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Mycobacterium marinum

Article  in  Microbiology Spectrum · April 2017

DOI: 10.1128/microbiolspec.TNMI7-0038-2016

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 Mycobacterium marinum
ALEXANDRA AUBRY,1,2,3 FAIZA MOUGARI,1,4,5
FLORENCE REIBEL,1,2,3 and EMMANUELLE CAMBAU1,4,5
1
Centre National de Référence des mycobactéries et résistance des Mycobactéries aux antituberculeux;
2
Sorbonne Université, Université Pierre et Marie Curie, AP-HP Hôpital Pitié-Salpêtrière;
3
Centre d’Immunologie et des Maladies Infectieuses, Team 13, INSERM U1135, Paris, France; 4Laboratoire de
Bactériologie, AP-HP Hôpital Lariboisière; 5Université Paris Diderot, IAME UMR 1137 Inserm, Paris, France

ABSTRACT Mycobacterium marinum is a well-known
pathogenic mycobacterium for skin and soft tissue infections
and is associated with fishes and water. Among nontuberculous
mycobacteria (NTM), it is the leading cause of extrarespiratory
human infections worldwide. In addition, there is a specific
scientific interest in M. marinum because of its genetic
relatedness to Mycobacterium tuberculosis and because
experimental infection of M. marinum in fishes mimics
tuberculosis pathogenesis. Microbiological characteristics
include the fact that it grows in 7 to 14 days with
photochromogenic colonies and is difficult to differentiate from
Mycobacterium ulcerans and other mycolactone-producing
NTM on a molecular basis. The diagnosis is highly suspected
by the mode of infection, which is related to the hobby of
fishkeeping, professional handling of marine shells, or swimming
in nonchlorinated pools. Clinics distinguished skin and soft tissue
lesions (typically sporotrichoid or subacute hand nodules) and
lesions disseminated to joint and bone, often related with the
local use of corticosteroids. In clinical microbiology, microscopy
and culture are often negative because growth requires low
temperature (30°C) and several weeks to succeed in primary
cultivation. The treatment is not standardized, and no
randomized control trials have been done. Therapy is a
combination of surgery and antimicrobial agents such as
cyclines and rifampin, with successful outcome in most
of the skin diseases but less frequently in deep tissue
infections. Prevention can be useful with hand protection
recommendations for professionals and all persons
manipulating fishes or fish tank water and use of alcohol
disinfection after contact.
INTRODUCTION AND HISTORY
The first report of a mycobacterium isolated in fish,
supposed to be Mycobacterium marinum, has been at-
tributed to Bataillon et al. (1897), who isolated acid-fast
bacilli named Mycobacterium piscium from a tubercu-
lous lesion in a common carp (Cyprinus carpio) (1).
M. marinum was then originally isolated and identified
from marine fish at the Philadelphia Aquarium (2).
M. marinum was initially thought to infect marine
fishes only and was named accordingly, but it is now
known to be a ubiquitous species. The above-mentioned
original freshwater isolate of M. piscium could be a
M. marinum variant. In the early literature, several other
marine Mycobacterium species were described, such as
M. platypoecilus, M. anabanti, and M. balnei. Compar-
ative sugar fermentative reactions together with pub-
lished morphological, cultural, and pathogenic data
suggested that they were all synonymous with M. mari-
num (3) even if M. piscium has not been recognized as a
species since its type culture is no longer available.
Human infection due to M. marinum was reported as
a tuberculoid infection in people using public swimming
pools in Sweden (1939) and in the United States (1951)
(4). Linell and Norden identified the causative organism
in 1954 after 80 persons had shown the same granulo-
matous skin lesions (4).These early findings led to the
disease’s name of “swimming pool granuloma.” Today,
however, due to sanitary chlorination practices, these
kinds of outbreaks have disappeared. The names “fish
Received: 24 December 2016, Accepted: 13 February 2017,
Published: 7 April 2017
Editor: David Schlossberg, Philadelphia Health Department,
Philadelphia, PA
Citation: Aubry A, Mougari F, Reibel F, Cambau E. 2017.
Mycobacterium marinum. Microbiol Spectrum 5(2):TNMI7-0038-
2016. doi:10.1128/microbiolspec.TNMI7-0038-2016.
Correspondence: Emmanuelle Cambau, emmanuelle.cambau@
aphp.fr
© 2017 American Society for Microbiology. All rights reserved.

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Aubry et al.
tank granuloma” and “fish handler’s disease” are now
used because of the association with home aquaria and
water-related activities such as swimming in natural out-
door waters, fishing, and boating (5).
Scientific interest in M. marinum is mainly due to
its genetic relatedness to M. tuberculosis and because
experimental infection of M. marinum in the goldfish
(Carassius auratus) mimics tuberculosis pathogenesis
(6). More recently, M. marinum interest was linked with
the emergence and burden of the M. ulcerans infection.
Lastly, clinical interest in M. marinum infections may
eventually emerge due to the expansion of aquarium-
related activities.
FUNDAMENTAL BIOLOGY OF M. MARINUM
Taxonomy
M. marinum is one of the >150 species of the genus
Mycobacterium (7–9), the only genus of the Myco-
bacteriaceae family. M. marinum is one of the non-
tuberculous mycobacteria (NTM), called also atypical
mycobacteria or mycobacteria other than M. tubercu-
losis. According to Runyon’s classification, it belongs
to group I, composed of photochromogenic species.
Although it can grow in less than 7 days, its character-
istics are far different from those of the so-called rapidly
growing species of mycobacteria, such as M. chelonae or
M. abscessus. Since it carries a single rRNA operon (10)
and its 16S rRNA sequence contains the molecular sig-
nature of slow-growing mycobacteria (11), it definitely
belongs to the slow-growing group of mycobacteria.
M. marinum is a pathogenic mycobacterium, which
sets it, along with the related species M. ulcerans, apart
from the other NTM that are opportunistic pathogens
(12).
From phylogenetic analysis based on the 16S rRNA,
rpoB, and hsp65, M. marinum appears close to the branch
of the M. tuberculosis complex (13). DNA-DNA hybrid-
ization and mycolic acid studies confirm that M. marinum
is one of the two species (along with M. ulcerans) most
closely related to M. tuberculosis (14, 15).
Genetics
The M. marinum genome (strain M) was one of the
genomes of major mycobacteria being sequenced. The
length of the M. marinum genome is 6.5 Mb, which is
larger than that of M. tuberculosis (4.4 Mb), that of
M. leprae (3.3 Mb), and that of M. ulcerans (5.8 Mb) (for
specific searches, see http://mycobrowser.epfl.ch/marinolist
.html). The M. marinum genome is comparable to the
M. ulcerans (16) and M. tuberculosis (17) genomes.
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M. marinum shares more than 98% nucleotide se-
quence identity with the M. ulcerans genome. On the
basis of sequences of the housekeeping and structural
genes used for species identification, such as those of
the ribosomal operon and those encoding RNA poly-
merase (rpoB), DNA gyrase (gyrA and gyrB), and the
65-kDa heat shock protein (hsp65), M. marinum cannot
be differentiated from M. ulcerans, the nucleotide dif-
ferences observed in some of these genes being related to
strain variation (17–19). The major conclusion is that
M. marinum seems to be an M. ulcerans ancestor (17,
20). Divergence would have occurred along with the
gain by M. ulcerans of genes (grouped on the virulence
pMUM megaplasmid) encoding the virulence factor
mycolactone (21) and of copies of the insertion se-
quences IS2404 and IS2606 (20, 22). IS2404 expansion
in the M. ulcerans genome has led to the inactivation of
many genes through disruption of coding and promoter
sequences and has mediated the deletion of approxi-
mately 1 Mbp of DNA from M. ulcerans compared to
M. marinum (20).
Mycobacteria that contain genes for the production of
mycolactone were designated “mycolactone-producing
mycobacteria” (MPM). These strains are all closely re-
lated, and there is some justification for considering
them to form the M. marinum complex or group (23).
All these MPM are specialized variants of a com-
mon M. marinum progenitor and were adapted to live
in restricted environments (24). M. pseudoshottsii,
M. shottsii, M. shinshuense, and M. liflandii are MPM
described for fishes only (25). Although M. marinum is
devoid of the mycolactone-producing coding sequences
as the one found in M. ulcerans, another mycolac-
tone (mycolactone F) has been isolated from strains of
M. marinum that have produced disease in fishes of the
Red Sea (26, 27).
The molecular biology of M. marinum has been de-
veloped because it is less pathogenic and grows faster
than M. tuberculosis, whereas it is a suitable model for
tuberculosis pathogenesis (6, 28). Genetic manipulations
such as transformation and transposition have been
successful (29, 30). Virulence genes have been studied by
gene expression in cultured macrophages or in in vitro
models of granuloma (6, 29, 31). Mutations in the vir-
ulence genes were often complemented by the corres-
ponding gene of M. tuberculosis that demonstrated
the high relatedness of the genomes of the two species.
Genome sequencing revealed that region of difference 1,
which contains the ESAT-6- and CFP-10-encoding genes
in M. tuberculosis, does exist also in M. marinum (32).
The ESAT-6-like secretion system is probably a major

secretion pathway for M. marinum, and this system is
responsible for the secretion of recently evolved PE_
PGRS and PPE proteins, which are especially abundant
in M. marinum. The Esx secretion system is critical for
virulence of both M. tuberculosis and M. marinum and
is highly conserved between the two species (17).
Pathogenesis
The availability of fish models (goldfish and zebrafish)
mimicking a natural mycobacterial infection (28, 33, 34)
enables the study of the pathogen-host interaction.
New models of infection have been described such as
Drosophila melanogaster (in which M. marinum infec-
tion is lethal at a low dose [35]), intraperitoneal infection
of adult leopard frogs (Rana pipiens), and infection of
embryonic zebrafish (Danio rerio) (36). Infections in
these animals are highly similar to M. tuberculosis in-
fection in the human host. In particular, the formation of
granuloma-like lesions in the host and the ability to
cause both acute and chronic diseases are conserved (37,
38). However, these models were mostly used as
surrogates for studying tuberculosis physiopathology or
for screening new antituberculosis drugs (39) and,
rarely, M. marinum infection itself (40).
M. marinum is an intracellular pathogen that pro-
liferates within macrophages in a nonacid (pH 6.1 to
6.5) phagosome that does not fuse with the lysosome
(41). Taking into account that the two species are also
genetically related, it is probable that analogous molec-
ular mechanisms are involved in the survival of these
organisms in a hostile cell environment. M. marinum is
therefore a very useful model system for studying in-
tracellular survival of mycobacteria and possibly other
host-pathogen interactions associated with tuberculo-
sis (34, 42), including innate susceptibility (43). Ultra-
structure studies have shown that M. marinum remains
within activated macrophages in granulomas. Some of
the genes that seem important in the capacity to replicate
in macrophages and to explain the persistence in gran-
ulomas are homologous to the PE_PGRS family of genes
discovered in the M. tuberculosis genome (31, 44).
The organism is able to survive, replicate in macro-
phages, and even escape from the phagosomes into the
cytoplasm, where it can induce actin polymerization
leading to direct cell spread (45, 46). It was shown re-
cently that M. marinum bacteria are ejected from the
cell through the ejectosome, an actin-based structure
spreading mechanism that requires a cytoskeleton reg-
ulator from the host and an intact mycobacterial ESX-1
secretion system (46, 47). Recent findings using the
zebrafish model infected by M. marinum but with vari-
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Mycobacterium marinum
ous genetic and pharmacologically induced macrophage
deficiencies try to explain the susceptibility of humans
with mononuclear cytopenia to mycobacterial infec-
tions and highlight the therapeutic potential of myeloid
growth factors in tuberculosis (48). Moreover, the vir-
ulence and immunomodulatory factors that were iden-
tified may constitute novel targets for antimycobacterial
drugs (49). It has been also shown recently that EsxA
contributes to mycobacterial virulence with its mem-
brane-permeabilizing activity required for cytosolic
translocation (50).
Experiments involving infection of zebrafish with
different strains of M. marinum showed that strains
can be divided into two types based on genetic diver-
sity and virulence. Cluster I contains mainly the strains
isolated from humans with fish tank granulomas,
whereas the majority of cluster II strains were isolated
from poikilothermic species. Acute disease progression
was noted only with cluster I strains, whereas chronic-
disease-causing isolates belonged to cluster II (51).
MICROBIOLOGICAL CHARACTERISTICS
OF M. MARINUM
Microscopy and Cell Wall
Under the microscope, M. marinum cannot be distin-
guished from M. tuberculosis. It is a pleiomorphic rod
(1.0 to 4.0 μm by 0.2 to 0.6 μm), not motile, true
branching, and difficult to stain by usual methods but
appears as an acid-fast bacillus after staining by the
reference carbol fuchsin or Ziehl-Neelsen method (52).
The formation of microscopic cords has been de-
scribed for M. marinum as classically described with
M. tuberculosis, and a link between cording and viru-
lence was observed in both species (53, 54).
The cell wall of M. marinum is mainly composed
of keto-mycolates and methoxy-mycolates that differ-
entiate it from those of M. tuberculosis and of other
mycobacteria except M. ulcerans (15, 55).
Specific Characteristics of M. marinum
Culture
Like other mycobacteria, M. marinum is a strict aerobe.
Its preferred carbon sources are glycerol, pyruvate, and
glucose, but ethanol can be also used by M. marinum.
M. marinum has an optimal growth temperature of
30°C, whereas small colonies or no growth is observed
at 37°C.
In primary culture, the growth rate might be low and
positive culture may be obtained only after several
3
Aubry et al.
weeks’ incubation. In subculture, the growth rate is be-
tween 1 and 2 weeks but can reach 4 to 5 days because of
its rapid ability to adapt to laboratory conditions.
M. marinum is less exigent than M. tuberculosis for
growth. It grows in all the media used for mycobacterial
growth (egg based, broth, or agar based) without any
additives or only 2 to 5% oleic acid-albumin-dextrose-
catalase instead of 10% for M. tuberculosis, and it
also grows on blood-containing agar. After subcultures,
some of the strains may even grow on ordinary culture
media.
Although its growth is dependent on oxygen like
for other mycobacteria, 2% to 5% carbon dioxide in
the gas phase above the medium improves the growth
of M. marinum.
Phenotypic characteristics
Colonies of M. marinum are typically smooth or inter-
mediate, white or beige when the media is kept in the
dark, and yellow to orange after exposure to light (pho-
tochromogenic) (52) (Fig. 1). It is included in group I of
Runyon’s classification along with M. kansasii. Differ-
entiation between these two pathogenic NTM is
done classically on the basis of biochemical character-
istics. The absence of nitrate reductase production and
growth on medium containing thiacetazone is in favor of
M. marinum.
Photochromogenicity is due to the active production
of beta-carotene mediated by the gene crtB and can be
inhibited by chloramphenicol (56).
Molecular identification
Molecular biology techniques have been successfully
applied for the identification of mycobacteria. Molecu-
FIGURE 1 Typical photochromogenic colonies of Mycobac-
terium marinum grown on Lowenstein-Jensen solid medium.
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lar methods are an alternative for species identification
offering the advantages of being rapid and accurate.
PCR-based methods have been developed, and two of
them are commercially available: INNOLiPA Myco-
bacteria v2 (Innogenetics), based on the amplification of
the ribosomal gene spacer (16S-23S), and GenoType
Mycobacteria CM/AS (Hain Lifescience), based on the
amplification of the 23S rRNA gene (57, 58). Both use
PCR coupled with reverse hybridization. So far, they
cannot differentiate M. marinum from M. ulcerans since
the rRNA sequences are similar (see “Genetics” above).
Specific PCR protocols have been described for de-
tection in fishes (59).
Genotyping
Although infection due to M. marinum is not contagious
between humans, strain genotyping has been undertaken
for three reasons: first, to relate environmental strains
to strains isolated in infected humans; second, in aqua-
culture, to differentiate strains isolated among fishes
or water-living animals (26); and third, to demonstrate
relapse or reinfection (60). The technique used was
mainly pulsed-field gel electrophoresis since PCR-based
methods showed low discriminative properties (61).
Mycobacterial interspersed repetitive unit–variable-
number tandem-repeat typing, which is one of the ref-
erence typing methods for M. tuberculosis, has been
applied to M. marinum and M. ulcerans. Unlike for
M. ulcerans, the M. marinum genotypes were not clearly
related to the geographic origins of the isolates, and
genotyping does not discriminate between relapse and
reinfection (62).
Multilocus sequence analysis applied to 22 M. mari-
num strains showed that the level of intraspecies nucle-
otide sequence divergence was higher than in M. ulcerans
strains (20). M. marinum isolates from humans and
fishes have also been compared by sequencing of the
16S rRNA and hsp65 genes, restriction mapping, and
amplified fragment length polymorphism analysis (63).
In that study, significant molecular differences separated
clinical isolates from water-related isolates.
M. MARINUM INFECTION
Manifestations of M. marinum Disease
Fish disease
M. marinum disease in fishes is very common, especially
in aquarium fishes. There is some evidence that the
gastrointestinal tract could be the primary route of in-
fection (64), and it has been demonstrated that poor
diet and stress exacerbate mycobacterial infections in

zebrafish (64–66). The severity of the infection ranges
from chronic infection associated with a low mortality
rate to a more acute form in which the entire popula-
tion died. The acute fulminating disease is rare and is
characterized by rapid morbidity and mortality with
few clinical signs. M. marinum infection is more often
a chronic progressive disease that may take years to
develop into a noticeable illness. Affected fishes show
comportmental changes, such as separating from other
fishes and refusing food. They may have skin ulcerations
or pigment alterations and develop spinal curvature.
Unilateral or bilateral exophthalmia is also a typical
feature. In fish, M. marinum infection is a systemic dis-
ease that can affect virtually any organ system but es-
pecially the spleen, kidneys, and liver (67, 68).
Human disease
Due to the optimal growth at 30°C and poor growth at
37°C, human infections with M. marinum are localized
primarily to the skin. Infection in HIV-positive patients
is usually not different from infection in HIV-negative
ones. Scarce cases of M. marinum infection occurring
in patients treated with tumor necrosis factor alpha
(TNF-α) inhibitor therapy have been reported since
2002; cutaneous lesions displaying rapid sporotrichoid
extension are more frequent than among other patients
(69). Given the small number of cases reported (about
30), it is not possible yet to draw any conclusions re-
garding the frequency or the severity of M. marinum
infection in this population (70–79). Nevertheless, these
medicines should be stopped during the course of an-
tibiotics. If not, the lesions may rapidly extend as already
described (78). We also recommend applying preventive
strategies (see “Prevention Strategies” below) especially
for those patients.
M. marinum infection has different clinical presenta-
tions (Table 1). Most commonly, as described for about
60% of the cases, M. marinum is a cutaneous disease
manifesting as a solitary papulonodular lesion on a
finger or hand (80). In 25% of the cases, M. marinum
disease takes on a sporotrichoid form (80, 81) (Fig. 2).
This occurs when the infection spreads along the lym-
phatic vessels to the regional lymph nodes, producing
multiple nodules resembling sporotrichosis. Occasion-
ally, skin lesions appear as pustular, nodulo-ulcerative,
granulomatous, or verrucous plaques.
Deep infections, such as tenosynovitis (the most fre-
quent), osteomyelitis, arthritis, and bursitis, occur in
20 to 40% of the cases (80–85). Unusual clinical pre-
sentations have also been reported, such as epididymo-
orchitis (86) or destructive nasal lesions mimicking
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Mycobacterium marinum
extranodal NK/T cell lymphoma (74) as well as severe
osteomyelitis (87).
Deep infections result from the extension of a cuta-
neous infection or direct inoculation of the organism
(88). Systemic dissemination is exceptional and has been
reported to occur only in immunocompromised patients
(e.g., solid-organ and hematopoietic stem cell transplant
recipients or those on anti-TNF treatment [74, 89–91]),
and general symptoms are lacking. Localized adeno-
pathy is rare (15% of the cases in reference 80), and
infection of deep organs, such as the lungs, is exceptional
(92). In these cases, identification of M. marinum should
be carefully checked.
There is often a several-month delay between the
onset of the lesions and the patient’s seeking medical
care (93, 94) because the lesions are subacute or chronic
and usually painless, as for M. ulcerans. Moreover, the
lesions can be self-limited and may heal spontaneously,
though healing can take months to several years. Initial
misdiagnosis of osteoarticular form of M. marinum
infection can lead to intralesional injection of cortico-
steroid that favors local dissemination (83). These forms
are often associated with a poor prognosis (8).
Extremities of the upper limbs, such as a finger or
hand, are the most common site of infection in relation
of fish or water animal exposure (94). Patients with skin
lesions on the lower limbs are swimming pool cases or
indirect cases. M. marinum is assumed to be introduced
in the skin accidentally through preexisting wounds or
abrasions. History of preceding minor trauma is com-
mon, and an occupation or hobby that resulted in a
likely environmental water exposure is the rule. How-
ever, since the incubation period is very long, on average
3 weeks up to 9 months (80, 95), minor abrasions or
wounds preceding the inoculation usually do not remain
at the time of the diagnosis.
Immunity
Tuberculin skin testing is usually positive because of
cross-reaction with M. tuberculosis (96). It may sug-
gest a mycobacterial infection but does not distinguish
M. marinum from tuberculosis or other mycobacterial
infections and is therefore of little utility in the workup.
False positivity of the interferon gamma release assays
performed today for the diagnosis of latent tuberculosis
infection have been also reported with M. marinum in-
fection (76). Indeed, as noted above, M. marinum shares
with M. tuberculosis the specific antigens (ESAT-6 and
CFP-10) used in these tests. However, interferon gamma
release assays were not found to be useful as a diagnostic
method for M. marinum infection (97, 98).
5
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Aubry et al.
TABLE 1 Published studies of M. marinum infections that include more than 10 patientsa

Antibiotic treatmenta

Monotherapy
No. patients
(no. with deep Fish Duration No. of Antibiotic and no. of Combination Surgery
Reference infection) exposure (%) Cure (%) (mo) (mean) patients patients (% cured) therapy (no.) (% cured)
Even-Paz, 1976 (106) 10 (0) 0 44 NA NA NA NA
Chow et al., 1987 (122) 24 (24) 87.5b 83 9 0 24 10 (70)
Bonafe 1992 (145) 27 (1) 93 >74 3.8 NA NA NA
Kozin and Bishop, 1994 (124) 12 (6) 100 100 6 7 D = 5 (100), Co = 2 (100), R = 1 (100) 5 12 (100)
Edelstein 1994 31 (0) NA 81 4 19 M = 14 (71), D = 3 (67), T = 1 (100), 10 NA
Co = 1 (100)
Ang et al., 2000 (5)c 38 (NA) 45 81 3.5 22 Co = 19 (93), M = 3 (100) 12 1 (100)
Casal et al., 2001 (139) 39 90 99 2–4 20 M = 12 (NA), R = 8 (NA) 7 NA
Aubry et al., 2002 (80) 63 (18) 84 87 3.5 23 M = 19 (100), C = 4 (100) 40 30 (16)
Ho 2006 (146) 17 (NA) 24 94 4.5 16 D = 4 (NA), Co = 1 (NA), M = 11 (NA) 1 0
Johnson and Stout, 2015 (88) 28 (19) 20 95c 5 2 NA 15 22 (79)
Sia et al., 2016 (94) 29 (7) 19 100 NA 3 NA 25 16 (100)
Blanc 2016 (147) 23 (5) NA 91c 3 11 C = 9 (NA), Z = 1 (NA), D = 1 (NA) 6 5
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aNA, not available; M, minocycline; C, clarithromycin; R, rifampin; D, doxycycline; T, tetracycline; Co, co-trimoxazole; Z, azithromycin.
b100% swimming pool exposure.
cPatients lost to follow-up were not assessed for the outcome.

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FIGURE 2 Sporotrichoid form of skin lesions typical of
M. marinum infection. (Courtesy of Hervé Darie, Noisy le
Grand, France.)
Diagnosis
Diagnosis can be difficult for the clinician (84) because
the presentation is often insidious and nonspecific.
If key historical information, such as fish exposure, is
not obtained, the diagnosis is commonly delayed (95).
Diagnosing an infection due to M. marinum requires a
high index of suspicion, a properly obtained exposure
history, and knowledge of the laboratory growth char-
acteristics of the organism (94).
Differential diagnosis includes infection due to other
NTM known to cause cutaneous infection (M. chelonae,
M. ulcerans, M. ulcerans subsp. shinshuense [99],
M. haemophilum, M. fortuitum, and M. tuberculosis),
sporotrichosis, and noninfectious diseases such as sar-
coidosis, skin tumors, and foreign-body reactions.
Though the diagnosis can be suspected clinically,
especially when exposure is established, the diagnosis
relies on isolation of a mycobacterium subsequently
identified as M. marinum.
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Mycobacterium marinum
Clinical significance
Isolation of M. marinum has a clinical significance
whatever the number of colonies or the smear positivity
of the specimen, since it usually does not grow from the
laboratory environment or from the uninfected human
body. This important point differentiates M. marinum
infection from infections due to other NTM such as
M. abscessus or M. chelonae (100). Thus, correct iden-
tification is required (8, 52).
Bacteriological findings
Microscopic examination of the specimen after Ziehl-
Neelsen staining is positive in only 30% of the cases.
Even when positive, smear microscopy cannot distin-
guish M. marinum from other mycobacteria, including
species of the M. tuberculosis complex.
A definite diagnosis is obtained by a positive culture.
Cultures are reported as positive in 70 to 80% of the
cases, but this number could be increased with attention
paid to the specimen collection and proper temperature
for incubation. The microbiologist should be aware of
suspicion of M. marinum infection in order to perform
cultures at 30°C.
Collection of specimens
Specimens containing M. marinum are taken from the
skin, either as a skin biopsy sample or as aspirate pus.
Swabs should be avoided for many reasons (81, 88).
Other specimens are articular fluids or subcutaneous
tissues and exudates often obtained via surgery (85,
87). Specimens must be collected before chemother-
apy begins. The container should be sterile and should
not contain any fixative or preservative. The collected
specimen should be kept at 4°C if there are delays in
delivery to the laboratory. Since M. marinum infection is
not a multibacillary infection, it is necessary to collect
the largest possible volume, especially in the case of skin
biopsy or surgery.
Isolation procedures
Laboratory processing for M. marinum disease diagno-
sis is not an emergency. A level 2 laboratory might be
sufficient for isolation and identification, although level
3 might be required for studies requiring large-volume
subcultures (52).
Safety measures are required for handling specimens
and cultures—wearing gloves, disinfection of the mate-
rial and benches, and avoiding the use of needles—so
that accidental inoculation does not occur.
Skin biopsy or wound fluids might be contaminated
with skin flora, such as staphylococci, and consequently
7
Aubry et al.
require a decontamination procedure (standard N-
acetyl-L-cysteine 2% NaOH procedure or 4% HCl de-
contamination) prior to culture. Specimens from sterile
deep structures (i.e., articular fluid) can be inoculated
directly without decontamination (52, 101).
Since M. marinum grows poorly at 37°C, the aspirate
or biopsy should be cultured at 30 to 32°C. Colonies
grow within 5 to 14 days, but primo-culture requires a
longer time and cultures should be kept for 6 to 12
weeks. Because other NTM can be responsible for the
infection, specimens should also be incubated at 37°C.
After successful isolation of a photochromogenic my-
cobacterium, further differentiation between M. marinum
and other organisms of Runyon group I is required
(see “Microbiological Characteristics of M. marinum”
above).
Methods based on molecular biology are limited by
the high homology between M. marinum and M. ulcerans
(see “Molecular identification” above). Matrix-assisted
laser desorption ionization–time of flight mass spec-
trometry cannot distinguish these two species but can be
performed as a rapid screening method before accurate
identification (102). Neither the commercial INNO-
LiPA v2 assay kits nor the GenoType Mycobacteria
CM/AS allow differentiation between M. marinum,
M. ulcerans, M. ulcerans subsp. shinshuense, M. shottsii,
and M. pseudoshottsii (103).
Molecular identification using the analysis of con-
served genes or DNA regions (hsp65, gyrA, rpoB, and
16S-23S internal transcribed spacer) associated with a
7-day culture of a photochromogenic colony is required
to identify M. marinum. However, in the case of absence
of photochromogen colonies or culture in broth, a gene
sequence belonging to M. marinum or M. ulcerans
(18, 19) coupled to the absence of IS2404 and IS2606
(22) may indicate M. marinum (104). We do recommend
waiting for the colony morphology to confirm the iden-
tification. In the past few years, a mycolactone-producing
subgroup of the M. marinum complex has been identi-
fied and analyzed. These IS2404-positive strains cause
pathology in frogs and fish, but not in humans so far (25)
(see “Fundamental Biology of M. marinum” above).
Histological findings
Tissue biopsy for histopathology is important but pro-
vides diagnosis of mycobacteriosis in only half of the
cases, since histological findings depend on the age of the
lesion.
Granulomas suggest diagnosis but are not patho-
gnomonic and are also present in other mycobacterial
infections. They are present in less than two-thirds
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of cases, and they may be confused with rheumatoid
nodules (105). During the first months, there is a non-
specific inflammatory infiltrate. Later, granulomas with
multinucleated giant cells are common findings (Fig. 3).
Fibrinoid necrosis, but not true caseation, can be ob-
served. Langhans giant cells are seen only occasionally.
Hyperkeratosis with focal parakeratosis, hyperplasia,
and liquefaction degeneration of the basal layer can be
observed (88, 106, 107). Although acid-fast bacilli are
seldom seen in the histological sections (67), staining
should be attempted.
Importantly, in one case out of five, the infiltrate
suggested no infectious origin, although deep skin bi-
opsies and synovial biopsies provided more informa-
tion. Therefore, for all forms of necrotic granuloma,
whether or not accompanied by collections of neutro-
phils, a culture should be carried out in a specific me-
dium, even in the absence of microscopic evidence of
bacilli (105).
ANTIMICROBIAL SUSCEPTIBILITIES
AND TREATMENT
Mode of Action and Resistance
Mechanisms in M. marinum
The permeability of the M. marinum cell wall has not
been investigated, but it has been shown to vary at
least 10-fold between mycobacterial species, M. tuber-
culosis being 10-fold more permeable than M. chelonae
(108). Considering the natural multidrug resistance of
M. marinum (see below), the permeability of its cell
wall could be close to that of M. chelonae. This low
FIGURE 3 Active-disease histopathologic section of tissue
from a patient with a M. marinum infection. The lesion shows
granulomatous infiltrate with epithelioid and giant cells.
(Courtesy of Bernard Cribier, Strasbourg, France.)
 Mycobacterium marinum

permeability probably allows survival in unfavorable
environments.
In the genome, several genes encoding antibiotic re-
sistance mechanisms have been reported. Genes en-
coding enzymes known to hydrolyze antibiotics were
found for β-lactams (blaC), aminoglycosides (aac2′), and
chloramphenicol (cph). Many potential efflux pumps
and ABC transporters have been also described, includ-
ing potential extruders for cyclines, macrolides, and
aminoglycosides (17).
and modal MIC are very close (109, 111). This con-
stitutes the natural or intrinsic susceptibility pattern of
M. marinum (Table 2).
Acquired resistance has not been described in
M. marinum so far for any of those antibiotics, even
in relapsed cases. Slight differences from the above-
described pattern of natural antibiotic susceptibility
that might be observed are usually due to misidentifi-
cation or differences in the method or the technique of
antibiotic susceptibility testing (115).

In Vitro Susceptibility to Antibiotics Susceptibility Testing

From the studies dealing with a large number of strains
and applying a standard method of testing, M. marinum
has a natural multidrug resistance pattern (109, 110).
Indeed, M. marinum has shown resistance to the anti-
tuberculosis drugs isoniazid, ethambutol, and pyrazin-
amide in most studies. Rifampin and rifabutin are the
most active drugs in term of MICs. MICs of minocy-
cline, doxycycline, clarithromycin, linezolid, sparfloxa-
cin, moxifloxacin, imipenem, sulfamethoxazole, and
amikacin are close to the susceptibility breakpoints, and
thus, these drugs may have moderate activity. MICs of
trimethoprim, azithromycin, telithromycin, quinupristin-
dalfopristin, ciprofloxacin, gemifloxacin, ofloxacin, and
levofloxacin are above the concentrations usually ob-
tained in vivo, and consequently, M. marinum may be
considered resistant to them (111–114).
All the strains have similar susceptibility patterns
since for each drug the MIC50, geometric mean MIC,
Etest has been shown to be an accurate and precise
method of MIC determination for bacteria other than
mycobacteria, for rapidly growing mycobacterial spe-
cies, and even for some of the slowly growing myco-
bacterial species (116–118). Different authors have
questioned the reliability of the Etest for M. marinum
and also for other mycobacteria, claiming that it may
cause reports of false resistance (109, 111). Agreement
between MICs, yielded by either the Etest method or
the agar dilution method used as a reference, depends
on the antibiotic and have been shown to be 83% for
minocycline, 59% for rifampin, 43% for clarithro-
mycin, and 24% for sparfloxacin (109, 119). Moreover,
reproducibility with the Etest was low, in contrast to
that with the agar dilution method. In conclusion, Etest
is not recommended for M. marinum; antibiotic sus-
ceptibility testing and the agar dilution method remain
the methods recommended.

TABLE 2 MICs of 17 antibiotics against 54 strains of Mycobacterium marinum determined by the agar dilution methoda

MIC50 (μg/ml) MIC90 (μg/ml) Modal MIC (μg/ml) Geometric mean ± SD (μg/ml) Range (μg/ml)
Rifampin 0.25 0.5 0.25 0.24 ± 1.7 0.125–4
Rifabutin 0.06 0.06 0.06 0.06 ± 1.8 0.015–1
Isoniazid 4 8 4 5.6 ± 1.5 4–16
Ethambutol 2 4 2 1.7 ± 1.6 1–4
Amikacin 2 4 4 1 ± 1.7 1–8
Doxycycline 8 16 8 5.7 ± 2 0.5–16
Minocycline 2 4 2 2.9 ± 1.7 0.5–8
Clarithromycin 1 4 2 1.2 ± 2.3 0.5–4
Azithromycin 32 128 32 NA 8→128
Ofloxacin 4 16 4 6.1 ± 1.7 2–32
Ciprofloxacin 4 8 4 3.8 ± 1.8 1–16
Levofloxacin 4 8 4 4.5 ± 1.7 2–32
Sparfloxacin 1 2 1 1 ± 1.8 0.5–4
Moxifloxacin 0.5 1 0.5 0.6 ± 1.7 0.25–4
Sulfamethoxazole 8 128 8 NA 4→128
Trimethoprim 64 128 128 67.4 ± 2.3 16–512
Imipenem 2 8 2 2.6 ± 2.6 0.5–16
Linezolid 1 2 NA NA 0.5–4
aData from references 109 and 120. NA, not available.

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Aubry et al.
FIGURE 4 Microbiological diagnosis of human infection due
to M. marinum.
Broth microdilution susceptibility testing is recom-
mended by the CLSI and may use the commercially
available Sensititre MIC plates (120). Although for
M. marinum it may be recommended to use the MIC
plate for slow-growing mycobacteria, we think that test-
ing antibiotics contained in the MIC plate for rapidly
growing mycobacteria may be more appropriate with
regard to the antibiotics with low MICs (Table 2).
Since no primary (acquired) resistance has been de-
scribed so far, routine susceptibility testing seems un-
necessary except for relapsed cases as recommended for
other atypical mycobacteria (80, 100).
Antimicrobial Therapy of
M. marinum Infections
Patients infected with M. marinum are usually treated
with antibiotics (Table 1). Different antibiotic regimens
have been reported (83). The choice of the regimen
appears to reflect more the personal experience and
preference of individual authors than demonstrated
efficacy. Antibiotic efficacy is unknown since (i) cases
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were reported separately in the literature, (ii) no thera-
peutic trial has been carried out, and (iii) M. marinum
infection may be cured spontaneously (12, 106, 121).
A variety of antibiotics have been used, including
cyclines, co-trimoxazole, rifampin plus ethambutol, and,
more rarely, clarithromycin, levofloxacin, and amikacin
(83, 121–123). Cure as well as failure has been described
with all of these drugs (83, 121, 124). Overall, most of
the patients are cured after therapy that includes cyclines
or clarithromycin and rifampin, but failure cases have
been also observed. Failure cases have rarely been ob-
served with cyclines, but most of the patients treated with
cyclines, and especially cyclines alone, have had mild
infection limited to skin and soft tissues. In contrast, ri-
fampin and rifabutin, which are the only antibiotics with
low MICs close to those found for M. tuberculosis, were
usually given in complicated cases with extension of the
infection to the deeper structures, such as tenosynovitis
and osteoarthritis, and failed to cure all cases. In our
study, failure was related to deep infections (only 72%
were cured) and to ulcer lesions (80).
Although MICs of the new fluoroquinolones, moxi-
floxacin and gatifloxacin, are lower than those of clas-
sical fluoroquinolones, and these compounds are very
potent antituberculosis drugs, their in vivo activity
against M. marinum has yet to be demonstrated. The
efficacy of linezolid, also with low MICs, needs also to
be tested in vivo.
We currently need results of in vivo experiments
with an animal model or therapeutic trials with humans
showing evidence of efficacy of some antibiotics. Until
these are obtained, it is reasonable to recommend
cyclines for M. marinum infection limited to the skin
and the combination of rifampin and clarithromycin for
infection extended to deeper structures.
In the literature, the duration of antimicrobial ther-
apy in M. marinum infection varies from 2 weeks to
18 months, depending on several factors, such as the
extension and severity of infection, the presence of un-
derlying disorders, and the clinical response (83, 84).
In many patients with mild disease, infection mostly re-
solves spontaneously, although complete resolution may
take up to several years (81, 83). In our study (80), the
duration of therapy ranged from 1 to 25 months and the
median was 3.5 months. This duration was significantly
longer for cases with infection spread to deeper struc-
tures except for the failure cases.
We may recommend to continue with antibiotherapy
at least until the lesions heal and then for 2 additional
months, especially in cases of infection extended to
deeper structures.
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Surgery
The place of surgery is controversial. For some authors,
surgical debridement along with antimicrobial therapy
is usually required for control (81). For others, surgical
debridement should be limited to the cases with criteria
known to be associated with a poor prognosis, including
steroid injections into the lesion, a persistent drainage
sinus tract after several months of antimicrobial therapy,
and persistent pain (122). Most of the infections spread
to deeper structures are treated with surgery, which
seems reasonable (125). For infections limited to skin
and soft tissue, there is no clear benefit of surgery and
surgical side effects are unknown.
Other therapies, such as cryotherapy, X-ray therapy,
and electrodessication, have been reported but have not
been evaluated (83).
It should also be recommended to stop TNF-α in-
hibitor or other immunosuppressive therapy during the
course of antibiotics when M. marinum infection occurs
in patients treated with these medications. Indeed, de-
spite the small number of cases described, it seems that
the lesions may progress if these medications are not
discontinued (78).
EPIDEMIOLOGY AND PREVENTION
Natural Habitats of M. marinum
M. marinum has been reported to affect a wide range of
freshwater and marine fish species, suggesting an ubiq-
uitous distribution. M. marinum is the main mycobac-
terium isolated from fish, although very little is known
about its prevalence and impact on fisheries (126).
Zanoni et al. reported that mycobacteria were found in
46.8% and 29.9% of the fishes imported into Italy and
which died and that M. marinum represented 2.4 to
5.3% of the isolates (127), whereas Slany et al. reported
the presence of M. marinum DNA in 41.7% of orna-
mental fishes of which 23.6% were culture positive in
the Czech Republic (128).
M. marinum is transmitted in fishes through the con-
sumption of contaminated feed, cannibalism of infected
fish, aquatic detritus, or release of pathogens into the
water due to gut or skin lesions or disintegration of
infected fishes (67). In this respect, potential sources
of infective material are numerous and include the soil
and water, in which the bacterial cells remain viable for
2 years or more (67).
M. marinum infection in other aquatic vertebrates
may be a source of infection to fishes. Frogs, snakes, and
turtles may become involved in the transmission cycle.
Snails are also thought to be a reservoir (67). Other
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Mycobacterium marinum
invertebrate organisms, such as shellfishes or water fleas,
have been shown to play a role in the transmission of this
agent.
Findings of genetic studies comparing M. marinum
isolates from humans and fish suggest that clinical cases
may have derived from the ornamental fish trade asso-
ciated with home aquaria and that only certain strains
of M. marinum have zoonotic potential (63, 129).
The prevalence of NTM was evaluated in the envi-
ronment of a swimming pool in Italy. M. marinum was
isolated in only 4.5% of the water samples and pool
edges, although 88.2% of pool water samples were pos-
itive for M. gordonae, M. chelonae, and M. fortuitum
(130).
In addition to fish and fish tanks, reptiles and related
poikilothermic animals and the vivaria in which such
animals are maintained could be sources of M. marinum
exposure. With millions of poikilothermic animals, such
as tropical reptiles, being kept in close contact with
people worldwide as new companion pets, one could
predict that an increasing number of “vivarium granu-
loma” cases are likely to be diagnosed. Therefore, doc-
tors should be aware that vivaria, in addition to fish
tanks, are a source of M. marinum exposure for patients
(131).
Epidemiology of M. marinum Infections
Like infections with other NTM, M. marinum infections
are not contagious from human to human.
Before 1962, most cutaneous M. marinum infec-
tions reported in the literature involved swimming
pool-associated injuries, including two large outbreaks
involving almost 350 patients (4, 93). A possible ex-
planation of the decline in pool-associated cases is
the improvement in swimming pool water disinfection
practices in recent decades. M. marinum survives only
briefly after exposure to free chlorine concentrations
of ≥0.6 μg/ml. There can be unexpected sources of ex-
posure, such as coal mine water (132). Furthermore,
outbreaks resulting from a common source of contami-
nation have been described (94, 133).
M. marinum skin infection is now often acquired
from aquarium maintenance and is called fish tank
granuloma (134). Since M. marinum infection is an im-
portant zoonosis, there is a significant risk to all per-
sonnel working with fishes, water-living animals, or
aquaria. M. marinum infection may be an occupational
hazard for certain professionals (for example, for pet
shop workers), but many infections occur in fish fanciers
who keep an aquarium at home, hence the name “fish
fanciers’ finger syndrome.” Although infection may be
11
Aubry et al.
caused by direct injury from fish fins or bites, most are
acquired during the handling of an aquarium, such as
cleaning or changing the water (95, 96). Indirect infec-
tion due to a bath that was used to clean out fish tanks
has also been described (80, 135, 136).
It is foreseen that the incidence of fish tank granuloma
will increase (135) due to the extension of fishkeeping
as a hobby and aquarium tourism. Fishkeeping is one of
the most popular hobbies in many countries, such as
Germany, the United States, and France, where about
10% of the population has an aquarium at home and
business related to fishkeeping has increased every year.
The frequency of M. marinum isolation in laborato-
ries is low, and M. marinum accounts for less than 1% of
the mycobacterial clinical isolates (137). A recent survey
in Europe showed that M. marinum represents about
1.3% of NTM isolated (138). In Spain, 39 cases were
reported from 1991 to 1998 involving 21 laboratories
(139). Less than half of the cases of M. marinum in-
fection are bacteriologically confirmed. The incidence
of M. marinum infection was estimated to be around
0.09 case per 100,000 inhabitants per year in France and
between 0.05 and 0.27 in the United States.
Prevention Strategies
For the prevention of swimming pool granuloma, the
Centers for Disease Control and Prevention recommend
that concentrations of free chlorine be kept between
0.4 and 1 mg/liter in swimming pool water and between
2 to 5 mg/liter in spa and hot tub water (93).
Sanitation, disinfection, and destruction of carrier
fishes are the primary methods of controlling M. mari-
num infection in fishes. This practice is mostly pursued
for the food fish; however, with expensive fish species,
this practice may be difficult to apply. Antimicrobial
treatment is not able to eliminate M. marinum from
affected fishes (140). Regarding importation of orna-
mental fish, there exists great variation in policy. For
example, Europe decided on an EU Directive 2003/858/
EC health certificate-derived template for all imported
live fish (including tropical ornamentals) (141).
Individual prevention is the first line of defense for
anyone involved with aquaria or anyone working or
recreating in a marine environment. Preventive strategies
should be developed for fish tank activity, such as
wearing gloves when cleaning the tank (95). Common-
sense measures include the following:
• Bandage or dress any open wound or cut before
exposure.
• Clean hands thoroughly before and after exposure
to aquarium water and components. Hydroalco-
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holic solutions may be used instead of hand
washing.
• Do not swallow aquarium water when checking
for salinity or siphoning water.
• Do not overcrowd aquaria, since this favors the
multiplication of mycobacteria.
• UV germicide lamps to treat aquarium water
are efficient for mycobacteria as long as they are
used in clean conditions at the correct flow rate
(142).
• Do not transfer tank filters or fishes in the bath
that is used for humans, or carefully clean it with
sodium hypochlorite (143).
• The exposed population should be educated in
order to recognize signs of M. marinum disease in
fishes and in humans so they can inform medical
staff, a point that will expedite the diagnosis.
• Fish salespersons should be educated. Indeed,
many tropical fish salespersons ignore warnings
about fish tank granuloma. In France, although
20% of them are at risk of M. marinum infection,
95% of them immerse their hands without gloves
in the fish tanks every day (144).
Some authors recommend against installing orna-
mental aquaria in hospital units, particularly units likely
to receive immunocompromised patients.
REMAINING PROBLEMS AND CONCLUSION
Treatment evaluation requires large-scale trials, proba-
bly at an international level. Infections limited to the
skin and soft tissue should be distinguished from in-
fections extended to deeper structures. Antibiotics such
as cyclines, rifampin, and clarithromycin need to be
evaluated along with the new fluoroquinolones and
linezolid. Surgery needs subsequent evaluation.
Surveillance of M. marinum infection, which is ex-
pected to increase due to fishkeeping as a hobby and
aquarium tourism, should be undertaken at least in
some highly exposed countries. A simple surveillance
could be based on culture-confirmed cases. Bacteriol-
ogy laboratories, dermatologists, and infectious disease
physicians should play a crucial role in case finding.
Since there is no human-to-human transmission of
M. marinum infection, the prevention of inoculation
from the environment is the main strategy for eradicat-
ing the disease. Simple recommendations such as hand
protection and hygiene measures and fish tank and
aquarium maintenance seem worthy of being largely
disseminated and evaluated.
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Professionals should also take M. marinum risk into
account and apply the recommendation for decreasing
M. marinum infection among farm fishes and among
professionals handling fishes.
Lastly, diagnosis should be expedited: think to (i) ask,
“Do you possess a fish tank at home? Who cleans it,
and how?”; (ii) sample the lesion for mycobacteriologi-
cal analysis; (iii) inform the laboratory that there is a
suspicion of M. marinum infection; and (iv) incubate
at 30°C in addition to 37°C and wait for weeks until
smooth photochromogenic colonies appear.
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