Maduromycosis

Actinomycetomas are mycetomas caused by microaerophilic actinomycetes, and mycetomas caused by true fungi are called eumycetomas. These conditions are to be differentiated from actinomycosis. Actinomycosis is an endogenous suppurative infection caused by Actinomyces israelii or other species of Actinomyces or related bacteria, affecting the cervical-facial, thoracic, and pelvic sites (the latter usually is associated with the use of intrauterine devices). The branching bacteria causing actinomycosis are non–acid-fast anaerobic or microaerophilic bacteria. These bacteria are less than 1 micrometer in diameter and are small compared to the larger diameter of eumycotic agents. On the other hand, the agents of actinomycetoma always are aerobic and sometimes are weakly acid-fast.

More than 20 species of fungi and bacteria can cause mycetoma. The ratio of mycetomas that are caused by bacteria (actinomycetoma) to those that are caused by true fungi (eumycetoma) is 197:67.

Pathophysiology: The body parts affected most commonly are the foot or lower leg, with infection of the dorsal aspect of the forefoot being typical. The hand is the next most common location; however, lesions can occur anywhere on the body. Lesions on the chest and back frequently are caused by Nocardia species, whereas lesions on the head and neck usually are caused by Streptomyces somaliensis.

The causative organism enters through sites of local trauma (eg, cut on the hand, foot splinter, local trauma related to carrying soil-contaminated material). A neutrophilic response initially occurs, which may be followed by a granulomatous reaction. Spread occurs through skin facial planes and can involve the bone. Hematogenous or lymphatic spread is uncommon.

Frequency:

• In the US: Mycetoma is rare. Pseudallescheria boydii (Scedosporium apiospermum) is the most common cause of this condition.

• Internationally: This condition is endemic in Africa, from Sudan and Somalia through Mauritania and Senegal. Other endemic countries are Mexico and India; however, the disease also can be found in natives of areas of Central and South America and the Middle or Far East between latitudes 15°S and 30°N. In Sudan, at least 300-400 patients are diagnosed in hospitals every year.

Mortality/Morbidity: The disease causes disfigurement but rarely is fatal; however, when the skull is involved, a risk to life exists. The lesions are painless and slowly progressive; however, pain may occur when secondary bacterial infection or bone expansion occurs. In advanced cases, deformities or ankylosis and their corresponding disabilities can appear. Patients who are immunocompromised or who have undergone transplantation can develop invasive infection.

Race: No particular risk based on race has been described.

Sex: The male-to-female ratio is 183:81.

Age: This condition most frequently occurs in patients aged 20-50 years.

• Several years later, a painless subcutaneous nodule is observed. After some years, massive swelling of the area occurs, with induration, skin rupture, and sinus tract formation.

• As the infection spreads to contiguous body parts, old sinuses close and new ones open.

• Pain occurs in nearly 20% of patients and usually is due to secondary bacterial infection or, less commonly, bone invasion.

• Constitutional symptoms and signs are rare.

• Patients may complain of a deep itching sensation.

Physical:

• Irrespective of the causal agent, the appearance of the lesion is similar and consists of the following:

• Initially, subcutaneous swelling is present.

• In a later phase, a subcutaneous nodule develops.

• Eventually, massive swelling with induration, rupture of the skin, and formation of sinus tracts occur.

• In general, eumycetomas are more circumscribed and progress slower than actinomycetomas.

• Regional lymphadenopathy is unusual, but when it does occur, it is due to one of the following:

• Lymphatic spread of mycetoma to regional nodes occurs in only 1-3% of patients.

• Secondary bacterial infection or local immunological reaction can cause enlargement of regional lymph nodes.

• Lymphatic obstruction and fibrosis can cause lymphedema and erythema.

• Pulmonary mycetoma has been found to develop and progress more rapidly in individuals infected with HIV.

Causes:

• This condition most often occurs in farmers, shepherds, Bedouins, nomads, or people living in rural areas.

• Frequent exposure to penetrating wounds by thorns or splinters is a risk factor.

• Actinomycetoma can be caused by the following:

• Actinomadura madurae

• Actinomadura pelletieri

• S somaliensis

• Nocardia species

• Eumycetoma is caused primarily by P boydii (S apiospermum).

Other Problems to be Considered:

Lab Studies:

• Staining

• Hematoxylin-eosin staining of a biopsy sample allows for detection of grains.

• Process hematoxylin-eosin and May-Grnwald-Giemsa staining of a cytologic smear of a sample obtained by fine-needle aspiration. Mycetoma grains can be distinguished from artifacts and other organisms by the intimate relationship between the grain and neutrophils. The appearance of the grains is determined as follows:
  • Actinomycetoma - Homogenously eosinophilic with hematoxylin-eosin stain; blue in the center with pink filaments in the periphery with May-Grnwald-Giemsa stain

  • Eumycetoma - Brownish color with hematoxylin-eosin stain; black with a green tinge with May-Grnwald-Giemsa stain

• The causal agent of each type of mycetoma can be visualized better with the following:
  • Tissue Gram stain to detect fine, gram-positive, branching filaments within the actinomycetoma grain

  • Gomori methenamine silver or periodic acid-Schiff stain to demonstrate the larger hyphae of eumycetoma

• Evaluation of the characteristics of the associated granules suggests an initial differential diagnosis, as follows:

• White-to-yellow grains are indicative of P boydii (S apiospermum), Nocardia species, or A madurae infection.

• Yellow-to-brown grains are indicative of S somaliensis infection.

• Black grains are indicative of Streptomyces paraguayensis, Madurella species, or Leptosphaeria species infection.

• Red-to-pink grains are indicative of A pelletieri infection.

• Culture the grains obtained from a deep-seated wedge biopsy or a sample obtained by puncture and fine-needle aspiration. The primary isolation media used should be Löwenstein-Jensen for actinomycetoma or blood agar for eumycetoma.

• Serologic diagnosis is available in a few centers and can be helpful with some patients for diagnosis or follow-up care during medical treatment. Antibodies can be determined by means of (1) immunodiffusion, (2) counterimmunoelectrophoresis, (3) enzyme-linked immunosorbent assay, or (4) Western blot.

• Caution: Superficial samples of the draining sinuses are inadequate for culture due to frequent contamination with bacteria.

Imaging Studies:

• Bone radiograph

• Once mycetoma has invaded the bone, several changes can be observed, as follows:
  • Cortical thinning is due to compression from the outside by the mycetoma.

  • Cortical hypertrophy or periosteal proliferation may present as a sunray appearance and a Codman triangle.

  • Multiple lytic lesions or cavities may be large, few in number, and with well-defined margins in eumycetoma or small, numerous, and with ill-defined margins in actinomycetoma.

  • Disuse osteoporosis may occur in late mycetoma.

• Bone involvement has been radiographically classified, as follows:
  • Stage 0 - Soft-tissue swelling without bone involvement

  • Stage I - Extrinsic pressure effects on the intact bones in the vicinity of an expanding granuloma

  • Stage II - Irritation of the bone surface without intraosseous invasion

  • Stage III - Cortical erosion and central cavitation

  • Stage IV - Longitudinal spreading along a single ray

  • Stage V - Horizontal spread along a single row

  • Stage VI - Multidirectional spread due to uncontrolled infection

• MRI helps with the differential diagnosis of the swelling and can provide a better assessment of the degree of bone and soft tissue involvement.

• Ultrasonography: Single or multiple thick-walled cavities with hyperreflective echoes and no acoustic enhancement always are observed with mycetoma, whereas these features are not demonstrated in nonmycetoma swellings.

• In eumycetoma, the hyperreflective echoes are sharp, corresponding to the grains in the lesion.

• In actinomycetoma, the hyperreflective echoes are fine and closely aggregated and commonly settle at the bottom of the cavities.

• CT scan provides a better detail of changes than those observed with conventional radiographs.

Procedures:

• Perform a deep-seated wedge biopsy or puncture and fine-needle aspiration to obtain a grain sample.

External beam radiotherapy in doses ranging from 3.5-14 Gy has been considered successful treatment in a few selected cases.

Surgical Care: Surgery is recommended for localized lesions that can be excised completely without residual disability. Surgical reduction of large lesions can improve the patient's response to medical treatment; however, partial surgical resection without subsequent use of appropriate antimicrobial or antifungal agents is prone to failure.

Actinomycetoma is a bacterial infection that can respond to antibiotics if treatment is administered early in the course of the disease. A combination of 2 drugs in 5-week cycles is used. If needed, the cycles can be repeated once or twice. The following agents have been used in combination: trimethoprim-sulfamethoxazole (TMP-SMZ), dapsone (diaminodiphenylsulfone), and streptomycin sulfate. Amikacin can be substituted for streptomycin but usually is kept as a second-line drug because of its cost. Rifampin has been used as a second-line drug in resistant cases. In one case report, a patient required salvage therapy with amikacin and imipenem for 6 months.

Eumycetoma may respond partially to antifungal agents, although surgical therapy is preferred if the disease is localized. Madurella mycetomatis may respond to ketoconazole (200 mg bid). P boydii (S apiospermum) may respond to itraconazole. Other agents of eumycetoma may respond intermittently to itraconazole (200 mg bid) or amphotericin B. The minimum treatment duration is 10 months. Voriconazole is the drug of choice for invasive infections caused by agents of eumycetoma in patients who are immunocompromised.

Drug Category: Antibiotics -- Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of a clinical setting suggestive of actinomycetoma.

Drug Name	Trimethoprim-sulfamethoxazole (Bactrim DS, Septra) -- DOC; inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Should be used continuously in combination with another antimicrobial for 5 wk. Cycle may be repeated prn.
Adult Dose	160 mg TMP/800 mg SMZ PO q6h
Pediatric Dose	<2 months: Not recommended >2 months: 8 mg/kg TMP 40 mg/kg SMZ PO bid
Contraindications	Documented hypersensitivity; megaloblastic anemia due to folate deficiency; do not use during pregnancy (at term) or breastfeeding
Interactions	May increase PT when used with warfarin (perform coagulation tests, and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly patients; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; higher risk of hematologic toxicity in renal allograft recipients; goiter, diuresis, and hypoglycemia may occur; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, patients with chronic alcoholism, elderly patients, patients receiving anticonvulsant therapy, patients with malabsorption syndrome); hemolysis may occur in patients deficient of G-6-PD; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation

Drug Name	Amikacin (Amikin) -- Irreversibly binds to 30S subunit of bacterial ribosomes, blocks recognition step in protein synthesis, and causes growth inhibition. Should be given continuously for 3 wk. Although somewhat expensive, it usually is active against the bacteria causing actinomycetoma. Use the patient's IBW for dosage calculation.
Adult Dose	15 mg/kg/d IV/IM qd or divided bid; not to exceed 1.5 g/d regardless of higher BW
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Coadministration with other aminoglycosides, penicillins, cephalosporins, and amphotericin B increases nephrotoxicity; enhances effects of neuromuscular blocking agents; causes respiratory depression; irreversible hearing loss may occur with coadministration of loop diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not intended for long-term therapy; caution in patients with renal failure (not on dialysis), hypocalcemia, myasthenia gravis, and conditions that depress neuromuscular transmission; risk of nephrotoxicity and ototoxicity

Drug Name	Dapsone (Avlosulfon) -- Bactericidal and bacteriostatic against mycobacteria. Mechanism of action is similar to sulfonamides where competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Lowest-cost regimen. Change to TMP-SMZ if no response occurs after 1 mo.
Adult Dose	100 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; G-6-PD deficiency
Interactions	May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists, eg, pyrimethamine (monitor for agranulocytosis during the second and third mo of therapy); probenecid increases toxicity; TMP may increase toxicity of both drugs; due to increase in renal clearance, levels may decrease significantly when administered concurrently with rifampin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Perform weekly blood counts for the first mo; then, perform WBC counts monthly for 6 mo and semiannually thereafter; discontinue if significant reduction in platelets, leukocytes, or hematopoiesis is observed; caution in methemoglobin reductase deficiency, G-6-PD deficiency (patients receiving >200 mg/d), or hemoglobin M due to high risk for hemolysis and Heinz body formation; caution in patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy can occur (rare); phototoxicity may occur when exposed to UV light

Drug Name	Rifampin (Rimactane, Rifadin) -- For use in combination with at least 1 other agent. Inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur.
Adult Dose	10 mg/kg/d PO qd
Pediatric Dose	10 mg/kg/d PO; not to exceed 600 mg/d
Contraindications	Documented hypersensitivity
Interactions	Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, dapsone, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue 1 or both agents if alterations in LFTs occur)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause abnormal liver function, drug fever, flu syndrome, or hematological cytopenias; obtain CBCs and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

Drug Name	Imipenem and cilastatin (Primaxin) -- For treatment of multiple-organism infections in which other agents do not have wide spectrum coverage or are contraindicated due to potential for toxicity.
Adult Dose	Base initial dose on severity of infection and administer in equally divided doses; 0.5-1 g IV q6h; not to exceed 3-4 g/d Alternate dose: 500-750 mg IM q12h
Pediatric Dose	<12 years: Not established; 15-25 mg/kg/dose IV q6h suggested for >3 mo Fully susceptible organisms: Not to exceed 2 g/d Infections with moderately susceptible organisms: Not to exceed 4 g/d
Contraindications	Documented hypersensitivity
Interactions	Coadministration with cyclosporine may increase adverse CNS effects of both agents; coadministration with ganciclovir may result in generalized seizures
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adjust dose in renal insufficiency; avoid use in children <12 y

Drug Category: Antifungal agents -- In combination with surgical therapy, antifungal agents may help to attain partial response in cases of eumycetoma.

Drug Name	Ketoconazole (Nizoral) -- Fungistatic activity. Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.
Adult Dose	200 mg PO bid
Pediatric Dose	<2 years: Not established >2 years: 3.3-6.6 mg/kg/d PO single dose
Contraindications	Documented hypersensitivity; fungal meningitis
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
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hepatotoxicity may occur; may reversibly decrease corticosteroid serum levels (adverse effects avoided with dose of 200-400 mg/d); administer antacids, anticholinergics, or H2 blockers at least 2 h after taking ketoconazole

Drug Name	Itraconazole (Sporanox) -- Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.
Adult Dose	200 mg/d PO; not to exceed 400 mg/d; increase in 100-mg increments if no improvement (administer >200 mg/d in divided doses) 200 mg IV bid for 4 doses, followed by 200 mg/d
Pediatric Dose	Not established; suggested dose of 100 mg/d
Contraindications	Documented hypersensitivity; coadministration with cisapride may cause adverse cardiovascular effects (possibly death)
Interactions	Antacids may reduce absorption of itraconazole; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (ie, lovastatin, simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce levels (phenytoin metabolism may be altered)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic insufficiencies

Drug Name	Amphotericin B (Fungizone) -- Polyene antibiotic produced by a strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death. Conventional formulation (complexed with deoxycholate) has a poor tolerability profile. Liposomal amphotericin B incorporates the drug into small unilamellar liposomes; this formulation retains the antifungal activity with less hypokalemia, anemia and infusion reactions, and far less nephrotoxicity than the conventional formulation. Although the acquisition cost of liposomal amphotericin B is considerably higher than that of the conventional formulation, when adverse effects are considered, the calculated total costs of treatment for fungal infections are not clearly different.
Adult Dose	3-5 mg/kg/d IV of liposomal amphotericin B over approximately 120 min
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; the risk of renal toxicity is increased with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients with neutropenia who are receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock

Drug Name	Voriconazole (VFEND) -- Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.
Adult Dose	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)
Pediatric Dose	Not established
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, and ergot alkaloids
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 drugs may need more frequent monitoring (eg, cyclosporine, tacrolimus, warfarin, HMG-CoA inhibitors, benzodiazepines, calcium channel blockers)
Pregnancy	C - Safety for use during pregnancy has not been established.
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