Of Newly Recognized Infrequently Encountered: Mycobacterial Diseases

CLINICAL MICROBIOLOGY REVIEWS, Jan. 1992, p. 1-25 Vol. 5, No.
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0893-8512/92/010001-25$02.00/0
Agents of Newly Recognized or Infrequently Encountered

Mycobacterial Diseases
LAWRENCE G. WAYNE* AND HILDA A. SRAMEK
Veterans Affairs Medical Center, Long Beach, California 90822
INTRODUCTION ............................................................................... 2
PREVIOUSLY WELL-DOCUMENTED SPECIES OF SLOWLY GROWING PPEM .............................3
M. kansasii .............................................................................. 3
Systematics .............................................................................. 3
Clinical and epidemiologic aspects .............................................................................. 3
M. marinum .............................................................................. 3
Systematics .............................................................................. 3
M. scrofulaceum .............................................................................. 4
Systematics .............................................................................. 4
M. simiae .............................................................................. 4
Systematics .............................................................................. 4
Clinical and epidemiologic aspects ............................................................................... 4
M. szulgai .............................................................................. 4
Systematics .............................................................................. 4
M. ulcerans ..............................................................................5
M. xenopi ..............................................................................5
Systematics .............................................................................. 5
PREVIOUSLY WELL-DOCUMENTED SPECIES OF RAPIDLY GROWING PPEM ............................5
M. fortuitum Complex .............................................................................. 5
Systematics ............................................................................... 5
MAJOR RECENT DEVELOPMENTS IN THE TAXONOMY OF AND CLINICAL CONDITIONS
ASSOCIATED WITH SOME COMMONLY ENCOUNTERED PPEM ..........................................6
M. avium Complex .............................................................................. 6
Systematics .............................................................................. 6
(i) Taxonomic status .............................................................................. 6
(ii) Identification .............................................................................. 7
Newer clinical and epidemiological aspects .............................................................................. 7
(i) AIDS ............................................................................... 7
(ii) Crohn's disease ............................................................................... 8
NEWLY CHARACTERIZED MYCOBACTERIA OR MYCOBACTERIAL DISEASES .........................8
M. asiaticum .............................................................................. 8
Systematics ............................................................................... 8
M. haemophilum ............................................................................. 9
Systematics .............................................................................. 9
M. malmoense ............................................................................. 11
Systematics .............................................................................. 11
(i) Taxonomic status .............................................................................. 11
(ii) Identification .............................................................................. 11
M. shimoidei ............................................................................. 13
Systematics .............................................................................. 13
SPECIES OF MYCOBACTERIA GENERALLY CONSIDERED TO BE NONPATHOGENIC ............... 13
M. gasi ............................................................................... 13
Systematics .............................................................................. 13
*
Corresponding author.
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2 WAYNE AND SRAMEK CLIN. MICROBIOL. REV.
M. gordonae ................................................ 14
Systematics .......................................................... 14
Clinical and epidemiologic aspects ................................................. 14
M. terrae Complex ................................................. 15
Systematics ................................................. 15
Rapid Growers Other than Members of the M. fortuitum Complex ................................................ 16
Systematics ................................................. 16
(i) M. flavescens ................................................ 16
(ii) M. neoaurum ................................................ 16
(iii) M. smegmatis ................................................ 16
(iv) M. thermoresistibile ................................................ 16
(v) Unknown species ................................................. 16
MEASURES TO MINIMIZE THE RISK OF FAILING TO ISOLATE OR MISIDENTIFYING
INFREQUENTLY ENCOUNTERED PPEM .................................................. 17
Isolation of the Organism from Appropriate Specimens .................................................. 17
Skin lesions .................................................. 17
Other specimens .................................................. 17
Identification of Organisms and Detection of Mixed Cultures .................................................. 18
Assessment of Significance .................................................. 18
CONCLUSIONS .................................................. 18
ACKNOWLEDGMENTS .................................................. 18
REFERENCES .................................................. 19
INTRODUCTION Although other investigators soon recognized that this iso-

late was actually a member of the genus Mycobacterium, it
For many years following the discovery of the human was not until 1965 that Runyon formally changed the name
tubercle bacillus, only the three acid-fast species presently from "N. intracellularis" to the present one, M. intracellu-
known as Mycobacterium tuberculosis, M. bovis, and M. lare (158). In 1951, Norden and Linell (134) published a
leprae were consistently recognized as human pathogens. As report on swimming pool granuloma and described and
early as 1935, Pinner applied the term "atypical acid-fast named "M. balnei," which was later recognized to be
microorganisms" to some isolates that appeared to be the synonymous with the fish pathogen, M. marinum, that
cause of human disease but that he could differentiate from Aronson had described in 1926 (3). In 1952, Prissick and
M. tuberculosis on the basis of colony morphology, pigment, Masson described a pigmented Mycobacterium species that
and virulence in animals (142, 143). In some cases passage in caused cervical adenitis in children (147); in 1956, they
animals seemed to cause these isolates to revert to the named this organism M. scrofulaceum (148). In 1953, Buhler
morphology and virulence characteristic of M. tuberculosis; and Pollak (19, 145) reported on a human pulmonary disease
Pinner speculated that transmutation of types could be caused by a novel acid-fast organism that was later named
occurring, although he took pains to point out that the M. kansasii by Hauduroy (74).
evidence was not conclusive. He also noted the inadequacy These descriptions of newly recognized mycobacterial
of taxonomic criteria that could be applied to the mycobac- pathogens of humans were largely based on a fairly small
teria at that time. This inadequacy forced him to rely almost number of case reports. In that same period, Timpe and
exclusively on the highly variable parameters of pathogenic- Runyon were systematically assembling a large collection of
ity testing. In retrospect, it seems likely that some of his mycobacteria other than classical tubercle bacilli that had
experiences of apparent reversion could be explained by been isolated from clinical specimens. They hoped to deter-
mixed infections in the original host, with gradual enrich- mine whether there was any correlation between the in vitro
ment of the cultures with the more virulent M. tuberculosis attributes of these strains and their association with disease.
after serial passage in animals. The failure of fulminating M. This effort was successful, and in 1954 they published their
tuberculosis disease to appear on first passage to guinea pigs landmark paper, in which they were able to show a relation-
might be attributed to a very high proportion of one of his ship between clinical significance and a few key phenotypic
"atypical" mycobacteria in the inoculum providing some properties of mycobacteria for which the previous ultimate
partial immunization before the tubercle bacilli gained the criteria of clinical significance had been animal pathogenicity
upper hand. (184).
In 1938, da Costa Cruz attributed a human postinoculation Timpe and Runyon applied the same term, "atypical,"
abscess to a rapidly growing Mycobacterium species that he that Pinner had used 20 years earlier to encompass clinical
described and named M. fortuitum (42). A decade passed isolates of mycobacteria that did not appear to be conven-
before MacCallum et al. described a serious skin disease tional human tubercle bacilli. This orientation of attitude
caused by a very fastidious new Mycobacterium sp. (114), based on the centrality of M. tuberculosis, with the corollary
later named M. ulcerans (53). A rash of new sightings of that M. tuberculosis was the standard against which all
mycobacteria then occurred, probably spurred by the intro- mycobacteria were judged, significantly impeded the orderly
duction of specific chemotherapy for tuberculosis. In 1949, development of a system of taxonomy for the mycobacteria
Cuttino and McCabe described a fatal disseminated infection (203). The other impediments were the slow growth and
in a child that was caused by a newly recognized microor- relative impermeability of acid-fast bacilli, which make most
ganism that they named "Nocardia intracellularis" (40). conventional bacteriologic tests inapplicable to mycobac-
VOL. 5, 1992 POTENTIALLY PATHOGENIC ENVIRONMENTAL MYCOBACTERIA 3
teria. As the emphasis shifted from the M. tuberculosis- section. Those species that were mentioned very briefly or
oriented animal virulence tests to a more general approach to not at all in the baseline articles are the main subjects of this
the systematics of the genus Mycobacterium, selected bio- review and will be discussed in detail. We will also present a
chemical tests began to be uniquely tailored to some of the brief review of the rare infections attributed to species that
physiologic peculiarities of these organisms (204). As the are normally considered nonpathogenic, i.e., M. gastri, M.
taxonomy evolved and it became evident that a number of gordonae, members of the M. terrae complex, and most
different types of mycobacteria had to be considered, each rapidly growing mycobacteria other than members of the M.
typical of its own species, objections to the designation fortuitum complex. Finally, we will present some sugges-
"atypical mycobacteria" were raised (234). Among other tions for practical measures that can help minimize the risk
broad-spectrum terms that have been applied, such as "my- of failing to isolate or misidentifying some of the more
cobacteria other than tubercle" bacilli, or MOTT, and obscure PPEM that are only infrequently recognized. Spe-
"nontuberculous" mycobacteria, none is without its incon- cial attention will be paid to the possibility that apparently
sistencies. The major practical distinction between M. tuber- aberrant strains of the more familiar species actually repre-
culosis and other mycobacterial pathogens is not the ability sent novel species and that rarely encountered pathogens
of the former to cause serious human disease characterized may be mistaken for nonpathogenic species.
by tubercles. It is, rather, a difference in the normal habitats
and relative contagiousness of all of these species. The PREVIOUSLY WELL-DOCUMENTED SPECIES OF
relatively greater susceptibility of M. tuberculosis to a SLOWLY GROWING PPEM
number of chemotherapeutic agents is another important
difference. M. tuberculosis is contagious, is not found free in The systematics of some of the species described in this
nature, and is normally transmitted only by an infected section remain essentially as described in the baseline doc-
mammalian host. Most of the other mycobacteria that cause uments (205, 224). In these cases, only new information will
human and animal diseases have demonstrated very little be cited.
person-to-person contagiousness, have been found in the The following species, which require >7 days for visible
environment (where they are probably commonly encoun- growth to appear from dilute inoculum, are considered slow
tered by humans), and must be considered opportunists. growers.
Therefore, we will refer to them as "potentially pathogenic
environmental mycobacteria" (PPEM). M. kansasii
As different tests, techniques, and classification strategies
proliferated in laboratories throughout the world, consolida- Systematics. Studies on the base sequences of 16S rRNA
tion and integration of the voluminous information being (155) and catalase serology (209) suggest that M. gastri, a
generated became necessary. In 1967 the International nonpathogenic, nonpigmented, slowly growing Mycobacte-
Working Group on Mycobacterial Taxonomy (IWGMT) was rium species that clusters separately from M. kansasii (207),
organized and a series of cooperative studies was under- is so close to the latter phylogenetically that M. gastri might
taken, using the recently developed principles of numerical be considered a subspecies of M. kansasii. This question has
taxonomy (172) to incorporate laboratory data from diverse not yet been resolved, and at this writing both species names
sources into a unified taxonomic scheme. Over the next 20 are valid; 5S and 23S rRNA sequence comparisons are
years, the results of those cooperative efforts helped to needed to help settle the question. The distinction between
consolidate the phenotypic taxonomy of mycobacteria (26, the two, whether at species or subspecies level, is very
66, 99, 125, 151, 161, 207, 215-220). During that same period, important because M. kansasii is usually significant when
and especially over the last decade, technologies emerged isolated from a clinical specimen, whereas M. gastri is
for the analysis of semantides, large information-bearing rarely, if ever, significant.
molecules such as nucleic acids and proteins (244), that Clinical and epidemiologic aspects. There is little change in
permitted comparisons to be made between phenotypic the information on clinical aspects of M. kansasii since
classification and evolutionary relationships. As will be publication of the baseline article (234) and a subsequent
discussed below, semantide-based classifications of myco- review (238). Infections due to M. kansasii were among the
bacteria have agreed quite well with phenetic conclusions, most common of the PPEM-caused infections in the United
serving to confirm the validity of most species and suggest- States in years past. According to a Veterans Administra-
ing recognition of some subspecies. tion-Armed Forces report in 1964 (79), M. kansasii ac-
Most of the balance of this review will concentrate on counted for twice as many cases as were caused by members
recent information on the systematics and clinical signifi- of the M. avium complex, but the relative incidence of this
cance of PPEM. The reader is referred to three baseline species has declined in succeeding decades to only 10% of
articles: Wolinsky's very thorough 1979 clinical review of the PPEM isolates reported to the Centers for Disease
the PPEM (234), the description of the taxonomic status of Control in 1980 (65). An increase in recoveries of M. kansasii
these organisms in the 1986 edition of Bergey's Manual has been reported in Japan over the same time period (191).
(224), and a 1985 review of identification procedures, includ- M. kansasii is encountered in infections of patients with
ing precise descriptions of the tests themselves (205) that are AIDS (63, 78, 144, 242).
still applicable to many of these organisms. The next section
includes brief reviews of species for which the clinical, M. marinum
epidemiologic, and systematic aspects are already well doc-
umented, e.g., M. kansasii, M. marinum, M. scrofulaceum, Systematics. Studies on the base sequences of 16S rRNA
M. simiae, M. szulgai, M. ulcerans, M. xenopi, and mem- demonstrate that the photochromogenic species M. mari-
bers of the M. fortuitum complex. Many aspects of the M. num lies on a branch of the genus that is close to the branch
avium complex were developed in the baseline references, containing members of the M. tuberculosis complex (155).
but because of new clinical and systematic information, this Clinical and epidemiologic aspects. Cutaneous manifesta-
group will be reviewed in some detail in a subsequent tions of M. marinum infections were discussed in the base-
line reference (234) and have been described more exten- isolated from AIDS patients in Sweden (80), but the Swedish
sively in subsequent reviews devoted to this condition (32, incidence of M. avium complex in patients with AIDS was
91). Recent literature has emphasized the deeper infections, only about one-fifth of that seen in the United States, so the
usually of the hand and including tenosynovitis, arthritis, actual incidence of M. scrofulaceum may be comparable in
bursitis, and osteomyelitis (12, 30, 84). Almost all cases are both countries.
associated with some aquatic activity, usually involving fish.
The increase in proportion of published reports dealing with M. simiae
these deep infections probably reflects an increased aware-
ness of these conditions, resulting in more frequent diagno- Systematics. Primary, secondary, and tertiary semantide
sis, as well as the recognition of the serious consequences of studies have all confirmed the status of M. simiae as a
inadequately treated deep infections (17). These lesions are distinct species (6, 155, 210). Comparisons of 16S rRNA
usually characterized by noncaseating granulomas and an structure place M. simiae on an isolated branch of the genus
absence of plasma cells (12, 84). Chemotherapy with some (155). DNA homology (6) and phenotypic properties (219,
combination of drugs such as rifampin and ethambutol is 220) offer some reason to consider dividing M. simiae into
usually effective, but surgery may be required (30, 84). two subspecies, but analysis of the tertiary semantide cata-
Chemotherapy is least likely to be sufficient in cases previ- lase (220) does not, and this division has never been pro-
ously treated by steroid injection (30), which is often asso- posed formally.
ciated with a poor prognosis. Early diagnosis and avoidance Clinical and epidemiologic aspects. Only two cases of M.
of steroids are critical to satisfactory management (17, 92). simiae infections, both pulmonary, were cited in the baseline
Infection of deep tissues with M. marinum has been associ- reference (234), and additional pulmonary and other infec-
ated with an antigen-specific T-cell anergy in 11 of 12 tions, such as in bone and kidney, were cited in a subsequent
otherwise healthy patients studied (44, 84), suggesting that review by Woods and Washington (238). M. simiae was also
the progression from the relatively benign superficial infec- isolated from the ascitic fluid of a pregnant woman (76). Few
tion to a tenosynovitis or other deep infection is usually cases of M. simiae infection in AIDS patients have been
facilitated by specific T-cell suppression. However, these reported (108, 139).
cases are well managed with chemotherapy alone when it is In 1979 and 1980, M. simiae accounted for <0.2% of
instituted early enough. Even in individuals positive for mycobacterial strains reported to the Centers for Disease
human immunodeficiency virus, with or without AIDS, Control (62, 65). From 1981 through 1983, 67 isolates of M.
superficial lesions cleared without any evidence of spread simiae, corresponding to 1.2% of the reported PPEM, were
(103, 141). Although most M. marinum infections occur in reported by the Centers for Disease Control, but in only 14
the hand, infections have also occurred, though rarely, in the instances, or 21% of the isolations of M. simiae, was disease
eye (166) and possibly the liver and lungs (102); these cases actually attributed to these organisms (135). The majority of
responded to chemotherapy. these occurrences were pulmonary disease in white male
urban residents aged 60 to 74 years. From 1975 to 1981, M.
M. scrofulaceum simiae was isolated in great numbers from clinical specimens
in Israel; 399 strains were isolated from 287 persons, all but
Systematics. As documented below in the discussion of the 1 of whom lived in the coastal plain of Tel Aviv (107). The
M. avium complex, primary, secondary, and tertiary seman- great majority of isolates were considered to be from envi-
tide analyses have all confirmed that the scotochromogenic ronmental sources, probably water. Of 18 patients from
M. scrofulaceum is a distinct species, is not closely related whom multiple isolates were recovered, all were middle-
to either M. avium or M. intracellulare, and should no longer aged or older and most had a history of tuberculosis; Lavy
be included in a complex with these two species. Compari- and Yoshpe-Purer concluded that M. simiae is capable of
sons of base sequences of 16S rRNA demonstrate a fairly prolonged or temporary colonization of previously damaged
deep branched separation between M. scrofulaceum and any lungs. This interpretation is compatible with the observa-
other currently recognized species (155). Although seman- tions of Wayne and colleagues (206) that individuals with
tide studies have not yet been applied to the question of prior pulmonary lesions commonly exhibit antibody reac-
whether the presently invalid species "M. paraffinicum" tions to several different serovars of PPEM, suggesting a
should be revived, in a recent IWGMT study (220), a cluster predilection to mycobacterial colonization. M. simiae was
that includes the erstwhile type that bears this name appears also isolated from the water supply of a hospital in Gaza
well separated from the M. scrofulaceum phenotypic clus- (106). In a study of stool specimens from 50 healthy Euro-
ter. All strains in the "M. paraffinicum" cluster exhibited pean subjects, Portaels and colleagues isolated mycobacteria
negative urease reactions, in contrast to the response of M. from 26 specimens; 14 of 26 strains were identified as M.
scrofulaceum. This suggests that the most common form of simiae (146). Thus, this organism appears to be common in
erstwhile "M. avium-M. intracellulare-M. scrofulaceum the environment in some geographic regions but is only
(MAIS) intermediate" mycobacteria, i.e., the urease-nega- rarely the cause of disease.
tive, slowly growing scotochromogens with high catalase
activity that do not hydrolyze Tween 80 (75), may actually M. szulgai
belong to a discrete species, members of which are rarely, if
ever, clinically significant (221). Systematics. Comparison by Rogall and colleagues (155) of
Clinical and epidemiologic aspects. Little novel information 16S rRNA sequences has shown M. szulgai to be very
on clinical aspects of M. scrofulaceum has appeared since closely related to M. malmoense, with a homology of 99.9%,
publication of the baseline article (234) and a subsequent although those authors note that the two species can be
review (238). M. scrofulaceum accounted for about 2% of differentiated from one another by the direct sequencing of
the mycobacterial infections in a series of 212 AIDS patients amplified DNA (154). Wayne and Diaz have distinguished
in the United States (63). Strains of serovars usually ascribed M. szulgai from M. malmoense and 10 other species by
to M. scrofulaceum accounted for about 15% of the PPEM specific precipitation of M-catalase with cross-absorbed an-
tiserum (210). Phenotypic resolution of M. szulgai from M. divided into subspecies and biovars. The complex is com-
malmoense is included in the discussion of M. malmoense posed of strains that produce visible growth from diluted
(below), and phenotypic distinctions between M. szulgai and inoculum in <7 days and give a positive reaction in the 3-day
other mycobacteria can be made easily (205). aryl sulfatase test (205). In addition to the systematic review
Clinical and epidemiologic aspects. In his 1979 baseline of the species and subspecies in this complex presented in
article (234), Wolinsky cited only 14 cases of disease caused the baseline references (205, 224), the status and descrip-
by M. szulgai. Ten of these cases were pulmonary, and the tions of the biovars are extensively developed in a recent
other conditions included bursitis, lymphadenitis, or skin review by Wallace and colleagues (196).
lesions. By 1987, the number of reported cases had risen to The broad but somewhat arbitrary division that has been
only 27, of which 18 were chronic pulmonary disease that made for many years (224) between the rapidly growing and
was indistinguishable from tuberculosis and occurred almost slowly growing mycobacteria has recently been validated by
exclusively in middle-aged males (116). The balance in- the observation of a major branching of the 16S rRNA
cluded three cases of olecranon bursitis, one of cervical diagram of the genus that corresponds to that division (155,
adenitis, one of tenosynovitis, three cutaneous cases (of 175). The overwhelming majority of those human infections
which one was combined with osteomyelitis), and one case that are attributed to rapidly growing mycobacteria are
of osteomyelitis alone. Most of the pulmonary infections caused by members of the M. fortuitum complex, which are
resolved satisfactorily when three or more drugs to which found throughout the environment; the very rare infections
the individual strain had tested susceptible were used. In attributed to members of rapidly growing species that do not
most of these cases, isoniazid was one of the drugs. Surgical give a 3-day aryl sulfatase reaction will be discussed below.
intervention was needed in at least five of the extrapulmo- Clinical and epidemiologic aspects. In his 1979 review,
nary cases. Two cases of M. szulgai infections have been Wolinsky provided a general description of pulmonary, skin,
reported in AIDS patients (63). bone and joint, and disseminated infections and descriptions
of single cases of infection occurring at other sites, all
M. ulcerans infections due to members of the M. fortuitum complex
(234). Tsukamura has also published extensive reviews of
Both the systematic status of M. ulcerans and the clinical the incidence of lung infections due to M.fortuitum (187) and
aspects of the skin infections caused by this organism remain M. chelonae (188).
essentially as described in the baseline references (224, 234) In 1983, Wallace and colleagues reviewed the spectrum of
and the later review by Woods and Washington (238). disease caused by M. fortuitum and M. chelonae as illus-
trated by 125 cases observed over a 4-year period (200).
M. xenopi Included in this review were 9 cases of disseminated disease,
74 cases of skin and/or soft tissue infections (including 34
Systematics. Studies on the base sequences of 16S rRNA examples of cutaneous infection caused by accidental
demonstrate that M. xenopi occupies an isolated, very deep trauma, with or without introduction of foreign bodies into
branch on the evolutionary tree of the genus (155). the tissues, and 40 postsurgical infections), 24 pulmonary
Clinical and epidemiologic aspects. The pulmonary infec- infections, 5 cases of keratitis, 4 cases of prosthetic valve
tions usually associated with M. xenopi have been described endocarditis, 4 cases of cervical adenitis, and 1 case each of
in the baseline reference (234). M. xenopi rarely produces meningitis, occult bacillemia, hepatitis, spinal epidural ab-
nonpulmonary lesions in patients who are not immunocom- scess following blunt trauma, and vertebral osteomyelitis.
promised (54, 149, 227). Cases of M. xenopi infections in Extensive reviews of the major emerging problem of M.
immunocompromised individuals, including renal transplant fortuitum complex infections that follow cardiac surgery
and peritoneal dialysis patients (16, 169, 226), as well as have also appeared recently (153, 197). Additional diseases
patients with AIDS (4, 51, 139), have also been reported. attributed to members of the M. fortuitum complex include
Although there are many reports of isolated cases of M. intestinal mycobacteriosis (56) and infections in patients
xenopi infection, these cases tend to occur in clusters. In undergoing peritoneal renal dialysis (105, 176, 237, 238).
some cases, these clusters have been associated with expo- The chemotherapy and other aspects of management of
sure of patients to waterborne organisms (38, 106, 150, 180), nonpulmonary infections due to M. fortuitum have also been
usually from hot-water sources, but sometimes the cluster reviewed by Wallace and colleagues (199). The clinical value
covers an entire area without implicating a specific point of in vitro drug susceptibility testing of most PPEM is
source (37, 68, 87, 181). questionable, but there are circumstances under which in
vitro susceptibility tests do appear to provide useful infor-
PREVIOUSLY WELL-DOCUMENTED SPECIES OF mation (2a). In the case of the M. fortuitum complex,
RAPIDLY GROWING PPEM specialized tests have been recommended (2a); quinolone
drugs appear to be particularly effective (199). Some of the
The systematics of some of the species described in this newer quinolones that have been used for treatment were
section remain essentially as described in the baseline doc- reviewed by Leysen and colleagues in 1989 (110).
uments (205, 224). In these cases, only new information will The literature on infections due to members of the M.
be cited. fortuitum complex, as well as the deep infections due to M.
The following species, which require 7 days or less for marinum, is replete with single case reports, unlike that for
visible growth to appear from dilute inoculum, are consid- most other mycobacteria. This may be related to the fact that
ered rapid growers. so many of the cases are associated with wound or surgical
trauma, are difficult to treat, and come to the attention of
M. fortuitum Complex clinical personnel who rarely encounter mycobacterial infec-
tions. Brown has called attention to the ubiquity of the M.
Systematics. The M. fortuitum complex includes the spe- fortuitum complex in the hospital environment (18) and
cies M. fortuitum and M. chelonae, each of which is further stressed the importance of preventing these nosocomial
infections by proper disinfection of medical devices. His designated A-catalase, has been found in members of the M.
recommendations were based on claims by Carson et al. (22) avium complex but not in other species (214). Furthermore,
that M. chelonae isolates from peritoneal fluids of patients plasmids have also been implicated in the variability of
and peritoneal dialysis machines were able to multiply in catalase production by members of the complex (140) and
"commercial sterile distilled water" and that water-grown may yet be found to influence other properties that are
organisms were more resistant to disinfectants than were important in defining the overall phenotypic relationships
cultures grown in rich media. (No chemical analysis of the within this group of organisms. Further information on the
water was described and the ability of these organisms to relationships within this complex may emerge from the
grow in the absence of minerals and with atmospheric gases comparative use of an IWGMT M. intracellulare reference
as nutrients has not been confirmed.) One outbreak of foot antigen and antiserum that have been made available to
infections due to M. chelonae was traced to ajet injector that interested investigators (151).
had been used to administer lidocaine. Between procedures, In contrast to the definitive resolution of M. avium and M.
the injector was held in a mixture of distilled water and a intracellulare as separate species, other recent studies of
quatemary ammonium halide disinfectant (230). mycobacterial semantides have demonstrated that M. lep-
On the other hand, Hoy and colleagues described a raemurium and M. paratuberculosis should both be reduced
pseudoepidemic of M. fortuitum in bone marrow cultures to subspecies of M. avium. M. lepraemurium has long been
(82) which was due to contamination of the specimen from considered a separate species pathogenic for rodents but not
ice used to transport the specimens for viral culture. Those for humans (138). Similarly, M. paratuberculosis has been
authors warn that patients may receive unnecessary chemo- considered a distinct species pathogenic for ruminants but
therapy when unusual organisms are cultured from normally not for humans (127). A 1984 report by Chiodini and asso-
sterile sources if contamination is not ruled out. Not only ciates (29) of the possible role of a mycobactin-dependent
does this place the patients at risk of adverse side effects Mycobacterium species in Crohn's disease led to a burst of
from the unnecessary antibiotic therapy, but it may cause a research on the taxonomy of this organism. In 1987, McFad-
serious delay in determining the actual cause of the illness. den and colleagues (121) described hybridization studies that
demonstrated that the DNA of the isolate from a patient with
MAJOR RECENT DEVELOPMENTS IN THE Crohn's disease exhibited complete homology to that of M.
TAXONOMY OF AND CLINICAL CONDITIONS paratuberculosis and that both were homologous to the
ASSOCIATED WITH SOME COMMONLY DNA of M. avium. M. Iepraemurium as well as the so-called
ENCOUNTERED PPEM wood pigeon bacillus were also confirmed to be synonymous
with M. avium by this criterion (83, 240). The synonymy of
M. avium Complex M. paratuberculosis with M. avium is further supported by
16S rRNA sequence matching (155, 175) and by reaction
The M. avium complex includes M. intracellulare, M. (unpublished data) of the T-catalase from the Linda strain
avium, M. paratuberculosis, M. Iepraemurium, the "wood isolated from a Crohn's disease patient with an antibody
pigeon" bacillus, and a possible new species. probe specific to M. avium catalase (213).
Systematics. (i) Taxonomic status. For many years the DNA restriction fragment length polymorphism (RFLP)
distinction between M. avium and M. intracellulare was analyses yielded patterns that are homogeneous among
blurred, with no phenotypic properties able to provide strains recognized as M. paratuberculosis and distinct from
definitive resolution (224). However, reports on primary, those of M. avium (120, 122). Calculations based on numbers
secondary, and tertiary semantide (244), i.e., DNA, RNA, and sizes of restriction endonuclease fragments demon-
and protein, structural relatedness have confirmed that M. strated a range of only 2 to 3% base substitutions within the
avium and M. intracellulare are distinct species (5, 6, 155, entire group embracing M. avium, M. paratuberculosis, and
164, 211, 213). On the evolutionary scale they are quite M. lepraemurium. DNA from different strains of M. intra-
distant from M. scrofulaceum (5, 155, 209) and, with the cellulare, on the other hand, had a 15% range of base
exceptions -noted below, from other species of mycobac- substitutions (122). Field inversion gel electrophoresis of the
teria. The definitive resolution between M. avium and M. relatively few, large DNA fragments resulting from treat-
intracellulare led to the redistribution of agglutinating sero- ment with the DraI endonuclease further illustrates the
vars between the two species; serovars 1, 2, 3, 4, 5, 6, 8, 9, unique patterns associated with M. paratuberculosis and the
10, and 11 are now assigned to M. avium, and serovars 7, 12, wood pigeon bacillus (109). The unusual level of homogene-
13 14, 15, 16, 17, 19, 20, and 25 are assigned to M. ity of RFLP patterns seen with M. paratuberculosis recov-
intracellulare (5, 164, 211). Serovar 18 appears to cross ered from different host species and geographic regions (27,
species lines: some isolates are M. intracellulare (164), some 231) compared with the heterogeneity seen within most other
are M. simiae (219), and yet others are not assignable to a species led Chiodini to speculate that "this organism has
species (213). Saito and colleagues have reported that most unidirectional genetic selection. It is therefore assumed to be
strains of serovars 22, 23, 26, and 28 that are phenotypically biologically isolated, occupying a unique and specific biolog-
compatible with the M. avium complex do not respond to ical niche" (27). It should be noted that Collins and associ-
nucleic acid probes specific for either M. avium or M. ates have described a second RFLP pattern in some strains
intracellulare (164). These results are compatible with recent isolated from sheep (33). A specific repetitive 0.2-kb se-
results of IWGMT numerical taxonomic and nucleic acid quence has been recognized in the DNA of M. paratubercu-
studies that suggest the existence of a third genospecies losis (33). The 1,451-bp insertion called IS900 that is unique
within the broad phenotypic range encompassing the M. to this species has been sequenced (69), and selected seg-
avium complex (221). ments of this molecule have been used as primers and probes
Wards and colleagues have reported that DNA restriction in polymerase chain reaction procedures to detect M.
endonuclease analysis patterns within the M. avium complex paratuberculosis in clinical specimens (195).
appear to reflect serotypes of strains, but the correlation is In 1988, Saxegaard and Baess proposed nomenclature
imperfect (201). A novel type of hydrophobic catalase, reducing M. paratuberculosis and the wood pigeon bacillus
to subspecies of M. avium (165), but the phenotypic criteria include the recognition of M. avium complex organisms as
for assigning a strain to the resultant subspecies were vague. frequent invaders of patients with AIDS and the isolation of
That proposal was never validated by announcement in the strains of M. avium subsp. paratuberculosis from tissues of
International Journal of Systematic Bacteriology, as re- some patients with Crohn's disease.
quired by the Bacteriological Code (104), so the proposed (i) AIDS. Soon after the recognition of AIDS as a novel
nomenclature is without standing. On the other hand, in clinical entity, it became evident that the characteristic
1990, Thorel and colleagues published the results of a profound suppression of cell-mediated immunity that nor-
numerical taxonomic analysis of these organisms in the mally is the major defense against mycobacterial diseases
journal, identified phenotypic criteria that corresponded to was permitting disseminated mycobacterioses to occur in
the nucleic acid-based divisions, and proposed three subspe- individuals with AIDS (70, 243). Approximately 90% of the
cies, M. avium, subsp. avium, M. avium subsp. paratuber- mycobacterioses in AIDS patients involve either M. avium
culosis, and (corresponding to the wood pigeon bacillus) M. or M. tuberculosis (63, 139). Many other species of PPEM,
avium subsp. silvaticum (182). These names are valid under e.g., M. asiaticum (63), M. flavescens (63), members of the
the Bacteriological Code. M. fortuitum complex (60, 63), M. gordonae (25, 60, 63, 144,
(ii) Identification. Individual clinical isolates can usually be 242), M. haemophilum (115, 156), M. kansasii (63, 78, 144,
identified to the level of M. avium complex by subjective 242), M. malmoense (63), M. marinum (103), M. scrofula-
interpretation of conventional phenotypic properties, as ceum (63, 80), M. simiae (108, 139), M. smegmatis (242), and
noted in the baseline references (205, 224), or, at a quanti- M. xenopi (4, 43, 51, 139), have been implicated in the
tatively defined level of reliability, by use of a computerized remaining 10% of the cases of mycobacterial disease in
probability matrix (223). A DNA probe for the complex is AIDS patients (63).
also available commercially (Gen-Probe, Inc., San Diego, The extraordinary susceptibility of AIDS patients to un-
Calif.). A positive aryl sulfatase test may suggest the pres- controlled infection with PPEM does not appear to be totally
ence of M. intracellulare, but biochemical tests do not determined by the perturbation of the T-cell populations in
provide a definitive resolution of M. avium from M. intra- these individuals. Peters and colleagues (139) have not found
cellulare. Such distinctions can be made by determining the mycobacterial infection in immunosuppressed individuals
agglutinating serovar (64), applying species- rather than who are not infected with human immunodeficiency virus,
complex-specific DNA probes (49, 133, 164), or applying a such as recipients of heart transplants and cancer patients,
panel of cross-absorbed antibody probes to T-catalase in a whose CD4/CD8 ratios were in the AIDS range, and they
dot blot configuration (213). Of the products needed to suggest that the isolation of PPEM is highly correlated with
distinguish between M. avium and M. intracellulare by any a human immunodeficiency virus-related immunosuppres-
of these three tests, only DNA probes are available commer- sion. There also appears to be some level of specificity of
cially (e.g., Accu-Probe, Gen-Probe, Inc; SNAP System, susceptibility to certain strains of mycobacteria in AIDS
Syngene, Inc., San Diego, Calif.) at this writing. Musial and patients. Using species-specific nucleic acid probes, Guth-
colleagues (133) presented a cost analysis of the nucleic acid ertz and colleagues reported that 98% of a series of 45 AIDS
probe technique and noted that considerable savings were patients with disease due to members of the M. avium
made by using the commercially available combined Gen- complex harbored only M. avium, whereas 40% of a series of
Probe M. avium complex probe that does not separate these patients without AIDS yielded M. intracellulare on culture
two species (61). This probe does not appear to react with (72). Furthermore, isolations of M. avium from subjects
members of the new phenotypic cluster in the M. avium without AIDS were more likely to represent colonization
complex described above. On the other hand, a so-called than infection, while the converse was true of M. intracel-
SNAP X probe has been added to the Syngene M. avium lulare in this group. Hampson and colleagues reported that
complex SNAP System. However, since the full phenotypic the DNA from strains isolated from AIDS patients tends to
description and the clinical and epidemiologic significance of exhibit one dominant RFLP pattern, which was distinct from
members of this new cluster are not yet established (llOa, patterns seen with isolates from patients without AIDS or
221), it is questionable whether members of this cluster from stools of healthy control subjects (73). Strains derived
should be represented in a combined M. avium complex from AIDS patients belonged almost exclusively to serovars
probe until it can be determined whether they are of com- belonging to M. avium, but the species or serovar distribu-
parable significance to the two established species. The tion of strains derived from patients who did not have AIDS
T-catalase serological probe offers promise of cost effective- was not reported, so it is not clear whether the homogeneity
ness; dots specific for many different species can all be of the RFLP pattern is simply a function of distribution of
applied to a single strip, which is allowed to react with a isolates between M. avium and M. intracellulare. Plasmids
single sonic lysate of the culture to be identified, thus have been found in all of 26 M. avium strains derived from
minimizing material and labor costs (213). Butler and AIDS patients and in only about one-third of M. avium
Kilburn (20) have also reported that analysis of reverse- complex strains from sources other than AIDS patients (39).
phase high-performance liquid chromatography patterns of Again, the species distribution from these other sources was
p-bromophenacyl esters of mycolic acids derived from the not reported, so the plasmid results may reflect differences in
bacilli permits differentiation of M. avium and M. intracel- distribution between M. avium and M. intracellulare. The
lulare. major serovars associated with mycobacterial disease in
Newer clinical and epidemiological aspects. The range and AIDS patients in the United States are 1, 4, and 8, with
management of clinical conditions associated with M. avium serovar 8 dominant in southern California and serovar 4
and M. intracellulare in individuals whose immune systems dominant in northern California and the eastern United
are not totally compromised have been reviewed thoroughly States (239). The distribution of serovars in Australia resem-
by Wolinsky (234) and will not be recapitulated here. How- bles that in the United States, including regional differences
ever, two developments since the publication of that base- in the relative proportions of serovars 1, 4, and 8. In
line article have led to a major revival of interest in these Sweden, on the other hand, serovar 6 is dominant, followed
organisms and their role in disease. These developments by serovars 4, 9, and 43, but serovar 8 is infrequently seen
(80). Horsburgh and Selik (81) conclude that PPEM infec- recognized as M. avium subsp. silvaticum (182) occur in
tions in AIDS patients are acquired by unpreventable envi- nature and can produce an enteritis identical to Johne's
ronmental exposure, and they emphasize the need for a disease in experimentally infected calves (183).
continuing search for effective chemotherapeutic agents. Mycobactin-dependent strains have been isolated from
Even though extraordinarily high loads of mycobacteria, only a small proportion of the human bowel specimens
ranging up to 106/ml of blood and 10'0/g of tissue (24, 235), examined, and evidence of the presence of other mycobac-
may be encountered in AIDS patients, there is still no terial species has been found in tissues from patients with
general agreement on the extent to which these mycobac- Crohn's disease (59, 67, 241). If Crohn's disease is caused by
teria contribute to the mortality of the patients. That is, M. mycobacteria, it may not be caused by a single species but
avium septicemia is usually a terminal event in AIDS; by any of a number of opportunistic mycobacteria. One or
reported maximal survival time after diagnosis of mycobac- more species of environmental mycobacteria have been
teriosis has ranged from 4 to 7 months (60, 242), but autopsy found in 52% of the cultures from 50 stool samples from
examination usually fails to support this infection as the healthy European volunteers (146). The questions of the
cause of death (97). Bacilli and inflammatory cells were seen relationship between Crohn's disease in humans and Johne's
to replace the adrenal cortex in one patient (97), but in most disease in ruminants and of the role of mycobacteria have
cases the disseminated M. avium complex infections in been reviewed in great detail by Chiodini in a previous issue
AIDS patients do not lead to extensive inflammation, well- of this journal (28).
defined granulomatous processes, or interference with organ
function (24, 179). This is in contrast to infections with M.
tuberculosis or M. kansasii, which do produce these effects NEWLY CHARACTERIZED MYCOBACTERIA OR
in AIDS patients (97, 179). Clinical signs and symptoms MYCOBACTERIAL DISEASES
attributable to the M. avium infection itself are also not
pronounced (24, 129, 242), and there is little evidence that M. asiaticum
chemotherapy has any effect on symptoms or survival (179, Systematics. The first reported strains of M. asiaticum
242). In contrast, chemotherapy of M. tuberculosis infec- were isolated from monkeys and described in 1965, but these
tions in AIDS patients does have a beneficial effect on strains were considered variants of the newly described
survival (179). photochromogenic species M. simiae (94). It was not until
Wayne and colleagues have detected no antibody to any of 1971 that Weiszfeiler and colleagues recognized four of these
the M. avium serovar-specific peptidoglycolipids in the sera strains to be members of a new species and named them M.
of AIDS patients who were proven to be infected with this asiaticum (228). Immunodiffusion studies with both unab-
organism (225), whereas patients without AIDS but with M. sorbed and cross-absorbed sera confirmed that M. asiati-
avium complex infections, as well as some individuals with- cum, although biochemically similar to M. simiae and M.
out demonstrable disease due to these organisms, do exhibit gordonae, is distinct from these two species (93). Similarly,
antibody to the serovar-specific peptidoglycolipids (206). Baess and Magnusson demonstrated the unique antigenic
Barrow and colleagues (11) have speculated that the super- identity of the type strain and one more of the original
ficial fibrillar, serovar-specific peptidoglycolipid sheath Weiszfeiler strains of M. asiaticum by reciprocal intradermal
around cells of M. avium shields the bacilli from host sensitin testing in guinea pigs, distinguishing the strains by
lysosomal enzymes. This raises the question of whether that this means from M. avium, M. intracellulare, M. kansasii,
same sheath may not also protect the host from toxic effects M. marinum, and M. simiae (6). They also demonstrated
of the bacteria. The differences in pathology between infec- very low DNA homology between M. asiaticum and M.
tions with M. tuberculosis and M. avium in AIDS patients simiae, but did not compare M. asiaticum with M. gordo-
might be due to differences in the topologic accessibility of nae. In 1988, Imaeda and colleagues demonstrated <60%
sulfatides and cord factor and the toxic responses thereto DNA homology between M. asiaticum and 16 other myco-
(13, 136), whereas in individuals with reasonably functional bacterial species, including M. simiae, M. gordonae, and M.
immune systems the immunologic component of the patho- szulgai (86). Wayne and Diaz used cross-absorbed antisera
genesis of both organisms might be the dominant determi- to mycobacterial M-catalase to distinguish M. asiaticum
nant of pathology. from M. gordonae, M. scrofulaceum, M. simiae, and M.
A voluminous literature on mycobacterial disease in AIDS szulgai (210). Using unabsorbed sera, they also generated an
patients has emerged since the first reports of this phenom- evolutionary divergence tree based on measurements of
enon, and it is beyond the scope of this paper to review all of immunologic distance between T-catalases, upon which tree
it. The reader is referred to several comprehensive articles M. asiaticum occupied a unique site (209). A similar tree was
from this and other journals (34, 81, 97, 129, 177, 242) for generated by Stahl and Urbance, who used 16S rRNA
additional information. similarity scores. On their tree, M. asiaticum branched close
(ii) Crohn's disease. Crohn's and Johne's diseases are both to its nearest neighbor, M. gordonae, but at a site sufficiently
inflammatory bowel diseases, Johne's disease occurring in distant to justify its status as a separate species (175).
cattle, sheep, and goats and Crohn's disease occurring in From the foregoing information it is evident that primary,
humans. An etiologic role for mycobacteria in Crohn's secondary, and tertiary semantide data (244) present con-
disease has long been the subject of speculation, but interest vincing evidence that M. asiaticum is a phylogenetically
was revived by the isolation of mycobactin-dependent my- distinct species. This is also reflected in its phenotypic
cobacteria from the bowel tissue of Crohn's disease patients clustering behavior in a numerical taxonomic analysis by the
(28, 29). As noted above, these organisms have been identi- IWGMT (220). Nevertheless, this cluster of 11 strains exhib-
fied conclusively as M. paratuberculosis, which is the agent ited considerable phenotypic overlap with M. gordonae,
of Johne's disease and which has been reduced to the status and, of most concern, there is only one easily determined
of a subspecies, M. avium subsp. paratuberculosis (122, property by which these two species can be distinguished
240). Other mycobactin-dependent strains of M. avium pre- from one another in a routine diagnostic laboratory: M.
viously designated wood pigeon bacilli but now validly gordonae is consistently scotochromogenic and M. asiati-
TABLE 1. Key features for distinguishing between phenotypically similar species of mycobacteria of comparatively high and low
clinical significance
Reaction'
Catalase
Mycobacteria Tween
>45
Nitrate 3-Galac- Aryl sul- Acid
Pigment hydrolysis Resists reduced tosidase fatase phospha- Urease
(10 days) mm
of foam 68C(10
6'
days) tase
M. malmoense None + - V - - - - V
M. shimoidei None + - + - - - +
M. gastri None + - - - - + + +
M. terrae complex None + + + V + V +
M. avium complex None - - V - - V
M. asiaticum P + + + - - V +
M. gordonae S + + + - - V V
M. szulgai S V + + + - - + +
Mycobacterium spp. (?), S V - +
"cluster 7"
a Symbols: +, -85%; -, u15%. V, 16 to 84% positive; P, photochromogenic; S, scotochromogenic.
cum is photochromogenic. In other respects, both species there but moved to southern Queensland, and one lived
hydrolyze Tween 80, have high catalase activity, and are about 600 km north of the area. They also noted that the
negative for urease and nitrate reduction (220, 224) (Table 1). monkeys from which the original strains of M. asiaticum
Distinction between these species is very important, since described by Weiszfeiler and colleagues (228) were isolated
M. gordonae is a common contaminant in clinical specimens had been imported to Hungary from India, which has a
but is rarely, if ever, clinically significant (see the discussion subtropical climate similar to that of Queensland. In the two
of this species in a later section of this review), whereas M. reports from the Centers for Disease Control on PPEM in the
asiaticum is not commonly encountered but, when it is United States in 1979 and 1980, two and four isolates,
recovered, is often the cause of the patient's disease (15). respectively, of M. asiaticum were reported (62, 65). There
Although M. szulgai is scotochromogenic when grown at was no mention of the clinical significance of these isolates,
37°C, it may exhibit photochromogenicity at 25°C and might and all were from the southeastern United States. In addi-
be confused with M. asiaticum. However, M. szulgai exhib- tion, Good (63) reported that, of 192 PPEM isolated from
its urease- and nitrate-reducing activities, which distinguish AIDS patients and identified by the Centers for Disease
it from M. asiaticum (205). Control, only 1 was M. asiaticum.
Clinical and epidemiologic aspects. The first published Blacklock and colleagues (15) concluded that the Austra-
report of M. asiaticum associated with human pulmonary lian patients benefited from antituberculosis therapy, which
disease did not appear until 1983 (15). M. asiaticum was included isoniazid, rifampin, ethambutol, pyrazinamide, ca-
isolated from pulmonary specimens of five Australian pa- preomycin, p-aminosalicylate, and/or streptomycin. There
tients. Two of these patients met the criteria for the diagno- are no detailed data on the antimicrobial susceptibility of M.
sis of pulmonary mycobacteriosis: chest roentgenograms asiaticum to conventional antituberculous agents. In a sur-
showed extension of old lesions and development of cavi- vey of the antimycobacterial activity of new quinolones,
ties, positive identification of M. asiaticum was made, and Leysen and colleagues (110) have reported that M. asiaticum
no M. tuberculosis was isolated. Both of these patients were is less susceptible than other mycobacteria to ciprofloxacin
male, aged 57 and 69 years, and both had smoked 20 and ofloxacin (MICs, 4 to 16 ,ug/ml).
cigarettes a day for at least 30 years. The 69-year-old patient
had undergone partial gastrectomy for peptic ulcer 23 years
before the diagnosis of mycobacteriosis, and he also had M. haemophilum
chronic bronchitis and emphysema. The other three pa-
tients, from whom the M. asiaticum cultures appear to have Systematics. M. haemophilum was first isolated, de-
been only casual isolates, were female, aged 48, 54, and 55 scribed, and named in 1978 by Sompolinsky and colleagues
years. All had chest roentgenograms demonstrating lesions (173). The description is limited because this species is very
compatible with mycobacterial disease, but they exhibited fastidious and yields few positive reactions in conventional
no progression of disease, and the authors concluded that tests for characterizing the slowly growing mycobacteria.
the repeated isolates of M. asiaticum represented chronic The description in Bergey's Manual (224) is still applicable:
secondary colonization of areas of damaged or poorly drain- M. haemophilum is a slow-growing nonpigmented Mycobac-
ing lung tissue. This interpretation is compatible with obser- terium species that requires hemin (173) or ferric ammonium
vations by Wayne and colleagues (206) that individuals with citrate (47) for growth, has little or no catalase activity, does
prior pulmonary lesions commonly exhibit antibody reac- not hydrolyze Tween 80, and gives positive reactions for
tions to several different serovars of PPEM, suggesting a nicotinamidase and pyrazinamidase but not urease. This
predilection to mycobacterial colonization. description suggests that the organism may be a fairly inert
Epidemiologically, Blacklock and colleagues suggested or fastidious subspecies of M. avium, analogous to what has
that the infecting strains most likely came from the Austra- recently been reported for M. paratuberculosis and M.
lian environment (15). Three of the patients lived in the same lepraemurium (83, 240), but this has not yet been demon-
general area near the Tropic of Capricorn, one was born strated by studies of semantides. Agglutination serotyping of
strains from both Israel and Australia indicates a single 37°C, but no mycobacteria were isolated. The acid-fast
common serotype for M. haemophilum (47, 174). bacteria seen on stained sections of tissue were assumed to
Clinical and epidemiologic aspects. M. haemophilum was be mycobacteria because of their morphology, but the
first recognized in 1978 in Israel in pus samples from a growth requirement of M. haemophilum for iron-containing
patient with Hodgkin's disease who had generalized skin products was not known at that time. Isoniazid, streptomy-
granulomata and subcutaneous abscesses. In 4 months, the cin, and p-aminosalicylate, singly or in combinations, were
few nodules increased to more than 30 lesions. Acid-fast used, often accompanied by surgical excision. It was difficult
rods with an optimum growth temperature of 30°C and a to determine which therapy worked, but all lesions healed.
growth requirement for hemoglobin or hemin were de- In retrospect, this miniepidemic among individuals who
scribed. M. haemophilum was characterized in vivo by were not known to be immunologically compromised may
exclusively intracellular development (174). reflect a relatively benign manifestation of M. haemophilum
Of ten additional cases that were reported between 1979 infection, which may be more common than is recognized
and 1983, eight were in female renal transplant patients 32 to and simply not diagnosed, since diagnosed infections with
58 years of age; seven of these women were from Australia
(1, 128, 132, 160), and one was from Cleveland, Ohio (45). the organism have been reported over a broad geographic
The two nontransplant cases were from Australia and in- range. Of special interest in this regard is a comparison of the
volved a 58-year-old male with lymphocytic lymphoma (128) age and sex distribution of specifically diagnosed cases in
and a 1-year-old, otherwise healthy child who developed immunocompromised individuals with that of the earlier
submandibular lymphadenitis (48). In 1985, M. haemo- cases of unproven etiology. Among 12 patients (excluding
philum was isolated in Europe from a 48-year-old male renal the AIDS patients) for whom M. haemophilum was demon-
transplant patient with cytomegalovirus infection (16), and in strated to be the cause of serious disseminated disease (1, 16,
1987 and 1988 it was isolated from three AIDS patients (115, 45, 48, 128, 160, 173, 233), 9 were females between 32 and 55
156), one in New York and two in Maryland, respectively. A years of age. Eight of these women had undergone renal
special awareness of M. haemophilum in Australia, stimu- transplants and the other suffered from lymphoma (Fig. 1A).
lated by the early case reports and studies on growth Of the three males, one was a "healthy" infant, and the
requirements undertaken in the State Department of Health other two were in the same age range as the females and had
Laboratory in Queensland (47, 48, 128), may be the reason lymphoma or a renal transplant. In contrast to the over-
this organism was recognized more frequently in that region. whelming predominance of immunocompromised females in
However, as Branger and colleagues have pointed out, the the middle-age range in the group of patients with confirmed
organism is ubiquitous (16). disseminated M. haemophilum is the bimodal distribution
Skin lesions are usually disseminated and most often seen among the nonimmunocompromised individuals with
involve the extremities. Clinical presentation of reported limited disease due to noncultivable mycobacteria (52) in the
cases include nodular skin lesions on the extremities (1, 16, northern United States and Canada (Fig. 1B). In that group,
45, 115, 128, 132); "infective lesions" on the breasts (128), approximately half of the limited skin infections in females
face (16), and abdomen (1); ulcers showing caseating inflam-
mation and positive synovial fluid cultures (1); multiple occurred before the women were 30 years old (and predom-
erythematous cutaneous lesions (115, 156); and suppurating inantly at age 15 or less), and an almost identical distribution
submandibular lymphadenitis (48). Acid-fast bacilli have was seen among young males and females. A marked second
been demonstrated in the lesions that have also been char- cluster of cases was seen among otherwise healthy females
acterized by necrosis, neutrophilic infiltrates (156), and after age 50, but no cases of male patients were seen in this
Langhan's giant cells (128). age range. Furthermore, a recent report describes the devel-
The lesions take months or years to heal; whether the opment of a localized skin lesion, culturally proven to be
eventual improvement is due to drug combinations or to the associated with M. haemophilum, in a nonimmunosup-
patient's improved immune function is still not clear. Strep- pressed 65-year-old woman (119). The lesion had developed
tomycin, ethambutol, isoniazid, p-aminosalicylate, rifampin, after cardiac bypass surgery and responded well to 5 months
ethionamide, and pyrazinamide have all been used in various of ciprofloxacin therapy. The data suggest that pre- or early
combinations (16, 45, 115, 128, 156, 160, 173). In one case, adolescents of either sex are somewhat susceptible to a mild
the patient improved simply by the reduction in dosage of and limited form of skin infection with a fastidious Myco-
the immunosuppressive drugs (1). bacterium species and that hormonal changes in mid-life
In their review in 1987, Woods and Washington (238) might reactivate this limited susceptibility in females. If the
concluded that recommendations on treatment cannot be fastidious Mycobacterium species in the northern United
made until more experience with infection due to M. hae- States/Canada episode was indeed M. haemophilum, then a
mophilum has accumulated. Antibiotic susceptibility pat- comparable type of infection might have been a precursor
terns have been difficult to assess (132), and Branger and condition in the patients documented in Fig. 1A, and the
colleagues have pointed out a need for standardization of superimposition of severe immunosuppression could ac-
methods (16). However, in most reports (16, 45, 47, 48, 115, count for the selective exacerbation and dissemination of a
128, 132, 156, 160, 173), M. haemophilum is described as fairly benign infection in these women. Infection with M.
susceptible to rifampin, p-aminosalicylate, or both and re-
sistant to isoniazid, streptomycin, ethionamide, pyrazina- haemophilum should be considered in any individual who
mide, and ethambutol. Rapid recovery has occurred when develops unexplained skin lesions in which noncultivable
surgery was performed (16, 48). acid-fast organisms are demonstrated. To diagnose these
In 1974, Feldman and Hershfield (52) reported on a cluster infections and provide insight into their distribution, all
of skin infections apparently caused by "noncultivable" specimens derived from skin lesions that contain acid-fast
mycobacteria in patients from the northern midwestern bacilli should be inoculated routinely to media containing
United States and southern Manitoba, Canada. Biopsy spec- ferric ammonium citrate (FAC) or hemin and incubated at
imens were cultured for mycobacteria and fungi at 25 and 30°C for at least 10 weeks.
20 A media. Growth can be accelerated and diagnostic detection

can be improved by supplementing the conventional media
with two modifications of Lowenstein-Jensen (LJ) medium,
oMale one adjusted to a pH between 6.0 and 6.5 and the other
*Female substituting 0.4% sodium pyruvate for the glycerol normally
used (96). M. malmoense is extensively described in
Bergey's Manual (224). In a subsequent report by the
12-
IWGMT (220), the numerical taxonomic cluster correspond-
ing to M. malmoense exhibited a mean internal matching
10.
score of 86.5% and matching scores of 79.9% or less to any
other cluster. Similarly, they exhibited a mean matching
lo score of 87.8% to the type strain of M. malmoense and
matching scores of 78.1% or less to any of the other 18 type
6 strains examined.
M. malmoense exhibited shallow branching separation
4- from M. szulgai in an evolutionary tree based on structural
divergence of 16S rRNA and was well separated from all
other species examined (154). Cross-absorbed antiserum to
0 M-catalase from M. szulgai failed to precipitate M-catalase
from M. malmoense (210). Furthermore, M. malmoense is
phenotypically distinct from M. szulgai, with a mean match-
-J r
0% a ing score of only 70.6% between the two species clusters and
a mean matching score of only 69.6% to the type strain of M.
szulgai (220).
0 (ii) Identification. Although well separated from M. shi-
16 moidei on the numerical taxonomic matrix, M. malmoense is
distinguished from M. shimoidei by only one feature, acid
14- phosphatase, in the short list of tests that are most com-
monly used to identify mycobacteria (Table 1). The seroag-
12- glutination and thin-layer chromatography patterns do not
appear to be reproducible enough for routine identification
10- -0 (220). Rogall and colleagues have reported that M. mal-
moense can be identified by determining the base sequence
a- v of a selected region of the rRNA gene after amplification by
6_
'K
f
polymerase chain reaction (154), but that technique depends
on the availability of the appropriate primers and the tech-
4-
nology to perform the assay, and sequence information is not
yet available for M. shimoidei. At this time, it is not possible
2 to assess the clinical importance of being able to distinguish
between M. malmoense and M. shimoidei, since the two
0- I I I I I I . appear to be of comparable clinical significance and the latter
0 10 20 30 40 50 60 70 80 90 species has been so rarely encountered. On the other hand,
AGE AT DIAGNOSIS
it is especially important that enough tests be performed to
distinguish between M. malmoense and the commonly en-
FIG. 1. Age and distribution of patients with skin lesions due
sex countered nonpathogenic M. gastri and members of the M.
to M. haemophilum noncultivable mycobacteria. (A) Patients
or terrae complex. Simple reliance on pigment, growth rate,
with disseminated skin lesions from which M. haemophilum was and Tween hydrolysis could lead to an isolate of M. mal-
isolated and then cultivated on medium containing hemin or FAC (1, moense being dismissed as one of these nonsignificant or-
16, 45, 48, 128, 160, 173, 233). (B) Patients with localized skin
lesions in which acid-fast bacilli could be seen microscopically but ganisms, and at least the full set of tests listed in Table 1 is
could not be cultured (52). These cases were reported before the recommended.
iron-requiring species M. haemophilum had been recognized. Clinical and epidemiologic aspects. The seven strains of
PPEM isolated in Sweden between 1968 and 1970 and later
named M. malmoense were recovered from four patients
M. malmoense with clinical and roentegenological signs of pulmonary my-
cobacteriosis (167). The cultures were recovered from pul-
Systematics. (i) Taxonomic status. In 1977, Schroder and monary secretions or from lung biopsies, and no other
Juhlin described seven strains of clinically significant, non- mycobacteria or other pathogens were isolated from the
pigmented, slowly growing mycobacteria that were distin- patients. The strains were susceptible in vitro to ethambutol,
guished from members of the M. avium complex by differ- ethionamide, kanamycin, and cycloserine and resistant to
ences in their reactions to tests for hydrolysis of Tween 80, isoniazid, streptomycin, rifampin, p-aminosalicylate, viomy-
phosphatase, esterase, and heat-resistant catalase. They cin, thiosemicarbazone, and capreomycin.
named these strains M. malmoense (167). They gave unique Reports of infections with M. malmoense were sparse
seroagglutination reactions and lipid thin-layer chromatogra- over the next decade. However, the Mycobacterium Refer-
phy patterns. These clusters grow just below the surface of ence Unit in Cardiff, Wales, had been keeping records of
semisolid media in a manner similar to that seen with M. PPEM isolations since 1952, and, in retrospect, Jenkins and
bovis (162) and grow poorly on conventional mycobacterial Tsukamura concluded that 61 strains of what is now recog-
nized as M. malmoense had been seen between 1952 and mised individual occurred in a 48-year-old female leukemia
1979 (90). A steady increase in incidence of disease due to patient in Ireland (57). This infection initially manifested
that organism in England and Wales began in 1981, when 5 itself as fever, night sweats, anorexia, lethargy, and weight
cases of pulmonary infection and 1 case of cervical adenitis loss associated with an enlarged necrotic supraclavicular
were reported, and reached a plateau by 1986, with an lymph node, in which acid-fast bacilli were demonstrated,
average of 34 cases of pulmonary infection and 12 cases of and some noncaseating granulomas in the liver. A presump-
cervical adenitis per year from 1986 through 1989; in addi- tive diagnosis of tuberculosis was made, but the patient
tion, the incidence of single isolations of this organism failed to respond to treatment with rifampin, isoniazid, and
reached 40 to 50 per year (88a, 89). Jenkins (88a) also has pyrazinamide. After 6 months of this treatment, multiple
advised us that, if one excludes M. avium infections in AIDS skin nodules developed on her limbs and torso. Biopsies
patients, M. malmoense is as common as members of the M. yielded M. malmoense on culture, and ultimately a thera-
avium complex and M. xenopi in Great Britain, but not as peutic regimen of ethambutol and cycloserine led to resolu-
common as M. kansasii. The increased awareness and tion of the condition. Elston described a cold abscess due to
consequent recognition of infections due to this organism in M. malmoense that developed at the site of a successfully
Britain led to a symposium in 1985 in which incidence, treated Staphylococcus aureus abscess in the hand of a
characterization, and treatment of the disease were reviewed diabetic individual, which was possibly associated with a
(7, 36, 89, 152). Most of the recognized infections repre- hydrocortisone injection (50). The lesion responded slowly
sented pulmonary disease, but there was also a very striking to treatment with rifampin, isoniazid, and pyrazinamide.
rise in the incidence of M. malmoense-associated cervical Two common threads run through the clinical reports of
adenitis in children and an increasing occurrence of single M. malmoense infections: (i) the difficulty in making the
isolates from sputum in adults (89). Between 1982 and 1984, diagnosis because of the slow growth of the organism and the
20 cases of pulmonary disease due to M. malmoense were possibility of its confusion with other mycobacteria (89) and
reported in Scotland, a country with only one-tenth the (ii) the poor correlation between in vitro drug susceptibility
population of England and Wales (55). These cases were results and clinical response to chemotherapy (8). Using
associated with chronic obstructive pulmonary disease, as specially modified medium, as discussed above, and holding
were those reported from the Cardiff laboratory (90), but in the cultures for 12 weeks before discarding them (90) should
contrast to the patients in the Cardiff studies, the Scottish enhance the recovery of M. malmoense from clinical speci-
patients did not have pneumoconiosis. mens, and application of the full battery of tests listed in
Between 1982 and 1985, the Cardiff laboratory identified Table 1 will improve the chances of correctly identifying it.
five strains of M. malmoense received from laboratories in Of some interest in this regard is a report of a novel primary
Ireland, five strains from Switzerland, and one strain from pulmonary infection attributed to a member of the M. terrae
Holland (89). Two cases of pulmonary infection were re- complex (98). The description of the organism included in
ported from Germany in 1982 (168). Two cases of M. that report includes a low catalase response, which is
malmoense cervical adenitis in children had been diagnosed characteristic of M. malmoense but not of members of the
in Finland by 1986 (95). The sources of infections with M. M. terrae complex; all other reported properties were com-
malmoense in nature have not been established; Portaels and patible with both members of that complex and M. mal-
colleagues have isolated this organism from the stool of 1 of moense. A subculture of that strain has been made available
50 healthy European volunteers (146). to us, and an extract of that culture exhibited a T-catalase
The isolation of M. malmoense was reported twice in the band on electrophoresis (212), which is not characteristic of
United States in 1979 (62) and 12 isolations were reported in the M. terrae complex; that T-catalase reacted strongly to an
1980 (65), the latter corresponding to 0.03% of the total antibody we have prepared to the T-catalase of M. mal-
number of reported isolates of PPEM. No particular regional moense. This case appears to have been due to a strain of M.
distribution of these isolates was seen, and no information malmoense that was misidentified as a member of the M.
was presented on the actual clinical significance of these terrae complex.
strains. In 1984, a case of pulmonary disease caused by an The selection of appropriate regimens for treatment of M.
organism confirmed to be M. malmoense was documented in malmoense is still somewhat problematic; a clear correlation
a 43-year-old man in the United States (202). Three years between in vitro susceptibility to chemotherapeutic agents
later, Alberts and colleagues reported two more confirmed and clinical response has not been established (7). Banks and
and one suspected case of pulmonary disease due to M. colleagues in Cardiff (7) reviewed the responses to chemo-
malmoense in the United States, as well as one case that was therapy of 34 patients in whom M. malmoense was consid-
considered to represent pulmonary colonization rather than ered the agent of pulmonary disease. Preexisting lung dis-
infection (2). The confirmed cases involved a 58-year-old ease was present in 22 patients, and 4 patients had received
woman whose disease responded to 11 months of treatment immunosuppressive therapy. Various combinations of drugs
with ethambutol and rifampin and a 72-year-old woman who had been used, but the best results were obtained with
responded to 8 months of treatment with isoniazid, etham- triple-drug chemotherapy consisting of rifampin, isoniazid,
butol, and rifampin, even though in vitro tests indicated that and ethambutol, even though the cultures were resistant in
her organism was resistant to these agents. Disease due to vitro to isoniazid. Omission of ethambutol, to which most
PPEM is not reportable in the United States, but O'Brien strains exhibited in vitro susceptibility, or discontinuation of
and colleagues conducted a survey among state and large- therapy after <18 months was associated with an unsatis-
city laboratories for the period from October 1981 through factory response. Resectional surgery was successfully per-
September 1983 and recorded four (0.07%) isolations of M. formed in four patients, but the failure of chemotherapy and
malmoense among a total of 5,469 PPEM reported (135). the need for surgery were probably the result of poor
In 1985, 1 strain of M. malmoense was reported among compliance with the prescribed drug regimen. Three patients
approximately 200 strains of PPEM causing disseminated who died of their pulmonary M. malmoense disease had not
disease in AIDS patients in the United States (63). Another started on chemotherapy until they had reached the terminal
M. malmoense infection in an immunologically compro- stages of illness. Barclay and colleagues (10) reported on a
patient who did not present for diagnosis of M. malmoense and rifampin, so the initial therapy was changed to strepto-
pulmonary disease until her left lung was almost destroyed. mycin and isoprodian when the organism was identified.
Even after a year of appropriate triple-drug therapy, the After 14 days of chemotherapy, the smears became negative,
disease continued to progress, and a pneumonectomy was and in 6 weeks, the cultures were negative. Rusch-Gerdes et
performed to save the patient's life. Continued chemother- al. suggest that the silicotic changes of the lungs favored the
apy led to a satisfactory resolution. France and colleagues infection and that the infection can be controlled by the
(55) surveyed results of treatment of M. malmoense pulmo- combined treatment described (159). Leysen and colleagues
nary disease in 20 patients in Scotland, with results that (110), studying the activity of new quinolones against myco-
agreed with those of the Cardiff group: ethambutol was an bacterial infection, reported that most strains of M. shimoi-
important component of a triple-drug regimen, and treatment dei were inhibited by ciprofloxacin and ofloxacin at concen-
failure or relapse were associated with use of too short a trations of about 1 to 2 ,ug/ml.
course of therapy with a regimen that included this agent. Although very few cases of this infection have been
White and colleagues (232) reviewed 19 cases of lymphad- reported, the wide geographic spread of known cases indi-
enitis due to PPEM, 5 of which were caused by M. mal- cates that M. shimoidei may be recognized more frequently
moense. In this series, chemotherapy was not effective, and throughout the world as awareness of the species and
total excision was the treatment of choice. However, in only familiarity with its few distinguishing characteristics in-
one case was ethambutol included and, even then, only for 1 crease. It is especially important that clinical microbiologists
month; the other drugs were isoniazid and rifampin. The recognize that use of a very limited number of diagnostic
unsatisfactory result with this regimen in lymphadenitis thus tests could lead to members of this species being confused
agrees with that seen in pulmonary disease. with the nonpathogenic members of the M. terrae complex,
resulting in a missed diagnosis.
M. shimoidei
SPECIES OF MYCOBACTERIA GENERALLY
Systematics. The original description and proposal of the CONSIDERED TO BE NONPATHOGENIC
name M. shimoidei were based on seven isolates, all from
the same patient, in Japan over the 11 years from 1962 to A few species of slowly growing mycobacteria, such as M.
1973 (193). The name lost standing when it was not included gastri, M. gordonae, members of the M. terrae complex (M.
in the "Approved Lists of Bacterial Names" (171), but the terrae, M. nonchromogenicum, and M. triviale), and most
IWGMT presented evidence based on cultures from the rapidly growing mycobacteria other than members of the M.
original patient and an additional culture from a patient in fortuitum complex discussed above, are so rarely associated
Australia that supported revival of the name (218); it was with human disease that they may reasonably be considered
formally revived in 1982 (186). It was not until 1988 that nonpathogens, rather than PPEM. Nevertheless, occasional
DNA homology studies that confirmed the status of M. reports do seem to implicate one of these organisms as an
shimoidei as a distinct species were published (86). By 1989, etiologic agent of a human infection. While it is conceivable
strains representing five different source patients had been that any Mycobacterium species could cause lesions under
described: the original clinically significant one from Japan, very special circumstances, careful review suggests that a
two from Australia (only one of which was considered significant proportion of the rare reports of infections attrib-
clinically significant), one from Mississippi of unknown uted to nonpathogenic mycobacteria are not well enough
significance (220), and one from a patient in Germany (159). documented to represent convincing evidence of their au-
The numerical taxonomic cluster that included the type thenticity. A review of the nonpathogenic species and of
strain of M. shimoidei exhibited a mean internal matching reports of infections attributed to them will be presented in
score of 86.5% and a mean matching score of 77.5% to the this section.
most closely related cluster, that of M. malmoense (220). It
had a matching score of 72.5% or less to clusters represent- M. gastri
ing any other recognized species. Despite the phenotypic
separation of the two clusters on numerical taxonomic Systematics. The phenotypic description and criteria for
analysis, only one of the more easily performed differential identification of M. gastri remain as described in the baseline
tests listed in Table 1, that for acid phosphatase, distin- references (205, 224). However, as discussed above in the
guishes M. shimoidei from M. malmoense (205, 220). M. section on M. kansasii, the 16S rRNA studies (155) and
shimoidei can be differentiated from the generally nonsignif- T-catalase serology (209) suggest that M. gastri, a nonpig-
icant members of the M. terrae complex on the basis of mented, slowly growing Mycobacterium species that clus-
catalase and P-galactosidase reactions. ters separately from M. kansasii on a phenotypic basis (207),
Clinical and epidemiologic aspects. The first reported iso- may be so closely related to the latter that M. gastri might be
lation of M. shimoidei was from a 56-year-old male patient in considered a subspecies of M. kansasii; this has never been
Japan in tuberculosislike cavitary lesions in the lungs that formally proposed and needs further study. The distinction
ultimately proved fatal (193). The second reported strain was between the two is important because of major differences in
isolated from sputum and was considered the cause of a their relative clinical significance.
patient's pulmonary disease in Australia (218). In 1985, Clinical and epidemiologic aspects. M. gastri is not fre-
Rusch-Gerdes and colleagues (159) reported the first case in quently encountered in the clinical laboratory. Good and
Germany of lung disease caused by M. shimoidei. The Snider recorded only 106 reports of isolation of this species
79-year-old German patient had an occupational disease, in the United States in 1980, in contrast to 1,133 isolates of
silicosis, for more than 30 years. His disease progressed, and M. kansasii (65). We have found reports of only three cases
the cavities enlarged. M. shimoidei was isolated from the of disease attributed to this organism. It was isolated in small
sputum 14 times, and M. tuberculosis was never isolated. numbers (only two colonies) from the peritoneal fluid of a
This patient was originally treated with isoniazid, protiona- symptomatic peritoneal dialysis patient, but larger numbers
mid, and rifampin. The organisms were resistant to isoniazid of acid-fast bacilli were detected on microscopic examina-
tion of fluid (liOb). Two cases of pulmonary disease have in AIDS patients, only one strain was clearly identified as
also been attributed to M. gastri (41). In none of these having been isolated from bone marrow and sputum (236),
reports were details given on the properties used to distin- and the limited description of the strain presented no reason
guish M. gastri from M. malmoense, which it closely resem- to doubt the identification. Of the remaining cases, no details
bles. were given to prove that the organism was involved in the
disease process for five cases (63, 242); no colony counts
M. gordonae were indicated, nor were any descriptions given of the
organism itself. In the remaining five AIDS cases, the
Systematics. The systematics of M. gordonae remain as scotochromogen was not described and was obtained in
described in the baseline references (205, 224). The 16S mixed culture with members of the M. avium complex from
rRNA sequence comparisons demonstrate a definite separa- sputum (242), so its role in the disease process is not clear.
tion between M. gordonae and M. asiaticum (175) and an We also reviewed reports of 17 cases in patients who did
even greater separation between the branch upon which not have AIDS. Of two patients with lung lesions attributed
these two species lie and the branches of all other named to M. gordonae, one yielded multiple isolates of the organ-
species (155). However, strains of scotochromogenic, slowly ism from sputum (31), but the strain was not described in
growing mycobacteria that hydrolyze Tween 80 and cluster detail; in the other patient, the strain was isolated from a
separately from M. gordonae on a phenotypic basis have resected nodule (35) and was urease positive, which is very
recently been recognized but not named (220, 221). Scrupu- unusual for M. gordonae. Four isolations from pleural
lous attention to biochemical properties and probe responses effusions have been reported (71): two associated with
is essential to permit these organisms, which are often malignant disease, one associated with congestive heart
associated with disease, to be distinguished from M. gordo- failure, and the other of unknown origin but which resolved
nae, which is rarely, if ever, pathogenic. Most of the strains without treatment. Although the colony counts were tabu-
in the "new" cluster of scotochromogens exhibit low cata- lated as "innumerable," which normally implies very large
lase activity and positive reactions for nicotinamidase and numbers, a footnote indicated that the organisms were
pyrazinamidase, behavior that contrasts with that of M. recovered in liquid medium, so actual counts were not
gordonae. A nucleic acid probe specific for M. gordonae is determined; the authors were doubtful of the significance of
available commercially (Gen-Probe), and a cross-absorbed these isolations, and the organisms themselves were not
antibody probe specific for the M-catalase of M. gordonae described. Of three reports of bone or joint disease, one
has also been described (210). report involved a patient with osteomyelitis from whose pus
Clinical and epidemiologic aspects. M. gordonae is ex- both S. aureus and M. gordonae were isolated and whose
tremely common in the environment; in a survey of PPEM lesions were cured with oxacillin alone (117). A second case
isolated from clinical specimens in the United States in the involved the olecranon bursa, and isolation of an unreported
year 1980 alone, 6,007 (30%) of 19,977 strains of PPEM number of colonies of the Mycobacterium species followed
reported were identified as M. gordonae (65). The only treatment of an S. aureus infection at that site; the Myco-
mycobacteria of comparable prevalence were members of bacterium strain was not described (113). The third case was
the M. avium complex, which accounted for 35% of the a spreading synovitis from which an unreported number of
isolates. In contrast to the M. avium complex, for which colonies of the scotochromogen was recovered (14); the
about half of all isolates have been interpreted as disease lesions responded to treatment with rifampin plus ethambu-
associated (135), we are aware of fewer than 50 cases of tol, suggesting that the Mycobacterium strain was the cause
human disease reported to be attributable to M. gordonae of the lesions, but no description of the culture was provided
over a 20-year period. For an organism of such widespread to permit judgment of the accuracy of the identification of M.
prevalence in the environment to be implicated in so few gordonae. Of three soft tissue infections reported, two
significant infections, the bacillus must have an extraordi- yielded an undisclosed number of mycobacterial colonies
narily low pathogenic potential. Furthermore, given that low and the organism was not described (21, 170). In the third
a potential, one must question the authenticity of even the case, infection in a foot wound spread to the wrist, and the
few clinical cases that have been described. Contaminated same scotochromogenic Mycobacterium species was recov-
water supplies and ice machines have been proven to be the ered from both sites (123). The organisms from both sites
sources of "pseudoepidemics" of M. gordonae caused by were described as giving identical lipid thin-layer chroma-
exogenous contamination of clinical specimens or specimen tography patterns "similar" to that of M. gordonae and were
sources (137, 176). urease positive. In one patient who had received long-term
Two questions must be asked in assessing a report of steroid therapy for asthma, multiple skin nodules developed.
disease due to any PPEM, but they are especially critical in The biopsy sample of one yielded a scotochromogen that
reports of M. gordonae infections. First, has enough of a produced a thin-layer chromatography pattern "resembling"
description been provided to ensure that the isolated organ- that of M. gordonae; the organism grew only in a pH range
ism really is M. gordonae? Second, how convincing is the of 5.8 to 6.1, much narrower than the range seen with
evidence that the isolated organism really is playing a role in authentic strains of this species (58). One case of chronic
the disease process? keratitis was reported. A biopsy sample from this patient
After reviewing seven papers describing 10 putative cases yielded only one colony of an undescribed scotochromogen,
of M. gordonae infections (7 pulmonary, 2 of bone or joint, simply cited as M. gordonae (130). Visceral infections have
and 1 of a prosthetic heart implant) published between 1970 been described in four individuals. One patient in whom a
and 1981, Tsukamura concluded (189) that none of these ventriculoperitoneal shunt had been in place for 9 years
reports provided sufficient evidence to prove either that the following brain tumor surgery and who had received chemo-
organism isolated was M. gordonae or that the organism therapy for metastases developed disseminating noncaseat-
isolated was the cause of the patients' disease. In reviewing ing granulomas (194). A scotochromogen, not described but
18 subsequent reports on 28 cases, we arrived at a similar called M. gordonae, was isolated from cerebrospinal fluid,
conclusion. From 11 cases of putative M. gordonae infection renal biopsy, and the shunt itself. A patient undergoing
continuous ambulatory peritoneal dialysis yielded multiple phylogenetic diagram that are well separated from all other
isolates in culture of a well-described typical M. gordonae species in the genus (155, 175). Despite the limited features
from dialysis and ascitic-fluid specimens, and the sympto- that can be used to distinguish among these three species
matic infection responded to a multiple-drug regimen includ- (205, 224), there is sufficient phenotypic distinction, as
ing isoniazid, rifampin, and ethambutol complemented with recognized in numerical taxonomic matrices (125, 220), to
limited courses of amikacin and pyrazinamide (112). A child meet the recommended (208) support for their nucleic acid-
with numerous granulomatous mesenteric lymph nodes con- based separation (155, 175).
taining many acid-fast bacilli as well as acid-fast bacilli in the Although clinical disease is so rarely associated with this
bone marrow yielded a Tween-hydrolyzing scotochromogen complex that identifying the organisms to species level is not
that did not reduce nitrate; results of urease or quantitative usually justified (101), the increasing incidence of serious
catalase tests were not described (126). One patient with a human disease due to M. malmoense (discussed above)
history of alcohol abuse developed liver disease, and a makes it essential to perform enough tests to ensure that
laparotomy disclosed diffuse peritoneal nodules with caseat- strains of M. malmoense are not misidentified as belonging
ing necrosis (100). A later percutaneous liver biopsy yielded to the M. terrae complex. Members of the complex all have
in excess of 50 colonies of a scotochromogen that hydro- high catalase activity, in contrast to the low activity of M.
lyzed Tween 80 but did not reduce nitrate; results of urease malmoense. Over 95% of combined strains of M. terrae and
or quantitative catalase tests were not described. M. nonchromogenicum (222) and 67% of strains of M.
In sum, of 11 patients with AIDS in whom infections were triviale (220) exhibit 3-galactosidase activity, but no other
attributed to M. gordonae, for only 1 patient was sufficient species of slowly growing mycobacteria exhibit this enzyme.
evidence presented to conclude that a significant infection Furthermore, all strains of M. triviale are reported to grow in
with a member of this species existed (25). Of 17 reports of the presence of 5% sodium chloride in egg medium (220), but
non-AIDS cases, 8 contained insufficient evidence to con- neither M. malmoense nor the other members of the M.
clude that the scotochromogen that was isolated, regardless terrae complex can tolerate it. Thus, any clinical isolate
of its identity, was actually causing disease (21, 71, 113, 117, presumptively identified as a member of the M. terrae
130, 170). In the remaining nine cases, in which the Myco- complex on the basis of slow growth, lack of pigment, and
bacterium species isolated did appear to be playing a role in rapid Tween hydrolysis should be further tested by the
the disease, five of the scotochromogens isolated were semiquantitative catalase, P-galactosidase, and 5% sodium
insufficiently described to confirm their identity as a typical chloride procedures (205) before a definitive report is issued.
M. gordonae (14, 31, 100, 126, 194); one of the isolates, from Clinical and epidemiologic aspects. The discussion pre-
the peritoneal dialysis patient (111), does fit the description sented above for M. gordonae about the difficulty in assess-
of M. gordonae, and the fluid may simply have represented ing the disease potential of common environmental myco-
a culture medium for the organism. Three cultures, from bacteria that are very rarely implicated in disease processes
lung (35), skin (58), and soft tissue (123), all exhibited applies to members of the M. terrae complex as well.
characteristics that were atypical of M. gordonae and may However, members of this complex are less frequently
have represented presently unrecognized taxa that closely encountered, having been reported in the United States at
resemble M. gordonae. only about one-seventh the frequency of M. gordonae (65).
Thus, as rare as reports are of human disease attributed to A review of 15 cases of human disease attributed to members
M. gordonae, the actual number of confirmed cases is of the M. terrae complex in the period 1981 through 1989 will
probably even lower. Therefore, any slow-growing sco- be presented here.
tochromogenic Mycobacterium strain that hydrolyzes In 1983, Tsukamura and colleagues described six patients
Tween 80 but exhibits a positive response in the nitrate with pulmonary disease in whom M. nonchromogenicum
reduction or urease tests or a foam column lower than 45 mm was considered the possible etiologic agent (190). The my-
in the catalase test or is under serious consideration as the cobacteria isolated from all six of the patients were nonpig-
possible etiologic agent of a patient's disease should be mented hydrolyzers of Tween 80 that exhibited high activity
tested against a specific M. gordonae nucleic acid probe (>45 mm of foam) in the catalase test. Three of the cases
(e.g., Accu-Probe [Gen-Probe]). If it fails to react to this represented a "primary infection" type, a term used by
probe, extensive studies of the strain should be undertaken Tsukamura et al. to refer to cases in which the isolation of
in a reference laboratory to determine whether it is an M. nonchromogenicum from sputum coincided with the
atypical strain of some other species or a representative of a appearance of a fresh cavitary lesion. Of the strains isolated
presently unrecognized species. It is important to avoid the from these three patients, only one gave a positive P-galac-
temptation to provide an answer by saying that an isolate tosidase reaction. In contrast, all three of the strains from
"resembles M. gordonae," which may be misleading in three patients categorized as having "secondary infection,"
making a clinical interpretation. Rather, it is better to report in whom cavitary tuberculosis had been recognized before
the strain as a scotochromogenic slow-growing hydrolyzer of the isolation of M. nonchromogenicum, exhibited P-galac-
Tween 80 that does not conform sufficiently to the descrip- tosidase reactivity. Although the identities of the strains
tion of any known species to justify a definitive identifica- from all six patients were supported by numerical taxonomic
tion. analysis, the only species represented in that analysis were
members of the M. terrae complex; no strain of M. mal-
M. terrae Complex moense was included. Of the three patients whose disease
was most likely attributable to the organism that was recov-
The M. terrae complex includes M. terrae, M. nonchro- ered, two had yielded organisms with an unusual lack of
mogenicum, and M. triviale. P-galactosidase. The three secondary-infection types of pa-
Systematics. The taxonomic status and methods for iden- tients, about whom Tsukamura et al. were more cautious in
tifying members of this complex are as presented in the ascribing etiology, yielded organisms that were more typical
baseline references (205, 224). M. terrae, M. nonchromoge- of members of the M. terrae complex. In 1983, another case
nicum, and M. triviale are found in regions of the 16S rRNA from Japan was described in which an organism ideptified as
a member of the M. terrae complex was isolated from a growing mycobacteria have been reviewed in the baseline
resected pulmonary lesion (101), but no description of the articles (205, 224). Phylogenetic relationships between a
organism was provided. In 1988, Krisher and colleagues (98) limited number of rapidly growing mycobacteria, including
described a case of pulmonary disease and the growth of the four independent species under review here, have been
large numbers of colonies reported to be M. terrae complex established by 16S rRNA sequence analysis (155, 175).
from three of four sputum specimens. The description of the Clinical and epidemiologic aspects. Rapid growers that do
culture was compatible with that complex except that it not belong to the M. fortuitum complex are rarely identified
exhibited low catalase activity; no P-galactosidase test re- to the species level. Of 19,977 PPEM reported to the Centers
sults were reported. As we discussed above in the subsec- for Disease Control in 1980, 2,127 (10.6%) belonged to the
tion on M. malmoense, our study of catalase from this strain M. fortuitum complex, but only 305 (1.5%) strains of as-
suggested that this strain is probably M. malmoense. In sorted rapid growers that did not belong to that complex
1989, Tonner and Hammond (185) reported heavy growth of were recorded (65).
a strain with high catalase activity that was compatible in (i) M. flavescens. M. flavescens is seen fairly commonly in
description to M. terrae and was isolated from the sputum of clinical specimens, but we have seen reports of only five
a patient with pulmonary disease. The patient's disease human infections either tentatively or confidently attributed
responded well to therapy with rifampin and ethambutol. to M. flavescens. In none of these reports was sufficient
However, the sputum remained strongly smear positive for description of the organism provided to permit the identifi-
some time after the cultures failed to yield growth. cation to be evaluated. Two of the isolates were from pleural
Four cases of tenosynovitis have been reported to yield effusions caused by metastatic breast cancer (two colonies)
cultures identified as M. terrae complex. In all cases, the and congestive heart failure (this strain was isolated in liquid
organisms were recovered from surgical specimens under medium), so these isolations were probably only incidental
conditions suggesting that they were clinically significant, (71). Many colonies of a strain were isolated from bronchial
but in none of these cases were the organisms themselves washings of a former melanoma patient who had developed
described. In two of the cases (85, 117), synovectomy alone, a pulmonary cavity (23). The symptoms associated with the
without chemotherapy, was sufficient to cure the disease. In pulmonary lesion disappeared after treatment with rifampin,
a third case (124), a combination of surgery and treatment isoniazid, and ethambutol, but the roentgenogram remained
with rifampin, isoniazid, and ethambutol produced remis- unchanged. Another strain was isolated from pus from a
sion, but premature termination of chemotherapy led to postinjection gluteal abscess that responded to simple inci-
relapse; resumption of chemotherapy led to a satisfactory sion and drainage without antibiotic treatment (131). Finally,
outcome. The fourth patient, in whom the disease developed Good has reported one strain of M. flavescens among 19-2
in the hand after a pin prick, developed systemic symptoms strains of PPEM that were isolated from AIDS patients and
and was treated with 20 direct injections of steroids over a sent to the Centers for Disease Control for identification
period of 2 years. Multiple isolations of the organism labelled (63).
M. terrae complex were reported. A very brief course of (ii) M. neoaurum. We have encountered one report of a
treatment with isoniazid and ethambutol was interrupted very well-characterized strain of M. neoaurum that was
because of toxicity. The patient's disease continued for at isolated on a number of occasions from cultures of blood
least 7 years. This poor outcome may be a consequence of from a patient whose carcinoma had been treated by sur-
the prolonged steroid therapy, analogous to the effects seen gery, chemotherapy, and radiation (46). This individual had
with M. marinum infections discussed above. a permanent indwelling catheter that was believed to have
Two cases of intestinal disease have been attributed to been responsible for other episodes of fungemia and bacte-
members of the M. terrae complex (56). In both cases, the remia as well. She responded to a 7-week course of treat-
organism was isolated from granulomatous tissue, but the ment with intravenous gentamicin and cefoxitin.
properties of the bacilli were not described. (iii) M. smegmatis. M. smegmatis appears to be more
To summarize, of 15 cases of disease attributed to an commonly associated with human disease than any other of
organism reported to be a member of the M. terrae complex, the rapidly growing mycobacteria that do not belong to the
six cases associated with chronic pulmonary disease (98, M. fortuitum complex. It is most often recovered from soft
101, 185, 190), four cases associated with tenosynovitis (85, tissue lesions associated with accidental or surgical trauma.
117, 118, 124), and two cases associated with intestinal Wallace and colleagues have published very thorough re-
disease showed convincing evidence of the mycobacterial views of the systematics of and clinical conditions associated
etiology of the lesions. However, in only two cases, both with M. smegmatis (197, 198). In addition, Young and
lung infections (185, 190), was enough evidence of the colleagues have reported the isolation of this species from
identity of the organism presented to permit its ascription two patients with AIDS (242). One isolate was recovered
with confidence to the M. terrae complex. from urine, and the other was recovered from semen.
(iv) M. thermoresistibile. Two human infections have been
Rapid Growers Other than Members of the attributed toM. thermoresistibile. One case involved pulmo-
M. fortuitum Complex nary abscesses (229), and the other case involved a solitary
pulmonary nodule in an immunocompromised host (111).
Most infections attributed to rapidly growing mycobac- The identities of both isolates were confirmed by Tsukamura
teria are associated with members of the M. fortuitum et al., who found that they resembled a collection of strains
complex, as discussed above. Rare infections have also been of M. thermoresistibile isolated from house dust more
attributed to members of four other species, M. flavescens, closely than they resembled the originally described strains
M. neoaurum, M. smegmatis, and M. thermoresistibile, and of this species, which were recovered from moist soil (192).
also to strains whose species were not known. In both patients, the pulmonary lesions resolved rapidly
Systematics. The taxonomic status and methods of identi- under regimens that included rifampin, ethambutol, and
fication of M. flavescens, M. neoaurum, M. smegmatis, and streptomycin (229).
M. thermoresistibile as well as of 19 other species of rapidly (v) Unknown species. Wallace and colleagues have pub-
lished a detailed description of a rapidly growing, scotochro- concentrate of FAC to a tube of conventional LJ medium
mogenic, acid-fast organism isolated from multiple blood and letting it diffuse through the medium overnight before
specimens of a febrile woman with metastatic breast carci- the medium is inoculated. Because of the slow growth of M.
noma (88). The description did not conform to that of any ulcerans and M. haemophilum on primary isolation, the
known mycobacterial species; no comparison was made cultures should be incubated for 12 weeks before being
with species of other closely related genera, such as Nocar- discarded as negative. Skin specimens may also be cultured
dia or Rhodococcus. The patient's fever responded to van- for M. malmoense by using the media described below.
comycin treatment. Saito and colleagues described a dif- Other specimens. Specimens from other tissues and body
ferent scotochromogenic rapid grower that was isolated secretions should be incubated on conventional mycobacte-
repeatedly from the pus of a subcutaneous abscess and rial culture medium at 35°C. (Although 37°C may be optimal
suggested that it probably belonged to a new species, but for most of the species likely to be recovered from these
wisely did not choose to actually propose a new species on specimens, this temperature is close to the maximum toler-
the basis of only one strain (163). No details were given of ated by some strains, and, given the occasional difficulty in
the clinical course of the patient's infection. fine temperature control, use of a slightly lower setting
minimizes the deleterious effect of small shifts in tempera-
MEASURES TO MINIMIZE THE RISK OF FAILING TO ture.)
ISOLATE OR MISIDENTIFYING INFREQUENTLY In view of the increasing incidence of disease due to M.
ENCOUNTERED PPEM malmoense and the seriousness of that disease when it is not
treated, as noted above, it is also important to add culture
The contribution of the clinical laboratory to the diagnosis media that will support the growth of this species. Katila and
of mycobacterial disease include three major components: colleagues have demonstrated that all of their strains grew
isolation, identification, and assessment of the significance poorly in LJ medium at pH 7 and recommended using
of the organism. medium adjusted to a pH between 6 and 6.5 for this species
(96). Furthermore, these investigators reported that, even at
Isolation of the Organism from Appropriate Specimens the low pH, some strains grew well in the presence of
glycerol, but no pyruvate, while for other strains the con-
Standard clinical laboratory manuals provide descriptions verse was true. One tube each of conventional LJ medium
of methods of isolating most PPEM, and we will review only adjusted to pH 6.0 and of LJ medium at pH 6.0 in which
special considerations that apply to some of the more 0.4% sodium pyruvate is substituted for the glycerol are
fastidious PPEM. recommended. This is especially important for patients for
The frequency with which the fastidious mycobacterial whom previous specimens have been reported to have
species are encountered may be too low to justify commer- positive smears but negative cultures.
cial production of the specially enriched media needed for How much effort should be expended to detect mycobac-
each. Moulsdale and colleagues (132) have reported that tin-dependent mycobacteria in human clinical specimens is
FAC will support the growth of M. haemophilum when not clear. The numbers of reports of recovery of M. avium
added to whole LJ medium, but not when added to LJ subsp. paratuberculosis from patients with Crohn's disease
medium that has been modified by the substitution of pyru- is still quite small, in spite of significant attempts to find this
vate for glycerol. Since the latter modification of LJ medium species since the earliest reports of its possible association
has been shown to be useful for the isolation of M. mal- with Crohn's disease. On the other hand, since mycobactin-
moense (96), it may not be feasible to modify the formula- enriched media are not used routinely in the human diagnos-
tions for the conventional commercially available media to tic laboratory, it is possible that M. avium subsp. paratuber-
make one medium approach a universal applicability to culosis or M. avium subsp. silvaticum, both of which have a
isolation of all fastidious mycobacteria. pathogenic potential in animals, may cause a variety of
An ideal system for cultivation of mycobacteria from human diseases without having been recognized. It would
clinical specimens would include conventional media plus probably be worthwhile for laboratories doing a large vol-
media with modifications that make it suitable for the various ume of mycobacteriologic examinations to conduct sur-
fastidious species. Parallel sets of selected media would be veys of the frequency of isolation of mycobactin-dependent
incubated at a minimum of two temperatures, 30 and 35°C, strains.
and preferably at 45°C as well, to accelerate recovery of M. Radiometric methods for detection of mycobacterial
xenopi. Practical constraints may make this unfeasible, and growth from clinical specimens (e.g., the BACTEC system;
each laboratory must develop its own strategy based on the Becton Dickinson Diagnostic Instrument Systems, Sparks,
types of patient populations and specimens encountered and Md.) have the advantage that the growth can be detected
its available resources. In any case, portions of inoculum, markedly earlier than on solid media (77). These methods
especially those derived from surgical or other tissue speci- have already been shown to be satisfactory for detection of
mens that may be difficult to obtain again, should be saved in such common PPEM as most members of the M. avium and
a freezer for later inoculation to specialized medium if M. fortuitum complexes (9, 77, 178). However, the unsup-
serious diagnostic questions remain after the primary cul- plemented medium used for radiometric detection will not
tures have been examined. Some general recommendations support the growth of such fastidious organisms as M. avium
follow. subsp. paratuberculosis, M. avium subsp. silvaticum, M.
Skin lesions. For specimens from skin lesions, conven- haemophilum or M. malmoense; the medium itself is prob-
tional medium should be incubated at both 30 and 35°C to ably adequate for the skin pathogens M. marinum and M.
permit recovery of the most common PPEM and of M. ulcerans, but the growth temperature in the standard radio-
marinum and M. ulcerans. A tube of LJ medium supple- metric system is too high for them and for M. haemophilum.
mented with 2% FAC should be incubated at 30°C for The feasibility of adding individual doses of specific growth
recovery of M. haemophilum. This medium could be pre- factors to bottles of radiometric detection media to make
pared by simply adding a small volume of a sterile stock them support growth of these species should be studied.
Addition of 0.3 ml of a sterile solution of hemin (500 ,g/ml) szulgai, M. asiaticum, and unusual forms that may represent
(156) or of blood (115) to a vial of BACTEC radiometric new species (221). A scotochromogenic Tween 80 hydro-
medium has already been shown to make this medium lyzer that is negative in tests for urease and nitrate reduction
suitable for growth of M. haemophilum. Preliminary studies and yields over 45 mm of foam in the semiquantitative
(42a) have shown that a number of strains of M. paratuber- catalase test is almost surely M. gordonae; only if a suspi-
culosis grew on subculture to bottles of BACTEC radiomet- ciously large number of colonies is seen need it be tested by
ric medium supplemented with mycobactin (2 p.g/ml), and a nucleic acid probe. If it deviates from the M. gordonae
these studies should be extended to attempts at direct biochemical pattern in any respect, it should be subjected to
isolation from clinical specimens. a full panel of identification tests (205).
Other problems with radiometric detection media, as with
other wholly liquid culture medium systems for primary Assessment of Significance
isolation of mycobacteria, are the inability to estimate the
numbers of bacilli in the original inoculum and difficulties in Assessing significance involves solving the anagramatic
recognizing the existence of mixed mycobacterial cultures or question, "Is this organism causal or casual?" In addition to
of recovery of mycobacteria when nonmycobacterial con- requiring the accurate identification of the isolate(s), the
tamination occurs (77). For all of these reasons, at least one answer depends to a significant extent on being able to
solid medium should be inoculated in parallel with radiomet- estimate the number of colonies in the specimen. For this
ric detection media. reason, an extra tube or bottle of solid medium should be
inoculated when the liquid radiometric media are used for
Identification of Organisms and Detection of Mixed Cultures primary isolation of mycobacteria to permit a colony count
to be made. For example, as noted above, a single colony of
The baseline references (205, 224) provide adequate de- an organism that resembles M. gordonae is almost certainly
scriptions of the most commonly encountered PPEM. Fur- a contaminant and of no clinical significance. A large number
thermore, the combined use of the BACTEC radiometric of colonies, on the other hand, would be more likely to be M.
isolation technique and direct examination of all positive szulgai, M. asiaticum, or a member of some new named or
cultures with the available Gen-Probe nucleic acid probes for unnamed species that is likely to be significant.
M. tuberculosis, M. avium, M. intracellulare, and M. gor- The tenacious waxy colonies of M. tuberculosis probably
donae should permit rapid identification of about 80% of the resist easy dispersion and cross seeding from wet surfaces,
isolates, according to species distributions in the United but the soft moist colonies of such species as M. gordonae,
States estimated by Good and Snider (65). We will review M. scrofulaceum, and M. avium are more easily dispersed;
only methods for distinguishing some of the less familiar fluid from initial inoculum or condensate in the tube can
species, especially pathogens that may resemble commonly flood a small colony and seed a broad area of the medium's
seen nonpathogens and that may thus escape recognition if surface, giving the false impression of a heavily positive
an adequate panel of tests is not employed. specimen. Caps should be loosened enough on first inocula-
Although subcultures from radiometric medium bottles tion to permit the medium surface to dry before the tube is
can be used to identify strains that do not react with one of moved for first examination.
the nucleic acid probes, it is preferable to inoculate at least
one tube or plate of solid medium from the original inoculum CONCLUSIONS
at the same time that the original BACTEC vial is inocu-
lated. This will permit (i) recognition of the presence of more Although PPEM have been recognized as the cause of
than one species of Mycobacterium, which might be difficult human disease for many decades, we are continuing to
to detect after enrichment of the faster-growing one in a discover previously unrecognized or unappreciated myco-
liquid medium and subculture to solid medium; (ii) detection bacterial pathogens. The recognition depends in part on
of mycobacterial colonies in the presence of a nonmycobac- advances that have been made in mycobacterial systematics;
terial contaminant, which would have overgrown the liquid these advances have included the description of new spe-
medium; and (iii) estimation of growth rate, which will be cies, the development of practical techniques for distinguish-
useful in deciding whether the additional identification tests ing between species that are phenotypically similar to one
to be performed should be selected from among those another, and improvement in methods for recovery of fas-
appropriate for fast or slow growers (224). tidious organisms. In part, however, the recognition of new
As an absolute minimum, all slowly growing mycobacte- disease entities associated with mycobacteria probably re-
rial cultures not recognized by one of the probes specified flects increased incidence of infection with environmental
above should be subjected to all of the tests listed in Table 1. organisms in individuals whose immunologic competence
If the culture is dependent on hemin or FAC, it is almost has been compromised by AIDS or by exposure to immu-
surely M. haemophilum, but enriched media should be nosuppressive agents used to treat other disease conditions.
employed to test for the properties characteristic of this An awareness of the possibility of infection with some of
species, most notably, the absence of catalase activity and these more obscure agents of disease and the application of
negative tests for Tween 80 hydrolysis and urease. Every appropriate primary culture techniques and an adequate
nonpigmented strain that hydrolyzes Tween 80 must be panel of identification tests are essential if these infections
meticulously examined to determine whether it is M. mal- are to be recognized and managed in an optimal manner.
moense, M. shimoidei, or a member of the M. terrae
complex; a high catalase reaction and positive P-galactosi- ACKNOWLEDGMENTS
dase test ensures that it is not M. malmoense or M. shimoi- This study was supported by the Medical Research Service of
dei, and further determination of species beyond the com- Veterans Affairs.
plex level is not necessary. All chromogenic hydrolyzers of We thank the Medical Library Service of the Long Beach Veter-
Tween must be distinguished as being M. gordonae, which is ans Affairs Medical Center for assistance in the acquisition of
seldom or never significant, or the potentially pathogenic M. references.
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CLINICAL MICROBIOLOGY REVIEWS, Jan. 1992, p. 1-25 Vol. 5, No.

Agents of Newly Recognized or Infrequently Encountered

INTRODUCTION Although other investigators soon recognized that this iso-

20 A media. Growth can be accelerated and diagnostic detection

REFERENCES 22. Carson, L. A., N. J. Petersen, M. S. Favero, and S. M. Aguero.

Int. J. Syst. Bacteriol. 27:241-246. Mycobacterium nonchromogenicum. Microbiol. Immunol. 27:

Bacteriol. 37:463-464. bacteria by the International Working Group on Mycobacterial

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