Chapter 185. Actinomycosis, Nocardiosis, and Actinomycetoma

Actinomyces and Nocardia are a group of filamentous bacteria belonging to the same class, Actinobacteria, and same order, Actinomycetales. They cause human disease with prominent skin involvement. Microorganisms under this category were wrongly classified as fungi for a long time, because of their tendency to produce branching filaments, mimicking radiating hyphae (from the Greek actino, meaning sun). Their taxonomy is still evolving, resulting in continuous reclassification of different species in old and new families. Anaerobic endogenous Actinomyces, part of our normal respiratory, intestinal, and genitourinary flora, will cause localized suppurative disease with fistula formation that is analogous to the lumpy jaw of cattle. Aerobic environmental Nocardia sp. cause diseases ranging from cellulitis to paronychia to abscesses, with the most striking presentation being a lymphocutaneous, sporotrichoid syndrome. In addition, other aerobic environmental species of Nocardia and Actinomyces will cause one of the two known forms of mycetoma, the actinomycetoma.

The sulfur granule or grain, a clumping of filamentous bacteria seen in infected living tissue, is considered characteristic of the infection by these microorganisms, but is not always present and is also not specific (Table 185-1). Practicing dermatologists should be aware of the various morphologic variants of these diseases, so that measures may be taken to ensure the appropriate culturing techniques required for isolation.

Epidemiology

Described by Israel in 1878, the disease has a worldwide distribution. It is more commonly seen in males, ages 20–60, with females affected at a younger age. In the preantibiotic era, the incidence in the Netherlands and Germany was 1:100,000 inhabitants/year; in the 1970s, the reported incidence in Cleveland, Ohio, was 1:300,000 inhabitants/year, and in 1984, in Cologne, Germany, it was estimated to be 1:40,000 inhabitants/year.1 Recently, an increased incidence of genitourinary actinomycosis has been described in females, related to the use of intrauterine devices (IUDs). Nowadays, there is a tendency of subtle cases with more limited involvement, many of them restricted to the oral cavity. Diagnosis in such circumstances requires a high index of suspicion.

Etiology and Pathogenesis

The term actinomycosis implies disease produced by endogenous, anaerobic, or microaerophile, Gram-positive, nonspore-forming bacteria, belonging to the families Actinomycetaceae and Propionibacteriaceae, of the order Actinomycetales; and Bifidobacteriaceae, of the order Bifidobacteriales.1 Their normal habitat is human or animal mucosal surfaces, with considerable host specificity, from the mouth to the upper respiratory, gastrointestinal, and female genital tract. Species known to cause disease in humans include A. israelii, Actinomyces naeslundii, Actinomyces gerencseriae, Actinomyces viscosus, Actinomyces odontolyticus, and Actinomyces meyeri, as well as Propionibacterium propionicum and Bifidobacterium dentium. The disease in most cases is mixed with other microorganisms sharing the same habitat, so it should be considered a synergistic infection, with the Actinomyces playing the role of guiding organism, defining the course, the symptoms, and the ultimate prognosis. Accompanying organisms may vary in number, from one to nine different species, and may include coagulase negative staphylococci, Staphylococcus aureus, α- and β-hemolytic streptococci, microaerophile and anaerobic streptococci, Fusarium and Bacteroides spp., and even Propionibacterium sp. other than P. propionicum.1 This concomitant flora may be in part responsible for the disease course. If pyogenic bacteria are involved, such as S. aureus or β-hemolytic streptococci, the lesion will be acutely inflammatory and painful. If, on the contrary, anaerobes predominate, the course will be subacute and insidious. A distinctive more chronic course is seen when A. israelii or A. gerencseriae is accompanied by Actinobacillus actinomycetemcomitans. In recent years, with better culturing techniques, more than one Actinomyces have been isolated from one single lesion in several patients, stressing the possibility that single bacterial isolation, common in the past, was a technical artifact.

The infection has its portal of entry at a break on a mucous membrane. Most cervical and facial cases originate from periapical abscesses or after dental procedures. Actinomyces bacteremia seems to occur quite commonly after dental procedures.2 Thoracic cases represent involvement of the chest wall by continuity either from pleural or lung disease acquired by obstruction or aspiration. The same mechanism of spreading applies to disease of the abdominal wall, secondary to gut or genital pathology, following appendicitis, diverticulitis, surgery, or trauma. Perineal disease occurs as a consequence of involvement of the internal organs of the pelvis, often secondary to use of an intravaginal device or IUD. The only exception to the endogenous origin of the infection is hand involvement that follows fist or bite trauma.3

In tissue, the bacteria cluster in filamentous aggregates, the so-called sulfur granules (grains; see Table 185-1). They are commonly surrounded by acute and chronic inflammation, usually neutrophils, granulation tissue, and fibrosis. Granuloma formation is unusual. The fistula formation may give way to drainage of granules, their presence at once should not be considered specific for this disease.

Clinical Findings

Actinomycosis should always be suspected when dealing with one of three features: (1) a mass-like inflammatory infiltrate of the skin and subcutaneous tissue, (2) sinus formation with drainage, and (3) a relapsing or refractory clinical course after short-term therapy with antibiotics. Actinomycotic granules may be seen macroscopically. Although most patients are immunocompetent, a recent series underlies the importance of Actinomyces as an emerging pathogen in patients with chronic granulomatous disease.4

Cervical actinomycosis is the most frequent form of disease,5 accounting for approximately 55% of cases. Commonly, there is a history of poor dental hygiene, dental or periodontal disease, dental procedure, surgery, or penetrating trauma through the oral mucosa. Most of the infections start as a periapical abscess. The most common location is on the jaw angle and high cervical area (60%), followed by the cheek (16%), the chin (13%), and less commonly, the temporomandibular joint and the retromandibular area. The lesion starts as a solid mass in any of those locations, and initially may be confused with a neoplastic process (Fig. 185-1). It may progress to form recurring abscesses and later will spread to adjacent structures, not respecting anatomic planes. Propagation to lymph nodes is uncommon but eventually may involve the orbit, cranium, spine, and even vascular structures. The lesion is sometimes reported as painless, but pain may be present, as well as fever and leukocytosis. With extension to the skin surface, sinus tracts appear (Fig. 185-2). The overlying skin may have a purplish red hue. Trismus may develop. Bone involvement, mostly of the jaw, is present in 10% of cases. More limited disease may produce a mass or an ulcer, affecting any structure in the mouth or the nasopharyngeal region. Extension to the ear may present as chronic otitis media or mastoiditis. In addition to orbital involvement, there are reported cases of lacrimal canaliculitis and endophthalmitis.

Thoracic actinomycosis comprises 15% of cases. The common source of infection is the aspiration of microorganism from the oropharynx, although other routes are possible, such as propagation of cervicofacial disease to the mediastinum. The disease may involve the lung, pleura, mediastinum, and chest wall. The course is indolent, with chest pain, fever, weight loss, cough, and less frequently, hemoptysis, mimicking tuberculosis. Radiologically, the disease will present as a mass or pneumonia, with pleural involvement by continuity. Relevant to dermatologists, up to 26% of cases will have chest wall involvement5 with the developing of a cutaneous abscess and sinus formation (Fig. 185-3). Parenchymal, pleural, and chest wall disease occurring together will make actinomycosis a most likely diagnosis. Mediastinal actinomycosis may show either as anterior chest wall disease (rarely sternal involvement), or paraspinal abscess. Involvement of breast tissue and breast implants has also been described.

Abdominal actinomycosis represents about 20% of all cases. It is as a consequence of spreading from the gastrointestinal tract or from the female genital tract. Appendicitis and diverticulitis are common precipitating events. Any organ in the peritoneal cavity may be affected; by continuity, the disease may spread to the abdominal wall. An inflammatory mass may appear in the skin surface of the abdominal region or the perineum, with later development of sinuses. In the perianal area, multiple abscesses and fistula formation may occur. From there on, spreading to buttocks, thigh, scrotum, or groin may follow.

Primary pelvic disease most commonly originates from ascending infection from the female genital tract and less commonly from abdominal disease. The role of IUD as a risk factor has been well-established and infection is usually associated with prolonged use, 8 years on average.

Punch or fist actinomycosis represents a particularly uncommon but interesting clinical presentation. It usually follows blunt trauma of a closed fist against an adversary's mouth; similar findings may originate from a human bite. It usually involves the proximal phalanges and metacarpal bones. First a soft tissue infection, it will eventually spread to the bony structures. Grains are commonly seen in this particular form.

Actinomycosis of the central nervous system (CNS) may present as brain abscess, meningitis, meningoencephalitis, subdural empyema, actinomycoma, and spinal abscess. It is usually secondary to hematogenous spread.

Laboratory Findings

Laboratory tests considered useful include direct examination of draining material, culture, and biopsy. Direct examination will show the presence of filamentous Actinomyces on Gram stain. The isolation of Actinomyces in culture should be considered diagnostic, if coming from a sterile site. However, positive culture rates are as low as 35% in some series. The processing should be done in anaerobic conditions, and when all techniques available today are used, the percentage of isolates that cannot to be identified is as low as 2.8%.1 Needle aspiration has been recently reported as an additional diagnostic procedure.6

The best material to culture is tissue, pus, or microscopic granules, and avoidance of any antibiotic treatment is recommended. Appropriate culture media include thioglycolate with 0.5 sterile rabbit serum at 35°C (95°F) for 14 days. Colonies may appear within 5–7 days, but up to 2 weeks may be required. A. israelii classically will produce a “molar tooth” colony on agar and will look clumpy on broth. A. odontolyticus colonies are red or rusty in color. Actinomyces are indole negative. The microbiologic identification of different species occurs only in a minority of cases. Tests for urease, catalase, gelatin hydrolysis, and fermentation of cellobiose, trehalose, and arabinose may also be performed, as well as gas liquid chromatography, indirect immunofluorescence testing, and sequencing or restriction analysis of amplified 16S ribosomal DNA.

The presence of granules, either microscopically or macroscopically, is very relevant, especially if obtained from tissues not connected to mucosal surfaces. Grains are usually yellow (hence the name sulfur granules), but can be white, pinkish gray, gray, or brown. In tissue samples, special stains, such as Brown–Brenn, Gram, Giemsa, or Gomori stains, are required to demonstrate filamentous structures. The number of grains is usually scanty: only one single granule was identified from 25% of specimens in a study of 181 cases.5 The microscopic examination of the granules may reveal the Splendore–Hoeppli phenomena, a rim of eosinophilic material surrounding the granules in tissue sections. The lack of staining with Fite-modified acid-fast stain separates Actinomyces from Nocardia sp. Eumycetoma granules stain positive with periodic acid-Schiff and Gomori stains, whereas granules from Botryomycosis should show clumps of bacteria. Direct immunofluorescent staining is available for some species, including A. israelii (see Table 185-1).

Differential Diagnosis

Depending on the site affected, the differential diagnosis will include infections such as tuberculosis, noninfectious inflammatory processes such as hidradenitis or inflammatory bowel disease, and neoplasia (Box 185-1).

Prognosis and Therapy

There is general agreement that the treatment of actinomycosis requires high-dose antibiotics to be given for a long period. The treatment of choice is penicillin G, 18–24 million units intravenously for 2–6 weeks, followed by oral penicillin or amoxicillin, to be given for 6–12 months. Cervicofacial disease or any more limited disease can receive a shorter course of therapy. A good rule to follow is to treat until there is full resolution of clinical disease. Alternative treatment for those allergic to penicillin includes tetracycline, doxycycline, erythromycin, and clindamycin. Imipenem has been used successfully as short-term therapy. Chloramphenicol is the alternative to penicillin in cases of CNS involvement. Risk factors for death or relapse include duration of disease longer than 2 months, lack of antibiotic therapy or surgical therapy, and needle aspiration rather than open drainage or excision.

With early diagnosis and more limited disease, as compared to the bulky disease of the past, treatment can be shorter: 30 days for cervicofacial disease and 3 months for pelvic or thoracic disease.7 Periapical actinomycosis can be successfully treated with curettage and 10 days of antibiotic therapy.

Surgery is indicated for bulky disease involving the chest, abdomen, pelvis, and CNS. It should be directed to resection of necrotic tissue, excision of sinus tracts, draining of empyemas and abscesses, and curettage of bone, always accompanied by antibiotic therapy.

Antibiotics effective against synergistic microbes that accompany the Actinomyces can reasonably be included in the initial therapy.

Prevention

Good oral hygiene and prevention of periodontal disease may decrease colonization by Actinomyces. Physicians managing patients using an IUD should be aware of the risk of developing the disease.

Epidemiology

The Nocardia sp. are aerobic, Gram-positive, filamentous, higher bacteria found worldwide in soil and decaying organic plant matter. They can be found in house dust, beach sand, garden soil, and swimming pools. They are able to cause disease in many organs, including the skin. Approximately 1,000 cases of nocardiosis occur annually in the United States.8 Cutaneous disease comprises 5%–22% of all cases.8 A higher incidence of primary cutaneous nocardiosis in Europe may be explained on the basis of more frequent isolation of Nocardia brasiliensis in the environment. Patients have also been reported in India and Argentina.9 Disease occurs more commonly in males.

Immunocompromised patients account for 50% of cases, mostly pulmonary, systemic, and CNS infections. They are commonly seen in transplant patients, patients with acquired immunodeficiency syndrome (AIDS)8 or malignancy, or those receiving steroids. Primary cutaneous disease is most commonly seen in immunocompetent patients and has been reported rarely in children in United States, mostly in the south and southwestern part of the country.10

Etiology and Pathogenesis

The Nocardia sp. of medical importance includes Nocardia asteroides, most commonly associated with lung and systemic disease, and N. brasiliensis, most commonly associated with skin infection. Other species include Nocardia farcinica, Nocardia otitidiscaviarum, Nocardia nova, Nocardia pseudobrasiliensis, Nocardia transvalensis, and Nocardia abscessus. It is only recently that many of these species have been completely separated, especially those of the N. asteroides group, including N. farcinica and N. nova. It is interesting to note that Nocardia sp. belong to a subgroup of bacteria called the aerobic nocardioform actinomycetes that also include Mycobacterium, Corynebacterium, Rhodococcus, and Gordona. All these microorganisms have mycolic acid as constituent of their cell wall, which explains the varying acid fastness on appropriate staining. The proposed etiologic agent for Whipple disease, Tropheryma whippelii, also belongs to this group.

The usual inflammatory response in infected tissue is neutrophilic, with branching, beading filamentous bacteria within abscesses. Sulfur granules are uncommon in primary cutaneous nocardiosis; they have been described in disseminated disease. They are more commonly seen when the clinical picture is that of mycetoma (see Section “Actinomycetoma”).

Certain virulent strains of Nocardia are resistant to neutrophil-mediated killing.11 They can inhibit phagosome–lysosome fusion in vitro, giving rise to L-forms able to survive inside macrophages. The existence of cell wall deficient L-forms may explain the occasional late relapse. The presence of superoxide dismutase in growth media is characteristic of the more virulent strains. Complex cell wall glycolipids also contribute to virulence.11

The initial neutrophilic reaction is followed by a more cell-related immune response that is responsible for clearing the infection from the lung tissue and prevents dissemination. If this fails, a chronic neutrophilic response results in a more indolent course. Reduced cellular immunity predisposes transplant and AIDS patients to infection, with transplant patients accounting for up to 13% of cases in the United States.9 Some species are considered more difficult to treat: N. farcinica has a high degree of resistance to various antibiotics, especially third-generation cephalosporins and aminoglycosides. Another recently described species, N. pseudobrasiliensis, has a higher rate of dissemination.

Clinical Findings

Cutaneous involvement by Nocardia can manifest either as cellulitis or more characteristically, as lymphocutaneous nodules in a sporotrichoid pattern. Disseminated disease can also present in the skin as a consequence of hematogenous spread. In most series, skin disease is second only to pulmonary involvement in frequency. Mycetoma due to Nocardia is discussed in Section “Clinical Findings” under “Actinomycetoma.”

Predisposing factors for primary cutaneous nocardiosis include soil or sand exposure while gardening or farming; or superficial injury from domestic shrubbery, outdoor falls, or accidents. The frequent history of thorn injury or gardening may suggest incorrectly a diagnosis of sporotrichosis. Cat scratches or insect bites may be also the portal of entry, especially in children.7

The most common cause of primary cutaneous nocardiosis is N. brasiliensis, but N. asteroides, N. otitidiscaviarum, N. nova, and N. farcinica have also been implicated. Most patients are immunocompetent, but Nocardia cutaneous infection may also occur in the context of immunosuppression. A recent series of nocardial infection in AIDS patients showed skin lesions in 11% of cases, most commonly cutaneous abscesses and suppurative adenitis.8 Nocardiosis has recently described in patients receiving antitumor necrosis factor (TNF) biologic therapy for Crohn's disease.12

The disease has been also described in ulcerobullous, linear/keloid, and nodulopustular forms (Fig. 185-4A) that may evolve into the more typical sporotrichoid pattern (see Fig. 185-4B). Patients may also present acutely with eccrine hidradenitis, or chronically with hyperkeratotic plaques. Cutaneous nocardiosis may begin suddenly, reactivate after months to years, or follow a chronic course for up to 10 years. A case of simultaneous infection in a husband and wife has been described. Very rarely, pure cutaneous disease may lead to systemic illness. The cellulitic form most commonly affects the lower extremities, as compared to sporotrichoid form, in which the upper extremities are most commonly involved. Children frequently present with cellulitis, abscesses, and lymphadenitis affecting lower extremities and trunk; 20% of cases will have lesions at multiple sites.10

Lymphocutaneous forms may account for 24% of all Nocardia cutaneous infections (see Fig. 185-4B).13 The first case proven to be because of N. brasiliensis was described by Alarcon14; the patient developed acute nodular suppurative lymphadenitis after injuring the finger with a rose thorn. Although the upper extremity is the most common location, disease of lower extremity and cervicofacial region have also been reported. A common history is appearance of a solitary papule or nodule on the upper limbs, 2–4 weeks after cutaneous inoculation. Then, proximal nodules develop along lymphatic drainage. The primary lesion is initially warm and tender, then becomes fluctuant and later ulcerates. Macroscopic grains may be seen, but draining sinuses are rare. Systemic symptoms are mild. Regional lymphadenitis is common but lymphangitis is unusual.

Sternal wound infections usually develop 1 month after thoracic surgery. The symptoms include erythema, clear-to-purulent drainage, wound dehiscence, and/or fever. Diabetes mellitus seems to be the only identifiable risk factor. At least in one outbreak, the hands of an anesthesiologist were culture positive for N. farcinica. In another case of sternal osteomyelitis and mediastinal abscess, the patient's occupation (carrying wooden crates loaded with vegetables) may have been the relevant risk factor for infection.

Pulmonary disease is the most common form of clinical infection, but, compared to primary cutaneous diseases, is often due to different species (N. asteroides predominates). The disease may take the form of an acute pneumonia or a chronic process with bronchopneumonia, abscesses, and development of cavities. Ten percent of pulmonary infections disseminate to the skin.

Bacteremia due to Nocardia is seen in debilitated patients with concomitant malignancy, and N. asteroides is the agent most commonly isolated. Cutaneous or subcutaneous nodules and abscesses occur in many patients, and the skin may be the portal of entry in some cases. Catheter-associated nocardemia is well-documented.

Laboratory Findings

Laboratory tests considered useful include direct examination of clinical specimens, culture, and biopsy. The importance of direct microscopic examination for the presence of granules cannot be overemphasized. Organisms are detected as Gram-positive, branched filamentous “hyphae,” and branching at right angles is diagnostic. Acid-fast stains, including Fite Faraco and the modified Kinyoun technique, show the filamentous bacteria. For isolation, cultures should be kept for up to 2–3 weeks. The microorganisms grow satisfactorily on most of the nonselective media used for isolation of bacteria, mycobacterium, and fungi. Because slow growth of Nocardia colonies over 2 days to 2 weeks on routine culture media allows bacterial overgrowth, isolation of this organism from soil and nonsterile sites may be difficult. Nocardia do not survive the digestive procedures used routinely in mycobacterial culture. Thayer–Martin and buffered charcoal–yeast extract agar may be used and pretreatment of specimens with a low pH potassium chloride-hydrochloric acid solution for 4 minutes is required.

After initial isolation, subcultures should be incubated at 25°C (77°F), 35°C (95°F), and 45°C (113°F). N. asteroides grows best at 35°C (95°F). Aerial hyphae, giving a chalky appearance, may be seen macroscopically in cultures; however, in the early stages of growth, they are only seen with the microscope. N. asteroides complex colonies vary from salmon pink to orange, whereas N. brasiliensis are usually orange, and N. otitidiscaviarum are usually pale. Identification of genus can be achieved by microscopic and colonial morphology, growth requirements, metabolism of glucose, arylsulfatase production, growth in lysozyme, and phenotypic molecular characteristics. Genotyping methods, including polymerase chain reaction, DNA hybridization, and sequencing of 16 ribosomal RNA, are useful, if available.

Histologic patterns described on histology include monocytic infiltrates, fibrinopurulent exudates, granuloma formation, chronic nodular dermatitis, microabscess formation, and coccobacillary organisms; the presence of granules has been described in disseminated cases.9

Differential Diagnosis

In cases of cellulitis, the differential diagnosis is extensive, including both infectious and noninfectious etiologies. However, in the lymphocutaneous form, the differential diagnosis can be approached more systematically. The sporotrichoid pattern should be differentiated from the more acute ulceroglandular syndrome, as is seen in tularemia and cat-scratch disease (Box 185-2).

Prognosis and Clinical Course

Primary cutaneous nocardiosis is usually subacute or chronic but has a good prognosis when treated appropriately. However, the disease has the potential to disseminate; sternal wound infections may be complicated with osteomyelitis.9 Systemic disease, especially sepsis, has a high mortality rate, 44%–85%, if the patient is nocardemic.11

Treatment

The treatment of Nocardia infection is appropriate antimicrobial therapy and surgical drainage and debridement. Factors to consider include site and severity of infection, the immune status of the host, potential for interactions and the species of Nocardia involved. The current standard for sensitivity testing is by the broth microdilution method.

Sulfonamides, alone or in combination with trimethoprim (TMP), are the cornerstone of therapy for Nocardia infections, but are ineffective against N. otitidiscaviarum.11 For primary cutaneous nocardiosis of mild to moderate intensity, sulfonamide (either sulfadiazine or sulfisoxazole) alone has been considered adequate therapy,11 but other authors consider TMP–sulfamethoxazole (SMX) the treatment of choice, despite lack of controlled trials. This is based on synergistic activity of these drugs in vitro against Nocardia. The commercially available preparation has a fixed ratio of 1:5, and the dose recommended at the present time is 5–10 mg/kg TMP and 25–50 mg/kg SMX in two to four divided doses. For primary cutaneous nocardiosis, 5 mg/kg of TMP should be sufficient. Clinical improvement should be seen within 3–10 days, and 1–4 months of treatment should be curative for sporotrichoid nodules and cutaneous ulcers. Prolonged therapy is required for immunosuppressed patients. Minocycline 100–200 mg twice a day is considered the alternative treatment in cases of sulfonamide hypersensitivity or poor tolerance.

In more severe cases or disease involving other organs, a combination of sulfonamide with a second agent is recommended. The second-line drugs most recommended are amikacin, imipenem, and ceftriaxone. Alternative second-line drugs include amoxicillin clavulanate and linezolid. Immunosuppression is a good indication for a two-drug regimen, including amikacin; 88% cure rate has been reported when this drug is used.9 Sternal infections due to N. asteroides have responded to oral ofloxacin therapy.8 N. farcinica has a high degree of resistance to various antibiotics, especially third-generation cephalosporin and imipenem, and combined therapy is highly recommended. Extended treatment for extracutaneous nocardiosis, with parenteral therapy followed by an oral regimen is necessary. Surgery is indicated in cases of abscesses (drainage) or extensive necrosis (debridement). Spontaneous resolution or good clinical response despite inappropriate therapy has been seen in children with Nocardia cellulitis or lymphadenitis.10

Prevention

The low incidence of Nocardia infections in immunodeficient states does not justify prophylactic use of antibiotics. AIDS patients receiving TMP–SMX for Pneumocystis are already protected against Nocardia.

(See also Chapter 185)

Epidemiology

Mycetomas are chronic infections of the skin, underlying tissues, sometimes bones, and rarely viscera, caused by both bacteria (actinomycetomas) and fungi (eumycetomas).10 Only actinomycetoma is discussed further in this chapter (for eumycetomas, see Chapter 185). The disease has a worldwide distribution but it is more frequent in the tropics, especially in India, Sudan, Somalia, Mexico, and Venezuela. Actinomadura pelletieri and Actinomadura madurae are common agents in Senegal.15 Occasional cases are seen in the United States, particularly in the south. Actinomycetoma affect mainly men, but frequency before 15 years of age is similar in both sexes.16

Etiology and Pathogenesis

Microorganisms reported to cause actinomycetomas include N. brasiliensis, A madurae, A. pelletieri, Streptomyces somaliensis, and less commonly, N. asteroides, N. otitidiscaviarum, Nocardiopsis dassonvillei, and N. transvalensis.17 N. pseudobrasiliensis, Nocardia veterana, Nocardia mexicana and Sesamia sudanensis sp. have also been reported. The new taxon N. pseudobrasiliensis has been associated with invasive or disseminated infections.18 The infection most commonly affects people living in rural areas in developing countries.

Recent studies using DNA hybridization and ribosomal RNA sequencing have confirmed marked heterogeneity among the genera of aerobic actinomycetes.

In North America (Mexico), South America, and Australia, N. brasiliensis is the leading cause of actinomycetomas; in Africa, Saudi Arabia, and India, S. somaliensis and A. madurae predominate; this species is also identified as the etiologic agent in 10%–15% of cases in Mexico and Venezuela.19

Cell-mediated immunity may influence mycetoma pathogenesis; CD8+ lymphocytes and macrophages are the main cells implicated. N. brasiliensis as an intracellular bacterium modulates macrophage cytokine production, which aids survival of the pathogen.20 In patients with actinomycetoma the levels of IgG1, IgG2, IgG3, IgG4, and IgM have demonstrated to be higher than in a control group. These findings suggest that the increase or deficiency of a determined immunoglobulin class, as well as the relationship between different subclasses, play a role in the pathogenesis of actinomycetoma.

Clinical Findings

Actinomycetoma is a chronic, localized, slowly progressive, painless disease of the skin and subcutaneous tissue. The pathologic process usually begins with a minor injury. Walking barefooted or wearing sandals may be considered a risk factor for these infections in rural communities. The lower limbs are involved in 64% of the cases (Fig. 185-5), the foot being the most common site (Fig. 185-6 and 185-7). The lower leg, knee, and thigh, as well as the hand, forearm (Figs. 185-8 and 185-9), face, neck, and abdominal wall, may also be affected. In Mexico, the upper back (Figs. 185-10 and 185-11) is involved in 17%–25% of cases in relation to occupational activity such as firewood collection. Actinomycetoma caused by Nocardia sp. is a very inflammatory process characterized by tumefaction, destructive granuloma with a nodular appearance, deformity, and discharging sinus tracts with communicating channels that exude pus. Ulceration, crusting, and scarring are also observed.14 Mycetoma due to A. madurae, A. pelletieri, and S. somaliensis are less inflammatory with smaller sinus tracts; A. madurae is mainly seen in women with plantar involvement.19 With all these agents, the granules may be seen with the naked eye (see Table 185-1), usually in a cream color; the exception will be A. pelletieri, in which the granules are red.

The course is chronic and progressive, with potential involvement of bones, lung, and abdominal viscera. In women, mycetomas increase in size during pregnancy and spontaneously improve after delivery. Advanced cases may cause functional disability. Atypical clinical forms include the cryptic mycetoma (without sinus tracts), the so-called mini-mycetoma (single or multiple small lesions observed mainly in children and adolescents), and the occasional inguinal “metastatic” lesions from a primary mycetoma of the foot.14

Laboratory Findings

Skin biopsy plays an important role in the diagnosis of actinomycetoma. Typically, in hematoxylin and eosin stained tissue sections, there is a suppurative reaction characterized by the presence of polymorphonuclear cells, fibrosis, neovascularization, and rarely, a granulomatous reaction with a tuberculoid granuloma.14 Nocardia infection is characterized by granules 30–200 μm in diameter, partially basophilic to amphophilic, with an amorphous, eosinophilic, radially arranged material on the periphery (the so-called Splendore–Hoeppli phenomenon). Granules of A. madurae are soft and bigger (1–3 mm diameter), purple with a cartographic shape and an eosinophilic fringe (Fig. 185-12). A. pelletieri granules are firm and red with a diameter of 200–500 μm. Granules of S. somaliensis are rounded, hard, pale, and 1.5–10.0 mm in diameter.14 These organisms stain in tissue with Gomori methenamine silver, periodic acid-Schiff, and the Brown–Brenn modification of the Gram stain.

Clinical specimens should be sent for direct examination (Gram stain) and culture. On direct examination, Nocardia granules are microscopic with a yellowish color. Granules produced by other agents are macroscopic: those of A. madurae are white, yellow, or cream, whereas grains from A. pelletieri are red and those of S. somaliensis are cream to brown color. Fine needle aspiration cytology has been reported as a good diagnostic tool. The cell block technique of mycetoma aspirates can be use for cytodiagnosis, showing findings similar to histopathologic sections.21

The microorganisms can be cultured on Sabouraud's dextrose agar or Lowenstein–Jensen at room temperature; Nocardia strains are white–yellow hard colonies. Microscopically, its very thin filaments are Gram-stain positive and acid-fast with the Kinyoun's stain. A. madurae produce slowly growing beige or pink colonies; A. pelletieri colonies are red. S. somaliensis produce beige or tanned colonies. All Actinomyces and Streptomyces sp. are acid-fast negative.14

Biochemistry can be used for identification. N. brasiliensis hydrolyzes casein and tyrosine, but not xanthine; N. otitidiscaviarum is negative to casein and tyrosine and positive to xanthine testing; N. asteroides is negative to all these tests.

An enzyme-linked immunosorbent assay has been described for the diagnosis of mycetoma due to N. brasiliensis; it has been proposed as a method to predict the response to therapy. This test detects antibodies against two immunodominant antigens (24 and 26 kDa). An additional advantage of this particular assay might be its demonstrated cross-reactivity with N. asteroids.22

The most common radiographic abnormalities are soft tissue swelling, periosteal reaction and sclerosis and bone cavities.23 Ultrasonography is also a useful modality. The utility of helical computed tomography (HCT) especially in trunk mycetomas provides evidence about the grade of invasion such as visceral, muscular, and vascular systems, and calculation of the affected area.24

Differential Diagnosis

The differential diagnosis includes other infections causing fistulae; such as eumycotic mycetoma, actinomycosis, botryomycosis, scrofuloderma, and atypical mycobacterial infections (Box 185-3). Botryomycosis is a condition that can mimic actinomycetoma and eumycetoma, both clinically and histologically. The disease can be caused by several organisms, most commonly S. aureus, Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Actinobacillus sp., Streptococcus sp., Gram-negative coccobacilli, Propionibacterium acne, and other anaerobic bacteria. The cutaneous form accounts for 75% of the cases; visceral involvement, mainly the lung, is rare. The disease is characterized by localized areas of infiltration, with mass effect and draining sinuses. Extension to the underlying structures, including bone, is not uncommon. Most commonly affected areas are exposed surfaces, such as hands, head, and feet. Patients usually have a predisposing factor such as local trauma, a foreign body, diabetes, or HIV infection. Botryomycosis is also characterized by the presence of granules, which can be seen macroscopically and microscopically. As in mycetoma, the center of the granule will show agglomeration of the causal agent, most commonly, Gram-positive cocci. Splendore–Hoeppli phenomenon may also be seen around the granules.

Treatment

Therapy for patients with actinomycetoma should be individualized. Economic considerations may influence the choice of therapy, particularly in developing countries.

Molecular identification of the causal agents and development of genetic markers for disease can improve management. Cure may be defined by a lack of clinical activity, absence of grains and negative cultures. The cure rates vary between 60% and 90%. Treatment periods are very long, especially with bone and visceral involvement, for which prognosis is poor.25

Combined antibiotic therapy prevents the development of drug resistance and eradicates any residual infection. The treatment of choice in actinomycetoma caused by N. brasiliensis is diaminodiphenylsulfone (Dapsone) 100–200 mg/day (3–5 mg/kg) plus TMP–SMX 160/800 mg twice a day for several months in initial cases; treatment should continue for up to 2 years.14 Dapsone can also be combined with streptomycin, 1 g/day; clofazimine, 100 mg/day; rifampin, 300 mg twice/day; tetracycline, 1 g/day; or isoniazid, 300–600 mg/day; alternative drugs include kanamycin and phosphomycin. Some resistant cases have been treated with amoxicillin, 500 mg, plus clavulanic acid, 125 mg/day for 5 months.

Amikacin alone or combined with imipenem are powerful antibiotics used as alternative treatments for severe or multiresistant mycetomas, especially those with bone and visceral involvement. In adults, amikacin is administered 15 mg/kg/day (500 mg intramuscularly twice a day) for 3 weeks; ototoxicity and nephrotoxicity may develop.26 Carbapenems as imipenem and meropenem have a broad microbicidal activity refractory to hydrolysis by β-lactamases. They have demonstrated good in vitro and in vivo activity against Nocardia asteroides complex, good in vitro sensitivity against A. madurae, and apparent low in vitro activity against N. brasiliensis. Imipenem has been proposed as a suitable option for severe N. brasiliensis infection refractory to other drug therapies.27 Patients treated with intravenous imipenem must be hospitalized; the drug can be given as monotherapy at 500 mg three times daily, or in combination with intravenous amikacina in a dose of 500 mg twice daily (15 mg/kg) in cycles of 21 days, especially in patients with pulmonary or peritoneal involvement.25

Ramam et al28 used a two-step regimen consisting of an intensive phase of therapy with intravenous penicillin (1,000,000 IU every 6 hours), intravenous gentamicin (80 mg twice a day), and oral TMP–SMX (80–400 mg twice a day) for 5–7 weeks. Linezolid, a new oxazolidinone, has shown in vitro antimicrobial activity against N. brasiliensis; it also has demonstrated efficacy in patients with nocardiosis. Its main disadvantage of this alternative is the cost. It is available as intravenous and oral preparations.

The use of clindamycin, ciprofloxacin, and moxifloxacin has been suggested in Nocardia infections.29

Patient follow-up is always important, and improvement can be monitored by clinical assessment as well as by laboratory tests: hemoglobin level, white cell count, C-reactive protein, erythrocyte sedimentation rate, enzyme-linked immunosorbent assay (when available), biopsy, and culture.

Amputation is not indicated in actinomycetoma because the very low risk of lymphangitic or hematogenous dissemination. Functional impairment is common with osseous, pulmonary, or abdominal visceral involvement. The disease may be fatal.