Mycobacterium marinum Infection

Etiology

M. marinum is a non-motile, non-spore-forming, gram-positive, acid-fast bacillus. M. marinum is slow-growing mycobacteria belonging to group 1 of the Runyon classification. It is a photochromogen and produces a yellow pigment when exposed to light. M. marinum grows best on Lowenstein-Jensen medium at 32 degrees Centigrade (C). Unlike Mycobacterium tuberculosis (MTB), the growth of M. marinum is inhibited at 37 degrees C. Phylogenetically, M. marinum is very closely related to M. ulcerans, and both are closely related to M. tuberculosis based on their 99.3% 16SrRNA sequence homology. In fact, M. marinum causes tuberculosis-like disease in fish and frogs. Like MTB, M. marinum can survive inside host cells and is proposed as a model to study MTB. Like in MTB infection, M. marinum may cause a positive tuberculin test.[4]

M. marinum has one rRNA operon per genome, which dictates the pace of mRNA-protein synthesis. Genomic analysis suggests that the rRNA operon is similar in both MTB and M. marinum. Unlike MTB, M. marinum is a rapid grower, so the reason for this difference is unknown. At the infection site, M. marinum has a generation time of 24 hours, similar to MTB, but in the laboratory, at 32 degrees C, the generation time is 4 hours. MTB generation time in the lab is 24 hours when grown at 37 degrees C. There is no one good antibiotic regimen for M. marinum.[5]

Epidemiology

Norden and Linell reported the first human case of M. marinum from Sweden in 1951.[6] The mycobacteria were isolated from the skin lesions of swimmers who had bathed in a contaminated pool. Chlorination to sanitize swimming pools is routine; therefore, swimming is no longer a risk factor for M. marinum infection. Potential risk factors are working in wet fields, participating in aquatic sports, or cleaning a home fish aquarium.[7] The annual incidence of M. marinum infection in the USA is 0.27 cases per 100.000 inhabitants.[8]

The two conditions required for M. marinum infection are injury or abrasion to the skin and exposure to a contaminated aqueous environment. In one study, almost half (49%) of M. marinum infections were aquarium-related, 27% were related to fish or shellfish injuries, and 9% were related to injuries associated with saltwater or brackish water. Risk factors for individuals with HIV are similar. Disseminated infection can occur in immunocompromised patients.[1][9] 

Histopathology

M. marinum lesions appear similar to other lymphatic and cutaneous infections and non-infectious skin diseases. An epidemiological as well as clinical suspicion could help identify M. marinum as the potential cause of these types of lesions.[10]

History and Physical

Patient evaluation should identify the likely exposure of the injured skin to aqueous material contaminated with M. marinum. Skin injury may be in the form of minor abrasions, cuts, or major trauma. Besides the aqueous environment, M. marinum is also found in plants and soil.[6][11] The most common clinical infections due to M. marinum are skin and soft tissue infections, most likely due to their propensity to flourish in cooler environments.[12] A skin infection may present as a solitary violaceous or red plaque or nodule. The nodular surface can be crusted or verrucous. The nodule may appear inflammatory and may have pus. There can be lymphangitic spread in a sporotrichoid presentation.[13][14] The lesions can follow a sporotrichoid lymphocutaneous pattern. [15]

M. marinum should be in the differential diagnosis of poorly healing nodular lesions not responding to antibiotics in the upper extremities.[12] Based upon exposure to M. marinum, skin lesions can also be present in the lower extremities. M. marinum infections in patients with HIV have been reported in the pre-anti-retroviral therapy (ART) era but are uncommon in the post-ART era. Disseminated infection can occur in non-HIV immunocompromised hosts as well.

Evaluation

Communication with the diagnostic laboratory is essential to making the diagnosis. When M. marinum infection is suspected, the laboratory team will utilize Lowenstein-Jensen agar cultures which can be incubated at 28 to 32 degrees C, in addition to incubating at 37 degrees C. Cultures will need to be observed for six weeks. The positivity rate of cultures ranges from 70% to 80%. Lesions have a very low concentration of microorganisms; hence cultures should be obtained even in the absence of microscopic evidence of bacilli. Typical tuberculoid granulomas are seen only in two-thirds of the cases, and the histopathology of nodules can be confused with rheumatoid nodules. One in five nodules may not appear to be of infectious origin in histology. Samples from the deeper parts of the nodule or skin or synovial biopsy may provide information at times, and repeating a biopsy can be helpful. M. marinum infections can mimic other histopathological patterns, such as a sarcoid-like granuloma or granuloma annulare as well.[16]

Polymerase chain reaction (PCR) amplification techniques using Mycobacterium genus-specific primers can help diagnose M. marinum infection directly in the biopsy sample. Ziehl-Neelsen stain of biopsy specimens or yellowish discharge is rarely positive since the number of mycobacteria in clinical specimens is low.  

M. marinum infection can also be opportunistic in patients treated with anti-tumor necrosis factor (TNF)-alpha and other biological drugs.[17] Therefore an underlying immunosuppressed state must be excluded upon the diagnosis of M. marinum infection. Tuberculin skin test using purified protein derivative is positive in 67% to 100% of cases. Quantiferon-TB Gold and the enzyme-linked immuno-spot assay may also be positive in M. marinum infections but are unhelpful for diagnosis. Positive blood culture findings have also been reported in disseminated infections. Recently in vivo imaging to monitor long-term anti-mycobacterial therapy has been proposed, and such diagnostic tools are being developed.[18]

Treatment / Management

Routine susceptibility testing is not recommended when treating M. marinum infections. There is not much correlation between in vitro susceptibilities and clinical response. The therapy is not standardized. Rifampin is the most active drug against M. marinum, with MIC90 of < 0.5mg/mL.[19] In one study, the MIC for ethambutol was 2.0 mg/mL to 4.0 mg/mL, for doxycycline was 16.0 mg/mL, for imipenem was 8.0 mg/mL, and for INH was 8.0 mg/mL. M. marinum is intrinsically resistant to pyrazinamide. M. marinum has moderately high MIC90 for ciprofloxacin and levofloxacin but is susceptible to moxifloxacin (MIC90) of 1 mg/mL to 2 mg/ml). Linezolid has activity against M. marinum as well.[20] Clinically clarithromycin-based regimens have had a high success rate irrespective of the in vitro MIC values.[21](B3)

There is no consensus on the regimen or the duration of therapy for M. marinum infections. A spectrum of antibiotic regimens has been used in published cases or case series. There are no randomized controlled trials. Minocycline monotherapy in immunocompetent patients has been used. Generally, combination therapy for immunosuppressed patients is used. Consider treatment with a chosen regimen for three months prior to changing the antibiotic therapy, as the response to treatment is slow. Surgical debridement is often needed. Effective antibiotic therapy is usually associated with the healing of all skin lesions within one month of commencing therapy. After that, immunocompetent patients should continue the medications for two more months. Immunocompromised patients must be treated with two agents for at least six months. In one report, a patient with AIDS was successfully treated with rifampin and ethambutol for six months. The lesion recurred after stopping therapy, so therapy was restarted with a clarithromycin regimen. Sometimes chronic lifelong suppressive treatment may be necessary.[3][19](B3)

Based on the available evidence, treating immunocompromised hosts with M. marinum infection with two agents, including clarithromycin, seems prudent. The optimal duration of therapy in the setting of the immunocompromised host is unknown. Most experts would treat for six months and possibly lifelong in cases of a persistent immunocompromised state. Disseminated disease is treated for a duration of one year in published case reports. Rifampin and ethambutol were frequently used in invasive M. marinum infections. In a study of 61 clinical isolates, rifamycins and clarithromycin were the most potent against M. marinum.[22](B3)

Differential Diagnosis

Cutaneous nodular infections, especially fungal and granulomatous infections, are in the differential. These include:

• Blastomycosis
• Coccidioidomycosis
• Cryptococcosis
• Histoplasmosis

Other cutaneous lymphatic infections that might have a similar presentation include: 

• Leishmaniasis
• Nocardiosis
• Sporotrichosis

Prognosis

In most cases, especially in patients with immunocompetent status, M. marinum infection with treatment carries an excellent prognosis. Treatment failure may result due to deeper-structure involvement and ulcerative skin lesions. There is a very low risk of antimicrobial resistance. Clinical outcomes of M. marinum infections in patients with HIV infection do not differ from those without HIV infections. A continued immunocompromised state and ongoing risk of exposure can increase the risk of disease. Some patients may need lifelong suppression therapy.

Complications

Chronic complications of the disease are minimal with early diagnosis and adequate treatment. Some patients may develop persistent ulceration at the site of initial exposure. With delayed treatment or improper selection/duration of antibiotic therapy, patients may develop deeper infections, including osteomyelitis, tenosynovitis, and disseminated disease, which may require amputation of the involved tissue.