Nontuberculous mycobacterial infections of the skin: A retrospective study of 25 cases

Nontuberculous mycobacterial infections of the skin: A retrospective study of 25 cases Roni Dodiuk-Gad, MD,a Pavel Dyachenko, MD,a Michael Ziv, MD,a Ayelet Shani-Adir, MD,a Yehudit Oren, MD,a Saul Mendelovici, MD,a Jan Shafer, MD,b Bibiana Chazan, MD,c Raul Raz, MD,c Yoram Keness, PhD,d and Dganit Rozenman, MDa Afula, Israel Background: Absence of a pathognomonic clinical picture and variable histologic findings often delay diagnosis of nontuberculous mycobacteria (NTM)-induced cutaneous infections, and antimicrobial therapy varies. Objective: We sought to investigate the clinical, microbiologic, and pathological findings of cutaneous NTM infections and response to different treatments. Methods: Records of patients with NTM infections of the skin confirmed by positive cultures or histologic findings were reviewed. Clinical, microbiologic, and epidemiologic data were collected and skin biopsy specimens were reassessed. Results: The series included 25 cases, one diagnosed by histology and 24 by positive culture: 16 cases with Mycobacterium marinum, 3 of atypical Mycobacterium without species identification, and one each with M chelonae, M xenopi, M abscessus, M gordonae, and M fortuitum. One of 16 patients with M marinum developed tenosynovitis. Mean interval between clinical presentation and diagnosis was 7.1 months (range: 1-27.3 months). All isolates analyzed for antimicrobial susceptibility pattern were sensitive to clarithromycin. Limitations: Limitations include methods of case collection, retrospective study, and relatively small number of patients. Conclusions: Diagnosis of NTM should be confirmed by histology and bacteriology studies of tissue cultures. Strong clinical suggestion of M marinum infection warrants initial empirical treatment to prevent progression to deep infection. The recommended treatment as indicated by the results of the in vitro susceptibility and clinical response is clarithromycin. ( J Am Acad Dermatol 2007;57:413-20.)

G

enus Mycobacterium has 95 well-characterized species. Two well-known species, M tuberculosis and M leprae, have been known for centuries to cause immense human suffering. The pathogenic potential of most other mycobacteria, present in the environment as saprophytes,

From the Department of Dermatology,a Institute of Pathology,b Infectious Diseases Unit,c and Microbiology Laboratory,d Ha’emek Medical Center. Funding sources: None. Conflicts of interest: None declared. Accepted for publication January 29, 2007. Reprint requests: Dganit Rozenman, MD, Department of Dermatology, Ha’emek Medical Center, Afula 18101, Israel. E-mail: [email protected]. Published online March 20, 2007. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2007.01.042

has been recognized since the beginning of the last century. These organisms have been called ‘‘atypical mycobacteria,’’ the term first coined by Pinner,1 and have also been referred to as anonymous, nontuberculous, environmental, opportunistic, and mycobacteria other than tubercle bacilli.2 Nontuberculous mycobacteria (NTM) are slender, nonmotile, acid-fast bacilli that are present in a variety of environments worldwide. Runyon distinguished a fast-growing and a slow-growing group; the latter subdivided according to pigment-forming properties in the culture.3 With the advent of the AIDS epidemic and the introduction of immunosuppressive therapies, the incidence of NTM-associated diseases has increased dramatically and NTMs have been acknowledged as important pathogens.4 Six major clinical syndromes caused by NTM can be differentiated, including pulmonary infection, local nontender lymphadenitis, skin and soft-tissue 413

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infections, disseminated infection, catheter-related infections, and chronic granulomatous infections of bursae, joints, tendon sheaths, and bones.5 Almost all NTM species have been incriminated in cutaneous disease. The most common species in the United States and Europe are M marinum and the rapidly growing mycobacteria M abscessus, M fortuitum, and M chelonae. M ulcerans is endemic in at least 32 countries in Africa, western Pacific, Asia, and South America.4 Infections with M marinum and M ulcerans, two species with marked preference for skin tissue invasion, result in well-defined clinicopathologic entities known, respectively, as swimming pool granuloma and Buruli ulcer.6,7 Other NTMs are associated with diverse clinical and histopathologic phenomena that are nonspecies specific.8 Cutaneous manifestations of NTM infections may be classified according to criteria such as cutaneous lesions and immune status,9 and different histopathologic patterns can be observed.10,11 Various treatment regimens are reported,4,6-8,12 but there are no large-scale comparative clinical trials on the treatment of skin diseases caused by these organisms. This retrospective study on NTM infections of the skin seen in a hospital dermatology outpatient clinic during a 14-year period was conducted to investigate the clinical, microbiologic, and pathological findings of NTM infections of the skin and to assess response to different treatments.

METHODS The records of patients with NTM infections of the skin who were seen in our dermatology clinic between 1991 and 2005 were reviewed. Only cases with positive cultures or histologic findings of NTM infection were included. The clinical, microbiologic, and epidemiologic data were collected. A detailed history was obtained by telephone interview with the patient. In addition, the skin biopsy specimens were reviewed. All tissue samples were processed according to standard methods using the MGIT (microbacteria growth indicator tube) system for liquid enrichment and Loewenstein Jensen agar for solid medium enrichment. The dermatologic specimens were routinely cultivated at 278C for psychrophilic mycobacteria. The NTM isolates were identified by metabolic profile testing, and later on during the study by the polymerase chain reaction (PCR)-based GenoType mycobacterium kit (Hain Life Science, Nehren, Germany). Antimicrobial susceptibility testing of the rapid-growing NTM was performed using the E-test method and the resistance ratio method for the

slow-growing mycobacteria.13 The routine workup of specimens included direct Kinyoun stain. Histopathology consisted of the routine process of hematoxylin-eosin stain. Ziehl-Neelsen stain was performed in most of the cases. Data analysis was performed using the software (SPSS 11.5 statistical package, SPSS Inc, Chicago, Ill). The association between categorical variables was examined using the Fisher’s exact test for small sample. Continuous variables were analyzed by MannWhitney test.

RESULTS The series included 25 patients, 17 male (68%) and 8 female (32%). Mean age at diagnosis was 44 years (median 44, range 14-81). The diagnosis was made by a positive culture in 24 cases (96%) and by histologic findings in one case (4%). Bacteriologic results The distribution of isolates was as follows: 16 cases with M marinum, 3 cases of atypical Mycobacterium without species identification, and one case each with M chelonae, M xenopi, M abscessus, M gordonae, and M fortuitum. Direct Kinyoun stains were negative for acid-fast bacilli in all specimens examined (21/25). Mean time to detection of growth in culture was 24.7 days (median 24, range 12-57), after which, mean time until identification of the bacteria and its antimicrobial susceptibility pattern was another 26 days (median 25.5, range 13-40 days). Mean time from taking a skin biopsy specimen for culture to receiving the final results of the bacterial profile and antimicrobial susceptibility pattern was 2.3 months (median 1.9, range 1.3-4.6 days). The antimicrobial susceptibility pattern of NTM is summarized in Table I. Bacteria were found to have different antimicrobial susceptibility patterns including the M marinum group. However, all isolates of NTM analyzed for antimicrobial susceptibility pattern were sensitive to clarithromycin (M gordonae had borderline sensitivity); all isolates of M marinum were sensitive to clarithromycin and ethionamide and most of them were resistant to rifampicin and ofloxacin. Clinical results The clinical data are summarized in Table II. Most of the cutaneous lesions were located on the upper extremities (74%), especially the fingers (59%) (Fig 1). In the 6 fishermen working in fishponds, most of the cutaneous lesions were located on the elbows. Sporotrichoid distribution was demonstrated in 33% of cases. The most frequent symptom was local pain (68%). The mean number of lesions was 3.6 (median

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Table I. In vitro susceptibility of nontuberculous mycobacteria to various antimycobacterial agents Antimicrobial drug

Mycobacterium marinum n = 15

M chelonae n=1

Ciprofloxacin

13.3% R (2) 33.3% B (5) 53.3% S (8) 100% S (15) 100% S (15) 66.7% R (10) 26.7% B (4) 6.7% S (1) 55.5% HR (5) 44.4% R (4) 7.1% HR (1) 92.9% S (13) 14.3% HR (2) 71.4% R (10) 7.1% B (1) 7.1% S (1) 100% HR (15)

100% S

100% R

100% S

100% S

100% S No data No data

100% S 100% HR 100% HR

100% B 100% S 100% S

100% S No data No data

100% R

No data

No data

No data

100% R

No data

100% S

No data

100% R

No data

100% HR

No data

100% R

No data

No data

No data

Clarithromycin Ethionamide Ofloxacin

Isoniazid Ethambutol Rifampicin

Streptomycin

M abscessus n=1

M gordonae n=1

M fortuitum n=1

B, Borderline; HR, highly resistant; R, resistant; S, sensitive.

3, range 1-10). The clinical appearance of the lesions was variable and included nodules, papules, plaques, ulcers, and cyst. A history of trauma preceded the lesions in 10 patients (44%). There was a significant delay between clinical presentation and diagnosis of NTM: mean 7.1 months (median 5.9, range 1-27.3 months). The initial treatment given by the family physician was changed because of misdiagnosis in 82% of cases. The mean duration of therapy was 3.2 months (median 3 months, range 1.5-6 months). Of the 16 patients who had skin infections with M marinum, 8 (50%) reared fish in home aquariums, 4 (25%) had a fish-related job, and 4 (25%) had no such risk factor. All these 16 patients were immunocompetent. There was a good clinical response in the 8 patients treated with clarithromycin (500 mg twice/d) with almost no side effects, with the exception of a bitter taste that disappeared after the treatment ended in one patient; no gastrointestinal side effects were reported. Of the 4 patients treated with minocycline, two responded well and the third responded poorly and was lost to follow-up. One patient was treated successfully with a combination of minocycline and itraconazole. None of our patients needed surgical intervention. In 3 patients a second antibiotic was added to clarithromycin because of suggested deep tissue involvement. There was no documentation of deep tissue or systemic involvement in the M marinum group, with the exception of one man who developed tenosynovitis in two metacarpal joints documented by magnetic resonance imaging (case 3) (Table II). This man, who

eventually lost his job because of pain and limitation of movement, was initially treated with intralesional steroids after misdiagnosis. He had skin lesions on the hand and fingers for 3 years until M marinum infection was suggested and identified in tissue culture. When treatment with clarithromycin gave a poor clinical response, ciprofloxacin was added and the skin lesions disappeared in 6 weeks. Four other cases are worthy of mention. One patient (case 17) (Table II) was referred to our clinic with a plaque of 6 months’ duration on his left elbow that was resistant to several antibiotic therapies. Although culture of a biopsy specimen from the lesion produced negative results and the histology findings were nonspecific, our suspicion was aroused by his work as a fisherman in fishponds, in which only his elbows were exposed, and the diagnosis of a coworker with M marinum skin infection on the elbow and knee (case 2) (Table II). A repeated skin biopsy specimen revealed acidfast bacilli, but PCR test performed on the skin culture revealed negative findings. Histologic investigation of fish from the pond disclosed one with granulomas in the liver and other internal organs that were acid-fast positive, and PCR test was positive for M marinum. The patient was treated successfully with clarithromycin. We subsequently gave another 3 fishermen the diagnosis of M marinum skin infection working in the same fishpond (cases 12, 14, and 16). The 26-year-old healthy young man with M gordonae skin infection (case 21) (Table II) worked part-time as a fisherman in fishponds and had a home aquarium. He was referred to our clinic for

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Table II. Clinical and histologic data on the 25 cases Case No.

Age, y/sex IMS

Risk factors

Site

1*

39/F No No

Fingers

2

60/M No Fisherman

3

55/M No Farmer

4*

44/M No No

5

43/M No Aquarium

Elbow, knee Fingers, hand Fingers, hand Finger

6

28/M No Aquarium

Culture

Cla, Cip/3

Healed

Cla/3

Healed

Nodules

Tender swelling M marinum

Cla, Cip/3

Tenosynovitis

Plaques

Pain

M marinum

Mino/ND

Plaque

Tender welling, drainage Tender welling, drainage

M marinum

Mino/2

Lost to follow-up Healed

M marinum

Mino/1.5

Healed

Pain Pain Pruritus Pruritus

M M M M

Healed Healed Healed Healed

Pruritus, pain

M marinum

Cla/2 Cla, Eth/2 Cla/3 Mino, Itra/ND Cla/3

Pruritus Pain

M marinum M marinum

Cla/3 Cla/3

Healed Healed

Pain

M marinum

Cip, Cla/3

Healed

Pain Asymptomatic Pain Tender swelling, purulent discharge Nodules Pain ND ND Nodules, Purulent plaques drainage, pruritus

M marinum M marinum No growth NTM

Cla/3 Cla/3 Cla/5 Cla/2

Healed Healed Healed Healed

NTM NTM M gordonae

Mino/2 ND Eth, Cip, Cla/6

Healed ND Healed

Shins

Nodules, ulcers

Tenderness, purulent discharge

M abscessus

Cip, Cla/2

Died

Shin

ND

ND

M xenopi

ND

Lost to follow-up Lost to follow-up Healed

Hand, finger, and arm Ankle Hand Hand Foot

Papules

11

35/F No Aquarium

12 13

17/M No Fisherman 81/M No Aquarium

14

14/M No Fisherman

15 16 17y 18*

59/M 16/M 61/M 58/F

19* 20* 21

Forearm ND Ankle

24*,y

41/M No Aquarium 45/M ND ND 26/M No Aquarium, fisherman, journey in South America 65/F Yes Metastaic endometrial carcinoma, treatment with chemotherapy and prednisone 44/M ND Lived in Africa, chronic osteomyelitis 51/M ND ND

Shin

ND

ND

M chelonae

ND

25

23/M No No

Shin

Ulcer

Pain, purulent discharge

M fortuitum

Cip, Cla/3

23

Aquarium Fisherman Fisherman Aquarium

Outcome

Papules, Tender swelling M marinum nodules Papules Asymptomatic M marinum

65/F 56/M 58/M 14/F

No No No No

Aquarium Aquarium Aquarium No

Symptoms

Therapy agent/ duration, mo

7 8* 9* 10*

22y

No No No No

Clinical appearance

Plaques Plaque ND Plaques

Arm, finger Nodules, plaque Elbow Nodules Fingers Papules, nodules Fingers, Papules, hand cyst Fingers Plaque Elbow Papules Elbow Plaque Arm, finger Nodules

marinum marinum marinum marinum

Healed

Cip, Ciprofloxacin; Cla, clarithromycin; Eth, ethambutol; F, female; IMS, immunosuppression; Itra, itraconazole; M, male; Mino, minocycline; ND, no data; NTM, nontuberculous nycobacteria. *Granuloma in biopsy specimen. y Positive Ziehl-Neelsen stain in biopsy specimen.

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Fig 1. Plaques on thumb and back of hand in patient with Mycobacterium marinum skin infection (case 4) (Table II).

evaluation of skin lesions on the right ankle of 2 years’ duration. On physical examination, indurated purple cutaneous nodules and plaques were noted on the right ankle, reported by the patient to intermittently emit a purulent discharge. He reported traveling to South America but could not recall whether the lesion appeared before or during the trip. Culture of a skin biopsy specimen revealed M gordonae. No granulomas were seen on histologic examination and staining with Ziehl-Neelsen produced negative results. There was no systemic involvement and the patient was treated for 6 months with a combination of ethambutol, ciprofloxacin, and clarithromycin according to the antimicrobial susceptibility pattern (Table I). Improvement was observed a month after the therapy was initiated, and after 6 months, only pigmentary changes on the skin were seen. The patient with M abscessus skin infection (case 22) (Table II) was a 65-year-old woman with metastatic endometrial carcinoma, for which she was received chemotherapy. She initially developed a purulent ulcer on the lower aspect of her abdomen that was diagnosed as pyoderma gangrenosum and treated successfully with prednisone. When the prednisone was tapered, a few nodules and ulcers appeared on the shins (Fig 2). Histology of skin biopsy specimens showed no granuloma, but ZiehlNeelsen staining produced positive findings. The skin biopsy specimen for culture revealed infection with M abscessus. She was treated with clarithromycin and ciprofloxacin according to the antimicrobial susceptibility pattern (Table I), which resulted in improvement, but she died after complications of the malignant disease. The patient with M fortuitum skin infection (case 25) (Table II) was a healthy 23-year-old man referred to our clinic for evaluation of a 2-month ulcer on the right shin. No risk factors were found and the patient was treated with a combination of clarithromycin

Fig 2. Nodules and ulcers on lower leg in patient with Mycobacterium abscessus skin infection (case 22) (Table II).

and ciprofloxacin according to the antimicrobial susceptibility pattern (Table I). After 3 months of treatment the lesions totally healed with a residual scar (Fig 3). Histology results Granuloma was present in 9 specimens (37.5%) (Fig 4) and acid-fast bacilli were identified using Ziehl-Neelsen stains in 3 of 18 specimens (16.7%). The mean duration of the skin lesions in which biopsy specimen revealed granulomas (7.9 months) was longer than in the nongranuloma group (4.7 months), but the difference was not statistically significant. Histologic changes in the epidermis differed in each case and included features such as acanthosis, pseudoepitheliomatous hyperplasia, and ulceration.

DISCUSSION NTMs have been associated with human disease since the 1930s.14 The literature contains only a few case series of NTM skin infections elaborating on the clinical response to treatment.15-17 Fourteen cases of NTM skin infection were reported by Street et al15: the most common species was M marinum (50%), the clinical manifestations were relatively nonspecific, recurrences were common, and prolonged treatment was often necessary. Escalonilla et al16 studied 13 patients with NTM skin infection: the most common species was M chelonae (62%) and was successfully treated with clarithromycin. Brutus

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Fig 4. Epitheloid cells forming nonnecrotizing sarcoidlike granuloma (case 18) (Table II). (Hematoxylin-eosin stain; original magnification: 3200.)

Fig 3. Skin lesions in patient with Mycobacterium fortuitum skin infection before (A) and after (B) 2 months of treatment with clarithromycin and ciprofloxacin (case 25) (Table II).

et al17 reported 8 cases of NTM skin infections of the hand: the most common species was M marinum (38%) and the treatments varied. To our knowledge, our series is the largest reported in the English-language literature on NTM skin infections that detail the clinical response to treatments, and the first to present the in vitro susceptibility pattern of the NTM. In agreement with the reported studies, the clinical manifestations in our series were relatively nonspecific. In addition, as in the majority of the reported studies, the most common NTM species in our series was M marinum (64%), risk factors included a history of preceding trauma, and most of those affected by M marinum had a home aquarium or worked in a fish-related job. Our findings point to the importance of questioning patients about skin injuries whenever there is clinical suggestion of NTM skin infection, and querying those with suggested M marinum skin infection about having an aquarium or a fish-related job. Different histopathologic patterns can be observed in cutaneous NTM infections. A granulomatous inflammatory infiltrate with tuberculoid granuloma formation, sarcoidlike granulomas, or rheumatoid-like nodules are frequently present. However, other findings have been described including dermal or subcutaneous abscesses, a diffuse

dermal or subcutaneous histiocytic infiltration, acute or chronic subcutaneous tissue inflammatory infiltrates (panniculitis), or nonspecific chronic inflammation.10,11 The histologic findings in our study revealed lower percentages of granuloma and staining for acid-fast bacteria in the biopsy specimens than were reported in two large reviews of the histologic findings in NTM.9,10 These results may be explained in part by the fact that a large portion of our patients had early stages of M marinum skin infection in which the histology usually demonstrates nonspecific inflammation.12 Because there is no pathognomonic clinical picture and the histologic findings vary, skin biopsy specimen is recommended for culture in addition to histology. PCR is a rapid, sensitive, and specific diagnostic tool,18 but it does not provide the antimicrobial susceptibility pattern of the bacteria. In view of the lack of consensus regarding the optimal drug regimen for the different NTM skin infections, and the wide variation in antimicrobial therapies reported in the literature,4,6-8,12 in part because of different antimicrobial susceptibility patterns (documented in our study as well) (Table I), it is unlikely that PCR can replace the performance of a bacterial culture for the time being. However, the technique can expedite the diagnosis and provide important information. Our data and previous studies6,10,11 show a significant delay between clinical presentation and diagnosis of M marinum and a long period of time to detection of growth in culture. One of our patients with M marinum infection (case 3) (Table II) developed tenosynovitis in two metacarpal joints probably as a result of delayed diagnosis and initial wrong treatment. Cases of M marinum tenosynovitis, osteomyelitis, bursitis, and arthritis have been reported in the literature.19-21 Thus, it seems that giving empiric therapy when clinical suggestion of M marinum

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skin infection is high is reasonable to prevent progression to deep infections. Such action may be justified when the clinical picture consists of a papule, nodule, or plaque on the upper extremities that appears after a recalled trauma in a patient with an aquarium or a fish-related occupation. The treatment can be modified later according to laboratory results. The type and duration of the antimicrobial therapy for NTM skin infections varies considerably in the literature. No single agent or combination of agents has been shown to be the treatment of choice.3,6,22,23 A recent review on NTM lists 4 options of therapy for M marinum skin infection: ethambutol and rifampin, clarithromycin, minocycline, and doxycycline.4 According to in vitro susceptibility and clinical response, the recommended treatment in our study was clarithromycin. It must be mentioned that the results of our study relate to the geographic location of the research and cannot be simply applied to other areas. In addition, the antimicrobial susceptibility testing of the various NTM to tetracyclines, including minocycline, was not performed by the microbiology laboratory in our study. Nevertheless, M marinum was found in various reports to be sensitive to clarithromycin in vitro and in vivo4,24-27; failures in treatment of M marinum cutaneous infections with minocycline or doxycycline have been reported.22,23 and resistance of M marinum to rifampin, seen in our study, was reported in the literature.24 Hence, it seems that the results of our study are in accord with the recent literature. Furthermore, clarithromycin seems to be superior to other drugs in terms of side effects, which are fewer than with the other antibiotics suggested and were rarely reported in our study. Nonetheless, when a deeper infection is suggested, an additional agent should be added as recommended in the literature.6 We tend to agree with the recommendation of at least 3 months of treatment in M marinum skin infection,4 because that was the duration of treatment in most of our successfully treated patients and none of them had a relapse of the disease. Nevertheless, clinicians need to tailor the treatment to each patient according to immunologic status, depth of infection, and response to treatment. In conclusion, the incidence of NTM cutaneous infections has increased dramatically and NTMs have been subsequently acknowledged as important pathogens. A high index of suspicion and a detailed history are important factors, but the diagnosis needs to be confirmed by histologic examination and bacteriologic studies of tissue cultures. Further studies are needed to expand our knowledge about NTM cutaneous infections and their optimal treatment.

REFERENCES 1. Pinner M. Atypical acid-fast microorganisms. Am Rev Tuberc 1935;32:424-45. 2. Katoch VM. Infections due to non-tuberculous mycobacteria (NTM). Indian J Med Res 2004;120:290-304. 3. Runyon EH. Anonymous mycobacteria in pulmonary disease. Med Clin N Amer 1959;43:273-90. 4. Wagner D, Young LS. Nontuberculous mycobacterial infections: a clinical review. Infection 2004;32:257-70. 5. Petitjean G, Fluckiger U, Scharen S, Laifer G. Vertebral osteomyelitis caused by non-tuberculous mycobacteria. Clin Microbiol Infect 2004;10:951-3. 6. Bhatty MA, Turner DPJ, Chamberlain ST. Mycobacterium marinum hand infection: case reports and review of the literature. Br J Plast Surg 2000;53:161-5. 7. Pszolla N, Sarker MR, Dtreacker W, Kern P, Kinzl L, Meyers WM, et al. Buruli ulcer: a systemic disease. Clin Infect Dis 2003; 37:78-82. 8. Palenque E. Skin disease and nontuberculous atypical mycobacteria. Int J Dermatol 2000;39:659-66. 9. Bartralot R, Garcia-Patos V, Sitjas D, Rodriguez-Cano L, Mollet J, Martin-Casabona N, et al. Clinical patterns of cutaneous nontuberculous mycobacterial infections. Br J Dermatol 2005;152: 727-34. 10. Bartralot R, Pujol RM, Garcia-Patos V, Sitas D, Martin-Casabona N, Coll P, et al. Cutaneous infections due to nontuberculous mycobacteria: histopathological review of 28 cases; comparative study between lesions observed in immunosuppressed patients and normal hosts. J Cutan Pathol 2000;27:124-9. 11. Travis WD, Travis LB, Roberts GD, Su DW, Weiland LW. The histopathologic spectrum in Mycobacterium marinum infection. Arch Pathol Lab Med 1985;109:1109-13. 12. Jogi R, Trying SK. Therapy of nontuberculous mycobacterial infections. Dermatol Ther 2004;17:491-8. 13. Nolte FS, Metchock B. Mycobacterium. In: Balows A, Hausler WJ, Herrman KL, editors. Manual of clinical microbiology. 6th ed. Washington, DC: American Society for Microbiology; 1995. pp. 400-37. 14. Brancj A. Avian tubercle bacillus infection, with special reference to mammals and to man: its reported association with Hodgkin’s disease. Arch Pathol 1931;12:253-74. 15. Street ML, Umbert-Millet IJ, Roberts GD, Su WP. Nontuberculous mycobacterial infections of the skin: report of fourteen cases and review of the literature. J Am Acad Dermatol 1991; 24:208-15. 16. Escalonilla P, Ebsteban J, Soriano ML, Farina MC, Pique E, Grilli R, et al. Cutaneous manifestations of infection by nontuberculous mycobacteria. Clin Exp Dermatol 1998;23:214-21. 17. Brutus JP, Baeten Y, Chahidi N, Kinnen L, Ledoux P, Moermans JP. Atypical mycobacterial infections of the hand: report of eight cases and literature review. Chir Main 2001;20:280-6. 18. Posteraro B, Sanguinetti M, Garcovich A, Ardito F, Zampetti A, Masucci L, et al. Polymerase chain reaction-reverse cross-blot hybridization assay in the diagnosis of sporotrichoid Mycobacterium marinum infection. Br J Dermatol 1998;139:872-6. 19. Wongworawat MD, Holtom P, Learch TJ, Fedenko A, Stevanovic MV. A prolonged case of Mycobacterium marinum flexor tenosynovitis: radiographic and histological correlation, and review of the literature. Skeletal Radiol 2003;32:542-5. 20. Wilson KC, Bielska B, Farber HW. Mycobacterium marinum osteomyelitis. Orthopedics 2003;26:331-2. 21. Alloway JA, Evangelisti SM, Sartin JS. Mycobacterium marinum arthritis. Semin Arthritis Rheum 1995;24:382-90. 22. Edelstein H. Mycobacterium marinum skin infections. Arch Intern Med 1994;154:1359-64.

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23. Cummins DL, Delacerda D, Tausk FA. Mycobacterium marinum with different responses to second-generation tetracyclines. Int J Dermatol 2005;44:518-20. 24. Flynn CM, Kelley CM, Barrett MS, Jones RN. Application of the Etest to the antimicrobial susceptibility testing of Mycobacterium marinum clinical isplates. J Clin Microbiol 1997;35:2083-6. 25. Bonnet E, Debat-Zoguereh D, Petit N, Ravaux I, Gallais H. Clarithromycin: a potent agent against infections due to Mycobacterium marinum. Clin Infect Dis 1994;18:664-6.

26. Brown BA, Wallace RJ, Onyi GO. Activities of clarithromycin against eight slowly growing species of nontuberculous mycobacteria, determined by using a broth microdilution MIC system. Antimicrob Agents Chemother 1992;36: 1987-90. 27. Aubry A, Chosidow O, Caumes E, Robert J, Cambau E. Sixtythree cases of Mycobacterium marinum infection: clinical features, treatment, and antimicrobial susceptibility of causative isolates. Arch Intern Med 2002;162:1746-52.