Etiology

Nocardia is a member of the order Actinomycetales, which includes gram-positive filamentous bacteria such as Actinomyces, Streptomyces, and mycobacteria. Nocardia organisms are environmental saprophytes that are ubiquitous in soil and decaying vegetable matter. These organisms are obligate aerobes and grow on ordinary culture media. Growth is achieved best at 37°C, although many isolates of Nocardia are thermophilic and grow at temperatures up to 50°C. At 25°C, the organisms grow very slowly. Colonies appear within 1-2 wk on brain-heart infusion agar and Lowenstein-Jensen media, usually as waxy, folded, or heaped colonies at the edges. With further incubation, the colonies develop aerial hyphae that tend to give them a white, chalky appearance. With modified Kinyoun acid-fast staining of biopsy specimens or body fluids, Nocardia demonstrates fragmented bacilli with stain concentrated in a beaded pattern along portions of the branching filaments.

Numerous taxonomic studies have established the heterogeneity of Nocardia asteroides, the most common species causing human nocardiosis. N. asteroides is identified from its colony and microscopic morphology, resistance to lysozyme, and inability to hydrolyze casein, tyrosine, xanthine, and hypoxanthine. N. asteroides, Nocardia farcinica, Nocardia otitidis-caviarum, Nocardia transvalensis, and Nocardia nova complex have similar features, a fact that has contributed to the apparent heterogeneity of Nocardia. Molecular techniques utilizing 16S recombinant RNA gene sequencing with a database search for matches have led to new Nocardia species identification in human disease (e.g., Nocardia beijingensis). N. brasiliensis is the 2nd most common etiologic agent of human nocardiosis. Some strains of N. brasiliensis have been assigned to a new species, Nocardia pseudobrasiliensis. Antibiotic susceptibility testing, biochemical testing, and newer molecular typing techniques such as gene sequencing have currently identified at least 16 species within the genus Nocardia.

N. asteroides complex includes the most common agents of systemic nocardiosis in the USA. N. brasiliensis is the principal cause of localized nocardial cellulitis and lymphadenitis in immunocompetent children and can also cause pulmonary and systemic disease, especially in immunocompromised persons. N. brasiliensis is found more commonly in the southern USA, Central America, South America, and Asia. Actinomadura madurae (Madura foot), Nocardia farcinica, Nocardia nova, and Nocardia transvalensis also cause human disease.

Epidemiology

Once thought to be a rare cause of human disease, nocardiosis is being recognized more frequently, and has been diagnosed in persons from 4 wk to 82 yr of age. Almost all patients have compromised cellular immunity from an underlying disease such as organ transplantation, malignancy, corticosteroids, diabetes, HIV infection, or primary immunodeficiency, especially chronic granulomatous disease (Chapter 124). Nocardia infections among stem cell transplant recipients are associated with a high rate of concomitant invasive fungal infection and a notable lack of protection with trimethoprim-sulfamethoxazole prophylaxis. An evaluation of opportunistic infections in 547 organ transplant recipients receiving Alemtuzumab (humanized monoclonal CD52 antibody) revealed that 62 opportunistic infections developed in 56 patients (10%), Nocardia being found in 4 patients.

Pathogenesis

Soil is the natural habitat of Nocardia, which has been isolated worldwide. The organism is inhaled in aerosolized dust and causes pulmonary infection, with widespread dissemination in susceptible hosts. It can be transmitted by direct cutaneous inoculation, including after arthropod and cat bites. Although human-to-human transmission is rare, a description of N. farcinica sternal wound infections among patients undergoing open heart surgery raises concern about Nocardia as a nosocomial pathogen.

Clinical Manifestations

Pulmonary nocardiosis accounts for 75% of cases of infection, almost all of which occur among immunocompromised patients or patients with underlying pulmonary disease. Demonstration of tissue invasion is important for identifying active pulmonary infection because the organism occasionally exists as a respiratory saprophyte. Clinical manifestations include pneumonia and necrotizing pneumonia with single or multiple abscesses.

Single or multiple metastatic lesions may occur anywhere in the body. The brain, the most common secondary site, is involved in 15-40% of cases of pulmonary nocardiosis. Brain abscess is the most common presentation, with meningitis the 2nd most common, being manifested by pleocytosis (with a lymphocytic or neutrophilic predominance), elevated cerebrospinal fluid protein, and hypoglycorrhachia. Persistent neutrophilic meningitis with sterile culture results is classic for central nervous system (CNS) infection. The onset may be gradual or sudden and includes manifestations varying from headache to coma.

The skin is the third most commonly involved organ, and its infection may be manifested by sporotrichoid nocardiosis or superficial ulcers (Fig. 183-1). Mycetoma is a chronic, progressive infection developing days to months after inoculation, usually on a distal location on the limbs. Renal nocardiosis, the 4th most common type, typically manifests as dysuria, hematuria, or pyuria. Lesions may extend from the cortex into the medulla. Gastrointestinal involvement may also be associated with nausea, vomiting, diarrhea, abdominal distention, and melena. Infection may spread to skin, pericardium, myocardium, spleen, liver, or adrenal glands. Bone involvement is rare. Almost all of the involved organs have several abscesses, but in contrast to actinomycosis, granules are rarely found in nocardiosis. Keratitis caused by N. farcinica has been associated with the use of semipermeable rigid contact lenses.

Figure 183-1 A 2 yr old girl with multiple pustules on the dorsum of the right foot caused by Nocardia brasiliensis.

(Courtesy of Jaime E. Fergie, MD.)

Diagnosis

Laboratory diagnosis of nocardiosis requires direct examination of clinical material for characteristic gram-positive, acid-fast organisms and isolation by culture methods. Smears of clinical material are stained with Gram stain or the modified Kinyoun acid-fast stain. N. asteroides complex and N. brasiliensis appear as delicately branched, gram-positive, coccoid to bacillary bacteria that tend to fragment. In properly stained and decolorized acid-fast smears, the organisms may appear as fragmented bacilli with the stain concentrated in a beaded pattern along the portions of the filaments. Speciation is accomplished by polymerase chain reaction and restriction fragment length polymorphism analysis.

Diagnosis of pulmonary nocardiosis is established in 30% of cases in adults by sputum analysis and culture. Bronchoalveolar lavage or lung biopsy may be required to establish the diagnosis in the remaining 60% of adults and in children.

Cranial CT or MRI is recommended for all immunocompromised patients with pulmonary nocardiosis, even if asymptomatic, because of the high frequency of CNS involvement, and should be considered for immunocompetent patients with pulmonary nocardiosis. Helical CT with three-dimensional reconstruction is valuable in cases of actinomycetoma.

Treatment

Surgical drainage of abscesses is important. The choice, dose, and duration of antimicrobial treatment depend on the site and extent of infection, host immune status, species of Nocardia, and initial clinical response. Sulfonamides have been the cornerstone of therapy for the treatment of nocardiosis since the 1940s. Trimethoprim-sulfamethoxazole is the formulation that is recommended, although sulfadiazine and sulfisoxazole demonstrate equal efficacy. A susceptibility study of 78 clinical isolates of the N. asteroides complex from the USA found that 95% of strains exhibited 1 of 5 antibiotic resistance patterns. The most common pattern, occurring in 35% of isolates, showed resistance to ampicillin and erythromycin but susceptibility to cefotaxime, ceftriaxone, and carbapenems. Approximately 20% of isolates, which were subsequently identified as N. farcinica, were resistant to cefotaxime and ceftriaxone. Another approximately 20% of the isolates, which were subsequently identified as N. nova, were susceptible to ampicillin and erythromycin. The remaining isolates had susceptibility patterns that included resistance to cephalosporins and susceptibility to ampicillin and carbenicillin, but intermediate susceptibility to carbapenems. The most active parenteral agents were amikacin (95%), imipenem (88%), ceftriaxone (82%), and cefotaxime (82%). The most active oral agents were sulfonamides (100%) and minocycline (100%). Additional antimicrobial agents with oral bioavailability are desirable because of the increasing reports of sulfonamide resistance and the adverse effects reported among patients with HIV infection. In vitro studies show susceptibility of all strains to linezolid, which appears to be an effective alternative treatment, but potential toxicity with long-term oral therapy with this agent must be kept in mind.

Combination therapy involving a carbapenem or a 3rd generation cephalosporin with or without amikacin is usually recommended for severely ill patients or with CNS involvement. The mortality rate approaches 50% when a sulfonamide is used alone for treatment. On the basis of in vitro susceptibility testing for specific N. asteroides complex isolates, alternative drug combinations may include erythromycin and newer macrolides (azithromycin and clarithromycin), carbapenems, streptomycin, minocycline, quinolones, 3rd-generation cephalosporins, and linezolid. The issues to be considered for use of linezolid include the limited data of use in children, the unknown adverse affects of long-term use, and the high cost. Clinical trials have shown that ampicillin and amoxicillin-clavulanate are effective in N. brasiliensis infections.

Antibiotic resistance has become an important issue in many Nocardia infections, with resistance to trimethoprim-sulfamethoxazole, streptomycin, and ampicillin reported. Susceptibility testing of Nocardia should be performed by a reference laboratory for isolates from deep-seated or disseminated infections, of strains such as N. farcinica and N. otitidis-caviarum that are commonly resistant to cephalosporins, if non-sulfonamide treatment regimens are being considered, for poor response to initial therapy, and for relapse.

Superficial cutaneous infection is treated for at least 1-3 mo. Mycetoma or pulmonary or systemic nocardiosis in immunocompetent persons is treated for at least 6 mo, and CNS infection for at least 12 mo. Relapses of systemic Nocardia infection that had been treated for <3 mo have occurred. Parenteral therapy can often be changed to oral therapy, such as high doses of trimethoprim-sulfamethoxazole, after 3-6 wk of parental therapy and good clinical response. Nocardiosis in patients with HIV infection should probably be treated indefinitely.

Prognosis

Despite appropriate therapy, the overall mortality rate for nocardiosis is >50%. This high rate may be secondary to delay in diagnosis or to the debilitated state of patients with severely compromised host defenses.