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Acid-fast bacteria as causative agents of skin and soft tissue infections: case presentations and literature review

ABSTRACT

Acid-fast bacteria can be implicated in skin and soft tissue infections. Diagnostic identification can be challenging or not feasible by routine laboratory techniques, especially if there is no access to the Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) technology. Here, we present two cases of skin and soft tissue infections caused by two different acid-fast bacteria, Nocardia brasiliensis and Mycobacterium marinum. They both grew on Löwenstein–Jensen medium, Sabouraud agar medium and blood agar medium. Both bacteria appeared acid-fast by Ziehl–Neelsen stain and Gram-positive by Gram stain. The identification was performed by MALDI-TOF MS and gene analysis. N. brasiliensis and nontuberculous mycobacterium M. marinum represent rare pathogens that cause severe skin and soft tissue infections. Failure to identify the causative agent and subsequent inappropriate or inadequate treatment may lead to severe complications or even disseminated disease, especially in immunocompromised individuals.

Nocardia brasiliensis; Mycobacterium marinum; Ziehl–Neelsen stain; Acid-fast bacteria; Skin and soft tissue infections; MALDI-TOF MS

INTRODUCTION

Skin and soft tissue infections (SSTIs) are among the most common infections in outpatient care and the most frequent causes of infection with referrals to emergency departments in the developed world, contributing to significant morbidity and healthcare expenditures. Despite the low mortality associated with SSTIs, the high rates of treatment failure and relapses are of concern. The diagnosis involves clinical history, physical examination, laboratory testing, diagnostic imaging, isolation and identification of the causative agent. Microbiological diagnosis is one of the cornerstones for the management of SSTIs. Prompt procurement and processing of the appropriate samples, evaluation of the laboratory findings (identification of potential pathogens, susceptibility testing) by expert personnel and critical reporting of obtained results support a favorable outcome. In various clinical contexts, the causative agents include Gram-positive cocci, mainly Staphylococcus aureus and Streptococcus pyogenes, Gram-negative bacteria, Propionibacterium, Corynebacterium, Clostridium, Pasteurella, Nocardia and Mycobacterium spp.

In case acid-fast bacilli are encountered in the clinical microbiology context, more advanced techniques are required in order to identify the causative agent. Two cases of SSTIs caused by two different acid-fast bacteria are presented. Clinical presentation, laboratory diagnosis, treatment, as well as difficulties in differentiation and identification of the causative agents are discussed below. A review of published cases during the last 5 years is also presented.

CASE REPORTS

Case 1

A 77-year-old woman, with a medical history of type 2 diabetes mellitus, was referred to the emergency department with painful, exudative and purulent ulceration of the left lower extremity (Figure 1A). The patient recalled a minor trauma two weeks before the presentation and reported sea swimming on a regular basis after the trauma. On admission, routine laboratory work-up revealed elevated WBCs (13,580/mm3, PMN 84%), C-reactive protein (19.6 mg/dL), and blood glucose (248 mg/dL). Bone X-ray was normal, whereas MRI scanning showed an extended inflammation of the subcutaneous tissue. Debridement of the lesions was performed and the tissue was submitted for microbiological and histological analyses. Both cultures on solid media and histological analyses failed to reveal any infectious agent despite the extended inflammation. However, a blood culture bottle inoculated with the purulent material returned positive after two days of incubation. Gram stain from blood culture smears showed fine and beaded Gram-positive branching bacilli (Figure 2A) and a partially acid-fast Ziehl–Neelsen (ZN) stain (Figure 2B). Subculture on blood (Figure 3A) and Sabouraud dextrose agar (Figure 3B) plates grew strictly adherent, chalky white colonies, with a moldy odor. In addition, upon completion of 10 days of incubation, growth was observed on Löwenstein–Jensen (LJ) medium (Figure 3C). MALDI-TOF MS analysis identified it at species level as Nocardia brasiliensis. MALDI-TOF MS was performed by VITEK® MS system (bioMérieux) by using the knowledge base 3.2 VITEK MS IVD. The identification confidence value was 99.9. The patient was treated with trimethoprim-sulfamethoxazole (TMP-SXT) and discharged with a prescription of a 2-month further course without evidence of relapse.

Figure 1
Clinical presentation: (a) N. brasiliensis, (b) M. marinum.

Figure 2
Gram stain of colonies grown on blood agar (a, c) and Ziehl–Neelsen stain of colonies grown on Löwenstein–Jensen medium (b, d), N. brasiliensis (a, b) and M. marinum (c, d).

Figure 3
Colonies of N. brasiliensis grown on blood (a), Sabouraud dextrose agar plates (b) and Löwenstein–Jensen medium (c). Colonies of M. marinum grown on blood (d), Sabouraud dextrose agar plates (e) and Löwenstein–Jensen medium (f).

Case 2

A 63-year-old Caucasian female, with a medical history of ankylosing spondylitis under immunotherapy, was referred to our hospital for having a 3-month history of a rapidly enlarging painful mass with malodorous discharge and surrounding edema on her right hand (Figure 1B). The patient reported that the lesion initially appeared on her right index finger following a minor penetrating trauma by a rose thorn. On admission, the routine laboratory work-up revealed a mild elevation of the erythrocyte sedimentation rate and C-Reactive Protein (45 mm/h and 2.58 mg/dL, respectively). All other tests, including HIV, VDRL and PPD (Mantoux), were either negative or within the normal range. Bone X-rays were normal, whereas an MRI scan revealed an inflammation of soft tissues at the dorsal surface of the hand and a minor lesion at the bone cortex of the lunate bone. Biopsy specimen was submitted for microbiological and histological analysis. Histological analysis failed to identify any infectious agent despite the extended inflammation. Initial cultures on blood and Sabouraud agar plates were negative, however, growth was observed on LJ medium (Figure 3F) after 18 days of incubation. The Gram stain showed short beaded Gram-positive bacilli (Figure 2C), whereas ZN revealed acid-fast bacilli (Figure 2D). Subsequent subcultures were performed on both blood (Figure 3D) and Sabouraud dextrose agar plates (Figure 3E), resulting in the rapid growth of moist, smooth colonies that acquired a yellowish color upon prolonged culture and light exposure. Identification as M. marinum was performed by MALDI-TOF MS analysis. MALDI-TOF MS was performed by VITEK® MS system (bioMérieux) using the knowledge base 3.2 VITEK MS IVD. The identification confidence value was 99.9. Results were confirmed by gene analysis using a commercially available DNA strip assay (GenoType Mycobacterium Common Mycobacteria, CM) (HAIN Lifescience, Nehren, Germany). The test is based on a PCR technique targeting the 23S rRNA gene region and reverse hybridization of the PCR product to a nitrocellulose strip with immobilized probes for different mycobacterial species. The patient was successfully treated with minocycline and rifampicin and discharged on oral minocycline.

DISCUSSION

We performed a systematic literature review through MEDLINE (U.S. National Library of Medicine) by using the term ‘Nocardia brasiliensis’ as well as the term ‘Mycobacterium marinum’. We restricted the search results to reports from 2019 to 2022. All articles written in English referring to skin and soft tissue infections were selected for full-text screening. Cases of disseminated infections and retrospective studies that involved case series published before 2019 were excluded. Regarding N. brasiliensis, 14 cases (13 articles) were retrieved, and presented in Table 111. Lovecchio A, Bazzacco G, Di Bella S, Di Meo N, Luzzati R. Uncommon lymphocutaneous cellulitis after insect bite: a case report of primary cutaneous nocardiosis and literature review. Infez Med. 2022;30:285-92.

2. Dumic I, Brown A, Magee K, Elwasila S, Kaljevic M, Antic M, et al. Primary lymphocutaneous Nocardia brasiliensis in an immunocompetent host: case report and literature review. Medicina (Kaunas). 2022;58:488.

3. Acevedo CT, Imkamp F, Maggio EM, Brugger SD. Primary cutaneous nocardiosis of the head and neck in an immunocompetent patient. BMJ Case Rep. 2021;14:e241217.

4. Mangieri NA, Guevara Nuñez D, Echavarría G, Bertona E, Castello L, Benchetrit G, et al. Nocardiosis esporotricoide por Nocardia brasiliensis. Rev Argent Microbiol. 2021;53:43-7.

5. Chen Y, Liu Y, Ding XJ, Chen YJ, Wang L, Zhang ZZ. Diagnosis and treatment of lymphocutaneous dermatosis caused by Nocardia brasiliensis: a case report. Ann Palliat Med. 2020;9:3663-7.

6. Gil Redondo R, Melgar Molero V, Martín Fuentes A, Eusebio Murillo E. Primary cutaneous Nocardiosis in a man treated with certolizumab. Actas Dermosifiliogr (Engl Ed). 2019;110:698-9.

7. Medina-Torres AM, Toussaint-Caire S, Hernández-Castro R, Bonifaz A. Skin nodules in a pediatric Mexican patient after chest trauma. Enferm Infecc Microbiol Clin (Engl Ed). 2019;37:611-3.

8. Wang R, Yao X, Li R. Mycetoma in China: a case report and review of the literature. Mycopathologia. 2019;184:327-34.

9. Li S, Xu X, Wu M, Zhu J, Cen P, Ding J, et al. Lymphocutaneous nocardiosis caused by Nocardia brasiliensis in an immunocompetent patient: a case report. J Int Med Res. 2020;48:300060519897690.

10. Mu YZ, Liu Y, Wang YJ, Zhang ZZ. A case report and review of lymphocutaneous nocardiosis caused by Nocardia brasiliensis reported in China. Dermatol Ther. 2019;32:e13001.

11. Steinmetz G, Panas K, Puffinbarger W. An acute Nocardia infection in a pediatric hand. J Hand Surg Am. 2019;44:343.e1-3.

12. Abu Sitta E, Hollingshead C, Luttmann K, Elsaghir H. Gardener with primary lymphocutaneous nocardiosis. BMJ Case Rep. 2019;12:e233586.
-1313. Al-Obaydi S, DeMaio J. Two cases of cutaneous nocardiosis after a natural disaster. Cureus. 2019;11:e6278, whereas regarding M. marinum 42 cases (39 articles) were retrieved and are shown in Table 2.

Table 1
Cases of skin and soft tissue infection caused by N. brasiliensis during the last four years (2019–2022).
Table 2
Published cases of skin and soft tissue infection caused by Mycobacterium marinum during the last four years (2019–2022).

Nocardia and Mycobacterium spp. both belong to the family Mycobacteriaceae suborder Corynebacterineae, order Actinomycetales, and, along with other members, such as Rhodococcus and Corynebacteria, include the most important acid-fast bacteria that may cause disease to humans.

Nocardiosis, although a primarily and increasingly (18-45%) opportunistic infection, affects immunocompetent individuals, some of whom have comorbidities, such as alcoholism and diabetes5353. Margalit I, Lebeaux D, Tishler O, Goldberg E, Bishara J, Yahav D, et al. How do I manage nocardiosis? Clin Microbiol Infect. 2021;27:550-8.. About 8-31% of the patients with nocardiosis manifest cutaneous lesions, more commonly in the context of a disseminated disease5454. Lafont E, Conan PL, Rodriguez-Nava V, Lebeaux D. Invasive nocardiosis: disease presentation, diagnosis and treatment: old questions, new answers? Infect Drug Resist. 2020;13:4601-13.. On the other hand, primary skin nocardiosis is a rare entity that typically affects individuals without severe immunodeficiencies. It is mainly (80%) caused by N. brasiliensis5555. Dodiuk-Gad R, Cohen E, Ziv M, Goldstein LH, Chazan B, Shafer J, et al. Cutaneous nocardiosis: report of two cases and review of the literature. Int J Dermatol. 2010;49:1380-5.. Clinical presentation can mimic any type of skin and soft tissue infection, such as mycetoma, superficial skin infection (ulceration, abscess, cellulitis) or lymphocutaneous infection with a sporotrichoid pattern5353. Margalit I, Lebeaux D, Tishler O, Goldberg E, Bishara J, Yahav D, et al. How do I manage nocardiosis? Clin Microbiol Infect. 2021;27:550-8.,5454. Lafont E, Conan PL, Rodriguez-Nava V, Lebeaux D. Invasive nocardiosis: disease presentation, diagnosis and treatment: old questions, new answers? Infect Drug Resist. 2020;13:4601-13.. Nocardia colonies usually grow in most culture media used for bacteria, fungi or mycobacteria isolation, after 2–5 days of incubation. In some cases, the growth is slow and incubation should be continued for 14-21 days5454. Lafont E, Conan PL, Rodriguez-Nava V, Lebeaux D. Invasive nocardiosis: disease presentation, diagnosis and treatment: old questions, new answers? Infect Drug Resist. 2020;13:4601-13.. Nocardia spp. typically appear weakly beaded or acid-fast upon traditional ZN staining and acid-fast on modified Kinyoun stain. In the Gram stain, Nocardia appear as Gram-positive beaded branching bacteria5454. Lafont E, Conan PL, Rodriguez-Nava V, Lebeaux D. Invasive nocardiosis: disease presentation, diagnosis and treatment: old questions, new answers? Infect Drug Resist. 2020;13:4601-13.. The use of biochemical tests for genus or species identification has been abandoned due to a lack of sensitivity and specificity. The gold standard for the identification of Nocardia spp. is molecular biology with amplification and sequencing of one or two gene(s) among rrs, hsp65, secA1 and soda. Nevertheless, MALDI-TOF MS adequately identifies most species in 94-100% of the cases and is increasingly being used5454. Lafont E, Conan PL, Rodriguez-Nava V, Lebeaux D. Invasive nocardiosis: disease presentation, diagnosis and treatment: old questions, new answers? Infect Drug Resist. 2020;13:4601-13.. MALDI-TOF MS profiles bacterial proteins from whole cell extracts and obtains a bacterial fingerprint able to identify microorganisms from different genera and species by matching this profile with a reference database. However, caution is required for less common Nocardia species and complexes, such as N. nova and N. abscessus. In rare species, misidentification is common and the use of molecular biology-based identification remains important in case of a low identification score. Nevertheless, despite its limitations, MALDI-TOF MS is a valuable tool in clinical laboratories enabling rapid identification at least at genus level5353. Margalit I, Lebeaux D, Tishler O, Goldberg E, Bishara J, Yahav D, et al. How do I manage nocardiosis? Clin Microbiol Infect. 2021;27:550-8.,5454. Lafont E, Conan PL, Rodriguez-Nava V, Lebeaux D. Invasive nocardiosis: disease presentation, diagnosis and treatment: old questions, new answers? Infect Drug Resist. 2020;13:4601-13..

Diagnosis of nocardiosis may be culture-independent relying only on a PCR-based assay directly on the clinical sample. Advantages include an earlier diagnosis and higher sensitivity, especially in patients already receiving antibiotics. However, just a positive molecular test may only represent colonization and lacks specificity mainly in respiratory samples. Most importantly, antibiotic susceptibility test results are lacking5454. Lafont E, Conan PL, Rodriguez-Nava V, Lebeaux D. Invasive nocardiosis: disease presentation, diagnosis and treatment: old questions, new answers? Infect Drug Resist. 2020;13:4601-13.. Regarding the management of primary skin nocardiosis, monotherapy using TMP-SXT is adequate in most cases. Alternative options involve linezolid as initial treatment and minocycline, fluoroquinolones or amoxicillin-clavulanic acid as maintenance treatment5353. Margalit I, Lebeaux D, Tishler O, Goldberg E, Bishara J, Yahav D, et al. How do I manage nocardiosis? Clin Microbiol Infect. 2021;27:550-8.. Total treatment duration of 3-6 months is traditionally recommended, although shorter courses may be reasonable in immunocompetent patients5353. Margalit I, Lebeaux D, Tishler O, Goldberg E, Bishara J, Yahav D, et al. How do I manage nocardiosis? Clin Microbiol Infect. 2021;27:550-8..

A literature review emphasizes the importance of accurate diagnosis, as in the majority of cases (11/14, 79%), inappropriate medication was administered initially, more commonly cephalosporins. In one case, antitubercular therapy was initially prescribed. Only one (7%) patient was receiving immunosuppressive therapy and two (14%) had diabetes mellitus; therefore, the vast majority were immunocompetent. Injuries have been identified in eight cases (57%), most commonly from gardening and insect bites. The predominant type of infection was the lymphocutaneous-sporotrichoid form (10/14, 71%), whereas primary cutaneous nocardiosis and mycetoma have been described in three cases (21%) and one case (7%), respectively. The lesions were most commonly located on the left hand/arm (9/14, 64%), and, at a lesser extent, on the right hand/arm (4 cases), right leg (1 case) and face (2 cases). All cases had a favorable outcome, most commonly by antimicrobial therapy alone, whereas adjuvant surgical debridement or drainage was required in three cases (21%). TMP-SXT monotherapy was used in eight cases (57%), whereas in six cases, the latter was combined with other regimens, namely amoxicillin/clavulanic, linezolid, amoxicillin and amikacin. TMP-SXT was discontinued in two cases due to cutaneous reactions.

Regarding mycobacterial cutaneous infections, including cutaneous manifestations of Mycobacterium tuberculosis infection, leprosy caused by Mycobacterium leprae and Mycobacterium lepromatosis, and infections caused by nontuberculous mycobacteria (NTM), they exhibit widely different clinical presentations, such as cellulitis, non-healing ulcers, subacute or chronic nodular lesions, abscesses, superficial lymphadenitis and verrucous lesions5656. Franco-Paredes C, Marcos LA, Henao-Martínez AF, Rodríguez-Morales AJ, Villamil Gómez WE, Gotuzzo E, et al. Cutaneous mycobacterial infections. Clin Microbiol Rev. 2018;32:e00069-18.. More specifically, NTM involve slowly growing M. ulcerans, M. marinum, M. kansasii, Mycobacterium avium-intracellulare complex and M. haemophilum and the rapidly growing mycobacteria: M. fortuitum, M. abscessus and M. chelonae. Although most NTM are opportunistic pathogens, M. marinum, as well as its related species, M. ulcerans, are pathogenic mycobacteria, and can cause disease in healthy individuals5656. Franco-Paredes C, Marcos LA, Henao-Martínez AF, Rodríguez-Morales AJ, Villamil Gómez WE, Gotuzzo E, et al. Cutaneous mycobacterial infections. Clin Microbiol Rev. 2018;32:e00069-18..

The two main predisposing factors for M. marinum infection are exposure to M. marinum-infected freshwater or saltwater, and the presence of superficial cuts or abrasions5757. Bonamonte D, Filoni A, Vestita M, Angelini G. Mycobacterium marinum skin infection. In: Bonamonte D, Angelini G, editors. Mycobacterial skin infections. Cham: Springer; 2017. p.325-58.. Thus, the aquarium or fishery workers and fish hobbyists are at risk, especially if they do not use waterproof gloves for protection.

Cutaneous manifestations vary but mainly include a solitary papule or nodule that may ulcerate and spread in a sporotrichoid pattern (lymphangitic spread). M. marinum may produce deep tissue involvement or disseminated disease, especially in immunocompromised hosts5757. Bonamonte D, Filoni A, Vestita M, Angelini G. Mycobacterium marinum skin infection. In: Bonamonte D, Angelini G, editors. Mycobacterial skin infections. Cham: Springer; 2017. p.325-58.. Because its optimal temperature for growth is around 30°C, cutaneous lesions most frequently occur in the upper or lower extremities5656. Franco-Paredes C, Marcos LA, Henao-Martínez AF, Rodríguez-Morales AJ, Villamil Gómez WE, Gotuzzo E, et al. Cutaneous mycobacterial infections. Clin Microbiol Rev. 2018;32:e00069-18.,5757. Bonamonte D, Filoni A, Vestita M, Angelini G. Mycobacterium marinum skin infection. In: Bonamonte D, Angelini G, editors. Mycobacterial skin infections. Cham: Springer; 2017. p.325-58..

M. marinum grows slowly and positive cultures may be obtained after 3-4 weeks, whereas in subculture, the growth rate can be slower between 4 to 14 days5757. Bonamonte D, Filoni A, Vestita M, Angelini G. Mycobacterium marinum skin infection. In: Bonamonte D, Angelini G, editors. Mycobacterial skin infections. Cham: Springer; 2017. p.325-58.. M. marinum is less demanding than M. tuberculosis and growth can be observed even on conventional media such as blood agar5757. Bonamonte D, Filoni A, Vestita M, Angelini G. Mycobacterium marinum skin infection. In: Bonamonte D, Angelini G, editors. Mycobacterial skin infections. Cham: Springer; 2017. p.325-58.. In our settings, M. marinum fluently grew on blood and even on Sabouraud dextrose agar (peptone, glucose and agar). This is the first report – to the best of our knowledge – of the abundant growth of M. marinum on Sabouraud agar medium. Phenotypically, colonies of M. marinum are white or beige when the media are kept in the dark, but yellowish-orange after exposure to light (photochromogenicity)5757. Bonamonte D, Filoni A, Vestita M, Angelini G. Mycobacterium marinum skin infection. In: Bonamonte D, Angelini G, editors. Mycobacterial skin infections. Cham: Springer; 2017. p.325-58.. According to recently proposed guidelines, all clinically relevant isolates of NTM should be identified by molecular methods5858. Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ Jr, Andrejak C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J. 2020;56:2000535.. PCR-based commercial methods developed for the identification of M. marinum include INNO-LIPA Mycobacteria v2 (Innogenetics), based on the amplification of the ribosomal gene spacer (16S-23S), and Genotype Mycobacteria CM/AS (Hain Lifescience), based on the amplification of a 23S rRNA gene5757. Bonamonte D, Filoni A, Vestita M, Angelini G. Mycobacterium marinum skin infection. In: Bonamonte D, Angelini G, editors. Mycobacterial skin infections. Cham: Springer; 2017. p.325-58.. The drawback is that they cannot differentiate M. marinum from M. ulcerans, as their rRNA sequences are similar5757. Bonamonte D, Filoni A, Vestita M, Angelini G. Mycobacterium marinum skin infection. In: Bonamonte D, Angelini G, editors. Mycobacterial skin infections. Cham: Springer; 2017. p.325-58.. On the other hand, the discriminatory power of MALDI-TOF MS method regarding NTM has increased with recent improvements of protein extraction protocols and databases but not all species and subspecies can be differentiated with this approach5858. Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ Jr, Andrejak C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J. 2020;56:2000535.. MALDI-TOF MS has achieved up to 98% agreement with 16S rRNA, hsp65 and rpoB genes sequencing5959. Rodríguez-Sánchez B, Ruiz-Serrano MJ, Marín M, López Roa P, Rodríguez-Créixems M, Bouza E. Evaluation of matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of nontuberculous mycobacteria from clinical isolates. J Clin Microbiol. 2015;53:2737-40.. Ancillary to physical examination and medical history, a positive result of an interferon-gamma release assay for tuberculosis may provide an important diagnostic clue, before the laboratory confirmation is provided3636. Nachimuthu N, Ganesh SY. Diagnosis of Mycobacterium marinum infection based on seroconversion of QuantiFERON-TB Gold Test. Cureus. 2020;12:e9208..

There is no consensus on the optimal treatment of M. marinum infection. Antimicrobials used include clarithromycin, ethambutol, rifampin, minocycline, doxycycline and trimethoprim-sulfamethoxazole. Monotherapy has been proven successful in most cases, especially for superficial cutaneous infections5757. Bonamonte D, Filoni A, Vestita M, Angelini G. Mycobacterium marinum skin infection. In: Bonamonte D, Angelini G, editors. Mycobacterial skin infections. Cham: Springer; 2017. p.325-58.. Treatment is continued 1-2 months after the resolution of skin lesions, typically 3-4 months in total5050. Kobayashi T, Ford B, Sekar P. A case of severe cutaneous Mycobacterium marinum infection in a patient with Crohn’s disease on chronic high-dose prednisone. BMJ Case Rep. 2019;12:bcr-2018-228516.. Combination therapy is preferred in deeper infections. Excellent outcomes have been reported for the combination of clarithromycin-rifampicin, as well as the combination of ethambutol-rifampicin. Nevertheless, the combination of clarithromycin and ethambutol seems to provide the optimal balance of efficacy and tolerability for most patients, with the addition of rifampicin in cases of osteomyelitis or other deep structure infection5858. Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ Jr, Andrejak C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J. 2020;56:2000535.. The latter approach is recommended by the Infectious Diseases Society of America and American Thoracic Society3131. Tuan J, Spichler-Moffarah A, Ogbuagu O. Mycobacterium marinum: nodular hand lesions after a fishing expedition. BMJ Case Rep. 2020;13:e238835.. Surgical debridement may be required for patients with deeper or more complicated infections, or in cases of poor response to treatment5757. Bonamonte D, Filoni A, Vestita M, Angelini G. Mycobacterium marinum skin infection. In: Bonamonte D, Angelini G, editors. Mycobacterial skin infections. Cham: Springer; 2017. p.325-58.. Thermotherapy and photodynamic therapy combined with fractional CO2 laser ablation have been reported as effective alternatives. Furthermore, consideration should be taken to limit immunosuppression in patients with M. marinum infection by discontinuing their treatment, particularly when receiving TNF-alpha inhibitors3131. Tuan J, Spichler-Moffarah A, Ogbuagu O. Mycobacterium marinum: nodular hand lesions after a fishing expedition. BMJ Case Rep. 2020;13:e238835..

The literature review reveals that in half of the cases (18/42, 43%) inappropriate medication was administered initially, more commonly cephalosporins, TMP-SXT, fluoroquinolones, as well as antifungals. In four cases, steroids were prescribed as the lesions were considered to have an allergic or autoimmune basis. Fourteen patients (33%) were receiving immunosuppressive therapy and the vast majority of them (12 patients) were under anti-TNFa regimens. In addition, another patient had Sjögren’s syndrome without receiving therapy, one had myelodysplastic syndrome and one was receiving steroid injections. Injuries have been identified in 25 cases (60%). Although in some cases patients do not recall a trauma, their habits or occupations (chef, fishermen, landscape enthusiasts) may predispose them to minor injuries. Source of exposure is speculated in almost all cases (39/42, 93%); specific direct exposure to fish occurred in 35 cases (83%), exposure to fresh or salt water (pool, pond, sea) in 3 cases (7%) and possible occupational exposure in one case (chef). The infection was presented as lymphocutaneous-sporotrichoid form in 43% (18/42) of the cases and the lesions were most commonly located on the upper extremities (37/42, 88%), specifically right hand/arm (18 cases, 43%), left hand/arm (15 cases, 36%), both arms (4 cases, 10%) and, at a lesser extent, on the right leg, face, neck and trunk. With the exception of two cases that exhibited slow or moderate improvement and two that did not include information regarding the follow up, all other cases had a favorable outcome, most commonly by antimicrobial therapy alone, whereas adjuvant surgical intervention was required in six cases (14%). In addition, the immunosuppressive therapy was discontinued in four cases (three cases considered patients receiving anti-TNFa). The most commonly used regimen combinations were clarithromycin plus rifampicin plus ethambutol (seven cases), clarithromycin plus rifampicin (five cases), and ethambutol and rifampicin (three cases). Clarithromycin and minocycline were used as monotherapy in five and three cases, respectively.

In this article, we have chosen to co-present these two pathogens as they share common properties. Both represent ‘rare’ causes of skin and soft tissue infections. Diagnosis is challenging as the clinical presentation overlaps with other more common pathogens. On the other hand, lymphocutaneous infection with the characteristic sporotrichoid pattern can drive diagnosis to both pathogens or sporotrichosis (caused by Sporothrix schenckii), almost obsolete in Europe. Both pathogens cause infections that are not transmissible between humans and are usually acquired from natural sources, like soil and water, through skin abrasions. Although other species of their genera typically affect immunocompromised individuals, N. brasiliensis and M. marinum can cause disease in immunocompetent persons. Nevertheless, we should keep in mind that although they mainly affect immunocompetent individuals, both diseases could be detrimental for immunocompromised patients and may lead to disseminated disease. Moreover, there are several difficulties in their isolation, as direct microscopy and cultures are often negative due to low bacterial load, inappropriate sampling – biopsies are preferable to swabs but more difficult to obtain –, improper laboratory handling, need for prolonged incubation, selective growth media and additional incubation at 30 ºC. In many cases, repeated sampling or biopsies are required in order to achieve the diagnosis. Nevertheless, although ‘uncommon’, these pathogens should be included in the differential diagnosis as they are encountered, especially in secondary and tertiary health care units. Most patients have undergone inappropriate treatment and seek advice in health care facilities providing specialist services, such as dermatologists, infectious disease physicians and clinical microbiologists, as well as specialized laboratory facilities.

A comparative presentation of N. brasiliensis and M. marinum colonies on culture media highlights their common features. Both bacteria can be isolated on media suitable for mycobacteria, such as LJ, as well as on common media, such as blood agar and Sabouraud dextrose agar plates. In addition, both isolates could be stained similarly by both Gram stain and ZN stain. N. brasiliensis isolate retained the characteristic beaded pattern on Gram stain and was easily stained by ZN, almost evenly, in both conventional and modified staining methods. In terms of M. marinum, it was readily stained by ZN, as expected, but it was also stained by Gram stain as Gram-positive; this finding, along with the ability to grow on conventional media, was challenging or even misleading to the species identification. Similarity in microbiological and clinical manifestation of nocardiosis and mycobacterial infections, resulting in the difficulty of accurate identification, has been already described in respiratory samples6060. Muricy EC, Lemes RA, Bombarda S, Ferrazoli L, Chimara E. Differentiation between Nocardia spp. and Mycobacterium spp.: critical aspects for bacteriological diagnosis. Rev Inst Med Trop Sao Paulo. 2014;56:397-401.. The literature review revealed that, in a nocardiosis case, the patient was treated for mycobacterial infection based on clinical appearance of the lesions and local epidemiology88. Wang R, Yao X, Li R. Mycetoma in China: a case report and review of the literature. Mycopathologia. 2019;184:327-34., whereas one patient with M. marinum cutaneous infection was treated for Nocardia spp. infection based on Gram and ZN stain of biopsy specimens5050. Kobayashi T, Ford B, Sekar P. A case of severe cutaneous Mycobacterium marinum infection in a patient with Crohn’s disease on chronic high-dose prednisone. BMJ Case Rep. 2019;12:bcr-2018-228516..

CONCLUSION

To conclude, skin and soft tissue infections can pose diagnostic dilemmas in the case that ‘uncommon’ pathogens are encountered. This can lead to misdiagnosis and unappropriated or delayed treatment. Therefore, close collaboration among physicians and clinical microbiologists, expertise of scientific personnel and application of current techniques, molecular and MALDI-TOF MS are essential prerequisites for a precise diagnosis. The laboratory should be informed if Nocardia or Mycobacterium spp. are included in the differential diagnosis. Proper processing of samples, including inoculation on suitable culture media and growth conditions, is vital to optimize the laboratory diagnosis. Laboratory results influence therapeutic decisions and may have a substantial impact on patient care and outcome.

REFERENCES

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Publication Dates

  • Publication in this collection
    14 Apr 2023
  • Date of issue
    2023

History

  • Received
    7 Oct 2022
  • Accepted
    27 Feb 2023
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