Mycobacterium marinum Remains an Unrecognized Cause of Indolent Skin Infections

Comment

Diagnosing the Infection
Diagnosis of M marinum infection remains problematic. In the 5 patients included in this study, the time between initial onset of symptoms and diagnosis of M marinum infection was delayed, as has been noted in other reports.^4-7 Delays as long as 2 years before the diagnosis is made have been described.⁷ The clinical presentation of cutaneous infection with M marinum varies, which may delay diagnosis. Nodular lymphangitis is classic, but papules, pustules, ulcers, inflammatory plaques, and single nodules also can occur.^1,2 Lymphadenopathy may or may not be present.^4,8,9 The differential diagnosis is broad and includes infection by other nontuberculous mycobacteria such as Mycobacterium chelonae; Mycobacterium fortuitum; Nocardia species, especially Nocardia brasiliensis; Francisella tularensis; Sporothrix schenckii; and Leishmania species. It is not surprising that 4 patients in our study were initially treated for a gram-positive bacterial infection and 3 were treated for a fungal infection before the diagnosis of M marinum was made. Distinctive features that may help to differentiate these infections are summarized in Table 2.

We found that the main cause of delayed diagnosis was the failure of physicians to obtain a thorough history regarding patients’ recreational activities and animal exposure. Patients often do not associate a remote aquatic exposure with their symptoms and will not volunteer this information unless directly asked.^2,10 It was only after repeated questioning in all of these patients that they recounted prior trauma to the involved hand related to the aquarium.

Biopsy and Culture
Histopathologic examination of material from a biopsied lesion can give an early clue that a mycobacterial infection might be involved. Biopsy can reveal either noncaseating or necrotizing granulomas that have larger numbers of neutrophils in addition to lymphocytes and macrophages. Giant cells often are noted.^5,9,11 Organisms can be seen with the use of a tissue acid-fast stain, but species cannot be differentiated by acid-fast staining.¹² However, the sensitivity of acid-fast stains on biopsy material is low.^3,13,14

Culture of the involved tissue is crucial for establishing the diagnosis of this infection. However, the rate of growth of M marinum is slow. Temperature requirements for incubation and delay in transporting specimens to the laboratory can lead to bacterial overgrowth, resulting in the inability to recover M marinum from the culture.¹³Mycobacterium marinum grows preferentially between 28°C and 32°C, and growth is limited at temperatures above 33°C.^13,15,16 As illustrated in the cases presented, recovery of the organism may not be accomplished from the first culture performed, and additional biopsy material for culture may be needed. Liquid media generally is more sensitive and produces more rapid results than solid media (eg, Löwenstein-Jensen, Middlebrook 7H10/7H11 agar). However, solid media carry the advantage of allowing observation of morphology and estimation of the number of organisms.^12,17

Rapid Detection
Advancements in molecular methods have allowed for more definitive and rapid identification of M marinum, substantially reducing the delay in diagnosis. Commercial molecular assays utilize in-solution hybridization or solid-format reverse-hybridization assays to allow mycobacterial detection as soon as growth appears.¹⁸ Use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry can substantially shorten the time to species identification.^19,20 Nonculture-based tests that have been developed for the rapid detection of M marinum infection include polymerase chain reaction-restriction fragment length polymorphism and polymerase chain reaction amplification of the 16S RNA gene.²¹ It should be noted, however, that M marinum and Mycobacterium ulcerans have a very homologous 16S ribosomal RNA gene sequence, differing by only 1 nucleotide; thus, distinguishing between M marinum and M ulcerans using this method may be challenging.^22,23

Management
Treatment depends on the extent of the disease. Generally, localized cutaneous disease can be treated with monotherapy with agents such as doxycycline, clarithromycin, or TMP-SMX. Extensive disease typically requires a combination of 2 antimycobacterial agents, typically clarithromycin-rifampin, clarithromycin-ethambutol, or rifampin-ethambutol.¹² Amikacin has been used in combination with other agents such as rifampin and clarithromycin in refractory cases.^22,24 The use of ciprofloxacin is not encouraged because some isolates are resistant; however, other fluoroquinolones, such as moxifloxacin, may be options for combination therapy. Isoniazid, pyrazinamide, and streptomycin are not effective to treat M marinum.

Susceptibility testing of M marinum usually is performed to guide antimicrobial therapy in cases of poor clinical response or intolerance to first-line antimicrobials such as macrolides.²⁵ The likelihood of M marinum developing resistance to the agents used for treatment appears to be low. Unfortunately, in vitro antimicrobial susceptibility tests do not correlate well with treatment efficiency.¹⁰

The duration of therapy is not standardized but usually is 5 to 6 months,^7,10,26 with therapy often continuing 1 to 2 months after lesions appear to have resolved.¹² However, in some cases (usually those who have more extensive disease), therapy has been extended to as long as 1 to 2 years.¹⁰ The ideal length of therapy in immunocompromised individuals has not been established²⁷; however, a treatment duration of 6 to 9 months was reported in one study.²⁸ Surgical debridement may be necessary in some patients who have involvement of deep structures of the hand or knee, those with persistent pain, or those who fail to respond to a prolonged period of medical therapy.²⁹ Successful use of less conventional therapeutic approaches, including cryotherapy, radiation therapy, electrodesiccation, photodynamic therapy, curettage, and local hyperthermic therapy has been reported.^30-32

Conclusion

Diagnosis and management of M marinum infection is difficult. Patients presenting with indolent nodular skin infections affecting the upper extremities should be asked about aquatic exposure. Tissue biopsy for histopathologic examination and culture is essential to establish an early diagnosis and promptly initiate appropriate therapy.

Acknowledgment
We would like to thank Carol A. Kauffman, MD (Ann Arbor, Michigan), for her thoughtful comments that greatly improved this manuscript.