Mycobacterium Marinum Infection of the Skin

M marinum is a slow-growing species that resides in both freshwater and saltwater environments, with optimal growth at 30-32°C. It is carried by many fish species and can result in human infection via inoculation of the skin by a fish bite, exposure of an open wound to contaminated water, contact with an aquarium, or contact with marine animals such as fish or turtles.[2] Exposure to M marinum via swimming pools is rare because most pools are chlorinated.[5]

The pathogen is classified as a photochromagen in Runyon group 1, which means that it produces yellow pigment when cultured and exposed to light. Culture growth occurs over 7-21 days and is optimal at 25-32°C (77-89.6°F) given the organism is adapted to infect ectotherms, such as fish. When endotherms, such as humans, are infected the infection favors the cooler extremities more than central sites. Systemic infection, usually of an immunocompromised host, has been reported. This indicates that the organism is capable of adapting to grow in conditions closer to 37°C.[6]

After inoculation into the host tissues via an abrasion or other wound, the mycobacteria are phagocytosed by macrophages. Inside the macrophage, they are able to interrupt the formation of the phagolysosome, which would normally kill the organisms. The mycobacteria, however, are able escape the lysosome and can move intracellularly and extracellularly via actin-based motility. This may contribute to cell-to-cell spread.

Tumor necrosis factor (TNF) is important for the immune response against mycobacteria. Studies have demonstrated that in the absence of TNF, macrophages engulf but do not destroy the mycobacteria. Instead, the mycobacteria survive and grow, finally killing the macrophage.[7] The importance of TNF is also supported by a number of reports of infection occurring in patients treated with TNF inhibitors, and these medications should be stopped during the course of antibiotic therapy. If not, the lesions may rapidly extend.[8, 9, 10]

Studies have revealed 2 pathophysiologically and genetically (ie, via amplified restriction-based polymorphism analysis) distinct populations of M marinum. One group can infect humans and causes acutely lethal disease in fish, while a second group cannot infect humans and causes chronic progressive disease in fish.

Special concerns

Utility of M marinum as an immunotherapy agent to elicit an antituberculosis response is currently being explored.[11] There is specific scientific interest in M marinum because of its genetic relatedness to Mycobacterium tuberculosis and because experimental infection of M marinum in fish mimics tuberculosis pathogenesis.[10]

Infections caused by M marinum are uncommon but well described in the literature. The estimated annual incidence in the United States is 0.05-0.27 case per 100,000 adult patients.[12, 10] Of the more than 160 cases described, most are case reports of cutaneous infection; some report concomitant osteomyelitis, tenosynovitis, arthritis, and/or disseminated infection. Nosocomial infection has never been described.

Infection occurs worldwide, most commonly in individuals with occupational and recreational exposure to nonchlorinated fresh water or saltwater.[13]

No racial or sexual predilections have been noted for M marinum skin infection. M marinum infection has been reported in persons of every age group; however, it appears to be rare in the pediatric population.[14, 15]

Patients at risk include anglers (commercial, recreational), oyster workers, swimmers, aquarium workers, and individuals with aquariums in their homes. Infection has also been reported following natural disasters involving the ocean.[16] In March 2014, the New York City Health Department reported an outbreak of roughly 30 cases secondary to seafood markets with live and raw fish in Chinatown. A single study found that 49% of M marinum infections were aquarium-related, 27% were associated with fish or shellfish injuries, and 9% were associated with injuries related to saltwater or brackish water.[1]

There are also documented reports of M marinum transmission via "fish manicures" or pedicures. In this practice, a client visits a spa and submerges their hands or feet into water containing live Garra rufa, doctor fish. The fish strip away the dead skin on the extremities, providing a form of exfoliation.[17]  Due to infection risk, these spa services are banned by law in several US states, as well as parts of Canada and Europe.

Patients may present with a papule, nodule, or ulcer at the site of trauma and a history of exposure to nonchlorinated water 2-3 weeks earlier. Patients may give a history of a papule or nodule that subsequently ulcerated and/or (1) spread up the finger or hand or (2) spread to involve a local joint or tendon. Over a period of months, localized cutaneous disease can spread to soft tissues. 

There is often a several-month delay between the onset of the lesions and the patient seeking medical care because the lesions are subacute or chronic and can be painless, although localized pain and induration are common.[10] Fever, lymphadenopathy, and systemic infection are rare, with the exception of in immunosuppressed patients. A thorough environmental exposure history should be conducted with consideration of infectious etiologies in patients with chronic skin conditions.[2]

An erythematous or bluish 0.5- to 3-cm papule or nodule develops at the inoculation site. Ulceration can occur later, and subsequent lesions may be present along the path of lymphatic drainage of the extremity. This occurs in 25-50% of patients and is termed sporotrichotic spread.

The upper extremity is the inoculation site in 90% of cases, although infection of other body areas, including the face, has been reported.[18] M marinum infections of the hands often present as nodular lesions which can be mistaken for rheumatoid nodules.[19, 20] Systemic dissemination is exceptional and has been reported to occur only in immunocompromised patients (eg, solid-organ and hematopoietic stem cell transplant recipients, patients on anti-tumor necrosis factor (TNF) treatment.[10] )

Lymphadenopathy may be present.

Patients may have deeper involvement, with tenosynovitis, bursitis, septic arthritis, and osteomyelitis of the underlying bone. Dissemination to the bone marrow and abdominal viscera is rare.

If diagnosis is delayed, the infections can mimic rheumatoid arthritis, gout, trauma-related tenosynovitis, foreign body, deep fungal infections, or malignancy.

The cause is infection with M marinum. Exposure of traumatized skin to affected aqueous environments (such as fish tanks) is the leading predisposing factor. Other animal exposures such as a reptile vivarium or seafood market may more rarely result in acquisition of the infection.[21] Individuals who are consistently exposed to the organism are more likely to develop the infection. Hosts who are immunocompromised are also at increased risk.

Culture is the criterion standard method of identification. Cultures are specific but not sensitive and may be positive in only 70-80% of cases.[27] Cultures at 25-32°C (77-89.6°F) may grow nonmotile acid-fast bacilli in 7-21 days, with an optimal growth temperature of 30°C.[10] The organisms are photochromogens (Runyon group 1), producing yellow pigment only when exposed to light. No niacin or nitrate production occurs; urease is produced, but the organism is a weak producer of catalase at 25°C (77°F).[28] It grows in all the media used for mycobacterial growth (egg based, broth, or agar based) without additives or only 2-5% oleic acid-albumin-dextrose-catalase instead of 10% for M tuberculosis, and it also grows on blood-containing agar. In addition, 2-5% carbon dioxide in the gas phase above the medium improves the growth of M marinum.[10]

If culture results are negative but the history and clinical findings are consistent with M marinum infection, then treatment should still be strongly considered; additionally, performing a lesional biopsy may help identify the organisms with an acid-fast bacillus stain. Of note, tuberculin skin testing is usually positive, owing to cross-reaction with M tuberculosis. This may suggest an underlying mycobacterial infection but cannot distinguish M marinum from tuberculosis or other mycobacterial infections and is of little utility in the workup.[10]

Polymerase chain reaction (PCR) studies of tissue are quick to perform and are increasingly being used to help distinguish the exact Mycobacterium species involved.[29] However, errors of identification have been reported when using PCR.[30, 31]

An enzyme-linked immunospot assay for interferon-gamma has been developed for Mycobacterium tuberculosis. Patients with infection by M marinum may also have a positive result with this test.[32]

Consider obtaining imaging studies (plain radiography, computed tomography scanning, or magnetic resonance imaging) if tenosynovitis, osteomyelitis, or deep infection is suspected.[33]

MRI may show exuberant tenosynovitis; however, unlike with purulent tenosynovitis, the underlying muscles and bony structures are rarely involved.

Mycobacteriophages are viruses that infect Mycobacterium. They are currently commercially available but are still being refined as a tool to rapidly identify the specific species in mycobacterial infections. They are also being developed as a future modality for diagnosis and treatment of these infections.[34]

Biopsy samples from cutaneous lesions or from intra-articular tissue should be obtained for histopathologic analysis. Acid-fast preparations, such as Ziehl-Neelsen and Fite stains, reveal acid-fast bacilli; however, staining is positive in only 30% of the cases. When positive, smear microscopy cannot distinguish M marinum from other mycobacteria.[10]

Surgical drainage of skin lesions often is unnecessary; however, if a deeper infection is diagnosed, drainage may be indicated.

The histopathologic findings vary depending on the duration of the lesion sampled and on the degree of granuloma formation. Histopathology provides diagnosis of mycobacteriosis in only half of the cases since histologic findings depend on the age of the lesion.[10]

Early lesions show a nonspecific mixed inflammatory infiltrate, but acid-fast stains typically reveal bacilli. Established lesions display characteristic tuberculoid granulomas, often containing a stellate abscess.

Abscess formation can vary from absent to marked.

Granulomas can vary from poorly formed, consisting of epithelioid histiocytes and lymphocytes with few multinucleated giant cells, to fully formed granulomas with numerous multinucleated giant cells, although caseation is rare.[35] Granulomas are present in less than two thirds of cases and can be confused with rheumatoid nodules.[36]

A lichenoid and granulomatous infiltrate has also been reported with M marinum infection.[22]

The epidermis frequently demonstrates papillomatosis, hyperkeratosis, and an acute inflammatory infiltrate, with or without ulceration.

Importantly, one study showed that in one case out of five, the infiltrate suggested no infectious origin, although deep skin biopsies and synovial biopsies provided more information. Therefore, for all forms of necrotic granuloma, whether or not accompanied by collections of neutrophils, a culture should be carried out in a specific medium, even in the absence of microscopic evidence of bacilli.[36]

Treatment is usually medical in nature, using bacteriocidal agents. The duration of therapy is empiric, with the recommendations to continue therapy for 4-6 weeks following clinical resolution of the lesions. Treatment of some infections may last as long as 25 months or longer.[10]

Effective antimicrobials include tetracyclines, fluoroquinolones, macrolides, sulfonamides, and others.

Drug resistance varies and has been reported with all classes of antibiotic treatment listed above. Combination therapy is used for cases with documented antimicrobial resistance or those not responding to single-agent therapy.[37]

Spontaneous resolution has been reported. Treatment with radiation, cryotherapy, and heat probes has been reported.

It should also be recommended to stop anti-tumor necrosis factor (TNF) therapy or other immunosuppressive therapy during the course of antibiotics when M marinum infection occurs in patients treated with these medications. Despite the small number of cases described, it appears that the lesions may progress if these medications are not discontinued.[10]

See Medication for further discussion of single- and combination-agent therapies.

Patients can be treated in an outpatient setting and should be seen frequently until they begin to respond to therapy, then less frequently until the infection is fully cured. Patients may benefit from seeing an infectious disease physician in an outpatient setting.

Surgical drainage of skin lesions is usually unnecessary.

Infection of deep structures such as the tendon sheaths, joint space, or bone should be managed with the help of a surgeon. Debridement of necrotic tissues of the synovium, tendon sheaths, and/or bone may be needed to control infection in spite of appropriate systemic antibiotic therapy. Amputations are rarely necessary.[38]

In an in vitro experimental M marinum model, the activated form of vitamin D (1α,25-dihydroxyvitamin D3) reduced M marinum survival through increased intracellular and extracellular levels of cathelicidin antimicrobial peptides.[39] It remains to be determined if supplementation with vitamin D in humans infected with M marinum will aid in clearance of the organisms.

The mainstay of therapy for infection by M marinum is antimicrobials, including antibiotics and antimycobacterials.

The organism is generally sensitive to rifampin plus ethambutol, tetracyclines (minocycline [MCN],[40] doxycycline [DCN]), trimethoprim-sulfamethoxazole (TMP-SMZ), clarithromycin,[41] and fluoroquinolones (ciprofloxacin, ofloxacin, sparfloxacin). Resistance to doxycycline and rifampin has been reported but is rare.[42, 43]

Antimicrobials are administered singly or in combination.[37] Single-agent therapy may be sufficient in uncomplicated infection of the skin; however, combination therapy is used when more extensive infection is treated. Combination antimycobacterial agents include the following:

• Rifampin and ethambutol: This combination is regarded as highly effective therapy, especially for severe disease or in patients with impaired immune systems.

• Streptomycin, ethambutol, and isoniazid

• Clarithromycin, alone or in combination: This agent has shown the most efficacy of the macrolide antibiotics. One case report discusses the use of azithromycin in combination with ethambutol. Erythromycin has not demonstrated efficacy for treating M marinum infections.

Combining rifabutin or rifampin with macrolide antibiotics is not recommended because of the decreased efficacy of the macrolide and the increased levels of rifabutin or rifampin.

Most strains of M marinum have been found to be resistant to medications typically used for Mycobacterium tuberculosis, including isoniazid, streptomycin, pyrazinamide, and para-aminosalicylic acid.[34] In contrast, ethambutol is effective in combination with antimycobacterial or antibiotics, but not as a single agent.

The duration of therapy is empiric; multiple sources recommend extended therapy for 4-6 weeks following clinical resolution of lesions.[37]

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Therapy must be taken regularly and continued for a sufficient period.

Rifampin (Rifadin, Rimactane)

Rifampin has been found to be effective as monotherapy and is successful when given in combination with another antimicrobial. It inhibits DNA-dependent bacterial RNA but not mammalian RNA polymerase. Cross-resistance may occur.

Ethambutol (Myambutol)

Ethambutol is only effective when combined with another antimicrobial agent, preferably rifampin. It diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). It impairs cell metabolism by inhibiting the synthesis of one or more metabolites, which, in turn, causes cell death. No cross-resistance has been demonstrated. Mycobacterial resistance is common with previous therapy.

Minocycline (Dynacin, Minocin) or Doxycycline (Doryx, Vibramycin)

Minocycline is effective monotherapy; however, strains of M marinum resistant to doxycycline but sensitive to minocycline have been reported. It also treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible Chlamydia, Rickettsia, and Mycoplasma species.

Trimethoprim and sulfamethoxazole (Bactrim, Septra)

Several case reports have shown the effectiveness of this drug combination. Reports indicate that it can help eradicate organisms unresponsive to either antituberculars or tetracyclines. It inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid.

Clarithromycin (Biaxin)

Cases of organisms resistant to conventional antitubercular therapy have responded to clarithromycin but not erythromycin. Use of azithromycin has not been reported. Clarithromycin inhibits bacterial growth, possibly by blocking the dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It has bactericidal activity against atypical Mycobacterium species (eg, M marinum).

Ciprofloxacin (Cipro)

Fluoroquinolones are effective alone or in combination with other medications to eradicate M marinum. Ciprofloxacin inhibits bacterial DNA synthesis and, consequently, growth.

Levofloxacin (Levaquin)

Levofloxacin is used for the treatment of tuberculosis and some atypical mycobacterial infections in combination with rifampin and other antituberculosis agents.