Mycobacterium Marinum Treatment Literature Review

mycobacteria Marinum Treatment Literature critical reviewAbstractBackgroundMycobacterium marinum is an atypical mycobacterium that can be strand in water environment. It is the agent of a characteristic splutter malady known overly as research tank granuloma. In some occasions it can circle as a nodulated lymphangitis, extend to tardily structures as come up as in particular(a) sideslips disseminate systemicaly . The infection is adquired after bear upon with look for or bemire water mainly from aquaria or fluent pools. Although the real incidence is understimate, it is a uncommon infection that needs high clinical suspicion to be diagnosed. As a consequence, curb in the diagnosing is common. Mycobacterium marinum is per se a multidrug resistant mycobacterium. in that location is no clear consesus in the management of this infection. normally it is managed either with mo nonherapy or with compounding of antibiotics nonnegative surgery in selected cases.Me thods backward workplace of cases of search tank granuloma compile from 2000 to 2009 in the dermatology surgery of The infirmary of equatorial Diseases (HTD) of the University College London hospitals.Systematic review of the literature with the terms Mycobacterium marinum and fish tank granuloma from 1999 to 2009.ResultsFrom the HTD dermatology surgery were necessitateed 7 cases. recognition of M. marinum was achievable all in 5. The repartee to treatment was accep get across at to the lowest degree in 5 of them. In the literature review there were inform a total of 516 cases. From those 133 could be analyzed as unmarried cases. Identification was likely in 89.5% of the cases. senior was inform in 82% of the cases. culminationThe key of the diagnosis is to collect accurately the score of moving-picture show. Histology, although no pathognomonic, pass on rise the suspicion if granuloma organization are found and will accelerate the distinguishableial diagnosis . Identification is through after culture with classical biochemical outpourings. Molecular biology techniques allow the advantage of accelerate the procedure. There is non enough evidence to propose every specific treatment. Currently, recommendations are ground in experts opinions. A prospective, randomized controlled clinical trial would be semiprecious to propose a base evident treatment.Contents PagesIntroductionM. marinum is an environmental atypical mycobacterium ubiquitous in fresh, salt, and brackish water. It is known that infects clement and tropical species of fish of at least 150 species, including ornamental fish. that also affects frogs, eels, oysters, aquatic mammals, toads and snakes 2, 11.It cause tuberculosis-like disease in fish, its natural army 129. The infection in fish has an sightly incubation period of 3 months. It affects viscera and produce anorexia with emaciation, spit bring out defects, distension of the abdomen, world cause of fast death 11, 12, 66.In 1904, Alexander depict 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 describe the bacilli as acid fast, chromogenic, pleomorphic and growing best at 18-20C. Aronson intimateed the name of Mycobacterium marinum 130.M. marinum is as well the causative agent of the homophile disease called fish tank granuloma, also known as liquid pool granuloma or fish fanciers finger syndrome. In 1951 Norden and Linell report for the first time the human disease in a fluent pool outbreak in rebro, Sweden. They set forth the lesions as inveterate papulous ulcerationations, ordinarily 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 reasond 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 colligate with swimming pools were not uncommon 134. As an example, nonpareil of the biggest epidemics was in Glenwood springs pool, Colorado in 1956 with 262 cases account 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 lavish floor of the same 136.The real global incidence of the disease is not know because the human activity of cases are under account, 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, Maryl and, where there is an incidence of 4 cases per cytosine000 people per yr 138. Meanwhile in California was estimated in 0.27 cases per blow000 adults 139. Or in Satowan, Micronesia, with an estimated prevalence of 10% of the population 115.Apparently the global annual incidence remains small and s bow 140. Even though an amplify number of reported cases has been noticed in The United States, going from an mean(a) of 40 cases per year in the 80s to an fair(a) of 198 cases per year in the 90s 141. What seems clearer is that differing from new(prenominal) atypical mycobacteria the prevalence of M. marinum has not additiond with the HIV epidemic 140.Oppo land site 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 with(predicate) eggs and through practice of feeding fish with fish carcas ses 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 impact humans. On the contrary, cluster II moreover affects fish producing the classical chronic disease with granuloma formation 9. This is also supported by a study through with(p) in Israel were it was seen that altogether certain strains of M. marinum touched humans. They also demonstrate that in Israel strains affecting humans came from ornamental fish and not from topical anaesthetic fish for consumption 5.The mode of transmission to humans is mainly mobile and fish borne. Person to person transmission has not been documented 137. However, It has been draw indirect transmission via fomites in at least 3 cases. ii very small children and one infant who acquired the infection after caning in containers that were previously used to clean the family fish tanks of tropical fish 27, 40, 142.As some other (a) environmental mycobacterium, M. marinum has commonly low pathogenicity. For this reason in normal conditions only affects disrupted skin 8. The main encounter grammatical constituent to contract the infection consists in having lesions or abrasions in the skin with video to non chlorinated water or marine animals infected 140. The most frequently at present is the motion-picture show to private aquaria. But some times the source of word picture is unknown. As a consequence, after the verbal description of cases following injuries with plants, it has been suggested the mishap 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 in conclusion 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 generation invasion of deep structures as tendons, articulations and bones occurs in 29% of the cases 144. general dissemination is unusual but has been described in immunocompromised patients 140. impulsive resolution , usually with scaring , has been documented from months after the infection up to 2 age 133, 135.The diagnosis is based on the chronicle of exposure and peril factors along with the characteristic clinical features. It is supported with histopathology, culture and bacteriological credit that in some cases require molecular biology techniques 94, 120. The fact is that the diagnos is 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 emanation of the disease 1. With this purpose different gangs of antibiotics gain 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 person(a) authors and is not based on controlled evidence 143.Aims and ObjectivesThe overall aim of the excogitate is to determine the current state of evidence for the diagnosis and treatment of M. marinum infection. world the specific objective to review the literature and the serial of HTD cases with the purpose of suggest appropriate diagnosis and case management of Mycobacterium marinum infection.Material and MethodsCases 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 include patients with either culture cocksure for M. marinum or clinical diagnosis plus response to appropriate treatment.The files of those patients were reviewed and info were collected in a questioner that included anthropological data, past medical checkup and drug history, risk factors and exposure, description and location of the lesions, spread or deep adjunct of the infection, incubation period , delay in diagnosis, diagnosis, treatment and ontogenesis (see questioner in annex). Additional information considered applicable was as well collected.A literature review in Medline and Cochrane databases was through. The review included the combination of the following terms Mycobacterium marinum or fish tank granuloma. It was expressage to cover 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 last, a miscellaneous category of papers that were considered relevant for the diagnosis and treatment of this infection.The information gathered in the questioners was com entrusterized in Microsoft excel 2007. No statistical analysis was done in view of the cases were expose not with this purpose. As a consequence probably important coverage bias would invalidate any statistical outcome. Simple description of the results was done.ResultsCases of The Hospital of Tropical DiseasesFrom 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 eld. All the cases a dmitted to take a leak had pass with an aquarium. In devil cases the exposure was occupational. integrity of them worked in the London Zoo being responsible of the management of the aquaria. The trice was a cook in a awaitaurant that store crustacean in an aquarium. All the cases presented nodular lesions located in one of the upper berth branchs, six of them with sporotrichoid spread and one with a solitary nodule (see photos is annex). iodin patient that was taking oral prednisolone due to severe atopic eczema presented with tendosynovitis 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. incompatible combinatio ns 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. eventually it was aged(a) 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 requisite in any pati ent. The final outcome was good in 5 patients being the other 2 lost of follow up (see hedge 1).Case No Age(y) /Sex Medical history Drug history Exposure Location Clinical characteristics Histology AFB results Culture Treatment Duration (months) ontogeny 1 9/M No Aquarium Upper leg quadruple 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 ramification 3 nodules Sporotrichoid spread AFB + 1-MIN 2 Improving Lost of follow up 3 64/M No Aquarium Upper sleeve 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 dread(a) atopic eczema Systemic steroids Aquarium Upper limb Multiple nodules Sporotrichoid spread tendosynovitis AFB + 1-DOX 2-RIF+EMB 3-RIF+EMB+CLR 4-ERI+MIN ? Lost of follow up 5 44/M No Aquari um Upper limb 5 nodules Purulent run through 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 reviewFrom 1999 to July 20009 there were found 233 results in Medline database and zip fastener 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 literatu re 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 defecate 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 pitch been reported in Europe, North America and to the 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 casesThe 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, Cronhs 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 amethopterin sodium 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 amateurish sailors.Opposite to papers from the 60s, only in 2 patient s 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. recital 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 clasp 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 a verage 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, palpebra 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 solve in 32 cases (24.1%), as well as swelling and pith 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 tendosynovitis with 34 cases (75.6%), follow ed 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 gravis103 in one case and polymyalgia rheumatica62 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 invading 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 immunosup pressive 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 ontogenesis 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 mont hs. 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 apocalyptical 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, Sweets syndrome, remote body granuloma or interstitial granuloma annulare (See table 3).mesa 3 Histology FindingsHistology 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 Fib rinoid corruption 1 Necrotizing paniculitis 2 Cystic degeneration 1 Pseudoepitheliomatous hyperplasia 4 stabbing 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 Sweets syndrome 2 Foreign body granuloma 2 interstitial granuloma annulare 2In 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 im aging techniques were multipurpose 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. ( effectualness 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 ampere-second% 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 DiseasePatients 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 degree Celsius% MIN 10 70% 1 nose candy% 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 + pyxie 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 SUSCEPTIBILITYDrug Number of patients Susceptible Resistant indeterminable 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 legion(predicate) 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 OUTCOMEReferences Age Sex Past medical history Type of infection Treatment Duration treatment (months) Evolution 25 67/M DM dermal disseminated RIF+EMB+CLR+CIP 3.7 deceased person Secondary bacterial infection 26 50/M No Tenosynovitis RIF+EMB Synovectomy 3 Dysfunctional list 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 + Fluoroqui nolone 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 gravis Systemic steroids Cutaneous and systemic dissemination 1-CIP 2-Hyperthermia 3-DOX intravenous 5 Deceased Bone marrow infected by M.marinumResults from papers that contain series of 14 or more casesThere 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 expos ure 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, t rimethoprim-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 infecti