**2. NTM cutaneous and subcutaneous infections**

#### **2.1.** *Mycobacterium abscessus*

*M. abscessus*, a fast-growing NTM, is commonly found in water drainage systems and sewage. It is a subset of the *M. chelonae* complex and it is vital to segregate from the *M. chelonae* complex due to the dissimilar antibacterial treatment option. It is well known that the clinical success of *M. abscessus* depends on the host's immune defense [37]. It was reported that *M. abscessus* caused posttransplant infection in cystic fibrosis (CF) patients in spite of having antimicrobial treatment [38]. They are responsible for the major causes of skin and soft tissue infections in the literatures [39] and they are the most common cause of identified NTM infections in Singapore (**Figure 1**). The path of entries for this organism is direct inoculation such as skin piercing or injury [40] or secondary involvement from disseminated infection [41]. The most likely source of infection is from tap water. Water and soil are the natural habitats for *M. abscessus* [4, 42]. *M. abscessus* outbreaks have been reported in clinic and hospitals worldwide and the contaminated instruments or disinfectants are the major sources of the outbreaks [41].

#### *2.1.1. Clinical features and causes of M. abscessus cutaneous and subcutaneous infections*

*M. abscessus* infected skin usually presents with painful, swollen and tender to the touch, accompanying with pus-filled vesicles. Nonspecific symptoms of infections may be present such as fever with chills, muscle aches, and malaise. Causes of *M. abscessus* infections include posttraumatic wound infections [20], postinjection wound infections [20] and surgical wound infections (mammoplasties, plastic surgeries, and heart surgeries) [20].

#### **2.2.** *Mycobacterium fortuitum*

*M. fortuitum* is a principal cause of cutaneous and subcutaneous infections associated with catheters [43, 44] as well as post surgical wound infections [45]. The route of entry for *M. fortuitum* is direct inoculation from contaminated water through the lesions.

#### *2.2.1. Clinical features and causes of M. fortuitum cutaneous and subcutaneous infections*

Small, erythematous papules are frequent signs of the early stages of infection and large, fluctuant, painful violaceous boils and ulcerations are signs for late stage infections [45, 46]. They can be caused by mesotherapy and present with indurated, erythematous and violaceous papules with 3–20 numbers, the diameter ranging from 0.5 to 6 cm, accompanied by inguinal or axillary lymphadenopathy [47]. *M. fortuitum* can also be recovered from blood and purulent discharge from patients with venous catheters [43, 44] and is the cause of post surgical wound infections such as liver transplant patients, electromyography and punch biopsy procedures [44, 48, 49].

#### **2.3.** *Mycobacterium chelonae*

**1.4. NTM incidence in Singapore (2007–2017)**

42 Basic Biology and Applications of Actinobacteria

**2.1.** *Mycobacterium abscessus*

**2.2.** *Mycobacterium fortuitum*

**2. NTM cutaneous and subcutaneous infections**

The incidences of NTM cases in Singapore are rising in the recent years, about 3000 cases per year [36] (**Figure 1**). Among NTM, *M. abscessus* is responsible for most of the identified NTM cases in Singapore, followed by *M. fortuitum, M. avium* complex and *M. chelonae* (**Figure 1**).

*M. abscessus*, a fast-growing NTM, is commonly found in water drainage systems and sewage. It is a subset of the *M. chelonae* complex and it is vital to segregate from the *M. chelonae* complex due to the dissimilar antibacterial treatment option. It is well known that the clinical success of *M. abscessus* depends on the host's immune defense [37]. It was reported that *M. abscessus* caused posttransplant infection in cystic fibrosis (CF) patients in spite of having antimicrobial treatment [38]. They are responsible for the major causes of skin and soft tissue infections in the literatures [39] and they are the most common cause of identified NTM infections in Singapore (**Figure 1**). The path of entries for this organism is direct inoculation such as skin piercing or injury [40] or secondary involvement from disseminated infection [41]. The most likely source of infection is from tap water. Water and soil are the natural habitats for *M. abscessus* [4, 42]. *M. abscessus* outbreaks have been reported in clinic and hospitals worldwide and the contaminated instruments or disinfectants are the major sources of the outbreaks [41].

*2.1.1. Clinical features and causes of M. abscessus cutaneous and subcutaneous infections*

infections (mammoplasties, plastic surgeries, and heart surgeries) [20].

*fortuitum* is direct inoculation from contaminated water through the lesions.

*2.2.1. Clinical features and causes of M. fortuitum cutaneous and subcutaneous infections*

*M. abscessus* infected skin usually presents with painful, swollen and tender to the touch, accompanying with pus-filled vesicles. Nonspecific symptoms of infections may be present such as fever with chills, muscle aches, and malaise. Causes of *M. abscessus* infections include posttraumatic wound infections [20], postinjection wound infections [20] and surgical wound

*M. fortuitum* is a principal cause of cutaneous and subcutaneous infections associated with catheters [43, 44] as well as post surgical wound infections [45]. The route of entry for *M.* 

Small, erythematous papules are frequent signs of the early stages of infection and large, fluctuant, painful violaceous boils and ulcerations are signs for late stage infections [45, 46]. They can be caused by mesotherapy and present with indurated, erythematous and violaceous papules with 3–20 numbers, the diameter ranging from 0.5 to 6 cm, accompanied by inguinal or axillary lymphadenopathy [47]. *M. fortuitum* can also be recovered from blood and *M. chelonae* infections are usually associated with immunocompromised hosts such as HIV patients [50]. It can be seen in postsurgical wounds and can disseminate hematogenoulsy to cause sepsis. Contaminated water is the most common source of infection and the route of entry is direct inoculation.

#### *2.3.1. Clinical features and causes of M. chelonae cutaneous and subcutaneous infections*

Circumscribed, red, infiltrative plaques, umbilicated papules, and pustules on the upper part of the body and face are features of *M. chelonae* skin lesions and frequently accompanied by cervical lymphadenopathy [51]. Immunocompromised patients, HIV/AIDS patients often contract *M. chelonae* infections [50]. Kidney transplant patients, liver transplant patients, tattooing, kidney dialysis patients and peritoneal dialysis patients are also frequently associated with *M. chelonae* infections [13, 52, 53]. Reports suggest that immunosuppressive drugs such as prednisolone, methotrexate, and adalimumab [54, 55], and autoimmune diseases such as Cushing's syndrome and rheumatoid arthritis are often associated with *M. chelonae* skin infections [55, 56].

#### **2.4. NTM cutaneous and subcutaneous infections**

The correct choice of antimicrobial agent, anatomic locations of the lesions, intracellular uptake and target binding are essential for the management of NTM cutaneous and subcutaneous infections. Moreover, an appropriate route of drug administration (oral, intravenous or intramuscular), acceptable and effective drug concentration is required for the treatment plan. Drug resistance mechanisms for rapidly growing mycobacteria (RGM) involving *erm* gene must be considered due to the prolonged treatment period. Therefore, it is critical to differentiate and identify rapidly growing mycobacterial at the subspecies level [25, 57]. The decision of choosing either surgical debridement in combination with mono or multidrug therapy, or only mono or multidrug therapy depends on the anatomical location and severity of the lesion, patient's immune status with presence of underlying pathology (**Table 1**) and the Minimum Inhibitory Concentration (MIC) breakpoints from the microbiology lab (**Tables 2** and **3**).

#### *2.4.1. M. abscessus cutaneous and subcutaneous infections*

Macrolides are the gold standard treatment for *M. abscessus* infections. They exhibit bactericidal actions against *M. abscessus* when the lesion has a small population of bacteria. Reports suggest that azithromycin and clarithromycin are the gold standard for treating *M. abscessus* infections in disseminated cases; however, there are reports suggesting the evolution of resistance against these drugs in prolonged monotherapy [11, 58]. Tigecycline, a new antibiotic,


cilastatin also account for 100%, clarithromycin stands for 80% and linezolid and doxycycline accounts for 50% [63]. Due to rising chances of bacterial resistance to macrolide due to the inducible *erm* gene, clarithromycin uses should be carefully assessed and monitored [52, 63, 64]. Linezolid is another good candidate for *M. fortuitum* in *in vitro*; however, more human clinical studies would be warranted for the future use [65]. The minimum 4 months duration of the combination of two drugs is required for severe or critical *M. fortuitum* cutaneous and subcutaneous infections. Reports are suggested that surgical debridement or surgical drainage is indicated for the better antimicrobial treatment therapy or helping to cure the *M. fortuitum* infections particularly in extensive disease and abscesses [66]. *M. fortuitum* usually possess the *erm* gene, which is inducible to promote resistance to clarithromycin. There was a report showing that sensitivity testing of *M. fortuitum* isolates showed trailing MICs against macrolides [67]. However, the relevance of the *erm* gene in *M. fortuitum* and clarithromycin

Imipenem New breakpoint (8–16 μg/ml) for reproducible MIC

Nontuberculous Mycobacterial Infections: Negligent and Emerging Pathogens

http://dx.doi.org/10.5772/intechopen.80444

45

Clofazimine is shown to be effective and the addition of sub MIC concentration of amikacin synergies with clofazimine against RGM including *M. chelonae* [68]. Tobramycin has been suggested to be a better treatment option than amikacin [69]. However, *M. chelonae* isolates showed resistant to cefoxitin and imipenem is the alternative option. There is MIC susceptibility of clarithromycin (100%), tobramycin (100%), linezolid (90%), imipenem (60%), amikacin (50%), doxycycline (25%), clofazimine (25%) and ciprofloxacin (20%) [63]. However, *M. chelonae* is susceptible only to clarithromycin, tobramycin, and tigecycline [70]. Monotherapy is not advisable for *M. chelonae* infections due to its facility to acquire drug resistance and combination treatment is advised [71]. Excision and treatment is still the optimal treatment step in combination with antibiotics in treating *M. chelonae* cutaneous and subcutaneous infections [66]. Treatment guidelines are not yet reported; however, current guidelines recommend

The most prevalent NTM strains causing eye infections are *M. fortuitum* and *M. chelonae* [72, 73]*.* Keratitis is standing as the most common real situation accounting for 69% of ocular

treatment remains to be determined in clinical management.

using antimicrobial susceptibility tests to predict therapeutic efficacy.

**3.1. Clinical features and causes of NTM eye infections**

*2.4.3. M. chelonae cutaneous and subcutaneous infections*

**RGM Drug Reporting**

**Table 3.** Reporting MICs of RGM [112].

*M. fortuitum* Clarithromycin Trailing endpoints, report as resistant

*M. abscessus* Amikacin If MIC is more than 64 μg/ml, need to repeat/confirm *M. chelonae* Tobramycin If MIC is more than 4 μg/ml, need to repeat/ confirm

**3. NTM eye infections**

NTM infections (**Table 4**).

**Table 1.** Clinicians' choice of antibiotic regimes for different RGM infections [112].


**Table 2.** MIC breakpoints for RGM [112, 113].

may be another choice for *M. abscessus* infections [59]. Amikacin is known to be the treatment of choice since it is active against all the subspecies of RGM and imipenem or cefoxitin can be added to overcome treatment failures [11, 58]. Surgical debridement plays a role in the better treatment outcomes for *M. abscessus* infections [60].

#### *2.4.2. M. fortuitum cutaneous and subcutaneous infections*

*M. fortuitum* infections are chronic in nature and *in vitro* drug susceptibility tests are required for a guidance of choosing the correct antibiotics. Usually, *M. fortuitum* are sensitive to several oral antimicrobials such as quinolones, sulfonamides, and macrolides [61, 62]. Amikacin is the treatment of choice for *M. fortuitum* with 100% efficacy, while sulfonamide and imipenem/


**Table 3.** Reporting MICs of RGM [112].

cilastatin also account for 100%, clarithromycin stands for 80% and linezolid and doxycycline accounts for 50% [63]. Due to rising chances of bacterial resistance to macrolide due to the inducible *erm* gene, clarithromycin uses should be carefully assessed and monitored [52, 63, 64]. Linezolid is another good candidate for *M. fortuitum* in *in vitro*; however, more human clinical studies would be warranted for the future use [65]. The minimum 4 months duration of the combination of two drugs is required for severe or critical *M. fortuitum* cutaneous and subcutaneous infections. Reports are suggested that surgical debridement or surgical drainage is indicated for the better antimicrobial treatment therapy or helping to cure the *M. fortuitum* infections particularly in extensive disease and abscesses [66]. *M. fortuitum* usually possess the *erm* gene, which is inducible to promote resistance to clarithromycin. There was a report showing that sensitivity testing of *M. fortuitum* isolates showed trailing MICs against macrolides [67]. However, the relevance of the *erm* gene in *M. fortuitum* and clarithromycin treatment remains to be determined in clinical management.

#### *2.4.3. M. chelonae cutaneous and subcutaneous infections*

Clofazimine is shown to be effective and the addition of sub MIC concentration of amikacin synergies with clofazimine against RGM including *M. chelonae* [68]. Tobramycin has been suggested to be a better treatment option than amikacin [69]. However, *M. chelonae* isolates showed resistant to cefoxitin and imipenem is the alternative option. There is MIC susceptibility of clarithromycin (100%), tobramycin (100%), linezolid (90%), imipenem (60%), amikacin (50%), doxycycline (25%), clofazimine (25%) and ciprofloxacin (20%) [63]. However, *M. chelonae* is susceptible only to clarithromycin, tobramycin, and tigecycline [70]. Monotherapy is not advisable for *M. chelonae* infections due to its facility to acquire drug resistance and combination treatment is advised [71]. Excision and treatment is still the optimal treatment step in combination with antibiotics in treating *M. chelonae* cutaneous and subcutaneous infections [66]. Treatment guidelines are not yet reported; however, current guidelines recommend using antimicrobial susceptibility tests to predict therapeutic efficacy.
