Mycobacterium marinum
Authors: Domenico Bonamonte MD PhD, Michelangelo Vestita MD
Authors (First Edition, 1991 and Second Edition 2002): David E. Griffith, M.D., Richard J. Wallace, Jr., M.D.
Microbiology
Mycobacterium marinum, a non-tuberculous pathochromogen with an intermediate growth rate between rapidly and slowly growing mycobacteria, belongs to group I of the Runyon classification (57a). M. marinum grows optimally at 28° to 32° C (within 2-3 weeks), while fails to grow on primary isolation at 37°C, a feature that distinguishes this species from M. kansasii. If M. mariunm infection is suspected, the laboratory staff should be notified so that cultures are incubated at optimal temperatures in order to isolate M. marinum. M. marinum lacks catalase and nitrate reductase activities; some isolates, but not all, hydrolyze Tween 80.
Epidemiology
M. marinum causes disease in many poikilothermic fresh or salt waterfish species over a wide geographic distribution (54). While endemic in fish, M. marinum infection in humans, due to contact with contaminated water or fish, is comparatively rare (4, 5, 5a, 12, 12a, 40). M. marinum, which was first isolated in 1926 by Aronson from dead saltwater fish in the Philadelphia aquarium (6), was recognized as a human pathogen in 1951 by Norden and Linell, who isolated it from skin lesions in swimmers who had bathed in a contaminated pool in Sweden (51). The infection was therefore labeled as "swimming pool granuloma" (3, 14, 23, 29, 34). Finally, in 1962 Swift and Cohen first reported 2 cases of M. marinum infection from a tropical fish tank; the term "fish tank granuloma" was then devised (64). Since those reports, "swimming pool granuloma" has essentially disappeared because of proper chlorination of this reservoir. Various other aquatic environments may imply potential risk, including household aquaria, skin diving (68), dolphin training (32), and a number of fishing and bathing activities (73).
In a retrospective survey carried out in 21 Spanish laboratories from 1991 to 1998, 39 bacteriologically confirmed cases were noted (17). Culture confirmed M. marinum infection was reported in 66 patients from 1996 to 1998 in France, with an infection incidence of about 0.04 cases per 100.000 inhabitants per year (7a). The annual incidence in the USA is 0.27 confirmed cases per 100.000 inhabitants (43).
The two major risk factors for M. marinum infection in immunocompetent patients are exposure to M. marinum-infested waters and the presence of superficial cuts or abrasions. Almost half (49%) of M. marinum infections are aquarium related, 27% are related to fish or shellfish injuries and 9% are related to injuries associated with salt water or brackish water (3). Risk factors for HIV-infected individuals would be similar exposures. Although there has been no reported change in M. marinum infection prevalence and frequency in the developed world since the AIDS epidemic, several cases of disseminated infection in AIDS patients have been described (46, 65). It would probably be prudent for HIV infected persons to avoid maintaining freshwater aquaria.
Clinical Manifestations
Suspicion of the diagnosis is based on occupational and recreational exposure history. The average incubation period for M. marinum infection is 21 days, although it may be as long as 270 days and 35% of cases have an incubation period of 30 days (3). Since lesions may appear somewhat remotely after the time of exposure, eliciting an appropriate history of swimming pool or seawall abrasion, barnacle scrapes, fish fin punctures or possession of tropical fish tanks is critical in making a timely and accurate diagnosis.
Given the optimal growth temperature of M. marinum, the infection is primarily localized to the coolest region of the body, which is the skin. Less commonly, it involves deeper structures such as the joints, tendons and bones (9, 55, 57, 58, 62). Dissemination of the infection more commonly occurs in immunocompromised hosts, like transplant recipients and subjects on corticosteroid therapy (30, 38, 63, 65), while being rarely reported in close-to-intact immunity individuals (45, 67).
Skin lesions usually appear as papules or nodules on one of the upper limbs, especially on the elbows, fingers and dorsum of hands, progressing to shallow ulceration and scar formation. Most lesions are solitary, although occasional "ascendic" lesions develop that resemble sporotrichosis. Clinical involvement of regional lymph nodes is uncommon.
Some of the authors directly observed 15 cases of aquarium-borne infection; among these 12 (80%) were male and 3 (20%) female; male to female ratio was 4:1 (12a). Age ranged from 15 to 55 years (mean: 39.9). The infection was occupational in 11 subjects (3 of them worked at an institute aquarium, 8 were in the aquarium selling business) and extra-occupational in 4 patients (all of them tended home aquariums). One of these latter patients was in the 8th month of pregnancy at the time of observation. Every patient had a documented history of former minor trauma, such as abrasion or superficial wound, acquired by handling fish, shellfish or alternativel caused by infected foreign bodies within the aquarium, like wood splinters or stones. The median incubation time after the traumatic inoculation was relatively long, ranging from 3 to 24 weeks (mean: 6.6). Three patients (20%) presented with a single papulo-verrucous plaque and 12 (80%) had a sporotrichoid distribution of nodular lesions. The anatomical distribution of lesions typically affected the upper limbs, at first involving hand fingers and dorsum (right hand in 13 cases, left hand in 2 cases), in 12 cases later spreading centripetally to the whole arm, trailing up the lymphatic vessels. In 3 of these 12 sporotrichoid cases, the first observed lesions were ulcerated nodules causing mild pain, as opposed to the remaining cases, which were painless. Associated systemic symptoms, localized adenopathy, deep structures involvement (tenosynovitis, osteomyelitis, bursitis, arthritis) were not present in any of the 15 cases, most likely because of the brief time lag between disease onset and clinical diagnosis. All patients were immunocompetent and reported no history of transplantation or immunosuppressive therapy. An interesting finding emerged from the anamnesis of the 12 sporotrichoid pattern cases: nodular lesions, arrangend in rosary-like chains, appeared one after the other at regular 1-2 weeks intervals. Moreover, every discrete lesion first involved deep cutaneous structures, presenting as a prominence covered by healthy skin, and later affected the overlapping "epidermis" (12a).
Laboratory Diagnosis
Diagnosis is essentially made through histological examination and culture. The laboratory staff should always be notified that M. marinum is suspected, so that Lowenstein-Jensen agar cultures at 28°-32°C, besides those at 37°C, are prepared. The material should be left 6 weeks in the agar. According to the literature, the positivity rate of cultures ranges from 70% to 80%; in the series of 15 cases described by some of the authors, M. marinum was isolated in 13 out of 15 patients (93.3%) (12a).
Concerning histopathology, it is widely known that the histological diagnosis of M. marinum infection can be difficult (24). Various aspects tend to vary according to the lesion age. In particular, a non-specific inflammatory infiltrate may be observed in the first 6 months; after such period, granuloma with epithelioid and multinucleated cells are much more likely (4,29). Various different patterns can be present: sarcoid-like granuloma, granuloma annulare, or rheumatoid-like nodules are frequently seen (1, 8, 26, 66). Epidermal chanches (hyperkeratosis, acanthosis, pseudoepitheliomatous hyperplasia, intraepidermal neutrophilic abscesses and ulceration), as well as dermal fibrosis (in chronic lesions) and small blood vessels proliferation are important constant findings (1, 24). Among the mentioned 15 cases, one lesion (6.7%) dating back 5 months showed tuberculoid granuloma, with lymphocytes, histiocytes, neutrophils, giant cells and no sign of central caseation. In the remaining 14 cases, in which lesions were 3 to 12 weeks old, a non-specific dermal and/or hypodermic mononuclear cell infiltrate (lymphocytes, histiocytes, plasma cells) was noted, with little or no tendency towards tubercular-like granuloma formation (12a).
A useful additional laboratory examination is PCR analysis. Identification of M. marinum through Zhiel-Neelsen stain of biopsy specimens, direct smears or yellowish discharge is only rarely positive, since the number of mycobacteria is low. Some of the authors were able to identify acid-fast bacilli only in one out of 15 cases (12a), a finding similar to the low detection rate reported in the international literature (4, 23, 29). Intradermal skin tests with the purified protein derivative (PPD) of M. marinum should be intensively positive in order to be diagnostically relevant, as it can cross-react with other mycobacteria PPD and M. tuberculosis especially, as the latter is closely related to M. marinum genomically (12a, 37, 62a).
As a complementary exam, in order to demonstrate contamination of aquarium waters, M. marinum can be isolated in dead fishes, through histological exam, direct observation or PCR analysis (12a).
Pathogenesis
Pathogenic mycobacteria initiate long-term infection by entering host macrophages where they cause extensive remodeling of their vacuolar environment to prevent vacuolar acidification and lysosomal fusion. M. marinum, which grows rapidly at 28°to 32° C, causes a systemic tuberculous-like disease in fish, frogs and other cold blooded animals which constitute its natural hosts. In warm blooded animals, including humans, it causes peripheral disease characterized by granulomas consisting of modified epithelioid cells. In humans dissemination of the infection occurs in immunocompromised hosts, like transplant recipients, while being rarely reported in immunocompetent individuals. In recent years, significant updates concening M. marinum physiopathology have been reported. A dynamic host-pathogen interaction has been evidenced: metabolically active bacteria are controlled by the host immune system and products of specific bacterial genes interfere with the host effort to eradicate the pathogen. In detail, the ESX-5 system of the mycobacteria is responsible for the secretion of various proline-proline-glutamic acid (PPE) and proline-glutamic acid (PE)-polymorphic GC-rich repetitive sequence (PGRS) proteins. Animal models studies suggest that such proteins interact with host immune components and possibly subvert critical innate immune pathways, establishing a moderate and persistent infection (19, 27, 39, 60, 70). In vitro observations on infected human macrophages further suggest that such proteins strongly modulate the human macrophage response and actively suppress T-lymphocyte receptor signaling-dependent innate immune cytokine secretion, thus allowing bacteria survival (2). In particular, the PPE38 protein, expressed on cell-wall surfaces, seems to be involved in bacterial surface proprieties such as cord formation, sliding motility and biofilm formation, as well as in the induction of pro-inflammatory cytokines in infected macrophages (70). Additionally, some authors presume that these proteins represent a source of antigenic variation which allows the pathogen to evade antigen-specific host responses (27). Considering the above data, it is easier to understand how immunological impairment is a significant factor in the establishment of M. marinum infection on a pathogenic level (56).
Recently, M. marinum infection has also gained a relevant role as an opportunistic infection in patients treated with anti-tumor necrosis factor (TNF)-alpha and other biological drugs (3, 16, 20, 44, 56a, 71); however, later reports support a safe re-exposition to anti-TNF-alpha therapy after bacteria elimination trough correct antibiotic therapy (33).
Susceptibility In Vitro and In Vivo
Rifampin and rifabutin are the most active drugs against M. marinum with typical MIC90 for these agents < 0.5 and 0.6 mg/ml, respectively. The MIC90 (the MIC that inhibits 90% of isolates) for older or traditional agents include ethambutol 2-4.0 mg/ml, sulfamethazole 8.0 mg/ml, doxycycline 16.0 mg/ml, minocycline 4.0 mg/ml, amikacin 4.0mg/ml, and imipenem 8.0 mg/ml (8, 15, 69). M. marinum isolates have moderately high MIC90, above concentrations usually obtained in tissues, to isoniazid (8.0 mg/ml), ciprofloxacin, ofloxacin, levofloxacin and streptomycin. M. marinum isolates are resistant to pyrazinamide (8, 15, 69). A number of newer agents have shown activity against M. marinum including clarithromycin (MIC90 of 4.0 mg/ml) and the 8-methoxy quinolones gatifloxacin and moxifloxacin (MIC90 of 1-2.0 mg/ml). Preliminary data suggests the new oxazolidinone linezolid also has activity against M. marinum in vitro (15a).
Because MICs or fixed concentration susceptibilities show little variation from strain to strain, susceptibilities are rarely indicated for treatment of M. marinum infections. Acquired mutational resistance with definite changes in drug susceptibility for M. marinum has not been reported. The NCCLS (National Committee for Clinical Laboratory Standards) recently (December, 2000) published tentative guidelines for susceptibility testing of M. marinum isolates (50). The Committee recommended that routine in vitro susceptibility testing not be done. When testing was deemed clinically necessary, no specific test method was recommended. Drugs to be tested included clarithromycin, minocycline/doxycycline, rifampin, ethambutol, trimethoprim/sulfamethoxazole (TMP/SMX) or a sulfonamide alone, and amikacin (50).
Antimicrobial Therapy
There is currently no consensus on the optimal treatment of M. marinum infection. Therapy is usually medical in nature, although adjunctive surgical procedures, cryotherapy and electrodessication may be needed to control resistant or deeper infections. Therapy duration varies widely in the literature: most authors recommend extended treatment for 1-2 months following clinical resolution, ranging from 2 to 12 months overall, given the absence of substantial dose-related and time-dependent side effects when using recommended drugs. Spontaneous resolution is possible but rare; complete regression can take up to 2 years (34). Various antibiotics are reported as effective options; in agreement with other authors, however, the final choice is primarily based on the clinician experience (7a, 25, 56). Moreover, randomized controlled trials comparing different antibiotic regimens are currently lacking. Widely used molecules include tetracyclines (mostly minocycline and doxycycline), sulphamethoxazole plus trimethoprim, rifampin and ethambutol. Less common alternatives comprehend clarithromycin, levofloxacin and amikacin (7a, 11, 22, 25, 29, 31, 35, 41, 42, 56). Other drugs, such as new macrolides and fluoroquinolones, also represent feasible solutions (7a) (Table 1). Success and failure are both reported for each of the listed molecules.
Monotherapy with minocycline, doxycycline and clarithromycin has been shown successful in most cases, especially in superficial cutaneous infections (35). Combination therapy, often with clarithromycin plus rifampin and/or ethambutol, is preferred in severe forms characterized by deep tissues involvement. The use of ethambutol, however, adds to the complexity of treatment as it requires monitoring for color vision and visual acuity (21). Limited published experience with clarithromycin exists (23, 59); however, its in vitro activity against M. marinum suggests that it would be quite effective. Rifampin alone has also been recommended, but there is scarce experience with this regimen (28).
The cited series of 15 cases of M. marinum infection endorses the results of previous reports on minocycline monotherapy efficacy, which was in fact sufficient in 13 cases over the course of 2-3 months. A single case with sporotrichoid pattern was treated with rifampin-isoniazid association for 2 months, after failure of sulfamethoxazole plus trimethoprim for one month. In a case of a pregnant woman, temporarily left untreated given the unfavorable benefit-risk ratio, the infection regressed spontaneously over a 3 months time-frame (12a). Some authors strongly advocate combination therapy in every case, since antibiotic susceptibility tests in M. marinum are often inaccurate, as well as to avoid selection of resistant strains. The latter, however, has yet to be observed, as no single antibiotic has a potent activity against M. marinum, as confirmed by in vitro susceptibility tests (7, 7a, 47).
Each regimen should be administered for a minimum of 3 months. The rate of clinical response is generally low with any regimen; therefore a minimum of 4 to 6 weeks of therapy should be given before considering the patient as a non-responder. Surgical debridement may also be important, especially for disease involving the closed spaces of the hand or disease responding poorly to drug treatment. If a lesion is surgically excised, appropriate antibiotic coverage in the perioperative period is generally recommended. It is not clear if chemotherapy following surgery improves treatment success (Table 2).
As of today, published observations on disseminated M. marinum disease in AIDS patients, or other immunocompromised individuals, is limited. Hanan et al described a patient with AIDS and sporotrichoid M. marinum infection who responded well to 6 months of rifampin and ethambutol, although recurrence was noted soon after therapy discontinuation (36). Bonnet et al. described an AIDS patient with fluctuant nodules due to M. marinum who failed 5 months of ofloxacin and minocycline (13). The patient was then shifted to rifampin, ciprofloxacin and amikacin, not showing a favorable clinical response until clarithromycin was added. Therefore it seems prudent to treat immunocompromised hosts with M. marinum infection with two agents at least, including clarithromycin (52). Duration of therapy in this setting is far for being standardized, but should be 6 months minimum and possibly lifelong in cases of worsening severe immunosuppression (Table 2).
Concerning the use of antibiograms for aimed therapy, antibiotic susceptibility testing is currently not recommended on a routine basis, with the exception of a patient failing treatment after several months (35). This is mainly because in vitro results do not necessarily relate to in vivo effectiveness, M. marinum is particularly susceptible to many commonly used antimicrobials, and the risk of acquired resistance to such drugs is negligible (47, 72).
Endpoints for Monitoring Therapy
The natural history of infection with M. marinum is variable. Spontaneous remission, particularly when trauma is minor, is fairly common in an immunocompetent person. However, chemotherapy is indicated when trauma results in frank ulceration, sporotrichoid lesions appear, a joint or tendon is involved, or the host is immunocompromised. Effective therapy should be associated with healing of all skin lesions within one month of therapy commencement. Immunocompetent patients should remain on drugs for another 2 months without evidence of active inflammation, again with total minimum therapy duration of 3 months.
Prevention
The use of adequate concentrations of free chlorine in swimming pools, spas and hot tubs water is advisable, as recommended by the Center for Disease Control and Prevention (18, 18a). Furthermore, fish-tank related infections may be prevented by the use of water-proof gloves during maintenance and by the appropriate care of potential upper limbs skin lesions (61). Concerning the latter, however, chlorine derivatives show a limited activity against mycobacteria (10). Recently, fish-tank water sterilization by UV filters, which easily inactivate mycobacteria, has been introduced in the market and a vaccine against M. marinum infection in fish has also been designed (49, 53).
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Tables
Table 1. Most widely used drugs in the treatment of M. marinum cutaneous infection according to the literature (15).
| Antimycobacterial agent | Dosage* | Duration |
|---|---|---|
| Minocycline | 50-100 mg/2/day | 2-6 months |
| Doxycycline | 50-100 mg/2/day | 4-5 months |
| Clarithromycin | 250-500 mg/2/day | 3-6 months |
| Ofloxacin | 200-300 mg/2/day | 1-2 months |
| Ciprofloxacin | 250-500 mg/2/day | 2-3 months |
| Levofloxacin | 250-500 mg/2/day | 2-3 months |
| Amikacin | 15mg/kg/day - max 1gr im | 2-5 months |
| Rifampin | 600-900 mg/day | 2-5 months |
| Rifamycin | 250 mg im/2/day | 2-5 months |
| Rifabutin | 450-600 mg/day | 2 months |
| Sulfamethoxazole+trimethoprim | 400 mg +80 mg /2/day | 3-4 months |
| Ethambutol hydrochloride | 15-25 mg/kg/day | 2-6 months |
*Wherever unspecified, administration is per os.
Table 2. Diagnostic Tests
| Localized cutaneous disease in immunocompetent host | Disseminated disease, including patients with AIDS | Adjuvant surgical treatment |
|---|---|---|
Monotherapy with one of the following agents: Clarithromycin, Minocycline, Doxycycline, Sulfamethoxazole+Trimethoprim, Rifampin+Ethambutol Administration for 1-2 months after symptom resolution. 3-4 months total duration of therapy |
Multidrug regimen with 2 or more active agents. Clarithromycin is recommended Optimal duration of therapy unknown, at least 6-12 months |
In case of involvement of the closed spaces of the hands In case of poor response to treatment |
What's New
None.
Guided Medline Search For:
Reviews
Cober E, Kaul DR. Non-Tuberculous Mycobacteria in Solid Organ Transplant Recipients.
Panadian TK, et al. Mycobacterium marinum infections in transplant recipients: case report and review of the literature. Transpl Infect Dis 2008;10(5):358-363.
Stinear T. et al. From Marinum to Ulcerans: a Mycobacterial Human Pathogen Emerges. Microbe 2007;2:187-194.
An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculosis Mycobacterial Diseases. Am J Respir Crit Care Med 2007:175;367-416.
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History
Stinear T. et al. From Marinum to Ulcerans: a Mycobacterial Human Pathogen Emerges. Microbe 2007;2:187-194.