eMedicine Specialties > Dermatology > Fungal Infections

South American Blastomycosis

Julie E Dixon, MD, FAAD, Private Practice, Ironwood Dermatology, Tucson, Arizona
Norman Levine, MD, Professor, Department of Medicine, Section of Dermatology, University of Arizona Health Sciences Center

Updated: Apr 29, 2009

Introduction

Background

South American blastomycosis is a serious, systemic mycotic infection caused by the thermally dimorphic fungus Paracoccidioides brasiliensis. The fungus is endemic to countries in Central America and South America, most notably Brazil, Argentina, Colombia, and Venezuela, in regions classified as subtropical mountain forests. Infection with P brasiliensis is usually subclinical; however, the fungus sometimes proliferates, causing severe disease.¹

Two general forms of the disease exist: the subacute juvenile form and the chronic adult form. The chronic adult form accounts for more than 90% of cases. The lungs, skin, mucous membranes, and lymph nodes most frequently are involved. Other internal organs sometimes are affected. Also see Blastomycosis (pediatrics) and Blastomycosis (pulmonology).

Pathophysiology

P brasiliensis is a thermally dimorphic fungus that grows as a mycelium in nature and as yeastlike cells in tissue. Although P brasiliensis has been cultured from the soil, its natural habitat is not well understood. The disease is believed to be initially acquired through the inhalation of the fungus, as with other dimorphic fungi. After the inhalation of conidia, the fungus transforms into yeast cells within the alveolar macrophages. In most patients who are immunocompetent, infection is subclinical, and fungal growth is halted. However, in some patients, after an incubation period of weeks to decades, the fungus reactivates and disseminates, causing granulomatous disease in multiple tissues.² Most commonly, the lungs are affected, followed by the mucous membranes, skin, lymph nodes, and various internal organs.

Frequency

United States

The fungus is not endemic to the United States. A number of cases have been reported in patients who previously visited or resided in endemic areas.³

International

South American blastomycosis is restricted to Central America and South America, with about 80% of cases occurring in Brazil. About 6-50% of people living in endemic regions have positive paracoccidioidin skin test results, which indicate prior infection. Antibodies to P brasiliensis have been detected in 27% of blood donors in Brazil.⁴ Of the 90 million people living in endemic areas, approximately 10 million are infected, although exact figures are difficult to obtain.⁵

Mortality/Morbidity

• The mortality rate is high for both the chronic adult and subacute juvenile forms if untreated. With treatment, the mortality rate is 7-10% for children and 1-10% for adults.⁶
• In patients with HIV, the mortality rate is 30-45%.
• Complications generally result from fibrotic scarring that occurs during healing. Patients can have residual chronic lung, oral, nasal, pharyngeal, and laryngeal problems after the lungs or mucous membranes heal. If internal organs, such as the adrenal glands, are affected, chronic organ dysfunction (ie, Addison disease) can develop.

Sex

• The chronic adult form affects men more frequently than women, with a ratio of about 15:1. The fungus has receptors that bind estrogen. Binding of estrogen prevents the transformation of the mycelium into the yeast phase, which is necessary for tissue invasion. This inhibition has been hypothesized to explain the extreme sex differences despite the fact that equal numbers of men and women have positive paracoccidioidin skin test results and that equal numbers of prepubertal boys and girls have the subacute juvenile type.
• The subacute juvenile form affects both sexes equally.

Age

• Most patients are adult men aged 30-50 years.
• Children are affected in only 3-5% of cases.

Clinical

History

After the inhalation of conidia, the fungus transforms into yeastlike cells inside the alveolar macrophages. This transformation induces a nonspecific inflammatory response, which generally limits the disease at this point. Most patients have no signs or symptoms.

• Adult chronic
  • After a latency period of weeks to decades, some adults have a chronic progressive form of the disease. The skin, mucous membranes, lungs, and lymph nodes primarily are affected.
  • Constitutional symptoms include low-grade fever, malaise, and weight loss.
  • Mucous membrane symptoms include pain at ulceration sites. Oral lesions may lead to pain with eating or drinking. Laryngeal and pharyngeal lesions can cause dysphagia, hoarseness, or stridor.
  • Respiratory symptoms include cough; mucous production, which may be blood-tinged; and dyspnea. Symptoms due to involvement of other organ systems are sometimes seen, such as abdominal pain from gastrointestinal involvement or headache from central nervous system involvement.
• Juvenile subacute
  • After a brief latency period, some children have a subacute severe disseminated form of the disease. In children, the major target of South American blastomycosis is the reticuloendothelial system.
  • Symptoms include fever, asthenia, anorexia, malaise, weight loss, and diarrhea.
  • Mucous membrane and respiratory symptoms are unusual.
  • Most other symptoms are related to lymph node enlargement, suppuration, and sinus tract formation.

Physical

• Adult chronic
  • Mucous membranes⁷ : Approximately one half of patients with chronic disseminated disease seek medical attention because of mucocutaneous lesions. Oral, nasal, pharyngeal, and laryngeal lesions begin as papules or plaques, which ulcerate. The lesions typically have granulomatous, mulberrylike surfaces and most commonly occur on the lips, gingiva, palate, buccal mucosa, and tongue. Lesions progress over months and are painful. Gingival lesions cause the loss of teeth, which makes eating difficult. Lesions slowly enlarge and coalesce, increasing the difficulties. Conjunctivitis and ulcerative lesions of the perianal area occasionally occur.

Ulcerated nodule on the tongue in a man with South American blastomycosis. Courtesy of Heidi Logemann, Professor of Mycology, Universidad de San Carlos, Guatemala.

• Skin: Skin lesions, which occur most commonly on the face, are polymorphous. They may be papular, nodular, ulcerated, papillomatous, or even tuberous. They most often arise from the direct extension of mucous membrane lesions. Occasionally, hematogenous spread results in widely scattered lesions and subcutaneous abscesses. Lymph node breakdown can lead to cutaneous fistulae. Without treatment, lesions gradually enlarge.

Crusted plaques over the central part of the face in a man with South American blastomycosis. Courtesy of Rolando Vasquez, MD, Professor of Dermatology, Guatemala.

• Lymph nodes: Extensive lymphadenopathy develops. Numerous visceral and subcutaneous nodes may be involved through hematogenous and lymphatic spread. Cervical nodes are commonly affected. Nodes are hypertrophic, firm, and painful. They sometimes suppurate, forming sinus tracts or ulcers in the skin.
• Respiratory: Lung involvement occurs in 70-80% of patients. In 25% of patients with the chronic adult type of disease, the lungs are the only organ system involved. The clinical picture often resembles that of tuberculosis. Chronic dyspnea, cough, and sputum production develop.
• Other: Hepatosplenomegaly, caused by hepatic and splenic lesions, occurs in approximately 5% of cases. Central nervous system involvement, both meningitis and parenchymal granulomatous disease, is observed in 5-25% of patients and causes mental status changes and seizures.⁸ Occasionally, adrenal insufficiency due to the destruction of the adrenal glands is observed. Intestinal ulcerations and osteomyelitis are other infrequent manifestations.
• Juvenile subacute
  • Mucous membranes: Mucosal involvement is rare, but mucosal ulcerations occasionally occur.
  • Skin: Subacute disease may be associated with an acneiform eruption or subcutaneous abscesses. Sometimes, scrofuloderma is produced as a result of suppuration of the underlying lymph nodes.
  • Lymph nodes: Lymphadenopathy is prominent. Nodes may enlarge to such a point that infection with P brasiliensis may be confused with leukemia or lymphoma. Lymph nodes often suppurate and form sinus tracts to the skin. Mesenteric adenopathy may lead to bowel obstruction.
  • Respiratory: Pneumonia sometimes occurs.
  • Other: Cachexia, hepatosplenomegaly, adrenal insufficiency, osteomyelitis, and gastrointestinal problems may also occur.

Causes

• The disease is caused by the inhalation of the fungus P braziliensis. Animal-to-human and human-to-human transmissions do not appear to occur. Direct inoculation of the skin or mucosal surfaces is rare.
• Rural workers, particularly woodcutters, are more frequently affected because of their increased contact with the soil.
• Alcohol and possibly tobacco smoking is associated with disseminated disease.
• South American blastomycosis has been identified as an AIDS-associated opportunistic infection. Patients with AIDS usually have a form of the disease that closely resembles the juvenile subacute type.⁹
• Otherwise healthy patients who develop disseminated disease appear unable to mount a sufficient cellular immune response to the organism.

Differential Diagnoses

Other Problems to Be Considered

Tuberculosis
Granulomatous candidosis
Histoplasmosis
Natural killer cell lymphoma
North American blastomycosis
Carcinomas
Lymphoma
Leukemia

Workup

Laboratory Studies

• Direct examination
  • The diagnosis of South American blastomycosis often is made recognizing the fungus on wet preparations.
  • The microscopic examination of pus or superficial scrapings from mucosal lesions reveals thick-walled spherical yeast cells with multiple peripheral buds encircling a mother cell (ie, pilot's wheal or mariner's wheal).
  • This pilot's wheel configuration measures as long as 60 µm in diameter and is highly characteristic of P brasiliensis.
  • If microscopic examination does not reveal spores with multiple buds, fungal culturing may be necessary to differentiate the organism from other fungal pathogens.
• Culturing
  • Cultures on Sabouraud agar at room temperature yield the mold in 3-4 weeks.
  • P brasiliensis is a slowly growing mold with a white-to-tan aerial mycelium.
  • Subcultures on rich media at 37°C yield the characteristic yeast form.
• Skin testing
  • The paracoccidioidin skin test is available but has little diagnostic value.
  • A positive skin test result indicates prior exposure, but it does not necessarily indicate current disease.
  • The test may be useful prognostically because the conversion from an anergic result to a positive result is associated with a good prognosis in patients with severe South American blastomycosis.
• Serologic testing
  • Immunodiffusion and complement fixation are useful for the diagnosis of South American blastomycosis.
  • Results with both tests are positive in about 85-95% of patients with active disease, although cross-reactions with histoplasmosis can occur.
  • Complement fixation is quantitative and, therefore, is useful for following disease progression and response to therapy.
  • Recently, monoclonal antibodies to antigenic compounds of P brasiliensis (43-kd and 70-kd glycoproteins) have been developed. Using inhibition enzyme-linked immunosorbent assays, the sensitivity and specificity of these antibodies exceed 95%. These tests may prove useful for diagnosing South American blastomycosis in anergic or immunocompromised patients and for monitoring response to treatment.^10,11,12

Imaging Studies

• If clinically indicated, a chest radiograph should be obtained. A chest radiograph often shows opaque bilateral lesions that are generally nodular but sometimes cavitary. Lesions usually involve the perihilar and basilar portions of the lungs. This finding can help to differentiate South American blastomycosis from tuberculosis, which has a propensity to involve the upper lobes of the lungs.
• If clinically indicated, computed tomography or magnetic resonance imaging of the brain should be obtained to evaluate central nervous system involvement.

Other Tests

• If warranted, pulmonary function tests may reveal obstructive abnormalities, but the results are generally mild compared with the radiographic findings.

Procedures

• Lesional biopsies are helpful in diagnosis.

Histologic Findings

Histologic examination reveals a granulomatous reaction with epithelioid and giant cells in association with a severe inflammatory infiltrate. Spores with the characteristic pilot's wheel may be found within giant cells or free in the inflammatory infiltrate. In skin and mucous membrane lesions, pseudoepitheliomatous hyperplasia with intraepidermal abscesses occurs. Caseous necrosis is seen within the lymph nodes. Tissue repair is seen as collagen fibrosis.

Treatment

Medical Care

• Systemic antifungal medications are the mainstay of medical management.
• Supportive measures and hospitalization may be warranted for patients with severe disease. If present, anemia and nutritional deficiencies should be treated.

Surgical Care

• Occasionally, specific surgical treatments are warranted for life- or organ-threatening disease, such as neurosurgical procedures to relieve granuloma-induced spinal cord compression or hydrocephalus.
• Reconstructive surgery is sometimes needed to alleviate fibrotic sequelae.

Consultations

• A pulmonologist or internal medicine specialist may be consulted, as warranted by the pulmonary symptoms or internal organ dysfunction.
• A consultation with an infectious disease specialist may be necessary if the diagnosis is uncertain.
• Rarely, consultation with a surgeon is needed.

Medication

Antifungal medications are the mainstay of treatment for South American blastomycosis. Most conditions respond well to these agents. Itraconazole, ketoconazole, fluconazole, amphotericin B, trimethoprim and sulfamethoxazole (TMP-SMZ), and sulfadiazine have all been successfully used to treat South American blastomycosis.¹³ Itraconazole and ketoconazole have become the drugs of choice in treatment; itraconazole is generally considered the superior of the two.^14,15

Historically, the sulfonamides have been the most widely used medications for the treatment of P braziliensis; their advantage is their low cost. However, relapses are more common with the sulfonamides than with other mediations, and longer courses of therapy are required. The percentage of patients who have a relapse after receiving sulfonamides is 20-30%, whereas with itraconazole it is 3.5-10% and with ketoconazole it is 7-11%. Further, 3-5 years of sulfonamide therapy may be required, whereas 6-10 months and 6-12 months are recommended with itraconazole and ketoconazole, respectively.

Fluconazole is not as effective as either itraconazole or ketoconazole. Its main advantages are that it is available in both oral and intravenous forms and that it penetrates into the cerebrospinal fluid (CSF) well.

Amphotericin B is used in patients with severe disease who cannot tolerate oral medications. It generally is given for 4-8 weeks and followed by sulfonamides for 2-3 years. Because of its high rate of adverse reactions and low patient tolerance, its use is reserved for the most ill patients. Its low cost is an advantage in Central America and South America. Amphotericin B is the only medication in this list in pregnancy category B; all the other medications are pregnancy category C or D.

At this time, sulfadiazine and TMP-SMZ are still used for South American blastomycosis because of their low cost.

Reports have documented successful treatment with voriconazole, posaconazole, and terbinafine.¹⁶

These guidelines may be helpful:Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.

Antifungal Agent, Systemic

The mechanism of action may involve an alteration of RNA or DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Itraconazole (Sporanox)

Considered DOC. Triazole antifungal agent that blocks the synthesis of ergosterol, an integral component of the fungal cell membrane.
IV formulation now available but no IV dose established for P brasiliensis treatment.

Dosing

Adult

100 mg PO qd for 6 mo

Pediatric

Not established; 5 mg/kg PO qd has been used in a few children with severe systemic fungal infections

Interactions

Elevates plasma levels of terfenadine, astemizole, cisapride, lovastatin, simvastatin, midazolam, triazolam, digoxin, cyclosporine, tacrolimus, quinidine, and methylprednisolone; cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes associated with concomitant terfenadine, astemizole, or cisapride; increases plasma levels of lovastatin and simvastatin, which is associated with rhabdomyolysis (do not coadminister); increases levels of midazolam and triazolam, which may lead to oversedation
Monitor digoxin, cyclosporine, and tacrolimus levels during treatment; tinnitus and decreased hearing associated with quinidine coadministration; may need to adjust methylprednisolone dose during treatment; may increase levels of oral hypoglycemic agents (closely monitor glucose levels for hypoglycemia); may increase levels of vincristine and vinblastine; may potentiate effects of warfarin (monitor PT); phenytoin, carbamazepine, phenobarbital, rifampin, rifabutin, and INH decrease levels (may need to adjust dose)
Edema reported in patients taking dihydropyridine calcium channel blockers; absorption depends gastric acidity (absorption decreased in patients taking antacids, H2 blockers, or proton pump inhibitors); may increase plasma levels of ritonavir or indinavir

Contraindications

Documented hypersensitivity; do not use with terfenadine, astemizole, cisapride, lovastatin, simvastatin, midazolam, or triazolam (itraconazole inhibits cytochrome P-450 3A4 enzyme, which may increase plasma levels of drugs metabolized through this pathway)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic insufficiency; should not be used during breastfeeding; capsules should be taken with food to enhance absorption; most common adverse effects include nausea, vomiting, diarrhea; less frequent adverse effects include edema, hypertension, fatigue, rash, headache, and elevated LFT results; hepatitis, hypertriglyceridemia, and anaphylaxis rare; regularly monitor LFT results; in known liver disease, benefits must outweigh risks; plasma levels are not affected by renal insufficiency or hemodialysis; caution in CHF or patients at risk for CHF due to edema that sometimes is caused by itraconazole; does not penetrate into CSF

Ketoconazole (Nizoral)

Fungistatic activity. Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing cellular components to leak and result in fungal cell death.

Dosing

Adult

200-400 mg PO qd for 6-12 mo

Pediatric

Not established for P brasiliensis; 3.3-6.6 mg/kg/d PO has been used in children > 2 y with severe fungal infections

Interactions

Isoniazid may decrease bioavailability; coadministration decreases effects of either rifampin or ketoconazole; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dosage can be adjusted); may decrease theophylline levels; decreases metabolism of repaglinide, thus increasing serum levels and effects

Contraindications

Documented hypersensitivity; fungal meningitis; concurrent use of cisapride, triazolam, or midazolam

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Should not be used during breastfeeding; should be taken with food to enhance absorption; administer antacid, anticholinergics, or H2 blockers at least 2 h after dose; most common adverse effects include nausea, vomiting, and dyspepsia; causes transient asymptomatic elevation of LFT results (approximately 20%), overt hepatitis (5%), and hepatic failure (several cases reported); LFT results usually revert to normal after discontinuance, but LFT results should be checked frequently during treatment; dose may need to be decreased in hepatic insufficiency; no adjustment needed in renal failure (not removed by dialysis); can interfere with endogenous steroid production, causing irregular menstrual bleeding, impotence and decreased libido in men, and adrenal insufficiency in decreased adrenal reserve; not well absorbed in achlorhydria; does not penetrate into CSF

Fluconazole (Diflucan)

Fungistatic activity. Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Not considered DOC in the treatment of South American blastomycosis.

Dosing

Adult

200-400 mg PO/IV qd for 6-12 mo

Pediatric

Not established for P brasiliensis; 6-12 mg/kg/d PO/IV has been used in some children with life-threatening systemic fungal infections

Interactions

Levels may increase with hydrochlorothiazides; levels may decrease with long-term coadministration of rifampin; may increase concentrations of theophylline, phenytoin, tolbutamide, cyclosporine, glyburide, and glipizide; effects of anticoagulants may increase with coadministration

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not safe to use during breastfeeding; most common adverse effects include headache, nausea, vomiting, and diarrhea; excreted primarily in urine, prolonged elimination in renal insufficiency, dose adjustments may be necessary in patients with renal disease; fluconazole is removed by dialysis; increases in LFT results rare and usually reversible (hepatotoxicity reported); elimination slowed in cirrhosis (dose adjustment may be necessary); reversible alopecia and exfoliative dermatologic disorders (rare); penetrates well into CSF

Amphotericin B (Amphocin, Fungizone)

Antifungal agent that binds to sterols in fungal cell membrane. Binding changes membrane permeability, which results in intracellular components to leak out of fungal cells. Indicated for the treatment of life-threatening fungal infections or when oral antifungal medications cannot be tolerated.

Dosing

Adult

0.7-1 mg/kg IV qd for 4-8 wk or a total dose of 35 mg/kg

Pediatric

Not established for P brasiliensis; 0.5-1 mg/kg IV qd has been used in life-threatening systemic fungal infections

Interactions

Antineoplastic agents, aminoglycosides, cyclosporine, and pentamidine may potentiate risk of drug-induced renal toxicity; corticosteroids may potentiate amphotericin B–induced hypokalemia; hypokalemia from amphotericin B may potentiate digitalis toxicity; monitor potassium levels and cardiac function; may increase flucytosine toxicity; imidazole antifungal agents may induce fungal resistance to amphotericin, do not use concomitantly

Contraindications

Documented hypersensitivity; non–life-threatening infection

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Not recommended for use during breastfeeding; acute reactions including fever, shaking chills, nausea, vomiting, hypotension, headache, and tachypnea common within 1-3 h of infusion, tolerance may be improved by pretreatment with antipyretics, antihistamines, antiemetics, or meperidine; rapid infusion associated with hypotension, hypokalemia, cardiac arrhythmias, and shock (infusions should be given over 2-6 h, depending on response); caution in renal insufficiency
Pretreatment with hydration and sodium may decrease risk of nephrotoxicity; some permanent renal impairment often occurs, especially with large doses
Closely monitor renal function and electrolyte levels, LFT results, and blood counts; associated with hypokalemia, hypomagnesemia, hypocalcemia, increased BUN and creatinine levels, elevated LFT results, and anemia; doses should generally start at 0.25 mg/kg qd and be titrated upward dependent on tolerance; never give >1.5 mg/kg/d (high doses can result in cardiopulmonary arrest); not removed by dialysis

Terbinafine (Lamisil)

Fungicidal activity. Inhibits squalene epoxidase, which decreases ergosterol synthesis, causing fungal cell death. Clinical experience with terbinafine is limited in the treatment of South American blastomycosis.

Dosing

Adult

Not established; 500 mg/d has been successful

Pediatric

Not established

Interactions

May decrease cyclosporine effects; may increase with rifampin and cimetidine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Discontinue use if hepatobiliary dysfunction, neutropenia, Stevens-Johnson syndrome, or changes in ocular lens or retina develop

Voriconazole (Vfend)

A triazole antifungal agent that inhibits fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.

Dosing

Adult

Not established for P brasiliensis
Loading dose: 6 mg/kg IV q12h infused over 2 h for 2 doses
Maintenance: 4 mg/kg IV q12h infused over 2 h; switch to 200 mg PO q12h when able to tolerate; may increase to 300 mg PO q12h if inadequate response
<40 kg: Average maintenance dose is 100 mg PO q12h (may increase to 150 mg PO q12h)
Based on experience with other azole antifungals will likely need 6-12 months of treatment

Pediatric

Not established; 4 mg/kg qd has been used in a few children with severe systemic fungal infections

Interactions

CYP450 2C19 (highest affinity), 2C9, and 3A4 (minor) substrate and inhibitor; CYP450 inducers (eg, rifampin) have shown to decrease steady state peak plasma levels by up to 93%; may increase serum levels of drugs metabolized by CYP450 2C19 or 2C9, of which some are contraindicated (eg, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids), other may need more frequent monitoring (eg, cyclosporine, tacrolimus, warfarin, HMG-CoA inhibitors, benzodiazepines, calcium channel blockers)

Contraindications

Documented hypersensitivity; CrCl <50 mL/min (decreased excretion of IV vehicle) if administering IV; coadministration with rifampin, rifabutin, carbamazepine, barbiturates, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Decrease maintenance dose in hepatic dysfunction; common adverse effects include visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, rash (including Stevens-Johnson syndrome and phototoxicity), and respiratory disorder; rare cases of severe hepatotoxicity reported; administer PO dosage form 1 h ac or pc

Posaconazole (Noxafil)

Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation, which results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.

Dosing

Adult

Not established for P brasiliensis
200 mg (5 mL) PO tid suggested, with food or liquid nutritional supplement to enhance absorption; based on experience with other azole antifungals, likely need 6-12 mo of treatment

Pediatric

Not established for P brasiliensis
<13 years: Not established
>13 years: Administer as in adults

Interactions

Metabolized via UDP glucuronidation; P-gp efflux substrate; CYP3A4 inhibitor UDP-G inducers (eg, rifabutin, phenytoin) and drugs that increase gastric pH (eg, cimetidine) decrease serum levels (avoid concomitant use unless benefit outweighs risk)
Inhibits CYP3A4 and may elevate serum levels of cyclosporine, tacrolimus, sirolimus, rifabutin, midazolam, phenytoin, calcium channel blockers (eg, nifedipine, bepridil), HMG-CoA reductase inhibitors (eg, lovastatin, pravastatin), ergot alkaloids, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, or vinca alkaloids (eg, vincristine, vinblastine)

Contraindications

Documented hypersensitivity; coadministration with ergot alkaloids; coadministration with CYP3A4 substrates (eg, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine) likely to result in serious toxicities

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and elevated liver enzyme levels; closely monitor patients with severe diarrhea or vomiting for breakthrough fungal infections; rare adverse events include arrhythmias caused by QTc prolongation, bilirubinemia, or liver function impairment; caution with preexisting cardiac risk factors (eg, history of arrhythmia, hypokalemia, hypomagnesemia); food improves absorption and provides optimal serum concentration; shake well before use; administer with measuring spoon provided in package; avoid if breastfeeding

Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Trimethoprim and sulfamethoxazole (Septra, Bactrim)

Sulfamethoxazole competes with para-aminobenzoic acid (PABA) and thereby inhibits microbial synthesis of dihydrofolate. Trimethoprim binds to and reversibly inhibits the enzyme dihydrofolate reductase, thereby blocking the production of tetrahydrofolic acid from dihydrofolic acid. Thus, 2 consecutive steps in the synthesis of essential nucleic acids and proteins are blocked. Used to treat South American blastomycosis in Central America and South America primarily because of its low cost. Not DOC.

Dosing

Adult

80 mg TMP/400 mg SMZ PO bid for 2-3 y

Pediatric

<2 months: Do not administer
>2 months: Not established for P brasiliensis; 8 mg/kg TMP/40 mg/kg SMZ PO divided bid has been used

Interactions

May increase PT in patients on warfarin (monitor PT); in elderly patients on certain diuretics, primarily thiazides, increased incidence of thrombocytopenia with purpura reported; may increase phenytoin levels (monitor phenytoin levels); may increase free methotrexate levels (monitor MTX levels); may increase digoxin levels (monitor digoxin levels); increased incidence of nephrotoxicity possible when coadministered with cyclosporine; concomitant indomethacin may increase SMZ levels; increased incidence of megaloblastic anemia reported with concomitant pyrimethamine (malaria prophylaxis); may potentiate effects of oral hypoglycemic agents, causing hypoglycemia; may decrease effectiveness of tricyclic antidepressants

Contraindications

Documented hypersensitivity; megaloblastic anemia due to folate deficiency; pregnancy or breastfeeding (possible kernicterus in infant); severe hepatic or renal insufficiency when LFT results or renal function cannot be monitored

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Most common adverse effects include nausea, vomiting, rash, and urticaria; caution in renal or hepatic insufficiency, folate deficiency, thyroid dysfunction, or porphyria; may cause hemolysis in G-6-PD deficiency; primarily excreted renally (may need to reduce doses in renal insufficiency); TMP component can cause hyperkalemia (caution in patients prone to increased potassium levels); hypoglycemia reported (usually in hepatic or renal insufficiency, malnutrition, or use of taking high doses for long period); hematologic changes possible, especially in elderly patients, preexisting folate deficiency, or renal insufficiency
Elderly patients at greater risk of severe skin reactions, bone marrow suppression, and thrombocytopenia; patients with AIDS have an increased risk of rash, fever, leukopenia, elevated LFT results, or hyperkalemia; prolonged use can lead to bone marrow depression; rare fatalities have been associated with administration of sulfonamides due to Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, aplastic anemia, and agranulocytosis; instruct patients to maintain adequate fluid intake to prevent crystalluria and nephrolithiasis

Sulfadiazine (Microsulfon)

Sulfonamide antimicrobial agent that exerts bacteriostatic action through competitive antagonism with PABA.
Microorganisms that require exogenous folic acid and do not synthesize folic acid are not susceptible to the action of sulfonamides. Used for the treatment of South American blastomycosis in Central America and South America primarily because of its low cost. Not DOC.

Dosing

Adult

500-1000 mg PO q4-6h for 2-5 y

Pediatric

<2 months: Do not administer
>2 months: 60-100 mg/kg/d PO divided q4-6h

Interactions

May potentiate effects of warfarin (monitor PT); may increase serum levels of free MTX; may potentiate effects of oral hypoglycemic agents, causing hypoglycemia (monitor glucose closely); may increase phenytoin levels (monitor levels); may decrease cyclosporine levels; effects decreased when administered concurrently with PABA or PABA metabolites of drugs (eg, proparacaine, tetracaine, sunscreens, procaine)

Contraindications

Documented hypersensitivity; pregnant or breastfeeding women (possible kernicterus in infant)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in impaired renal or hepatic function; adjust dose in renal insufficiency; may cause hemolysis in G-6-PD deficiency; instruct patients to maintain adequate fluid intake to prevent crystalluria and nephrolithiasis; rare deaths associated with hypersensitivity reactions to sulfonamides due to agranulocytosis, aplastic anemia, and other blood disorders; frequently monitor blood counts and urinalysis results

Follow-up

Further Inpatient Care

• Patients with severe disease who cannot tolerate oral medications must be admitted to the hospital for intravenous antifungal medication and supportive care.

Further Outpatient Care

• During and after treatment with antifungal medications, patients must be regularly evaluated to ensure an adequate response and a lack of relapse.
• Complement fixation tests can be used to track the response to therapy; antibody levels decrease with improvement. Complement fixation also can be used to detect relapse because antibody levels increase again. The new antibody tests directed against P brasiliensis antigenic glycoproteins may prove useful in monitoring disease activity and response to therapy.
• Absence of symptoms for 2 years after antifungal therapy is considered by some to indicate a cure. Others believe that mycologically negative results in 3 specimens after the cessation of therapy are considered to indicate a cure.

Inpatient & Outpatient Medications

• Antifungal medications, as described in Medication, are indicated.

Deterrence/Prevention

• No vaccine against P brasiliensis has been developed, although a peptide vaccine is currently being studied.
• No known control measures prevent South American blastomycosis.

Complications

• Superinfection with bacteria or other fungal pathogens is always a concern because patients often have open wounds and an immune system that is already under stress. Superinfection can significantly complicate recovery or even lead to sepsis and death.
• The destruction of mucous membranes can lead to perforation of the palate or nasal septum.
• The destruction of the adrenal glands can cause Addison disease.
• The severe fibrosis that accompanies healing often results in long-term sequelae. These sequelae occur despite adequate treatment.
  • Facial lesions heal with disfiguring facial scarring.
  • Severe pulmonary fibrosis can occur and lead to chronic dyspnea and even cor pulmonale.
  • Mucous membrane scarring can lead to buccal atresia, dysphonia, laryngeal stenosis, or tracheal stenosis.

Prognosis

• With appropriate antifungal therapy, most patients survive.
• Relapses are common, and patients must be evaluated regularly.

Miscellaneous

Medicolegal Pitfalls

• Failure to consider the diagnosis in a patient who previously resided in or visited an endemic area

Special Concerns

• Pregnancy
  • South American blastomycosis is uncommon in women of childbearing age. However, in one large epidemiologic study in Brazil, 6 patients were pregnant during treatment. In one case, P brasiliensis was found in the placenta, but the child was not infected.
  • Amphotericin B is the only antifungal medication in pregnancy category B that is effective against P brasiliensis. All of the other medications that are currently used are category C or D.
• Patients with HIV/AIDS
  • Patients with AIDS acquire a form of South American blastomycosis that resembles the subacute juvenile type. Widespread disease quickly develops.
  • The meninges are more commonly involved in patients with AIDS than in patients who do not have AIDS.
  • In recent years, South American blastomycosis has been recognized as an AIDS-associated opportunistic infection. However, the incidence is lower than that expected by comparison to other endemic fungal infections.
  • The use of TMP-SMZ for Pneumocystis pneumonia prophylaxis and ketoconazole for oropharyngeal candidiasis prophylaxis has aided in the reduction in disseminated P brasiliensis infections.
  • AIDS is primarily seen in urban areas, whereas South American blastomycosis is seen primarily in rural areas further contributing to the lower than expected rate of disease.
  • The paracoccidioidin skin test is often negative in infected AIDS patients. Levels of circulating antibodies to P brasiliensis are often low and, therefore, inaccurate in patients with AIDS.
  • The following guidelines may be helpful:
    • Treating opportunistic infections among HIV-infected adults and adolescents. Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America.
    • Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America.

Multimedia

Media file 1: Crusted plaques over the central part of the face in a man with South American blastomycosis. Courtesy of Rolando Vasquez, MD, Professor of Dermatology, Guatemala.

Media file 2: Ulcerated nodule on the tongue in a man with South American blastomycosis. Courtesy of Heidi Logemann, Professor of Mycology, Universidad de San Carlos, Guatemala.

References

1. Lupi O, Tyring SK, McGinnis MR. Tropical dermatology: fungal tropical diseases. J Am Acad Dermatol. Dec 2005;53(6):931-51, quiz 952-4. [Medline].

2. Benard G, Kavakama J, Mendes-Giannini MJ, Kono A, Duarte AJ, Shikanai-Yasuda MA. Contribution to the natural history of paracoccidioidomycosis: identification of the primary pulmonary infection in the severe acute form of the disease--a case report. Clin Infect Dis. Jan 1 2005;40(1):e1-4. [Medline].

3. Mayr A, Kirchmair M, Rainer J, Rossi R, et al. Chronic paracoccidioidomycosis in a female patient in Austria. Eur J Clin Microbiol Infect Dis. Dec 2004;23(12):916-9. [Medline].

4. Maluf ML, Pereira SR, Takahachi G, Svidzinski TI. [Prevalence of paracoccidioidomycosis infection determined by sorologic test in donors' blood in the Northwest of Parana, Brazil]. Rev Soc Bras Med Trop. Jan-Feb 2003;36(1):11-6. [Medline].

5. Blotta MH, Mamoni RL, Oliveira SJ, et al. Endemic regions of paracoccidioidomycosis in Brazil: a clinical and epidemiologic study of 584 cases in the southeast region. Am J Trop Med Hyg. Sep 1999;61(3):390-4. [Medline].

6. Pereira RM, Tresoldi AT, da Silva MT, Bucaretchi F. Fatal disseminated paracoccidioidomycosis in a two-year-old child. Rev Inst Med Trop Sao Paulo. Jan-Feb 2004;46(1):37-9. [Medline].

7. Sant'Anna GD, Mauri M, Arrarte JL, Camargo H Jr. Laryngeal manifestations of paracoccidioidomycosis (South American blastomycosis). Arch Otolaryngol Head Neck Surg. Dec 1999;125(12):1375-8. [Medline].

8. de Almeida SM, Queiroz-Telles F, Teive HA, Ribeiro CE, Werneck LC. Central nervous system paracoccidioidomycosis: clinical features and laboratorial findings. J Infect. Feb 2004;48(2):193-8. [Medline].

9. Corti M, Villafane MF, Negroni R, Palmieri O. Disseminated paracoccidioidomycosis with peripleuritis in an AIDS patient. Rev Inst Med Trop Sao Paulo. Jan-Feb 2004;46(1):47-50. [Medline].

10. Marques da Silva SH, Queiroz-Telles F, Colombo AL, Blotta MH, Lopes JD, Pires De Camargo Z. Monitoring gp43 antigenemia in Paracoccidioidomycosis patients during therapy. J Clin Microbiol. Jun 2004;42(6):2419-24. [Medline].

11. Yasuda MA. Pharmacological management of paracoccidioidomycosis. Expert Opin Pharmacother. Mar 2005;6(3):385-97. [Medline].

12. da Silva SH, Grosso Dde M, Lopes JD, et al. Detection of Paracoccidioides brasiliensis gp70 circulating antigen and follow-up of patients undergoing antimycotic therapy. J Clin Microbiol. Oct 2004;42(10):4480-6. [Medline].

13. Hay RJ. Antifungal drugs used for systemic mycoses. Dermatol Clin. Jul 2003;21(3):577-87. [Medline].

14. Queiroz-Telles F, Goldani LZ, Schlamm HT, Goodrich JM, Espinel-Ingroff A, Shikanai-Yasuda MA. An open-label comparative pilot study of oral voriconazole and itraconazole for long-term treatment of paracoccidioidomycosis. Clin Infect Dis. Dec 1 2007;45(11):1462-9. [Medline].

15. Travassos LR, Taborda CP, Colombo AL. Treatment options for paracoccidioidomycosis and new strategies investigated. Expert Rev Anti Infect Ther. Apr 2008;6(2):251-62. [Medline].

16. Ollague JM, de Zurita AM, Calero G. Paracoccidioidomycosis (South American blastomycosis) successfully treated with terbinafine: first case report. Br J Dermatol. Jul 2000;143(1):188-91. [Medline].

17. Crissey JT, Lang H, Parish LC. Manual of Medical Mycology. Cambridge, Mass: Blackwell Sciences; 1995:128-34.

18. Elder D, Elenitsas E, Jawarsky C, et al, eds. Lever's Histopathology of the Skin. 10^th ed. Philadelphia, Pa: Lippincott-Raven; 2008.

19. Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases: Principles, Pathogens, and Practice. 2^nd ed. New York, NY: Churchill Livingstone; 2006.

20. Richardson MD, Warnock DW, eds. Fungal Infection: Diagnosis and Management. 3^rd ed. London, England: Bailliere Tindallk; 2003.

21. Stickland GT, ed. Hunter's Tropical Medicine and Emerging Infectious Diseases. 8^th ed. Philadelphia, Pa: WB Saunders; 2000:559-61.

Keywords

South American blastomycosis, paracoccidioidomycosis, Lutz mycosis, Brazilian blastomycosis, granuloma, Paracoccidioides brasiliensis, P brasiliensis, Lutz-Splendore-Almeida disease, blastomycosis sudamericana, blastomycose sud-americaine

Contributor Information and Disclosures

Author

Julie E Dixon, MD, FAAD, Private Practice, Ironwood Dermatology, Tucson, Arizona
Julie E Dixon, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Norman Levine, MD, Professor, Department of Medicine, Section of Dermatology, University of Arizona Health Sciences Center
Norman Levine, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Medical Editor

Franklin Flowers, MD, Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, University of Florida College of Medicine
Franklin Flowers, MD is a member of the following medical societies: American College of Mohs Micrographic Surgery and Cutaneous Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey J Miller, MD, Associate Professor of Dermatology, Penn State University College of Medicine; Staff Dermatologist, Penn State Milton S Hershey Medical Center
Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Professors of Dermatology, North American Hair Research Society, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Clinical trials

• A Pharmacokinetics Study of JK1211, Itraconazole Oral Solution, in Patients With Deep Mycosis and Those With Febrile Neutropenia Due to a Suspected Fungal Infection
• Evaluation of the Association of Polymorphisms in the Innate Immune System With the Risk for Blastomycosis Dermatitidis Infection in Patients Not Infected With HIV and Complications Associated With Blastomycosis Dermatitidis Infection

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