Mycetoma caused by Nocardia madurae JAN M. SAKSUN,* B SC, MD; JULIUS KANE,t M SC, SM (AAM); R.K. SCHACHTER4 MD, FRCP[C]

Actinomycotic mycetoma was diagnosed in a woman from Jamaica living in Ontario. This is the first case reported in Canada in which the infection was caused by Nocardia madurae. Pespite oral therapy with trimethoprimsulfamethoxazole, local excision of newly appearing nodules was required periodically for clinical improvem.nt. Laboratory procedures were modified to aid in identification of pathogenic actinomycetes.

Two main types of organism cause

the "mycetoma syndrome": actinomycetes (bacteria) and eumycetes (fungi).2 The differential diagnosis of a chronically discharging localized disease in an extremity caused by either type is extensive and should include true neoplasms, coccidioidomycosis, chromoblastomycosis, blastomycosis, sporotrichosis, tuberculosis, yaws, syphilis, botryomycosis and cutaneous leishmaniasis.' Un mycetome actinomycotique a ete The granules found in the disdiagnostiqu6 chez une femme de charge are of utmost importance in Jamaique habitant l'Ontario. C'est le diagnosis since they represent masses premier cas a .tre signale au Canada of filaments of the causative organou l'infection a ete causee par Nocardia ism. Expert observation of their madurae. En depit d'un tra.iement colour as well as the size and staining oral au trim6thoprim-sulfa.i6thaxozoIe, of the individual filaments can deterl'excision locale des nouveaux nodules mine whether their origin is bacterial a ete periodiquement necessaire or fungal. Culture of the granule is pour une amelioration clinique. Les also important because definitive techniques de laboratoire ont ete isolation of the causative organism modifiees pour faciliter l'identification des actinomycetes pathog.nes. allows institution of correct treatment.2'4" Specifically, a fungal myMycetoma, or maduromycosis, is an cetoma cannot be treated with antiinfection produced by a number of bacterial agents. Microscopically an abscess is seen agents that results in chronic disdeep in the dermis; it often contains charging nodules and sinuses. It was first described by Carter in 1860.1 granules consisting of filaments surThe discharge characteristically con- rounded by degenerating polymorphotains tiny granules that are actually nuclear leukocytes. At the periphery microcolonies of the organism. The of the abscess epithelioid cells and disease process is usually localized foreign body giant cells are frequentto an extremity and may extend to ly found. A case of mycetoma due to Nocarfascia, muscle and bone. In most cases infection follows traumatic im- dia madurae, the first to be reported plantation of the organism into the in Canada, is described below.

subcutaneous tissue of an exposed limb; the disease is therefore most common in men between the ages of 30 and 50 years who work outdoors, and is most prevalent in rural areas with a tropical or subtropical climate.1 *Resident in dermatology, faculty of medicine, University of Toronto tChief mycologist, laboratory services branch, Ontario Ministry of Health; lecturer, department of medicine, University of Toronto .Associate professor, department of medicine, University of Toronto; head, division of dermatology, Women's College Hospital, Toronto Reprint requests to: Mr. Julius Kane, Chief mycologist, Laboratory services branch, Ontario Ministry of Health, Box 9000, Terminal A, Toronto, Ont. M5W 1R5

taking the medication irregularly treatment was discontinued and more tissue was obtained for culture. (Results of initial cultures of excised nodules and granules had been negative.) Five months after the patient's presentation a delicate, branching Streptomyces-like organism was isolated; therefore treatment with 50 mg of dapsone orally three times a day was begun. After 2 months the patient discontinued the medication because of nausea and vomiting. The woman was admitted to hospital a further 4 months later for supervised medical management of the mycetoma. The foot was now swollen and painful. The nausea and vomiting had persisted, and the patient had been having frequent episodes of nocturnal epigastric pain that was severe enough to disturb her sleep but was promptly relieved by antacids. The patient was obese but otherwise healthy. Abnormal findings were limited to the right foot: nonpitting edema was accompanied by numerous tender, soft nodules (1 cm in diameter) and sinuses over the dorsal aspect of the foot (Fig. 1). Some were eroded, and the serosanguineous drainage contained tiny yellow granules. There was no regional lymphadenopathy or lymphangiitis. Motor and sensory findings were normal, as were the reflexes. Laboratory data The hemoglobin value was 12.5 g/dL and the leukocyte count was 4.6 x lO'!L. Normal results were obtained in

tests for sickle cell anemia, glucose-6phosphate dehydrogenase deficiency and syphilis, and for liver and renal

function, and in three studies of stool

Case report

for occult blood. Normal values were

Clinical history and findings A 37-year-old woman who immigrated to Canada from Jamaica appeared in a dermatologist's office for treatment of a chronic infection of the right foot that had been present for 2 years. The foot was swollen and its surface was studded with numerous soft nodules, some of which were eroded and discharging a watery substance containing small yellow granules. The patient was briefly treated with several antibiotics for a superimposed bacterial infection, then a 3-month course of trimethoprim-sulfamethoxazole (Septra) was begun. There was some clinical improvement, but because the patient was

obtained for the serum folic acid concentration. Results of serum electrophoresis were normal. A chest roentgenogram was normal. An upper gastrointestinal roentgenographic series revealed an active duodenal ulcer. Roentgenograms of the right foot (Fig. 2) showed soft-tissue swelling, sclerotic change and several areas of rarefaction in the proximal phalanx of the great toe, and minimal subperiosteal bone resorption of the distal end of the neck of the first metatarsal. These findings were reported as nonspecific changes of chronic osteomyelitis compatible with the clinical diagnosis of mycetoma.

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FIG. 1-Draining sinuses, tissue swelling and cutaneous discoloration of medial aspect of great toe affected by actinomycotic mycetoma.

FIG. 2-Soft-tissue swelling in great toe, and areas of sclerosis and rarefaction in proximal phalanx of that toe.

FIG. 3-Section of curetting from nodule: mass of filaments deep in dermis (Gram's stain; original magnification X 130).

FIG. 4-Slide culture prepared on peptone-dextrose agar: poorly developed filaments less than 1 ,im in diameter (original magnification X 400).

FIG. 5-Slide culture prepared on sodium pyruvate-yeast extract agar: well developed branching mycelia about 1 ..tm in diameter (original magnification X 400).

FIG. 6-After several months of treatment tissue swelling and draining nodules have cleared; only postinflammatory hyperpigmentation remains.

912 CMA JOURNAL/OCTOBER 21, 1978/VOL. 119

Histologic examination of an excised nodule showed a mass of filaments approximately 1 ,.m in diameter deep in the dermis. The filaments were grampositive (Fig. 3). Microbiologic findings Several round, yellow granules 2 to 4 mm in diameter in the exudate from the draining sinuses were seen, when crushed, to be composed of gram-positive branching hyphae. The organism appeared only after 4 weeks' incubation on peptone-dextrose agar at 28 0C. The contaminated primary growth was purified on a specially prepared medium consisting of 0.5% sodium pyruvate, 0.05% yeast extract and 2% agar, with the bromcresol purple (BCP) indicator adjusted to a pH of 6.8. The initial colony was irregular, wrinkled and about 1 cm in diameter. The early colouring was buff (comparable to #45 on the Rayner mycologic colour chart [RMCC] of the British Mycological Society, 1970), but later a wine-red (#84 RMCC) central heaped-up area appeared. Slide cultures on blocks of peptone-dextrose agar showed fine, nonsporulating, poorly branched filaments less than 1 ,...m in diameter (Fig. 4). Another slide culture was prepared on a block of sodium pyruvate-yeast extract agar. After about 2 weeks' incubation at 280C, characteristic well developed branching mycelia approximately 1 .m in diameter appeared (Fig. 5). Kinyoun staining of growth from BCP milk broth was negative for acid-fastness. Initially the isolate decomposed cascm but not tyrosine. With a modification of Gordon's method, consisting of pulverizing the tyrosine crystals in 10 mL of 70% ethyl alcohol prior to addition to the basic medium, decomposition of tyrosine did occur.6'7 Xanthine was not decomposed. There was poor growth in diluted gelatin,8 and glucose, glycerol, mannitol and arabinose were utilized after 4 weeks' incubation. Hydrolysis of esculin occurred, as did growth at 370C. The organism was tentatively identified as a Nocardia species resembling pelletieri. It was then sent to Dr. Ruth Gordon at Rutgers University, New Brunswick, New Jersey, for further study; she identified it as N. madurae. Treatment Treatment in hospital included an active antiduodenal ulcer regimen as well as specific treatment of the mycetoma, as follows: application of aluminum acetate 1/40 compresses four times a day to the right foot, followed by application of povidine iodine to any ulcerated areas and a dry bandage;

bed rest with elevation of the right foot; and administration of trimethoprim-sulfamethoxazole, two tablets orally twice daily (one tablet containing 80 mg of trimethoprim and 400 mg of sulfamethoxazole). After several months of this treatment the eosinophil count returned to normal, the foot improved clinically (Fig. 6) and the symptoms of the duodenal ulcer were relieved. The patient was discharged from hospital after 4 weeks' stay. Follow-up management was conducted in the outpatient department. Although the woman returned to gainful employment and the condition of the foot was much improved, small nodules positive for Nocardia continued to develop every few months and were treated by local excision. With continued oral treatment neutropenia developed, the leukocyte count ranging from 3.5 x 109/L to 4.1 x 109/L, with 39% neutrophils, 55% lymphocytes, 1% eosinophils and 5% monocytes. Discussion Mycetoma is endemic in subtropical and tropical countries, generally those areas between the latitudes 300N and 150S, around the world.1 The areas in which infection with N. madurae usually occurs include Africa, the Sudan and India, although cases have been reported from Central and South America, the Mediterranean, southern Europe and the southwestern United States.1 The identification of the organism in this case as a Nocardia species was facilitated by the introduction of modified microbiologic techniques by one of us (J.K.). The first procedure made use of a pyruvate medium that facilitated purification of the contaminated tissue. The specimen was inoculated onto sodium pyruvate-yeast extract agar plates, where N. madurae grew as a buff-coloured, wrinkled colony, while the other bacteria grew in typical soft, shiny colonies. This morphologic difference facilitated subculturing to obtain a pure growth. The second procedure consisted of preparing a slide culture on the pyruvate medium; the organism then exhibited well developed, nonsporulating, Nocardia-like branched myceha instead of poorly developed filamentation, as was seen on the peptone-dextrose agar. Georg9 emphasized the importance of recognizing true aerial-branching mycelia to dis-

tinguish aerobic actinomycetes from branching mycobacteria. The modification of Gordon's method7 consisted of pulverizing the coarse tyrosine crystals and then incorporating them into the agar base to reduce the particle size and allow the organism easier access to the amino acid. The resulting hydrolysis was evident as a clear area in the uniformly opaque medium. This change in tec'hnique allowed demonstration of tyrosine decomposition not seen initially, when the larger crystals were used. The presence of granules composed of walled-off microorganisms contained in fibrosed tissue and purulent abscesses as well as the innate virulence of the organism and its varying sensitivity to antibiotics make simple effective medical treatment of Nocardia infections difficult. N. madurae produces a collagenase that increases its penetration into healthy tissue; therefore, the infection tends to be chronic and diffusely spreading in humans. This may have been the reason Rey, Baylet and Camain'0 initially suggested radical surgery, as used in some cases of cancer, for the cure of such infections. It is believed that in early localized stages of infection, before vital structures such as bone and muscle are invaded, excision of the mycetoma in toto can effect a cure with little resulting disability.11 However, once disease is extensive or well established, demarcation between healthy and diseased tissue is impossible, so that amputation is the only surgical possibility. This drastic measure has been proved unnecessary if chemotherapy is used effectively. Sulfones, and dapsone in particular, were first used in 1946 by Latapi'2 to treat nocardial infections. Since then, long-term therapy with dapsone has been shown to produce good results.'315 Sulfonamides remain the preferred treatment of nonfungal mycetomas. Recently, however, nocardiosis has been treated with the combination trimethoprim-sulfamethoxazole.1622 In most cases cure has been achieved by continuation of therapy with this drug for months after clinical improvement has been noted. The mechanism of action consists of selective inhibition of the microbial dihydrofolate reductase by the trimethoprim moiety and competitive inhibition of

CMA JOURNAL/OCTOBER 21, 1978/VOL. 119 913

the incorporation of para-aminobenzoic acid into dihydrofolate by the sulfamethoxazole moiety. Once folate coenzymes cannot be produced, the essential metabolic pathway of bacterial ribonucleic and deoxyribonucleic acid synthesis is blocked and the microorganism dies.!S.M With longterm therapy several adverse side effects have been noted, 7% of which have been referable to the skin and gastrointestinal system;25 these have consisted of urticarial, morbilliform or maculopapular eruptions and occasionally the Stevens-Johnson syndrome, as well as nausea, vomiting, glossitis and stomatitis. Few adverse hematologic effects - mainly neutropenia, thrombocytopenia and, rarely, agranulocytosis - have been reported;24'26'27 the overall frequency of these abnormalities seems to be the same as that known to occur with sulfonamides.28 Reports of megaloblastic change attributed to the drug are rare but can occur when the patient's folate status is jeopardized by, for example, alcoholism or poor nutrition.26 This can be avoided with oral administration of folic acid supplements. Preliminary testing to rule out glucose-6phosphate dehydrogenase deficiency should be done to avoid the precipitation of significant hemolytic anemia in susceptible black patients or those of Mediterranean origin. The use of rifampin and tetracycline in this type of infection is presently being investigated.29 With our patient, repeated excision of tissue harbouring residual infection combined with long-term administration of trimethoprim-sulfamethoxazole were responsible for the clinical improvement. Cure was not achieved, possibly because tissue concentrations of the drug were not high enough or because host defence mechanisms were not adequate to eradicate the residual foci of infection. The treatment regimen was, however, in accordance with current policy, which stresses that once the causative organism is accurately identified, therapy must be individualized if amputation is to be avoided."6'0" We thank Dr. Ruth Gordon for verifying the species of Nocardia. and Dr. Sidney Steinberg for providing clinical dctails of the case. A contribution from Burroughs Well-

come Ltd., manufacturers of Septra. made possible the publication of the coloured illustrations.

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Mycetoma caused by Nocardia madurae.

Mycetoma caused by Nocardia madurae JAN M. SAKSUN,* B SC, MD; JULIUS KANE,t M SC, SM (AAM); R.K. SCHACHTER4 MD, FRCP[C] Actinomycotic mycetoma was di...
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