Course Code: Course TitleMLS-028

Module #6 Student Activity Sheet

Lesson title: OPPORTUNISTIC MYCOSES Materials:

Learning Targets: Module, Reference Book, Manual, Laptop
At the end of the module, students will be
able to: References:

1. differentiate various characteristic of
various opportunistic fungi based on
morphology and mode of transmission
2. explain the pathophysiology of various
opportunistic fungi
3. distinguish specific method used for the
identification of different opportunistic fungi
1. Beneke, Everett (1999). Smith, Ph.D. Scope of Monograph on
Human Mycoses, Kalamazoo, Michigan; Upjohn Company
2. Bulmer, glenn(1995). Fungus Disease in the Orient,3rd ed.
Manila: Rex Bookstore
3. McPherson and Pincus. (2018). HENRY’s Clinical Diagnosis
and Management by Laboratory Methods 23rd ed.,Singapore:
Elsevier Pte.Ltd.

Internet Sources:
Access, Biomedical Science. The Opportunistic Fungi. Retrieved
Sept. 21,2021 from
https://accessbiomedicalscience.mhmedical.com/content.aspx?
bookid=2268&sectionid=176088518

A. LESSON PREVIEW/REVIEW
Good day! For this module you will be learning about Opportunistic Mycosis.
The “opportunistic fungi” are usually found as members of the resident human microbiota or a saprophyte I the
environment. With breakdown of host defenses, they can cause infections ranging from skin/mucus membrane
involvement to life- threatening, systemic disease. The most common opportunistic infections are caused by two
species: the yeast Candida species, a common inhabitant of the gastrointestinal and genital microbiota; and them
old Aspergillus fumigatus which is widespread in the environment (Access, biomedical Science).

NOTE: You may click the link for internet sources provided.

Introduction

OPPORTUNISTIC MYCOSES
- are infections due to fungi with low inherent virulence which means that these pathogens constitute an almost
limitless number of fungi.  These organisms are common in all environments.  
- The disease equation: 
= Disease  
Number of organisms  x  Virulence 

- With opportunistic infections, the equation is tilted in favor of "disease" because resistance is lowered when
the host is immunocompromised. In fact, for the immunocompromised host, there is no such thing as a
non-pathogenic fungus.
- The fungi most frequently isolated from immunocompromised patients are saprophytic (i.e. from the
environment) or endogenous (a commensal).  The most common species
are Candida species, Aspergillus species, and Mucor species.
- The upward trend in the diagnoses of opportunistic mycoses reflects increasing clinical awareness by
physicians, improved clinical diagnostic procedures and better laboratory identification techniques. Another
important factor contributing to the increasing incidence of infections by fungi that have not been previously
known to be pathogenic has been the rise in the number of immunocompromised patients who are
susceptible hosts for the most uncommon agents. Patients with primary immunodeficiencies are susceptible
to mycotic infections particularly when cell-mediated immunity is compromised. In addition, several types

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of secondary immunodeficiencies may be associated with an increased frequency of fungal infections. (Dr Art
DiSalvo,OPPORTUNISTIC MYCOSES, microbiology and Immunology On-Line, University of South caroloina
School of Medicine)

B.MAIN LESSON
When a fungus is isolated from an immunocompromised patient, the attending physician has to distinguish between:
- Colonization (which is of no major concern)
- Transient fungemia (often involving C. albicans)
- Systemic infection
The diagnosis of opportunistic infections requires a high index of suspicious. Without this curiosity, the clinician may not
consider mycotic infections in the compromised patient because:
- Patients present with atypical signs and symptoms
- Unusual histopathology
- The fungus may have an unusual organ affinity
- The etiological agent may be considered a saprophyte or contaminant
- The systemic mycoses may occur outside the known endemic area
- The serologic response may be suppressed
Causes of Immunodeficiency commonly encountered are:
- Malignancies (Leukemias, lymphomas, Hodgkin's Disease).
- In one study of cancer patients, fungal septicemia and pneumonias accounted for almost a third of deaths.  
- Drug therapies.  Anti-neoplastic substances, steroids, immunosuppressive drugs.
- Antibiotics. Over-use or inappropriate use of antibiotics can also contribute to the development of fungal
infections by altering the normal flora of the host and facilitating fungal overgrowth or by selecting for resistant
organisms.
Therapeutic Procedures can predispose for fungal infections;
- Solid Organ and Bone Marrow transplantation  
- Open heart surgery
- Indwelling catheters (urinary, I.V. drugs or parenteral hyperalimentation).  In cases of fungemia, the
contaminated catheter must  be removed before starting anti-fungal therapy.
- Artificial heart valves can be colonized by a variety of infectious agents, including Candida species. In a case
of infection of an artificial heart valve, antifungal treatment is only efficient if the infected valve is replaced.
- Radiation therapy.  
Other Factors Associated with Increasing frequency of Mycotic infections are:
- Severe burns
- Diabetes
- Tuberculosis
- I.V. Drug use
- AIDS. Virtually all AIDS patients will have a fungal infections sometimes during the course of disease.

NOTE: Certain fungi may be frequently associated with some of the predisposing factors listed above. However any one
of the ubiquitous saprophytes (most of which do not cause disease in immunocompetent hosts) aw well as occasional
pathogens may cause disease in these patients.

- Unusual Histopathology.
✔ Even the inflammatory reaction may be different in biopsy specimens.  The normal host reaction to
fungal invasion is usually pyogenic or granulomatous.  In the immunodeficient host, the inflammatory
reaction is necrotic.  
Immunocompromised Patients are at risk for:
- Systemic Invasive Aspergillosis
- Candidiasis
- Cryptoccocal meningitis
- Rhinocerebral/Horacic mucormycosis

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1. Aspergillosis
• Acquired through inhalation of spores
• Common laboratory contaminant
• Growth rate: 3-10 days

• Clinical forms:
• Allergic forms ( allergic bronchopulmonary)
• The fungus grows in the bronchial tree
Granulomatous (Pulmonary)
- Necrotizing disease of the lungs which often disseminates hematogenusly to various organs (GIT, brain,
kidney, heart, skin, eye)
Fungus ball (or aspergilloma)
- Most common form f Pulmonary Aspergillosis
- Fungus taken u residence in an old lug cavity which are usually the result of old TB lesions
- Organisms remain in these cavities. It grows huge ass of mycellium -> FUNGUS BALL

Etiologic agent:
- A. Aspergillus fumigatus = most often seen in clinical laboratory
- B. Aspergilus flavus = causes oncomycosis
- C. Aspergilllus niger = major cause of otomycosis
✔ Characteristic microscopic appearance;
- In tissue or sputum ( 10-20% KOH): HYALINE, DICHOTOMOUSLY BRANCHED, SEPTATE
HYPHAE

NOTE: A and B are clinically significant among o hosts who have undergone organ transplantation( bone marrow
transplant) and chemotherapy.
- PAS = recommended to visualize the fungus on smear from internal organs
- Cultures are MONOMORPHIC on SDA at RT or at 35-37˚C
- Confirmatory test for ID: Based on microscopic morphology

Allergic Disease
Fungal Sinusitis:
- Previously, Aspergillus was thought to be the most common fungus responsible for allergic sinusitis, but it is
now appreciated that disease due to dematiaceous fungi actually comprises the majority of cases. The most
common are Bipolaris spp, Curvularia spp., Exserohilum spp. and Alternaria spp. This is a hypersensitivity
phenomenon and does not involve invasive disease. Diagnosis generally depends on demonstration of
allergic mucin, with or without actual culture of the organism. Therapy consists of surgery to remove the
mucin, which is often tenacious, and systemic steroids. Antifungal therapy, usually in the form of itraconazole,
may play a role in reducing the requirement for steroids, but this is not routinely recommended. Other azoles
have only rarely been used for this disease. Immunotherapy with weekly injections of fungal antigens have
shown promise in preliminary studies.

Allergic Bronchopulmonary Mycosis (ABPM):

- This is a fairly recent concept, similar in presentation to allergic bronchopulmonary aspergillosis (ABPA),
which is typically seen in patients with asthma or cystic fibrosis. The most common fungi are Bipolaris spp.
andCurvularia spp.Therapy is primarily systemic steroids, usually prednisone at 0.5 mg/kg/day for 2 weeks,
followed by a slow taper over 2-3 months or longer, if necessary. Itraconazole has been used as a steroid
sparing agent, but its efficacy is not clear and routine use of itraconazole is not generally recommended.

Sinus Fungus Balls

- Black fungi are also commonly responsible for sinus fungus balls,
including Bipolaris spp, Curvularia spp., Exserohilum spp., and Alternaria spp. Therapy consisting of surgical
resection of the fungus ball, and aeration of the sinus is generally curative. Unless invasion of the surrounding
mucosa or bone is demonstrated, antifungal agents do not appear to be of additional benefit.

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Pneumonia
- Non-allergic pulmonary disease usually occurs in immunocompromised patients, and may be due to a wide
variety of species (including Bipolaris spp., Ochroconis, Galloparum, and Chaetomium spp.); in contrast to
allergic disease. However, cases in immunocompetent patients may also be seen. It is unclear what specific
risk factors may contribute to pulmonary infection with these fungi, which are commonly found in the
environment. Therapy usually consists of intravenous amphotericin B or oral itraconazole initially, followed by
itraconazole for a more prolonged period. Mortality rates are high in immunocompromised patients.
Experience with voriconazole and posaconazole is accumulating.

2. Candidiasis/ Monilliasis/ Mycotic vulvovginitis/ Candida endocarditis

- is a type of fungal infection due to any type of Candida.
- Normal flora of the skin, mouth, GIT and vagina
- It is not transmitted
- When local or host defense are impaired, disease may result
- Most frequently encountered opportunistic fungal infection
Clinical Formation:
- 1.Thrush = a disease of the oral mucous membrane
✔ Hallmark:
⮚ Formulation of white creamy patches ( pure cultures of fungus)
- 2. Nail infection (PARONYCHIA)
✔ simulates ringworm infection
- 3. Mycotic Volvuvaginitis
✔ Common among diabetics, prenant womn and those on birth control pills

3. Systemic Candidiasis (acute disseminated candidiasis)

- is an infection of blood or other normally sterile site (e.g., pleural and peritoneal fluid) with Candida species,
usually in association with fever, hypotension, and/or leukocytosis.  Candida organisms may be disseminated to multiple
sites, notably retina, kidney, liver and spleen, bones, and the central nervous system. Chronic disseminated candidiasis
usually implies involvement of liver and/or spleen in association with recovery from chemotherapy-induced
neutropenia.(Sobel, J.D.,et.al.,2020.; Systemic Candidiasis. https://bestpractice.bmj.com/topics/en-us/1062)
- May caused pulmonary disease or endocarditis or may even evolved the meninge
- Etioloic agent:
✔ Candida species frequently Candida albicans
- Microscopic features of Tissue forms:
✔ 10-20% KOH:
⮚ Budding yeast cells or blastoconidia
⮚ Pseudohyphae showing regular points of constriction resembling link of sausage appearance
⮚ True septate hyphae
- Microscopic features from Culture:
✔ Chlamydospore test
⮚ Using Cornmeal agar with 1% Tween 80 for 24-72 hrs at RT
⮚ Non-Candida species = budding yeast cells only
▪ Candida species except C. albicans = yeast cells and pseudohyphae
▪ C. albicans = yeast cells, pseudohyphae and chlamydospores
▪ Spider colonies on EMB
- Confirmatory test on ID:
✔ GERM TUBE TEST:
⮚ Yeast colony in serum incubated at 35-37˚C 2 hrs.
⮚ For rapid presumptive identification of C. albicans
⮚ Candida albicans
▪ Germ tube: (+)
▪ Chlamydospores: (+)
▪ Sugar assimilation:
❖ Glucose =(+) A,G
❖ Maltose = (+)A,G

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❖ Sucrose = (+)A
❖ Fructose = (-)
- Urine culture:
colony count of 104-105 colonies/ml indicates SYSTEMIC INFECTION

3. Zygomysis/ Phycomysis/ Mucormysis

- A systematic disease caused by a number of closely isolated fungi belonging to class phycomycetes
- 3 genera:
✔ 1. Rhizopus
✔ 2. Mucor
✔ 3. Absidia

NOTE: Mucor spp: No rhizoids or stolons

Rhizopus spp. : Unbranched sporangiophores with rhizoids where stolon arises
Absidia spp.: Rhizoids originates between sporangiophores

- Confirmatory test for ID:

✔ Based on the characteristic morphological features

4. Cryptococcosis/ Torulosis/ European Blastomycosis

- Acute/ chronic pulmonary systemic or meningeal mycosis
- Transmitted through inhalation of spores from bird droppings (excreta of pigeons)
- Growth rate: 3-10 days

- Etiologic agent: Cryptococcus neoformans

Filobasidiella neoformans (sexual stage)
- Characteristic microscopic appearance: India Ink Wet mount:
✔ Encapsulated yeast cells
✔ Cells usually spherical, vary in size may have more than one “pinched-off” bud present on parent cell
- Most widely used method for rapid detection of C. neoformans in clinical specimen
✔ Culture: Produces moist, shiny and mucoid colony (resembles Klebsiella)
- Confirmatory test for ID:
✔ Presumptive ID:
⮚ Urease (+):
❖ (+) contol = C. neoformans
❖ (-) = C. albicans
✔ Phenol oxidase (+):
✔ Inorganic Nitrate substrate (-)
- Final ID:
✔ Carbohydrate utilization
✔ Pigment production on Niger Seed Agar
- Other Test for ID:
✔ L-DOPA Ferric Citrate Test
Result:
▪ Black (melanin)
▪ Indicates (+) for C. neoformans
✔ Serologic test: Cryptococcal Latex Agglutination test (+)

SAPHROPHYTIC FUNGI COMMONLY ENCOUNTERED IN THE CLINICAL LABORATORY

1. HYALINE MOLD
- Characteristic Microscopic Appearance:
✔ Acremonium spp.
● Single unbranched tube-like phialides,”conidia in clusters” at the tip of phialides
✔ B. Pencillium sp.
● “brush-like conidiophores”

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✔ C. fusarium sp.
● “Sickle or Boat – shaped macroconidia”
✔ Scopulariosis
● Conidiophore “Penicillium – like” structure
- Alternaria sp.
✔ Chains of large brown conidia resembling “drumstick”
- B. Cladosporium sp.
✔ Single celled conidia resembling “shield cells”
- C. Dreschlera (Helminthosporium)
✔ Large multiseptate elongated conidia “zigzag’ appearance

2. DEMATIACEOUS MOLD

- Over 100 species and 60 genera of dematiaceous, or pigmented fungi have been implicated in human
disease (Matsumoto T, Ajello L, Matsuda T, Szaniszlo PJ, Walsh TJ. Developments in hyalohyphomycosis and
phaeohyphomycosis. J Med Vet Mycol 1994; 32 Suppl 1:329-349.).
- The vast majority are filamentous fungi or moulds, though a few yeast species are also important pathogens.
Though they represent a very heterogeneous group of fungi, the distinguishing characteristic common to all
these various species is the presence of melanin in their cell walls, which imparts the dark color to their
conidia or spores and hyphae (Rinaldi MG. Phaeohyphomycosis. Dermatol Clin 1996; 14:147-153.  [PubMed]).
- The colonies are typically brown to black in color as well. As the number of patients immunocompromised
from diseases and medical therapy increases, additional species are being reported as causes of human
disease, expanding an already long list of potential pathogens. As many of these are rarely seen clinically,
referral to a mycology reference lab may be needed to accurately identify isolates to species level.

EPIDEMIOLOGY
- Dematiaceous fungi are generally found in soil or associated with plants and distributed worldwide. Those causing the
specific conditions of mycetoma and chromoblastomycosis are primarily found in tropical regions. Occasionally, species
appear to be geographically restricted, such as Ramichloridium mackenzei, which has only been seen in patients from the
Middle East. Exposure is thought to be from inhalation or minor trauma, which may not even be noticed by the patient.
Surveys of outdoor air for fungal spores routinely observe dematiaceous fungi. As these are widespread in the
environment, individuals are constantly exposed to them, though they remain uncommon causes of disease
(http://www.antimicrobe.org/new/f05.asp).

CLINICAL MANIFESTATION
- A variety of infectious syndromes are attributed to dematiaceous fungi. Two unique conditions, mycetoma and
chromoblastomycosis, are caused by a small number of species and are usually seen in tropical regions. Mycetoma may
be caused by a variety of other pathogens as well, including Nocardia and non-dematiaceous fungi, though they will not
be discussed here. It is commonly associated with chronic swelling and draining sinus tracts, usually of the lower
extremities. It can be debilitating and difficult to treat. Chromoblastomycosis often presents with verrucous lesions that
may occur anywhere on the body, but usually on the lower extremities. This is a chronic, slowly progressive subcutaneous
mycosis. Minor trauma typically precedes the lesions. Initially, nodular lesions are present, which may progress over years
to form large, verrucous plaques. In contrast, phaeohyphomycosis is a catch-all term that encompasses many clinical
syndromes due to a wide variety of fungi. Conditions include superficial infections such as keratitis and subcutaneous
nodules, allergic diseases, and invasive infections such as brain abscess and disseminated disease. In general, these
diseases have been reported worldwide(http://www.antimicrobe.org/new/f05.asp).

LABORATORY DIAGNOSIS
- Unlike other more common fungal infections, there are no simple diagnostic tests to identify these fungi, particularly to the
species level. No routine serologic, antigen or polymerase chain reaction (PCR) methods are available, which is at least
partly due to the tremendous diversity of these pathogens. However, studies have begun to examine the potential of
identifying species within this diverse group of fungi using PCR of highly conserved regions of ribosomal DNA. Currently,
the diagnosis of infection due to dematiaceous fungi relies on pathologic examination of clinical specimens and careful
gross and microscopic examination of cultures, occasionally requiring the expertise of a mycology reference lab for
unusual or newly described pathogens. In the case of mycetoma and chromoblastomycosis, pathognomonic histologic

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findings are very useful. The presence of black mycotic granules or grains can establish the diagnosis of mycetoma due to
dematiaceous fungi. Histologically, they appear to be composed of fungal cells surrounded by a dense extracellular matrix
composed primarily of a melanin compound, which gives it a dark color. Chromoblastomycosis is characterized by the
production of characteristic dark sclerotic bodies in tissue, which are thick walled with septae. Phaeohyphomycosis does
not have such pathognomonic features, though the histologic appearance is often characterized by irregular hyphal
elements and beaded, yeast-like forms. However, it may still be difficult to differentiate this pathologically from infection
due to other moulds such as Aspergillus. In such cases, the Fontana-Masson stain, which is specific for melanin, can
usually be used to confirm the presence of dematiaceous hyphae (Rinaldi MG. Phaeohyphomycosis. Dermatol Clin 1996;
14:147-153.  [PubMed]).

PATHOGENESIS
- Relatively little is known regarding the pathogenic mechanisms by which many of these fungi cause disease,
particularly in immunocompetent individuals. One of the likely candidate virulence factors is the presence of
melanin in the cell wall, which is common to all dematiaceous fungi. Melanin has been found to be an
important virulence factor in certain fungi, including Cryptococcus (C.) neoformans and Wangiella
(W.) dermatitidis, which is a dematiaceous yeast. In these fungi, disruption of specific genes involved in
melanin production leads to markedly reduced virulence in animal models. There are several mechanisms
proposed by which melanin may act as a virulence factor. It is thought to confer a protective advantage by
scavenging free radicals and hypochlorite that are produced by phagocytic cells in their oxidative burst that
would normally kill most organisms (http://www.antimicrobe.org/new/f05.asp).

SUSCETIBILITY IN VITRO AND IN VIVO

Single Drugs
- In vitro antifungal testing has only recently become standardized, and the first standardized method for
filamentous fungi was not available until 2002 (http://www.antimicrobe.org/new/f05.asp).

Amphotericin B
- Amphotericin B has in vitro activity against many clinically important dematiaceous fungi. However,
some species have been consistently resistant (minimum inhibitory concentration (MIC) ≥2 μg/mL),
including Scedosporium (S.) prolificans and Scopulariopsis (S.) brumptii. Other species have occasionally
found to be resistant, including Chaetomium spp., Curvularia spp., Phialemonium spp.,Exophiala spp.
and Ramichloridium (R.) mackenzei  (http://www.antimicrobe.org/new/f05.asp).

Flucytosine (5- fluorocytosine; 5-FC)

- http://www.antimicrobe.org/new/f05.asp)..
Azoles
- . http://www.antimicrobe.org/new/f05.asp).

Ketoconazole:
- http://www.antimicrobe.org/new/f05.asp).

Itraconazole:
- http://www.antimicrobe.org/new/f05.asp).

Voriconazole:
- http://www.antimicrobe.org/new/f05.asp).

Posaconazole:
- http://www.antimicrobe.org/new/f05.asp).Ravuconazole: Ravuconazole is an investigational,
broad-spectrum azole with activity against a wide variety of moulds. In vitro activity is demonstrated
against Chaetomium spp., F. pedrosoi, and Phialophora spp. S. prolificans is resistant.

Isavuconazole:

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- http://www.antimicrobe.org/new/f05.asp).

Terbinafine
- http://www.antimicrobe.org/new/f05.asp).

Echinocandins
- The echinocandins are the latest group of antifungals agents to be developed and have a unique
mechanism of action, inhibiting β-1,3 glucan synthesis and thereby disrupting the fungal cell wall . They
are generally well-tolerated.
Caspofungin:
- Caspofungin was the first of the class available for clinical use. In vitro studies with dematiaceous fungi
are limited, though some activity is demonstrated against Curvularia, Bipolaris, and F. pedrosoi C.
bantiana has higher MICs and S. prolificans appears resistant In general, MICs for dematiaceous fungi are
higher than for Aspergillus sp.

Micafungin:
- Micafungin has been evaluated against only a few species in vitro, with activity shown against C.
bantiana, F. pedrosoi, andExophiala (E.) spinifera . MICs may be somewhat lower than for caspofungin.

Anidulafungin:
- http://www.antimicrobe.org/new/f05.asp).

Combination Drugs
- This is a potentially useful strategy for refractory infections, though it has not been studied extensively
in dematiaceous fungi. The combination of itraconazole or voriconazole with terbinafine was found to
be synergistic against S. prolificans, which is otherwise generally resistant to all agents). The mechanism
is presumably potent inhibition of ergosterol synthesis at two different steps of the pathway by these
agents. However, this should be interpreted with caution, as terbinafine is not generally used for
systemic infections. Another report suggested synergy for S. prolificans with voriconazole and
caspofungin . Animal studies with C. bantiana show benefit with combination antifungal therapy over
monotherapy, though it is unclear which is the optimal combination. Older literature also suggests
additive activity and synergy with 5-FC and ketoconazole or amphotericin B for a variety of
dematiaceous fungi.This may be applicable to other azoles as well.
http://www.antimicrobe.org/new/f05.asp).

CHECK FOR UNDERSTANDING

A. ILLUSTRATE AND BRIEFLY DISCUSS THE DIFFERENCE BETWEEN YEAST AND MOLD (Pass your
output through google classroom)(

C. LESSON WRAP UP

In Immunocompromised patients, common fungal infections may have an unusual presentation because of:
- Atypical signs and symptoms.
✔ Malassezia furfur (Figure 2) usually causes a rather benign and self-limited disease in normal hosts
(Tinea versicolor) (figure 3), but in immunocompromised patients may show a rash with disseminated
disease and sepsis.  This organism requires long-chain fatty acids for growth.  Patients receiving
parenteral fat emulsions for nutrition become a walking petri plate. 
- Unusual Organ affinity.

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✔ Candida (figure 5) may invade liver, heart valves; Oral thrush (figure 4) occurs in people who are
relatively immunocompetent while esophageal candidiasis occurs in those patients who are
immunologically compromised.  Cryptococcus may cause pulmonary, cutaneous and cardiac (figure
5A) infections.   
- Infections with systemic dimorphic fungi occurring outside endemic areas. These factors complicate the
diagnosis and management of these disease.
Drug of Choice
- Voriconazole, posaconazole and itraconazole demonstrate the most consistent in vitro activity against this
group of fungi. Oral itraconazole had been considered the drug of choice for most situations, given its
extensive clinical experience . However, voriconazole is now preferred due to better tolerability, safety
and the availability of an intravenous formulation, and may have advantages for central nervous system
infections due to its ability to achieve good cerebrospinal fluid levels, unlike itraconazole. Posaconazole
is a broad-spectrum alternative that is well-tolerated, though with less clinical experience. All likely
achieve adequate brain tissue levels. http://www.antimicrobe.org/new/f05.asp).

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