Harrisons Manual of Medicine, 18th Ed.

CHAPTER 102. Nocardiosis and Actinomycosis

NOCARDIOSIS

Microbiology

Nocardiae are branching, beaded, gram-positive filaments that usually give positive results with modified acid-fast stains. These saprophytic aerobic actinomycetes are common in soil.

• Nine species or species complexes are most commonly associated with human disease.

• Speciation of nocardiae is precluded in most clinical laboratories because it is nearly impossible without molecular phylogenetic techniques.

• Nocardia brasiliensis is most often associated with localized skin lesions.

Epidemiology

Nocardiosis occurs worldwide and has an incidence of ~0.375 cases per 100,000 persons in Western countries. The risk of disease is greater than usual among persons who have deficient cell-mediated immunity—e.g., that associated with lymphoma, transplantation, glucocorticoid therapy, or HIV infection with <250 CD4+ T cells/μL.

Pathogenesis

Pneumonia and disseminated disease follow inhalation of fragmented bacterial mycelia.

• Nocardiosis causes abscesses with neutrophilic infiltration and necrosis.

• Organisms have multiple mechanisms for surviving within phagocytes.

Clinical Manifestations

• Respiratory tract disease: Pneumonia is usually subacute, presenting over days to weeks, but can be acute in immunocompromised pts.

– A prominent cough productive of small amounts of thick purulent sputum, fever, anorexia, weight loss, and malaise are common; dyspnea, hemoptysis, and pleuritic chest pain are less common.

– CXR may demonstrate single or multiple nodular infiltrates of varying sizes that tend to cavitate. Empyema is noted in one-quarter of cases.

– Extrapulmonary disease is documented in >50% of cases.

• Extrapulmonary disease: In 20% of cases of disseminated disease, lung disease is absent.

– Nocardial dissemination manifests as subacute abscesses in brain (most commonly), skin, kidneys, bone, and/or muscle.

– Brain abscesses are usually supratentorial, are often multiloculated, can be single or multiple, and tend to burrow into ventricles or extend into the subarachnoid space.

– Meningitis is uncommon, and nocardiae are difficult to recover from CSF.

• Disease following transcutaneous inoculation: usually presents as cellulitis, lymphocutaneous disease, or actinomycetoma

– Cellulitis presents 1–3 weeks after a break in the skin (often with contamination by soil).

• The firm, tender, erythematous, warm, and nonfluctuant lesions may involve underlying structures, but dissemination is rare.

• N. brasiliensis and species in the N. otitidiscaviarum complex are most common in cellulitis.

– Lymphocutaneous disease resembles sporotrichosis and presents as a pyodermatous nodule at the inoculation site, with central ulceration and purulent or honey-colored discharge.

• Subcutaneous nodules often appear along lymphatics that drain the primary lesion.

– Actinomycetoma progresses from a nodular swelling at the site of local trauma (typically on the feet or hands, although other sites can be affected) to fistula formation; dissemination is rare.

• The discharge is serous or purulent and can contain granules consisting of masses of mycelia.

• Lesions, which spread slowly along fascial planes to involve adjacent skin and SC tissue and bone, can cause extensive deformity after months or years.

• Eye disease: Endophthalmitis can occur after eye surgery or during disseminated disease.

Diagnosis

• Sputum or pus should be examined microscopically and by culture for the presence of nocardiae. In pts with nocardial pneumonia, sputum smears are often negative, and bronchoscopy may be needed to obtain adequate specimens.

– Cultures take 2–4 weeks to yield the organism. To maximize the likelihood of isolation, the laboratory should be alerted if nocardiosis is being considered.

– Sputum cultures positive for nocardiae should be assumed to reflect disease in immunocompromised hosts, but may represent colonization in immunocompetent pts.

• Discharge from lesions suspected to be an actinomycetoma should be examined for granules, the appearance of which can help differentiate this diagnosis from eumycetoma (cases involving fungi) and botryomycosis (cases involving cocci or bacilli).

– Granules from actinomycetomas consist of fine filaments (0.5–1 μm wide) radiating from a central core.

– In contrast, granules from eumycetoma cases have broader filaments (2–5 μm wide) encased in a matrix, and those of botryomycosis are loose masses of bacteria.

• Brain imaging should be considered in pts with pulmonary or disseminated disease.

TREATMENT Nocardiosis

• Sulfonamides are the empirical drugs of choice, and trimethoprim-sulfamethoxazole (TMP-SMX; 10–20 mg of TMP/kg qd and 50–100 mg of SMX/kg qd initially, with later reduction to 5 and 25 mg/kg qd, respectively) may be more effective than sulfonamides alone.

– Susceptibility testing, particularly in severe cases or cases failing to improve, can guide alternative treatments and should be performed at reference labs (e.g., the Mycobacteria/Nocardia Laboratory at the University of Texas Health Science Center; phone, 903-877-7685).

– Alternative oral agents that are often effective include minocycline, linezolid (whose long-term use is complicated by side effects), amoxicillin/clavulanic acid, and fluoroquinolones.

– Effective parenteral agents include amikacin, ceftriaxone, cefotaxime, and imipenem.

• Pts with severe disease are initially treated with a combination of TMP-SMX, amikacin, and either ceftriaxone or imipenem. After definite clinical improvement, the regimen can usually be simplified to a single oral agent.

• Surgical management of nocardial infections is similar to that of other bacterial diseases.

– Brain abscesses that are large or unresponsive to antibiotics should be aspirated.

– Medical therapy is generally sufficient for actinomycetomas.

• Relapse is common.

– Long courses of therapy are required (Table 102-1).

TABLE 102-1 TREATMENT DURATION FOR NOCARDIOSIS

Images

– Pts should be followed for at least 6 months after therapy is complete.

ACTINOMYCOSIS

Microbiology

Actinomycosis is caused by anaerobic or microaerophilic bacteria, primarily of the genus Actinomyces (e.g., A. israelii, A. naeslundii, A. odontolyticus), that colonize the mouth, colon, and vagina. Most infections are polymicrobial, but the role of other species in the pathogenesis of the disease is unclear.

Epidemiology

Actinomycosis is associated with poor dental hygiene, prolonged use of intrauterine contraceptive devices (IUCDs), and treatment with bisphosphonates.

Pathogenesis

After disruption of the mucosal barrier, resident Actinomyces can infect locally and spread contiguously in a slow progressive manner, ignoring tissue planes. The hallmark of actinomycosis is the development of single or multiple indurated lesions with fibrotic walls often described as “wooden.” Central necrosis of lesions with neutrophils and sulfur granules is virtually diagnostic of the disease.

Clinical Manifestations

• Oral-cervicofacial disease: Infection starts as a soft-tissue swelling, abscess, or mass, often at the angle of the jaw, with occasional contiguous extension to the brain, cervical spine, or thorax. Pain, fever, and leukocytosis are variable. Radiation therapy and particularly bisphosphonate treatment are associated with actinomycosis of the maxilla and mandible.

• Thoracic disease: The pulmonary parenchyma and/or pleural space is usually involved. Chest pain, fever, and weight loss are common.

– Radiographic studies demonstrate a mass lesion or pneumonia. Cavitary disease or hilar adenopathy may occur, and >50% of pts have pleural thickening, effusion, or empyema.

– Lesions cross fissures or pleura and may involve the mediastinum, contiguous bone, or the chest wall. In the absence of these findings, the disease is often mistaken for a neoplasm or for pneumonia.

• Abdominal disease: The diagnosis is challenging given that it may not present clinically until months or years after the initial event (e.g., appendicitis, diverticulitis, bowel surgery) and that any abdominal organ or region can be involved.

– The disease usually presents as an abscess, mass, or lesion fixed to underlying tissue and is often mistaken for cancer.

– Sinus tracts to the abdominal wall, perianal region, or other organs may develop and mimic inflammatory bowel disease. Recurrent disease or a wound or fistula that fails to heal suggests actinomycosis.

• Pelvic disease: Pelvic actinomycosis is often associated with IUCDs that have been in place for >1 year. The presentation is indolent and may follow removal of the device.

– Pts have fever, weight loss, abdominal pain, and abnormal vaginal bleeding or discharge. Endometritis progresses to pelvic masses or tuboovarian abscess.

– When there are no symptoms and Actinomyces-like organisms are identified on Papanicolaou-stained specimens, the pt should undergo close follow-up but the IUCD should be not removed.

• Miscellaneous sites: Actinomycosis can involve musculoskeletal tissue, soft tissue, or (rarely) the CNS. Hematogenous dissemination, most commonly to the lungs and liver, can occur.

Diagnosis

Actinomycosis should be considered when a chronic progressive process with mass-like features crosses tissue boundaries, a sinus tract develops, and/or the pt has evidence of a refractory or relapsing infection despite short courses of antibiotics.

• Aspirations, biopsies, or surgical excision may be required to obtain material for diagnosis.

• Microscopic identification of sulfur granules (an in vivo matrix of bacteria, calcium phosphate, and host material) in pus or tissues establishes the diagnosis.

• Cultures usually require 5–7 days to become positive but may take 2–4 weeks; even a single antibiotic dose can affect the yield of cultures.

TREATMENT Actinomycosis

• For serious infection and bulky disease, IV therapy for 2–6 weeks (usually with penicillin, 18–24 million units IV daily) followed by oral therapy for 6–12 months (e.g., with penicillin or ampicillin) is suggested.

– Less extensive disease, particularly that involving the oral-cervicofacial region, may be cured with a shorter course.

– If treatment is extended beyond the point of resolution of measurable disease (as quantified by CT or MRI), relapse is minimized.

• Suitable alternative agents include the tetracyclines (e.g., doxycycline or minocycline, 100 mg PO/IV q12h) or clindamycin (900 mg IV q8h or 300–450 mg PO q6h).

Images

For a more detailed discussion, see Filice GA: Nocardiosis, Chap. 162, p. 1322; and Russo TA: Actinomycosis, Chap. 163, p. 1326, in HPIM-18.