Mycobacterium marinum: ubiquitous agent of waterborne granulomatous skin infections
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- Petrini, B. Eur J Clin Microbiol Infect Dis (2006) 25: 609. doi:10.1007/s10096-006-0201-4
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Mycobacterium marinum is a waterborne mycobacterium that commonly infects fish and amphibians worldwide. Infection in humans occurs occasionally, in most cases as a granulomatous infection localized in the skin, typically following minor trauma on the hands. For this reason, infection is especially common among aquarium keepers. Such local infection may—though infrequently—spread to tendon sheaths or joints. Disseminated disease, which is rare, can occur in immunosuppressed patients. In order to obtain a definitive diagnosis, culture and histopathological examination of biopsies from skin or other tissues are recommended. Infections sometimes heal spontaneously, but drug treatment is usually necessary for several months in order to cure the infection. Doxycycline or clarithromycin is used most commonly, although in severe cases, a combination of rifampicin and ethambutol is recommended.
Mycobacterium marinum is a ubiquitous waterborne organism that grows optimally at temperatures around 30°C. When inoculated into animals such as mice, bats, amphibians, and fish, it has been observed to cause infection . It is prevalent worldwide in saltwater, brackish water, and fresh water that is still or streaming, and it naturally infects at least 150 fish and frog species, as well as freshwater eels and oysters [2, 3]. It may be highly prevalent in fish tanks [4–6] and can cause illness, with a more or less typical clinical picture, and death in different fish species . Dolphins, manatees (dugongs), and other aquatic mammals can be infected as well [8, 9]. In addition, M. marinum infections have been observed in African toads and in a royal python [10, 11]. In Africa, M. marinum has been isolated from normal human skin as well as from soil .
M. marinum grows on Löwenstein-Jensen substrate within 2–3 weeks at 30°C and produces a yellow pigment upon exposure to light . Although M. marinum shares some important characteristics with Mycobacterium tuberculosis, several genetic differences reflect the adaptation of these bacteria to their respective specialized niches [13, 14]. M. marinum has been used to study the function of M. tuberculosis genes involved in intracellular survival and replication . A well-established goldfish model has been useful for the study of the pathogenicity of M. marinum and other mycobacterial species , and a zebrafish embryo model provides a convenient means for observing granuloma formation . A vaccine against M. marinum infection in fish has been developed .
It has been shown experimentally that mice infected with M. marinum at temperatures below 30°C develop pulmonary lesions and succumb, while animals kept at 34°C do not develop such lesions . Furthermore, the combination of low temperature and immunodeficiency in mice produces overwhelming M. marinum infection . In pathogen-free M. marinum-inoculated mice, however, footpad swelling was shown to be little affected by T-cell depletion . Even the fruit fly, Drosophila melanogaster, can be infected at a temperature of 30°C, thus providing a convenient model for the study of systemic M. marinum infection . Moreover, the intracellular replication of M. marinum within the free-living amoeba, Dictyostelium discoideum, has also been used as a model of mycobacterial pathogenicity [22, 23]. It is probable, but not proven, that M. marinum uses—as is known for other mycobacteria—environmental amoebas as natural intermediate hosts [24–26]. When maintained at temperatures similar to those at which infection occurs in vivo, M. marinum may also persist in vitro in eukaryotic cells . M. marinum strains can be divided into two separate virulence groups on the basis of their genetic diversity . Moreover, molecular differences between M. marinum strains isolated from various environments have been reported .
Mycobacterium marinum infection in humans
Superficial infection and localized invasive infection
M. marinum infection in humans is comparatively rare. The approximate annual incidence in the USA is 0.27 confirmed cases per 100,000 inhabitants . The most frequent site of M. marinum skin infection is the hands, with aquarium owners affected most commonly. The temperature of human skin is advantageous for the establishment of superficial infection, which is commonly preceded by minor traumatic lesions. Years ago, prior to the chlorination of swimming pools, skin infections on the elbows were associated with bathing in swimming pools. It is believed that the bacteria entered the skin through minor traumata that were caused by resting the elbows on the pool border . Today, chlorination of swimming pool water reduces the exposure of swimmers to mycobacteria . The reduction of chlorination in a Swedish dolphinarium has coincided with several of the animals contracting cutaneous and subcutaneous infections with M. marinum, probably because of increased growth of M. marinum in the water (B. Petrini, B. Röken, unpublished observation, 2005).
Following abrasions or superficial wounds, humans infected by contaminated water develop purulent superficial or deep, granulomatous skin lesions. The infection develops within weeks or months of exposure [33–39]. Infection also may be acquired by handling fish or shellfish or following trauma caused by infected foreign bodies such as wood splints [2, 3, 40]. The administration of systemic corticosteroids to diminish inflammatory reactions may delay the diagnosis and treatment of M. marinum infection. M. marinum infection is rare in infants .
Deep-seated invasive infections
In rare cases, M. marinum infection may become disseminated, especially in immunosuppressed patients such as transplant recipients. Immunosuppressed patients on corticosteroid therapy are affected most frequently and may develop cutaneous, pulmonary, or visceral infection [50–54]. A rare case of laryngeal lesions with M. marinum has been reported . Disseminated infection by M. marinum has been described rarely in persons with close-to-intact immunity [55, 56].
The precise mechanism of how M. marinum circumvents the host’s immune response is still unclear. However, it has been shown that super-infecting M. marinum may traffic rapidly into pre-existing mycobacterial granulomas, bypassing cellular immune responses that are established by the primary infection and thus circumventing eradication by these immune responses . Moreover, it has been demonstrated that M. marinum can, by an intricate cellular mechanism, actively induce actin-polymerization within phagosomes, propelling itself by actin-based motility into adjacent cells . M. marinum can thus escape into the cytoplasm of infected macrophages and spread directly from cell to cell, again circumventing the mechanisms of host defense and promoting persistent infection.
Culture of secretions may lead to the diagnosis of M. marinum, but culture from tissue biopsies may be more sensitive. In the latter case, concomitant histopathological examination is a valuable complementary investigation that may reveal granulomatous inflammation, and, in a minority of cases, acid-fast bacteria . Diagnosis via biopsy is also preferable for differential diagnosis of, for example, sporotrichosis (caused by the dimorphic fungus Sporothrix schenckii) or cutaneous leishmaniasis (caused by the protozoa Leishmania donovani) in endemic areas or of nocardiosis (caused by various Nocardia spp.) . Similar lesions also may be caused by other uncommon diseases such as protothecosis (algosis caused by the ubiquitous Chlorella), cowpox (a viral zoonosis), or botryomycosis, a rare bacterial granuloma (caused mainly by Staphylococcus aureus or Pseudomonas spp.). The tuberculin skin test is often positive in M. marinum infection  but has a low predictive value since cross-reacting antigens are present in various mycobacteria.
Antibiotic therapy is usually the preferred treatment for M. marinum infection. In vitro drug sensitivity testing of M. marinum is not generally recommended because the risk of mutational resistance to the commonly used drugs is minimal and the natural antimycobacterial sensitivity pattern is well known . However, microbiological investigation may be considered in cases of treatment failure and/or persistently positive (over a period of several months) cultures.
Recommended treatment modalities in Mycobacterium marinum infection (alphabetical order)
Recommended dose per day
500 mg b.i.d.
500 mg b.i.d.+ethambutol 15 mg/kg
Doxycycline or minocycline
600 mg+ethambutol 15 mg/kg
Surgical debridement and/or excision may be indicated on the basis of general surgical principles, especially when deep structures are involved in the infection . In localised infection, excision of the affected area may be an alternative if medical treatment is not feasible. Hyperthermic local treatment has been used experimentally, but experience with this modality is limited [66, 67].
M. marinum infection should be suspected in cases of granulomatous inflammation of the hand, especially when accompanied by lymphogenous sporotrichoid spread in fish tank owners. It should be included in the differential diagnosis of any patient displaying a chronic cutaneous infection that developed after a minor trauma associated with water contact. Local, deep-seated disease may occur, sometimes requiring surgery, while disseminated disease is rare. Extended treatment with tetracycline or clarithromycin is often effective in local disease, while rifampicin combined with ethambutol is a treatment option for invasive infection.