**3. NTM eye infections**

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

Doxycycline/minocycline ≤1 2–4 ≥8 Imipenem/meropenem ≤4 8–16 ≥32 TMP/SMX ≤2/38 – ≥4/76 Tobramycin ≤2 4 ≥8 Moxifloxacin ≤1 2 ≥4

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

Linezolid Doxycycline Clarithromycin

tigecycline

Linezolid

Gatifloxacin Doxycycline Linezolid Clarithromycin

Trimethoprim/sulfamethoxazole

tigecycline or oral drug)

**Susceptible Intermediate Resistant**

Combination of amikacin, quinolones or tobramycin (imipenem)

Combination of clarithromycin, amikacin, cefoxitin (imipenem) or

Combination of clarithromycin, linezolid (tobramycin, imipenem,

*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/

treatment outcomes for *M. abscessus* infections [60].

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

*2.4.2. M. fortuitum cutaneous and subcutaneous infections*

**RGM Disease pattern Antimicrobial agents**

*M. fortuitum* 2–8 week duration with

44 Basic Biology and Applications of Actinobacteria

symptoms

*M. abscessus* 2–8 week duration with

symptoms

symptoms

*M. chelonae* 2–8 week duration with

significant signs and symptoms

significant signs and symptoms

significant signs and symptoms

After IV treatment or disease with reduced signs and

After IV treatment or disease with reduced signs and

After IV treatment or disease with reduced signs and

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

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 NTM infections (**Table 4**).


management and clarithromycin, amikacin, and fourth generation fluoroquinolones are mentioned [85]. Topical delivery is the most used method followed by the combination of topical and systemic administration [14]. Amikacin is known to be the treatment of choice for NTM keratitis, however, there have been reports showing corneal toxicity toward the long-term usage of amikacin in high concentration [86]. According to the systemic review, amikacin was given alone in the majority of NTM keratitis cases, followed by amikacin and macrolide (**Table 6**) [14]. Fluoroquinolones, particularly fourth-generation fluoroquinolones, have been accepted as effective for eye infections [3, 86]. Fourth generation fluoroquinolones offer noteworthy benefits over the older generations because of their superior bactericidal activity, decreased risk for resistance and higher corneal concentrations. In contrast, one report suggested that the majority of nontuberculous mycobacteria are resistant to second-generation fluoroquinolones, highlighting the better efficacy properties of fourth generation fluoroq-

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Recent reports suggest a strong synergism between amikacin and fourth generation fluoroquinolone, gatifloxacin, in treating nontuberculous mycobacteria in *in vitro* and *in vivo* mouse keratitis model [88]. Moreover, it was reported that the NTM habitat in a keratitis infection is in the biofilm mode (**Figure 2**) hindering antibiotic penetration and adding DNase to the antibiotic may make a more effective treatment [88]. Surgical debridement can help to facilitate penetration and lower the bacterial load. Topical steroids are controversial for NTM keratitis and one study suggested that a steroid accelerates the infection [89]. Careful follow up of NTM

Varying degree of pain Multiple lesions or single lesion surrounded by the radiating projections

**Different antibiotic regimen Percentage** Amikacin only 29.2 Combination of amikacin and macrolide 14.1 Combination of amikacin and fluoroquinolone 12.5 Combination of amikacin, fluoroquinolone and macrolide 9.4 Combination of fluoroquinolone and macrolide 8.3 Other antibiotics 7.3 Fluoroquinolone only 6.8

uinolones [87].

**Symptoms Signs**

Tearing and foreign body sensation Hypopyon

**Table 6.** Different antibiotic regimens for NTM keratitis [14].

**Table 5.** Signs and symptoms of NTM keratitis.

Photophobia Cracked windshield appearance

Decreased visual acuity Mild or Silent anterior chamber

**Table 4.** Different types of ocular infection caused by NTM [14].

Late presentation of symptoms and diagnosis was reported in NTM keratitis [74]. Pain, decreased vision, and photophobia were present in gradual increasing patterns in the course of NTM keratitis [75]. The multifocal or single lesion surrounded by radiating corneal infiltrates, 'cracked windshield' appearance, was reported [74, 76, 77]. Infiltrates had irregular margins, mimicking fungal keratitis [78]. Hypopyon is present in untreated or poorly treated cases [74]. There have been reports of infectious crystalline keratopathy, intrastromal opacity and minimal inflammation in some cases of NTM keratitis leading to a misleading diagnosis of herpetic keratitis [79, 80] (**Table 5**).

The most common association of NTM keratitis is LASIK (47.6%), followed by trauma (14.8%), foreign body (17.6%), implants (17.3%) and contact lens (6.4%) [14]. LASIK is the most popular refractive corrective surgery implemented worldwide since it offers less stromal scarring and rapid recovery of visual acuity. The symptoms for post-LASIK mycobacterial keratitis are less severe than other causes [26]. The time frame of 3 to 14 weeks duration is reported to present post-LASIK NTM keratitis. Some cases of post-LASIK mycobacterial keratitis present within 10 days post surgery [26, 81]. The most probable route of entry for post-LASIK NTM keratitis is during the surgery. Corneal infiltrates are within the lamellar flap or interface presenting with either single white lesion or multiple white granular appearances. Anterior extension of corneal infiltrates is common to form a corneal ulceration. Late diagnosis or treatment can result in the posterior extension into the corneal stroma. The anterior chamber is usually silent or has the mild inflammatory reaction [26, 82].

#### **3.2. Treatment of NTM eye infections**

Management of NTM keratitis is challenging due to its rarity, potential to acquire antibiotic resistance, natural resistance to a variety of commercially available antibiotics and delayed response to antibiotics. Identification of NTM keratitis can be delayed and one report revealed that the time to identification was delayed for 4 months due to slow growth of the organism [83]. Drug sensitivity tests need to be carried out using a prolonged incubation time, resulting in the delayed treatment of NTM eye infections. Moreover, there are several reports showing that a wide range of antibiotic sensitivities exists in different isolates [84]. Consequently, a combination of two or three drugs helps to prevent acquired antibiotic resistance in long-term management and clarithromycin, amikacin, and fourth generation fluoroquinolones are mentioned [85]. Topical delivery is the most used method followed by the combination of topical and systemic administration [14]. Amikacin is known to be the treatment of choice for NTM keratitis, however, there have been reports showing corneal toxicity toward the long-term usage of amikacin in high concentration [86]. According to the systemic review, amikacin was given alone in the majority of NTM keratitis cases, followed by amikacin and macrolide (**Table 6**) [14]. Fluoroquinolones, particularly fourth-generation fluoroquinolones, have been accepted as effective for eye infections [3, 86]. Fourth generation fluoroquinolones offer noteworthy benefits over the older generations because of their superior bactericidal activity, decreased risk for resistance and higher corneal concentrations. In contrast, one report suggested that the majority of nontuberculous mycobacteria are resistant to second-generation fluoroquinolones, highlighting the better efficacy properties of fourth generation fluoroquinolones [87].

Recent reports suggest a strong synergism between amikacin and fourth generation fluoroquinolone, gatifloxacin, in treating nontuberculous mycobacteria in *in vitro* and *in vivo* mouse keratitis model [88]. Moreover, it was reported that the NTM habitat in a keratitis infection is in the biofilm mode (**Figure 2**) hindering antibiotic penetration and adding DNase to the antibiotic may make a more effective treatment [88]. Surgical debridement can help to facilitate penetration and lower the bacterial load. Topical steroids are controversial for NTM keratitis and one study suggested that a steroid accelerates the infection [89]. Careful follow up of NTM


**Table 5.** Signs and symptoms of NTM keratitis.

**Different types of ocular NTM infection Percentage**

Late presentation of symptoms and diagnosis was reported in NTM keratitis [74]. Pain, decreased vision, and photophobia were present in gradual increasing patterns in the course of NTM keratitis [75]. The multifocal or single lesion surrounded by radiating corneal infiltrates, 'cracked windshield' appearance, was reported [74, 76, 77]. Infiltrates had irregular margins, mimicking fungal keratitis [78]. Hypopyon is present in untreated or poorly treated cases [74]. There have been reports of infectious crystalline keratopathy, intrastromal opacity and minimal inflammation in some cases of NTM keratitis leading to a misleading diagnosis

The most common association of NTM keratitis is LASIK (47.6%), followed by trauma (14.8%), foreign body (17.6%), implants (17.3%) and contact lens (6.4%) [14]. LASIK is the most popular refractive corrective surgery implemented worldwide since it offers less stromal scarring and rapid recovery of visual acuity. The symptoms for post-LASIK mycobacterial keratitis are less severe than other causes [26]. The time frame of 3 to 14 weeks duration is reported to present post-LASIK NTM keratitis. Some cases of post-LASIK mycobacterial keratitis present within 10 days post surgery [26, 81]. The most probable route of entry for post-LASIK NTM keratitis is during the surgery. Corneal infiltrates are within the lamellar flap or interface presenting with either single white lesion or multiple white granular appearances. Anterior extension of corneal infiltrates is common to form a corneal ulceration. Late diagnosis or treatment can result in the posterior extension into the corneal stroma. The anterior chamber is usually silent

Management of NTM keratitis is challenging due to its rarity, potential to acquire antibiotic resistance, natural resistance to a variety of commercially available antibiotics and delayed response to antibiotics. Identification of NTM keratitis can be delayed and one report revealed that the time to identification was delayed for 4 months due to slow growth of the organism [83]. Drug sensitivity tests need to be carried out using a prolonged incubation time, resulting in the delayed treatment of NTM eye infections. Moreover, there are several reports showing that a wide range of antibiotic sensitivities exists in different isolates [84]. Consequently, a combination of two or three drugs helps to prevent acquired antibiotic resistance in long-term

 a. Keratitis 69 b. Scleritis 4.3 c. Conjunctivitis 0.7 2. Periocular and adnexal infections 13.3 3. Intraocular infections and uveitis 12.6

**Table 4.** Different types of ocular infection caused by NTM [14].

of herpetic keratitis [79, 80] (**Table 5**).

or has the mild inflammatory reaction [26, 82].

**3.2. Treatment of NTM eye infections**

1. Ocular surface infections

46 Basic Biology and Applications of Actinobacteria


**Table 6.** Different antibiotic regimens for NTM keratitis [14].

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

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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

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 opti-

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

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

, cefoxitin 200 mg/kg/day, and

per year [103].

*4.2.1. MAC lung infections*

mal treatment strategies.

*4.2.2. RGM lung infections*

**4.2. Treatment of NTM lung infections**

first 2 or 3 months of therapy in severe disease [63].

consist of amikacin 10–15 mg/kg/day, imipenem 500–1000 mg2

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

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.
