Introduction

The family Mycobacteriaceae belongs to the order Actinomyetales and the phylum Actinobacteria [1•]. To date, there are more than 150 mycobacterial species identified with the availability of modern molecular techniques including the 16s ribosomal DNA sequencing, polymerase chain reaction (PCR) analysis employing restriction length polymorphisms, and high-performance liquid chromatography [2••]. Most mycobacterial species are harmless saprophytes often found in soils or aquatic environments [1•]. However, many mycobacterial species evolved to cause animal and human disease from a plethora of ecological matrixes (soils, natural water reservoirs, or engineered water systems) [3]. In other cases, human infections represent zoonosis such as in the case of Mycobacterium bovis [4,5,6] or Mycobacterium leprae [7,8,9], or infection occurs through the person-to-person transmission route such as in the case of Mycobacterium tuberculosis [5, 6]. Mycobacterial infections may affect any organ of the human host, but most common sites of involvement include pulmonary, cutaneous (skin and soft tissues including superficial lymphadenitis), and disseminated clinical forms [10••, 11••].

Skin and soft tissue infections caused by nontuberculous mycobacteria groups (NTMs) are usually the result of direct inoculation of these pathogens linked to specific environmental exposures [10••, 11••]. Cutaneous mycobacterial infections are emerging diseases of increasing medical concern because of cohabitation of environmental habitats with mycobacteria [10••]. Indeed, humans venture with increasing frequency into habitats where environmental mycobacteria are highly prevalent [12]. For example, growing human incursion into aquatic environments has been frequently associated with infection caused by Mycobacterium marinum, Mycobacterium ulcerans, and Mycobacterium haemophilum [13,14,15]. Cutaneous mycobacterial infections are also transmitted in the hospital setting through contaminated medical products, indwelling catheters, and surgical procedures [11••, 16]. There is also evidence that nontuberculous mycobacteria are emerging pathogens among immunosuppressed hosts such as those with HIV/AIDS or among those receiving immunosuppressive therapies including biological therapies for immune-mediated inflammatory disease, solid organ transplantation, hematologic malignancies, and hematopoietic stem cell or solid organ transplantation [17].

Clinical Manifestations of Cutaneous Mycobacterial Infections

Mycobacterial infections of the skin and subcutaneous tissues are important causes of human disease. M. leprae, M. ulcerans, and M. tuberculosis are the most frequently recognized mycobacterial pathogens causing diseases involving the skin and soft tissues. Additionally, all environmental mycobacterial species of the nontuberculous group may also produce cutaneous disease. They may manifest as localized or disseminated forms and the spectrum of clinical manifestations ranges from nodules, plaques, sporotrichoid lesions, chronic nonhealing ulcers, single or multiple abscesses, chronic draining sinuses, superficial lymphadenitis (scrofula), and cellulitis (Table 1) [11••]. Local spread of cutaneous mycobacterial diseases into deeper tissues may also be associated with tenosynovitis, septic arthritis, and osteomyelitis [10••, 11••]. Leprosy, the prototype of the cutaneous mycobacterial infections, has inflicted incalculable suffering for millennia by causing deforming cutaneous lesions and peripheral nerve damage resulting in neurologic dysfunction, deformity, and limb loss [10••]. Despite major gains in controlling this ancient plague, leprosy remains an important cutaneous mycobacterial infection in many areas of the world [18, 19]. In fact, since 2000, there have been approximately 3 million new cases of leprosy [20]. In susceptible human hosts, M. leprae may produce a broad spectrum of clinical phenotypes with different degrees of clinical severity and risk of leprosy reactions (Table 1). Similarly, the wide range of clinical forms of cutaneous tuberculosis depends on the mode of acquisition of the infection (exogenous versus endogenous spread), host immune status, and history of previous exposure to the tuberculous bacilli [21••]. Tuberculosis of the skin and soft tissues represents only 1–2% of all combined clinical forms of pulmonary and extrapulmonary tuberculosis [21••]. Infection due to M. ulcerans produces a cutaneous infection that ranges from a localized painless nodule or ulceration to diffuse cutaneous ulcerative or non-ulcerative forms with bone involvement [22, 23]. The disease is termed Buruli ulcer or Bairnsdale ulcer. In 2015, more than 2000 cases were reported to the World Health Organization with most cases reported in Africa. Individuals may acquire M. ulcerans infection through mild skin injuries and subsequent exposure to contaminated water or soils leading to the entry of M. ulcerans into the subcutaneous tissue, or insect vectors may play a role in its transmission [22, 23]. The disease is produced by the production of a potent macrolide toxin, mycolatone which is capable of subcutaneous tissue destruction, modulate pain locally, and that is immunosuppressive [22, 23]. Buruli ulcer is an important neglected tropical disease that can produce important physical impairment, functional sequelae, deformity, and dysfunction [24].

Table 1 Clinical manifestations of cutaneous mycobacterial infections
Full size table

The NTM constitutes mycobacterial species other than those causing tuberculosis, leprosy, and Buruli ulcer and includes two major groups defined by their ability to grow in solid culture media (rapid or slow growers) [25•]. In the USA and other countries, recent reports have suggested that the prevalence of nontuberculous mycobacteria disease is increasing especially among older adults [26]. The NTM pulmonary diseases in patients with chronic pulmonary diseases are those with bronchiectasis, chronic obstructive pulmonary disease, cystic fibrosis, and others, or those with some degree of esophageal dysfunction or gastroesophageal reflux disease, and disseminated disease in immunocompromised hosts [27]. Additionally, NTMs may cause skin and soft tissue infections after trauma or surgery, or as part of disseminated forms of the disease [10••, 11••]. Of the NTMs, the rapidly growing mycobacteria Mycobacterium fortuitum, Mycobacterium chelonae, and Mycobacterium abscessus complex frequently manifest as skin and soft tissue infections (Table 1).

Diagnosis of Cutaneous Mycobacterial Infections

Diagnosing mycobacterial infections of the skin and soft tissues is challenging due to the broad spectrum of clinical manifestations and non-specific histopathologic findings on tissue biopsy. Nonetheless, assessing skin biopsy specimens for acid-fast bacilli staining and mycobacterial cultures or from draining material is crucial in order to confirm the diagnosis of cutaneous mycobacterial infections. Mycobacteria may be identified on direct smear and tissue or recovered in Lowenstein-Jensen agar, BACTEC broth, and Middlebrook 7H10 agar [2••]. Some mycobacterial species have specific growth requirement such as M. haemophilum, which requires iron or hemin supplementation and incubation at 30 °C. Additionally, molecular detection methods including direct probe or sequencing can detect mycobacterial species may assist in confirming the diagnosis. Modern molecular techniques such as the16s ribosomal DNA sequencing, polymerase chain reaction (PCR) analysis employing restriction length polymorphisms, and high-performance liquid chromatography aid in defining the specific mycobacterial species involved in skin and soft tissue infections [2••]. The diagnosis of leprosy is a clinical diagnosis based on characteristic plaques, macules, or nodules associated with sensory loss (hypoesthesia or anesthesia), thickened peripheral nerves. Biopsy confirmation of a skin lesion demonstrates acid-fast bacilli (Fite-Faraco staining) inside peripheral nerves (endoneurium). Buruli ulcer is often diagnosed based on the presence of characteristic nodules or ulcers, ecological risk factors, and at risk age groups (often identified in individuals younger than 15 years) residing in endemic settings. M. ulcerans requires a temperature between 29 and 33 °C and a low-oxygen concentration (2.5%). Due to these limitations, molecular techniques such as qPCR are preferred for confirming a diagnosis of M. ulcerans, and point-of-care testing is underdevelopment [2••].

Performing susceptibility testing of mycobacterial isolates is important to decide on optimal antimycobacterial therapies since the MIC to specific antimicrobials correlate clinically with in vivo response to therapy (i.e., rifampin in the case of Mycobacterium kansasii). M. marinum requires microdilution broth MIC at 30 °C as the preferred susceptibility method. It is recommended that rapidly growing mycobacteria be tested against selected antibacterial drugs such as clarithromycin, cefoxitin, imipenem, amikacin, tobramycin (in the case of M. chelonae), fluoroquinolones, and others [10••]. Since M. leprae is not cultivable, susceptibility testing for M. leprae requires assessments of genetic markers of resistance [28].

Treatment of Cutaneous Mycobacterial Infections

The choice of antibacterial therapy and length of treatment for cutaneous mycobacterial infections is species-specific. Antimycobacterial therapy of M. leprae involves the use of multidrug therapy with a combination of dapsone, rifampin, and clofazimine with length of therapy depending on the clinical staging of the disease. Treatment of cutaneous tuberculosis follows the treatment guidelines for extrapulmonary disease with standard multidrug therapy with length of treatment depending upon the type of cutaneous tuberculosis. Antimycobacterial treatment of M. ulcerans is effective in early limited disease with an 8 week combination of streptomycin, rifampin, and clarithromycin [24].The most frequently encountered members of the rapidly growing mycobacteria group (M. abscessus complex, M. fortuitum, or M. chelonae) are intrinsically resistant to antituberculosis drugs such as isoniazid, rifampin, and ethambutol. The treatment of RGM is species-specific often requiring multidrug therapy with agents such as imipenem, cefoxitin, doxycycline, trimethoprim-sulfamethoxazole, amikacin or tobramycin, linezolid, fluoroquinolones, and other agents [10••, 11••]. M. abscessus and M. chelonae are resistant to doxycycline and trimethoprim-sulfamethoxazole [10••]. Some subspecies of M. abscessus and M. fortuitum possess an erm (41) gene (which produces a 23S RNA methylase) confers inducible resistance to macrolides, and therefore this is an important therapeutic consideration in deciding the specific antimycobacterial drug combination [16].

Conclusions

Cutaneous mycobacterial infections are important causes of human suffering and that manifest with localized or diffuse involvement of skin and soft tissues. The mode of acquisition of cutaneous mycobacterial infections differs among mycobacterial species and ranges from specific environmental exposures, zoonotic transmission, or through the person-to-person route. Leprosy remains an important disease in many areas of the world, while cutaneous tuberculosis represents approximately 1–2% of cases of all clinical forms of tuberculosis. In many settings, particularly in some areas in Africa, infection due to M. ulcerans is an important cause of limb deformity and dysfunction. Skin and soft tissue infection caused by many species of the nontuberculous mycobacteria is usually the result of direct inoculation via trauma followed by exposure to natural aquatic environments, manufactured water networks, soils, or in the hospital setting. Disseminated mycobacterial infections spreading from an either a pulmonary foci or through lymphatic spread may also manifest with diffuse or localized cutaneous involvement.