Abstract

Background

Mycobacterium marinum is an atypical mycobacterium that can be found in water environment. It is the agent of a characteristic skin disease known also as fish tank granuloma. In some occasions it can spread as a nodular lymphangitis, extend to deep structures as well as in exceptional cases disseminate systemicaly . The infection is adquired after contact with fish or contaminated water mainly from aquaria or swimming pools. Although the real incidence is understimate, it is a uncommon infection that needs high clinical suspicion to be diagnosed. As a consequence, delay in the diagnosis is common. Mycobacterium marinum is intrinsically a multidrug resistant mycobacterium.There is no clear consesus in the management of this infection. Usually it is managed either with monotherapy or with combination of antibiotics plus surgery in selected cases.

Methods

  1. 1. Retrospective study of cases of fish tank granuloma collected from 2000 to 2009 in the dermatology surgery of The Hospital of Tropical Diseases (HTD) of the University College London Hospitals.
  2. 2. Systematic review of the literature with the terms “Mycobacterium marinum? and “fish tank granuloma? from 1999 to 2009.

Results

From the HTD dermatology surgery were collected 7 cases. Identification of M. marinum was possible only in 5. The response to treatment was good at least in 5 of them. In the literature review there were reported a total of 516 cases. From those 133 could be analyzed as individual cases. Identification was possible in 89.5% of the cases. Cured was reported in 82%of the cases.

Conclusion

The key of the diagnosis is to collect accurately the history of exposure. Histology, although no pathognomonic, will rise the suspicion if granuloma formation are found and will facilitate the differential diagnosis. Identification is done after culture with classical biochemical tests. Molecular biology techniques have the advantage of accelerate the procedure. There is not enough evidence to propose any specific treatment. Currently, recommendations are based in experts opinions. A prospective, randomized controlled clinical trial would be valuable to propose a base evident treatment.

Contents Pages

Introduction

M. marinum is an environmental atypical mycobacterium ubiquitous in fresh, salt, and brackish water. It is known that infects temperate and tropical species of fish of at least 150 species, including ornamental fish. But also affects frogs, eels, oysters, aquatic mammals, toads and snakes [2, 11].

It cause tuberculosis-like disease in fish, its natural host [129]. The infection in fish has an average incubation period of 3 months. It affects viscera and produce anorexia with emaciation, skin defects, distension of the abdomen, being cause of sudden death [11, 12, 66].

In 1904, Alexander described for first time lesions in a cod fish that were associated with acid fast bacilli. But it was Aronson in 1926 that isolated the bacteria from tubercles of fish that died in an aquarium of Philadelphia. He described the bacilli as acid fast, chromogenic, pleomorphic and growing best at 18º-20ºC. Aronson suggested the name of Mycobacterium marinum [130].

M. marinum is as well the causative agent of the human disease called fish tank granuloma, also known as swimming pool granuloma or fish fancier´s finger syndrome. In 1951 Norden and Linell reported for the first time the human disease in a swimming pool outbreak in Örebro, Sweden. They described the lesions as chronic papulous ulcerations, usually located in the elbows. The pathogen was isolated from the walls of that swimming pool as well as from the lesions of the patients. They called the pathogen isolated Mycobacterium balnei [131]. It was not until 1959 when Bojalil demonstrated that M. marinum and M. balnei were in fact, the same mycobacterium [132].

M. marinum is the most frequent cause of skin infection among the environmental mycobacterium that affects humans [86, 133]. Nowadays the frequency of human infections is mainly sporadic. But in the past, outbreaks related with swimming pools were not uncommon [134]. As an example, one of the biggest epidemics was in Glenwood springs pool, Colorado in 1956 with 262 cases reported [135].

That was before chlorination became a common practice. Chlorination makes water safer. As was seen recently in Bologna, were water from swimming pools were free of M. marinum. But still could be isolated in 4.5% of the samples from the shower floor of the same [136].

The real global incidence of the disease is not know because the number of cases are underreported, due probably to the difficulties in the diagnosis [94]. It is world wide distributed but with a tendency to aggregate geographically [137]. Like in Chesapeake bay, Maryland, where there is an incidence of 4 cases per 100000 population per year [138]. Meanwhile in California was estimated in 0.27 cases per 100000 adults [139]. Or in Satowan, Micronesia, with an estimated prevalence of 10% of the population [115].

Apparently the global annual incidence remains small and stable [140]. Even though an increase number of reported cases has been noticed in The United States, going from an average of 40 cases per year in the 80s to an average of 198 cases per year in the 90s [141]. What seems clearer is that differing from other atypical mycobacteria the prevalence of M. marinum has not increased with the HIV epidemic [140].

Opposite to humans, the incidence in fish is increasing in hatchery fish, probably due to the high population density of fish. Transmission is possible fish to fish and between fish and amphibians. In addition it has been proposed transmission through eggs and through practice of feeding fish with fish carcasses [140].

There are 2 groups or clusters of M. marinum with different pathogenicity. Cluster I is characterized by producing acute disease and death in fish and also for affecting humans. On the contrary, cluster II only affects fish producing the classical chronic disease with granuloma formation [9]. This is also supported by a study done in Israel were it was seen that only certain strains of M. marinum affected humans. They also demonstrate that in Israel strains affecting humans came from ornamental fish and not from local fish for consumption [5].

The mode of transmission to humans is mainly waterborne and fish borne. Person to person transmission has not been documented [137]. However, It has been described indirect transmission via fomites in at least 3 cases. Two very small children and one infant who acquired the infection after bathing in containers that were previously used to clean the family fish tanks of tropical fish [27, 40, 142].

As other environmental mycobacterium, M. marinum has commonly low pathogenicity. For this reason in normal conditions only affects disrupted skin [8]. The main risk factor to contract the infection consists in having lesions or abrasions in the skin with exposure to non chlorinated water or marine animals infected [140]. The most frequently nowadays is the exposure to private aquaria. But some times the source of exposure is unknown. As a consequence, after the description of cases following injuries with plants, it has been suggested the possibility that could be other reservoirs different from water and fish. Although at the present moment this possibility has not been demonstrated [30, 43].

The incubation period is usually 3 to 4 weeks [135]. Following, the most common manifestation is a cutaneous lesion at the site of inoculation. It initiates as a solitary nodule or pustule that eventually evolutes to an ulcer , abscess or verrucous plaque [143]. It affects more frequently the extremities, probably because the pathogen grows better at low temperatures [144].

The severity of the disease depends, among other factors, on the number of microorganisms inoculated [134] In 20% of the cases the cutaneous lesions spread along ascending lymphatic vessels. This is called sporotrichoid spread or nodular lymphangitis [143]. As a result of direct extension invasion of deep structures as tendons, articulations and bones occurs in 29% of the cases [144]. Systemic dissemination is unusual but has been described in immunocompromised patients [140]. Spontaneous resolution , usually with scaring , has been documented from months after the infection up to 2 years [133, 135].

The diagnosis is based on the history of exposure and risk factors along with the characteristic clinical features. It is supported with histopathology, culture and bacteriological identification that in some cases require molecular biology techniques [94, 120]. The fact is that the diagnosis is not easy and in most of the cases is either delayed or remain being presumptive based in the history and response to treatment.

The objective of the treatment is to increase the speed of resolution and prevent progression of the disease [1]. With this purpose different combinations of antibiotics plus the support, in selected cases, of surgery are the common practices in the treatment of this infection. Although the election of the drugs still depends of the preference of individual authors and is not based on controlled evidence [143].

Aims and Objectives

The overall aim of the project is to determine the current state of evidence for the diagnosis and treatment of M. marinum infection. Being the specific objective to review the literature and the series of HTD cases with the purpose of suggest appropriate diagnosis and case management of Mycobacterium marinum infection.

Material and Methods

Cases with diagnosis of fish tank granuloma were review. The cases were diagnosed and treated from 2000 to 2009 in the dermatology surgery of The Hospital of Tropical Diseases of the University College London Hospitals. There were included patients with either culture positive for M. marinum or clinical diagnosis plus response to appropriate treatment.

The files of those patients were reviewed and data were collected in a questioner that included: anthropological data, past medical and drug history, risk factors and exposure, description and location of the lesions, spread or deep extension of the infection, incubation period , delay in diagnosis, diagnosis, treatment and evolution (see questioner in annex). Additional information considered relevant was as well collected.

A literature review in Medline and Cochrane databases was done. The review included the combination of the following terms: “Mycobacterium marinum? or “fish tank granuloma?. It was limited to papers from 1999 to July 2009, English and Spanish literature and humans. The papers obtained in the search were divided in 3 categories. First, case reports in which it was possible to collect data from individual cases. Information of those papers was collected in the questionnaire previously mentioned. Second, case series of 14 or more cases in which data from individual cases was not reported. And finally, a miscellaneous category of papers that were considered relevant for the diagnosis and treatment of this infection.

The information gathered in the questioners was computerized in Microsoft Excel 2007. No statistical analysis was done in view of the cases were publish not with this purpose. As a consequence probably important reporting bias would invalidate any statistical outcome. Simple description of the results was done.

Results

Cases of The Hospital of Tropical Diseases

From 2000 to July 2009 there were collected 7 cases with diagnosis of Mycobacterium marinum infection. The 7 cases included 6 males and 1 female and their ages ranged form 31 to 65 years. All the cases admitted to have had contact with an aquarium. In two cases the exposure was occupational. One of them worked in the London Zoo being responsible of the management of the aquaria. The second was a cook in a restaurant that store crustacean in an aquarium. All the cases presented nodular lesions located in one of the upper limbs, six of them with sporotrichoid spread and one with a solitary nodule (see photos is annex).

One patient that was taking oral prednisolone due to severe atopic eczema presented with tenosynovitis of the left hand, sporotrichoid spread and palpable regional lymphonodes. The rest of the patients were not immunosuppressed.
Biopsy of the lesions was performed in all the cases. However AFB were found just in one case. Whereas cultures were positive in 5 cases for M. marinum. In the other two cases the diagnosis was done based on history of exposure, clinical characteristics and positive response to treatment.

Different combinations of antibiotics were used with no clear advantage of any regimen in particular. In 4 patients it was need to change the regiment. The reasons were drug intolerance in one case and lack of improvement in the rest. There was also one case that initially was improving with a regimen of rifampicin plus minocycline. But after simplification of the regiment to clarithromycin monotherapy presented worsening of the lesions. This case was eventually controlled switching to minocycline plus ethambutol. There was one patient who presented a relapse after one year of the previous infection. Finally it was cured with 6 months of rifampicin plus clarithromycin.

Susceptibility test was done in 3 cases. It was detected resistance to trimethoprim-sulfamethoxazole and rifampicin in one case and susceptibility to clarithromycin, ethambutol and doxycycline in 3 cases. The average time of duration of the treatment was 6 months with a range of 2 to 9 months. Surgery was not required in any patient. The final outcome was good in 5 patients being the other 2 lost of follow up (see table 1).

Case
No Age(y)
/Sex Medical history
Drug history Exposure Location Clinical characteristics Histology
AFB results Culture Treatment Duration
(months) Evolution
1 9/M No Aquarium Upper limb Multiple nodules
sporotrichoid spread Granulomatous
inflammation
AFB - + 1-RIF+DOX
2-RIF+EMB+DOX
3-RIF+EMB+CLR 7 Cured
2 61/F Psoriasis
Chronic paronychia Aquarium Upper limb 3 nodules
Sporotrichoid spread AFB - + 1-MIN 2 Improving
Lost of follow up
3 64/M No Aquarium Upper limb Multiple nodules
Sporotrichoid spread Noncaseating
granuloma

- 1-EMB+TET
2-RIF+EMB+INH 9 Relapse
after 1year
3(*) 65/M Fish tank granuloma Aquarium Upper limb Multiple nodules
Sporotrichoid spread 1-RIF+CLR 6 Cured
4 59/M Severe atopic eczema
Systemic steroids Aquarium Upper limb Multiple nodules
Sporotrichoid spread
Tenosynovitis AFB + - 1-DOX
2-RIF+EMB
3-RIF+EMB+CLR
4-ERI+MIN ? Lost of follow up
5 44/M No Aquarium Upper limb 5 nodules
Purulent discharge
Sporotrichoid spread Necrotizing
granulomatous inflammation
AFB- + 1-RIF+MIN
2-CLR
3-MIN+EMB 3.5 Cured
6 31/M No Aquaria
(London Zoo) Finger Solitary nodule AFB - + 1-CLR+EMB 4 Cured
7 49/M No Aquarium
(Restaurant) Upper limb 5 nodules
Sporotrichoid spread + 1-RIF+EMB 5 Cured
(*) Notice that case number 3 is repeated. It belongs to the same patient that the one above but one year later. The patient presented a relapse after one year of being cured.

Results from the literature review

From 1999 to July 20009 there were found 233 results in Medline database and zero In Cochran Library. From those, 127 were considered relevant and consequently analysed in this review. From the 127 papers reviewed, 108 contained case reports and the 19 remaining were a miscellaneous of reviews or original articles covering issues related with diagnosis and treatment. No clinical trials or randomized control trials were found. In those years the literature reported a total of 516 cases of M. marinum infection. From those cases reported only 133 could be analyzed as individual cases. The rest of cases were reported as series of cases (See figure 1).

The number of cases reported per year since 1999 up to July 2009 have been variable with a minimum of 6 cases per year in 2004 to a maximum of 88 cases in 2000. No clear tendency to increase neither decrease has been notice (see Figure 2).

The majority of the cases have been reported in Europe, North America and South East Asia. No cases have been reported in Africa and only one case in South America (see Figure 3).

Results from papers that could be analyzed as individual cases

The reports included 82 men and 51 women. The average age was 46.7 years with a minimum of 18 months and a maximum of 87 years (see Figure 4). 70% of the patients had no relevant past medical history. 9% of the patients were immunosuppressed: 5 patients had HIV infection, 4 were recipients of solid organ transplant, 1 patient had a myelodisplastic syndrome, 1 had Non-Hodking Lymphoma and 1 had Chronic Lymphocytic Leukaemia. Among other relevant pathologies were reported 12 diabetic patients, 11 with rheumatic diseases and finally 5 that were suffering from other problems as: asthma, bullous pemphigoid, myasthenia gravis, Cronh´s disease and sarcoidosis. The majority of the patients were not taking any relevant drug. However, 20 of them were on systemic steroids, 12 had received steroids as local injection, 10 took methotrexate and 9 TNF-blockers.

The most frequent exposure referred was the contact with an aquarium usually of tropical fish, it was reported in 51% of the cases. It was followed in 26 cases (20%) by other kind of contact with fish mainly referred as contact while cooking or cleaning fish. Finally 16 cases (14%) had other kind of contact with water environment. That included mostly fishermen or recreational sailors.

Opposite to papers from the 60s, only in 2 patients referred contact with swimming pools. In 15 cases (11%) the source of exposure was not recall or reflected in the papers. Injury related with plants was reported in 3 cases. In one case the exposure was a bucket. The bucket was used to bath a child of 18 months after being used to put fish from an aquarium. As a result the child got infected [40]. History of trauma with skin barrier impairment was referred in 46 cases (71%) of the patients. Among those, 18 cases (39%) recall direct injury with either fin fish, fish hook or crab bite.

Occupational exposure was reported in 20 cases (15%). The most frequent occupational risk was to be cook and have injuries while cleaning fish. Another common job of high risk was to work in a pet shop, with the duty of cleaning aquaria. Finally fishermen are evidently in direct contact with water and fish and prone to suffer injures with fish hooks.
The incubation period was documented only in 30 patients. It went from 1 day up to 4 months with and average of 48.9 days. The cases that presented an incubation period less than two weeks had in common to have suffered penetrating injuries with fish (figure 5).

The upper limbs were affected in 120 case (90.2%), being the fingers the most frequent location. The lower limbs were affected in 11 cases (8.3%). The face in 7 cases (5.3%) and that included delicate locations as nostrils, eyelid and cornea. Finally, cutaneous dissemination was reported in 7 cases (5.3%). Sporotrichoid spread was found in 53 cases (39.8%). Lymphonodes affectation was recorded in only in 7 cases (5.3%) of the cases.

The lesions were described as nodules in 63 cases (7%), plaques in 23 (17.35%), papules in 13 (9.8%) and ulcers in 22 (16.5%). There was purulent discharge in 32 cases (24.1%), as well as swelling and tenderness in 37 (27.8%) and 42 (72.4%) cases respectively.

Involvement of deep structures was referred in 45 cases (33.8%) of the cases being the most frequent tenosynovitis with 34 cases (75.6%), followed by arthritis with 12 (26.7%) and osteomyelitis with 6 (13.3%). Systemic dissemination with documented bacteraemia was reported in 3 cases. The 3 of them were males from 66 to 87 years. In 2 cases the patients were on systemic steroids, due to myasthenia gravis[103] in one case and polymyalgia rheumatica[62] in the other. Sadly the third case that initially was not taking drugs, after being misdiagnosed as rheumatoid arthritis was put on systemic steroids, infliximab (TFN blocker) and methotrexate [59].

From the patients with invasive disease, including involvement of deep structures or systemic dissemination, 21 (46.6%9 were taken some kind of immunosuppressive drug. Meanwhile only 13 (15.5%) of the rest of the patients were taken them (see figure 6). Other interesting characteristic of the patients with invasive disease was that 15 (33.3%) of them referred direct fish injury. Only 3 (3.4%) of the rest had this exposure (see figure 7).

Patients that for any reason were taken immunosuppressive drugs presented different characteristics from the rest of the patients. More than half of them presented invasive disease compared with only 20% of the rest (see table 2).

Patients taking immunosuppressive drugs (*) Patients no taking any drugs
Number of patients 36 91
Average age (years) 53.2 44.9
Female % 14 / 38.9% 36 / 39.6 %
Sporotrichoid spread 13 / 36.1% 39 / 42.8%
Involvement deep structures 21 / 58.3% 19 / 20.8%
Systemic dissemination 3 / 8.3% 0
AFB positive 19 / 52.7% 33 / 36.3%
Culture 33 / 91.6% 75 / 82.4%
Bad evolution 2 / 5.5% 3 / 3.3%
(*)Immunosuppressive drugs including: TNF-Blockers, systemic steroids, local injectable steroids, methotrexate and azathioprine.
The time of evolution until the patients presented for consultation was as short as 4 days and as long as 18 years with an average of 8.6 months. The time until the diagnosis was finally done was only reflected in 17 patients. However the delay went from 21 days to 2 years with an average of 6.3 months.
Tuberculosis skin test was only done in 19 patients. From those 86.4% were positive. Biopsy of the lesions was done in 120 cases (90.2%). Aspirate was reported only in 19 cases (14.3%).
Histology characteristics suggestive of mycobacterial infection with granuloma formation were found in 45.5% of the biopsies. However, only 21% of those were described as caseating granulomas. Other frequent finding reported was mix infiltrates with chronic and acute inflammatory cells. In some cases a wrong diagnosis was done due to confusion with rheumatoid nodules, Sweet’s syndrome, foreign body granuloma or interstitial granuloma annulare (See table 3).

Table 3: Histology Findings

Histology description Number of patients
Non caseating granuloma 19
Caseating granuloma 12
Granuloma( type not specified) 26
Infiltrates of chronic and acute inflammatory cells (lymphocytes , neutrophils, histiocytes) 18
Granulation tissue 6
Abscess formation 9
Necrotizing folliculitis 1
Focal dermal necrosis 3
Fibrinoid degeneration 1
Necrotizing paniculitis 2
Cystic degeneration 1
Pseudoepitheliomatous hyperplasia 4
Acute suppurative paniculitis 1
Fibrinous exudates 3
Lichenoid inflammation 1
Acanthosis in epidermis 2
Necrotic Corneal Stroma 1
Dermal fibrosis 2
• Pseudocarcinomatous hyperplasia of follicles
• Nodular and perifollicular infiltrate of neutrophils and histiocytes
• Dermal fibrosis
• Collections of neutrophils within follicles 1 patient with lesions of 18 years evolution
Confusion with other pathologies
Rheumatoid Arthritis ( rheumatoid nodule) 2
Sweet´s syndrome 2
Foreign body granuloma 2
Interstitial granuloma annulare 2

In the samples collected AFB was found in 41.7%, was negative in 34.6% and was not reported in 23.6%. In total identification of M. marinum was possible in 119 cases (89.5%). Culture was positive in 114 cases (85.7%). The time until the cultures grew went from 8 to 56 days, with an average of 23.3 days. Identification with PCR was done in 19 cases (14.2%).

The imaging techniques were useful to diagnose extension of the infection. Radiographies were used in 25 cases (18.7%) to rule out bone involvement. Magnetic resonance imaging was used in 16 cases (12%) resulting in the diagnosis of tenosynovitis, abscess, join effusions or osteomyelitis.

About the treatment, 126 patients were treated with antibiotics; in the rest of the cases the management is not mentioned. Surgery was need in 38 patients (84.4%) with affectation of deep structures and in 21 patients (25%)with cutaneous lesions.

Monotherapy was used in 54 cases (42.8%), bitherapy in 38 cases (29.4%), triple therapy in 20 cases (15%) and combination of 4 or more drugs in 5 cases (4%). Finally combinations of drugs that included classical tuberculosis treatment were used in 10 cases (8.7%). In 41 patients the regimen of drugs needed to be change, either for non effectiveness or non tolerance. The regiment was change one time in 29 cases (21.8%), two times in 10 cases (7.5%), and up to 3 times in 2 patients (1.5%).

The drug more frequently used as monotherapy was clarithromycin, followed by minocycline, doxycycline, ciprofloxacin and trimethoprim-sulfamethoxazole. The combinations of drugs more frequently used were rifampicin + ethambutol followed by clarithromycin + rifampicin and clarithromycin + ethambutol. (Effectiveness of the different regimens depending of the extension of the disease can be seen in table 4)

Susceptibility test were reported in 34 patients. Rifampicin was susceptible in 86.4% of the test, ethambutol in 91.3%, clarithromycin in 95% and minocycline in 62.5%. Isoniazid was resistant in 100% of the tests done and streptomycin in 66.6% (see table 5).

The average time of duration of antibiotic treatment was 5.4 months, with a range of 12 days to 15 months. After completion of the treatment the final evolution of 109 patients (81.9%) was reported as good outcome or cured. Only in 8 patients (6%) the evolution was reported as bad outcome. No mention about the evolution was done in the rest of cases. Among 12 patients in which long follow up was reported, only one patient presented recurrence of the infection after 3 months course of doxycycline. (Characteristics of the cases with bad outcome are resumed in table 6.

Table 4:: Antibiotic Combinations Used Depending On The Extension of The Disease

Patients with only cutaneous lesions Patients with Invasive disease
Number of
patients Effectiveness Number of patients Effectiveness
Monotherapy 38 52.5% 16 75%
CLR 8 75% 5 100%
MIN 10 70% 1 100%
DOX 8 50% 1 100%
CIP 4 25% 2 50%
CTX 2 100% 3 33.3%
AZI 3 0% 0
AMK 1 0% 0
ERI 0 1 0%
LEV 0 1 0%
MOX 1 0% 0
OFL 1 0% 2 50%
Combinations of 2 drugs 26 92% 11 83.3%
CLR + EMB 6 100% 2 100%
CLR + CIP 1 100% 0
CLR + MIN 1 100% 0
CLR + RIF 5 80% 0
CLR +CTX 1 100% 0
RIF + EMB 9 100% 5 60%
RIF + CTX 0 1 100%
RIF + INH 0 1 100%
CIP +DOX 1 100% 0
CIP + EIR 1 0% 0
DOX +CTX 0 2 100%
CIP + EMB 1 100% 0
Combinations of 3 drugs 13 72.7% 7 66.6%
CLR + EMB + CIP 0 1 0%
CLR + EMB + RIF 2 100% 5 100%
CLR + EMB +RFB 0 1 0%
CLR +CTX + CIP 1 0% 0
EMB + AZI + MIN 1 0% 0
RIF + CLR + AMK 1 100% 0
RIF + INH + CLR 1 0% 0
RIF + EMB + CTX 5 100% 0
RIF + EMB + DOX 1 0% 0
RIF + EMB + MOX 1 0% 0
Combinations of > than 3 drugs 2 100% 3 33.3%
CIP+RIF + EMB + CLR + RFB + AMK 0 1 100%
CLR + DOX + RIF + EMB 0 1 0%
RIF + EMB + CLR + AMK + IMP 0 1 0%
RIF + EMB + AZ I+ CTX 1 100% 0
RIF + EMB + CLR + CIP 1 100% 0
Combinations with TB treatment 1 100% 9 55.5%
INH + RIF + EMB + CLR 1 100% 1 0%
INH + RIF + EMB 0 3 100%
INH + RIF + EMB + PZA 0 4 50%
INH + RIF + EMB + PZA + CLR 0 1 0%

TABLE 5: PATTERN OF SUSCEPTIBILITY

Drug Number of patients Susceptible Resistant Indeterminate
Isoniazid 9 9
Rifampicin 22 19 3
Ethambutol 23 21 2
Pyrazinamide 1 1
Streptomycin 6 1 4 1
Rifabutin 2 2
Azithromycin 4 1 3
Clarithromycin 20 19 1
Minocycline 8 5 1 2
Doxycycline 6 6
Tetracycline 2 1 1
Trimethoprim-sulfamethoxazole 6 5 1
Ciprofloxacin 11 6 1
Levofloxacin 1 1
Moxifloxacin 4 4
Gatifloxacin 1 1
Amikacin 9 9
Linezolid 1 1
Imipenem 2 2
Erythromycin 2 1 1
Cefotaxime 2 1 1
Kanamycin 3 3
Ethionamide 3 3
Ansamycin 1 1
The table reflects in how many patients each drug was tested and in how many it resulted as susceptible, resistant or indeterminate.

TABLE 6: CHARACTERISTICS OF CASES WITH BAD OR POOR OUTCOME

References Age
Sex Past medical history Type of infection Treatment Duration treatment (months) Evolution
[25]
67/M DM Cutaneous disseminated RIF+EMB+CLR+CIP 3.7 Deceased
Secondary bacterial infection
[26]
50/M No Tenosynovitis RIF+EMB
Synovectomy 3 Dysfunctional index finger
[46]
62/F No Tenosynovitis CLR
4 debridements 6 Amputation index finger
[46]
26/M No Tenosynovitis DOX+CTX
4 debridements 3.5 Persistent infection
Need of grafting
[73]
56/M No Tenosynovitis Local gentamicin
Synovectomy
3 drainages ? Deformity
[83]
47/M HIV infection Osteomyelitis 1-INH+RIF+EMB+PZA
2-Avobe + Fluoroquinolone
3-RFB+EMB+CIP
4-RFB+CIP ? Amputation Knee
[88]
60/F NHL
Systemic steroids Cutaneous disseminated 1-Ofloxacine
2-RIF+EMB+LEV+CLR
3-Above+STR+IG
4-CTX+MOX ? Continue with signs of active infection
[103]
81/M Myasthenia gravis
Systemic steroids Cutaneous and systemic dissemination 1-CIP
2-Hyperthermia
3-DOX intravenous 5 Deceased
Bone marrow infected by M.marinum

Results from papers that contain series of 14 or more cases

There were 14 papers that contained series of cases with no available information of individual cases. As a consequence, individual cases could not be analyzed separately. There were 2 papers that reported the same series of cases in different years, the cases were counted just once.

The principal characteristics of the papers are described in the table 7. There were 363 cases reported, 68% were males with an average of 44.3 years. In most of the cases the past medical history was not relevant; only 4 cases of HIV infection were reported. The most frequent exposure was to own an aquarium in 134 cases (37%). There was other kind of contact with fish in 37 cases (10%), swimming pool contact in 7 cases (2%) and other kind of contact with water in 58 cases (16%). In the rest of cases exposure was not mention. Finally occupational exposure was referred in 68 cases (19%). The incubation period was not reported.

The upper limbs were affected in 245 cases (67%), the lower limbs in 78 cases (21%), the face in 3 cases (0.8%) and there was cutaneous dissemination in 10 cases (3%). Sporotrichoid spread was reported in 46 cases (12%). The lesions were described as plaques in 92 cases (25%) and nodules in 54 cases (15%). Deep structures were affected in 45 cases (12%): 41 tenosynovitis (91%), 8 arthritis (18%) and 3 osteomyelitis (6%). There were no cases of systemic dissemination described in any of the series.

The average in the delay until the diagnosis was done was 3.8 months. The drugs more commonly used as monotherapy were doxycycline, minocycline, trimethoprim-sulfamethoxazole and clarithromycin. The combinations more prescribed were rifampicin plus ethambutol, rifampicin plus clarithromycin and clarithromycin plus ethambutol. The effectiveness of the treatments were not frequently reported. Consequently is not possible to point the advantage of any concrete regimen (see table 8). The average duration of the treatment was 5 months. Surgery was reported in 73 cases (20%). The evolution was good in 225 cases (62%), poor in 15 cases (4%) and not mention in the rest.

There were 5 papers that contained series of cases of atypical mycobacterial infections of the skin including fish tank granuloma cases. M. marinum was the most frequent mycobacterial found in those series. In the different series it represented from 30 to 64% of the cases

TABLE 7: CHARACTERISTICS OF THE SERIES OF CASES
Reference N Average age(y)
[range] Sex
Medical history
Drug history Exposure Most frequent location
Clinical characteristics Culture Treatment
Average duration (months) Evolution
Satowan
2009 [115]
39 26
[8-82] 29M
10F No relevant 87% Bomb-lakes 44% Knee Large warty plaques 100% - DOX 3 ?
Israel
2007 [116]
16 42 12M
4F 50% Aquarium
25% Fishermen 74% Upper limb Sporotrichoid 33%
Tenosynovitis 1case 100% + CLR
MIN
CLR+CIP
CLR+EMB 3.2 94% Cured
Taiwan
2007 [117]
19 48
[21-78] 11M
8F 21% Immunosuppressed 63% Marine animals 95% Upper limb 100% + CLR +EMB
DOX
RIF
64%Surgery ? Cured
Hong Kong
2006 [118]
17 44
[21-75] 11M
6F 12% Aquarium
12% Fishermen 94% Upper limb Plaque 70%
Nodules 17% 100% + MIN
DOX
INH+RIF+PZA+(MINorEMB) 4.9 94% Cured

Maryland
2005 [121]
29 50
[28-70] 26M
3F 7% Syst. steroids
34% Local steroids inj. 69% Aquatic activities 100%
Upper limb Tenosynovitis 86% 100% + EMB+RIF (59%)
100%Surgery 6
Spain
2005 [119]
22 86% Aquarium
9% S. pool Sporotrichoid63% 100% +
France
2002 [122]
63 46
[4-77] 37M
26F 6% HIV infection 84% Aquarium 95% Upper limb Sporotrichoid 25%
Deep infection 28% 100% + CLR
MIN
DOX
RIF+EMB
47%Surgery 3.5 87% Cured
Taiwan
2002 [123]
14 49
[9-72] 8M
6F 36% DM
14% Local steroids inj. 35% Aquarium
93%
Upper limb Sporotrichoid 28%
Arthritis 1case 100% + Combinations with:
INH, RIF, EMB, PZA, CLR, DOX, CTX, CIP 3 64% cured
Spain
2001 [124]
45 5M
20F 77% Aquarium
17% S. pool 82% hand 86% + MIN
CLR
RIF+EMB 2-4 99% Cured
Singapore
2000 [126]
38 44
[14-85] 30M
8F 34% Aquarium
10% fishermen 73%
Upper limbs Plaques 65%
Nodules 26%
Sporotrichoid 5% 2.9% + MIN
CTX
Surgery 1case 3.7 68% cured
UK
2000 [127]
14 49
[9-76] 12M
2F 85% Aquarium 93%
Upper limbs Sporotrichoid 57% 100% +
Thailand
1999 [128]
18 100% + CTX 3-4 Most Cured

TABLE 8: DRUGS REGIMENS USED IN THE SERIES OF CASES
Treatment Number
patients Good
response No
improvement Evolution
not known
DOX 51 10 (19.6%) 41
CTX 38 13 (34.2%) 2 23
CLR 13 9 (69.2%) 4
MIN 42 17 (40.5%) 2 23
RIF 2 2 (100%) 0 0
DOX + CTX 1 1 (100%) 0
CLR + MIN 7 1 6
CLR + CIP 7 3 (42.8%) 4
CLR + EMB 10 3 (30%) 7
RIF + EMB 25 15 (60%) 4 6
RIF + CLR 20 1 19
RIF + DOX 7 7
RIF + MIN 3 3
CTX + MIN 5 5 (100%) 0 0
INH + RIF + PZA + MIN 1 1 (100%) 0 0
INH + RIF + PZA + EMB 9 1 (11%) 4 4
INH + RIF + EMB 2 1 (50%) 1 0
INH + RIF + EMB +CLR 1 1 (100%) 0 0
CLR + RIF + DOX + CIP 1 1 (100%) 0 0
CLR + RIF + EMB 1 1 (100%) 0 0
INH + RIF + EMB + CLR + CIP 1 1(100%) 0 0

Discussion

Diagnosis

Patients tend to present late when the lesions are already progressed. This plus the fact that delayed in the diagnosis is the norm can have as a consequence severe or invasive infections.

Clinical History

As we could see in this review history of exposure to contaminate water or fish with disrupted skin is present in the majority of the cases. As a consequence it must be consider as an important clue for the diagnosis. Owning an aquarium is the most common risk of exposure reflected in the literature. Males from 40 to 60 years old are most affected, probably because this age group is more prone to enjoy with the relaxing hobby of keeping tropical fish.

In a review done in 2000 was seen that the incubation period the 40 cases studied was as variable as 5 to 270 days, with an average of 21 days[100]. Meanwhile in this review the mean incubation period was a bit higher, almost 50 days, but as variable as the previous described.

Although immunosuppression is a risk factor for environmental mycobacterial infection, in the case of M. marinum is not so obvious. It seems more a factor for bad evolution and less a risk for increase the frequency of the disease. In this review there has been only 9 cases described in HIV patients and 4 in recipients of organ transplant. In fact there are only 6 cases described in the literature of cases in recipients of solid organ transplant [31].

Cutaneous lesions have been described as nodules in most of the cases but also can appear as papules or pustules and eventually abscess or ulcers or even as non-healing wounds[56]. Lesions that do no resolve spontaneously and have a very long time evolution have been described in Satowan island as large warty plaques[115].

The location is predominant in upper limbs but this is related to the site of inoculation and depends on the way of transmission. In other words, meanwhile exposure to aquaria are manifested as lesions in hands, in Satowan where the main affected population are taro farmers swimming in bomb crater lakes, knees are the most frequent location[115].

Sporotrichoid spread usually appears 4-8 weeks after the initial lesion but can occur from days up to 18 months of the same [139]. Nodular lymphangitis was one of the main characteristics of the HTD patients. It was also was frequently described, almost 40%, in the papers of this review. It is an important sign that shorten the list of differential diagnosis.
In patients with cutaneous dissemination it has been recommended to investigate the possibility of invasive disease as they are more at risk[96].

In this review from 7 cases of cutaneous dissemination 5 presented invasive diseases, including 2 cases of bacteraemia.
In 35% of the cases there was invasive disease, but because there is a tendency to publish the most severe cases, it is not easy to estimate the real risk of the involvement of deep structures. As an example in a review done form 1972 t0 2008 there were only 17 cases reported of osteomyelitis[29].

Invasive disease and systemic dissemination with bacteraemia has been associated with delayed in the diagnosis and not surprisingly with immunosuppression[145]. In this review 46.6% of the cases of invasive disease were associated to immunosuppressive drugs. Reports of systemic dissemination are very rare, from 1999 on 3 cases have been published and all of them were associated to the use of systemic steroids.

Deep involvement could be associated with deep penetration of the pathogen as happens when there is a penetrating injury [137] or direct injury from fish[51, 123]. In this review 33.3% of the cases of invasive disease were associated to direct fish injury as an exposure.

It is helpful to know that 60 to 85% of the patients convert the PPD to positive. Although this is not useful for the diagnosis it could be practical to avoid unnecessary TB prophylaxis in those patients [27, 134, 146].

Imaging

The importance of the imaging is mainly to recognise affectation of deep structures. X ray is useful to exclude osteomyelitis. In cases of tenosynovitis, with an MRI can be seen collections of fluid around the tendon with the tendon intrinsically normal. Although the imaging is not specific, it has been recommended to suspect atypical mycobacterial infection when exuberant tenosynovitis with normal muscle and bones is found [79, 80].

Histology

The desired microbiological diagnosis is better achieved if the samples for cultures are taken from tissue biopsies rather than from aspirates or secretions[2]. It has been recommended to take the biopsy from a non-ulcerate area close to the lesion.[7] The biopsy even if is non pathognomonic, is of great value for histological examination and differential diagnosis, [1, 2].

More than one biopsy could be required in order to have positive cultures[68]. Half of the sample must go for culture. The other half must be stained in hematoxylin-eosin for histology as well as stained for acid fast bacilli detection [146]. Most of the times AFB can not be found in the lesions [141]. In this review AFB was positive in less than half of the cases. On the contrary in immunosuppressed patients numerous AFB are usually found [147]. In this review it was also observed this difference (see table 2).

In the histology of early lesions of less that 3 months can be found non specific inflammation with mixed infiltrates of lymphocytes, neutrophils and histiocytes [7, 147]. In chronic lesions is more frequent to find granuloma formation. The granulomas are usually without caseation and can be tuberculoid-like, sarcoid–like or also can mimic rheumatoid nodules [7, 147]. In epidermis the changes consist in papillomatosis, hyperkeratosis, ulceration and acute inflammatory infiltrate. Subcutaneous tissue is rarely involved unless there is sporotrichoid spread[147].

Because culture is not always possible histology can be very important in the diagnosis. As in the series of cases of Singapore where in the 38 cases reported the granulomas were the clue of the diagnosis, just in one of the cases could be identified M. marinum in the culture[126]. The histology can be not only suspicious of mycobacterial infection and but useful for the differential diagnosis.

Microbiological Identification

M. marinum belongs to the group of facultative pathogens of the genus mycobacterium. It has been classified by Runyon as a slow-growing photochromogen [148]. Slow growing means that grows in 2-3 weeks. Actually it grows more rapid than the other mycobacteria of this group[132], producing smooth, shiny and creamy colonies after 7-21 days of incubation [140]. In this review the average was 23 days. It grows on ordinary media for mycobacteria, like Lowenstein Jensen. It is recommended to maintain the cultures for 6 weeks[133].

The term photochromogen means that produce yellow pigment when exposed to light, the colour change from white to yellow-orange[7, 132]. An important quality of M.marinum that differentiates it from other mycobacterium is that it grows at low temperatures. The optimal temperature is 25-32ºC. It also can grow at 37ºC if the strains are maintained on laboratory media[140]. Some biochemical characteristics important for the identification are: niacin negative , nitrate production negative, catalase at 25ºC positive, urease positive and Tween-80 hydrolysis positive[149]

Opposite to the diagnosis of other atypical mycobacterial infections[150] , when M. marinum is isolated there is no need to rule out contamination. In a study done in a New York Hospital from 2000 to 2003 , 100% of the isolates for M. marinum met criteria for disease [151].

Identification can be made by morphology and biochemical characteristics. The problem is that cultures are not always positive and the identification based on conventional biochemical tests is a laborious and a time consuming procedure. Molecular biology methods have the advantage of being accurate and rapid, making possible to discriminate species in days [60]. Polymerase chain reaction-based sequencing has been considered the gold standard in the species identification. It also permits identification when the mycobacteria do not grow in the culture.

It exist a web page were it can be compared the pattern obtained by PCR (http://www.hospvd.ch:8005) [94]. Depending of the target used additional gene regions need to be sequenced to differentiate M.marinum form M. ulcerans (that is a close related species) [3]. In the practice that does not use to be a problem due to the difference in geographical distribution and clinical manifestation of those two mycobacteria. However these techniques are not yet implemented in most of the facilities. In this review only in 19 cases the identification was done by PCR.

Differential Diagnosis

Histology is important in the differential diagnosis, as well as culture for other bacteria and fungus. Rheumatoid arthritis is not a rare misdiagnosis. Unfortunately it can led to immunosuppressive treatments that can seriously deteriorate the situation[59]. Some of the important causes of misdiagnosis can be seen in table 12.

It is also important to be aware that coinfection with other pathogens as Nocardia has been described [69]. If the manifestations are bursitis plus nodular lymphangitis the differential diagnosis can be reduced to M. marinum and Sporothrix chenckii [107].

TABLE 12: DIFFERENTIAL DIAGNOSIS [11, 22, 53, 55, 83, 101, 103, 144]

Infectious Causes Non Infectious Causes
Bacterial • Other atypical mycobacterial
• M. tuberculosis
• Leprosy
• Leishmaniasis
• Nocardiosis
• Tularemia
• Syphilis
• Bartonella hensellae
• Bartonella quintana
• Chronic pyogenic infection
• Cellulitis
• Erysipela
• Sarcoidosis
• Skin malignancies
• Foreign body reactions
• Pyoderma gangrenosum
• Rheumatoid arthritis
• Gout
• Psoriasis
• Verrucous lichen planus
• Majocchi’s syndrome
• Granuloma annulare
Fungal • Sporotrichosis
• Histoplasmosis
• Coccidioidomycosis
• Blastomycosis
• Scopularopsis blochi
Viral • Cowpox infection
• Verruca vulgaris
Alga • Cutaneous protothecosis

Treatment

The infection can have a spontaneous resolution or can become chronic and persist for decades. However always have the potential of invade deep structures [146]. Even with treatment cutaneous lesions can heal with scar and deep infections can result in impaired function of the member. The management is mainly medical and will depend on the severity of the case and the response to the treatment. The objective of the same is to increase the speed of resolution and prevent progression of the infection to deep structures [1]. Recrudescence after cured is possible as its seen in one of the HTD cases described.

Medical Treatment

The species must initially be considered susceptible to rifampicin, ethambutol, doxycycline, minocycline, trimethoprim-sulfamethoxazole and clarithromycin[152]. For this reason routine susceptibility testing is considered in most of the cases not necessary. However it is recommended in special situations as base line data, in treatment failure , in relapses or when the cultures continue being positive despite appropriate treatment[152, 153]. In those special situations the pattern of resistance is valuable as a guide to modify the antibiotic regimen.

It has been proposed for its clinical relevance to do a susceptibility test for doxycycline, minocycline, ethambutol, rifampicin and sulphonamide[153]. There are other authors who consider relevant to test also for clarithromycin and amikacin[152]. Finally it would have no benefit to test for isoniazid and pyrazinamide[153]. However it is useful to be aware that sometimes in vitro susceptibility do not corresponds with in vivo outcomes[67].

From 1999 to 2009 there were 5 papers that described the susceptibility pattern to different antibiotics of M. marinum. In general the strains were susceptible to the most common antibiotics used as; clarithromycin, minocycline and rifampicin. Different conclusions were found for quinolones among those studies (see table 9).

Table 9: Susceptibility Patterns of Mycobacterium Marinum

References Number strains isolated Results
France (1999)
[15]
10 • CIP : good in vitro activity , bacteriostatic in macrophage model
• OFL : poor in vitro activity , bacteriostatic in macrophage model
• GRE: good in vitro activity , bactericidal in macrophage model
Sweden (2001)
[16]
33 Homogeneous population
• 100% Susceptible : AMK, CLR, RIF, CTX, EMB
• 50%: Resistant: DOX
France (2000) [18]
53 Homogenous susceptibility pattern
• Susceptible: RIF, RFB, AMK, MIN, DOX, CLR, SMX, IMP
• Resistant: INH, EMB, OFL,CIP, LEV, AZI,TMP
• Indeterminate: MOX, SPR
Sweden (2002) [19]
43 • CLR was the most active, followed by LIN
• Quinolones MICs were close to the peak concentrations in serum. In decreasing order of activity: CIP = GAT = MOX > LEV > GEM
• Resistance: ERI and QD
USA ( 2002)
[17]
37 • CRL, MIN, AMK, GAT: 100% Susceptible
• CIP: 70.3% Susceptible
• RIF: 24.3% Resistance
• CTX: 2.7% Resistance
• DOX: 5.4% Resistance

Especial mention needs to be done to the literature review done by Rallis from 1986 to 2006 [1]. Minocycline and doxycycline were the most frequent regimens prescribed. About the macrolides, clarithromycin was used alone or in combination with good results, erythromycin was not effective and there was not sufficient experience with azithromycin. Clinical experience with new fluoroquinolones was not enough. Amikacin was use in very few cases with success but the parenteral administration discourages its use. Combinations of antibiotics were chosen in severe cases. In all the regimens were reported treatment failures. Good outcomes could not be related with any concrete regimen. His advises about the treatment are in concordance with the recommendations done by the American Thoracic Society in 1997 [153] (See tables 10 and 11).

Treatment with more than one drug can be advisable to reduce the risk of resistance [7]. However the risk of secondary resistances is very low. Currently there is only one case reported in the literature of development of secondary resistances. It was an immunodeficient baby with a disseminated M.marinum infection that coursed with bacteraemia and eventually died. The baby developed resistances to rifampicin and isoniazid after several months of treatment first with isoniazid + rifampicin + trimethoprim-sulfamethoxazole and after with amikacin + rifampicin + trimethoprim-sulfamethoxazole + clarithromycin. [154].

Therapy with rifampicin plus ethambutol was the first line recommended by Chapman in 1977[134]. This combination still can be considered as one of the first choices. In a review of 35 cases of deep infection, it was the most frequent regimen prescribed [145]. In this review it is also the most popular combination of drugs with an efficacy of 85.7%.

Combinations of 3 or 4 drugs have been advocated in cases of disseminated infections [21]. In this review from the 3 cases of systemic dissemination, 2 were treated with 3 drugs (CLR+EMB+DOX and CLR+RIF+EMB) with good results [59, 62]. The third case that unfortunately died was treated with parenteral doxycycline[103].
Trimethoprim-sulfamethoxazole is one of the drugs frequently used as part of the treatment. However, In this review there were 2 cases reported of infection meanwhile the patients were taken prophylaxis with trimethoprim-sulfamethoxazole to prevent P.jirovecii pneumonia[83, 97].

It is known that TNF-blockers increase the risk of granulomatous infections. There are many descriptions of cases of tuberculosis meanwhile taking this treatment. But there have been just few cases related to M.marinum infection. However the logical recommendation is to stop the TNF-blocker when the diagnosis of fish tank granuloma is done until adequate treatment has been completed. There is no guidance of how to manage the reintroduction[20, 155]. Same recommendations can be applied in the case of other immunosuppressors.

There are no clear rules about the duration of treatment. In a review of 35 cases of invasive disease it had an average of 11.4 months[145]. In this review the general average was 5 months and the average in the cases of deep affectation was 6 months.

Table 10: Rallis Recommendations [1]

Regimens recommended
Superficial cutaneous infection Severe cases
Sporotrichoid spread
Immunosuppression Disseminate infection
Bacteraemia
• Minocycline
• Clarithromycin
• Doxycycline
• Trimethoprim-sulfamethoxazole
Alternatives:
• Ciprofloxacin
• Azithromycin Rifampicin + Ethambutol Combination of 3 parenteral drugs that includes antimycobacterial
Regimens to avoid
• Isoniazid
• Streptomycin
• Pyrazinamide
Duration of treatment
• Average of 3 months
• Continue 4-6 weeks after resolution
Surgery indications
• Usually no necessary
• Excision : in small lesions that do not respond to medical treatment
• Debridement: deep infection with extensive damage
• Amputation: severe cases
Not effective Counterproductive
• Topical treatment
• Irradiation therapy • Intralesional steroids injections

Table 11: American Thoracic Society Recommendations [153]

Treatment Regimen Dose Duration
Clarithromycin 500mg (twice a day) At least 3 months
Minocycline 100mg (twice a day)
Trimethoprim-sulfamethoxazole 160/800mg (twice a day)
Rifampicin + Ethambutol 600mg / 15mg/kg (daily)
When consider treatment failure
If no response after 4-6 weeks of treatment
Surgery indications
Affectation of closed spaces of hand No clear duration of medical treatment after surgery
Poor response to medical treatment

Surgery

There are different points of view and recommendations for the role of the surgery in the management of M. marinum infection. But the when the indication of surgery is done it has been recommended to follow the intervention with an extended course of antibiotics [63]. In Satowan were the lesions were treated only with surgery bad evolution with recurrence and disfigurement was the norm[115].

In a review of the literature done by Lahey, surgery was necessary in 69% of 35 cases of invasive infection, followed by combination therapy in 88% of the cases[145]. In a series of 24 cases of involvement of deep structures of the hand conservatory treatment with antibiotics was chosen due to bad outcomes with surgery in the experience of the authors.

Finally it was need debridement in only 42% of the cases. Those were cases with bad evolution with medical treatment. Interestingly they were associated with some unfavourable prognostic factors at presentation, identify as: persistent pain , discharging sinus and previous local steroid injection[156]. In this review surgery was need in 84.4% of the invasive cases.

In a review of 47 cases of deep involvement of structures of the hand, it was suggested to do a close follow up due to the elevate risk of recurrences in those cases[51].

Others

Sporadically have been published cases treated with success with different adjunctive therapies; however there is not enough experience to recommend any of them.

Photodynamic Therapy

An appropriate light can activate porphyrins in the mycobacteria that as a result develop cytotoxic compounds damaging the cell. It was proved effective in one case of a 59 years old male no immunosuppressed who develop a single lesion. It was not improving with doxycycline. Then photodynamic therapy was used once a week during 3 weeks with not only resolution but no recurrence of the lesion[54]

Hyperthermic Therapy

The rational of this therapy lies in that M. marinum can not grow at high temperature. It has been used hyperthermia at 40ºC 5-6 hour daily in conjunction with minocycline with good results in one case reported in Japan[86].

Topical Antibiotic Treatment

It is not recommended due to lack of effectiveness [1]

Immunoglobulins

The use of immunoglobulin has been reported as a success in two cases. First in an 87 year old woman on systemic steroids due to polymialgia rheumatic who presented with disseminated cutaneous infection with bacteraemia. The other case was a 60 year old woman with a Non-Hodgkin’s Lymphoma and a disseminated cutaneous infection. Both patients were treated with different appropriate combinations of antibiotics. But it was not until the immunoglobulins were added to the regiment when presented a significant improvement. Although in the second case immunoglobulins had to be stopped due to renal failure [62, 88].

Immunomodulatory Agents

Lenalidomide is a derivate of thalidomide that could be useful in infections due to its immunomodulatory effect. There is one case reported of a 64 year old man with sporotrichoid spread. After 9 months of 2 different combinations of antibiotic including clarithromycin, ciprofloxacin, doxycycline and trimethoprim-sulfamethoxazole presented no improvement. Then he was started on Lenalidomide for a Chronic Lymphocytic Leukaemia and after 14 days the lesions had an important improvement with no recurrence of the same after 18 months[36].

Occupational Therapy

It has been presented as important after surgery to preserve tendon gliding and prevent adhesions[79]

Recommendations

Microbiological diagnosis is not always possible. For this reason, history of exposure will be essential in the diagnosis. Granuloma formation is not pathognomonic; however histology is important to support the diagnosis and to facilitate the differential diagnosis. Imaging techniques are useful to asses the extension of the infection. Currently, identification is done mainly after culture with classical biochemical tests. Implementation of molecular biology techniques in more centers will be an advantage for the diagnosis, in terms of accuracy and rapidity.

The literature shows mainly case reports and small series of cases. No clinical trials have been done. Consequently there is not enough evidence to propose any specific treatment. At present, recommendations are based in experts’ opinions. However, monotherapy with clarithromycin, minocycline or trimethoprim-sulfamethoxazole has been used with acceptable success for non severe cutaneous lesions. In severe cases seems preferably to use combination therapy with rifampicin + ethambutol. M. marinum is intrinsically a multidrug resistance mycobacterium. Although secondary resistances are rarely documented, susceptibility pattern will be an asset in cases that do not respond to treatment. Surgery indications must be carefully individualized.

A prospective, randomized controlled clinical trial, that probably would need to be interhospitalary, would be valuable to propose a base evident treatment.

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ANNEX
QUESTIONER
CASE NUMBER
YEAR: COUNTRY:
AGE: SEX: Male Female OCCUPATION:

PPD: Positive Negative
Cutaneous lesions: Single More than one
Sporotrichoid spread: Yes No
Tender: Yes No
Deep structures involvement: Yes No
Type of lesion: Plaque Nodule Papule Ulcer Pustule Swelling

Incubation Period
Time evolution until consultation
Time until diagnosis
DIAGNOSIS
AFB: Positive Negative
Granuloma: Yes No
Culture: Positive Negative
SUSCEPTIBILITY TEST