FUNGAL INFECTIONS

Terminology and Microbiology classified into specific categories based on both

anatomic location and epidemiology.

The most common general anatomic categories are mucocutaneous and deep organ infection.

The most common general epidemiologic categories are endemic and opportunistic.

Although mucocutaneous infections can cause serious morbidity, they are rarely fatal. Deep organ infectionsalso cause severe illness in many cases but, in contrast to mucocutaneous infections, are often fatal.

Endemic mycoses (e.g., coccidioidomycosis) are infections caused by fungal organisms that are not part of the normal human microbial flora and are acquired from environmental sources. In contrast, opportunistic mycosesare caused by organisms (e.g., Candida and Aspergillus) that frequently are components of the normal human flora and whose ubiquity in nature renders them easily acquired by the immunocompromised host.

Endemic mycoses cause more severe illness in immunocompromised patients than in immunocompetentindividuals.

Three other terms frequently used in clinical discussions of fungal infections are yeast, mold, and dimorphic fungus

Yeasts are seen as rounded single cells or as budding organisms: Candida and Cryptococcus

Molds grow as filamentous forms called hyphae both at room temperature and when they invade tissue: Aspergillus, Rhizopus

Dimorphic is the term used to describe fungi that grow as yeasts or large spherical structures in tissue but as filamentous forms at room temperature in the environment: blastomycosis, paracoccidioidomycosis, coccidioidomycosis, histoplasmosis, blastomycosis, and sporotrichosis.

Opportunistic infections have increased in frequency as a consequence :

Immunosuppression in organ and stem cell transplantation and many other diseases,

Administration of cytotoxic chemotherapy for cancers,

Liberal use of antibacterial agents.

GENUS TYPICAL GROWTH

SEPTATIONa SEXUAL FORM

PHYLUM MEDICAL CLASSIFICATION

Aspergillus Mold + ? Ascomycota Opportunistic

Blastomyces Dimorphic + ? Ascomycota Systemic

Candida Dimorphic + ? Ascomycota Opportunistic

Coccidioides Dimorphic + ? Ascomycota Systemic

Cryptococcus Yeast + Basidiomycota Systemic

Epidermophyton Mold + + Ascomycota Superficial

Histoplasma Dimorphic + + Ascomycota Systemic

Microsporum Mold + + Ascomycota Superficial

Mucor Mold – + Zygomycota Opportunistic

Pneumocystis Cysts ? Ascomycota Opportunistic

Rhizopus Mold – + Zygomycota Opportunistic

Sporothrix Dimorphic + ? Ascomycota Subcutaneous

Trichophyton Mold + + Ascomycota Superficial

Diagnosis The definitive diagnosis of any fungal infection requires

histopathologic identification of the fungus invading tissue, accompanied by evidence of an inflammatory response

The stains : PAS and GMS.

Candida, unlike other fungi, is visible on gram-stained tissue smears. H&E stain is not sufficient to identify Candida in tissue specimens. When positive, an India ink preparation of CSF is diagnostic for cryptococcosis. Most laboratories now use calcofluor white staining coupled with fluorescent microscopy to identify fungi in fluid specimens.

Diagnosis of deep organ fungal infections : The most reliable tests are the detection of Ab to C. immitis and

H. capsulatum in serum and CSF, the detection of cryptococcalpolysaccharide Ag in serum and CSF, and the detection of Histoplasma Ag in urine or serum. The test for galactomannanapproved for diagnosis of aspergillosis.

Numerous PCR assays to detect Ag are in the developmental stages, as are nucleic acid hybridization techniques

lysis-centrifugation technique increases the sensitivity of B/C for less common organisms (e.g., H. capsulatum) and should be used when disseminated fungal infection is suspected.

Candida species can be detected with any of the automated B/C systems widely used at present.

Serodiagnosis: Except in the cases of coccidioidomycosis, cryptococcosis, and histoplasmosis, there are no fully validated and widely used tests for serodiagnosis of disseminated fungal infection.

Skin tests for the endemic mycoses are no longer available.

Treatment Amphotericin B (AmB)(The lipid formulations include liposomal AmB

(L-AB; 3-5 mg/kg per day) and AmB lipid complex (ABLC; 5 mg/kg per day)

side effects: nephrotoxicity

• Azoles: Fluconazole, Voriconazole(first-line drug of choice for

treatment of aspergillosis), Itraconazole, Posaconazole

• Echinocandins: caspofungin, anidulafungin, and micafungin

• Flucytosine (5-Fluorocytosine)

• Griseofulvin and Terbinafine

• Topical Antifungal Agents :clotrimazole, econazole, miconazole,

oxiconazole, sulconazole, ketoconazole, tioconazole, butaconazole, and terconazole, Nystatin, ciclopirox olamine, halprogin, terbinafine,

naftifine, tolnaftate, and undecylenic acid.

Candidiasis

Candidiasis The genus Candida encompasses more than 150

species, only a few of which cause disease in humans, human pathogens are C. albicans, C. guilliermondii, C. krusei, C. parapsilosis, C. tropicalis, C. kefyr, C. lusitaniae, C. dubliniensis, and C. glabrata

They inhabit the GI tract (including the mouth and oropharynx), the female genital tract, and the skin

In the USA, these species are the 4th most common isolates from the blood of hospitalized patients.

Candidiasis Candida is a small, thin-walled, ovoid yeast that

measures 4–6 μm in diameter and reproduces by budding

occur in three forms in tissue: blastospores, pseudohyphae, and hyphae

Candida grows readily on simple medium; lysiscentrifugation enhances its recovery from blood

A Few Common Risk Factors for CandidalInfections:

Hiv and other immunodeficiency statesAntibioticsTopical or oral steroidsSkin trauma or occlusionDiabetes and other endocrinopathiesNutritional deicienciesAge (very young or very old)Malignancies

Clinical Manifestations Mucocutaneous Candidiasis:

Thrush: white, adherent, painless, discrete or confluent patches in

the mouth, tongue, or esophagus . The occurrence of thrush in a young, otherwise healthy-appearing person should prompt an investigation for underlying HIV infection

Vulvovaginal candidiasis: pruritus, pain, and vaginal discharge

paronychia: painful swelling at the nail-skin interface

onychomycosis

Intertrigo: erythematous irritation with redness and pustules in the

skin folds

Balanitis: erythematous-pustular infection of the glans penis

Mucocutaneous Candidiasis

erosio interdigitalis blastomycetica: Infection between the digits of the hands or toes;

folliculitis, with pustules developing most frequently in the area of the beard

perianal candidiasis: a pruritic, erythematous, pustular infection surrounding the anus

diaper rash: a common erythematous-pustular perineal infection in infants

Generalized disseminated cutaneous candidiasis: occurs primarily in infants, is characterized by widespread eruptions over the trunk, thorax, and extremities

Mucocutaneous Candidiasis

Chronic mucocutaneous candidiasis: infection of the hair,

nails, skin, and mucous membranes that persists despite intermittent therapy

Deeply Invasive Candidiasis

Nonhematogen:

Deep esophageal infection

joint or deep wound infection

kidney infection

infection of intraabdominal organ

gallbladder infection

Deeply Invasive Candidiasis

Hematogenous: The brain, chorioretina , heart, and kidneys are

most commonly infected and the liver and spleen less commonly so (most often in neutropenic patients). In fact, nearly any organ can become involved, including the endocrine glands, pancreas, heart valves (native or prosthetic), skeletal muscle, joints (native or prosthetic), bone, and meninges.

Diagnosis visualization of pseudohyphae or hyphae on wet

mount (saline and 10% KOH), tissue Gram's stain, PAS stain, or methenamine silver stain in the presence of inflammation; the presence of ocular or macronodularskin lesions is highly suggestive of widespread infection of multiple deep organs.

Recovery of Candida from sputum, urine, or peritoneal catheters may indicate mere colonization rather than deep-seated infection

Treatment: Treatment of Mucocutaneous Candidal

Infections

DiseasePreferred TreatmentAlternatives

CutaneousTopical azoleTopical nystatin

VulvovaginalOral fluconazole (150 mg) or azole cream or suppository

Nystatin suppository

ThrushClotrimazole trochesNystatin

EsophagealFluconazole tablets (100–200 mg/d) or itraconazole solution (200 mg/d)

Caspofungin, micafungin, or

amphotericin B

Treatment:Candidemia and Suspected Hematogenously

Disseminated Candidiasis: because there is no reliable way to distinguish benign candidemia from deep-organ infection, and because antifungal drugs less toxic than amphotericin B are available, it has become the standard of practice to treat all patients with candidemia, whether or not there is clinical evidence of deep-organ involvement, and if an indwelling intravascular catheter may be involved, it is best to remove or replace the device whenever possible.

Unless azole resistance is considered likely, fluconazole is the agent of choice for the treatment of candidemia and suspected disseminated candidiasis in nonneutropenic, hemodynamicallystable patients

AgentRoute of AdministrationComment

Amphotericin B deoxycholateIV onlyBeing replaced by lipid formulations

Amphotericin B lipid formulationsNot FDA approved as primary therapy, but used commonly because less toxic than amphotericin B deoxycholate; ABCD associated with frequent infusion reactions

Liposomal (AmBisome, Abelcet)IV only

Lipid complex (ABLC)IV only

Colloidal dispersion (ABCD)IV only

Azoles

FluconazoleIV and oralMost commonly used

VoriconazoleIV and oralMultiple drug interactions

EchinocandinsBroad spectrum against Candida species

CaspofunginIV onlyApproved for disseminated candidiasis

AnidulafunginIV onlyApproved for disseminated candidiasis

MicafunginIV onlyUnder evaluation for disseminated candidiasis

Recovery of Candida from sputum is almost never indicative of underlying pulmonary candidiasis and does not by itself warrant antifungal treatment.

Candida in the urine of a patient with an indwelling bladder catheter may represent colonization only rather than bladder or kidney infection; however, the threshold for systemic treatment is lower in severely ill patients in this category since it is not possible to distinguish colonization from lower or upper urinary tract infection.

The significance of the recovery of Candidafrom abdominal drains in postoperative patients is also unclear, but again, the threshold for treatment is generally low because most of the affected patients have been subjected to factors predisposing to disseminated candidiasis.

Removal of the infected valve and long-term antifungal therapy constitute appropriate treatment for Candida endocarditis

All patients with candidemia should undergo ophthalmologic examination because of the relatively high frequency of this ocular complication. Not only can this examination detect a developing eye lesion early in its course; in addition, identification of a lesion signifies a probability of ~90% of deep-organ abscesses and may prompt prolongation of therapy for candidemia beyond the recommended 2 weeks after the last positive blood culture.

.

Recommended treatment for Candidameningitis is a polyene plus flucytosine

Typical oral thrush with curdlikewhite patches over the tongue

Numerous Candida plaques

seen in the duodenum

(upper panels) and

esophagus (lower panels).

Severe Candida folliculitis in beard distribution

Macronodular lesions

of disseminated

candidiasis.

Candida spinal osteomyelitis.

Candida abscesses in the liver, kidney, and spleenon magnetic resonance imaging.

Advanced hematogenousCandida endophthalmitis.