**4. NTM lung infections**

#### **4.1. Clinical features and causes of NTM lung infections**

NTM lung infections are often due to *Mycobacterium avium* complex (MAC) and RGM. NTM lung disease may be misdiagnosed as Tuberculosis and require weeks or months [90]. The clinical diagnosis and treatment remain challenging due to its nonspecific symptoms such as low-grade fever, wet chronic cough, weight loss and malaise similar to *M. tuberculosis* [91]. Radiological imaging is a vital test to screen for NTM lung disease. A broad range of radiological patterns such as bronchiectasis, cavitary lesions, nodular lesions and parenchymal lesions, have been observed in NTM lung disease [92]. However, two major radiological findings have been listed, fibrocavitary and nodular bronchiectatic forms [93]. The first form is similar to pulmonary TB and it usually affects elderly male with underlying pathology of the lung. Cavities with increased opacity are usually seen in the upper parts of the lung in the fibrocavitary form [94]. Thin-walled cavities without lymph node involvement and atelectasis are the common findings in this form [95]. The nodular bronchiectatic form often presents with bilateral, small nodules and multilobar bronchiectasis in the lower and middle parts of the lung [96]. This disease pattern is associated with elderly nonsmoking women without underlying lung diseases [97]. There is a connection between bronchiectasis and NTM lung diseases [98]. Because of NTM's nonspecific symptoms and similar radiological findings as *M. tuberculosis* and other lung pathologies, it is extremely hard to diagnose NTM lung disease. Risk factors causing NTM lung disease are still poorly understood but immune status is vital for NTM lung disease. A study showed that disseminated NTM infection is often associated in patients with profound immunosuppression [99]. NTM are important pathogens for patients who have undergone or are awaiting lung transplant and cystic fibrosis patients [100]. Defects in the crucial elements of the host defense such as interleukin-12 (IL-12) and interferon-gamma (IF-γ) increase susceptibility to NTM lung infections [101]. Increasing usage of tumor necrosis factor (TNF-α) receptor antagonists usage enhances NTM infections [102]. The rate of NTM prevalence in TNF-α receptor antagonists usage is 74/100,000 persons per year [103].

### **4.2. Treatment of NTM lung infections**

#### *4.2.1. MAC lung infections*

keratitis patients is suggested; if the lesion is in progression, or stromal thinning and symptoms persistence continues after 2 days of antibiotics, drug sensitivity should be rechecked for an alternative sensitive antimicrobial. However, there is no agreed-upon treatment plan for NTM keratitis and more research including evaluation of new treatment plans and an in-depth knowledge of NTM keratitis pathogenesis is warranted to treat NTM keratitis effectively.

**Figure 2.** Slit lamp photograph showing central haziness in NTM keratitis mouse model. Confocal microscopy images showing presence of atypical mycobacterial microcolonies biofilm formation (green color) with abundance of

NTM lung infections are often due to *Mycobacterium avium* complex (MAC) and RGM. NTM lung disease may be misdiagnosed as Tuberculosis and require weeks or months [90]. The clinical diagnosis and treatment remain challenging due to its nonspecific symptoms such as low-grade fever, wet chronic cough, weight loss and malaise similar to *M. tuberculosis* [91]. Radiological imaging is a vital test to screen for NTM lung disease. A broad range of radiological patterns such as bronchiectasis, cavitary lesions, nodular lesions and parenchymal lesions, have been observed in NTM lung disease [92]. However, two major radiological findings have been listed, fibrocavitary and nodular bronchiectatic forms [93]. The first form is similar to pulmonary TB and it usually affects elderly male with underlying pathology of the lung. Cavities with increased opacity are usually seen in the upper parts of the lung in the fibrocavitary form [94]. Thin-walled cavities without lymph node involvement and atelectasis are the common findings in this form [95]. The nodular bronchiectatic form often presents

**4. NTM lung infections**

48 Basic Biology and Applications of Actinobacteria

**4.1. Clinical features and causes of NTM lung infections**

extracellular DNA (a major constituent of mycobacterial biofilm matrix in red color) [88].

Macrolides are the treatment of choices for MAC lung infections [104]. Rifampin or ethambutol can be added to macrolide administration for 18–24 months [63]. Rifampin 600 mg/kg, ethambutol 25 mg/kg with either azithromycin 500 mg/kg or clarithromycin 1000 mg/kg is frequently given as three-times-weekly intermittent therapy for NTM noncavitary lung disease [63]. It has been suggested that intermittent therapy is more efficient and reduced toxicity than daily therapy [105]. A cocktail of rifampin 10 mg/kg/day, ethambutol 15 mg/kg/day with either azithromycin 250 mg/kg/day or 1000 mg/kg is given daily for cavitary nodular bronchiectatic NTM lung disease, with a possibility of adding either streptomycin or amikacin in the first 2 or 3 months of therapy in severe disease [63].

The addition of moxifloxacin to the standard treatment showed a better response if a standard treatment plan fails [106]. Clofazimine has shown that it can be an alternative option to the rifampin or in refractory MAC lung infections [107]. The successful treatment of NTM lung infections totally relies on the prevention of macrolide-resistant MAC infections with the optimal treatment strategies.

#### *4.2.2. RGM lung infections*

The management for RGM lung infections typically depends on drug's toxicity and drug sensitivity tests. Treatment for *M. abscessus* lung infection is challenging as shown in previous studies [108]. The recommended guideline for treating RGM lung infection includes a combination of treatment which involves two parenteral antibiotics and an oral macrolide for a relatively long duration (several months) [63]. The most active and useful parenteral agents consist of amikacin 10–15 mg/kg/day, imipenem 500–1000 mg2 , cefoxitin 200 mg/kg/day, and tigecycline 50 mg/day [108]. Moxifloxacin has been shown as an alternative option for treating RGM lung infections [109]. Aggressive parenteral therapy is suggested for initial 4 months of treatment accompanied later by a treatment combination of macrolide and linezolid or clofazimine or fluoroquinolone for coping with toxicity [108]. Treatment with macrolides for RGM infection should be carefully accessed on the patient's tolerance and treatment compliance due to the possibility of drug resistance evolved [110]. Surgical resection should be considered to combine with chemotherapy in treating RGM lung infections [111].

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