapses are frequent.245,252
Drug Interactions.  Formal drug-drug interactions studies have
not been conducted with pentamidine.250 Because of the potential for
additive nephrotoxicity, concomitant or sequential use with other
nephrotoxic agents (e.g., amphotericin B preparations, aminoglyco-
sides, vancomycin, foscarnet, cisplatin) should be avoided. If such
combinations are required, close monitoring of renal function is
advisable.
Side Effects.  Intravenous pentamidine is associated with a number
of significant drug-related adverse events.245,246,250 Hypotension fre-
quently results if pentamidine is infused over a period shorter than 1
hour. Mild-to-moderate nephrotoxicity is also common during therapy,
as are electrolyte disturbances. Pentamidine is toxic to pancreatic beta-
islet cells, occasionally thereby causing abrupt release of insulin and
hypoglycemia.253 Cumulative islet cell damage can lead to drug-
induced diabetes mellitus. Pancreatitis, cardiac arrhythmias, and QT
prolongation may also occur.
Aerosol pentamidine is generally well tolerated except for local
irritation (coughing or bronchospasm) during therapy, which responds
to symptomatic management. Hypoglycemia may be seen but is less
common than with IV pentamidine therapy.253
Other Therapies for P. jirovecii Infection
Dapsone combined with TMP, primaquine combined with clindamy-
cin, and atovaquone are all alternative therapies for mild-to-moderate
severity infections in both adults and children.245,246 These agents can
also be used for prophylaxis and are discussed in further detail in
Chapters 29, 33, 40, and 271.
AGENTS USED TO TREAT
MICROSPORIDIA
Limited options exist for treatment of infections caused by micro­
sporidia.254 Because this intracellular organism emerges as a pathogen
primarily in immunosuppressed patients, improvement in immune
status (e.g., initiation of antiretroviral therapy) is the key first step.
Albendazole (discussed further in Chapter 41) at 400 mg twice daily

appears reliable for species other than Enterocytozoon bieneusi.
Based on carriage of a marker for benzimidazole resistance, it is likely
that Vittaforma corneae (Nosema corneum) would also respond poorly
to albendazole.256 When albendazole is inactive, fumagillin may be
used orally for gastrointestinal infections and topically for ocular
infections. Other successful approaches to ocular infections have
included local débridement,257 topical therapy with a 1% voriconazole
solution,258 and topical therapy with fluoroquinolone solution (e.g.,
0.3% ciprofloxacin, 0.5% levofloxacin).259
Fumagillin
Originally identified as an antiangiogenic natural product of Aspergil-
lus fumigatus, fumagillin acts by binding to methionine aminopepti-
dase 2.260 Fumagillin is available in 20-mg capsules and is primarily
used in veterinary applications, such as control of Nosema infections
in honey bees.261
Given orally at 20  mg three times daily262-264 for courses of 7 to
14 days, fumagillin has been curative in cases of symptomatic diar-
rhea caused by Enterocytozoon bieneusi. Systematic studies of drug-
drug interactions and adverse events in humans are not available.
The most commonly noted adverse events are leukopenia and throm-
Key References
The complete reference list is available online at Expert Consult.
8. Arikan S. Current status of antifungal susceptibility testing
methods. Med Mycol. 2007;45:569-587.
9. Andes D. Pharmacokinetics and pharmacodynamics of
antifungals. Infect Dis Clin North Am. 2006;20:679-697.
11. Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formu-
lations of amphotericin B: clinical efficacy and toxicities.
Clin Infect Dis. 1998;27:603-618.
27. Andes D, Stamsted T, Conklin R. Pharmacodynamics of
amphotericin B in a neutropenic-mouse disseminated-
candidiasis model. Antimicrob Agents Chemother. 2001;45:
922-926.
28. Hope WW, Goodwin J, Felton TW, et al. Population phar-
macokinetics of conventional and intermittent dosing of
liposomal amphotericin B in adults: a first critical step for
rational design of innovative regimens. Antimicrob Agents
Chemother. 2012;56:5303-5308.
29. Pizzo PA. Management of fever in patients with cancer and
treatment-induced neutropenia. N Engl J Med. 1993;328:
1323-1332.
47. Prentice HG, Hann IM, Herbrecht R, et al. A randomized
comparison of liposomal versus conventional amphoteri-
cin B for the treatment of pyrexia of unknown origin in
neutropenic patients. Br J Haematol. 1997;98:711-718.
114. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treat-
48. Wingard JR, White MH, Anaissie E, et al. A randomized,
double-blind comparative trial evaluating the safety of
115. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial
liposomal amphotericin B versus amphotericin B lipid
complex in the empirical treatment of febrile neutropenia.
Clin Infect Dis. 2000;31:1155-1163.
50. Bates DW, Su L, Yu DT, et al. Mortality and costs of acute
116. Rex JH, Pappas PG, Karchmer AW, et al. A randomized and
renal failure associated with amphotericin B therapy. Clin
Infect Dis. 2001;32:686-693.
51. Lanternier F, Lortholary O. Liposomal amphotericin B:
what is its role in 2008? Clin Microbiol Infect. 2008;14:
71-83.
117. Saag MS, Powderly WG, Cloud GA, et al. Comparison of
54. Perfect JR. Aerosolized antifungal prophylaxis: the winds
of change? Clin Infect Dis. 2008;46:1409-1411.
60. Smith D, Andes D. Therapeutic drug monitoring of anti-
fungals: pharmacokinetic and pharmacodynamic consid-
118. Van der Horst CM, Saag MS, Cloud GA, et al. Treatment
erations. Ther Drug Monit. 2008;30:167-172.
61. Andes D, Pascual A, Marchetti O. Antifungal therapeutic
drug monitoring: established and emerging indications.
Antimicrob Agents Chemother. 2009;53:24-34.
119. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines
68. Dismukes WE, Cloud G, Gallis HA, et al. Treatment of
cryptococcal meningitis with combination amphotericin B
and flucytosine for four as compared with six weeks. N Engl
129. Winston DJ, Chandrasekar PH, Lazarus HM, et al. Fluco-
J Med. 1987;317:334-341.
69. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice
guidelines for the management of cryptococcal disease:
2010 update by the Infectious Diseases Society of America.
Clin Infect Dis. 2010;50:291-322.
130. Marr KA, Seidel K, Slavin MA, et al. Prolonged flu-
71. Brouwer AE, Rajanuwong A, Chierakul W, et al. Com­
bination antifungal therapies for HIV-associated crypto-
coccal meningitis: a randomised trial. Lancet. 2004;363:
1764-1767.
72. Dromer F, Bernede-Bauduin C, Guillemot D, Lortholary
O. Major role for amphotericin B-flucytosine combination
131. Wingard JR, Merz WG, Rinaldi MG, et al. Increase in
in severe cryptococcosis. PLoS One. 2008;3:e2870.
493
245,246,254,255
bocytopenia. These may be severe but reverse quickly upon discon-
tinuation of therapy.
Microsporidial keratitis has been treated topically with a solution
of fumagillin in saline.265-270 The solution used has varied because of
Chapter 39  Drugs Active against Fungi, Pneumocystis, and Microsporidia
use of different sources of material with differing proportions of fuma-
gillin relative to inactive components (e.g., “bicyclohexylammonium
fumagillin at 0.113 mg/mL”268 or “Fumidil B (Mid-Con) 5.2 mg/mL
(0.11 mg/mL active fumagillin)”266), but it appears that active drug at
approximately 70 to 100 mg/L is effective.
INVESTIGATIONAL ANTIFUNGAL
AGENTS
Drugs being evaluated in preclinical studies include novel azoles, novel
echinocandin-like compounds, sordarins (inhibit protein synthesis by
their effect on fungal elongation factor 2), nikkomycin Z (inhibits
chitin synthesis), and various peptides with unknown mechanisms of
action.271,272 Iron chelation has been explored as a therapy, but addition
of deferasirox to liposomal amphotericin B was associated with
increased mortality in a small study.273 Immunomodulators hold
promise, but insufficient clinical data exist to determine where and
how these drugs might be used. 274-277
77. Pfaller MA. Antifungal drug resistance: mechanisms, epi-
demiology, and consequences for treatment. Am J Med.
marrow transplantation and neutropenia treated prophy-
lactically with fluconazole. N Engl J Med. 1991;325:
2012;125:S3-S13. 1274-1277.
78. Pfaller MA, Andes D, Arendrup MC, et al. Clinical 136. Manzoni P, Stolfi I, Pugni L, et al. A multicenter, random-
breakpoints for voriconazole and Candida spp. revisited: ized trial of prophylactic fluconazole in preterm neonates.
review of microbiologic, molecular, pharmacodynamic, N Engl J Med. 2007;356:2483-2495.
and clinical data as they pertain to the development of 137. Kaufman D. Strategies for prevention of neonatal invasive
species-specific interpretive criteria. Diagn Microbiol Infect candidiasis. Semin Perinatol. 2003;27:414-424.
Dis. 2011;70:330-343. 147. Hussaini T, Ruping MJ, Farowski F, et al. Therapeutic drug
80. Arikan-Akdagli S. Azole resistance in Aspergillus: global monitoring of voriconazole and posaconazole. Pharmaco-
status in Europe and Asia. Ann N Y Acad Sci. 2012;1272: therapy. 2011;31:214-225.
9-14. 148. Dolton MJ, Ray JE, Chen SC, et al. Multicenter study of
90. Tucker RM, Haq Y, Denning DW, Stevens DA. Adverse voriconazole pharmacokinetics and therapeutic drug mon-
events associated with itraconazole in 189 patients on itoring. Antimicrob Agents Chemother. 2012;56:4793-
chronic therapy. J Antimicrob Chemother. 1990;26: 4799.
561-566. 149. Park WB, Kim NH, Kim KH, et al. The effect of therapeutic
91. Stevens DA, Lee JY. Analysis of compassionate use itracon- drug monitoring on safety and efficacy of voriconazole in
azole therapy for invasive aspergillosis by the NIAID invasive fungal infections: a randomized controlled trial.
Mycoses Study Group criteria. Arch Intern Med. 1997;157: Clin Infect Dis. 2012;55:1080-1087.
1857-1862. 157. Zwald FO, Spratt M, Lemos BD, et al. Duration of vori­
95. Galgiani JN, Cloud GA, Catanzaro A, et al. A comparison conazole exposure: an independent risk factor for skin
of oral fluconazole or itraconazole for progressive, non- cancer after lung transplantation. Dermatol Surg. 2012;38:
meningeal coccidioidomycosis. Ann Intern Med. 2000;133: 1369-1374.
676-686. 160. Herbrecht R, Denning DW, Patterson TF, et al. Voricon-
97. Sharkey-Mathis PK, Kauffman CA, Graybill JR, et al. Treat- azole versus amphotericin B for primary therapy of inva-
ment of sporotrichosis with itraconazole. Am J Med. sive aspergillosis. N Engl J Med. 2002;347:408-415.
1993;95:279-285. 161. Marr KA, Schlamm H, Rottinghaus ST, et al. A ran-
domised, double-blind study of combination antifungal
ment of candidiasis. Clin Infect Dis. 2004;38:161-189. therapy with voriconazole and anidulafungin versus vori-
conazole monotherapy for primary treatment of invasive
comparing fluconazole with amphotericin B for the treat- aspergillosis. 22nd European Congress of Clinical Micro-
ment of candidemia in patients without neutropenia. biology and Infectious Diseases. Abstract LB2812. London,
N Engl J Med. 1994;331:1325-1330. 2012.
172a.  Krishna G, Ma L, Martinho M, O’Mara E. Single-dose
blinded multicenter trial of high-dose fluconazole plus phase I study to evaluate the pharmacokinetics of posacon-
placebo versus fluconazole plus amphotericin B as therapy azole in new tablet and capsule formulations relative to
for candidemia and its consequences in nonneutropenic oral suspension. Antimicrob Agents Chemother. 2012;56:
subjects. Clin Infect Dis. 2003;36:1221-1228. 4196-4201.
172b.  Krishna G, Ma L, Martinho LM, et al. A new solid oral
amphotericin B with fluconazole in the treatment of acute tablet formulation of posaconazole: a randomized clinical
AIDS-associated cryptococcal meningitis. N Engl J Med. trial to investigate rising single- and multiple-dose phar-
1992;326:83-89. macokinetics and safety in healthy volunteers. J Antimicrob
Chemother. 2012;67:2725-2730.
of cryptococcal meningitis associated with the acquired 173. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or
immunodeficiency syndrome. N Engl J Med. 1997;337: fluconazole for prophylaxis in severe graft-versus-host
15-21. disease. N Engl J Med. 2007;356:335-347.
174. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole
for the management of cryptococcal disease. Clin Infect vs. fluconazole or itraconazole prophylaxis in patients with
Dis. 2000;30:710-718. neutropenia. N Engl J Med. 2007;356:348-359.
178. Dolton MJ, Ray JE, Marriott D, McLachlan AJ. Posacon-
nazole prophylaxis of fungal infections in patients with azole exposure-response relationship: evaluating the utility
acute leukemia. Results of a randomized placebo- of therapeutic drug monitoring. Antimicrob Agents Che-
controlled, double-blind, multicenter trial. Ann Intern mother. 2012;56:2806-2813.
Med. 1993;118:495-503. 196. Pfaller MA, Castanheira M, Lockhart SR, et al. Frequency
of decreased susceptibility and resistance to echinocandins
conazole prophylaxis is associated with persistent protec- among fluconazole-resistant bloodstream isolates of
tion against candidiasis-related death in allogeneic marrow Candida glabrata. J Clin Microbiol. 2012;50:1199-1203.
transplant recipients: long-term follow-up of a random- 200. Pfaller MA, Diekema DJ, Andes D, et al. Clinical break-
ized, placebo-controlled trial. Blood. 2000;96:2055- points for the echinocandins and Candida revisited: inte-
2061. gration of molecular, clinical, and microbiological data to
arrive at species-specific interpretive criteria. Drug Resist
Candida krusei infection among patients with bone Updat. 2011;14:164-176.
 494
212. Kartsonis NA, Saah AJ, Joy Lipka C, et al. Salvage therapy
with caspofungin for invasive aspergillosis: results from the
caspofungin compassionate use study. J Infect. 2005;50:
196-205.
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
219. Benjamin DK Jr, Driscoll T, Seibel NL, et al. Safety and
pharmacokinetics of intravenous anidulafungin in children
with neutropenia at high risk for invasive fungal infections.
Antimicrob Agents Chemother. 2006;50:632-638.
234. Kuse ER, Chetchotisakd P, da Cunha CA, et al. Micafungin
versus liposomal amphotericin B for candidaemia and
invasive candidosis: a phase III randomised double-blind
trial. Lancet. 2007;369:1519-1527.
245. Kaplan JE, Benson C, Holmes KH, et al. Guidelines for
prevention and treatment of opportunistic infections in
HIV-infected adults and adolescents: recommendations
from CDC, the National Institutes of Health, and the HIV
Medicine Association of the Infectious Diseases Society of
America. MMWR Recomm Rep. 2009;58:1-207; quiz
CE1-4.
246. Mofenson LM, Brady MT, Danner SP, et al. Guidelines for
the Prevention and Treatment of Opportunistic Infections
among HIV-exposed and HIV-infected children: recom-
mendations from CDC, the National Institutes of Health,
the HIV Medicine Association of the Infectious Diseases
Society of America, the Pediatric Infectious Diseases
Society, and the American Academy of Pediatrics. MMWR
Recomm Rep. 2009;58:1-166.

References
1. Balakrishnan AR, Easwaran KR. CD and NMR studies on
29. Pizzo PA. Management of fever in patients with cancer and
the aggregation of amphotericin B in solution. Biochim
Biophys Acta. 1993;1148:269-277.
rational design of innovative regimens. Antimicrob Agents
Chemother. 2012;56:5303-5308.
treatment-induced neutropenia. N Engl J Med. 1993;328:
494.e1
52. Kuiper L, Ruijgrok EJ. A review on the clinical use of
inhaled amphotericin B. J Aerosol Med Pulm Drug Deliv.
2009;22:213-227.
53. Rijnders BJ, Cornelissen JJ, Slobbe L, et al. Aerosolized

Chapter 39  Drugs Active against Fungi, Pneumocystis, and Microsporidia

1323-1332. liposomal amphotericin B for the prevention of invasive
2. Hsu SF, Burnette RR. The effect of amphotericin B on the
30. Product information. Abelcet (amphotericin B lipid pulmonary aspergillosis during prolonged neutropenia:
K-channel activity of MDCK cells. Biochim Biophys Acta.
complex injection). Gaithersburg, MD, Sigma-Tau Phar- a randomized, placebo-controlled trial. Clin Infect Dis.
1993;1152:189-191.
maceuticals, 2010. 2008;46:1401-1408.
3. Clemons KV, Schwartz JA, Stevens DA. Experimental
31. Product information. AmBisome (amphotericin B) lipo- 54. Perfect JR. Aerosolized antifungal prophylaxis: the winds
central nervous system aspergillosis therapy: efficacy, drug
some for injection. Northbrook, IL, Astellas Pharma US, of change? Clin Infect Dis. 2008;46:1409-1411.
levels and localization, immunohistopathology, and toxic-
2012. 55. Drew RH. Aerosol and other novel administrations for
ity. Antimicrob Agents Chemother. 2012;56:4439-4449.
32. Product information. Amphotec (amphotericin B choles- prevention and treatment of invasive aspergillosis. Med
4. Ben-Ami R, Lewis RE, Kontoyiannis DP. Immunopharma-
teryl sulfate complex for injection). Cranberry Township, Mycol. 2009;47:S355-S361.
cology of modern antifungals. Clin Infect Dis. 2008;47:
PA, Three Rivers Pharmaceuticals, 2005. 56. Block ER, Bennett JE, Livoti LG, et al. Flucytosine and
226-235.
33. Safdar A, Ma J, Saliba F, et al. Drug-induced nephrotoxicity amphotericin B: hemodialysis effects on the plasma con-
5. Arikan S, Rex JH. Resistance to antifungal agents. In:
caused by amphotericin b lipid complex and liposomal centration and clearance. Studies in man. Ann Intern Med.
Collier L, Balows A, Sussman M, et al, eds. Topley and
amphotericin B: a review and meta-analysis. Medicine. 1974;80:613-617.
Wilson’s Microbiology and Microbial Infections. 10th ed.
2010;89:236-244. 57. Pfaller MA, Messer SA, Boyken L, et al. In vitro activities
London: Arnold Publishing; 2005:168-181.
34. White MH, Bowden RA, Sandler ES, et al. Randomized, of 5-fluorocytosine against 8,803 clinical isolates of
6. Blum G, Perkhofer S, Haas H, et al. Potential basis for
double-blind clinical trial of amphotericin B colloidal dis- Candida spp.: global assessment of primary resistance
amphotericin B resistance in Aspergillus terreus. Antimi-
persion vs. amphotericin B in the empirical treatment of using National Committee for Clinical Laboratory Stan-
crob Agents Chemother. 2008;52:1553-1555.
fever and neutropenia. Clin Infect Dis. 1998;27:296-302. dards susceptibility testing methods. Antimicrob Agents
7. Merz WG. Candida lusitaniae: frequency of recovery, colo-
35. Bowden R, Chandrasekar P, White MH, et al. A double- Chemother. 2002;46:3518-3521.
nization, infection, and amphotericin B resistance. J Clin
blind, randomized, controlled trial of amphotericin B col- 58. Brandt ME, Pfaller MA, Hajjeh RA, et al. Trends in anti-
Microbiol. 1984;20:1194-1195.
loidal dispersion versus amphotericin B for treatment of fungal drug susceptibility of Cryptococcus neoformans iso-
8. Arikan S. Current status of antifungal susceptibility testing
invasive aspergillosis in immunocompromised patients. lates in the United States: 1992 to 1994 and 1996 to 1998.
methods. Med Mycol. 2007;45:569-587.
Clin Infect Dis. 2002;35:359-366. Antimicrob Agents Chemother. 2001;45:3065-3069.
9. Andes D. Pharmacokinetics and pharmacodynamics of
36. Walsh TJ, Hiemenz JW, Seibel NL, et al. Amphotericin B 59. Stamm AM, Diasio RB, Dismukes WE, et al. Toxicity of
antifungals. Infect Dis Clin North Am. 2006;20:679-697.
lipid complex for invasive fungal infections: analysis of amphotericin B plus flucytosine in 194 patients with cryp-
10. Ostrosky-Zeichner L, Marr KA, Rex JH, Cohen SH.
safety and efficacy in 556 cases. Clin Infect Dis. 1998;26: tococcal meningitis. Am J Med. 1987;83:236-242.
Amphotericin B: time for a new “gold standard”. Clin Infect
1383-1396. 60. Smith D, Andes D. Therapeutic drug monitoring of anti-
Dis. 2003;37:415-425.
37. Walsh TJ, Seibel NL, Arndt C, et al. Amphotericin B lipid fungals: pharmacokinetic and pharmacodynamic consid-
11. Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formu-
complex in pediatric patients with invasive fungal infec- erations. Ther Drug Monit. 2008;30:167-172.
lations of amphotericin B: clinical efficacy and toxicities.
tions. Pediat Inf Dis J. 1999;18:702-708. 61. Andes D, Pascual A, Marchetti O. Antifungal therapeutic
Clin Infect Dis. 1998;27:603-618.
38. Hamill RJ, Sobel J, El-Sadr W, et al. Randomized double- drug monitoring: established and emerging indications.
12. Chavanet PY, Garry I, Charlier N, et al. Trial of glucose
blind trial of AmBisome (liposomal amphotericin B) and Antimicrob Agents Chemother. 2009;53:24-34.
versus fat emulsion in preparation of amphotericin for use
amphotericin B in acute cryptococcal meningitis in AIDS 62. Kaspar RL, Drutz DJ. Rapid, simple bioassay for
in HIV-infected patients with candidiasis. Br Med J.
patients. 39th Interscience Conference on Antimicrobial 5-fluorocytosine in the presence of amphotericin B. Anti-
1992;305:921-925.
Agents and Chemotherapy. Abstract No. 1161. San Fran- microb Agents Chemother. 1975;7:462-465.
13. Nath CE, Shaw PJ, Gunning R, et al. Amphotericin B in
cisco, 1999. 63. Huang CM, Kroll MH, Ruddel M, et al. An enzymatic
children with malignant disease: a comparison of the tox-
39. Johnson PC, Wheat LJ, Cloud GA, et al. Safety and efficacy method for 5-fluorocytosine. Clin Chem. 1988;34:59-62.
icities and pharmacokinetics of amphotericin B adminis-
of liposomal amphotericin B compared with conventional 64. Harding SA, Johnson GF, Solomon HM. Gas-
tered in dextrose versus lipid emulsion. Antimicrob Agents
amphotericin B for induction therapy of histoplasmosis in chromatographic determination of 5-fluorocytosine in
Chemother. 1999;43:1417-1423.
patients with AIDS. Ann Intern Med. 2002;137:105-109. human serum. Clin Chem. 1976;22:772-776.
14. Cleary JD, Rogers PD, Chapman SW. Variability in polyene
40. Ng TT, Denning DW. Liposomal amphotericin B (AmBi- 65. Diasio RB, Lakings DE, Bennett JE. Evidence for conver-
content and cellular toxicity among deoxycholate ampho-
some) therapy in invasive fungal infections. Evaluation of sion of 5-fluorocytosine to 5-fluorouracil in humans: pos-
tericin B formulations. Pharmacotherapy. 2003;23:572-578.
United Kingdom compassionate use data. Arch Intern Med. sible factor in 5-fluorocytosine clinical toxicity. Antimicrob
15. Bindschadler DD, Bennett JE, Abernathy RS. A pharmaco-
1995;155:1093-1098. Agents Chemother. 1978;14:903-908.
logic guide to the clinical use of amphotericin B. Br J Infect
41. Mills W, Chopra R, Linch DC, Goldstone AH. Liposomal 66. Harris BE, Manning BW, Federle TW, Diasio RB. Conver-
Dis. 1969;120:427-436.
amphotericin B in the treatment of fungal infections in sion of 5-fluorocytosine to 5-fluorouracil by human intes-
16. Espada R, Josa JM, Valdespina S, et al. HPLC assay for
neutropenic patients: a single-center experience of 133 tinal microflora. Antimicrob Agents Chemother. 1986;29:
determination of amphotericin B in biological samples.
episodes in 116 patients. Br J Haematol. 1994;86:754-760. 44-48.
Biomed Chromatogr. 2008;22:402-407.
42. Tollemar J, Ringden O, Ambisome Users Group. Early 67. Hospenthal DR, Bennett JE. Flucytosine monotherapy for
17. Deshpande NM, Gangrade MG, Kekare MB, Vaidya VV.
pharmacokinetic and clinical results from a noncompara- cryptococcosis. Clin Infect Dis. 1998;27:260-264.
Determination of free and liposomal amphotericin B in
tive multicentre trial of amphotericin B encapsulated in 68. Dismukes WE, Cloud G, Gallis HA, et al. Treatment of
human plasma by liquid chromatography-mass spectros-
a small unilamellar liposome (AmBisome). Drug Invest. cryptococcal meningitis with combination amphotericin B
copy with solid phase extraction and protein precipitation
1992;4:232-238. and flucytosine for four as compared with six weeks. N Engl
techniques. J Chromatogr B Analyt Technol Biomed Life Sci.
43. Ringden O, Meunier F, Tollemar J, et al. Efficacy of ampho- J Med. 1987;317:334-341.
2010;878:315-326.
tericin B encapsulated in liposomes (AmBisome) in the 69. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice
18. Cleary JD, Chapman SW, Hardin TC, et al. Amphotericin
treatment of invasive fungal infections in immunocompro- guidelines for the management of cryptococcal disease:
B enzyme-linked immunoassay for clinical use: compari-
mised patients. J Antimicrob Chemother. 1991;28(suppl B): 2010 update by the Infectious Diseases Society of America.
son with bioassay and HPLC. Ann Pharmacother.
73-82. Clin Infect Dis. 2010;50:291-322.
1997;31:39-44.
44. Ellis M, Spence D, de Pauw B, et al. An EORTC interna- 70. Saag MS, Cloud GA, Graybill JR, et al. A comparison of
19. Merz WG, Fay D, Thumar B, Dixon D. Susceptibility testing
tional multicenter randomized trial (EORTC number itraconazole versus fluconazole as maintenance therapy for
of filamentous fungi to amphotericin B by a rapid radio-
19923) comparing two dosages of liposomal amphotericin AIDS-associated cryptococcal meningitis. Clin Infect Dis.
metric method. J Clin Microbiol. 1984;19:54-56.
B for treatment of invasive aspergillosis. Clin Infect Dis. 1999;28:291-296.
20. Sawaya BP, Weihprecht H, Campbell WR, et al. Direct
1998;27:1406-1412. 71. Brouwer AE, Rajanuwong A, Chierakul W, et al. Com­
vasoconstriction as a possible cause for amphotericin
45. Cornely OA, Maertens J, Bresnik M, et al. Liposomal bination antifungal therapies for HIV-associated crypto-
B-induced nephrotoxicity in rats. J Clin Invest. 1991;87:
amphotericin B as initial therapy for invasive mold infec- coccal meningitis: a randomised trial. Lancet. 2004;363:
2097-2107.
tion: a randomized trial comparing a high-loading dose 1764-1767.
21. Anderson CM. Sodium chloride treatment of amphotericin
regimen with standard dosing (AmBiLoad trial). Clin Infect 72. Dromer F, Bernede-Bauduin C, Guillemot D,
B nephrotoxicity. Standard of care? West J Med. 1995;162:
Dis. 2007;44:1289-1297. Lortholary O. Major role for amphotericin B-flucytosine
313-317.
46. Walsh TJ, Finberg RW, Arndt C, et al. Liposomal ampho- combination in severe cryptococcosis. PLoS One. 2008;3:
22. Echevarria J, Seas C, Cruz M, et al. Oral rehydration solu-
tericin B for empirical therapy in patients with persistent e2870.
tion to prevent nephrotoxicity of amphotericin B. Amer J
fever and neutropenia. N Engl J Med. 1999;340:764-771. 73. Smego RA Jr, Perfect JR, Durack DT. Combined therapy
Trop Med Hyg. 2006;75:1108-1112.
47. Prentice HG, Hann IM, Herbrecht R, et al. A randomized with amphotericin B and 5-fluorocytosine for Candida
23. Cruz JM, Peacock JE Jr, Loomer L, et al. Rapid intravenous
comparison of liposomal versus conventional amphoteri- meningitis. Rev Infect Dis. 1984;6:791-801.
infusion of amphotericin B: a pilot study. Am J Med. 1992;
cin B for the treatment of pyrexia of unknown origin in 74. Polak A, Scholer HJ, Wall M. Combination therapy of
93:123-130.
neutropenic patients. Br J Haematol. 1997;98:711-718. experimental candidiasis, cryptococcosis and aspergillosis
24. Drutz DJ. Rapid infusion of amphotericin B: is it safe, effec-
48. Wingard JR, White MH, Anaissie E, et al. A randomized, in mice. Chemotherapy. 1982;28:461-479.
tive, and wise? Am J Med. 1992;93:119-121.
double-blind comparative trial evaluating the safety of 75. Denning DW, Hanson LH, Perlman AM, Stevens DA. In
25. Ellis ME, Al-Hokail AA, Clink HM, et al. Double-blind
liposomal amphotericin B versus amphotericin B lipid vitro susceptibility and synergy studies of Aspergillus
randomized study of the effect of infusion rates on toxicity
complex in the empirical treatment of febrile neutropenia. species to conventional and new agents. Diagn Microbiol
of amphotericin B. Antimicrob Agents Chemother.
Clin Infect Dis. 2000;31:1155-1163. Infect Dis. 1992;15:21-34.
1992;36:172-179.
49. Roden MM, Nelson LD, Knudsen TA, et al. Triad of acute 76. Heel RC, Brogden RN, Carmine A, et al. Ketoconazole: a
26. Imhof A, Walter RB, Schaffner A. Continuous infusion of
infusion-related reactions associated with liposomal review of its therapeutic efficacy in superficial and systemic
escalated doses of amphotericin B deoxycholate: an open-
amphotericin B: analysis of clinical and epidemiological fungal infections. Drugs. 1982;23:1-36.
label observational study. Clin Infect Dis. 2003;36:943-951.
characteristics. Clin Infect Dis. 2003;36:1213-1220. 77. Pfaller MA. Antifungal drug resistance: mechanisms, epi-
27. Andes D, Stamsted T, Conklin R. Pharmacodynamics of
50. Bates DW, Su L, Yu DT, et al. Mortality and costs of acute demiology, and consequences for treatment. Am J Med.
amphotericin B in a neutropenic-mouse disseminated-
renal failure associated with amphotericin B therapy. Clin 2012;125:S3-S13.
candidiasis model. Antimicrob Agents Chemother. 2001;
Infect Dis. 2001;32:686-693. 78. Pfaller MA, Andes D, Arendrup MC, et al. Clinical
45:922-926.
51. Lanternier F, Lortholary O. Liposomal amphotericin B: breakpoints for voriconazole and Candida spp. revisited:
28. Hope WW, Goodwin J, Felton TW, et al. Population phar-
what is its role in 2008? Clin Microbiol Infect. 2008; review of microbiologic, molecular, pharmacodynamic,
macokinetics of conventional and intermittent dosing of
14:71-83. and clinical data as they pertain to the development of
liposomal amphotericin B in adults: a first critical step for
 494.e2
species-specific interpretive criteria. Diagn Microbiol Infect
Dis. 2011;70:330-343.
79. Rex JH, Rinaldi MG, Pfaller MA. Resistance of Candida
species to fluconazole. Antimicrob Agents Chemother. 1995;
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
39:1-8.
80. Arikan-Akdagli S. Azole resistance in Aspergillus: global
status in Europe and Asia. Ann N Y Acad Sci. 2012;1272:
9-14.
81. Product information. Sporanox (itraconazole capsules).
Titusville, NJ, Ortho-McNeil-Janssen Pharmaceuticals,
2011.
82. Stevens DA. Itraconazole in cyclodextrin solution. Phar-
macotherapy. 1999;19:603-611.
83. Barone JA, Moskovitz BL, Guarnieri J, et al. Enhanced bio-
availability of itraconazole in hydroxypropyl-beta-cyclo-
dextrin solution versus capsules in healthy volunteers.
Antimicrob Agents Chemother. 1998;42:1862-1865.
84. de Repentigny L, Ratelle J, Leclerc JM, et al. Repeated-dose
pharmacokinetics of an oral solution of itraconazole in
infants and children. Antimicrob Agents Chemother. 1998;
42:404-408.
85. Saag M. Itraconazole oral solution: pharmacokinetics and
absorption. AIDS Patient Care STDS. 1997;11:S16-S17.
86. Reynes J, Bazin C, Ajana F, et al. Pharmacokinetics of itra-
conazole (oral solution) in two groups of human immuno-
deficiency virus-infected adults with oral candidiasis.
Antimicrob Agents Chemother. 1997;41:2554-2558.
87. Jaruratanasirikul S, Kleepkaew A. Influence of an acidic
beverage (Coca-Cola) on the absorption of itraconazole.
Eur J Clin Pharmacol. 1997;52:235-237.
88. Smith D, van de Velde V, Woestenborghs R, Gazzard BG.
The pharmacokinetics of oral itraconazole in AIDS
patients. J Pharm Pharmacol. 1992;44:618-619.
89. Hostetler JS, Heykants J, Clemons KV, et al. Discrepancies
in bioassay and chromatography determinations explained
by metabolism of itraconazole to hydroxyitraconazole:
studies of interpatient variations in concentrations. Antimi-
crob Agents Chemother. 1993;37:2224-2227.
90. Tucker RM, Haq Y, Denning DW, Stevens DA. Adverse
events associated with itraconazole in 189 patients on
chronic therapy. J Antimicrob Chemother. 1990;26:
561-566.
91. Stevens DA, Lee JY. Analysis of compassionate use itracon-
azole therapy for invasive aspergillosis by the NIAID
Mycoses Study Group criteria. Arch Intern Med. 1997;157:
1857-1862.
92. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial
of itraconazole in allergic bronchopulmonary aspergillosis.
N Engl J Med. 2000;342:756-762.
93. Mangino JE, Pappas PG. Itraconazole for the treatment of
histoplasmosis and blastomycosis. Int J Antimicrob Agents.
1995;5:219-225.
94. Tucker RM, Denning DW, Dupont B, Stevens DA. Itracon-
azole therapy for chronic coccidioidal meningitis. Ann
Intern Med. 1990;112:108-112.
95. Galgiani JN, Cloud GA, Catanzaro A, et al. A comparison
of oral fluconazole or itraconazole for progressive, non-
meningeal coccidioidomycosis. Ann Intern Med. 2000;133:
676-686.
96. Badley AD, Van Scoy RE. Long-term follow-up of multifo-
cal osteoarticular sporotrichosis treated with itraconazole.
Clin Infect Dis. 1996;23:394-395.
97. Sharkey-Mathis PK, Kauffman CA, Graybill JR, et al. Treat-
ment of sporotrichosis with itraconazole. Am J Med. 1993;
95:279-285.
98. Van Hecke E, Van Cutsem J. Double-blind comparison of
itraconazole with griseofulvin in the treatment of tinea
pedis and tinea manuum. Mycoses. 1988;31:641-649.
99. Hecht FM, Wheat J, Korzun AH, et al. Itraconazole main-
tenance treatment for histoplasmosis in AIDS: a prospec-
tive, multicenter trial. J Acquir Immune Defic Syndr Hum
Retrovirol. 1997;16:100-107.
100. Morgenstern GR, Prentice AG, Prentice HG, et al. A ran-
domised controlled trial of itraconazole versus fluconazole
for the prevention of fungal infections in patients with
haematological malignancies. Br J Haematol. 1999;105:
901-911.
101. Nucci M, Biasoli I, Akiti T, et al. A double-blind, random-
ized, placebo-controlled trial of itraconazole capsules as
antifungal prophylaxis for neutropenic patients. Clin Infect
Dis. 2000;30:300-305.
102. Menichetti F, Del Favero A, Martino P, et al. Itraconazole
oral solution as prophylaxis for fungal infections in neutro-
penic patients with hematologic malignancies: a random-
ized, placebo-controlled, double-blind, multicenter trial.
Clin Infect Dis. 1999;28:250-255.
103. Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and
oral itraconazole versus intravenous amphotericin B
deoxycholate as empirical antifungal therapy for persistent
fever in neutropenic patients with cancer who are receiving
broad-spectrum antibacterial therapy: a randomized, con-
trolled trial. Ann Intern Med. 2001;135:412-422.
104. Wilcox CM, Darouiche RO, Laine L, et al. A randomized,
double-blind comparison of itraconazole oral solution and
fluconazole tables in the treatment of esophageal candidia-
sis. J Infect Dis. 1997;176:227-232.
105. Graybill JR, Vazquez J, Darouiche RO, et al. Randomized
trial of itraconazole oral solution for oropharyngeal
candidiasis in HIV/AIDS patients. Am J Med. 1998;104:
33-39.
106. Momeni AZ, Jalayer T, Emamjomeh M, et al. Treatment of
cutaneous leishmaniasis with itraconazole. Randomized
double-blind study. Arch Dermatol. 1996;132:784-786.
107. Product information. Diflucan (fluconazole tablets, fluco-
nazole injection, fluconazole for oral suspension). New
York, Roerig Division, Pfizer, 2011.
108. Zervos M, Meunier F. Fluconazole (Diflucan): a review. Int
J Antimicrob Agents. 1993;3:147-170.
109. DeMuria D, Forrest A, Rich J, et al. Pharmacokinetics and
bioavailability of fluconazole in patients with AIDS. Anti-
microb Agents Chemother. 1993;37:2187-2192.
110. Bliss JM, Wellington M, Gigliotti F. Antifungal pharmaco-
therapy for neonatal candidiasis. Semin Perinatol. 2003;
27:365-374.
111. Stevens DA, Diaz M, Negroni R, et al. Safety evaluation
of chronic fluconazole therapy. Chemotherapy. 1997;43:
371-377.
112. Diaz M, Negroni R, Montero-Gei F, et al. A Pan-American
5-year study of fluconazole therapy for deep mycoses in the
immunocompetent host. Pan-American Study Group. Clin
Infect Dis. 1992;14(suppl 1):S68-S76.
113. Mølgaard-Nielsen D, Pasternak B, Hviid A. Use of flucon-
azole during pregnancy and the risk of birth defects. N Engl
J Med. 2013;369:830-839.
114. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treat-
ment of candidiasis. Clin Infect Dis. 2004;38:161-189.
115. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial
comparing fluconazole with amphotericin B for the treat-
ment of candidemia in patients without neutropenia. N
Engl J Med. 1994;331:1325-1330.
116. Rex JH, Pappas PG, Karchmer AW, et al. A randomized and
blinded multicenter trial of high-dose fluconazole plus
placebo versus fluconazole plus amphotericin B as therapy
for candidemia and its consequences in nonneutropenic
subjects. Clin Infect Dis. 2003;36:1221-1228.
117. Saag MS, Powderly WG, Cloud GA, et al. Comparison of
amphotericin B with fluconazole in the treatment of acute
AIDS-associated cryptococcal meningitis. N Engl J Med.
1992;326:83-89.
118. Van der Horst CM, Saag MS, Cloud GA, et al. Treatment
of cryptococcal meningitis associated with the acquired
immunodeficiency syndrome. N Engl J Med. 1997;337:
15-21.
119. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines
for the management of cryptococcal disease. Clin Infect
Dis. 2000;30:710-718.
120. Powderly WG, Saag MS, Cloud GA, et al. A controlled trial
of fluconazole or amphotericin B to prevent relapse of
cryptococcal meningitis in patients with the acquired
immunodeficiency syndrome. N Engl J Med. 1992;326:
793-798.
121. Haubrich RH, Haghighat D, Bozzette SA, et al. California
Collaborative Treatment Group. High-dose fluconazole for
treatment of cryptococcal disease in patients with human
immunodeficiency virus infection. J Infect Dis. 1994;170:
238-242.
122. Larsen RA, Bozzette SA, Jones BE, et al. Fluconazole
combined with flucytosine for treatment of cryptococcal
meningitis in patients with AIDS. Clin Infect Dis. 1994;
19:741-745.
123. Catanzaro A, Galgiani JN, Levine BE, et al. Fluconazole in
the treatment of chronic pulmonary and nonmeningeal
disseminated coccidioidomycosis. Am J Med. 1995;98:
249-256.
124. Castro LGM, Belda W, Cucé LC, et al. Successful treatment
of sporotrichosis with oral fluconazole: a report of three
cases. Br J Dermatol. 1993;128:352-356.
125. McKinsey DS, Kauffman CA, Pappas PG, et al. Fluconazole
therapy for histoplasmosis. Clin Infect Dis. 1996;23:
996-1001.
126. Goodman JL, Winston DJ, Greenfield RA, et al. A con-
trolled trial of fluconazole to prevent fungal infections in
patients undergoing bone marrow transplantation. N Engl
J Med. 1992;326:845-851.
127. Slavin MA, Osborne B, Adams R, et al. Efficacy and safety
of fluconazole prophylaxis for fungal infections after bone
marrow transplantation: a prospective, randomized,
double-blind study. J Infect Dis. 1995;171:1545-1552.
128. Menichetti F, Del Favero A, Martino P, et al. Preventing
fungal infection in neutropenic patients with acute leuke-
mia: fluconazole compared with oral amphotericin B. The
GIMEMA Infection Program. Ann Intern Med. 1994;120:
913-918.
129. Winston DJ, Chandrasekar PH, Lazarus HM, et al. Fluco-
nazole prophylaxis of fungal infections in patients with
acute leukemia. Results of a randomized placebo-
controlled, double-blind, multicenter trial. Ann Intern
Med. 1993;118:495-503.
130. Marr KA, Seidel K, Slavin MA, et al. Prolonged fluconazole
prophylaxis is associated with persistent protection against
candidiasis-related death in allogeneic marrow transplant
recipients: long-term follow-up of a randomized, placebo-
controlled trial. Blood. 2000;96:2055-2061.
131. Wingard JR, Merz WG, Rinaldi MG, et al. Increase in
Candida krusei infection among patients with bone
marrow transplantation and neutropenia treated prophy-
lactically with fluconazole. N Engl J Med. 1991;325:
1274-1277.
132. Wingard JR, Merz WG, Rinaldi MG, et al. Association of
Torulopsis glabrata infections with fluconazole prophylaxis
in neutropenic bone marrow transplant patients. Antimi-
crob Agents Chemother. 1993;37:1847-1849.
133. Havlir DV, Dube MP, McCutchan JA, et al. Prophylaxis
with weekly versus daily fluconazole for fungal infections
in patients with AIDS. Clin Infect Dis. 1998;27:1369-1375.
134. Schuman P, Capps L, Peng G, et al. Weekly fluconazole for
the prevention of mucosal candidiasis in women with HIV
infection. A randomized, double-blind, placebo-controlled
trial. Terry Beirn Community Programs for Clinical
Research on AIDS [see comments]. Ann Intern Med.
1997;126:689-696.
135. Norris S, Wheat J, McKinsey D, et al. Prevention of relapse
of histoplasmosis with fluconazole in patients with
acquired immunodeficiency syndrome. Am J Med. 1994;
96:504-508.
136. Manzoni P, Stolfi I, Pugni L, et al. A multicenter, random-
ized trial of prophylactic fluconazole in preterm neonates.
N Engl J Med. 2007;356:2483-2495.
137. Kaufman D. Strategies for prevention of neonatal invasive
candidiasis. Semin Perinatol. 2003;27:414-424.
138. Product information. Vfend (voriconazole) tablets, oral
suspension, and IV. New York, Pfizer, 2011.
139. Product Information. Vfend tablets (voriconazole). Vfend
IV (voriconazole for injection). New York, Pfizer, 2002.
140. Muijsers RBR, Goa KL, Scott LJ. Voriconazole in the treat-
ment of invasive aspergillosis. Drugs. 2002;62:2655-2665.
141. Kerkering TM, Grifasi ML, Baffoe-Bonnie AW, et al. Early
clinical observations in prospectively followed patients
with fungal meningitis related to contaminated epidural
steroid injections. Ann Intern Med. 2012;158:154-161.
142. Hassan A, Burhenne J, Riedel KD, et al. Modulators of very
low voriconazole concentrations in routine therapeutic
drug monitoring. Ther Drug Monit. 2011;33:86-93.
143. Mikus G, Scholz IM, Weiss J. Pharmacogenomics of the
triazole antifungal agent voriconazole. Pharmacogenomics.
2011;12:861-872.
144. Pascual A, Calandra T, Bolay S, et al. Voriconazole thera-
peutic drug monitoring in patients with invasive mycoses
improves efficacy and safety outcomes. Clin Infect Dis.
2008;46:201-211.
145. Bruggemann RJM, Donnelly JP, Aarnoutse RE, et al. Thera-
peutic drug monitoring of voriconazole. Ther Drug Monit.
2008;30:403-411.
146. Pasqualotto AC, Shah M, Wynn R, Denning DW. Vori­
conazole plasma monitoring. Arch Dis Child. 2008;93:
578-581.
147. Hussaini T, Ruping MJ, Farowski F, et al. Therapeutic drug
monitoring of voriconazole and posaconazole. Pharmaco-
therapy. 2011;31:214-225.
148. Dolton MJ, Ray JE, Chen SC, et al. Multicenter study of
voriconazole pharmacokinetics and therapeutic drug mon-
itoring. Antimicrob Agents Chemother. 2012;56:4793-4799.
149. Park WB, Kim NH, Kim KH, et al. The effect of therapeutic
drug monitoring on safety and efficacy of voriconazole in
invasive fungal infections: a randomized controlled trial.
Clin Infect Dis. 2012;55:1080-1087.
150. Steinbach WJ, Benjamin DK. New antifungal agents under
development in children and neonates. Curr Opin Infect
Dis. 2005;18:484-489.
151. Pannaraj PS, Walsh TJ, Baker CJ. Advances in antifungal
therapy. Pediatr Infect Dis J. 2005;24:921-922.
152. Product information. Vfend (voriconazole). New York,
Pfizer, 2012. Available at http://www.ema.europa.eu/docs/
en_GB/document_library/EPAR_-_Product_Information/
human/000387/WC500049756.pdf.
153. Zonios DI, Bennett JE. Update on azole antifungals. Semin
Respir Crit Care Med. 2008;29:198-210.
154. Zonios DI, Gea-Banacloche J, Childs R, Bennett JE. Hal-
lucinations during voriconazole therapy. Clin Infect Dis.
2008;47:E7-E10.
155. Cortez KJ, Walsh TJ, Bennett JE. Successful treatment of
coccidioidal meningitis with voriconazole. Clin Infect Dis.
2003;36:1619-1622.
156. Clancy CJ, Nguyen MH. Long-term voriconazole and skin
cancer: is there cause for concern? Curr Infect Dis Rep.
2011;13:536-543.
157. Zwald FO, Spratt M, Lemos BD, et al. Duration of vori­
conazole exposure: an independent risk factor for skin
cancer after lung transplantation. Dermatol Surg. 2012;38:
1369-1374.
158. Singer JP, Boker A, Metchnikoff C, et al. High cumulative
dose exposure to voriconazole is associated with cutaneous

squamous cell carcinoma in lung transplant recipients.
J Heart Lung Transplant. 2012;31:694-699.
159. Wang TF, Wang T, Altman R, et al. Periostitis secondary to
prolonged voriconazole therapy in lung transplant recipi-
ents. Am J Transplant. 2009;9:2845-2850.
160. Herbrecht R, Denning DW, Patterson TF, et al. Voricon-
azole versus amphotericin B for primary therapy of inva-
sive aspergillosis. N Engl J Med. 2002;347:408-415.
161. Marr KA, Schlamm H, Rottinghaus ST, et al. A ran-
domised, double-blind study of combination antifungal
therapy with voriconazole and anidulafungin versus vori-
conazole monotherapy for primary treatment of invasive
aspergillosis. 22nd European Congress of Clinical Micro-
biology and Infectious Diseases. Abstract LB2812. London,
2012.
162. Denning DW, Ribaud P, Milpied N, et al. Efficacy and safety
of voriconazole in the treatment of acute invasive aspergil-
losis. Clin Infect Dis. 2002;34:563-571.
163. Ally R, Schurmann D, Kreisel W, et al. A randomized,
double-blind, double-dummy, multicenter trial of voricon-
azole and fluconazole in the treatment of esophageal can-
didiasis in immunocompromised patients. Clin Infect Dis.
2001;33:1447-1454.
164. Kullberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole versus
a regimen of amphotericin B followed by fluconazole for
candidaemia in non-neutropenic patients: a randomised
non-inferiority trial. Lancet. 2005;366:1435-1442.
165. Ostrosky-Zeichner L, Oude Lashof AM, Kullberg BJ,
Rex JH. Voriconazole salvage treatment of invasive candi-
diasis. Eur J Clin Microbiol Infect Dis. 2003;22:651-655.
166. Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treat-
ment for less-common, emerging, or refractory fungal
infections. Clin Infect Dis. 2003;36:1122-1131.
167. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole com-
pared with liposomal amphotericin B for empirical anti-
fungal therapy in patients with neutropenia and persistent
fever. N Engl J Med. 2002;346:225-234.
168. Powers JH, Dixon CA, Goldberger MJ. Voriconazole
versus liposomal amphotericin B in patients with neutro-
penia and persistent fever. N Engl J Med. 2002;346:
289-290.
169. U.S. Product Information. NOXAFIL (posaconazole)
delayed-release tablets, 100 mg and NOXAFIL (posacon-
azole) oral suspension 40 mg/mL. Kenilworth, NJ, Scher-
ing Corporation, 2013.
170. Krishna G, Ma L, Vickery D, et al. Effect of varying
amounts of a liquid nutritional supplement on the pharma-
cokinetics of posaconazole in healthy volunteers. Antimi-
crob Agents Chemother. 2009;53:4749-4752.
171. Courtney R, Wexler D, Radwanski E, et al. Effect of food
on the relative bioavailability of two oral formulations of
posaconazole in healthy adults. Brit J Clin Pharmacol.
2004;57:218-222.
172a.  Krishna G, Ma L, Martinho M, O’Mara E. Single-dose
phase I study to evaluate the pharmacokinetics of posacon-
azole in new tablet and capsule formulations relative to
oral suspension. Antimicrob Agents Chemother. 2012;56:
4196-4201.
172b.  Krishna G, Ma L, Martinho LM, et al. A new solid oral
tablet formulation of posaconazole: a randomized clinical
trial to investigate rising single- and multiple-dose phar-
macokinetics and safety in healthy volunteers. J Antimicrob
Chemother. 2012;67:2725-2730.
172. Ezzet F, Wexler D, Courtney R, et al. Oral bioavailability of
posaconazole in fasted healthy subjects: comparison
between three regimens and basis for clinical dosage rec-
ommendations. Clin Pharmacokinet. 2005;44:211-220.
173. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or
fluconazole for prophylaxis in severe graft-versus-host
disease. N Engl J Med. 2007;356:335-347.
174. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole
vs. fluconazole or itraconazole prophylaxis in patients with
neutropenia. N Engl J Med. 2007;356:348-359.
175. Nagappan V, Deresinski S. Reviews of anti-infective agents:
posaconazole: a broad-spectrum triazole antifungal agent.
Clin Infect Dis. 2007;45:1610-1617.
176. Steinbach WJ. Antifungal agents in children. Pediat Clin N
Amer. 2005;52:895-915.
177. Thompson GR 3rd, Rinaldi MG, Pennick G, et al. Posacon-
azole therapeutic drug monitoring: a reference laboratory
experience. Antimicrob Agents Chemother. 2009;53:
2223-2224.
178. Dolton MJ, Ray JE, Marriott D, McLachlan AJ. Posacon-
azole exposure-response relationship: evaluating the utility
of therapeutic drug monitoring. Antimicrob Agents Che-
mother. 2012;56:2806-2813.
179. Vazquez JA, Skiest DJ, Nieto L, et al. A multicenter
randomized trial evaluating posaconazole versus flucon-
azole for the treatment of oropharyngeal candidiasis
in subjects with HIV/AIDS. Clin Infect Dis. 2006;42:
1179-1186.
180. Vazquez JA, Skiest DJ, Tissot-Dupont H, et al. Safety and
efficacy of posaconazole in the long-term treatment of
azole-refractory oropharyngeal and esophageal candidiasis
in patients with HIV infection. HIV Clin Trials. 2007;8:
86-97.
181. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive
aspergillosis with posaconazole in patients who are refrac-
tory to or intolerant of conventional therapy: an externally
controlled trial. Clin Infect Dis. 2007;44:2-12.
182. Raad II, Hachem RY, Herbrecht R, et al. Posaconazole as
salvage treatment for invasive fusariosis in patients with
underlying hematologic malignancy and other conditions.
Clin Infect Dis. 2006;42:1398-1403.
183. Stevens DA, Rendon A, Gaona-Flores V, et al. Posaconazole
therapy for chronic refractory coccidioidomycosis. Chest.
2007;132:952-958.
184. Negroni R, Tobon A, Bustamante B, et al. Posaconazole
treatment of refractory eumycetoma and chromoblastomy-
cosis. Rev Inst Med Trop São Paulo. 2005;47:339-346.
185. Tarani L, Costantino F, Notheis G, et al. Long-term
posaconazole treatment and follow-up of rhino-orbital-
cerebral mucormycosis in a diabetic girl. Pediatr Diabetes.
2009;10:289-293.
186. Calcagno A, Baietto L, De Rosa FG, et al. Posaconazole
cerebrospinal concentrations in an HIV-infected patient
with brain mucormycosis. J Antimicrob Chemother. 2011;
66:224-225.
187. Raad II, Graybill JR, Bustamante AB, et al. Safety of
long-term oral posaconazole use in the treatment of refrac-
tory invasive fungal infections. Clin Infect Dis. 2006;42:
1726-1734.
188. Pasqualotto AC, Denning DW. New and emerging treat-
ments for fungal infections. J Antimicrob Chemother.
2008;61(suppl 1):i19-i30.
189. Kurtz MB, Rex JH. Glucan synthase inhibitors as antifungal
agents. Adv Protein Chem. 2001;56:463-475.
190. Cappelletty D, Eiselstein-McKitrick K. The echinocandins.
Pharmacotherapy. 2007;27:369-388.
191. Kim R, Khachikian D, Reboli AC. A comparative evalua-
tion of properties and clinical efficacy of the echinocan-
dins. Expert Opin Pharmacother. 2007;8:1479-1492.
192. Paderu P, Garcia-Effron G, Balashov S, et al. Serum
differentially alters the antifungal properties of echinocan-
din drugs. Antimicrob Agents Chemother. 2007;51:2253-
2256.
193. Pfaller MA, Boyken L, Hollis RJ, et al. In vitro susceptibility
of invasive isolates of Candida spp. to anidulafungin,
caspofungin, and micafungin: six years of global surveil-
lance. J Clin Microbiol. 2008;46:150-156.
194. Pappas PG, Rotstein CMF, Betts RF, et al. Micafungin
versus caspofungin for treatment of candidemia and other
forms of invasive candidiasis. Clin Infect Dis. 2007;45:
883-893.
195. Wiederhold NR. Attenuation of echinocandin activity at
elevated concentrations: a review of the paradoxical effect.
Curr Opin Infect Dis. 2007;20:574-578.
196. Pfaller MA, Castanheira M, Lockhart SR, et al. Frequency
of decreased susceptibility and resistance to echinocandins
among fluconazole-resistant bloodstream isolates of
Candida glabrata. J Clin Microbiol. 2012;50:1199-1203.
197. Bowman JC, Hicks PS, Kurtz MB, et al. The antifungal
echinocandin caspofungin acetate kills growing cells of
Aspergillus fumigatus in vitro. Antimicrob Agents Che-
mother. 2002;46:3001-3012.
198. Odds FC, Motyl M, Andrade R, et al. Interlaboratory com-
parison of results of susceptibility testing with caspofungin
against Candida and Aspergillus species. J Clin Microbiol.
2004;42:3475-3482.
199. Perlin DS. Resistance to echinocandin-class antifungal
drugs. Drug Resist Updat. 2007;10:121-130.
200. Pfaller MA, Diekema DJ, Andes D, et al. Clinical break-
points for the echinocandins and Candida revisited: inte-
gration of molecular, clinical, and microbiological data to
arrive at species-specific interpretive criteria. Drug Resist
Updat. 2011;14:164-176.
201. Product information. Cancidas (caspofungin acetate) for
injection. Whitehouse Station, NJ, Merck, 2010.
202. Deresinski SC, Stevens DA. Caspofungin. Clin Infect Dis.
2003;36:1445-1457.
203. Stone JA, Xu X, Winchell GA, et al. Disposition of caspo-
fungin: role of distribution in determining pharmacokinet-
ics in plasma. Antimicrob Agents Chemother. 2004;48:
815-823.
204. McCormack PL, Perry CM. Caspofungin: a review of its
use in the treatment of fungal infections. Drugs. 2005;
65:2049-2068.
205. Mora-Duarte J, Betts R, Rotstein R, et al. Comparison of
caspofungin and amphotericin B for invasive candidiasis.
N Engl J Med. 2002;347:2020-2029.
206. Villanueva A, Gotuzzo E, Arathoon E, et al. A randomized
double-blind study of caspofungin versus fluconazole for
the treatment of esophageal candidiasis. Am J Med.
2002;113:294-299.
207. Villanueva A, Arathoon EG, Gotuzzo E, et al. A random-
ized double-blind study of caspofungin versus amphoteri-
cin for the treatment of candidal esophagitis. Clin Infect
Dis. 2001;33:1529-1535.
494.e3
208. Arathoon EG, Gotuzzo E, Noriega LM, et al. Randomized,
double-blind, multicenter study of caspofungin versus
amphotericin B for treatment of oropharyngeal and esoph-
ageal candidiasis. Antimicrob Agents Chemother. 2002;46:
Chapter 39  Drugs Active against Fungi, Pneumocystis, and Microsporidia
451-457.
209. Kartsonis N, DiNubile MJ, Bartizal K, et al. Efficacy of
caspofungin in the treatment of esophageal candidiasis
resistant to fluconazole. J Acquir Immune Defic Syndr Hum
Retrovirol. 2002;31:183-187.
210. Maertens J, Glasmacher A, Herbrecht R, et al. Multicenter,
noncomparative study of caspofungin in combination with
other antifungals as salvage therapy in adults with invasive
aspergillosis. Cancer. 2006;107:2888-2897.
211. Maertens J, Raad I, Petrikkos G, et al. Efficacy and safety
of caspofungin for treatment of invasive aspergillosis in
patients refractory to or intolerant of conventional antifun-
gal therapy. Clin Infect Dis. 2004;39:1563-1571.
212. Kartsonis NA, Saah AJ, Joy Lipka C, et al. Salvage therapy
with caspofungin for invasive aspergillosis: results from the
caspofungin compassionate use study. J Infect. 2005;50:
196-205.
213. Caillot D, Thiebaut A, Herbrecht R, et al. Liposomal
amphotericin B in combination with caspofungin for inva-
sive aspergillosis in patients with hematologic malignan-
cies: a randomized pilot study (Combistrat trial). Cancer.
2007;110:2740-2746.
214. Marr KA, Boeckh M, Carter RA, et al. Combination anti-
fungal therapy for invasive aspergillosis. Clin Infect Dis.
2004;39:797-802.
215. Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin
versus liposomal amphotericin B for empirical antifungal
therapy in patients with persistent fever and neutropenia.
N Engl J Med. 2004;351:1391-1402.
216. Reed C, Bryant R, Ibrahim AS, et al. Combination polyene-
caspofungin treatment of rhino-orbital-cerebral mucormy-
cosis. Clin Infect Dis. 2008;47:364-371.
217. Product information. Eraxis (anidulafungin) for injection.
New York, Roerig Division, Pfizer, 2012.
218. Vehreschild JJ, Kummerle T, Karthaus M, Cornely OA.
Anidulafungin—state of affairs from a clinical perspective.
Mycoses. 2007;50:38-43.
219. Benjamin DK Jr, Driscoll T, Seibel NL, et al. Safety and
pharmacokinetics of intravenous anidulafungin in children
with neutropenia at high risk for invasive fungal infections.
Antimicrob Agents Chemother. 2006;50:632-638.
220. Hoffman JA, Walsh TJ. Echinocandins in children. Pediatr
Infect Dis J. 2011;30:508-509.
221. Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin
versus fluconazole for invasive candidiasis. N Engl J Med.
2007;356:2472-2482.
222. Krause DS, Reinhardt J, Vazquez JA, et al. Phase 2, ran­
domized, dose-ranging study evaluating the safety and
efficacy of anidulafungin in invasive candidiasis and
candidemia. Antimicrob Agents Chemother. 2004;48:
2021-2024.
223. Ruhnke M, Paiva JA, Meersseman W, et al. Anidulafungin
for the treatment of candidaemia/invasive candidiasis in
selected critically ill patients. Clin Microbiol Infect. 2012;
18:680-687.
224. Vazquez JA, Sobel JD. Anidulafungin: a novel echinocan-
din. Clin Infect Dis. 2006;43:215-222.
225. Product information. Mycamine (micafungin) for injec-
tion. Deerfield, IL, Astellas Pharma US, 2012.
226. Wiederhold NP, Lewis JS 2nd. The echinocandin micafun-
gin: a review of the pharmacology, spectrum of activity,
clinical efficacy and safety. Expert Opin Pharmacother.
2007;8:1155-1166.
227. Queiroz-Telles F, Berezin E, Leverger G, et al. Micafungin
versus liposomal amphotericin B for pediatric patients with
invasive candidiasis: substudy of a randomized double-
blind trial. Pediatr Infect Dis J. 2008;27:820-826.
228. Zaoutis TE, Benjamin DK, Steinbach WJ. Antifungal treat-
ment in pediatric patients. Drug Resist Update. 2005;8:
235-245.
229. Hope WW, Seibel NL, Schwartz CL, et al. Population phar-
macokinetics of micafungin in pediatric patients and
implications for antifungal dosing. Antimicrob Agents Che-
mother. 2007;51:3714-3719.
230. Seibel NL, Schwartz C, Arrieta A, et al. Safety, tolerability,
and pharmacokinetics of micafungin (FK463) in febrile
neutropenic pediatric patients. Antimicrob Agents Che-
mother. 2005;49:3317-3324.
231. Hope WW, Smith PB, Arrieta A, et al. Population pharma-
cokinetics of micafungin in neonates and young infants.
Antimicrob Agents Chemother. 2010;54:2633-2637.
232. Hiemenz J, Cagnoni P, Simpson D, et al. Pharmacokinetic
and maximum tolerated dose study of micafungin in com-
bination with fluconazole versus fluconazole alone for pro-
phylaxis of fungal infections in adult patients undergoing
a bone marrow or peripheral stem cell transplant. Antimi-
crob Agents Chemother. 2005;49:1331-1336.
233. Sirohi B, Powles RL, Chopra R, et al. A study to determine
the safety profile and maximum tolerated dose of micafun-
gin (FK463) in patients undergoing haematopoietic stem
 494.e4
cell transplantation. Bone Marrow Transplant. 2006;38:
47-51.
234. Kuse ER, Chetchotisakd P, da Cunha CA, et al. Micafungin
versus liposomal amphotericin B for candidaemia and
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
invasive candidosis: a phase III randomised double-blind
trial. Lancet. 2007;369:1519-1527.
235. Ostrosky-Zeichner L, Kontoyiannis D, Raffalli J, et al.
International, open-label, noncomparative, clinical trial of
micafungin alone and in combination for treatment of
newly diagnosed and refractory candidemia. Eur J Clin
Microbiol Infect Dis. 2005;24:654-661.
236. Arrieta A, Queiroz-Telles F, Berezin E, et al. Micafungin
versus liposomal amphotericin B (AmBisome®) in paediat-
ric patients with invasive candidiasis or candidaemia. 17th
European Congress of Clinical Microbiology and Infec-
tious Diseases. Abstract No. 1732_85. Munich, 2007.
237. de Wet NTE, Bester AJ, Viljoen JJ, et al. A randomized,
double blind, comparative trial of micafungin (FK463) vs.
fluconazole for the treatment of oesophageal candidiasis.
Aliment Pharmacol Ther. 2005;21:899-907.
238. de Wet N, Llanos-Cuentas A, Suleiman J, et al. A random-
ized, double-blind, parallel-group, dose-response study of
micafungin compared with fluconazole for the treatment
of esophageal candidiasis in HIV-positive patients. Clin
Infect Dis. 2004;39:842-849.
239. van Burik JA, Ratanatharathorn V, Stepan DE, et al. Mica-
fungin versus fluconazole for prophylaxis against invasive
fungal infections during neutropenia in patients undergo-
ing hematopoietic stem cell transplantation. Clin Infect Dis.
2004;39:1407-1416.
240. Denning DW, Marr KA, Lau WM, et al. Micafungin
(FK463), alone or in combination with other systemic anti-
fungal agents, for the treatment of acute invasive aspergil-
losis. J Infection. 2006;53:337-349.
241. Kohno S, Masaoka T, Yamaguchi H, et al. A multicenter,
open-label clinical study of micafungin (FK463) in the
treatment of deep-seated mycosis in Japan. Scand J Infec
Dis. 2004;36:372-379.
242. Huang L, Cattamanchi A, Davis JL, et al. HIV-associated
Pneumocystis pneumonia. Proc Am Thorac Soc. 2011;8:
294-300.
243. Wharton JM, Coleman DL, Wofsy CB, et al. Trimethoprim-
sulfamethoxazole or pentamidine for Pneumocystis carinii
pneumonia in the acquired immunodeficiency syndrome.
A prospective randomized trial. Ann Intern Med. 1986;
105:37-44.
244. Klein NC, Duncanson FP, Lenox TH, et al. Trimethoprim-
sulfamethoxazole versus pentamidine for Pneumocystis
carinii pneumonia in AIDS patients: results of a large
prospective randomized treatment trial. AIDS. 1992;6:
301-305.
245. Kaplan JE, Benson C, Holmes KH, et al. Guidelines for
prevention and treatment of opportunistic infections in
HIV-infected adults and adolescents: recommendations
from CDC, the National Institutes of Health, and the HIV
Medicine Association of the Infectious Diseases Society of
America. MMWR Recomm Rep. 2009;58:1-207; quiz
CE1-4.
246. Mofenson LM, Brady MT, Danner SP, et al. Guidelines for
the Prevention and Treatment of Opportunistic Infections
among HIV-exposed and HIV-infected children: recom-
mendations from CDC, the National Institutes of Health,
the HIV Medicine Association of the Infectious Diseases
Society of America, the Pediatric Infectious Diseases
Society, and the American Academy of Pediatrics. MMWR
Recomm Rep. 2009;58:1-166.
247. Carr A, Swanson C, Penny R, Cooper DA. Clinical and
laboratory markers of hypersensitivity to trimethoprim-
sulfamethoxazole in patients with Pneumocystis carinii
pneumonia and AIDS. J Infect Dis. 1993;167:180-185.
248. Sun T, Zhang Y. Pentamidine binds to tRNA through non-
specific hydrophobic interactions and inhibits aminoacyla-
tion and translation. Nucleic Acids Res. 2008;36:1654-
1664.
249. Harstad TW, Little BB, Bawdon RE, et al. Embryofetal
effects of pentamidine isethionate administered to preg-
nant Sprague-Dawley rats. Am J Obstet Gynecol. 1990;
163:912-916.
250. Product information. Pentam 300 (pentamidine isethion-
ate for injection). Schaumberg, IL, APP Pharmaceuticals,
2008.
251. Bronner U, Gustafsson LL, Doua F, et al. Pharmacokinetics
and adverse reactions after a single dose of pentamidine in
patients with Trypanosoma gambiense sleeping sickness.
Br J Clin Pharmacol. 1995;39:289-295.
252. Product information. NebuPent (pentamidine isethionate).
Schaumberg, IL, APP Pharmaceuticals, 2008.
253. Assan R, Perronne C, Assan D, et al. Pentamidine-induced
derangements of glucose homeostasis. Determinant roles
of renal failure and drug accumulation. A study of 128
patients. Diabetes Care. 1995;18:47-55.
254. Didier ES, Weiss LM. Microsporidiosis: current status.
Curr Opin Infect Dis. 2006;19:485-492.
255. Molina JM, Chastang C, Goguel J, et al. Albendazole for
treatment and prophylaxis of microsporidiosis due to
Encephalitozoon intestinalis in patients with AIDS: a ran-
domized double-blind controlled trial. J Infect Dis. 1998;
177:1373-1377.
256. Franzen C, Salzberger B. Analysis of the beta-tubulin gene
from Vittaforma corneae suggests benzimidazole resis-
tance. Antimicrob Agents Chemother. 2008;52:790-793.
257. Fan NW, Wu CC, Chen TL, et al. Microsporidial keratitis
in patients with hot springs exposure. J Clin Microbiol.
2012;50:414-418.
258. Khandelwal SS, Woodward MA, Hall T, et al. Treatment of
microsporidia keratitis with topical voriconazole mono-
therapy. Arch Ophthalmol. 2011;129:509-510.
259. Loh RS, Chan CM, Ti SE, et al. Emerging prevalence of
microsporidial keratitis in Singapore: epidemiology, clini-
cal features, and management. Ophthalmology. 2009;116:
2348-2353.
260. Zhang Y, Yeh JR, Mara A, et al. A chemical and genetic
approach to the mode of action of fumagillin. Chem Biol.
2006;13:1001-1009.
261. Higes M, Nozal MJ, Alvaro A, et al. The stability and effec-
tiveness of fumagillin in controlling Nosema ceranae
(Microsporidia) infection in honey bees (Apis mellifera)
under laboratory and field conditions. Apidologie. 2011;42:
364-377.
262. Lanternier F, Boutboul D, Menotti J, et al. Microsporidiosis
in solid organ transplant recipients: two Enterocytozoon
bieneusi cases and review. Transpl Infect Dis. 2009;11:
83-88.
263. Molina JM, Tourneur M, Sarfati C, et al. Fumagillin treat-
ment of intestinal microsporidiosis. N Engl J Med. 2002;
346:1963-1969.
264. Champion L, Durrbach A, Lang P, et al. Fumagillin for
treatment of intestinal microsporidiosis in renal transplant
recipients. Am J Transplant. 2010;10:1925-1930.
265. Rosberger DF, Serdarevic ON, Erlandson RA, et al. Suc-
cessful treatment of microsporidial keratoconjunctivitis
with topical fumagillin in a patient with AIDS. Cornea.
1993;12:261-265.
266. Wilkins JH, Joshi N, Margolis TP, et al. Microsporidial
keratoconjunctivitis treated successfully with a short
course of fumagillin. Eye (Lond). 1994;8(pt 6):703-704.
267. Lowder CY, McMahon JT, Meisler DM, et al. Microsporid-
ial keratoconjunctivitis caused by Septata intestinalis in a
patient with acquired immunodeficiency syndrome. Am J
Ophthalmol. 1996;121:715-717.
268. Chan CM, Theng JT, Li L, Tan DT. Microsporidial kerato-
conjunctivitis in healthy individuals: a case series. Ophthal-
mology. 2003;110:1420-1425.
269. Diesenhouse MC, Wilson LA, Corrent GF, et al. Treatment
of microsporidial keratoconjunctivitis with topical fuma-
gillin. Am J Ophthalmol. 1993;115:293-298.
270. Garvey MJ, Ambrose PG, Ulmer JL. Topical fumagillin in
the treatment of microsporidial keratoconjunctivitis in
AIDS. Ann Pharmacother. 1995;29:872-874.
271. Arikan S, Rex JH. New agents for the treatment of systemic
fungal infections-current status. Expert Opin Emerging
Drugs. 2002;7:3-32.
272. Ostrosky-Zeichner L, Casadevall A, Galgiani JN, et al. An
insight into the antifungal pipeline: selected new molecules
and beyond. Nat Rev Drug Discov. 2010;9:719-727.
273. Spellberg B, Ibrahim AS, Chin-Hong PV, et al. The
Deferasirox-AmBisome therapy for mucormycosis
(DEFEAT Mucor) study: a randomized, double-blinded,
placebo-controlled trial. J Antimicrob Chemother. 2012;67:
715-722.
274. Segal BH, Safdar A, Stevens DA. Immunotherapy for
difficult-to-treat invasive fungal diseases. In: Safdar A, ed.
Principles and Practice of Cancer Infectious Diseases.
Current Clinical Oncology series. New York: Springer
Science+Business Media; 2011.
275. Antachopoulos C, Walsh TJ. Immunotherapy of Cryptococ-
cus infections. Clin Microbiol Infect. 2012;18:126-133.
276. Antachopoulos C, Katragkou A, Roilides E. Immunother-
apy against invasive mold infections. Immunotherapy.
2012;4:107-120.
277. van de Veerdonk FL, Kullberg BJ, Netea MG. Adjunctive
immunotherapy with recombinant cytokines for the treat-
ment of disseminated candidiasis. Clin Microbiol Infect.
2012;18:112-119.
278. Hamilton-Miller JM. Fungal sterols and the mode of action
of the polyene antibiotics. Adv Appl Microbiol. 1974;17:
109-134.
279. Gale EF. Perspectives in chemotherapy. Br Med J. 1973;4:
33-38.
280. Pratt WB. Chemotherapy of Infection. New York: Oxford
University Press; 1977.
281. Vanden Bossche H, Warnock DW, Dupont B, et al. Mecha-
nisms and clinical impact of antifungal drug resistance.
J Med Vet Mycol. 1994;32(suppl 1):189-202.
282. Francis P, Walsh TJ. Evolving role of flucytosine in immu-
nocompromised patients: new insights into safety, pharma-
cokinetics, and antifungal therapy. Clin Infect Dis. 1992;
15:1003-1018.
283. Paine MF, Hart HL, Ludington SS, et al. The human intes-
tinal cytochrome P450 “pie”. Drug Metab Dispos. 2006;
34:880-886.
284. Inoue Y, Saito T, Takimoto M, et al. Highly activated
oral bioavailability of tacrolimus on coadministration of
oral voriconazole. Int J Clin Pharmacol Ther. 2011;49:
291-292.
285. Spriet I, Grootaert V, Meyfroidt G, et al. Switching from
intravenous to oral tacrolimus and voriconazole leads to a
more pronounced drug-drug interaction. Eur J Clin Phar-
macol. 2012;69:737-738.
286. Bruggemann RJ, Alffenaar JW, Blijlevens NM, et al. Clinical
relevance of the pharmacokinetic interactions of azole anti-
fungal drugs with other coadministered agents. Clin Infect
Dis. 2009;48:1441-1458.