These organisms are aerobic, facultatively anaerobic, or obligately anaerobic; only the aerobic actinomycetes are discussed in this chapter. Aerobic actinomycetes belong to the order Actinomycetales. Actinomycetes comprise more than 40 genera, but only the clinically relevant aerobic actinomycetes genera are considered here (Table 19-1). In this chapter, only aerobic actinomycetes that exhibit branching and/or partial acid-fastness are addressed. Although both the Corynebacterium and Mycobacterium genera belong to the order Actinomycetales, Corynebacterium spp. do not usually exhibit branching filaments or partial acid-fastness, and Mycobacterium spp. do not exhibit branching and are strongly (acid-alcohol) acid-fast; for these reasons, the Corynebacteriaceae and Mycobacteriaceae are addressed in Chapters 17 and 43, respectively. Another clinically significant aerobic actinomycete is Tropheryma whipplei; because this organism has not been cultured on artificial media, it is reviewed in Chapter 44. For purposes of discussion, the remaining genera of aerobic actinomycetes are divided into the two large groups: those with cell walls that contain mycolic acid and are therefore partially acid-fast and those with cell envelopes that do not contain mycolic acid and therefore are non–acid-fast.

TABLE 19-1

Clinically Relevant Aerobic Actinomycetes *

Cell Wall Containing Mycolic Acid	Genus
Present	Nocardia Rhodococcus Gordonia Tsukamurella Corynebacterium
Absent	Streptomyces Actinomadura Dermatophilus Nocardiopsis Oerskovia

^*The genera Williamsia, Skermania, and Dietzia are also aerobic actinomycetes but to date are not clinically relevant.

In general, the aerobic actinomycetes are not frequently isolated in the clinical laboratory; nevertheless, these organisms are causes of serious human disease. Not only are infections caused by these organisms difficult to recognize in the clinical laboratory, the organisms are also difficult to isolate. Further complications include difficulty classifying, identifying, and performing antibiotic susceptibilities on aerobic actinomycetes isolated from clinical specimens. At the time of this writing, the taxonomy of the aerobic actinomycetes is complex and continues to evolve. New and reliable methods that can identify cell wall amino acids and sugars and characterize mycolic acid, menaquinones, and phospholipids in conjunction with nucleic acid phylogenetic studies are proving extremely useful for resolving the taxonomy of the actinomycetes.

General Characteristics

The genera Nocardia, Rhodococcus, Gordonia, and Tsukamurella are partially acid-fast aerobic actinomycetes. Nocardia and Rhodococcus belong to the family Nocardiaceae, and Gordonia and Tsukamurella are in the Gordoniaceae and Tsukamurellaceae families, respectively. However, the variability associated with the classification of an organism as partially acid-fast depends on the particular strain and culture conditions. Therefore, this characteristic should be interpreted with caution. The genus Actinomadura includes approximately 67 species and subspecies, with significant variation. The cell walls of this group contain the sugar madurose, a characteristic shared with the genus Dermatophilus.

Partially Acid-Fast Aerobic Actinomycetes

Nocardia spp.

Organisms belonging to the genus Nocardia are gram positive (often with a beaded appearance), variably acid-fast, catalase positive, and strictly aerobic. As they grow, Nocardia spp. form branched filaments that extend along the agar surface (substrate hyphae) and into the air (aerial hyphae). As the organisms age, nocardiae fragment into pleomorphic rods or coccoid elements. Nocardiae also are characterized by the presence of mesodiaminopimelic acid (DAP) and the sugars arabinose and galactose in peptidoglycan in the cell wall.

Currently, the taxonomy in the genus Nocardia is changing rapidly. Recognition and description of new species continue and remain controversial regarding the number of validly described species; recent publications cite 22 to 30 valid species. Of significance, Cloud et al.¹ reported that the most commonly identified species was Nocardia cyriacigeorgica, not N. asteroides, as determined by partial 16S rRNA DNA sequencing, followed by N. farcinica, N. nova, N. africana, and N. veterana. The species considered human pathogens or that have been implicated as human pathogens are listed in Box 19-1. N. asteroides, N. nova, N. farcinica, N. brasiliensis, N. otitidiscaviarum (formerly N. caviae), N. pseudobrasiliensis, and N. transvalensis account for most of the diseases in humans caused by Nocardia spp.

Rhodococcus, Gordonia, Tsukamurella spp.

Organisms belonging to the Rhodococcus, Gordonia, and Tsukamurella genera are similar to Nocardia spp. in that they are gram-positive, aerobic, catalase-positive, partially acid-fast, branching, filamentous bacteria that can fragment into rods and cocci. The extent of acid-fastness depends on the amount and complexity of mycolic acids in the organism’s cell envelope and on culture conditions. The differentiation of these three genera, as well as species identification, is difficult. In particular, the genus Rhodococcus consists of a very diverse group of organisms in terms of morphology, biochemical characteristics, and ability to cause disease. As previously mentioned, the taxonomy of these organisms continues to evolve; species included in these three genera, as of this writing, are summarized in Table 19-2.

TABLE 19-2

Species Included in the Genera Rhodococcus, Gordonia, and Tsukamurella

Genus	Species
Rhodococcus	equi, erythropolis, rhodnii, rhodochrous (other species of unknown significance include globerulus, marinonascens, and ruber)
Gordonia	aichiensis, bronchialis, polyisoprenivorans, rubripertincta, sputi, terrae (remaining species isolated from environmental sources)
Tsukamurella	paurometabola, pulmonis, tyrosinosolvens, strandjordae (T. ichonensis, T. wratislaviensis isolated from nature)

Data compiled from Brown JM et al: In Murray PR, Baron EJ, Pfaller MA et al, editors: Manual of clinical microbiology, ed 10, Washington, DC, 2003, American Society for Microbiology; Goodfellow M, Chun J, Stubbs S et al: Lett Appl Microbiol 19:401, 1994; Klatte S, Rainey FA, Kroppenstedt RM: Int J Syst Bacteriol 44:769, 1994; Lasker BA, Brown JM, McNeil MM: Clin Infect Dis 15:233, 1992; Maertens J et al: Clin Microbiol Infect 4:51, 1998; Riegel P et al: J Clin Microbiol 34:2045, 1996; Yassin AF, Rainey FA, Burrghardt J et al: Int J Syst Bacteriol 47:607, 1997; Arenskötter M et al: Appl Environ Microbiol 70:3195, 2004

Non–acid-Fast Aerobic Actinomycetes: Streptomyces, Actinomadura, Dermatophilus, Nocardiopsis, and the Thermophilic Actinomycetes

The non–acid-fast aerobic actinomycetes (i.e., Streptomyces, Actinomadura, Dermatophilus, Nocardiopsis, and the thermophilic actinomycetes) are gram-positive, branching filaments that do not contain mycolic acids in their cell envelopes and are therefore non–acid-fast. This group of actinomycetes is heterogeneous and is encountered infrequently in the clinical laboratory. Only the non–acid-fast actinomycetes associated with human disease are addressed (Table 19-3).

TABLE 19-3

Non–Acid-Fast Aerobic Actinomycetes Associated with Human Disease

Genus	Number of Species	Species Associated with Human Disease
Streptomyces	>3000	S. somaliensis S. paraguayensis S. anulatus

Actinomadura 27

Dermatophilus 2

Nocardiopsis 8

N. synnemataformans

Another group of non–acid-fast actinomycetes, the thermophilic actinomycetes, are associated with infections in humans and include the medically relevant genera Thermoactinomyces, Saccharomonospora, and Saccharopolyspora.

Nocardia organisms are normal inhabitants of soil and water and are primarily responsible for the decomposition of plant material. Infections caused by Nocardia spp. are found worldwide. Because they are ubiquitous, isolation of these organisms from clinical specimens does not always indicate infection. Rather, isolation may indicate colonization of the skin and upper respiratory tract or laboratory contamination, although the latter is rare. Nocardia infections can be acquired either by traumatic inoculation or inhalation. N. asteroides sensu stricto type VI is evenly distributed throughout the United States, as is N. farcinica. The prevalence of other species varies regionally; N. brasiliensis is associated with tropical climates and has a higher prevalence in the southwestern and southeastern United States.

Nocardia spp., particularly N. asteroides, are facultative intracellular pathogens capable of growth in various human cells. The mechanisms of pathogenesis are complex and not completely understood. However, the virulence of N. asteroides appears to be associated with several factors, such as stage of growth at the time of infection, resistance to intracellular killing, tropism for neuronal tissue, and ability to inhibit phagosome-lysosome fusion; other characteristics, such as production of large amounts of catalase and hemolysins, may also be associated with virulence.

Rhodococcus, Gordonia, Tsukamurella spp.

Rhodococcus, Gordonia, and Tsukamurella spp. can be isolated from several environmental sources, especially soil and farm animals, as well as from fresh water and salt water. The organisms are believed to be acquired primarily by inhalation. For the most part, these aerobic actinomycetes are infrequently isolated from clinical specimens.

To date, Rhodococcus equi has been the organism most commonly associated with human disease, particularly in immunocompromised patients, such as those infected with the human immunodeficiency virus (HIV). R. equi is a facultative intracellular organism that can persist and replicate within macrophages. Determinants of the virulence of R. equi are under investigation and may involve cell wall mycolic acids that may play a role in intracellular survival, production of interleukin-4, and granuloma formation. Although Gordonia spp. and Tsukamurella are able to cause opportunistic infections in humans, little is known about their pathogenic mechanisms.

Non–acid-Fast Aerobic Actinomycetes: Streptomyces, Actinomadura, Dermatophilus, Nocardiopsis, and the Thermophilic Actinomycetes

Aspects of the epidemiology of the non–acid-fast aerobic actinomycetes are summarized in Table 19-4. Little is known about how these agents cause infection.

TABLE 19-4

Epidemiology of the Non–Acid-Fast Aerobic Actinomycetes

Organism	Habitat (Reservoir)	Distribution	Routes of Primary Transmission
Streptomyces somaliensis	Sandy soil	Africa, Saudi Arabia, Mexico, South America	Penetrating wound/abrasions in the skin
S. anulatus	Soil	Most common isolate in United States	Penetrating wound/abrasions in the skin
Actinomadura madurae	Soil	Tropical and subtropical countries	Penetrating wound/abrasions in the skin
A. pelletieri, A. latina	Unknown, possibly soil	Tropical and subtropical countries	Penetrating wound/abrasions in the skin
Dermatophilus congolensis	Unknown; skin commensal or saprophyte in soil(?)	Worldwide, but more prevalent in humid, tropical, and subtropical regions	Trauma to the epidermis caused by insect bites and thorns; contact with tissues of infected animals through abrasions in the skin
Nocardiopsis dassonvillei*	Unknown	Unknown	Unknown
Thermophilic actinomycetes	Ubiquitous; water, air, soil, compost piles, dust, hay	Worldwide	Inhalation