[Emerging Infectious Diseases * Volume 3 * Number 2 * April-June 1997]

Synopses

Rhodococcus equi and Arcanobacterium haemolyticum: Two "Coryneform"
Bacteria Increasingly Recognized as Agents of Human Infection

Regina Linder
Hunter College, New York, New York, USA
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      Rhodococcus equi and Arcanobacterium haemolyticum, formerly
      classified in the genus Corynebacterium, are members of the
      loosely defined taxon "coryneform" bacteria. Although they are
      the etiologic agents of distinct human infections, both
      organisms are frequently overlooked, which results in missed or
      delayed diagnoses. R. equi, long known as an important pathogen
      of immature horses, has become in the past three decades an
      opportunistic pathogen of severely immunosuppressed humans.
      Most cases are secondary to HIV infection. When specifically
      sought in throat swab cultures, A. haemolyticum is found
      responsible for 0.5% to 2.5% of bacterial pharyngitis,
      especially among adolescents. These two microorganisms
      represent a spectrum of disease in humans: from a mild, common
      illness to a rare life-threatening infection. Each organism
      elaborates lipid hydrolyzing enzymes (cholesterol oxidase by R.
      equi and sphingomyelinase D by A. haemolyticum) that are toxic
      to animals and humans and damaging to mammalian cell membranes.
      The participation of the cytotoxins in pathogenicity is
      discussed. Greater awareness of the properties of these two
      bacteria may promote faster, more accurate diagnoses and better
      clinical management.

A variety of factors contribute to the underreporting of human infections
caused by bacteria in the genus Corynebacterium and closely related genera.
The group, often referred to as "coryneform," comprises taxonomically
diverse gram-positive rods resembling Corynebacterium diphtheriae and
displaying pleomorphism and irregular cellular arrangements (1,2). The
group includes human and animal pathogens, as well as commensal bacteria.
The control of diphtheria in industrialized countries and the subsequent
deemphasis of the genus Corynebacterium have contributed to discounting
isolates characteristic of the genus as contaminants. Even reference
laboratories report difficulty in the speciation of gram-positive
pleomorphic rods that resemble corynebacteria (1). Because of the emergence
of a number of coryneform bacteria as important human pathogens, rigorous
biochemical and molecular tools have increasingly been applied to isolates.
The resulting improved epidemiology and taxonomy have led, for example, to
the definition of CDC groups JK and D-2 in the genus Corynebacterium, now
recognized as important opportunistic pathogens (1). Similarly, more
accurate characterization of some species caused them to be removed from
the genus Corynebacterium. Excellent reviews of the pathogenicity and
epidemiology of these diverse genera have been published (1,2). This
article explores two pathogenic coryneform bacteria: Rhodococcus equi, a
rare often fatal human pathogen, in which virtually all human infections
occur among compromised hosts; and Arcanobacterium haemolyticum, which is
responsible for many respiratory infections in healthy people. This article
aims to bring about improved recognition of these two easily overlooked
pathogens and considers mechanisms underlying the diseases, the immune
response of the hosts, and treatment protocols.

Eidemiology and Clinical Presentation

R. equi

Originally isolated by Magnusson in 1923 from granulomatous lung infections
in young horses (3), Corynebacterium (now Rhodococcus equi) remains an
important pathogen of foals. Much of the considerable body of knowledge
about R. equi, including its pathogenicity and immune response to
infection, derives from veterinary studies and has been recently updated
(4).

R. equi is readily found in soil, especially where domesticated livestock
graze (5). The stool of horses and other animals is the source of soil
contamination. Infection in humans derives from environmental exposure
(2,5), and the organism may be ubiquitous in soil (6). While early cases
occurred mostly in persons with a history of contact with horses, only 20%
to 30% of recent cases can be traced to such contact (7). A review of cases
in the three decades since the first reported human infection in 1967 is
presented in Table 1.

 Table 1. Rhodococcus equi case reports in humans: 1967-1996
 -------------------------------------------------------------------------
                                           Primary
                                            site
                                             of
                Predisposing condition    infection
  Years  Cases         (number)           (number)  Deaths  References(a)
 -------------------------------------------------------------------------
 1967-76 7     Corticosteroid (1)        Lung (6)   0      8-10
               Cancer/immunosuppressant  Lymphatic
               (3)                       (1)
               Renal transplant (2)
               None(b)(1) 

 1977-86 15    Corticosteroid (1)        Lung (14)  8      8-10,22
               Cancer/immunosuppressant
               (4)                       Blood (1)
               Renal transplant (2)
               HIV (7)
               Alcoholism (1)

 1987-96 93    Cancer/immunosuppressant  Lung (72)  34     8-13,22
               (8)

               Renal transplant (3)      Lymphatic
                                         (2)
               HIV (67)                  Blood (8)
               Other(c) (8) (1(b))       Wound (6)

               None (7) (4(b))           Other(d)
                                         (5)
 -------------------------------------------------------------------------
 (a)In the interest of space, case compilations are cited in lieu of
 individual case reports.
 (b)Child
 (c)Includes intravenous drug use, lab infection, emphysema, kidney
 disease.
 (d)Central nervous system, gastrointestinal

R. equi is a rare opportunistic pathogen found in severely compromised
patients, and most commonly in recent years, in human immunodeficiency
virus (HIV)-infected persons. Early cases, most in patients receiving
immunosuppressant therapy, were more likely to be successfully treated with
antimicrobial agents than cases in AIDS patients (8). Most often, patients
have a slowly progressive granulomatous pneumonia, with lobar infiltrates,
frequently developing to cavitating lesions visible on chest x-ray. Other
sites of infection include abscesses of the central nervous system, pelvis,
and subcutaneous tissue, and lymphadenitis (7,8-10). Cases of lung
infection caused by inhalation and cutaneous lesions caused by wound
contamination have been documented; the latter are almost the only R. equi
infections reported in healthy persons, frequently children (11). Delays in
accurate diagnosis of R. equi are still common (2,7), despite increased
awareness of this organism as an opportunistic pathogen in humans. Factors
for delayed diagnosis include the insidious onset of disease, clinical
resemblance of the infection to mycobacterial, fungal, and actinomycotic
infections, and the relatively nondescript bacteriologic profile of R.
equi. Morphology, partial acid fastness, and a distinctive histopathologic
profile in bronchial specimens (Figure 1 A and B) contribute to accurate
diagnosis. Numerous polymorphonuclear leukocytes with intracellular
pleomorphic gram-positive bacteria, microabscesses, pseudotumors, and
malakoplakia are noted on tissue (7,11). Malakoplakia is a relatively rare
granulomatous inflammation not typically associated with histology of lung
infection and can be of help in forming a differential diagnosis (11,12).
Firm diagnosis and differentiation from similar pathogens require the
isolation and identification of R. equi from sputum, bronchial washings,
open-lung biopsy, or other specimens reflective of pathology. Blood
cultures from severely immunosuppressed patients with focal R. equi
infection often contain the organism. In sixty-five percent of cases
secondary to HIV infection, the organism is found in patients' blood
cultures (11). Deaths exceed 50% among AIDS patients with documented R.
equi pneumonia and are almost always preceded by multiple relapses, which
are common even when successful treatment is ultimately achieved (Table 1;
13).

                   A[Figure 1A] [Figures not available in ASCII version]

                   B[Figure 1B] [Figures not available in ASCII version]

                   Figure 1. A. Bronchial tissue Gram
                   stain showing intrahistiocytic
                   coccobacillary forms of Rhodococcus
                   equi. Original magnification, x
                   1,000. B.Open lung biopsy showing
                   coalescent microabscesses with
                   numerous histiocytes containing
                   Rhodococcus equi organisms. PAS
                   stain. Original magnification x 250.
                   Figure provided by Dr. Margie Scott,
                   Vanderbilt University Medical
                   Center.

Corynebacterium haemolyticum

A. haemolyticum was first described and named by MacClean et al. (14), who
isolated it from pharyngeal infections in U.S. soldiers and natives in the
South Pacific. Classification of the organism generated controversy until
the definition in 1982 of a new genus, Arcanobacterium (secretive
bacterium), in which it remains the only species (15).

Unlike R. equi infection, where invasive clinical disease underscores the
need to detect and identify the causative agent of infection, A.
haemolyticum infection is often reported from deliberate screening for the
organism of a large number of patients with sore throats. After it was
identified during World War II from patients with pharyngitis (14), it was
occasionally reported from Europe, the United States, and in 1981, Sri
Lanka (16 cases) (16). Most cases involve pharyngitis and/or tonsillitis,
and approximately 50% are exudative. Throat infections are often
accompanied by cervical lymphadenopathy (17,18). Diagnosis of cases
(distinct from screening studies) often occurs only after recurrent
infections, which are thought to be related to incorrect initial diagnosis,
resulting in less-than-optimum treatment (19). Infection is most common in
15- to 25-year-old persons, and is thought to result from droplet transfer
from infected persons (20). Symptoms resemble those of -hemolytic
streptococci or viral infection. The spectrum of disease ranges from sore
throat to, in rare cases, a life-threatening membranous pharyngitis
resembling diphtheria (18,20). An erythematous morbilliform or scarlatinal
rash of the trunk, neck, or extremities is associated with 20% to 25% of
cases (19), enhancing the possibility of misdiagnosis as streptococcal
infection or penicillin allergy, because -lactam therapy is frequently
initiated without accurate diagnosis. A recent report describes in detail
the dermatologic manifestations of A. haemolyticum infection (20).

The demonstration that A. haemolyticum is not a component of the human
commensal flora was essential to establishing its role in human infection.
Studies of more than 2,000 cases each found the organism only in
association with clinical symptoms (17,19). Table 2 summarizes several case
compilations, including the incidence of infection among culture-positive
bacterial sore throats, as well as data on coinfection. Some 0.5% to 3% of
cases of pharyngitis can be traced to A. haemolyticum depending on the
population studied, with the highest numbers among 15- to 30-year-old
patients (19). Clearly, accurate diagnosis depends on differentiating A.
haemolyticum from more common pathogens. A. haemolyticum occurs relatively
often in polymicrobic infections together with typical respiratory
pathogens such as streptococci. The isolation of classical pathogens from
specimens that also contain A. haemolyticum exacerbates the tendency to
overlook the organism.

Table 2. Representative pharyngitis screenings for Arcanobacterium
haemolyticum
---------------------------------------------------------------------------
  Period of                                                    Clinical
    study     Number of                        Incidence(a)    features
 (reference)  isolations Rash   Coinfection        (%)       (population)
---------------------------------------------------------------------------
1978-80 (16) 16         0    13 (C.            NR           Symptomatic
                             diphtheriae,                   throat
                             S. pyogenes, E.               swabs and
                             coli,                          pyoderma (Sri
                             P. aeruginosa)                 Lanka)
1981-85 (19) 81(b)      37   NR                2.0          Symptomatic
                                                            throat
                                                            swabs (Sweden)
1990-92 (17) 42         17   NR                0.36         Symptomatic
                                                            throat
                                                            swabs; 5 cases
                                                            onospot
                                                            positive
                                                            (Ottawa,
                                                            Canada)
1991-92 (42) 19         5    11                0.49         Symptomatic
                             (streptococci,                 throat swabs,
                             groups A, B, G)                3922(c);
                                                            (Finland)
1992-95 (43) 16         12   5 (streptococci,  0.75         Symptomatic
                             groups A, B,                   throat swabs,
                             -hemolytic)                   2121(c);
                                                            (Czech
                                                            Republic)
---------------------------------------------------------------------------
NR-not reported
(a) Incidence refers to the proportion of sore throat cases in each study
cited yielding A. haemolyticum.
(b)1 of 550 asymptomatic specimens yielded A. haemolyticum.
(c)Figures refer to the total specimens screened.

Taxonomy, Bacteriology, and Differential Identification

R. equi

On the basis of the chain length of mycolic acids and other properties of
its lipids, R. equi was reclassified in the suprageneric taxon nocardioform
actinomycetes (1,2,5). R. equi is a strictly aerobic gram-positive
bacterium displaying rod-to-coccus pleomorphism, with fragmenting and
occasionally palisading forms. It is nonfastidious. Colonies on blood agar
from clinical specimens can be mucoid and coalescing. Typical salmon pink
pigmentation develops on blood agar, but often only after 2 to 3 days
incubation. Growth on Lowenstein-Jensen medium allows earlier detection of
pigment (M. Scott, pers. comm.). Positive routine biochemical tests include
catalase and urease, but R. equi is generally nonreactive. Acid-fast
staining of direct smears and fresh isolates is helpful in identification
but is rarely observed on subculture (5,7). Some diagnostic laboratories
use a commercial kit (API Coryne strip (bioMerieux-Vitek, Hazelwood, MO)
for identification.

Also helpful in identifying R. equi is synergistic hemolysis (resembling
the CAMP test), displayed by cross-streaking on sheep blood agar with any
of a number of other bacteria, including A. haemolyticum, Staphylococcus
aureus, and Corynebacterium pseudotuberculosis (21; Figure 2). Synergistic
hemolysis is discussed among mechanisms of pathogenesis (below). In
addition, antagonism between imipenem and other -lactam antibiotics used
against strains of R. equi provides the opportunity of differentiating the
organism from taxonomically related species (22).

[Figure] [Figures not available in ASCII version]

Figure 2. Cooperative (and antagonistic) hemolytic reactions on sheep
blood agar, demonstrating cooperative hemolysis between Rhodococcus equi,
Arcanobacterium haemolyticum, and Staphylococcus aureus. Partial hemolysis
by S. aureus (cross-hatched on diagram) is inhibited in the proximity of
A. haemolyticum.

A. haemolyticum

Organisms are gram-positive rodsslender at first, sometimes clubbed, or in
angular arrangements. Coccal forms predominate as the organism grows. The
organism is facultatively anerobic. Growth is enhanced in blood and in the
presence of CO2. Some sugars are fermented, and the organism is catalase
negative. Hemolysis is best observed on human blood, and Gaston et al. (20)
suggest routine plating of specimens suspected of containing A.
haemolyticum on human blood agar to distinguish Streptococcus pyogenes.
Pitting beneath colonies on human blood agar is helpful in identification.
Synergistic hemolysis with R. equi (or inhibition of the hemolytic zone of
S. aureus, (Figure 2) is useful in identification, especially as it may
rule out group B streptococci. Poor growth on tellurite assists in
differentiation from Corynebacterium diphtheriae.

Pathogenesis and the Immune Response

R. equi

Because R. equi is a rare and recently emergent cause of human infection,
mechanisms of its pathogenicity are not well defined. However, the
much-studied infection in foals and an experimental model in mice provide
data which, together with the available human data, give insight into the
workings of the pathogen. Its nature as a facultatively intracellular
bacterium, able to persist, grow, and ultimately destroy macrophages
(23-25), is the property of R. equi most closely associated with virulence
in each host. Foal alveolar macrophages having ingested R. equi did not
undergo phagosome-lysosome fusion and were irreversibly damaged in electron
micrographs (26). Results of pathology tests (microscopy and
roentgenography) reflect significant inflammation, consistent with that
found in such other intracellular pathogens as Mycobacterium tuberculosis,
which elude pulmonary clearance. Open lung biopsies in humans show numerous
polymorphonuclear leukocytes, foam cells, and cavitating lesions with
intracellular bacteria (7,11; Figure 1). Also as in mycobacteria, cell wall
mycolic acids are present. These acids may contribute to the ability of R.
equi to grow in macrophages; virulence of strains for mice was found
related to the carbon chain length of the molecules (27). Granuloma
formation was observed when killed R. equi strains, regardless of
virulence, were introduced into inbred mice, supporting a role for mycolic
acids or other cell wall glycolipids in pulmonary inflammation (28).

A key contributor to virulence in the foal and the mouse model is a group
of large (85-90 kb) plasmids, encoding 15-17 kDa antigens among strains
isolated from almost all natural infections in foals (29). Strains cured of
the plasmid are cleared in experimental infections, and intracellular
replication in murine macrophages is greatly diminished in its absence
(25,28). In contrast, of 39 strains isolated from humans (29 with AIDS), 31
strains did not express the virulence associated plasmid and were
non-virulent in mice (6). The investigators suggest that intracellular
growth and, therefore, virulence among human strains may not be explained
by the same determinants as foals, while mycolic acids may play a role.

Nordmann (23) found that intracellular growth in mouse and human
macrophages of strains isolated from AIDS patients was related to -lactam
resistance, the production of a bacteriophage, and virulence in inbred
mice. Virulence was not attributable to 17kDa virulence antigens, but
soluble cytotoxic substances were associated with the virulent phenotype.
The cytotoxic activity remains to be characterized, and its relationship to
known cytotoxic activities of R. equi remains to be elucidated. In addition
to numerous hydrolytic enzymes typical of the genus Rhodococcus (5),
strains of R. equi, irrespective of virulence, produce cholesterol oxidase,
which is responsible for the organism's participation in synergistic
hemolytic reactions with other bacteria (30; Figure 2). Experiments using
cultured mouse macrophages with phagocytosed R. equi suggest a role for
cholesterol oxidase in macrophage destruction in infections. Macrophages
undergo oxidation of membrane cholesterol, and the accumulation of oxidized
cholesterol is significantly enhanced by the cophagocytosis of C.
pseudotuberculosis, a related coryneform bacterium producing
sphinomyelinase D (31). Toxicity to vertebrates as a result of enzymatic
oxidation of membrane cholesterol is documented in diverse systems, most
dramatically by lethality to hypercholesterolemic rabbits (31).

Because R. equi is uniquely an opportunistic pathogen in humans, it is of
interest to consider the precise nature of the immune deficiency that
underlies susceptibility to this organism. Recent investigations in
immunodeficient mice are especially instructive. T-cell subsets,
specifically functional CD4+ lymphocytes, are necessary to effect complete
clearance of R. equi challenge (23,32). Specifically, Kanaly et al. showed
that CD4+ Th1 cells (expressing interferon-gamma) are sufficient to achieve
clearance from the lungs of mice (32,33). Consistent with these data,
peripheral mononuclear cells, from patients with AIDS, challenged in vitro
with R. equi failed to secrete high levels of interferon-gamma in
comparison with cells from healthy donors (34). Investigations implicating
a specific defect in the Th1 phenotype in the pathogenicity of AIDS make
these studies especially provocative and suggest a role for immunotherapy
in R. equi infection (33).

While cell-mediated immunity appears to have a primary role in protecting
against R. equi infection, the participation of humoral antibody has been
established in foals. Passive immunization with hyperimmune serum is
efficacious in prophylaxis, and severity of disease is inversely related to
circulating antibody (1,5). Mastroianni et al. (35) demonstrated antibody
to the major antigens of R. equi in four AIDS patients with cavitating
pneumonia. The role of such antibody in the natural history of the
infection remains to be elucidated.

A. haemolyticum

Little is known about the mechanisms by which A. haemolyticum produces
infection or brings about the skin manifestations frequently associated
with it. The organism is known to produce uncharacterized hemolytic
agent(s) (20) and two biochemically defined extracellular products: a
neuraminidase and a phospholipase D (PLD) acting preferentially on
sphingomyelin and generating ceramide phosphate in the target membrane
(36). Of these, PLD is known to bring about tissue damage, as elaborated by
this organism as well as the closely related bacterium, C.
pseudotuberculosis, an important pathogen of sheep. Soucek et al. (36)
found that the enzyme was responsible for the dermonecrotic, as well as the
synergistic hemolytic, activity of the organisms that elaborate it. The PLD
gene from A. haemolyticum has been cloned and shown to have a high degree
of homology with that of C. pseudotuberculosis, where it is thought to
participate in vascular permeability and dissemination of the pathogen
(37). Evidence relates PLD with toxicity of C. pseudotuberculosis. Targeted
mutagenesis of the PLD gene of C. pseudotuberculosis confirmed the role of
the enzyme in virulence and specifically in dissemination in the host (38).
Mutant bacteria had a reduced ability to establish infection in goats and
were unable to disseminate by the lymphatics to secondary sites. A PLD
sharing many properties with corynebacterial PLDs, including biochemical
and biological activities, is responsible for the toxicity of the venom of
the brown recluse spider (39). The role of potentiated cytotoxicity caused
by the combined activity of PLD and cooperative agents such as cholesterol
oxidase in disease is not established, but suggested by in vitro data
involving cophagocytosis as described above (31).

Treatment

R. equi

Increased recognition of R. equi as a cause of life-threatening infection
in severely immunocompromised persons has promoted a number of studies of
in vitro antimicrobial susceptibility of clinical isolates (11,13,40,41).
While variations exist, most strains were susceptible to inhibition by
glycopeptide antibiotics (including vancomycin and teicoplanin) and
rifampin. Macrolide antibiotics, such as erythromycin and clarithromycin,
were also inhibitory to many strains. Resistance to -lactam antibiotics
(with the exception of carbapenems, specifically imipenem) was generally
reported, and is not related to the production of a -lactamase.

Because of relapse in spite of treatment in a majority of cases (11) and
high mortality rate, especially among AIDS patients (Table 1), there is no
standard treatment protocol for pulmonary and/or systemic R. equi
infections. However, several principles reflect the accumulated experience
of investigators. Careful and repeated culture and susceptibility testing
during treatment is required to discover acquired resistance, in a manner
similar to the treatment of mycobacterial infection (11,22). Tolerance to
the cidal effects of some drugs and the need for long-term therapy
(generally 2 months to life-long treatment; 40,41) make bactericidal
testing a useful addition to laboratory studies. In consideration of the
severe immunosuppression of patients and proclivity to relapse,
investigators generally promote a combination of at least two drugs
parenterally (usually including a glycopeptide or rifampin) followed by
oral maintenance therapy (11,41). Recommendation of lipophilic
antimicrobials that penetrate macrophages is controversial (11,41). A
proposed regimen involves parenteral glycopeptide plus imipenem for at
least 3 weeks, followed by an oral combination of rifampin, plus either
macrolides or tetracycline (41). Examples of efficacious protocols for
parenteral treatment are available (Table 1).

Surgical lung resection has been reported occasionally since the emergence
of human cases, especially where large focal lesions develop (9,10), and
has sometimes been efficacious in combination with antimicrobial therapy.
As cases of R. equi continue to be recognized among AIDS patients,
antimicrobial prophylaxis against this opportunistic pathogen may prove a
benefit.

A. haemolyticum

In vitro testing of A. haemolyticum isolated from human infections shows
susceptibility to erythromycin, gentamicin, clindamycin, and cephalosporins
(42). Reports of treatment failure with penicillin in spite of low minimum
inhibitory concentrations have been attributed to tolerance and to failure
to penetrate the intracellular location of the pathogen. Erythromycin has
been proposed as the drug of choice, with parenteral antimicrobial drugs
used for serious infections (20). The general similarity of the
susceptibility pattern of A. haemolyticum to more commonly encountered
pharyngeal pathogens, including S. pyogenes, makes culture and accurate
diagnosis essential if cases are to be recognized for their true etiology.
Its participation in polymicrobic infections (Table 2) requires that A.
haemolyticum be specifically sought in appropriate specimens to obtain
accurate diagnosis and to allow epidemiologic analysis.

R. equi and A. haemolyticum represent distinct poles of infectious disease:
one a ubiquitous soil organism producing life-threatening opportunistic
infections and the other a readily treatable respiratory infection of
healthy young persons. In both instances, a high degree of suspicion is
required to make accurate and timely diagnoses of infections. Diagnostic
failure may result in a graver clinical profile including deaths for R.
equi and, in many undiagnosed or misdiagnosed cases, for A. haemolyticum.
As members of the morphologically defined taxon "coryneform" bacteria,
these organisms exemplify properties of the group that require further
elucidation. Weakly pathogenic and noninvasive, the group includes
environmental bacteria; animal pathogens "crossing-over" to become human
opportunistic pathogens; commensals similarly infecting compromised hosts;
and producers of a wide variety of hydrolytic enzymes bearing a poorly
defined relation to virulence (1). Both R. equi and A. haemolyticum
elaborate a cytotoxic protein (cholesterol oxidase or sphingomyelinase D)
known to be responsible for systemic harm to animals. Coincidentally, these
products potentiate each other's cytotoxic action. The participation of the
agents in harm to a host, alone or in combination with other substances, is
consistent with available data, but yet unproven. Of particular interest is
the role of cholesterol oxidase in destruction of alveolar macrophages in
R. equi pneumonia.

Clarifying the role of synergistic or cooperative cytotoxins in one or more
infectious diseases will surely improve our understanding of others because
of the common occurrence of these agents among bacterial pathogens (21). It
is difficult to envision the potentiated hemolytic combination of R. equi
and A. haemolyticum at the site of an infectious lesion. However,
cooperatively hemolytic combinations have been shown to result from the
partnership of hydrolytic enzymes (e.g., phospholipases, which are
ubiquitous in tissue) with the cytotoxins of pathogenic bacteria (10).
Similarly, the hydrolytic enzymes of commensal bacteria or copathogens that
occur, for example, in A. haemolyticum pharyngitis, can readily be
envisioned to participate in potentiated cytotoxicity in host tissue.
Together with improved recognition of these two pathogens, greater
understanding of their toxic products should prove beneficial.

Acknowledgments

I am grateful to Dr. Margie Scott for providing additional information on
her cases and the micrographs in Figure 1. I thank Dr. Alan Bernheimer for
his critical review of the manuscript and Dr. Patrice Nordmann for helpful
discussions.

Dr. Linder is associate professor of health sciences at Hunter College,
City University of New York, and director of the Medical Laboratory
Sciences Program, which prepares undergraduates for careers in laboratory
medicine. Her research involves the mechanisms of action and role of
bacterial cytotoxins in infection.

Address for correspondence: Regina Linder, School of Health Sciences,
Hunter College, 425 East 25th St., New York, NY 10010,
USA;fax:212-420-9135;e-mail:rlinder@shiva.hunter.cuny.edu.

References

  1. Coyle MB, Lipsky BA. Coryneform bacteria in infectious diseases:
     clinical and laboratory aspects. Clin Microbiol Rev 1990;3:227-46.
  2. McNeil MM, Brown JM. The medically important aerobic actinomycetes:
     epidemiology and microbiology. Clin Microbiol Rev 1994;7:357-417.
  3. Magnusson H. Spezifische infektioese Pneumonie beim Fohlen. Ein neuer
     Eitererreger beim Pferd. Archiv fur Wissenschaftliche und Praktische
     Tierheilkunde 1923;50:22-37.
  4. Prescott JF, Holmes MA, Yager JA, Takai S, editors. Rhodococcus equi
     and immunology of the foal. Vet Microbiol. In press.
  5. Prescott, JF. Rhodococcus equi: an animal and human pathogen. Clin
     Microbiol Rev 1991;4:20-34.
  6. Takai S, Sasaki Y, Ikeda T, Uchida Y, Tsubaki S, Sekizaki T. Virulence
     of Rhodococcus equi isolates from patients with and without AIDS. J
     Clin Microbiol 1994;32:457-60.
  7. Scott MA, Graham BS, Verall R, Dixon R, Schaffner W, Tham KT.
     Rhodococcus equi-an increasingly recognized opportunistic pathogen. Am
     J Clin Pathol 1995;103:649-55.
  8. Doig C, Gill MJ, Church DL. Rhodococcus equi-an easily missed
     opportunistic pathogen. Scand J Infect Dis 1991;23:1-6.
  9. Harvey RL, Sunstrum JC. Rhodococcus equi infection in patients with
     and without human immunodeficiency virus infection. Reviews of
     Infectious Diseases 1991;13:139-45.
 10. Linder R. Rhodococcus equi: an emerging opportunist in humans. PHLS
     Microbiology Digest 1994;11:87-91.
 11. Verville TD, Huycke MM, Greenfiled RA, Fine DP, Kuhls TL, Slater LN.
     Rhodococcus equi infections in humans. Medicine 1994;73:119-32.
 12. Sutor GC, Fibich C, Kirschner P, Kuske M, Schmidt RE, Schedel I,
     Deicher H. Poststenotic cavitating pneumonia due to Rhodococcus equi
     in HIV infection. AIDS 1996;10:339-40.
 13. Donisi A, Suardi MG, Casari S, Longo M, Cadeo GP, Carosi G.
     Rhodococcus equi infection in HIV-infected patients. AIDS
     1996;10;359-62.
 14. MacLean PD, Liebow AA, Rosenberg AA. A hemolytic corynebacterium
     resembling Corynebacterium ovis and Corynebacterium pyogenes in man. J
     Infect Dis 1946;79:69-90.
 15. Collins MD, Jones D, Schofield GM. Reclassification of Corynebacterium
     haemolyticum in the genus Arcanobacterium gen. nov. as Arcanobacterium
     haemolyticum nom.rev.,comb.nov. Journal of General Microbiology
     1982;128:1279-81.
 16. Wickremesinghe RSB. Corynebacterium haemolyticum infections in Sri
     Lanka. Journal of Hygiene-Cambridge 1981;87:271-7.
 17. Mackenzie A, Fuite LA, Chan FTH, King J, Allen A, MacDonald N,
     Diaz-Mitoma F. Incidence and pathogenicity of Arcanobacterium
     haemolyticum during a 2-year study in Ottawa. Clin Infect Dis
     1995;21:177-81.
 18. Green SL, LaPeter KS. Pseudodiphtheritic membranous pharyngitis caused
     by Corynebacterium hemolyticum. JAMA 1981;2330-1.
 19. Banck G, Nyman M. Tonsilitis and rash associated with Corynebacterium
     haemolyticum. J Infect Dis 1986;154:1037-40.
 20. Gaston DA, Zurowski SM. Arcanobacterium haemolyticum pharyngitis
     exanthem. Arch Dermatol 1996;132:61-4.
 21. Fraser G. The effect on animal erythrocytes of combinations of
     diffusible substances produced by bacteria. J Pathol Bacteriol
     1964;88:43-58.
 22. Nordmann P, Nicolas MH, Gutmann L. Penicillin-binding proteins of
     Rhodococcus equi: potential role in resistance to imipenem. Antimicrob
     Agents Chemother 1993;37:1406-9.
 23. Nordmann P, Zinzendorf N, Keller M, Lair I, Ronco E, Guenounou M.
     Interaction of virulent and non-virulent Rhodococcus equi human
     isolates with phagocytes, fibroblast- and epithelial-derived cells.
     FEMS Immunol Med Microbiol 1994;9:199-206.
 24. Hietala SK, Ardans AA. Interaction of Rhodococcus equi with phagocytic
     cells from R. equi-exposed and non-exposed foals. Vet Microbiol
     1987;14:307-20.
 25. Hondalus MK, Mosser DM. Survival and replication of Rhodococcus equi
     in macrophages. Infect Immun 1994;62:4167-75.
 26. Zink MC, Yager JA, Prescott JF, Fernando MA. Electron microscopic
     investigation of intracellular events after ingestion of Rhodococcus
     equi by foal alveolar macrophages. Vet Microbiol 1987;14:295-305.
 27. Gotoh K, Mitsuyama M, Imaizumi S, Yano I. Mycolic acid-containing
     glycolipid as a possible virulence factor of Rhodococcus equi for
     mice. Microbiol Immunol 1991;35:175-85.
 28. Takai S, Madarame H, Matsumoto C, Inoue M, Sasaki Y, Hasegawa Y, et
     al. Pathogenesis of Rhodococcus equi infection in mice: roles of
     virulence plasmids and granulomagenic activity of bacteria. FEMS
     Immunol Med Microbiol 1995;11:181-90.
 29. Tkachuk-Saad O, Prescott J. Rhodococcus equi plasmids: isolation and
     partial characterization. J Clin Microbiol 1991;29:2696-2700.
 30. Linder R, Bernheimer AW. Enzymatic oxidation of membrane cholesterol
     in relation to lysis of sheep erythrocytes by corynebacterial enzymes.
     Arch Biochem Biophys 1982;213:395-404.
 31. Linder R, Bernheimer AW. Cytotoxicity of Rhodococcus equi related to
     generation of cholestenone in macrophage and erythrocyte membranes.
     Vet Microbiol. In press.
 32. Kanaly ST, Hines SA, Palmer GH. Transfer of a CD4+ Th1 cell line to
     nude mice effects clearance of Rhodococcus equi from the lung. Infect
     Immun 1996;64:1126-32.
 33. Kanaly ST, Hines SA, Palmer GH. Cytokine modulation alters pulmonary
     clearance of Rhodococcus equi and development of granulomatous
     pneumonia. Infect Immun 1995;63:3037-41.
 34. Delia S, Mastroianni CM, Lichtener M, Mengoni F, Moretti S, Vullo V.
     Defective production of interferon-gamma and tumour necrosis
     factor-alpha by AIDS mononuclear cells after in vitro exposure to
     Rhodo-coccus equi. Mediators of Inflammation 1995:4:306-9.
 35. Mastroianni CM, Lichtner M, Vullo V, Delia S. Humoral immune response
     to Rhodococcus equi in AIDS patients with R. equi pneumonia. J Infect
     Dis 1994;169:1179-80.
 36. Soucek A, Michalec C, Souckova A. Identification and characterization
     of a new enzyme of the group "phospholipase D" isolated from
     Corynebacterium ovis. Biochim Biophys Acta 1971;227:116-28.
 37. Cuevas WA, Songer JG. Arcanobacterium haemolyticum phospholipase D is
     genetically and functionally similar to Corynebacterium
     pseudotuberculosis phospholipase D. Infect Immun 1993;61:4310-6.
 38. McNamara PJ, Bradley GA, Songer JG. Targetted mutagenesis of the
     phospholipase D gene results in decreased virulence of Corynebacterium
     pseudotu-berculosis. Mol Microbiol 1994;12:921-30.
 39. Bernheimer AW, Campbell BJ, Forrester LJ. Com-parative toxinology of
     Loxosceles reclusa and Corynebacterium pseudotuberculosis. Science
     1985;228:590-1.
 40. McNeil MM, Brown JM. Distribution and antimicrobial susceptibility of
     Rhodococcus equi from clinical specimens. Eur J Epidemiol
     1992;8:437-43.
 41. Nordmann P. Antimicrobial susceptibility of human isolates of
     Rhodococcus equi. Medical Microbiology Letters 1995;4:277-86.
 42. Carlson P, Renoken OV, Kotainen S. Arcanobacterium haemolyticum and
     streptococcal pharyngitis. Scand J Infect Dis 1994;26:283-7.
 43. Chalupa P, Jezek P, Jurankova J, Sevcikova A. Isolation of
     Arcanobacterium haemolyticum from throat culture samples in the Czech
     Republic. Infection 1995;23:397.

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Emerging Infectious Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA

URL: ftp://ftp.cdc.gov/pub/EID/vol3no2/ascii/linder.txt
Updated: 97/05/21