The CLSI-recommended standardized broth dilution method for determining in
vitro antifungal susceptibilities for certain spore-producing molds, namely
Aspergillus species, Fusarium species, Rhizopus species, Pseudallescheria boydii,
and Sporothrix schenckii, is the M38-A2 method.
susceptibilities is also commercially available (AB Biodisk) and correlates well
with the CLSI M38-A method for AmB and itraconzole.
microdilution, flow cytometry, and agar-based testing methods are under
development. Despite these recent advances, the determination of in vitro
susceptibilities or resistance in clinical practice is of limited utility and not readily
available for yeasts or molds in most institutions.
Susceptibility testing for clinical isolates is not routinely recommended because
susceptibility is usually predictable. However, published data on the susceptibility of
the identified species of yeasts or molds should guide the clinician’s therapeutic
choice. Clinical isolates from patients failing high-dose therapy (i.e., refractory oral
pharyngeal candidiasis) or unusual pathogenic yeasts in patients with AIDS can be
20 Testing should be performed in a laboratory where the staff is
trained in mycoses. Despite these limitations, certain patterns are common. First,
AmB has broad in vitro activity and clinical efficacy against the yeasts and
filamentous molds. The echinocandins have cidal activity in vitro versus Candida
species and static activity for Aspergillus species; they are not active in vitro against
Cryptococcus species and many endemic mycoses.
generally reliable against the yeasts and most dimorphic fungi. Additionally,
itraconazole, voriconazole, and posaconazole have excellent in vitro activity against
Aspergillus species, with associated clinical efficacy. Unlike other azoles,
posaconazole and isavuconazole have some activity in vitro and reported clinical
evidence of efficacy against zygomycetes, for which previously only AmB
formulations were therapeutic options.
Routine susceptibility testing of fluconazole, voriconazole, and an echinocandin
against C. glabrata is increasing recommended, especially for isolates from blood
normally sterile fluids, tissue, or abscess owing to recent reports of increasing
echinocandin and multidrug resistance.
26–28 Additionally, any patient with invasive
disease and clinical failure of initial therapy should be considered for susceptibility
following consultation with an experience microbiologist.
New Frontiers for Antifungal Therapy
Various investigative efforts have been directed toward enhancing efficacy, reducing
the toxicity, and improving the oral bioavailability of older antifungal drugs. Aerosol
delivery of AmB products, itraconazole, voriconazole, and caspofungin in
immunocompromised patients has been investigated for the prevention of invasive
pulmonary aspergillosis. Reduction in invasive pulmonary aspergillosis was
demonstrated in a randomized, placebo-controlled trial of aerosolized liposomal
29 Additional well-designed clinical trials are still needed to establish the role
of aerosolized delivery of antifungal agents. Optimal antifungal dose and nebulized
system required for effective prophylaxis have yet to be established compared with
traditional GI regimens (Table 78-4).
Antimycotic Prophylaxis Regimens and Approximate Costs
Nystatin 4–12 million units Oral
Clotrimazole 30–80 mg Troche TID–QID 125–450
Ketoconazole 200–400 mg Oral Daily 0.75–1.50
Itraconazole 200–400 mg Oral Daily 18–36.25
Fluconazole 50–400 mg Oral Daily 4.50–35.25
Posaconazole 600–800 mg suspension
aAverage wholesale price, on average.
GI, gastrointestinal; QID, four times daily; TID, three times daily.
Source: [No authors listed]. Red Book. Montvale, NJ: PDR Network, LLC; 2011.
Identification of new antifungal compounds has been challenging. One significant
barrier is that both mammalian cells and fungal cells are eukaryotes and share many
similar biochemical processes, unlike bacterial cells, which are prokaryotes.
Traditionally, the drug discovery process depended on the ability to detect
compounds (either natural products or synthetic compounds) that selectively inhibit
or destroy fungal cells. This process is accomplished by either or both of two
approaches: (a) the evaluation of existing compounds (natural or synthetic) for
potentially useful antifungal activity and (b) the design and synthesis of new
compounds that selectively block fungal targets. Recent advances in genomic
sequencing of C. albicans, C. glabrata, Aspergillus fumigatus, Rhizopus oryzae
(delmar), and C. neoformans have facilitated the search for new targets. Other less
conventional drug discovery approaches include targeting known traditional
virulence factors (e.g., adhesions and secreted enzymes). This approach is based on
the principle that killing of the microbe need not occur for an anti-infective agent to
be efficacious. Promising lead compounds include nikkomycins, sordarins, lytic
peptides, hydroxypyridones, and cathelicidins.
SUPERFICIAL AND CUTANEOUS MYCOSES
made. What therapeutic options are available for C.W.?
Selection of antifungal therapy should be based on the extent and type of infection.
Superficial or cutaneous infections should initially be approached topically. Any
follicular, nail, or widespread (>20% of body surface area) infection should be
treated systemically under medical supervision owing to poor penetration of topical
applications. Topical antifungals have been reviewed as a class by the FDA advisory
review panel on over-the-counter (OTC) antimicrobial drug products and on an
individual basis as newer products have been released. To receive a class I
recommendation, each agent (or combination) must have been tested in well-designed
clinical trials that show that the drug is microbiologically and clinically effective
against dermatophytosis or candidiasis with insignificant toxicity (irritation). Class I
agents are listed in Table 78-3. Class II agents (camphor, candicidin, coal tar,
menthol, phenolates, resorcinol, tannic acid, thymol, and tolindate) are considered to
have higher risk–benefit ratios associated with their pharmacotherapy. Class III
agents (benzoic acid, borates, caprylic acid, oxyquinolines, iodines, propionic acid,
salicylates, triacetin, and gentian violet) lack adequate scientific data to determine
efficacy. Topical therapy with any class I agent applied twice daily to the affected
area for 2 to 6 weeks should be adequate. Therapy should be titrated to response.
C.W. could continue tolnaftate powder for 2 to 6 weeks or switch to an antifungal
cream or lotion (e.g., miconazole and terbinafine), and these products should be
applied to the web spaces between all the affected toes twice daily. C.W. should
also be careful to use nonocclusive footwear (e.g., cotton rather than synthetic fiber
socks and leather rather than vinyl boots). Application of an absorbent or antifungal
powder to his footwear would also be helpful (see Chapter 39, Dermatotherapy and
Tinea Unguium (Onychomycosis): Treatment
CASE 78-1, QUESTION 2: If C.W. also suffered from an infection of the toenail (onychomycosis), what
additional therapy could be offered to him?
Onychomycosis is typically caused by a dermatophyte, a hyphal fungi, or Candida.
Nail scrapings and culture should be performed to help plan initial therapy. Once
culture results are known, therapy can be initiated with either terbinafine 250 mg/day
or itraconazole 200 mg/day for 6 (fingernail) to 12 (toenail) weeks. In some cases,
however, successful therapy of tinea unguium can require 3 to 6 months for
fingernails and 6 to 12 months for toenails. Therapy should be considered successful
when several millimeters of healthy nail have emerged from the nailfold to the
margin of infected nail or when a 25% reduction in the size of the infected site has
For dermatophyte nail or paronychial infections, griseofulvin therapy could be
used if an azole or allylamine is contraindicated. Griseofulvin (microsized or
ultramicrosized) administered orally at 10 mg/kg/day and titrated to response should
25 Owing to the large doses given for prolonged periods, C.W. should be
monitored closely at each prescription refill for signs and symptoms of adverse
reactions. The most common adverse events associated with terbinafine or
itraconazole are headache, rash, and GI distress. Griseofulvin is more toxic, often
causing hypersensitivity (urticaria, angioedema, and type II hypersensitivity
reactions), photosensitivity dermatitis, GI distress, and neurologic complications
(headache, paresthesias, and altered sensorium).
Antimycotic pulse therapy is a novel approach to the treatment of onychomycosis.
An FDA-approved alternative to daily therapy can now include a course of
itraconazole 200 mg twice daily for 1 week in two consecutive months for fingernail
infections. Double-blind, placebo-controlled trials revealed that this regimen was
associated with a 77% clinical response and 73% mycologic response.
responses and toxicity to therapy were more desirable with pulse regimens than with
traditional regimens. Comparative studies demonstrate promising results for
itraconazole pulse therapy for toenail infections
37 and fluconazole pulse therapy
administered as a 150- to 450-mg dose once weekly for up to 12 months for mild
38,39 Relapse rates after pulse (intermittent) terbinafine for 4 months have
been frequent, and longer courses of therapy are under study to enhance long-term
40 Longer courses of therapy are being evaluated.
Removal of the nail as the sole therapy is not recommended because of the high
relapse rate without concomitant systemic therapy. Likewise, IV antifungals are not
Many patients with superficial, cutaneous, or nail fungal infections will have local
inflammation and secondary bacterial infections. Inflammation is primarily a type IV
hypersensitivity reaction. Topical corticosteroids in conjunction with antifungals can
relieve itching and erythema secondary to inflammation. Bacterial (Proteus or
Pseudomonas species) superinfection can also occur in these inflamed or macerated
areas requiring concomitant topical antibacterial therapy. Pharmaceutical
manufacturers of OTC preparations often combine a drying agent or astringent (e.g.,
alcohol, starch, talc, and camphor) to their preparations to increase desquamation of
the stratum corneum. Hyperhidrosis also can be relieved by these pharmaceutical
additions. Such combination treatments should not be used routinely, however,
because they increase the risk of toxicity and do not increase efficacy. If required for
symptomatic relief, they should be used only for the initial days of treatment.
The affected web spaces between C.W.’s toes are macerated and cracked, and
vesicles are present at the base of his toes. A topical corticosteroid cream will
probably facilitate the healing process and make him more comfortable during the
first few days of antifungal therapy. The selection of topical corticosteroid
formulations is presented in Chapter 39, Dermatotherapy and Drug-Induced Skin
cephalexin treatment. On physical examination, O.M. is afebrile. A 1.5 cm
2 ulcer is present on the dorsum of
is now growing S. schenckii. What is the recommended therapy for O.M.?
S. schenckii is the dimorphic fungi found in the soil and on many plants. Infection
is usually secondary to inoculation into the skin from a thorn or sharp plant matter. S.
schenckii infection most commonly causes lymphocutaneous disease (Fig. 78-1) as
illustrated by this case. Rarely, extracutaneous disease may occur and usually
involves the lungs, bones, or joints.
In the 1930s and 1940s, local heat was applied to very mild plaque or
lymphocutaneous disease. Germination rates of this dimorphic fungus can actually be
decreased by increased temperature, and heat therapy 1 hour/day for 3 months is
effective in 90% of patients with plaques (very mild disease).
be particularly useful in pregnant patients when pharmacotherapy may be
Itraconazole is more active in vitro against S. schenckii than other imidazoles or
saturated solution of potassium iodide. Saturated solution of potassium iodide is
seldom used for therapy secondary to treatment-limiting toxicity. Cure rates for
sporotrichosis cutaneous and lymphocutaneous disease are greater than 90% with
itraconazole 100 to 200 mg/day for 3 to 6 months. For extracutaneous disease, higher
dosages of itraconazole (200 mg twice a day [BID]) for 1 to 2 years achieve
response rates of 81%, but relapse frequently occurs (27%) after therapy is
Itraconazole is well tolerated in these patients. Patients with
extracutaneous disease who are unable to tolerate the higher itraconazole dosages or
whose disease continues to progress should be treated with AmB or a lipid-based
amphotericin product. A total dose of 2.0 to 2.5 g is most often recommended if
conventional AmB is used. Although voriconazole, posaconazole, and ravuconazole
demonstrate in vitro activity against S. schenckii (albeit less than itraconazole), their
role in the treatment of sporotrichosis has not been defined.
nor fluconazole is effective in the treatment of sporotrichosis.
Figure 78-1 Lymphocutaneous sporotrichosis.
Terbinafine has a good in vitro activity against S. schenckii and has been used
44 An unpublished clinical trial comparing 250 or 500
mg BID for 3 months for lymphocutaneous disease appeared clinically equivalent to
itraconazole. Adverse reactions include GI distress (dysgeusia, dyspepsia, and
diarrhea), skin rash, and weight gain.
Therefore, in the case of lymphocutaneous disease, itraconazole 100 mg/day for a
minimum of 3 months is the treatment of choice. If significant improvement is not
observed in the first 6 weeks, the itraconazole dosage should be increased to 200
mg/day and continued for 6 months or until both the ulcer and lymphangitis have
resolved. Most patients will respond to this dosage, but an occasional patient may
require dosages of 300 or 400 mg/day.
CASE 78-2, QUESTION 2: What instructions should O.M. receive for taking his antifungal agent?
The peak serum concentrations of itraconazole capsules are ninefold higher when
the drug is taken with food (0.18 mcg/mL with food vs. 0.02 mcg/mL in fasting
45 The influence of food on absorption appears to be dependent on food
46 Patients who have difficulty
eating (e.g., patients with AIDS and those with cancer receiving antineoplastic
therapy) or with hypochlorhydria may not absorb a sufficient amount from the capsule
to achieve therapeutic plasma concentrations after a typical oral dose.
itraconazole manifests nonlinear serum pharmacokinetics (i.e., administering the total
dose in two divided doses is associated with higher peak serum concentrations than a
single larger dose), there is no clinical benefit in splitting the dose. Therefore, O.M.
could be instructed to take his itraconazole capsule with his highest-fat-content meal
of the day or itraconazole solution could be substituted to improve absorption.
Itraconazole oral solution is a cyclodextrin formulation that has 55%
bioavailability in a fed patient; this increases in a fasting patient (Table 78-5).
Furthermore, bioavailability of this formulation is not affected by level of gastric
acidity. Average serum concentration in a cohort of patients with advanced HIV
infection was 2.7 mcg/mL after a 28-day twice-daily dosing regimen.
take his itraconazole solution on an empty stomach BID if this formulation is
CASE 78-2, QUESTION 3: How would instructions for taking itraconazole capsules be modified if O.M.
monitored for an assessment of efficacy?
Itraconazole capsules, as with ketoconazole, require an acidic environment for
dissolution and absorption. Thus, patients who are achlorhydric, as a result of
medications, surgery, or underlying disease (e.g., AIDS gastropathy), may not absorb
itraconazole capsules adequately.
47,49 The use of ketoconazole in achlorhydric
patients has historically required concomitant administration of 4 mL, 0.2 N
hydrochloric acid aqueous solution. Etching of tooth enamel by the acid can occur;
thus, other alternatives have been explored. The administration of ketoconazole and
itraconazole with a low pH liquid (e.g., 8–16 fluid ounces of a carbonated cola
beverage or orange juice) improves absorption in 65.2% of healthy patients who are
49 Refer to Azole–Drug Interactions section for
more detailed information on problematic therapeutic combinations.
Voriconazole does not require an acidic environment for adequate oral absorption,
plasma concentrations are fourfold higher after administration with food or a high-fat
nutritional supplement. A newer formulation of posaconazole, which releases the
drug in the pH-dependent manner in the duodenum, is not dependent on low gastric
pH for dissolution and does not require administration with food to achieve
Isavuconazole is unique among triazole antifungals because it
is administered IV or orally as a prodrug (isavuconazonium sulfate), which is rapidly
cleaved by plasma esterases to the active antifungal, isavuconazole. Absorption of
the prodrug is relatively complete (>90% bioavailability) and does not require low
gastric pH or coadministration with food. IV isavuconazonium is water-soluble and,
unlike voriconazole or posaconazole parenteral formulations, is not solubilized in
Because serum ketoconazole, itraconazole, and voriconazole concentrations less
than 0.25 to 1.0 mcg/mL have been associated with an increased risk of treatment
failure and increased mortality in neutropenic patients, therapeutic drug monitoring is
justified in patients in whom therapy is failing or suspected risk factors for low
blood levels (i.e., poor gut function, drug interactions, and pediatric patients) or, in
the case of voriconazole, suspected CNS toxicity, which is more frequent in patients
with trough levels exceeding 5.5 mcg/mL.
54 Similarly, posaconazole serum
concentrations less than 0.7 mcg/mL have been associated with an increased risk of
breakthrough infection during prophylaxis, and trough or random levels approaching
1.5 mcg/mLhave been associated with improved probability of treatment response in
documented invasive aspergillosis.
54 Serum antimycotic concentrations may be more
easily monitored in the future because assays, potentially performed at the point of
care (patient bedside or clinic), become available, and correlations between
concentration and efficacy or toxicity are more clearly established.
Pharmacokinetic Properties of Systemically Active Non-polyene Antifungals
Imidazoles Triazoles Echinocandins Other
1.9 3.29 0.63 1.4 0.851/2.76 7.50 2.3–
1.9(0.7) 42 8.619/51.62 121.4 9–11
99 99.8 11 99 95 58 80 96.5 99.5 2–4 >99
<10 <10 <10 60 ND ND ∼50 ND ND ND 60 <10
150 mg/day parenterally; and terbinafine (TBF) 250 mg/day orally.
bWith meals (fasting), absorption altered by gastric acidity.
cDose-dependent and/or infusion-dependent.
dAbsorption decreased when administered with high-fat meal; Cmax
and AUC reduced by 34% and 24%, respectively.
time of maximum concentration; t1/2
subjective and objective data in this case suggest a possible Candida infection?
Although it is possible that L.K. might be infected with bacterial pathogens not
susceptible to vancomycin and meropenem, the possibility of a candidal infection
should be considered. Candida species are the most common nosocomial fungal
pathogens. Candida species were responsible for 72.2% of mycoses in hospitalized
cases, and C. albicans accounted for 55% of these cases in the Centers for Disease
Control, National Nosocomial Infections Surveillance System. Attributable mortality
associated with disseminated candidiasis from all species is 38% and it is ~12% for
extremely low-birth-weight neonates.
56 These statistics may underestimate the true
occurrence because systemic candidiasis is difficult to diagnose. To reinforce this
point, the diagnosis of systemic candidal infection is made in 30% to 50% of
neutropenic patients with hematologic malignancies at postmortem.
morbidity for systemic candidiasis may be even higher because of the limited ability
The diagnosis and monitoring of therapeutic outcomes for systemic candidal infection
are difficult because the characteristics of systemic candidal infection are subtle.
Salient clinical features include constitutional symptoms (e.g., fever, chills, and
hypotension) and evidence of end-organ dissemination, such as nodular erythematous
skin lesions, endophthalmitis, liver abscess, and spleen abscess. In addition, 50% of
patients or fewer will have a single positive Candida blood culture. The Mycoses
Study Group utilizes a single positive culture from a sterile body site and
hypotension (systolic blood pressure [SBP] <100 mm Hg or a SBP decrease >30 mm
Hg) or abnormal temperature (<35.5°C or >38.6°C on one occasion or >37.8°C on
two separate occasions more than 4 hours apart), or inflammation at an infected site
Risk factors for candidemia include central venous catheters, broad-spectrum
antibiotic use, extensive surgical procedures, Candida colonization, TPN,
pancreatitis, neutropenia or neutrophil dysfunction, and immunosuppression (e.g.,
premature infants, burn patients, patients with mannose-binding lectin deficiency, and
L.K. has chills, a temperature of 39.1°C, and is hypotensive. He is probably
immunosuppressed as a result of multiple surgical procedures and receipt of
most bacterial pathogens. Because L.K. still has manifestations of an infection
despite 3 days of antibiotics, additional diagnostic studies are warranted.
CASE 78-3, QUESTION 2: What diagnostic tests could be ordered for L.K. to evaluate a possible fungal
The diagnosis of fungal infection may be made with varying levels of certainty.
Sometimes, the diagnosis is absolutely certain, such as the isolation of a pathogenic
fungus from a clinical specimen in an immunocompromised patient. Such a finding is
referred to as a definitive or microbiologically confirmed diagnosis. At other times,
only a high probability of infection can be determined, that is, a presumptive
diagnosis. To illustrate this, a patient with a chest radiograph showing nodular
lesions and a high complement fixation (CF) antibody against H. capsulatum would
have a presumptive diagnosis of histoplasmosis. This finding may be as certain a
diagnosis as is possible without performing a more invasive procedure to obtain lung
tissue. In this event, a trial of drug therapy can be undertaken on the presumptive
diagnosis alone. A diverse spectrum of tests is available for clinicians to diagnose
and monitor therapeutic responses.
Direct examination of the specimen is often useful in diagnosing fungal infection.
Traditionally, the specimen is treated with 10% KOH to digest the cells and debris,
resulting in clear visualization of the hyphae or yeast. Treatment of cerebrospinal
fluid (CSF) specimens with KOH is not necessary because this fluid is naturally
clear. India ink can be added to CSF to increase contrast and outline the organisms.
Calcofluor white, a fluorescent fabric brightener that binds to fungi and fluoresces
brilliantly when viewed under the ultraviolet microscope, can also be used to assist
in the recognition of fungal elements.
Histologic examination of biopsy specimens is an important tool for diagnosing
and monitoring fungal infection, but identifying the exact fungus may be difficult. This
is because only the tissue phase can be observed, and the fungal organisms in the
specimen may be few. Because recognizing a fungus in hematoxylin-stained or eosin-
stained sections may be difficult, a number of special stains have been developed.
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