Figure 78-2 Disseminated Blastomyces dermatitidis skin ulcers.
Figure 78-3 Chest radiograph of pulmonary Blastomyces dermatitidis. Arrow marks abnormality.
CASE 78-5, QUESTION 2: What specific therapy should be initiated for C.P.?
Historically, AmB formulations were considered the treatment of choice for
blastomycosis, and total doses of more than 2 g were associated with 97% cure rates,
low relapse rates, but also, however, substantial associated toxicity.
effectiveness of azoles for the treatment of chronic pulmonary and extrapulmonary
disease associated with blastomycosis and histoplasmosis. In uncontrolled
rates of about 89%, failure rates of about 6%, and relapse rates of about 5%.
similar studies, itraconazole capsules 200 to 400 mg/day for a median of 6.2 months
resulted in cure rates of 88% to 95%.
131 Fluconazole was ineffective at dosages less
than 400 mg/day. Higher dosages (400–800 mg/day), however, are as effective as
ketoconazole in non–life-threatening diseases.
132 Although these trials are neither
comparative nor controlled, itraconazole is less toxic than ketoconazole and with the
best benefit (efficacy) to risk (toxicity) ratio.
C.P. has mild-to-moderate disease and can be treated with an initial itraconazole
dosage of 200 mg/day. If no clinical improvement is seen within 2 weeks or if the
disease progresses, the dosage of itraconazole can be titrated upward in 100-mg
increments to a maximal dosage of 400 mg/day. Treatment should be continued for at
least 6 months. If C.P. experiences severe or meningeal disease, itraconazole should
be discontinued and AmB or a lipid-based AmB product should be initiated. C.P.
should be followed up for 12 months owing to the risk of relapse. Unlike
histoplasmosis, skin test and serologic testing are not sufficiently sensitive to
diagnose blastomycosis or evaluate the effectiveness of treatment.
patients should be evaluated closely for resolution of symptoms (constitutional and
pulmonary), negative microbiologic samples, and improvement in radiographic
positive. How does this information change the therapeutic options for her?
Data on the safety of antimycotics for treating patients who are pregnant or
lactating are limited but are comprehensively reviewed according to FDA categories
of the teratogenic risks of drugs (see Chapter 49, Obstetric Drug Therapy).
systemic azoles are categorized with risk factor C. A recent Danish registration study
did not find evidence of birth defects in women who took itraconazole during their
136,137 However, the majority of women analyzed in this registry
received low cumulative doses of triazoles for thrush. However, these agents should
be avoided in pregnant or lactating women who are breastfeeding because of their
potential teratogenicity and endocrine toxicity in the fetus or newborn. As with the
azoles, griseofulvin and flucytosine have been classified with risk factor C. These
agents should not be used in C.P. because the risk clearly outweighs the therapeutic
benefit. Few or no data exist on the secretion of these agents in breast milk.
Therefore, breastfeeding should be discouraged in women receiving these antifungal
AmB and terbinafine are classified as risk factor B. Therapeutic agents in this
category have no fetal risk based on animal studies, or when risk has been found in
animals, controlled human studies have not confirmed the results. There are limited
data regarding the use of terbinafine in pregnancy. Consequently, clinicians should
avoid terbinafine use in pregnancy until published data support a B classification.
Furthermore, considerable clinical experience with AmB formulations in pregnant
women has documented successful treatment of systemic mycoses with no excess
toxicity to either the mother or the fetus. Thus, AmB formulations have been the
mainstay of antifungal therapy in pregnancy.
QUESTION 1: J.N., a 47-year-old man with severe rheumatoid arthritis, has been maintained on daily
Hematocrit, 29% (normal, 39%–45% SI units, 0.29)
WBC count, 3,500 cells/μL (normal, 4,000–11,000 cells/μL) (SI units, 3.5 × 10
Platelet count, 78,000 cells/μL (normal, 130 to 400,000 cells/μL)
UA, 8 to 10 WBC/high-power field
SCr, 1.9 mg/dL (SI units, 167.96 μmol/L)
BUN, 42 mg/dL (SI units, 14.99 mmol/L urea)
parameters should be monitored to assess the efficacy and toxicity of J.N.’s therapy?
The treatment benefits of antifungal therapy in systemic histoplasmosis have not
been well investigated. Treatment options for histoplasmosis are outlined in Table
138 Accordingly, J.N. should be treated with an IV amphotericin product or
itraconazole 2.8 mg/kg/day, and his course of therapy should be monitored for both
efficacy and toxicity. The decision was made to use conventional amphotericin for
Blood and urine cultures, WBC and platelet counts (histoplasma is associated with
pancytopenia), constitutional symptoms, serum lactate dehydrogenase, and
hepatosplenomegaly are useful measures for evaluating the outcome of antifungal
therapy of J.N.’s histoplasmosis. Anemia and chest radiographs are poor measures of
treatment response. Chest radiographs often reflect calcified granulomas in chronic
disease with scarring, which rarely resolve even with extensive therapy. Therefore,
evaluation of deterioration on radiograph, but not of improvement, is possible. In
addition, AmB-induced renal disease with secondary anemia can confuse evaluation
of disease resolution. Anemia must be excluded as a prognostic indicator in patients
receiving AmB for durations of 3 weeks regardless of the dose.
peripheral blood showing leukocytes with intracellular organisms.
ITZ 50–100 mg/day (3–6 months)
Respiratory distress AmB lipid formulation 3–5
(Pao2 <70 mm Hg) AmB 0.5–1.0 mg/kg/day ITZ 1.5–2.8 mg/kg/day (≥6
(TD 250–500 mg) ± corticosteroids
(methylprednisolone 0.5–1 mg/kg) ×
ITZ (has not been investigated in
Active ITZ (1.5–2.8 mg/kg/day 9
Inactive or KTZ 400 mg/day (≈6 mos)
Histoplasmoma No treatment N/A
mg/kg) or lipid AmB then ITZ 2.8
Indicated only for serious symptoms (i.e., hemoptysis).
ITZ 200 mg daily or twice a day for 6–18 months for most patients.
eFluconazole should only be used in patients who cannot take ITZ.
AmB, amphotericin B deoxycholate; ITZ, itraconazole; KTZ, ketoconazole; TD, total dose.
Diligent follow-up of patients is required because relapses occur in 5% to 15% of
AmB-treated patients within 3 years. Relapses have occurred in patients who
received less than 30 mg/kg total dose of generic AmB or had concomitant untreated
Addison disease, immunosuppression, vascular infections (endocarditis, grafts, and
aneurysms), or meningeal infections.
138 More than 90% of HIV-positive patients
experience a relapse of histoplasmosis subsequent to adequate AmB therapy. A
in immunocompromised patients (HIV) revealed that liposomal AmB was superior
to AmB deoxycholate. It is not known how itraconazole is compared with liposomal
139 Even the initiation of subsequent
immunosuppressive therapy is of particular concern because of the potential for
reactivation (relapse) and dissemination of histoplasmosis from dormant foci,
especially in patients with residual granulomas. The residual disease has been
hypothesized to lead to chronic inflammatory responses and secondary strokes.
thrombophlebitis). In addition, J.N.’s adrenal status should be monitored closely
because of his long-term corticosteroid therapy and his histoplasmosis. Patients who
are addisonian secondary to histoplasmosis infections appear to experience more
episodes of AmB-induced acute hypotension.
ketoconazole is the cause of J.N.’s impotence?
Ketoconazole has been associated with more adverse reactions and greater
potential for drug interactions compared with itraconazole and fluconazole. The most
common side effects of ketoconazole, however, are nausea and vomiting. GI distress
is dose-related, with fewer GI effects with 400 mg/day compared with 800
138 Endocrine and hepatic toxicities are the most significant adverse effects of
ketoconazole. Dose-splitting from daily to twice daily may decrease nausea and
vomiting. Dose-related endocrinologic toxicities (hypoadrenalism, oligospermia, and
diminished libido) have been observed during ketoconazole therapy secondary to the
inhibition of mammalian sterol synthesis
13,141 and usually have been resolved with
drug discontinuation. Therefore, J.N.’s complaints of impotence might well be
attributed to his ketoconazole. Liver enzymes should also be monitored because an
approximate 10% risk exists of elevation in transaminases and an occasional case of
serious hepatitis and hepatic failure.
The triazoles—itraconazole, fluconazole, and voriconazole—are much better
tolerated and require less monitoring than ketoconazole therapy. This result has been
attributed to the greater affinity of the triazoles for fungal cytochrome enzymes and
less interference with mammalian enzymes.
mg/kg/day), and voriconazole do not exhibit antiandrogenic effects, and nausea and
vomiting are less common when compared with imidazoles. Abnormal elevations in
liver function have been reported in 2.7% of patients receiving voriconazole during
clinical trials. Abnormalities in liver function tests may be associated with higher
azole dosages or serum concentrations but generally resolve either with continued
therapy or dosage modification, including drug discontinuance. Liver function should
be determined before and periodically throughout azole therapy because cases of
serious hepatic reactions have been reported.
142 A unique adverse event associated
with voriconazole is enhanced perception to light, which may be associated with
higher plasma concentrations or doses. Generally, drug discontinuance is not
required, although monitoring of visual acuity, visual field, and color perception is
advised if therapy lasts longer than 28 days. Diarrhea, asthenia, flatulence, and eye
pain have been reported with posaconazole therapy.
should be given a trial of itraconazole.
CASE 78-6, QUESTION 3: J.N. chose to continue his ketoconazole therapy. He now returns with
of this serious problem in J.N.?
Drug interactions with systemic azoles and polyenes vary from mild
inconveniences to life-threatening events. Historically, the interaction between azoles
-selective antihistamines has been serious, leading to QT
prolongation and ventricular arrhythmias.
143 Although it is possible that concomitant
use of corticosteroids could reduce antifungal efficacy, no clinical trial has
addressed this important question. Corticosteroid serum concentrations can double
with concomitant use of ketoconazole, leading to recommendations to decrease the
steroid dose by 50% when ketoconazole is used. The interaction has been suggested
between glucocorticoids and other azoles.
In addition, dexamethasone has been
demonstrated to increase the clearance of caspofungin.
Other significant drug interactions with the azole antifungals involve their ability
to inhibit the CYP450 enzyme system. All azoles inhibit CYP3A4, but with varying
potency: Ketoconazole is the most potent inhibitor, followed by itraconazole and
voriconazole, then posaconazole and fluconazole. Data on relative inhibition potency
for isavuconazole are still pending. In addition to therapeutic interactions, numerous
other agents are substrates to cytochrome CYP3A4 but have yet to be evaluated.
Because azole antifungals could increase serum concentrations with associated
potential toxicity, caution should be exercised during concomitant use. Adding
complexity to voriconazole’s interactions includes its propensity to inhibit CYP2C9
and CYP2C19, two isoenzymes exhibiting polymorphism, thus increasing
concentrations of CYP2C9 or CYP2C19 substrates. Conversely, agents that either
induce or inhibit the CYP450 system may decrease or increase, respectively,
antifungal drug concentrations. Posaconazole is a substrate for p-glycoprotein efflux
and is metabolized via uridine diphosphate glucuronidation; therefore, inhibitors or
inducers of these clearance pathways may affect posaconazole concentrations.
Although hundreds of drug interactions have been documented with antifungals
(particularly azoles), the number of theoretical interactions probably exceeds
145 Therefore, patient medication profiles should be carefully screened before
initiating and stopping antifungal therapy to assess the risk for serious drug
interactions. Preferably, this screening should be performed with a frequently
updated computerized interaction database, which are available commercially
(Lexicomp) or free of cost (www.fungalpharmacology.org), including software for
mmHg) was documented at lumbar puncture. Analysis of the CSF showed:
Glucose, 18 mg/dL (normal, 60% of serum glucose)
Protein, 190 mg/dL (normal, <50 mg/dL)
The most important serologic tests for fungal infections use CF, immunodiffusion,
and EIA techniques. Tests for complement-fixing antibodies (i.e., CF) to the
dimorphic fungi (Table 78-1) are well established, and various antigens have been
used. Coccidioidin is the mycelial-phase antigen for Coccidioides immitis. Of
patients with coccidioidomycosis, 61% will have coccidioidin CF titers of at least
1:32, and 41% will have titers of 1:64. Rising titers are a bad prognostic sign, and
falling titers indicate clinical improvement. Therefore, F.W.’s CSF CF titer of 1:32
is consistent with active coccidioidomycosis. Immunodiffusion testing for
coccidioidomycosis using coccidioidin reveals that seropositive results appear 1 to
3 weeks after the onset of primary infection in 75% of patients, and this positivity
usually disappears within 4 months if the infection resolves.
These tests offer sensitivities of more than 92% and specificities of 98% for serum
and CSF. EIA reactivity appears earlier than CF reactivity.
ANTIFUNGAL CENTRAL NERVOUS SYSTEM PENETRATION
CASE 78-7, QUESTION 2: What is a pharmacokinetic explanation for the treatment failure of F.W.? How
might this problem be overcome?
F.W. has received prolonged parenteral AmB administration, and the CSF still
contains fungal organisms. Treatment failures in this case may partly be owing to the
limited penetration of free AmB into the CSF.
88 Because generic AmB or lipid
formulation– dissociated AmB is highly bound to lipid (90%–95%), CSF
concentrations achieved are only 2% to 4% of the serum concentration
peritoneal, synovial, and pleural fluid concentrations are less than 50% of the serum
concentrations (Table 78-5). Flucytosine is not significantly bound to protein and
penetrates the CSF, vitreous, and peritoneal fluids; its volume of distribution
approximates that of total body water.
149 Flucytosine concentration in the CSF is 74%
of the serum concentration, resulting in its extensive use in treatment of CNS
mycoses, particularly cryptococcal meningitis. Flucytosine, however, has no activity
in coccidioidomycosis and, therefore, cannot be used in F.W.
The volume of distribution of fluconazole approaches that of total body water,
and concentrations of fluconazole in CSF are approximately 60% of simultaneous
serum concentrations. Ketoconazole penetrates CSF poorly, because it is highly
bound to plasma proteins (>80%) and to erythrocytes (15%). Itraconazole is similar
to ketoconazole in that it is greater than 99% protein-bound. Itraconazole
concentrates intracellularly in host alveolar macrophages, which may account for its
efficacy against some fungal CNS infections despite its inability to penetrate into the
151 Echinocandins also poorly (<5%) penetrate into the CSF. Reliable data on
terbinafine, isavuconazole and posaconazole penetration are currently unavailable.
Therefore, fluconazole might be an alternative to CNS instillation of AmB based
upon pharmacokinetic considerations.
Fluconazole, investigated at dosages of 400 mg/day, is useful in patients with
coccidioidomycosis meningitis. Similar to amphotericin products, relapse rates are
high once fluconazole therapy is stopped. Oral itraconazole 200 mg twice daily was
not found to be superior to fluconazole in a controlled trial of nonmeningitis disease;
however, a trend toward greater efficacy was observed, particularly in skeletal
Augmentation of systemic antifungal administration with intraventricular or
intrathecal administration may improve the outcome for antifungals with poor
penetration into the CSF. Intrathecal generic AmB doses in adults normally range
from 0.25 to 0.5 mg diluted in 5 mL of 5% glucose.
155,156 A few studies suggest that
doses larger than 0.7 mg improve the cure rate and decrease relapse. Cisternal or
intraventricular administration is recommended as the routes of choice because of
flow characteristics of CSF from the ventricles to the spinal cord. When lumbar
administration has been necessary, agents are administered in a hypertonic solution
of 10% glucose, and the patient is placed in a Trendelenburg position in an attempt to
improve distribution of the drug to the basilar meninges and ventricles and reduce
local toxicity. Voriconazole, caspofungin, and the lipid amphotericin formulations
have been used, but not evaluated in controlled trials.
Cisternal antifungal administration has been associated with headaches, nausea,
vomiting, cranial nerve paresis, and cisternal hemorrhage caused by needle trauma.
An Ommaya reservoir often is used to facilitate intraventricular administration of
AmB formulations. Common complications of these devices include shunt occlusion,
bacterial colonization or bacterial meningitis, Parkinsonian symptoms, and
In the past, lumbar administration was used because it is simpler, but
it often must be discontinued because of chemical arachnoiditis, headache, transient
radiculitis, paresthesia, nerve pulses, difficulty voiding, impaired vision, vertigo,
and tinnitus. Acute toxic delirium, demyelinating peripheral neuropathy, and spinal
cord injury have also been reported.
159–162 Regardless of the substantial and serious
adverse effects, intraventricular administration may be effective in treating patients
with meningitis who have severe disease or who are pharmacologic nonresponders.
EMPIRIC THERAPY (NEUTROPENIC HOST)
QUESTION 1: M.Z., an otherwise healthy 29-year-old man, who received an allogeneic stem cell
morning, he was complaining of fever, chest pain, and headache. On physical examination, his
in his right lung. What therapeutic options should be considered for this patient?
Empiric antifungal therapy in a neutropenic host should be initiated when a patient
is febrile for more than 96 hours on appropriate antibiotics. Routine empiric therapy
for a patient without evidence of deep-seated fungal infection was historically
generic AmB 0.3 to 0.6 mg/kg/day or fluconazole 200 to 400 mg/day until the
absolute neutrophil count is greater than 500 cells/μL.
163 Therapy results in resolution
of signs and symptoms in up to 64% of patients.
CASE 78-8, QUESTION 2: What is the role of lipid formulations of AmB?
Because mold infections are of concern in this neutropenic patient who received
an allogeneic stem cell transplant, mold-active antifungal therapy should be started
immediately. A large, well- controlled, double-blind AmB 0.6 mg/kg/day was
compared with liposomal AmB 3.0 mg/kg/day in febrile neutropenic patients.
Patients who were febrile more than 96 hours and neutropenic (<500 cells/μL)
experienced equal survival and clinical success of approximately 50% for both the
164 Success rates have been similar with other agents, including liposomal
165 voriconazole, or itraconazole.
important to remember that fever is a late and insensitive measure of infection.
Prevention of breakthrough invasive fungal infection may be the most important
indicator of an agent’s efficacy. Using this measure comparing the various trials,
voriconazole appears to be the most effective agent, voriconazole versus liposomal
AmB (1.9% vs. 5%) and AmB versus liposomal AmB (3.2% vs. 7.8%), although
crude mortality rates were similar in the two patient groups (8% vs. 6%,
164,167 Selection of expensive, but less toxic, agents should be weighed
against the morbidity and mortality associated with invasive fungal disease.
CASE 78-8, QUESTION 3: Fiberoptic bronchoscopy performed to evaluate the nodular lesion in chest CT
revealed fragmented, closely septated hyphal bodies branched at 45° angles. The samples were sent to
What treatment steps should be taken?
Drug therapy should be approached by first determining whether the infection is
likely to be invasive or noninvasive disease (Fig. 78-5). Most patients inhale
Aspergillus species and never become symptomatic or exhibit only mild
hypersensitivity pneumonitis. Pepper can be a common food source for Aspergillus
exposure. Invasive infections are more likely to occur in immunocompromised
patients, especially those with prolonged neutropenia or patients who receive high
dose (i.e., more than 1 mg/kg/day prednisone equivalent) or corticosteroids or other
T-cell immunosuppressive therapy (i.e., alemtuzumab and anti-thymocyte globulin) to
treat acute graft versus host disease following stem cell transplantation or organ
rejection after solid organ transplantation. Allogeneic hematopoietic stem cell
transplantation (HSCT) has a much greater infection rate and mortality compared
168 A classic observation reported by radiology is a “halo”
sign or a “crescent” sign identified on CT, which is highly suggestive of invasive
aspergillosis. However, the halo sign is not specific, because other bacterial viral,
malignant, or autoimmune conditions can produce similar radiographic findings. The
halo sign is also transient and is less common after 1-week of infection. Typically
these nodular lesions will enlarge (even with effective antifungal therapy) and then
cavitate when a patient’s neutrophil count recovers, forming another distinguishing
CT abnormality for invasive mold disease—the air crescent sign.
A majority invasive aspergillosis cases are now diagnosed based on a compatible
clinical and radiographic picture described above and the results of an ELISA
antigen test for a cell wall polysaccharide in Aspergillus spp.-galactomannan. Serum
galactomannan test is a fairly sensitive and specific test (80%–90%) in neutropenic
patients with aspergillosis who rapidly progress to angioinvasive disease in the lung.
The test is less sensitive in non-neutropenic patients who initially present with
bronchial invasive patterns of pneumonia before angioinvasion or in patients
receiving mold-active antifungal therapy.
In these populations, testing of bronchial
alveolar lavage fluid for galactomannan antigen has better sensitivity than serum.
False-positive test findings have been associated with Bifidobacterium sp.
colonization in pediatric GI tracts, other eukaryotic infections (i.e., Trichosporon,
Fusarium, Saccharomyces, Hisplasma, or Acremonium), and administration of
piperacillin–tazobactam or calcium gluconate, which is of concern for clinicians
using this test for screening in areas with low case rates. Galactomannan antigen is a
useful prognostic indicator for therapeutic outcome in confirmed cases or as a screen
in areas with high case rates. The subjective and objective data in this case clearly
represent invasive symptomatic disease necessitating aggressive treatment.
Aspergillosis is a model for invasive mold infections that have a propensity to
invade blood vessels and tissue. Antifungal therapy should be initiated rapidly and
aggressively (Table 78-8) in conjunction with the removal or reversal of
immunosuppression if possible. Definite or probable invasive aspergillosis should
be treated with voriconazole, isavuconazole, or lipid amphotericin B formulation
(i.e., liposomal AmB 3–5 mg/kg/day), or combination therapy.
European organization for research and treatment of cancer (EORTC)/Mycoses study
group (MSG) trial performed in patients with probable or proven aspergillosis, a
combination therapy with voriconazole plus anidulafungin for at least 2 weeks was
associated with an 8% reduction in 6-week all-cause mortality versus voriconazole
monotherapy alone, although this difference was not statistically different in the
context of the design of the clinical trial.
174 Therefore, the optimal approach for using
combination therapy in invasive aspergillosis remains unresolved. Despite early and
intensive therapy, mortality from invasive aspergillosis can be greater than 50%.
unresponsive patients, a lipid AmB formulation in combination therapy or possibly
triazole should be considered.
Importantly, some less common molds
intrinsically resistant to several antifungal classes (i.e., Mucorales, Fusarium spp.
Scedosporium spp.) occasionally present as infections or breakthrough infections that
may be indistinguishable from invasive aspergillosis.
Patients with mild-to-moderate Aspergillus should be treated with voriconazole or
166 Clinical and microbiologic cure rates of 50% to 71% have been
reported for voriconazole- or isavuconazole-treated invasive aspergillosis. In a
comparative trial of voriconazole versus isavuconazole for patients with proven or
probable aspergillosis, patients randomized to receive isavuconazole had similar
clinical response and mortality rates as voriconazole-treated patients with lower
rates of ocular, hepatic, and cutaneous adverse reactions.
Figure 78-5 Classification of aspergillosis infections. COAD, chronic obstructive airway disease.
Therapeutic Options for Treatment of Aspergillosis
Prednisone 1 mg/kg/day followed by 0.5
mg/kg/day or every other day × 3–6
Aspergilloma Observation Surgery
Systemic (invasive) Isavuconazole 300 mg IV 3 times daily for
48 hours LD, then 300 mg daily
Amphotericin B lipid formulation
Posaconazole 300 mg twice daily LD, then
Combination therapy with an echinocandin
durations or total doses should be used only as a compass to help guide therapy.
Indicated only for serious symptoms (e.g., hemoptysis).
cLipid formulations of amphotericin B should be utilized preferentially in these patients.
danidulafungin (AFG) 200 mg parenterally; caspofungin (CFG) 70 (50) mg parenterally on Day 1 (2–14);
micafungin (MFG) 70 mg parenterally; flucytosine (5FC) 150 mg/day parenterally.
AmB, amphotericin B; BID, twice daily; ITZ, itraconazole; LD, loading dose; TID, three times daily.
significant for Hodgkin lymphoma, which is in remission. Lumbar puncture revealed the following:
Opening pressure of 280 mm Hg (normal, 10 mm Hg)
WBC count, 50 leukocytes/μL (normal, 0 leukocytes/μL)
Positive India ink preparation
Cryptococcal antigen titer, 1:4,096
diagnosis is cryptococcal meningitis. What are the treatment options for D.W.?
Currently, only two therapeutic options exist for meningeal cryptococcal disease:
an AmB formulation with or without flucytosine and fluconazole. Flucytosine cannot
be used alone for therapy or prophylaxis because of the rapid development of
resistance. This yeast is also resistant to echinocandins. Patients, whether infected
with HIV or not, have improved treatment outcomes when the combination of AmB
180,181 Furthermore, when flucytosine (100–150 mg/kg/day
divided into four daily doses) is used in combination therapy, the dose of AmB may
be reduced to 0.3 to 0.6 mg/kg/day, which decreases the frequency of dose-related
AmB toxicity. In patients who cannot be treated with flucytosine, the dosage of AmB
must be increased to more than 0.6 mg/kg/day. AmB 1 mg/kg/day is more rapidly
fungicidal than 0.7 mg/kg/day when used with 5FC. Liposomal AmB 3 mg/kg/day can
and probably should be used instead of the nonlipid formulations in this disease
owing to presumed increase in safety.
Fluconazole is an alternative to AmB in patients infected with HIV with
cryptococcal meningitis. It is important to be mindful of the following caveats,
however: Sterilization of the CSF occurs more rapidly, and mortality is lower during
the first 2 weeks of therapy in patients treated with AmB as compared with
182 Early mortality was especially high in fluconazole-treated patients
who presented with altered mental status.
183–185 Thus, initial therapy of cryptococcal
meningitis in patients with mental status changes should be initiated with AmB for at
least 2 weeks or until the patient has stabilized clinically.
A landmark study on patients with cryptococcal meningitis compared patients
randomized to receive either amphotericin B 1 mg/kg/day for 4 weeks or a 2 week
induction regimen of amphotericin B 1 mg/kg/day plus flucytosine (1 mg/kg/day) or
fluconazole (400 mg twice daily).
185 At Day 70 after randomization, significantly
fewer deaths were observed in patients receiving amphotericin B plus flucytosine
versus patients receiving amphotericin B alone (hazard ratio: 0.61, 95% CI: 0.39–
0.97, P = 0.04). Combination therapy with fluconazole did not significantly impact
survival over amphotericin B monotherapy. Notably, the amphotericin B-flucytosine
combination was associated with more rapid clearance of yeast from the CSF versus
other regimens. Rates of adverse effects were similar in all groups even though
monotherapy (34% and 32% vs. 19%, P = 0.04).
Fluconazole 400 mg/day may be an acceptable option in patients with less severe
disease in all other patients. Another alternative may include liposomal AmB 4 to 6
mg/kg/day for 21 days. Until larger clinical studies have been completed, however,
this regimen cannot be recommended over generic AmB (see Chapter 77,
Opportunistic Infections in HIV-Infected Patients).
In D.W., initial treatment should focus on elimination of all factors leading to
immunosuppression. Antifungal therapy should be initiated immediately with AmB
0.3 to 0.6 mg/kg/day plus flucytosine 100 to 150 mg/kg/for a minimum of 6 weeks to
optimize the chance of a cure, especially in transplant recipients.
hypertension, usually presenting as headache, should be resolved through therapeutic
spinal tap. Acetazolamide should be avoided in these cases.
consequence of eliminating immune suppression is immune reconstitution syndrome
(IRIS). This syndrome is most commonly observed in HIV-infected patients started
on antiretrovirals who experience complications secondary to new onset
inflammatory reactions from replenished leukocytes. IRIS may make it appear these
patients are failing antifungal therapy.
CASE 78-9, QUESTION 2: What parameters should be monitored while D.W. is treated with flucytosine?
The most common side effect of flucytosine is GI distress (e.g., nausea, vomiting,
and diarrhea). Although flucytosine is not metabolized per se by mammalian cells,
gut flora may be responsible for metabolism of flucytosine to fluorouracil. This toxic
metabolite has been speculated to account, in part, for the GI distress and bone
marrow toxicity associated with flucytosine therapy.
effects include leukopenia, thrombocytopenia, and hepatotoxicity. Dose-dependent
bone marrow suppression, which can be fatal, generally is seen in patients whose
serum concentration of flucytosine is greater than 100 mcg/mL. Thus, it is important
to monitor blood concentrations and maintain concentrations below this level.
assays for flucytosine serum concentrations are unavailable, signs and symptoms of
bone marrow suppression or worsening renal function should result in a dosage
reduction or discontinuation of the drug. Flucytosine is eliminated by glomerular
filtration, with 80% to 95% of the dose excreted unchanged in the urine. Renal
excretion of flucytosine is directly related to creatinine clearance, and dosages
should be adjusted based on creatinine clearance to prevent the accumulation to toxic
concentrations in patients with renal impairment.
clearances of 10 to 40 mL/minute should have the dosage of flucytosine reduced by
50% (usual dose, 37.5 mg/kg every 12 hours). For patients with creatinine clearance
less than 10 mL/minute, dosing should be initiated at 37.5 mg/kg/day, with frequent
monitoring of flucytosine serum concentrations. Dosage adjustment and close
monitoring also are required for patients receiving hemodialysis, and it is
recommended that the dose be given postdialysis.
CASE 78-9, QUESTION 3: When is combination antifungal therapy indicated?
In vitro results of antifungal combinations against many common mycotic
pathogens have been variable. These incomplete and inconsistent findings have been
attributed to variable incubation times, variable concentrations of antifungal agents,
and the sequence of antifungal addition. As a result, clinical decisions about
combination therapy should be based on patient-specific in vivo evaluations.
Because of the limited clinical data, combination antifungal therapy should be
initiated cautiously. Except for the treatment of cryptococcal meningitis and
disseminated aspergillosis, combination therapy should be reserved for cases of
treatment failure (disseminated candidiasis) with no other established pharmacologic
options for therapy or mold infections with high mortality rates.
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