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AUTHOR AND EDITOR INFORMATION

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Author: Basilio J Anía, MD, Consultant in Internal Medicine, Associate Professor of Infectious Diseases, Department of Internal Medicine, Division of Infectious Diseases, Hospital Negrín & Universidad de Las Palmas de Gran Canaria, Spain

Coauthor(s): Margarita Asenjo, MD, Associate Professor, Department of Radiology, Medical School of the University of Las Palmas De Gran Canaria, Spain; Raphael J Kiel, MD, Associate Professor of Medicine, Wayne State University School of Medicine; Associate Program Director, Head of Infectious Disease Section, Department of Internal Medicine, Oakwood Hospital

Editors: Larry I Lutwick, MD, Professor of Medicine, State University of New York, Downstate Medical School; Director, Infectious Diseases, Veterans Affairs New York Harbor Health Care System, Brooklyn Campus; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Michael Stuart Bronze, MD, Professor, Stewart G Wolf Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital; Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Author and Editor Disclosure

Synonyms and related keywords: mycetoma, maduromycosis, Madura foot, actinomycetoma, eumycetoma, bacterial mycetoma, fungal mycetoma, actinomycetes, pulmonary mycetoma, mycetoma grain, Pseudallescheria boydii, P boydii, Actinomadura madurae, A madurae, Actinomadura pelletieri, A pelletieri, Streptomyces somaliensis, S somaliensis, Nocardia, Scedosporium apiospermum, S apiospermum, Streptomyces paraguayensis, S paraguayensis, Leptosphaeria, Madurella mycetomatis, M mycetomatis


INTRODUCTION

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Background

Mycetoma is a chronic subcutaneous infection caused by actinomycetes or fungi. This infection results in a granulomatous inflammatory response in the deep dermis and subcutaneous tissue, which can extend to the underlying bone. Mycetoma is characterized by the formation of grains containing aggregates of the causative organisms that may be discharged onto the skin surface through multiple sinuses. Mycetoma was first described in the mid 1800s and initially named Madura foot, after the region of Madura in India where the disease was first identified.

Mycetoma caused by microaerophilic actinomycetes is termed actinomycetoma, and mycetoma caused by true fungi is called eumycetoma. These conditions are to be differentiated from actinomycosis, which 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 is usually associated with the use of intrauterine devices). The branching bacteria that cause actinomycosis are non–acid-fast anaerobic or microaerophilic bacteria. These bacteria are smaller than 1 µm in diameter, smaller than eumycotic agents. On the other hand, the agents that cause actinomycetoma are always aerobic and are sometimes weakly acid-fast.

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

Pathophysiology

The body parts affected most commonly in persons with mycetoma include 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, mycetoma lesions can occur anywhere on the body. Lesions on the chest and back are frequently caused by Nocardia species, whereas lesions on the head and neck are usually 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

United States

Mycetoma is rare in the United States. Some cases are due to increasing international travel. Rarely, mycetoma is acquired on US soil.1 Pseudallescheria boydii (Scedosporium apiospermum) is the most common cause of this condition.

International

Mycetoma is endemic in Africa, from Sudan and Somalia through Mauritania and Senegal. Other endemic countries include Mexico and India; however, mycetoma can also 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 Sudanese hospitals, at least 300-400 patients are diagnosed with mycetoma every year.

Mortality/Morbidity

Mycetoma causes disfigurement but is rarely fatal in the absence of skull involvement. The lesions are painless and slowly progressive; however, secondary bacterial infection or bone expansion may cause pain. 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

Mycetoma has no apparent racial predilection.

Sex

Mycetoma has a male-to-female ratio of 183:81.

Age

Mycetoma is most common in persons aged 20-50 years.


CLINICAL

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History

  • The earliest sign of mycetoma is a painless subcutaneous swelling. Some patients have a history of a penetrating injury at that site.
  • 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.
  • Nearly 20% of patients with mycetoma experience associated pain, usually due to secondary bacterial infection or, less commonly, bone invasion.
  • Constitutional symptoms and signs of mycetoma are rare.
  • Patients may report a deep itching sensation.

Physical

  • Irrespective of the causal agent, the appearance of the mycetoma lesion is consistent, as follows:
    • 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, eumycetoma is more circumscribed and progresses slower than actinomycetoma.
  • Regional lymphadenopathy is unusual; 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 affected patients.
    • Secondary bacterial infection or a local immunologic reaction may enlarge the 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

  • Mycetoma occurs most often in farmers, shepherds, Bedouins, nomads, and 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).


DIFFERENTIALS

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Aspergillosis

Other Problems to be Considered

Botryomycosis
Thorn granuloma
Fibrolipoma
Neurofibroma
Necrotizing fasciitis
Cold abscess


WORKUP

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Lab Studies

  • Staining
    • Hematoxylin-eosin staining of a biopsy sample allows for detection of mycetoma grains.
    • Process hematoxylin-eosin and May-Grünwald-Giemsa staining of a cytologic smear of a sample obtained via 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 as follows:
      • Actinomycetoma - Homogenously eosinophilic with hematoxylin-eosin stain; blue in the center with pink filaments in the periphery with May-Grünwald-Giemsa stain
      • Eumycetoma - Brownish color with hematoxylin-eosin stain; black with a green tinge with May-Grünwald-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 indicate P boydii (S apiospermum), Nocardia species, or A madurae infection.
    • Yellow-to-brown grains indicate S somaliensis infection.
    • Black grains indicate Streptomyces paraguayensis, Madurella species, or Leptosphaeria species infection.
    • Red-to-pink grains indicate A pelletieri infection.
  • Culture the grains obtained from a deep wedge biopsy or a sample obtained via 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 in some cases for diagnosis or follow-up care during medical treatment. Antibodies can be determined via (1) immunodiffusion, (2) counterimmunoelectrophoresis, (3) enzyme-linked immunosorbent assay, or (4) Western blot.
  • Caution: Superficial samples of the draining sinuses are inadequate for culture because of frequent contamination with bacteria.

Imaging Studies

  • Bone radiography
    • Once mycetoma has invaded the bone, the following changes may be observed:
      • 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 and few in number with well-defined margins (eumycetoma) or small and numerous with ill-defined margins (actinomycetoma).
      • Disuse osteoporosis may occur in late stages 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: This study helps with the differential diagnoses of the swelling and can provide a better assessment of the degree of bone and soft-tissue involvement. The dot-in-circle sign is a recently proposed MRI sign of mycetoma, which is likely to be highly specific.2
  • Ultrasonography
    • Single or multiple thick-walled cavities with hyperreflective echoes and no acoustic enhancement are always 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 scanning: This modality provides a better detail of changes than conventional radiography.

Procedures

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

Histologic Findings

Grains are surrounded closely and sometimes infiltrated by neutrophils. The causal agent can be stained better in biopsy samples with Gram stain (actinomycetoma) or Gomori methenamine silver or periodic acid-Schiff stains (eumycetoma).

Staging

Radiographic staging of bone involvement can be found in Imaging Studies.


TREATMENT

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Medical Care

In the treatment of mycetoma, antibiotic or antifungal therapy should be attempted first and may need to be combined with limited surgery, especially for small eumycetoma lesions in the extremities.3

External beam radiotherapy in doses ranging from 3.5-14 Gy has been considered successful treatment in a few selected cases.4

Surgical Care

Surgery is recommended for localized mycetoma 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.

Consultations

Consultation with specialists in infectious disease or tropical medicine is advised in areas of the world where mycetoma is unfamiliar.


MEDICATION

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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 is usually 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.5 An effective and convenient regimen combining a short course of intravenous gentamicin with a 6-month oral course of cotrimoxazole and doxycycline has recently been described.6

Eumycetoma may respond partially to antifungal agents, although surgical therapy is preferred for localized disease. Madurella mycetomatis mycetoma may respond to ketoconazole (200 mg bid). P boydii (S apiospermum) mycetoma should be treated primarily with voriconazole, although it may also respond to itraconazole. Other agents that cause 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 immunocompromised patients.

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 NameDoxycycline (Bio-Tab, Doryx, Doxy, Periostat, Vibramycin, Vibra-Tabs)
DescriptionDrug of choice. Broad-spectrum, synthetically derived bacteriostatic antibiotic in the tetracycline class. Almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations. Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. May block dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult Dose200 mg/d PO/IV divided bid
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; severe hepatic dysfunction
InteractionsBioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
PregnancyD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
PrecautionsPhotosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one-half of pregnancy through age 8) can cause permanent discoloration of teeth; Fanconi-like syndrome may occur with outdated tetracyclines

Drug NameTrimethoprim-sulfamethoxazole (Bactrim DS, Septra)
DescriptionDOC; 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 Dose160 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
ContraindicationsDocumented hypersensitivity; megaloblastic anemia due to folate deficiency; do not use during pregnancy (at term) or breastfeeding
InteractionsMay 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
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsDiscontinue 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 NameAmikacin (Amikin)
DescriptionIrreversibly 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 Dose15 mg/kg/d IV/IM qd or divided bid; not to exceed 1.5 g/d regardless of higher BW
Pediatric DoseAdminister as in adults
ContraindicationsDocumented hypersensitivity
InteractionsCoadministration 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
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
PrecautionsNot 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 NameDapsone (Avlosulfon)
DescriptionBactericidal 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 Dose100 mg PO bid
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; G-6-PD deficiency
InteractionsMay 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
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
PrecautionsPerform 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 NameRifampin (Rimactane, Rifadin)
DescriptionFor use in combination with at least 1 other agent. Inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur.
Adult Dose10 mg/kg/d PO qd
Pediatric Dose10 mg/kg/d PO qd; not to exceed 600 mg/d
ContraindicationsDocumented hypersensitivity
InteractionsInduces 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)
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
PrecautionsMay 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 NameImipenem and cilastatin (Primaxin)
DescriptionFor treatment of multiple-organism infections in which other agents do not have wide spectrum coverage or are contraindicated due to potential for toxicity.
Adult DoseBase 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
>12 years: Administer as in adults
ContraindicationsDocumented hypersensitivity
InteractionsCoadministration with cyclosporine may increase adverse CNS effects of both agents; coadministration with ganciclovir may result in generalized seizures
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
PrecautionsAdjust dose in renal insufficiency; avoid use in children <12 y

Drug NameGentamicin (Garamycin)
DescriptionAminoglycoside antibiotic for gram-negative coverage bacteria, including Pseudomonas species. Synergistic with beta-lactamase against enterococci. Interferes with bacterial protein synthesis by binding to 30S and 50S ribosomal subunits. Dosing regimens are numerous and are adjusted based on CrCl and changes in volume of distribution, as well as body space into which agent needs to distribute. Gentamicin may be given IV/IM. Each regimen must be followed by at least trough level drawn on third or fourth dose, 0.5 h before dosing; may draw peak level 0.5 h after 30-min infusion.
Adult Dose80 mg IV bid
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; non-dialysis dependent renal insufficiency
InteractionsCoadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; because aminoglycosides enhance effects of neuromuscular blocking, agents prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
PregnancyD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
PrecautionsNarrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Drug Category: Antifungal agents

In combination with surgical therapy, antifungal agents may help to attain partial response in cases of eumycetoma.

Drug NameKetoconazole (Nizoral)
DescriptionFungistatic activity. Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.
Adult Dose200 mg PO bid
Pediatric Dose<2 years: Not established
>2 years: 3.3-6.6 mg/kg/d PO single dose
ContraindicationsDocumented hypersensitivity; fungal meningitis
InteractionsIsoniazid 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
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
PrecautionsHepatotoxicity 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 NameItraconazole (Sporanox)
DescriptionFungistatic 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 Dose200 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 DoseNot established; suggested dose of 100 mg/d
ContraindicationsDocumented hypersensitivity; coadministration with cisapride may cause adverse cardiovascular effects (possibly death)
InteractionsAntacids 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)
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
PrecautionsCaution in hepatic insufficiencies

Drug NameAmphotericin B (Fungizone)
DescriptionPolyene 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 Dose3-5 mg/kg/d IV of liposomal amphotericin B over approximately 120 min
Pediatric DoseAdminister as in adults
ContraindicationsDocumented hypersensitivity
InteractionsAntineoplastic 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
PregnancyB - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
PrecautionsMonitor 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 NameVoriconazole (VFEND)
DescriptionUsed for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or S apiospermum infections. A triazole antifungal agent that inhibits fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.
Adult DoseLoading 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 DoseNot established
ContraindicationsDocumented 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
InteractionsCYP450 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)
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
PrecautionsDecrease 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


FOLLOW-UP

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Further Outpatient Care

Patients with mycetoma should receive maintained medical treatment and follow-up care for at least 10 months.

Deterrence/Prevention

Educate patients to avoid activities that expose them to agents of mycetoma. Instruct patients to avoid carrying sticks and thorny branches that have had contact with the soil.

Complications

  • Complications of mycetoma result mainly from toxicity due to prolonged administration of antimicrobial or antifungal drugs.
  • Amputation may result from neglected chronic infections.

Prognosis

  • Mycetoma carries a good prognosis if the disease is promptly diagnosed and treated. Although mycetoma carries a low risk of mortality, amputations or ankylosis can lessen the quality of life.
  • In late stages of mycetoma, the treatment response is limited.


MISCELLANEOUS

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Medical/Legal Pitfalls

  • Mistaking actinomycosis for actinomycetoma is possible.
  • Performing incomplete surgery as the sole therapy for this disease can lead to recurrence and a poor cosmetic outcome.


MULTIMEDIA

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Media file 1:  Actinomycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years.
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Media file 2:  Frontal view of actinomycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years.
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Media file 3:  MRI coronal section of actinomycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years. On this T1-potentiated image, a large heterogenous mass surrounds the cranium. Bone invasion can be observed only in the area of the zygomatic fossa.
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Media type:  MRI

Media file 4:  MRI with coronal view of actinomycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years. The actinomycetoma mass invades the left parapharyngeal space and almost reaches the lumen of the pharynx.
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Media type:  MRI


REFERENCES

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Mycetoma excerpt

Article Last Updated: Aug 30, 2008