Nontuberculous Mycobacterial Infections in Pediatric Solid Organ Transplant and Hematopoietic Cell Transplant Recipients

Albert, Jonathan; Daley, Charles L; Lin, Philana Ling

doi:10.1093/jpids/piae003

Abstract

The diagnosis of nontuberculous mycobacterial infections is challenging in pediatric solid organ transplant and hematopoietic cell transplant recipients due to the absence of specific clinical manifestations, limitations of sampling, prolonged times for culture and identification, and difficulty discerning colonization from clinical disease. Treatment is dependent on the nontuberculous mycobacterial species, disease type, and pattern of drug resistance. Treatment of nontuberculous mycobacterial infections involves prolonged durations of therapy using multiple medications, which are limited by toxicities and drug–drug interactions.

INTRODUCTION

Infections with nontuberculous mycobacteria (NTM) are increasingly recognized among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients. Despite this, timely diagnosis remains a challenge as clinical manifestations, laboratory, and radiographic findings of NTM disease are highly variable in immunocompromised hosts. Diagnosis of NTM disease requires a high index of suspicion, knowledge of the laboratory methods necessary to isolate these organisms, and critical evaluation to distinguish colonization and disease. Optimal management of these infections also remains challenging. Treatment of NTM disease requires prolonged courses of multiple antibiotic agents which require careful forethought and management of drug toxicities and interactions with the patient’s existing drug regimen. The infectious diseases clinician must help to guide multidisciplinary, risk-vs-benefit decision-making to balance antimicrobial management with the rest of the patient’s clinical needs. This review will discuss the risk factors, clinical manifestations, diagnosis, and management of NTM disease in SOT and HCT recipients.

EPIDEMIOLOGY AND RISK FACTORS

Though data are limited, pediatric SOT recipients have higher rates of invasive NTM disease than the general population [1, 2]. Risk factors for NTM disease can be categorized into pre- and post-SOT components that reflect deficits in organ function and immune status (Table 1). Lung transplant recipients have the greatest risk of NTM disease with an estimated prevalence of 0.4%–14% [3–6]; the wide range in prevalence may reflect data gathered before 2007 when specific diagnostic criteria were published [7]. In contrast, the prevalence of NTM disease is lower in other graft types: heart transplant (0.24%–2.8%), renal transplant (0.16%–0.38%), and liver transplant (0.04%) [3, 4]. The time to diagnosis of NTM disease in SOT recipients is generally more than 12 months (median 21 months [4]) from transplant, though the amount of time varies by graft type. For example, the median times to NTM disease by graft type are as follows: liver transplant (10 months), lung transplant (15 months), renal transplant (24 months), and heart transplant (30 months) [3].

Table 1.

Open in new tab

Risk Factors for NTM Disease in SOT Candidates and Recipients [4, 20, 26, 40, 45, 50]

Pre-Transplant Risk Factors	Post-Transplant Risk Factors
Prior colonization or infection with NTM	Rejection
Cystic fibrosis	Receipt of anti-thymocyte globulin
Structural lung disease	Receipt of lymphocyte-specific antibody
Primary or acquired immunodeficiency	Receipt of corticosteroids
	Lymphopenia
	CMV mismatch
	Frequent or recent hospitalization
	African American race

Pre-Transplant Risk Factors	Post-Transplant Risk Factors
Prior colonization or infection with NTM	Rejection
Cystic fibrosis	Receipt of anti-thymocyte globulin
Structural lung disease	Receipt of lymphocyte-specific antibody
Primary or acquired immunodeficiency	Receipt of corticosteroids
	Lymphopenia
	CMV mismatch
	Frequent or recent hospitalization
	African American race

Table 1.

Open in new tab

Risk Factors for NTM Disease in SOT Candidates and Recipients [4, 20, 26, 40, 45, 50]

Pre-Transplant Risk Factors	Post-Transplant Risk Factors
Prior colonization or infection with NTM	Rejection
Cystic fibrosis	Receipt of anti-thymocyte globulin
Structural lung disease	Receipt of lymphocyte-specific antibody
Primary or acquired immunodeficiency	Receipt of corticosteroids
	Lymphopenia
	CMV mismatch
	Frequent or recent hospitalization
	African American race

Pre-Transplant Risk Factors	Post-Transplant Risk Factors
Prior colonization or infection with NTM	Rejection
Cystic fibrosis	Receipt of anti-thymocyte globulin
Structural lung disease	Receipt of lymphocyte-specific antibody
Primary or acquired immunodeficiency	Receipt of corticosteroids
	Lymphopenia
	CMV mismatch
	Frequent or recent hospitalization
	African American race

Lung transplant candidates are at particularly high risk as their underlying structural and functional lung disease is inherently favorable to the growth of NTM. For example, NTM colonization among people with cystic fibrosis (pwCF) poses a unique risk and was estimated at 9.6% in 2021, which is decreased from an estimate of 14% in 2019 [8]. While these are likely underestimates, even less is known about children as fewer than 30% of pwCF below 20 years of age have a sputum sample tested for mycobacterial growth [8]. In a comprehensive review of the literature between 2010 and 2019, the estimated prevalence of NTM infection (not colonization) in pwCF was 7.9% [9]. Infection with Mycobacterium avium complex accounted for 3.7% while M. abscessus was ~4.1% [9]. Mycobacterium abscessus is of particular concern, as pwCF with advanced lung disease and those who are colonized or infected with M. abscessus are at increased risk of death without transplant, and their risk of disease after lung transplant is significantly higher [10, 11]. Limited data are available for pediatric patients, though a single-center study of children with CF with chronic M. abscessus infection after lung transplant reported worse survival at 30 and 90 days after transplant [12]. Regardless, rates of NTM colonization are substantial and likely have meaningful impact on pwCF who require lung transplant.

HCT recipients reportedly have a 50–600 times greater incidence of NTM disease than the general public [13]. The estimated prevalence rate ranges from 0.04% to 10% with the highest rates among those receiving allogeneic HCT [13–15]. Risk factors are multifactorial and are influenced by the patient’s underlying condition and immune suppressive regimen (Table 2). Unlike SOT recipients, the onset of NTM disease in HCT occurs within the first 5 months, though catheter-related NTM infections typically occur sooner [13, 16].

Table 2.

Open in new tab

Risk Factors for NTM Disease in HCT Recipients [2, 15, 16, 51, 52]

Prior colonization or infection with NTM (especially among those with primary immune deficiency)

Relapse of underlying malignancy prior to HCT

Myeloablative conditioning regimen

T cell depletion

Delayed time to immune reconstitution

Low CD4 count

Structural lung disease

Allogeneic HCT greater risk compared to autologous HCT

MICROBIOLOGY

Clinically relevant NTM isolates can be divided into 2 groups based on their growth rates by conventional culture methods. Clinically relevant “rapidly growing” mycobacteria (defined as growth within 7 days in subculture) include M. abscessus, M. fortuitum, M. chelonae, and M. mucogenicum. The more common “slow growing” mycobacteria grow from media after >7 days and include M. avium complex (which includes over 12 different species and subspecies), M. kansasii, M. marinum, M. xenopi, M. szulgai, and M. haemophilum [17, 18]. Among SOT recipients, M. avium complex is the most common followed by M. chelonae, M. fortuitum, and M. kansasii [18]. The most common NTM species among HCT recipients include M. avium complex, M. abscessus, M. chelonae, and M. haemophilum [16].

CLINICAL MANIFESTATIONS

A range of manifestations of NTM disease is observed in both SOT and HCT recipients. Among SOT recipients, the most common manifestations of NTM disease include pulmonary infections (57.6%), skin/soft tissue infections (21%), and disseminated disease (16.5%) [4] with an equal distribution of rapid and slow-growing NTM. The clinical spectrum can vary by SOT graft types (Table 3). In contrast, catheter-related infections are the most common clinical manifestation (40%) in HCT recipients and are uncommon in SOT recipients [19, 20]. These are often caused by rapid-growing NTM within the first 3 months of HCT [2, 20, 21]. The second and third most common manifestations of NTM disease in HCT recipients are pulmonary (30%) and cutaneous (20%) disease, respectively [20, 22]. The most common NTM disease categories, clinical manifestations, commonly associated NTM species, and transplant type-specific features are summarized in Table 3.

Table 3.

Open in new tab

Clinical Features of NTM Disease in SOT and HCT Recipients [3, 4, 13, 16, 19, 20, 25, 39, 45, 50]

Clinical Disease	More Common NTM	SOT	HCT	Typical Manifestations
Pulmonary	M. avium complex^a M. abscessus M. kansasii M. xenopi M. szulgai	Accounts for ~60% in SOT Most common in lung transplant Also common in heart and liver transplant Extrapulmonary involvement is common Concomitant fungal infection may occur	Accounts for 20%–30% in HCT Cavitary disease less common in HCT	Cough ± sputum Dyspnea Fever Weight loss Pleuritic chest pain Hemoptysis (less common) Radiographic features: Nodules Tree-in-bud opacities Bronchiectatic changes Parenchymal infiltrates Hilar adenopathy Cavitations or cavitary nodules Consolidation
Cutaneous	M. chelonae M. fortuitum M. abscessus M. marinum	Accounts for 20% in SOT Site of trauma or surgery Most common manifestation among renal transplant recipients Often as component of disseminated disease	Site of trauma or surgery Multifocal cutaneous disease may occur	Painful, violaceous nodules Papules Plaques Abscess with purulent or serous fluid Folliculitis Panniculitis Sporotrichoid distribution Ulcers Typically on extremities Absence of systemic symptoms
Musculoskeletal disease	M. avium complex M. ulcerans M. marinum M. kansasii M. hemophilum M. fortuitum M. chelonae	Occurs via direct inoculation or dissemination More common in heart and lung transplant recipients	Occurs via direct inoculation or dissemination	Muscle wasting Persistent pain and swelling of affected site(s) Draining sinus May be related to foreign device
Disseminated	M. avium complex^a M. marinum M. kansasii M. chelonae M. fortuitum M. abscessus	Accounts for 15% in SOT Can involve liver, spleen, bone marrow, lymph nodes, and graft organ Common in renal, liver, and heart	Associated with neutropenia Can involve liver, spleen, bone, peritoneum, or sinuses	Fever, weight loss Abdominal pain Fatigue
Catheter related	M. chelonae M. fortuitum M. abscessus M. mucigenicum	Uncommon in SOT	Most common manifestation in HCT (40%)	May have localized erythema and/or pain at catheter exit site

Clinical Disease	More Common NTM	SOT	HCT	Typical Manifestations
Pulmonary	M. avium complex^a M. abscessus M. kansasii M. xenopi M. szulgai	Accounts for ~60% in SOT Most common in lung transplant Also common in heart and liver transplant Extrapulmonary involvement is common Concomitant fungal infection may occur	Accounts for 20%–30% in HCT Cavitary disease less common in HCT	Cough ± sputum Dyspnea Fever Weight loss Pleuritic chest pain Hemoptysis (less common) Radiographic features: Nodules Tree-in-bud opacities Bronchiectatic changes Parenchymal infiltrates Hilar adenopathy Cavitations or cavitary nodules Consolidation
Cutaneous	M. chelonae M. fortuitum M. abscessus M. marinum	Accounts for 20% in SOT Site of trauma or surgery Most common manifestation among renal transplant recipients Often as component of disseminated disease	Site of trauma or surgery Multifocal cutaneous disease may occur	Painful, violaceous nodules Papules Plaques Abscess with purulent or serous fluid Folliculitis Panniculitis Sporotrichoid distribution Ulcers Typically on extremities Absence of systemic symptoms
Musculoskeletal disease	M. avium complex M. ulcerans M. marinum M. kansasii M. hemophilum M. fortuitum M. chelonae	Occurs via direct inoculation or dissemination More common in heart and lung transplant recipients	Occurs via direct inoculation or dissemination	Muscle wasting Persistent pain and swelling of affected site(s) Draining sinus May be related to foreign device
Disseminated	M. avium complex^a M. marinum M. kansasii M. chelonae M. fortuitum M. abscessus	Accounts for 15% in SOT Can involve liver, spleen, bone marrow, lymph nodes, and graft organ Common in renal, liver, and heart	Associated with neutropenia Can involve liver, spleen, bone, peritoneum, or sinuses	Fever, weight loss Abdominal pain Fatigue
Catheter related	M. chelonae M. fortuitum M. abscessus M. mucigenicum	Uncommon in SOT	Most common manifestation in HCT (40%)	May have localized erythema and/or pain at catheter exit site

^aDenotes most common pathogen in relevant clinical category.

Table 3.

Open in new tab

Clinical Features of NTM Disease in SOT and HCT Recipients [3, 4, 13, 16, 19, 20, 25, 39, 45, 50]

Clinical Disease	More Common NTM	SOT	HCT	Typical Manifestations
Pulmonary	M. avium complex^a M. abscessus M. kansasii M. xenopi M. szulgai	Accounts for ~60% in SOT Most common in lung transplant Also common in heart and liver transplant Extrapulmonary involvement is common Concomitant fungal infection may occur	Accounts for 20%–30% in HCT Cavitary disease less common in HCT	Cough ± sputum Dyspnea Fever Weight loss Pleuritic chest pain Hemoptysis (less common) Radiographic features: Nodules Tree-in-bud opacities Bronchiectatic changes Parenchymal infiltrates Hilar adenopathy Cavitations or cavitary nodules Consolidation
Cutaneous	M. chelonae M. fortuitum M. abscessus M. marinum	Accounts for 20% in SOT Site of trauma or surgery Most common manifestation among renal transplant recipients Often as component of disseminated disease	Site of trauma or surgery Multifocal cutaneous disease may occur	Painful, violaceous nodules Papules Plaques Abscess with purulent or serous fluid Folliculitis Panniculitis Sporotrichoid distribution Ulcers Typically on extremities Absence of systemic symptoms
Musculoskeletal disease	M. avium complex M. ulcerans M. marinum M. kansasii M. hemophilum M. fortuitum M. chelonae	Occurs via direct inoculation or dissemination More common in heart and lung transplant recipients	Occurs via direct inoculation or dissemination	Muscle wasting Persistent pain and swelling of affected site(s) Draining sinus May be related to foreign device
Disseminated	M. avium complex^a M. marinum M. kansasii M. chelonae M. fortuitum M. abscessus	Accounts for 15% in SOT Can involve liver, spleen, bone marrow, lymph nodes, and graft organ Common in renal, liver, and heart	Associated with neutropenia Can involve liver, spleen, bone, peritoneum, or sinuses	Fever, weight loss Abdominal pain Fatigue
Catheter related	M. chelonae M. fortuitum M. abscessus M. mucigenicum	Uncommon in SOT	Most common manifestation in HCT (40%)	May have localized erythema and/or pain at catheter exit site

Clinical Disease	More Common NTM	SOT	HCT	Typical Manifestations
Pulmonary	M. avium complex^a M. abscessus M. kansasii M. xenopi M. szulgai	Accounts for ~60% in SOT Most common in lung transplant Also common in heart and liver transplant Extrapulmonary involvement is common Concomitant fungal infection may occur	Accounts for 20%–30% in HCT Cavitary disease less common in HCT	Cough ± sputum Dyspnea Fever Weight loss Pleuritic chest pain Hemoptysis (less common) Radiographic features: Nodules Tree-in-bud opacities Bronchiectatic changes Parenchymal infiltrates Hilar adenopathy Cavitations or cavitary nodules Consolidation
Cutaneous	M. chelonae M. fortuitum M. abscessus M. marinum	Accounts for 20% in SOT Site of trauma or surgery Most common manifestation among renal transplant recipients Often as component of disseminated disease	Site of trauma or surgery Multifocal cutaneous disease may occur	Painful, violaceous nodules Papules Plaques Abscess with purulent or serous fluid Folliculitis Panniculitis Sporotrichoid distribution Ulcers Typically on extremities Absence of systemic symptoms
Musculoskeletal disease	M. avium complex M. ulcerans M. marinum M. kansasii M. hemophilum M. fortuitum M. chelonae	Occurs via direct inoculation or dissemination More common in heart and lung transplant recipients	Occurs via direct inoculation or dissemination	Muscle wasting Persistent pain and swelling of affected site(s) Draining sinus May be related to foreign device
Disseminated	M. avium complex^a M. marinum M. kansasii M. chelonae M. fortuitum M. abscessus	Accounts for 15% in SOT Can involve liver, spleen, bone marrow, lymph nodes, and graft organ Common in renal, liver, and heart	Associated with neutropenia Can involve liver, spleen, bone, peritoneum, or sinuses	Fever, weight loss Abdominal pain Fatigue
Catheter related	M. chelonae M. fortuitum M. abscessus M. mucigenicum	Uncommon in SOT	Most common manifestation in HCT (40%)	May have localized erythema and/or pain at catheter exit site

^aDenotes most common pathogen in relevant clinical category.

Pulmonary Disease

As environmental NTM are ubiquitous, NTM colonization in lung transplant recipients is common and should be distinguished from disease as transplant centers have reported that only 2.3%–14% of lung transplant recipients colonized with NTM meet criteria for pulmonary disease [23, 24]. Criteria for diagnosis of NTM pulmonary disease include clinical (pulmonary or systemic symptoms), radiologic (nodular or cavitary disease on chest radiograph or bronchiectasis and multiple nodules on high-resolution CT), and microbiologic features (NTM positive culture from 2 separate sputum samples or positive culture from ≥1 bronchial lavage or wash, or histopathologic features of mycobacterial disease from lung biopsy and confirmed by culture of sputum or bronchial wash) [25]. While these criteria have not been validated in SOT or HCT recipients, most reports have used the same or similar criteria to discern colonization from pulmonary disease [4, 10, 16, 20, 26]. Systemic or pulmonary symptoms are often chronic and may include worsening cough with or without sputum production and other nonspecific symptoms and radiographic features (Table 3) [4, 19, 27, 28].

Cutaneous/Musculoskeletal Disease

Cutaneous lesions can vary but can be minimally painful, nodular, plaque-like, ulcerative, and erythematous to violaceous. Occurring as single or clusters of skin lesions, they are often slow-growing without systemic symptoms. Lymphangitis with characteristic sporotrichoid distribution may be seen as well as tenosynovitis and osteoarticular disease. Disease can be localized via direct inoculation (eg, trauma or infected hardware) or diffuse as a sign of disseminated NTM disease. Diagnosis often requires histopathologic confirmation and culture with evaluation for Nocardia and fungal organisms [19]. Skin lesions and hardware involvement are most associated with M. fortuitum, M. abscessus, and M. chelonae. Catheter-related infections can have skin manifestations along the catheter tunnel or exit site [2, 13].

Disseminated Disease

Definitive diagnosis of disseminated disease requires histopathological confirmation of sterile site involvement, mycobacterial culture from blood, and other affected sites which often requires imaging to assess extent of involvement. In HCT recipients, it can be the result of catheter-related infections if the catheter is not removed promptly [13]. Disseminated disease can occur in all SOT recipients, though it is most common in renal transplant recipients [19], accounting for 40% of cases in 1 series, with M. chelonae being the most common NTM species [29]. Unfortunately, mortality in renal transplant recipients is as high as 20% (both directly from NTM and other sequelae), and 30% of cases lost graft function [29]. Pulmonary disease is present in nearly half of cases, with involvement of other sites that include the GI tract, endovascular sites, skin, lymph node, bone marrow, and other organs (Table 3) [4, 19].

DIAGNOSIS

Diagnostic work-up of NTM should be driven by clinical suspicion, histopathological confirmation, and appropriate culture results that often require careful interpretation as these organisms exist in the environment and could be considered contaminants. Tissues or sterile fluids are preferred over swabs, although sometimes cultures from non-sterile sites (eg, sputum) are the only available specimen. Expertise in appropriate mycobacterial lab protocols is essential in facilitating decontamination of non-sterile samples, optimal growth in selective media, temperature conditions (eg, 36.1°C for slow growers and 28°C for rapid growers), and incubation duration. AFB smear and culture are considered the gold standard in identifying NTM. Communication to the mycobacterial lab should be conducted when certain NTM types are suspected to ensure optimal growth conditions are performed. For example, when M. haemophilum is suspected, it requires special iron-supplemented media and growth at lower temperatures (28–30°C) [17]. Given the long incubation periods required for NTM growth, rapid methods of identification have been developed and are reviewed in Table 4. Laboratory techniques and workflows likely vary by institution based on laboratory capacity, expertise, and cost. Importantly, these methods do not replace conventional culture methods as susceptibility testing for clinically relevant antibiotics must be performed using broth microdilution that requires live culture [30].

Table 4.

Open in new tab

Microbiologic Aspects of Processing and Identification of Clinically Relevant NTM [17, 53, 54]

Assay Technique	Key Aspect(s)	Disadvantage	Advantage
Decontamination	Critical for all non-sterile sites to reduce contamination and increase yield of mycobacterial recovery	Reduces viability of NTM
N-acetyl-l-cysteine, NaOH, oxalic acid (NALC-NaOH-OxA)		Reduces viability of NTM Optimal recovery when used with the MOD9 liquid media
Chlorhexidine			Advantageous in cystic fibrosis sputum samples as Pseudomonas is often resistant to (NALC-NaOH-OxA)
Smear (eg, Kinyon, Ziehl-Neelsen)	Gold standard with culture Indicates presence of Mycobacterial spp. Bleach treatment and concentrating sample may improve sensitivity	Limited sensitivity Does not provide species identification	Rapid detection of Mycobacterium spp.
Culture	Gold standard with smear Bodily fluids preferred over swabs Both liquid and solid media should be planted	Long duration of time required for growth and identification	More sensitive than other assays
Liquid culture	Typically set up in commercial continuous detection systems	Higher risk of bacterial contamination Can take up to 6 weeks for results	Shorter time to detection compared to solid media
Solid culture(egg vs agar-based methods)	Provides pure growth from isolate to facilitate species identification and susceptibility testing	Slower time to detection Takes up to 8 weeks	Provides semi-quantitative measures Selective agar-based media available for rapid-growing NTM
Conventional phenotypic identification	Identification based on growth rate, colony morphology, pigment, and biochemical testing	Requires solid media growth Takes weeks of incubation May not distinguish all species of NTM Not reliable and no longer recommended
Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)	Method of rapid identification of NTM Requires pure growth of isolate on solid media	Identifies most, but not all, NTM species Identification may be limited by spectra database Unable to distinguish closely related NTM	Simpler than nucleic acid amplification techniques Low cost Rapid turnover
Nucleic Acid Hybridization Probe	Rapid identification of select NTM	Limited NTM isolates identified Discontinued by manufacturers Limited sensitivity as no amplification used	Rapid, cheap Easy to use
Nucleic Acid Amplification Techniques (NAAT)	Faster than conventional identification methods	Limited sensitivity Limited spectrum of resistant testing available	May be used for rapid ID and resistance testing
Line Probe Assays	Reverse hybridization assay involving amplification of different mycobacterial targets and subsequent identification of specific amplicon	Labor intensive Not FDA approved Limited NTM identified	Can provide rapid identification Can identify resistant markers Labor intensive
PCR-DNA based Sequencing	Whole genome sequencing or Sanger sequencing of conserved genes (eg, 16s rRNA, and hsp65)	Dependent on sequence database High cost and complexity (usually reference lab) Limited sensitivity depending on sample type Unable to detect phenotypic resistance Variable performance	Faster than standard culture methods New species can be identified Can detect resistance genotypes (eg, rpoB)

Assay Technique	Key Aspect(s)	Disadvantage	Advantage
Decontamination	Critical for all non-sterile sites to reduce contamination and increase yield of mycobacterial recovery	Reduces viability of NTM
N-acetyl-l-cysteine, NaOH, oxalic acid (NALC-NaOH-OxA)		Reduces viability of NTM Optimal recovery when used with the MOD9 liquid media
Chlorhexidine			Advantageous in cystic fibrosis sputum samples as Pseudomonas is often resistant to (NALC-NaOH-OxA)
Smear (eg, Kinyon, Ziehl-Neelsen)	Gold standard with culture Indicates presence of Mycobacterial spp. Bleach treatment and concentrating sample may improve sensitivity	Limited sensitivity Does not provide species identification	Rapid detection of Mycobacterium spp.
Culture	Gold standard with smear Bodily fluids preferred over swabs Both liquid and solid media should be planted	Long duration of time required for growth and identification	More sensitive than other assays
Liquid culture	Typically set up in commercial continuous detection systems	Higher risk of bacterial contamination Can take up to 6 weeks for results	Shorter time to detection compared to solid media
Solid culture(egg vs agar-based methods)	Provides pure growth from isolate to facilitate species identification and susceptibility testing	Slower time to detection Takes up to 8 weeks	Provides semi-quantitative measures Selective agar-based media available for rapid-growing NTM
Conventional phenotypic identification	Identification based on growth rate, colony morphology, pigment, and biochemical testing	Requires solid media growth Takes weeks of incubation May not distinguish all species of NTM Not reliable and no longer recommended
Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)	Method of rapid identification of NTM Requires pure growth of isolate on solid media	Identifies most, but not all, NTM species Identification may be limited by spectra database Unable to distinguish closely related NTM	Simpler than nucleic acid amplification techniques Low cost Rapid turnover
Nucleic Acid Hybridization Probe	Rapid identification of select NTM	Limited NTM isolates identified Discontinued by manufacturers Limited sensitivity as no amplification used	Rapid, cheap Easy to use
Nucleic Acid Amplification Techniques (NAAT)	Faster than conventional identification methods	Limited sensitivity Limited spectrum of resistant testing available	May be used for rapid ID and resistance testing
Line Probe Assays	Reverse hybridization assay involving amplification of different mycobacterial targets and subsequent identification of specific amplicon	Labor intensive Not FDA approved Limited NTM identified	Can provide rapid identification Can identify resistant markers Labor intensive
PCR-DNA based Sequencing	Whole genome sequencing or Sanger sequencing of conserved genes (eg, 16s rRNA, and hsp65)	Dependent on sequence database High cost and complexity (usually reference lab) Limited sensitivity depending on sample type Unable to detect phenotypic resistance Variable performance	Faster than standard culture methods New species can be identified Can detect resistance genotypes (eg, rpoB)

Table 4.

Open in new tab

Microbiologic Aspects of Processing and Identification of Clinically Relevant NTM [17, 53, 54]

Assay Technique	Key Aspect(s)	Disadvantage	Advantage
Decontamination	Critical for all non-sterile sites to reduce contamination and increase yield of mycobacterial recovery	Reduces viability of NTM
N-acetyl-l-cysteine, NaOH, oxalic acid (NALC-NaOH-OxA)		Reduces viability of NTM Optimal recovery when used with the MOD9 liquid media
Chlorhexidine			Advantageous in cystic fibrosis sputum samples as Pseudomonas is often resistant to (NALC-NaOH-OxA)
Smear (eg, Kinyon, Ziehl-Neelsen)	Gold standard with culture Indicates presence of Mycobacterial spp. Bleach treatment and concentrating sample may improve sensitivity	Limited sensitivity Does not provide species identification	Rapid detection of Mycobacterium spp.
Culture	Gold standard with smear Bodily fluids preferred over swabs Both liquid and solid media should be planted	Long duration of time required for growth and identification	More sensitive than other assays
Liquid culture	Typically set up in commercial continuous detection systems	Higher risk of bacterial contamination Can take up to 6 weeks for results	Shorter time to detection compared to solid media
Solid culture(egg vs agar-based methods)	Provides pure growth from isolate to facilitate species identification and susceptibility testing	Slower time to detection Takes up to 8 weeks	Provides semi-quantitative measures Selective agar-based media available for rapid-growing NTM
Conventional phenotypic identification	Identification based on growth rate, colony morphology, pigment, and biochemical testing	Requires solid media growth Takes weeks of incubation May not distinguish all species of NTM Not reliable and no longer recommended
Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)	Method of rapid identification of NTM Requires pure growth of isolate on solid media	Identifies most, but not all, NTM species Identification may be limited by spectra database Unable to distinguish closely related NTM	Simpler than nucleic acid amplification techniques Low cost Rapid turnover
Nucleic Acid Hybridization Probe	Rapid identification of select NTM	Limited NTM isolates identified Discontinued by manufacturers Limited sensitivity as no amplification used	Rapid, cheap Easy to use
Nucleic Acid Amplification Techniques (NAAT)	Faster than conventional identification methods	Limited sensitivity Limited spectrum of resistant testing available	May be used for rapid ID and resistance testing
Line Probe Assays	Reverse hybridization assay involving amplification of different mycobacterial targets and subsequent identification of specific amplicon	Labor intensive Not FDA approved Limited NTM identified	Can provide rapid identification Can identify resistant markers Labor intensive
PCR-DNA based Sequencing	Whole genome sequencing or Sanger sequencing of conserved genes (eg, 16s rRNA, and hsp65)	Dependent on sequence database High cost and complexity (usually reference lab) Limited sensitivity depending on sample type Unable to detect phenotypic resistance Variable performance	Faster than standard culture methods New species can be identified Can detect resistance genotypes (eg, rpoB)

Assay Technique	Key Aspect(s)	Disadvantage	Advantage
Decontamination	Critical for all non-sterile sites to reduce contamination and increase yield of mycobacterial recovery	Reduces viability of NTM
N-acetyl-l-cysteine, NaOH, oxalic acid (NALC-NaOH-OxA)		Reduces viability of NTM Optimal recovery when used with the MOD9 liquid media
Chlorhexidine			Advantageous in cystic fibrosis sputum samples as Pseudomonas is often resistant to (NALC-NaOH-OxA)
Smear (eg, Kinyon, Ziehl-Neelsen)	Gold standard with culture Indicates presence of Mycobacterial spp. Bleach treatment and concentrating sample may improve sensitivity	Limited sensitivity Does not provide species identification	Rapid detection of Mycobacterium spp.
Culture	Gold standard with smear Bodily fluids preferred over swabs Both liquid and solid media should be planted	Long duration of time required for growth and identification	More sensitive than other assays
Liquid culture	Typically set up in commercial continuous detection systems	Higher risk of bacterial contamination Can take up to 6 weeks for results	Shorter time to detection compared to solid media
Solid culture(egg vs agar-based methods)	Provides pure growth from isolate to facilitate species identification and susceptibility testing	Slower time to detection Takes up to 8 weeks	Provides semi-quantitative measures Selective agar-based media available for rapid-growing NTM
Conventional phenotypic identification	Identification based on growth rate, colony morphology, pigment, and biochemical testing	Requires solid media growth Takes weeks of incubation May not distinguish all species of NTM Not reliable and no longer recommended
Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)	Method of rapid identification of NTM Requires pure growth of isolate on solid media	Identifies most, but not all, NTM species Identification may be limited by spectra database Unable to distinguish closely related NTM	Simpler than nucleic acid amplification techniques Low cost Rapid turnover
Nucleic Acid Hybridization Probe	Rapid identification of select NTM	Limited NTM isolates identified Discontinued by manufacturers Limited sensitivity as no amplification used	Rapid, cheap Easy to use
Nucleic Acid Amplification Techniques (NAAT)	Faster than conventional identification methods	Limited sensitivity Limited spectrum of resistant testing available	May be used for rapid ID and resistance testing
Line Probe Assays	Reverse hybridization assay involving amplification of different mycobacterial targets and subsequent identification of specific amplicon	Labor intensive Not FDA approved Limited NTM identified	Can provide rapid identification Can identify resistant markers Labor intensive
PCR-DNA based Sequencing	Whole genome sequencing or Sanger sequencing of conserved genes (eg, 16s rRNA, and hsp65)	Dependent on sequence database High cost and complexity (usually reference lab) Limited sensitivity depending on sample type Unable to detect phenotypic resistance Variable performance	Faster than standard culture methods New species can be identified Can detect resistance genotypes (eg, rpoB)

Importantly, once the diagnosis of NTM disease is confirmed, a comprehensive assessment of other potential sites of disseminated disease (eg, brain, chest, abdomen, and pelvis) and mycobacterial blood cultures should be performed as this can have important implications for monitoring, treatment, and outcome.

TREATMENT

Susceptibility testing of NTM clinical isolates is essential to planning definitive therapy as multiple antimycobacterial agents are required for treatment and prevention of resistance. In vitro susceptibility results do not always correlate with clinical outcomes and are specific to the NTM species. The optimal duration of treatment is not known and is dependent on the NTM species, microbiologic, clinical, and radiologic response to treatment. In general, the treatment course typically lasts several months after resolution of symptoms to reduce the risk of relapse given the prolonged nature of these infections. When possible, reduction in immune suppression at the initiation of therapy is recommended. Treatment is further complicated by the side effects of antimycobacterial agents, inherent multi-drug resistance of some species, and drug–drug interactions with the patient’s immune-suppressing medications (Table 5) [1, 16]. Coordination with a therapeutic drug monitoring team is essential to maximize drug effectiveness, mitigate drug toxicities, and identify alternative medications when necessary [31]. Most of the literature regarding treatment is based on the most common species (ie, M. avium complex, M. kansasii, and M. abscessus) which is important to consider when treating extrapulmonary disease. Consultation with an NTM expert is a critical part of treatment as the optimal regimen and duration of treatment is made on a case-by-case basis.

Table 5.

Open in new tab

Common Drug–Drug Interactions with Antimycobacterial Agents [1, 16]

Drug	Agents Commonly Used in SOT and HCT Recipients
Rifamycin	↓ calcineurin inhibitor ↓ cyclosporin ↓ mycophenolate ↑ cyclophosphamide Loss of sirolimus effectiveness ↓ steroid effect Possible ↓ vincristine ↓ ruxolitinib ↓ dasatinib ↓ ibrutinib ↓ triazole antifungals ↓ echinocandins
Macrolide (Greater risk of interactions with clarithromycin than azithromycin)	↑ calcineurin inhibitor ↑ sirolimus ↑ cyclosporin ↑ triazole antifungals ↑ risk of steroid adverse events ↑ risk of vincristine toxicity
Aminoglycoside	Additive renal toxicity with calcineurin inhibitor
Fluoroquinolones	Calcineurin inhibitor—↑ risk of QTc prolongation Possible ↓ mycophenolate Triazole antifungals—↑ risk of QTc prolongation
Imipenem	Additive neurotoxicity with cyclosporin
Isoniazid	↑ voriconazole Additive hepatotoxicity with acetaminophen

Drug	Agents Commonly Used in SOT and HCT Recipients
Rifamycin	↓ calcineurin inhibitor ↓ cyclosporin ↓ mycophenolate ↑ cyclophosphamide Loss of sirolimus effectiveness ↓ steroid effect Possible ↓ vincristine ↓ ruxolitinib ↓ dasatinib ↓ ibrutinib ↓ triazole antifungals ↓ echinocandins
Macrolide (Greater risk of interactions with clarithromycin than azithromycin)	↑ calcineurin inhibitor ↑ sirolimus ↑ cyclosporin ↑ triazole antifungals ↑ risk of steroid adverse events ↑ risk of vincristine toxicity
Aminoglycoside	Additive renal toxicity with calcineurin inhibitor
Fluoroquinolones	Calcineurin inhibitor—↑ risk of QTc prolongation Possible ↓ mycophenolate Triazole antifungals—↑ risk of QTc prolongation
Imipenem	Additive neurotoxicity with cyclosporin
Isoniazid	↑ voriconazole Additive hepatotoxicity with acetaminophen

Table 5.

Open in new tab

Common Drug–Drug Interactions with Antimycobacterial Agents [1, 16]

Drug	Agents Commonly Used in SOT and HCT Recipients
Rifamycin	↓ calcineurin inhibitor ↓ cyclosporin ↓ mycophenolate ↑ cyclophosphamide Loss of sirolimus effectiveness ↓ steroid effect Possible ↓ vincristine ↓ ruxolitinib ↓ dasatinib ↓ ibrutinib ↓ triazole antifungals ↓ echinocandins
Macrolide (Greater risk of interactions with clarithromycin than azithromycin)	↑ calcineurin inhibitor ↑ sirolimus ↑ cyclosporin ↑ triazole antifungals ↑ risk of steroid adverse events ↑ risk of vincristine toxicity
Aminoglycoside	Additive renal toxicity with calcineurin inhibitor
Fluoroquinolones	Calcineurin inhibitor—↑ risk of QTc prolongation Possible ↓ mycophenolate Triazole antifungals—↑ risk of QTc prolongation
Imipenem	Additive neurotoxicity with cyclosporin
Isoniazid	↑ voriconazole Additive hepatotoxicity with acetaminophen

Drug	Agents Commonly Used in SOT and HCT Recipients
Rifamycin	↓ calcineurin inhibitor ↓ cyclosporin ↓ mycophenolate ↑ cyclophosphamide Loss of sirolimus effectiveness ↓ steroid effect Possible ↓ vincristine ↓ ruxolitinib ↓ dasatinib ↓ ibrutinib ↓ triazole antifungals ↓ echinocandins
Macrolide (Greater risk of interactions with clarithromycin than azithromycin)	↑ calcineurin inhibitor ↑ sirolimus ↑ cyclosporin ↑ triazole antifungals ↑ risk of steroid adverse events ↑ risk of vincristine toxicity
Aminoglycoside	Additive renal toxicity with calcineurin inhibitor
Fluoroquinolones	Calcineurin inhibitor—↑ risk of QTc prolongation Possible ↓ mycophenolate Triazole antifungals—↑ risk of QTc prolongation
Imipenem	Additive neurotoxicity with cyclosporin
Isoniazid	↑ voriconazole Additive hepatotoxicity with acetaminophen

Given the lack of evidence-based treatment regimens and complications in treatment and outcome, shared decision-making with other care teams, the patient, and patient’s family are often necessary to weigh the risks and benefits of long-term treatment. Pediatric dosing and expected toxicities of common antimycobacterial agents is outlined in Table 6. For SOT recipients, treatment should continue until there is a period of immune stability (ie, no rejection). For HCT recipients, antimycobacterial therapy should continue through transplant and reconstitution of cell-mediated immunity. Surgical intervention should be considered as an adjunctive therapy for cases in which diseased tissue can be debrided. For NTM catheter-related bloodstream infections, the infected central catheter should be removed to prevent relapse and/or dissemination of disease [13, 32].

Table 6.

Open in new tab

Pediatric Dosing and Common Toxicities of Antimycobacterial Agents [3, 35, 36]

Drug	Pediatric Dose	Common Toxicities
Azithromycin	10–12 mg/kg PO or IV daily, max dose 500 mg	Hepatotoxicity Ototoxicity (prolonged use) QTc prolongation
Clarithromycin	15–30 mg/kg/day PO divided Q12, max single dose 500 mg	Hepatotoxicity Ototoxicity (prolonged use) QTc prolongation
Ethambutol	Infants and Children: 15–25 mg/kg PO daily, max dose 2500 mg Adolescents: 15 mg/kg PO daily, max dose 2500 mg	Impaired visual acuity or color vision Peripheral neuropathy
Rifabutin	10–20 mg/kg PO daily, max dose 300 mg	Hepatotoxicity Leukopenia Orange-colored secretions
Rifampin	10–20 mg/kg PO daily, max dose 600 mg	Hepatoxicity Leukopenia Orange-colored secretions
Ciprofloxacin	20 mg/kg/day IV divided Q12, max single dose 400 mg; 20–30 mg/kg/day PO divided Q12, max single dose 750 mg	QTc prolongation Possible tendinopathy Possible aneurysm formation
Levofloxacin	Infants and Children <5 years: 20 mg/kg/day IV or PO divided Q12, max single dose 750 mg Children ≥5 years: 10 mg/kg IV or PO daily, max dose 750 mg	QTc prolongation Possible tendinopathy Possible aneurysm formation
Moxifloxacin	10 mg/kg IV or PO daily, max dose 400 mg	QTc prolongation Possible tendinopathy Possible aneurysm formation
Amikacin	Infants and Children: 15–30 mg/kg/day IV daily or divided Q12, max single dose 1500 mg Adolescents: 10–15 mg/kg IV daily^a, max dose 1500 mg	Nephrotoxicity Ototoxicity Vestibular toxicity
Streptomycin	Infants and Children: 20–40 mg/kg IV or IM daily, max dose 1000 mg Adolescents: 15 mg/kg IV daily, max dose 1000 mg	Nephrotoxicity Ototoxicity Vestibular toxicity
Tobramycin	5 mg/kg IV daily or 3×/week	Nephrotoxicity Ototoxicity Vestibular toxicity
Linezolid	20–24 mg/kg/day IV or PO divided Q12, max single dose 600 mg	Myelosuppression Peripheral neuropathy
Isoniazid	10–15 mg/kg PO or IM daily, max dose 300 mg^b	Hepatotoxicity
Doxycycline	4.4 mg/kg/day IV or PO divided Q12, max single dose 100 mg	Photosensitivity Pill esophagitis (if PO)
Minocycline	≥8 years: 4 mg/kg IV or PO once (max dose 200 mg), followed by 4 mg/kg/day IV or PO divided Q12 (max single dose 100 mg)	Photosensitivity
Tigecycline	8–11 years: 2.4 mg/kg/day IV divided Q12, max single dose 50 mg 12–18 years: 100 mg/day IV divided Q12	GI intolerance
Cefoxitin	160 mg/kg/day IV divided Q6, max single dose 3000 mg
Imipenem	30–40 mg/kg/day IV divided Q12, max single dose 1000 mg	Myelosuppression Hepatotoxicity
Trimethoprim/sulfamethoxazole	15 mg/kg/day IV by TMP component, divided Q8, max single dose 320 mg by TMP component	Myelosuppression Rash

Drug	Pediatric Dose	Common Toxicities
Azithromycin	10–12 mg/kg PO or IV daily, max dose 500 mg	Hepatotoxicity Ototoxicity (prolonged use) QTc prolongation
Clarithromycin	15–30 mg/kg/day PO divided Q12, max single dose 500 mg	Hepatotoxicity Ototoxicity (prolonged use) QTc prolongation
Ethambutol	Infants and Children: 15–25 mg/kg PO daily, max dose 2500 mg Adolescents: 15 mg/kg PO daily, max dose 2500 mg	Impaired visual acuity or color vision Peripheral neuropathy
Rifabutin	10–20 mg/kg PO daily, max dose 300 mg	Hepatotoxicity Leukopenia Orange-colored secretions
Rifampin	10–20 mg/kg PO daily, max dose 600 mg	Hepatoxicity Leukopenia Orange-colored secretions
Ciprofloxacin	20 mg/kg/day IV divided Q12, max single dose 400 mg; 20–30 mg/kg/day PO divided Q12, max single dose 750 mg	QTc prolongation Possible tendinopathy Possible aneurysm formation
Levofloxacin	Infants and Children <5 years: 20 mg/kg/day IV or PO divided Q12, max single dose 750 mg Children ≥5 years: 10 mg/kg IV or PO daily, max dose 750 mg	QTc prolongation Possible tendinopathy Possible aneurysm formation
Moxifloxacin	10 mg/kg IV or PO daily, max dose 400 mg	QTc prolongation Possible tendinopathy Possible aneurysm formation
Amikacin	Infants and Children: 15–30 mg/kg/day IV daily or divided Q12, max single dose 1500 mg Adolescents: 10–15 mg/kg IV daily^a, max dose 1500 mg	Nephrotoxicity Ototoxicity Vestibular toxicity
Streptomycin	Infants and Children: 20–40 mg/kg IV or IM daily, max dose 1000 mg Adolescents: 15 mg/kg IV daily, max dose 1000 mg	Nephrotoxicity Ototoxicity Vestibular toxicity
Tobramycin	5 mg/kg IV daily or 3×/week	Nephrotoxicity Ototoxicity Vestibular toxicity
Linezolid	20–24 mg/kg/day IV or PO divided Q12, max single dose 600 mg	Myelosuppression Peripheral neuropathy
Isoniazid	10–15 mg/kg PO or IM daily, max dose 300 mg^b	Hepatotoxicity
Doxycycline	4.4 mg/kg/day IV or PO divided Q12, max single dose 100 mg	Photosensitivity Pill esophagitis (if PO)
Minocycline	≥8 years: 4 mg/kg IV or PO once (max dose 200 mg), followed by 4 mg/kg/day IV or PO divided Q12 (max single dose 100 mg)	Photosensitivity
Tigecycline	8–11 years: 2.4 mg/kg/day IV divided Q12, max single dose 50 mg 12–18 years: 100 mg/day IV divided Q12	GI intolerance
Cefoxitin	160 mg/kg/day IV divided Q6, max single dose 3000 mg
Imipenem	30–40 mg/kg/day IV divided Q12, max single dose 1000 mg	Myelosuppression Hepatotoxicity
Trimethoprim/sulfamethoxazole	15 mg/kg/day IV by TMP component, divided Q8, max single dose 320 mg by TMP component	Myelosuppression Rash

Abbreviations: IM, intramuscular; IV, intravenous; PO, by mouth; Q6, every 6 h dosing; Q8, every 8 h dosing; Q12, every 12 h dosing.

^aMay be transitioned from daily to thrice weekly dosing for ease of administration [35, 36].

^bConsider pyridoxine 1–2 mg/kg/day for patients who are malnourished, patients on milk or meat-deficient diets, breastfeeding infants, and patients predisposed to neuritis.

Table 6.

Open in new tab

Pediatric Dosing and Common Toxicities of Antimycobacterial Agents [3, 35, 36]

Drug	Pediatric Dose	Common Toxicities
Azithromycin	10–12 mg/kg PO or IV daily, max dose 500 mg	Hepatotoxicity Ototoxicity (prolonged use) QTc prolongation
Clarithromycin	15–30 mg/kg/day PO divided Q12, max single dose 500 mg	Hepatotoxicity Ototoxicity (prolonged use) QTc prolongation
Ethambutol	Infants and Children: 15–25 mg/kg PO daily, max dose 2500 mg Adolescents: 15 mg/kg PO daily, max dose 2500 mg	Impaired visual acuity or color vision Peripheral neuropathy
Rifabutin	10–20 mg/kg PO daily, max dose 300 mg	Hepatotoxicity Leukopenia Orange-colored secretions
Rifampin	10–20 mg/kg PO daily, max dose 600 mg	Hepatoxicity Leukopenia Orange-colored secretions
Ciprofloxacin	20 mg/kg/day IV divided Q12, max single dose 400 mg; 20–30 mg/kg/day PO divided Q12, max single dose 750 mg	QTc prolongation Possible tendinopathy Possible aneurysm formation
Levofloxacin	Infants and Children <5 years: 20 mg/kg/day IV or PO divided Q12, max single dose 750 mg Children ≥5 years: 10 mg/kg IV or PO daily, max dose 750 mg	QTc prolongation Possible tendinopathy Possible aneurysm formation
Moxifloxacin	10 mg/kg IV or PO daily, max dose 400 mg	QTc prolongation Possible tendinopathy Possible aneurysm formation
Amikacin	Infants and Children: 15–30 mg/kg/day IV daily or divided Q12, max single dose 1500 mg Adolescents: 10–15 mg/kg IV daily^a, max dose 1500 mg	Nephrotoxicity Ototoxicity Vestibular toxicity
Streptomycin	Infants and Children: 20–40 mg/kg IV or IM daily, max dose 1000 mg Adolescents: 15 mg/kg IV daily, max dose 1000 mg	Nephrotoxicity Ototoxicity Vestibular toxicity
Tobramycin	5 mg/kg IV daily or 3×/week	Nephrotoxicity Ototoxicity Vestibular toxicity
Linezolid	20–24 mg/kg/day IV or PO divided Q12, max single dose 600 mg	Myelosuppression Peripheral neuropathy
Isoniazid	10–15 mg/kg PO or IM daily, max dose 300 mg^b	Hepatotoxicity
Doxycycline	4.4 mg/kg/day IV or PO divided Q12, max single dose 100 mg	Photosensitivity Pill esophagitis (if PO)
Minocycline	≥8 years: 4 mg/kg IV or PO once (max dose 200 mg), followed by 4 mg/kg/day IV or PO divided Q12 (max single dose 100 mg)	Photosensitivity
Tigecycline	8–11 years: 2.4 mg/kg/day IV divided Q12, max single dose 50 mg 12–18 years: 100 mg/day IV divided Q12	GI intolerance
Cefoxitin	160 mg/kg/day IV divided Q6, max single dose 3000 mg
Imipenem	30–40 mg/kg/day IV divided Q12, max single dose 1000 mg	Myelosuppression Hepatotoxicity
Trimethoprim/sulfamethoxazole	15 mg/kg/day IV by TMP component, divided Q8, max single dose 320 mg by TMP component	Myelosuppression Rash

Drug	Pediatric Dose	Common Toxicities
Azithromycin	10–12 mg/kg PO or IV daily, max dose 500 mg	Hepatotoxicity Ototoxicity (prolonged use) QTc prolongation
Clarithromycin	15–30 mg/kg/day PO divided Q12, max single dose 500 mg	Hepatotoxicity Ototoxicity (prolonged use) QTc prolongation
Ethambutol	Infants and Children: 15–25 mg/kg PO daily, max dose 2500 mg Adolescents: 15 mg/kg PO daily, max dose 2500 mg	Impaired visual acuity or color vision Peripheral neuropathy
Rifabutin	10–20 mg/kg PO daily, max dose 300 mg	Hepatotoxicity Leukopenia Orange-colored secretions
Rifampin	10–20 mg/kg PO daily, max dose 600 mg	Hepatoxicity Leukopenia Orange-colored secretions
Ciprofloxacin	20 mg/kg/day IV divided Q12, max single dose 400 mg; 20–30 mg/kg/day PO divided Q12, max single dose 750 mg	QTc prolongation Possible tendinopathy Possible aneurysm formation
Levofloxacin	Infants and Children <5 years: 20 mg/kg/day IV or PO divided Q12, max single dose 750 mg Children ≥5 years: 10 mg/kg IV or PO daily, max dose 750 mg	QTc prolongation Possible tendinopathy Possible aneurysm formation
Moxifloxacin	10 mg/kg IV or PO daily, max dose 400 mg	QTc prolongation Possible tendinopathy Possible aneurysm formation
Amikacin	Infants and Children: 15–30 mg/kg/day IV daily or divided Q12, max single dose 1500 mg Adolescents: 10–15 mg/kg IV daily^a, max dose 1500 mg	Nephrotoxicity Ototoxicity Vestibular toxicity
Streptomycin	Infants and Children: 20–40 mg/kg IV or IM daily, max dose 1000 mg Adolescents: 15 mg/kg IV daily, max dose 1000 mg	Nephrotoxicity Ototoxicity Vestibular toxicity
Tobramycin	5 mg/kg IV daily or 3×/week	Nephrotoxicity Ototoxicity Vestibular toxicity
Linezolid	20–24 mg/kg/day IV or PO divided Q12, max single dose 600 mg	Myelosuppression Peripheral neuropathy
Isoniazid	10–15 mg/kg PO or IM daily, max dose 300 mg^b	Hepatotoxicity
Doxycycline	4.4 mg/kg/day IV or PO divided Q12, max single dose 100 mg	Photosensitivity Pill esophagitis (if PO)
Minocycline	≥8 years: 4 mg/kg IV or PO once (max dose 200 mg), followed by 4 mg/kg/day IV or PO divided Q12 (max single dose 100 mg)	Photosensitivity
Tigecycline	8–11 years: 2.4 mg/kg/day IV divided Q12, max single dose 50 mg 12–18 years: 100 mg/day IV divided Q12	GI intolerance
Cefoxitin	160 mg/kg/day IV divided Q6, max single dose 3000 mg
Imipenem	30–40 mg/kg/day IV divided Q12, max single dose 1000 mg	Myelosuppression Hepatotoxicity
Trimethoprim/sulfamethoxazole	15 mg/kg/day IV by TMP component, divided Q8, max single dose 320 mg by TMP component	Myelosuppression Rash

Abbreviations: IM, intramuscular; IV, intravenous; PO, by mouth; Q6, every 6 h dosing; Q8, every 8 h dosing; Q12, every 12 h dosing.

^aMay be transitioned from daily to thrice weekly dosing for ease of administration [35, 36].

^bConsider pyridoxine 1–2 mg/kg/day for patients who are malnourished, patients on milk or meat-deficient diets, breastfeeding infants, and patients predisposed to neuritis.

Treatment of Slow-Growing NTM

Treatment of disease caused by slow-growing NTM is challenging (Table 7). In vitro susceptibility to macrolides and amikacin correlate with clinical outcomes for treatment of M. avium complex disease. The treatment of choice for macrolide-susceptible M. avium complex is a combination of a macrolide, rifamycin, and ethambutol [25, 33, 34]. Rifabutin is a less potent inducer of cytochrome P450 than rifampin and is, therefore, the preferred rifamycin for treatment of SOT recipients, though levels of immunosuppressant medications may still be difficult to maintain. If the isolate is susceptible, intravenous amikacin is added to the 3-drug regimen for cases with severe burden of disease (eg, cavitary lung disease). Intravenous amikacin can be transitioned from daily to thrice weekly for ease of administration [35, 36]. No prospective randomized trials have been conducted on pediatric SOT or HCT recipients to provide evidence-based recommendations regarding optimal dose, duration, or which cases should receive 4 vs 3 drugs (though most would experts would use 4 drugs in severe cases [25, 37]). Therefore, management of each case must be considered individually.

Table 7.

Open in new tab

Treatment of Slow Growing Nontuberculous Mycobacteria [3, 25, 33, 34, 37]

NTM Species	First Line Regimen	Second Line Drugs	Notes
M. avium complex Pulmonary disease: 3 drugs 4 drugs in severe disease	Azithromycin^a Rifabutin Ethambutol	Clarithromycin^a Rifampin Amikacin^a or streptomycin	Pulmonary disease: Treat for ≥12 months after sputum conversion. Never use macrolide monotherapy
M. kansasii Pulmonary disease: 3 drugs	Rifabutin^a Ethambutol Azithromycin^a or Isoniazid	Moxifloxacin Rifampin Azithromycin or clarithromycin^a Sulfamethoxazole Amikacin or streptomycin	Pulmonary disease: Treat for 12 months.
M. xenopi Pulmonary disease: 3–4 drugs	Azithromycin and/or moxifloxacin Rifabutin Ethambutol ±4th agent	Azithromycin and moxifloxacin Rifampin Amikacin or streptomycin	Pulmonary disease: Treat for ≥12 months after sputum conversion. Unclear whether 3 or 4 drugs is superior.
M. haemophilum Mild to Moderate: 3 drugs Severe: 4 drugs	Azithromycin Rifabutin Ciprofloxacin Severe disease: Amikacin	Rifampin Azithromycin or clarithromycin Sulfonamide Doxycycline	Intrinsic resistance to ethambutol. Variable susceptibility to doxycycline and sulfonamide.
M. marinum Moderate to Severe: 3 drugs	Azithromycin Ethambutol Extensive disease: Rifabutin	Rifampin Azithromycin or clarithromycin Sulfonamide Doxycycline or minocycline	Treat ≥2 months after resolution and 3–4 months total.

NTM Species	First Line Regimen	Second Line Drugs	Notes
M. avium complex Pulmonary disease: 3 drugs 4 drugs in severe disease	Azithromycin^a Rifabutin Ethambutol	Clarithromycin^a Rifampin Amikacin^a or streptomycin	Pulmonary disease: Treat for ≥12 months after sputum conversion. Never use macrolide monotherapy
M. kansasii Pulmonary disease: 3 drugs	Rifabutin^a Ethambutol Azithromycin^a or Isoniazid	Moxifloxacin Rifampin Azithromycin or clarithromycin^a Sulfamethoxazole Amikacin or streptomycin	Pulmonary disease: Treat for 12 months.
M. xenopi Pulmonary disease: 3–4 drugs	Azithromycin and/or moxifloxacin Rifabutin Ethambutol ±4th agent	Azithromycin and moxifloxacin Rifampin Amikacin or streptomycin	Pulmonary disease: Treat for ≥12 months after sputum conversion. Unclear whether 3 or 4 drugs is superior.
M. haemophilum Mild to Moderate: 3 drugs Severe: 4 drugs	Azithromycin Rifabutin Ciprofloxacin Severe disease: Amikacin	Rifampin Azithromycin or clarithromycin Sulfonamide Doxycycline	Intrinsic resistance to ethambutol. Variable susceptibility to doxycycline and sulfonamide.
M. marinum Moderate to Severe: 3 drugs	Azithromycin Ethambutol Extensive disease: Rifabutin	Rifampin Azithromycin or clarithromycin Sulfonamide Doxycycline or minocycline	Treat ≥2 months after resolution and 3–4 months total.

^aClinically relevant drug susceptibility testing recommended.

Table 7.

Open in new tab

Treatment of Slow Growing Nontuberculous Mycobacteria [3, 25, 33, 34, 37]

NTM Species	First Line Regimen	Second Line Drugs	Notes
M. avium complex Pulmonary disease: 3 drugs 4 drugs in severe disease	Azithromycin^a Rifabutin Ethambutol	Clarithromycin^a Rifampin Amikacin^a or streptomycin	Pulmonary disease: Treat for ≥12 months after sputum conversion. Never use macrolide monotherapy
M. kansasii Pulmonary disease: 3 drugs	Rifabutin^a Ethambutol Azithromycin^a or Isoniazid	Moxifloxacin Rifampin Azithromycin or clarithromycin^a Sulfamethoxazole Amikacin or streptomycin	Pulmonary disease: Treat for 12 months.
M. xenopi Pulmonary disease: 3–4 drugs	Azithromycin and/or moxifloxacin Rifabutin Ethambutol ±4th agent	Azithromycin and moxifloxacin Rifampin Amikacin or streptomycin	Pulmonary disease: Treat for ≥12 months after sputum conversion. Unclear whether 3 or 4 drugs is superior.
M. haemophilum Mild to Moderate: 3 drugs Severe: 4 drugs	Azithromycin Rifabutin Ciprofloxacin Severe disease: Amikacin	Rifampin Azithromycin or clarithromycin Sulfonamide Doxycycline	Intrinsic resistance to ethambutol. Variable susceptibility to doxycycline and sulfonamide.
M. marinum Moderate to Severe: 3 drugs	Azithromycin Ethambutol Extensive disease: Rifabutin	Rifampin Azithromycin or clarithromycin Sulfonamide Doxycycline or minocycline	Treat ≥2 months after resolution and 3–4 months total.

NTM Species	First Line Regimen	Second Line Drugs	Notes
M. avium complex Pulmonary disease: 3 drugs 4 drugs in severe disease	Azithromycin^a Rifabutin Ethambutol	Clarithromycin^a Rifampin Amikacin^a or streptomycin	Pulmonary disease: Treat for ≥12 months after sputum conversion. Never use macrolide monotherapy
M. kansasii Pulmonary disease: 3 drugs	Rifabutin^a Ethambutol Azithromycin^a or Isoniazid	Moxifloxacin Rifampin Azithromycin or clarithromycin^a Sulfamethoxazole Amikacin or streptomycin	Pulmonary disease: Treat for 12 months.
M. xenopi Pulmonary disease: 3–4 drugs	Azithromycin and/or moxifloxacin Rifabutin Ethambutol ±4th agent	Azithromycin and moxifloxacin Rifampin Amikacin or streptomycin	Pulmonary disease: Treat for ≥12 months after sputum conversion. Unclear whether 3 or 4 drugs is superior.
M. haemophilum Mild to Moderate: 3 drugs Severe: 4 drugs	Azithromycin Rifabutin Ciprofloxacin Severe disease: Amikacin	Rifampin Azithromycin or clarithromycin Sulfonamide Doxycycline	Intrinsic resistance to ethambutol. Variable susceptibility to doxycycline and sulfonamide.
M. marinum Moderate to Severe: 3 drugs	Azithromycin Ethambutol Extensive disease: Rifabutin	Rifampin Azithromycin or clarithromycin Sulfonamide Doxycycline or minocycline	Treat ≥2 months after resolution and 3–4 months total.

^aClinically relevant drug susceptibility testing recommended.

Treatment of M. kansasii typically involves a combination of 3 drugs (Table 7). Rifampin susceptibility testing is important as resistant strains have been associated with treatment failure. For M. kansasii infections, a fixed duration of 12 months may be adequate rather than 12 months after culture conversion [25].

Treatment of Rapid-Growing NTM

There is variability in antibiotic susceptibility among rapid-growing NTM (Table 8). Optimal treatment of M. abscessus is dependent on the subspecies involved: subsp. abscessus and boletti can have constitutive or inducible macrolide resistance. Inducible macrolide resistance is detected by presence of the erythromycin resistance methylase gene, named erm(41), or after 14 days of incubation. In contrast, most isolates of M. abscessus subsp. massiliense are susceptible to macrolides as they lack a functional erm(41) gene. When susceptible, macrolide use has been associated with improved rates of culture conversion and more favorable outcomes based on studies comparing treatments [25, 38]. Determination of M. abscessus subspecies and its susceptibility to macrolides and amikacin are recommended. Other parenteral antibiotics that are generally effective include imipenem, cefoxitin, amikacin, and tigecycline. For pulmonary disease, at least 3 active drugs are recommended for intensive treatment with preference to a macrolide with parenteral treatment when susceptible. In cases where the isolate is resistant to macrolides, 4 drugs may be warranted [25, 37]. Treatment often includes an intensive phase of therapy (4–16 weeks) with several parenteral antibiotics until improvement can be measured. Subsequent transition to a continuation phase using an oral regimen with 3 drugs is reasonable. Mycobacterium chelonae is generally susceptible to tobramycin (more active than amikacin), macrolides (as they do not have an erm(41) gene, though acquired resistance has been reported), clofazimine, imipenem, and sometimes fluoroquinolones [39]. Mycobacterium chelonae is usually resistant to cefoxitin. For pulmonary disease, at least 2 drugs should be used, with at least 3 drugs for severe disease (Table 8). Mycobacterium fortuitum isolates are typically resistant to macrolides but susceptible to fluoroquinolones, doxycycline, sulfonamides, amikacin, cefoxitin, and imipenem. At least 2 drugs should be used for mild disease or 3 drugs for severe disease (Table 8) [16].

Table 8.

Open in new tab

Treatment of Rapid-Growing Nontuberculous Mycobacteria [3, 7, 25, 38, 39]

NTM Species	Intensive	Continuation	Notes
M. abscessus (Macrolide susceptible)	≥3 drugs total: Parenteral (pick 1–2): Amikacin^a Imipenem Tigecycline Oral (pick 2): Azithromycin^a Clofazimine Omadacycline Linezolid or tedizolid Bedaquline	2–3 drugs: Azithromycin^a Clofazimine Omadacycline Linezolid or tedizolid Inhaled amikacin Bedaquiline	Consider drainage/resection
M. abscessus (Macrolide resistant)	≥4 drugs total: Parenteral (pick 2): Amikacin^a Imipenem or cefoxitin Tigecycline Oral (pick 2): Clofazimine Omadacycline Linezolid or tedizolid Bedaquline	2–3 drugs: Clofazimine Omadacycline Linezolid or tedizolid Inhaled amikacin Bedaquiline	Consider drainage/resection
M. chelonae Mild to Moderate: ≥2 drugs Severe: ≥3 drugs	4–16 weeks: Azithromycin PLUS ≥1 other drug: Tobramycin Imipenem Linezolid Tigecycline	Azithromycin PLUS ≥1 other drug: Moxifloxacin Clofazimine Linezolid or tedizolid	Inducible macrolide resistance not possible. Pulmonary disease: Treat for ≥12 months after sputum conversion. Extrapulmonary disease: Consider drainage/resection
M. fortuitum Mild to Moderate: ≥2 drugs Severe: ≥3 drugs	4–16 weeks: Moxifloxacin ± another oral agent PLUS ≥1 IV drug: Amikacin Cefoxitin Imipenem	≥2 oral drugs: Moxifloxacin Sulfonamide Doxycycline or minocycline Clofazimine Linezolid or tedizolid	Most strains have inducible erm gene. Pulmonary disease: Treat for ≥12 months after sputum conversion. Extrapulmonary disease: Consider drainage/resection

NTM Species	Intensive	Continuation	Notes
M. abscessus (Macrolide susceptible)	≥3 drugs total: Parenteral (pick 1–2): Amikacin^a Imipenem Tigecycline Oral (pick 2): Azithromycin^a Clofazimine Omadacycline Linezolid or tedizolid Bedaquline	2–3 drugs: Azithromycin^a Clofazimine Omadacycline Linezolid or tedizolid Inhaled amikacin Bedaquiline	Consider drainage/resection
M. abscessus (Macrolide resistant)	≥4 drugs total: Parenteral (pick 2): Amikacin^a Imipenem or cefoxitin Tigecycline Oral (pick 2): Clofazimine Omadacycline Linezolid or tedizolid Bedaquline	2–3 drugs: Clofazimine Omadacycline Linezolid or tedizolid Inhaled amikacin Bedaquiline	Consider drainage/resection
M. chelonae Mild to Moderate: ≥2 drugs Severe: ≥3 drugs	4–16 weeks: Azithromycin PLUS ≥1 other drug: Tobramycin Imipenem Linezolid Tigecycline	Azithromycin PLUS ≥1 other drug: Moxifloxacin Clofazimine Linezolid or tedizolid	Inducible macrolide resistance not possible. Pulmonary disease: Treat for ≥12 months after sputum conversion. Extrapulmonary disease: Consider drainage/resection
M. fortuitum Mild to Moderate: ≥2 drugs Severe: ≥3 drugs	4–16 weeks: Moxifloxacin ± another oral agent PLUS ≥1 IV drug: Amikacin Cefoxitin Imipenem	≥2 oral drugs: Moxifloxacin Sulfonamide Doxycycline or minocycline Clofazimine Linezolid or tedizolid	Most strains have inducible erm gene. Pulmonary disease: Treat for ≥12 months after sputum conversion. Extrapulmonary disease: Consider drainage/resection

^aClinically relevant drug susceptibility testing recommended.

Table 8.

Open in new tab

Treatment of Rapid-Growing Nontuberculous Mycobacteria [3, 7, 25, 38, 39]

NTM Species	Intensive	Continuation	Notes
M. abscessus (Macrolide susceptible)	≥3 drugs total: Parenteral (pick 1–2): Amikacin^a Imipenem Tigecycline Oral (pick 2): Azithromycin^a Clofazimine Omadacycline Linezolid or tedizolid Bedaquline	2–3 drugs: Azithromycin^a Clofazimine Omadacycline Linezolid or tedizolid Inhaled amikacin Bedaquiline	Consider drainage/resection
M. abscessus (Macrolide resistant)	≥4 drugs total: Parenteral (pick 2): Amikacin^a Imipenem or cefoxitin Tigecycline Oral (pick 2): Clofazimine Omadacycline Linezolid or tedizolid Bedaquline	2–3 drugs: Clofazimine Omadacycline Linezolid or tedizolid Inhaled amikacin Bedaquiline	Consider drainage/resection
M. chelonae Mild to Moderate: ≥2 drugs Severe: ≥3 drugs	4–16 weeks: Azithromycin PLUS ≥1 other drug: Tobramycin Imipenem Linezolid Tigecycline	Azithromycin PLUS ≥1 other drug: Moxifloxacin Clofazimine Linezolid or tedizolid	Inducible macrolide resistance not possible. Pulmonary disease: Treat for ≥12 months after sputum conversion. Extrapulmonary disease: Consider drainage/resection
M. fortuitum Mild to Moderate: ≥2 drugs Severe: ≥3 drugs	4–16 weeks: Moxifloxacin ± another oral agent PLUS ≥1 IV drug: Amikacin Cefoxitin Imipenem	≥2 oral drugs: Moxifloxacin Sulfonamide Doxycycline or minocycline Clofazimine Linezolid or tedizolid	Most strains have inducible erm gene. Pulmonary disease: Treat for ≥12 months after sputum conversion. Extrapulmonary disease: Consider drainage/resection

NTM Species	Intensive	Continuation	Notes
M. abscessus (Macrolide susceptible)	≥3 drugs total: Parenteral (pick 1–2): Amikacin^a Imipenem Tigecycline Oral (pick 2): Azithromycin^a Clofazimine Omadacycline Linezolid or tedizolid Bedaquline	2–3 drugs: Azithromycin^a Clofazimine Omadacycline Linezolid or tedizolid Inhaled amikacin Bedaquiline	Consider drainage/resection
M. abscessus (Macrolide resistant)	≥4 drugs total: Parenteral (pick 2): Amikacin^a Imipenem or cefoxitin Tigecycline Oral (pick 2): Clofazimine Omadacycline Linezolid or tedizolid Bedaquline	2–3 drugs: Clofazimine Omadacycline Linezolid or tedizolid Inhaled amikacin Bedaquiline	Consider drainage/resection
M. chelonae Mild to Moderate: ≥2 drugs Severe: ≥3 drugs	4–16 weeks: Azithromycin PLUS ≥1 other drug: Tobramycin Imipenem Linezolid Tigecycline	Azithromycin PLUS ≥1 other drug: Moxifloxacin Clofazimine Linezolid or tedizolid	Inducible macrolide resistance not possible. Pulmonary disease: Treat for ≥12 months after sputum conversion. Extrapulmonary disease: Consider drainage/resection
M. fortuitum Mild to Moderate: ≥2 drugs Severe: ≥3 drugs	4–16 weeks: Moxifloxacin ± another oral agent PLUS ≥1 IV drug: Amikacin Cefoxitin Imipenem	≥2 oral drugs: Moxifloxacin Sulfonamide Doxycycline or minocycline Clofazimine Linezolid or tedizolid	Most strains have inducible erm gene. Pulmonary disease: Treat for ≥12 months after sputum conversion. Extrapulmonary disease: Consider drainage/resection

^aClinically relevant drug susceptibility testing recommended.

CONTROVERSIES AND FUTURE DIRECTIONS

Many pre-transplant strategies attempting to reduce the risk of NTM disease have been proposed. Prophylaxis strategies in SOT candidates colonized with NTM remain poorly defined [40]. Prophylactic azithromycin to prevent surgical site infections in patients colonized with rapid-growing NTM has been considered; however, there are no supporting efficacy data [40]. The optimal duration of treatment for NTM disease prior to lung transplant is unclear. One center reported successful lung transplants in 3 of 4 patients with chronic M. abscessus prior to transplant after receiving aggressive antimicrobial treatment (ie, ≥2 IV and ≥3 oral antibiotics) for at least 12 weeks [41]. A minimum of 6 months of treatment prior to lung transplant was reported in a small study of 5 pediatric lung transplant recipients with M. abscessus [42, 43]. In a recent international survey of transplant surgeons, infectious diseases, and pulmonology specialists, most agreed that mycobacterial respiratory culture should be done prior to lung transplant, regardless of risk factors [44]. For lung transplant candidates with M. avium complex on active treatment and whose most recent sputum culture was negative, most agreed it would be appropriate to transplant. In contrast, the panelists agreed to transplant candidates with M. abscessus with negative cultures for 12 months and for M. kansasii a minimum of 6 months of negative sputum cultures [44]. Some centers consider prior M. abscessus treatment to be a contraindication to transplant though better outcomes are associated with aggressive treatment and surveillance in these high-risk patients [11]. The 2021 International Society for Heart and Lung Transplantation Consensus advises against this as a contraindication, and if transplant is considered, candidates are recommended to seek care at centers with mycobacterial expertise to ensure aggressive treatment before, during, and after the transplant period. In such situations, there should be a full discussion of the risks and benefits of therapy prior to transplant [11].

Intra-operative strategies to reduce the NTM burden prior to transplant have been proposed and novel treatment modalities are on the horizon. Intra-operative amikacin washes at the time of transplant followed by IV treatment [42] and recipient lymph node excision to reduce the overall NTM burden has been suggested [12]. Other experts have recommend withholding anti-thymocyte globulin and reducing tacrolimus and cyclosporin levels to reduce the degree of immune suppression and risk of NTM disease [45]. These strategies are based on expert opinion as no efficacy data exist. Other medications active against NTM but for which there are limited data include dual-beta lactam combinations with or without beta-lactamase inhibitors, clofazimine, bedaquiline, linezolid or tedizolid, and omadacycline [45–47].

Lastly, bacteriophages have been used to treat extremely drug-resistant NTM [48, 49] and may be considered for recalcitrant cases; however, data regarding dosing, host–phage interactions, and efficacy are limited. In the United States, phages are only accessible through single-patient Investigational New Drug applications submitted to the US Food and Drug Administration. As NTM infections continue to emerge in HCT and SOT recipients, more innovative approaches to prevent and treat infection will evolve.

Notes

Financial support. This work was supported by The Otis Child’s Trust (PNC Charitable Trust, UPMC Children’s Foundation, PLL).

Supplement sponsorship. This article appears as part of the supplement “Advances in Pediatric Transplant Infectious Diseases,” sponsored by Eurofins Viracor.

Potential conflicts of interest. JDA—“No conflict,” PLL—“No conflict,” CLD—Consultant: Genentech, Pfizer. Advisory Board Member: AN2, AstraZeneca, Hyfe, Insmed, MannKind, Matinas BioPharma Holdings, Inc., Nob Hill, Paratek Pharmaceuticals, Spero Therapeutics, and Zambon. Data Monitoring Committee: Ostuka Pharmaceutical, Eli Lilly and Company, Bill and Melinda Gates Foundation. Contracted Research: AN2 Therapeutics, Bugworks, Insmed, Juvabis, and Pharmaceuticals.

REFERENCES

1.

Friedman

DZP

,

Doucette

K.

Mycobacteria: selection of transplant candidates and post-lung transplant outcomes

.

Semin Respir Crit Care Med

2021

;

42

:

460

–

70

.

Google Scholar

PubMed

OpenURL Placeholder Text

WorldCat

2.

Al-Anazi

KA

,

Al-Jasser

AM

,

Al-Anazi

WK.

Infections caused by non-tuberculous mycobacteria in recipients of hematopoietic stem cell transplantation

.

Front Oncol

2014

;

4

:

311

.

Google Scholar

PubMed

OpenURL Placeholder Text

WorldCat

3.

Longworth

SA

,

Daly

JS

;

AST Infectious Diseases Community of Practice

.

Management of infections due to nontuberculous mycobacteria in solid organ transplant recipients-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

.

Clin Transplant

2019

;

33

:

e13588

.

4.

Mejia-Chew

C

,

Carver

PL

,

Rutjanawech

S

, et al. .

Risk factors for nontuberculous mycobacteria infections in solid organ transplant recipients: a multinational case-control study

.

Clin Infect Dis

2023

;

76

:

e995

–

e1003

.

5.

Abad

CL

,

Razonable

RR.

Non-tuberculous mycobacterial infections in solid organ transplant recipients: an update

.

J Clin Tuberc Other Mycobact Dis

2016

;

4

:

1

–

8

.

6.

Asif

H

,

Rahaghi

FF

,

Ohsumi

A

, et al. .

Management of nontuberculous mycobacteria in lung transplant cases: an international Delphi study

.

ERJ Open Res

2023

;

9

:

00377

–

2022

.

7.

Griffith

DE

,

Aksamit

T

,

Brown-Elliott

BA

, et al. ;

ATS Mycobacterial Diseases Subcommittee

.

An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases

.

Am J Respir Crit Care Med

2007

;

175

:

367

–

416

.

8.

Foundation CF

.

Patient Registry 2021: Annual Data Report

.

2021

. https://www.cff.org/sites/default/files/2021-11/Patient-Registry-Annual-Data-Report.pdf.

Accessed 27 June, 2023

.

9.

Prieto

MD

,

Alam

ME

,

Franciosi

AN

,

Quon

BS.

Global burden of nontuberculous mycobacteria in the cystic fibrosis population: a systematic review and meta-analysis

.

ERJ Open Res

2023

;

9

:

00336

–

2022

.

10.

Rao

M

,

Silveira

FP.

Non-tuberculous mycobacterial infections in thoracic transplant candidates and recipients

.

Curr Infect Dis Rep

2018

;

20

:

14

.

11.

Leard

LE

,

Holm

AM

,

Valapour

M

, et al. .

Consensus document for the selection of lung transplant candidates: an update from the International Society for Heart and Lung Transplantation

.

J Heart Lung Transplant

2021

;

40

:

1349

–

79

.

12.

Kavaliunaite

E

,

Harris

KA

,

Aurora

P

, et al. .

Outcome according to subspecies following lung transplantation in cystic fibrosis pediatric patients infected with Mycobacterium abscessus

.

Transpl Infect Dis

2020

;

22

:

e13274

.

13.

El Zein

S

,

Mendoza

MA

,

Wilson

JW.

Nontuberculous mycobacterial infections in patients with hematologic malignancies and recipients of hematopoietic stem cell transplantation

.

Transpl Infect Dis

2023

;

25

:

e14127

.

14.

Unal

E

,

Yen

C

,

Saiman

L

, et al. .

A low incidence of nontuberculous mycobacterial infections in pediatric hematopoietic stem cell transplantation recipients

.

Biol Blood Marrow Transplant

2006

;

12

:

1188

–

97

.

15.

Wobma

H

,

Chang

AK

,

Jin

Z

, et al. .

Low CD4 count may be a risk factor for non-tuberculous mycobacteria infection in pediatric hematopoietic cell transplant recipients

.

Pediatr Transplant

2021

;

25

:

e13994

.

16.

Bergeron

A

,

Mikulska

M

,

De Greef

J

, et al. ;

European Conference on Infections in Leukaemia group

.

Mycobacterial infections in adults with haematological malignancies and haematopoietic stem cell transplants: guidelines from the 8th European Conference on Infections in Leukaemia

.

Lancet Infect Dis

2022

;

22

:

e359

–

69

.

17.

Forbes

BA

,

Hall

GS

,

Miller

MB

, et al. .

Practical guidance for clinical microbiology laboratories: mycobacteria

.

Clin Microbiol Rev

2018

;

31

:

e00038

–

17

.

18.

Narsana

N

,

Alejandra Perez

M

,

Subramanian

A.

Mycobacteria in organ transplant recipients

.

Infect Dis Clin North Am

2023

;

37

:

577

–

91

.

19.

Keating

MR

,

Daly

JS

;

AST Infectious Diseases Community of Practice

.

Nontuberculous mycobacterial infections in solid organ transplantation

.

Am J Transplant

2013

;

13

:

77

–

82

.

20.

Doucette

K

,

Fishman

JA.

Nontuberculous mycobacterial infection in hematopoietic stem cell and solid organ transplant recipients

.

Clin Infect Dis

2004

;

38

:

1428

–

39

.

21.

Knoll

BM.

Update on nontuberculous mycobacterial infections in solid organ and hematopoietic stem cell transplant recipients

.

Curr Infect Dis Rep

2014

;

16

:

421

.

22.

Lamb

GS

,

Starke

JR.

Mycobacterium abscessus infections in children: a review of current literature

.

J Pediatric Infect Dis Soc

2018

;

7

:

e131

–

44

.

23.

Knoll

BM

,

Kappagoda

S

,

Gill

RR

, et al. .

Non-tuberculous mycobacterial infection among lung transplant recipients: a 15-year cohort study

.

Transpl Infect Dis

2012

;

14

:

452

–

60

.

24.

George

IA

,

Santos

CA

,

Olsen

MA

,

Bailey

TC.

Epidemiology and outcomes of nontuberculous mycobacterial infections in solid organ transplant recipients at a Midwestern Center

.

Transplantation

2016

;

100

:

1073

–

8

.

25.

Daley

CL

,

Iaccarino

JM

,

Lange

C

, et al. .

Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline

.

Eur Respir J

2020

;

56

:

2000535

.

26.

Longworth

SA

,

Vinnard

C

,

Lee

I

,

Sims

KD

,

Barton

TD

,

Blumberg

EA.

Risk factors for nontuberculous mycobacterial infections in solid organ transplant recipients: a case-control study

.

Transpl Infect Dis

2014

;

16

:

76

–

83

.

27.

Nolt

D

,

Michaels

MG

,

Wald

ER.

Intrathoracic disease from nontuberculous mycobacteria in children: two cases and a review of the literature

.

Pediatrics

2003

;

112

:

e434

.

28.

Freeman

AF

,

Olivier

KN

,

Rubio

TT

, et al. .

Intrathoracic nontuberculous mycobacterial infections in otherwise healthy children

.

Pediatr Pulmonol

2009

;

44

:

1051

–

6

.

29.

Song

Y

,

Zhang

L

,

Yang

H

, et al. .

Nontuberculous mycobacterium infection in renal transplant recipients: a systematic review

.

Infect Dis (Lond)

2018

;

50

:

409

–

16

.

30.

Brown-Elliott

BA

,

Woods

GL.

Antimycobacterial susceptibility testing of nontuberculous mycobacteria

.

J Clin Microbiol

2019

;

57

:

e00834

–

19

.

31.

Alffenaar

JW

,

Martson

AG

,

Heysell

SK

, et al. .

Therapeutic drug monitoring in non-tuberculosis mycobacteria infections

.

Clin Pharmacokinet

2021

;

60

:

711

–

25

.

32.

Tagashira

Y

,

Kozai

Y

,

Yamasa

H

,

Sakurada

M

,

Kashiyama

T

,

Honda

H.

A cluster of central line-associated bloodstream infections due to rapidly growing nontuberculous mycobacteria in patients with hematologic disorders at a Japanese tertiary care center: an outbreak investigation and review of the literature

.

Infect Control Hosp Epidemiol

2015

;

36

:

76

–

80

.

33.

Tanaka

E

,

Kimoto

T

,

Tsuyuguchi

K

, et al. .

Effect of clarithromycin regimen for Mycobacterium avium complex pulmonary disease

.

Am J Respir Crit Care Med

1999

;

160

:

866

–

72

.

34.

Wallace

RJ

Jr,

Brown

BA

,

Griffith

DE

,

Girard

WM

,

Murphy

DT.

Clarithromycin regimens for pulmonary Mycobacterium avium complex. The first 50 patients

.

Am J Respir Crit Care Med

1996

;

153

:

1766

–

72

.

35.

Namkoong

H

,

Morimoto

K

,

Nishimura

T

, et al. .

Clinical efficacy and safety of multidrug therapy including thrice weekly intravenous amikacin administration for Mycobacterium abscessus pulmonary disease in outpatient settings: a case series

.

BMC Infect Dis

2016

;

16

:

396

.

36.

Peloquin

CA

,

Berning

SE

,

Nitta

AT

, et al. .

Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases

.

Clin Infect Dis

2004

;

38

:

1538

–

44

.

37.

Haworth

CS

,

Banks

J

,

Capstick

T

, et al. .

British Thoracic Society Guideline for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD)

.

BMJ Open Respir Res

2017

;

4

:

e000242

.

38.

Park

J

,

Cho

J

,

Lee

CH

,

Han

SK

,

Yim

JJ.

Progression and treatment outcomes of lung disease caused by Mycobacterium abscessus and Mycobacterium massiliense

.

Clin Infect Dis

2017

;

64

:

301

–

8

.

39.

Lange

C

,

Bottger

EC

,

Cambau

E

, et al. ;

expert panel group for management recommendations in non-tuberculous mycobacterial pulmonary diseases

.

Consensus management recommendations for less common non-tuberculous mycobacterial pulmonary diseases

.

Lancet Infect Dis

2022

;

22

:

e178

–

90

.

40.

Huang

HC

,

Weigt

SS

,

Derhovanessian

A

, et al. .

Non-tuberculous mycobacterium infection after lung transplantation is associated with increased mortality

.

J Heart Lung Transplant

2011

;

30

:

790

–

8

.

41.

Raats

D

,

Lorent

N

,

Saegeman

V

, et al. .

Successful lung transplantation for chronic Mycobacterium abscessus infection in advanced cystic fibrosis, a case series

.

Transpl Infect Dis

2019

;

21

:

e13046

.

42.

Robinson

PD

,

Harris

KA

,

Aurora

P

,

Hartley

JC

,

Tsang

V

,

Spencer

H.

Paediatric lung transplant outcomes vary with Mycobacterium abscessus complex species

.

Eur Respir J

2013

;

41

:

1230

–

2

.

43.

Kang

Y

,

Sue

PK

,

Filkins

L

,

Chery

GS.

1395. Epidemiology of non-tuberculous mycobacteria infection among immunocompromised children: a single center experience

.

Open Forum Infect Dis

2021

;

8

:

S783

.

Google Scholar

Crossref

WorldCat

44.

Asif

H

,

Rahaghi

FF

,

Ohsumi

A

, et al. .

Management of nontuberculous mycobacteria in lung transplant cases: an international Delphi study

.

ERJ Open Res

2023

;

9

:

00377

–

2022

.

45.

Anjan

S

,

Morris

MI.

Nontuberculous mycobacteria in solid organ transplant

.

Curr Opin Organ Transplant

2019

;

24

:

476

–

82

.

46.

Martiniano

SL

,

Wagner

BD

,

Levin

A

,

Nick

JA

,

Sagel

SD

,

Daley

CL.

Safety and effectiveness of clofazimine for primary and refractory nontuberculous mycobacterial infection

.

Chest

2017

;

152

:

800

–

9

.

47.

Siddiqa

A

,

Khan

S

,

Rodriguez

GD

,

Urban

C

,

Segal-Maurer

S

,

Turett

G.

Omadacycline for the treatment of Mycobacterium abscessus infections: case series and review of the literature

.

IDCases

2023

;

31

:

e01703

.

48.

Hatfull

GF.

Phage therapy for nontuberculous mycobacteria: challenges and opportunities

.

Pulm Ther

2023

;

9

:

91

–

107

.

49.

Dedrick

RM

,

Smith

BE

,

Cristinziano

M

, et al. .

Phage therapy of mycobacterium infections: compassionate use of phages in 20 patients with drug-resistant mycobacterial disease

.

Clin Infect Dis

2023

;

76

:

103

–

12

.

50.

Longworth

SA

,

Blumberg

EA

,

Barton

TD

,

Vinnard

C.

Non-tuberculous mycobacterial infections after solid organ transplantation: a survival analysis

.

Clin Microbiol Infect

2015

;

21

:

43

–

7

.

51.

Beswick

J

,

Shin

E

,

Michelis

FV

, et al. .

Incidence and risk factors for nontuberculous mycobacterial infection after allogeneic hematopoietic cell transplantation

.

Biol Blood Marrow Transplant

2018

;

24

:

366

–

72

.

52.

Ford

TJ

,

Silcock

RA

,

Holland

SM.

Overview of nontuberculous mycobacterial disease in children

.

J Paediatr Child Health

2021

;

57

:

15

–

8

.

53.

Khare

R

,

Brown-Elliott

BA.

Culture, identification, and antimicrobial susceptibility testing of pulmonary nontuberculous mycobacteria

.

Clin Chest Med

2023

;

44

:

743

–

55

.

54.

Pennington

KM

,

Vu

A

,

Challener

D

, et al. .

Approach to the diagnosis and treatment of non-tuberculous mycobacterial disease

.

J Clin Tuberc Other Mycobact Dis

2021

;

24

:

100244

.

© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: [email protected].

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://dbpia.nl.go.kr/pages/standard-publication-reuse-rights)

Download all slides

Month:	Total Views:
February 2024	136
March 2024	285
April 2024	91
May 2024	106
June 2024	49
July 2024	62
August 2024	48
September 2024	56
October 2024	82
November 2024	74
December 2024	54
January 2025	27
February 2025	60
March 2025	80
April 2025	25
May 2025	4

Article Contents

Nontuberculous Mycobacterial Infections in Pediatric Solid Organ Transplant and Hematopoietic Cell Transplant Recipients

Abstract

INTRODUCTION

EPIDEMIOLOGY AND RISK FACTORS

MICROBIOLOGY

CLINICAL MANIFESTATIONS

Pulmonary Disease

Cutaneous/Musculoskeletal Disease

Disseminated Disease

DIAGNOSIS

TREATMENT

Treatment of Slow-Growing NTM

Treatment of Rapid-Growing NTM

CONTROVERSIES AND FUTURE DIRECTIONS

Notes

REFERENCES

Citations

Views

Altmetric

Email alerts

Citing articles via

Latest

Most Read

Most Cited

Article Contents

Nontuberculous Mycobacterial Infections in Pediatric Solid Organ Transplant and Hematopoietic Cell Transplant Recipients

Abstract

INTRODUCTION

EPIDEMIOLOGY AND RISK FACTORS

MICROBIOLOGY

CLINICAL MANIFESTATIONS

Pulmonary Disease

Cutaneous/Musculoskeletal Disease

Disseminated Disease

DIAGNOSIS

TREATMENT

Treatment of Slow-Growing NTM

Treatment of Rapid-Growing NTM

CONTROVERSIES AND FUTURE DIRECTIONS

Notes

REFERENCES

Citations

Views

Altmetric

Email alerts

Citing articles via

Latest

Most Read

Most Cited

This Feature Is Available To Subscribers Only