Abstract
Nontuberculous mycobacterial disease has been increasing worldwide in the general population and also among specific vulnerable disease groups. In this chapter, the microbiology, epidemiology, routes of transmission, clinical manifestations, management and treatment, and prevention of this infection are reviewed. The chapter also includes discussion of the surgical treatment options, nonpharmacologic therapy, and extrapulmonary manifestations of nontuberculous mycobacterial disease.
Keywords
nontuberculous mycobacteria, Mycobacterium abscesses complex, Mycobacterium avium complex
There is widespread agreement that detection of nontuberculous mycobacteria (NTM) is increasing worldwide within surveys of the general population and among specific vulnerable disease groups. The true incidence of disease caused by NTM is difficult to accurately track. Available data almost certainly underestimate the burden of infection due to the low clinical suspicion, the low sensitivity of available diagnostic techniques, and the lack of mandatory public health reporting of NTM infections. The most common presentation of NTM disease in children is cervical lymphadenitis, and skin and soft tissue infection. Pulmonary NTM disease in children occurs in the setting of preexisting lung disease, and is most often associated with cystic fibrosis (CF). Disseminated disease may occur in the setting of immune compromise, often due to HIV/AIDS or a variety of rare conditions. The accurate diagnosis of pulmonary NTM disease can be challenging because of the limitations of available diagnostic tests and the common occurrence of transient or indolent infections in the absence of new or worsening symptoms.
Microbiology
The genus Mycobacterium consists of a diverse group of obligate aerobes that grow most successfully in tissues with high oxygen content, such as the lungs. These nonmotile, nonspore-forming, pleomorphic rods feature a cell wall rich in mycolic acids. The lipid-rich cell wall makes them impermeable to many stains unless the dyes are combined with phenol. Once stained, the cells resist decolorization with acidified organic solvents, resulting in their hallmark trait of “acid-fastness.” This property is demonstrated with basic fuchsine stain techniques, such as the Ziehl-Neelsen and Kinyoun methods, or the more sensitive fluorochrome method using auramine and rhodamine stains.
More than 170 species of Mycobacterium have been described, with new species being identified each year. Many NTM are nonpathogenic in humans, and others have been described to cause disease very rarely in case reports or small cases series of immunocompromised individuals. NTM species are often categorized using the Runyon classification system based on rate of growth and pigmentation. The most commonly encountered NTM are among the “slow growers” and classified together as the Mycobacterium avium complex (MAC), which includes the species M. avium, M. intracellulare, M. chimaera among several other species and subspecies. MAC is genetically close to the Mycobacterium tuberculosis complex, and is susceptible to several of the antibiotics effective in the treatment of tuberculosis. Another disease-causing slow growing NTM is Mycobacterium kansasii. Also of clinical significance is the Mycobacterium abscessus species complex (MABSC), which includes three subspecies, M. abscessus, M. massiliense, and M. bolletii. MABSC are classified as “rapid growers,” and are genetically quite distinct from MAC.
Advances in diagnosis and treatment of NTM infection have lagged, in part, due to challenges relating to the culture, detection, and identification of the organisms. Methods developed for the isolation of Mycobacterium tuberculosis from clinical samples have been adapted for the isolation of NTM. Current recommendations are that both liquid and solid media are used for NTM culture with incubation for at least 6 weeks. Isolation on solid media of slow-growing NTM takes 2–6 weeks; only the rapid growers reliably form visible colonies in less than 10 days. However, automated systems using liquid media allow detection of most species of mycobacteria more rapidly. Sensitivity is increased and the time for isolation is decreased by a larger specimen size and a higher bacterial burden. In the setting of CF, adequate sample decontamination to remove overgrowth of Pseudomonas aeruginosa and other coinfections is essential to permit culture-based detection of NTM. Importantly, decontamination protocols can reduce NTM viability in samples, resulting in false negative results. Current best practice for CF isolates consists of a two-step approach of (N-acetyl- l -cysteine–2% sodium hydroxide (NALC-NaOH) decontamination prior to mycobacterial culture with the addition of a second decontamination using 5% oxalic acid or 1% chlorhexidine to permit the recovery of NTM from persistently contaminated samples, albeit with reduced sensitivity.
Traditional identification of NTM relies on statistical probabilities of a characteristic reaction pattern in a battery of biochemical tests. Molecular methods have now surpassed biochemical tests for NTM identification in many laboratories. These tests include line probe assays, polymerase chain reaction (PCR) product restriction analysis, and partial gene sequencing. For subspeciation of MABSC, a multilocus sequence typing approach has recently been validated. Each of these methods has significant strengths as well as disadvantages, and there is no consensus regarding the gold standard for NTM identification. However, recently published guidelines sponsored by the CF Foundation (CFF) and the European CF Society (ECFS) recommend that all NTM isolates from individuals with CF should undergo molecular identification. All MABSC isolates from individuals with CF should be identified to the subspecies level, and other NTM identified to the species level, except for M. avium, M. intracellulare, and M. chimaera, where identification can be limited to MAC.
Epidemiology
Prevalence
General Population
Several problems compound the epidemiologic description of NTM infections in children. NTM infection is rarely a cause of death, with an overall mortality rate of 2.3 deaths per 1,000,000 person-years attributed to NTM in the United States. In individuals age 24 years and younger, age-adjusted mortality rates range from 0.04 to 0.12 per 1,000,000 in the absence of an HIV diagnosis, and are even lower in the presence of an HIV diagnosis. Smaller laboratories that isolate NTM often do not refer isolates to reference laboratories for identification and drug-susceptibility testing, so statistics from reference laboratories grossly underestimate the incidence of NTM disease. Finally, as opportunistic environmental bacteria with relatively low pathogenic potential, isolation of an NTM from a clinical specimen is rarely sufficient for the diagnosis of disease. Distinguishing among environmental contaminants, transient recovery of the bacteria, colonizers, and truly pathogenic organisms requires clinical correlation that is not available based simply on laboratory reports. A recent study of NTM disease prevalence in the United States estimated 27.9 cases per 100,000 population, based primarily on Medicare beneficiary data. These authors estimated 31% of cases were less than 65 years old, but the actual number of pediatric cases is unknown. Substantial differences in susceptibility to NTM pulmonary disease appear linked to race and ethnicity. Within the Hawaiian Islands, which has a rate of NTM pulmonary disease four times greater than the national average in the United States, prevalence was highest among Japanese, Chinese, and Vietnamese patients (>300/100,000 persons) and lowest among Native Hawaiians and Other Pacific Islanders (50/100,000).
Cystic Fibrosis
The best estimates for the prevalence of positive NTM cultures comes from CF populations, where the rate of infection has been studied in prospective and retrospective clinical trials, as well as in extensive longitudinal data collection through national registries. In the largest studies, the overall prevalence is 6%–13%. Since 2010, the US CF Patient Care Registry has tracked the presence of positive NTM culture, and over a 4-year span (2011–2015), 19% of patients who were cultured had one or more species isolated. There is widespread agreement that the prevalence of NTM is increasing in the CF population ; however, it is often difficult to compare reports from single centers or even national surveys because of widely differing methods of ascertainment, regional environmental differences, culture methods, and the definitions of colonization, infection, and disease. CF features underlying progressive pulmonary disease and chronic airway infections with highly pathogenic bacteria such P. aeruginosa and Staphylococcus aureus. In this setting, it is challenging to assess the role of an NTM infection in an individual patient. While the isolation of an NTM from a CF patient’s sputum may be associated with a worsening clinical and radiographic course, in the majority of patients a positive NTM culture may be a transient occurrence or not associated with measurable acceleration of disease.
In CF patients in whom NTM disease is diagnosed, there are apparent differences between those infected with MABSC and MAC. Patients infected with MABSC are often younger, and may include children, with relatively more severe lung disease. Those infected with MAC are often older and more frequently heterozygous for residual function cystic fibrosis transmembrane conductance regulator (CFTR) mutations, resulting in a less severe phenotype, which may not be diagnosed until adulthood. There are, of course, many exceptions to this general observation, and children with CF can develop NTM disease from either MAC or MABSC. Disease from MABSC is the more feared infection due to a more difficult course of treatment, a poorer response to antibiotic therapy, an often more severe clinical course, and frequent exclusion from lung transplant in the setting of failure to eradicate the bacteria.
Human Immunodeficiency Virus Infection/Acquired Immune Deficiency Syndrome
Clinical disease due to NTM is common in adults and children with AIDS. MAC accounts for most cases, followed in incidence by M. kansasii. The predominant risk factor appears to be a CD4 cell number below 50 cells/mm 3 , and can occur as either disseminated or localized disease. Other NTM that have been described as disease-causing in HIV/AIDS include Mycobacterium xenopi, Mycobacterium haemophilum, Mycobacterium fortuitum or Mycobacterium chelonae, Mycobacterium genavense, Mycobacterium simiae, and Mycobacterium szulgai. A high clinical suspicion is needed for either unexplained lymphadenitis, cutaneous or systemic presentations in patients with CD4 cell < 50 cells/mm 3 .
Mendelian Susceptibility to Mycobacterial Disease and Other Immunocompromised Conditions
Mendelian susceptibility to mycobacterial diseases (MSMD, MIM # 209950 ) is caused by genetic defects in the mononuclear phagocyte/T helper cell type 1 (Th1) arm of host defense. Patients with MSMD have increased susceptibility to systemic NTM infections, even including the Bacillus Calmette-Guérin vaccine strain. All the MSMD conditions feature defects in the interferon gamma (IFN-gamma)-interleukin-12 pathway and/or supporting accessory pathways ( Table 30.1 ). In about half of patients with MSMD, the genetic etiology has yet to be identified.
| Mendelian susceptibility to mycobacterial diseases (MSMD) | Autosomal recessive complete interferon-gamma receptor deficiencies Autosomal dominant partial interferon-gamma receptor deficiencies IFN-gamma-R1 (IFNGR1) or IFN-gamma-R2 (IFNGR2) Autosomal recessive partial IFN-gamma receptor deficiencies IL-12 receptor beta1 (IL12RB1) deficiency IL-12 p40 (IL12B) deficiency Autosomal recessive signal transducer and activator of transcription 1 (STAT1) deficiency Autosomal dominant STAT1 (STAT1) deficiency Tyrosine kinase 2 (TYK2) deficiency Autosomal recessive IFN regulatory factor 8 (IRF8) deficiency Autosomal dominant IFN regulatory factor 8 (IRF8) deficiency GATA2 (GATA2) deficiency (monoMAC syndrome) Autosomal recessive IFN-stimulated gene 15 (ISG15) deficiency RAR-related Orphan Receptor C (RORC) dysfunction |
| X-linked MSMD | Nuclear factor-κB essential modulator (IKBKG) (NEMO) deficiency X-linked chronic granulomatous disease due to mutations in gp91(phox) subunit (CYBB) of NADPH oxidase |
| Other immune disorders | Anti-IFNγ autoantibody formation Natural-resistance-associated macrophage protein 1 (NRAMP1) gene polymorphisms |
| T-cell disorders | Severe combined immune deficiency Isolated CD4+ T cell deficiency HIV/AIDS |
| Phagocyte defects | Chronic granulomatous disease |
| Iatrogenic immunosuppression | Recipients of solid organ transplants Recipients of hematopoietic or stem cell transplants Anti-TNFα treatment Inhaled or systemic corticosteroids Other immunosuppressive medications |
| Structural lung disease | Cystic fibrosis (CF) Alpha-1 antitrypsin deficiency Non-CF bronchiectasis Pneumoconiosis Pulmonary alveolar proteinosis Chronic obstructive pulmonary disease |
Disseminated disease with pulmonary involvement caused by NTM has been described in patients with a variety of other rare immunodeficiency states, as well as malignancies including leukemia and lymphoma. Inherited and acquired defects in the host immune response include auto-antibodies to IFN-gamma, CD4 lymphopenia due to HIV or other causes, and use of tumor necrosis factor-alpha inhibitors, particularly infliximab and adalimumab. A wide variety of biologic and synthetic small molecules target aspects of host defense against NTM, and carry high theoretical risks for the infection. NTM disease also has been reported in adults and children after organ transplantation.
Environmental Risk Factors and Spatial Clusters
Distribution of NTM in the general population and in vulnerable populations varies dramatically by regions, reflecting, in part, the environmental origin of the bacteria. In the United States, the greatest number of estimated cases per 100,000 populations was 164.6 in Hawaii, followed by Florida (53.6), Mississippi (52), and Arizona (48.9). The states with the lowest rates were largely clustered in the upper Midwest, including Montana (5.4), South Dakota (6.5), North Dakota (7.4), and Minnesota (9.3). These differences likely reflect a combination of host and environmental risk factors within these regions. A greater understanding of environmental risk factors and spatial clusters of NTM infection has come from the analysis of Medicare and Medicaid data, combined with population and socioeconomic data from the US Census Bureau, and environmental and climatic data from the US Census Bureau, US Forest Service, and the US Geological Survey. Counties in high-risk areas were significantly larger, had greater population densities, and higher education and income levels than low-risk counties. High-risk counties also had higher mean daily potential evapotranspiration levels and percentages covered by surface water, and were more likely to have greater copper and sodium levels in the soil, with lower manganese levels. Similar conclusions have been found from combining CF Patient Registry data with climatic databases, where higher saturated vapor pressure increased the risk for NTM (odds ratio = 1.06; 95% confidence interval = 1.02–1.10).
The species of NTM causing infection also demonstrates significant regional differences. Nearly all surveys from European countries have established that MABSC is the most frequent NTM isolated from CF patients in those regions. In contrast, reports from the United States have consistently shown MAC to be the predominant NTM infection. In somewhat isolated regions, other NTM may be highly represented. For example, M. simiae is reported as the most frequent cause of NTM pulmonary disease in CF patients on the Island of Gran Canaria and is also common in Israel. Even within the US CF population, dramatic state-by-state differences in prevalence of various NTM species have been reported. When CF Patient Registry data were analyzed, 60% of positive cultures nationwide were identified as MAC, ranging by state from 29% in Louisiana to 100% in Nebraska and Delaware.
Acquisition and Potential for Transmission
Nearly all acquisition of NTM by children occurs from environmental sources, including soil, water, dust, and aerosols. MAC species are found frequently in animals, particularly birds and swine, which may be important natural reservoirs for the organisms. However, there is little evidence to suggest that animal-to-human transmission is a major factor in human infection.
The number of reported clusters of health-care-associated disease caused by various species of NTM is growing. Most common are outbreaks by the rapid growers. Both clusters and sporadic NTM infections have been associated with a variety of surgical procedures, including sternal wound infections after open heart surgery, augmentation mammoplasty, corneal surgery, implantation of pressure equalizing tubes in the tympanic membranes, and insertion of central venous catheters. A number of outbreaks or pseudo-outbreaks of respiratory tract colonization caused by various NTM species have been associated with contaminated ice machines, showers, potable water supplies, laboratory supplies, topical anesthetics, and tap water in hospitals. Contamination of endoscopes, bronchoscopes or bronchoscopy supplies has been implicated in some of these outbreaks.
There is also growing concern over the potential for human-to-human transmission. Until recently, this was believed to never occur, but with improved surveillance and increased availability of whole genome sequencing, several outbreaks have been reported. Well-described clusters of highly similar strains of M. massiliense have been reported in CF centers in Seattle, Washington, and Papworth, United Kingdom, in patients who were seen within the same clinic or hospital ward over a relatively short interval of time. Mechanisms of NTM transmission are not well understood, but in well-defined localized outbreaks, it seems that shared exposure of a contaminated clinical space is a more plausible mechanism of pathogen spread than direct patient-to-patient transmission. Strict infection control procedures following the Seattle outbreak have been associated with a cessation of any additional cases. More recently, a much larger study found highly similar clusters of both M. massiliense and M. abscessus represented in collections of clinical isolates from United States, European, and Australian CF centers, indicating transcontinental dissemination of these clades. Unlike the previous outbreaks in Seattle or Papworth, there was no clear epidemiologic link between patients or physicians traveling between these different centers worldwide. In many cases, shared strains have been associated with increased virulence, antibiotic resistance and/or worse outcomes. There is ongoing debate about whether these findings represent global transmission of strains of MABSC between CF centers through yet-to-be-defined mechanisms, or dominant environmental strains that are present worldwide with extremely low genetic diversity, or a combination of both.
Apparent Increase in Nontuberculous Mycobacteria Vulnerable Populations and in the Modern Environment
The incidence of detecting various NTM organisms in surveys of the general population, as well as individuals with CF appears to be increasing. The underlying cause of this apparent increase is almost certainly multifactorial and interconnected. Within the CF population, impressive gains in projected lifespan puts greater numbers of patients at risk for NTM. Infection with MAC, in particular, is clearly age-related and associated with long-term survivors with a milder phenotype. Certainly, improved culture techniques and greater awareness among providers to consider NTM infection has contributed to the increase in positive NTM cultures. There is also considerable debate as to whether various medications and CF treatment strategies directly place patients at increased risk. Some reports have implicated systemic steroids, high-dose ibuprofen, the higher use of antipseudomonal antibiotics, and chronic azithromycin therapy as being associated with higher prevalence of NTM-positive cultures and/or disease. However, for each of these medications, the opposite findings have also been reported.
To a certain extent, these same considerations may apply to individuals within the general population with less well-defined risks for NTM. Certainly, humanity has never before included as many individuals with various forms of immunosuppression, ranging from HIV/AIDS to malignancies, and to the use of steroid and immunomodulatory drugs. Presumably, physicians caring for these individuals are increasingly aware of the potential risks for NTM infection, and are practicing appropriate culture surveillance. Certainly, nosocomial risks for acquisition of NTM are well described, particularly in the setting of surgery or other invasive procedures, and this may extend to patient-to-patient transmission in some settings, as discussed above. Finally, there is growing evidence that many features of the modern environment may favor NTM survival and a higher potential burden of exposure. These factors may include high density urban populations, plumbing and water supply systems, the use of showers, and lower temperatures of hot water heaters in homes and hospitals. Climate change has also been implicated in the apparent increase in NTM, as higher temperatures are linked to increased evaporation of water, and the increase in natural disasters, which have been correlated with local outbreaks of NTM. While risks related to nosocomial acquisition can be addressed, most of the other factors identified as relating to increased prevalence of NTM in the modern environment, and in vulnerable patient populations, are expected to increase for the foreseeable future, and to result in a continued increase of infections by NTM.
Clinical Manifestations of Nontuberculous Mycobacteria Pulmonary Disease
Clinical and radiographic manifestations of NTM pulmonary disease are described in Table 30.2 . Children can present with any combination of clinical signs and symptoms, though most patients experience chronic cough and sputum production that do not improve with the antibiotic treatment that is used for more typical lung pathogens, or with the use of corticosteroids. Radiographic signs include presence of single or multiple pulmonary nodules, tree-in-bud opacities, large areas of consolidation, or bronchiectasis ( Fig. 30.1 ). Additionally, cavitation is an important finding representing more significant tissue destruction. Importantly, in patients with CF, there is significant overlap of both clinical and radiographic NTM manifestations with underlying pulmonary disease and chronic airway infection due to more common CF pathogens such as P. aeruginosa or S. aureus, as well as symptoms related to CF comorbidities, including CF-related diabetes and allergic bronchopulmonary aspergillosis (ABPA). In patients with CF, one should suspect NTM infection in those with constitutional or respiratory symptoms above baseline, unexplained increased decline in lung function, and progressive radiographic disease that are not responsive to typical CF therapies and antibiotics.
| Symptoms |
|
| Physical Exam |
|
| Imaging |
|
Diagnosis of Nontuberculous Mycobacteria Pulmonary Disease
Clinical Criteria
To make the diagnosis of NTM pulmonary disease in a child, a patient must meet both microbiologic and clinical criteria with appropriate exclusion of other diagnoses ( Box 30.1 ). Clinical and radiographic findings are described above. In patients with CF, it is essential to first treat underlying typical CF pathogens, maximize airway clearance, and adequately assess for and treat CF-related comorbidities to ensure the clinical syndrome is not a consequence of underlying CF alone, prior to diagnosing NTM pulmonary disease.
Clinical Criteria (Both Required):
- 1.
Pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution computed tomography scan that shows multifocal bronchiectasis with multiple small nodules.
- 2.
Appropriate exclusion of other diagnoses.
Microbiologic Criteria (One of the Following Required):
- 1.
Positive culture results from at least two separate expectorated sputum samples.
- 2.
Positive culture results from at least one bronchial wash or lavage.
- 3.
Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture positive for NTM.
AFB, Acid-fast bacilli; NTM, nontuberculous mycobacteria.
Cite: Catanzaro A, Daley C, Gordin F, et al/2007/Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases/175(4)/367-416
The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
Microbiologic Criteria
In contrast to M. tuberculosis, a single positive culture for NTM does not necessarily constitute a disease that requires treatment in patients both with and without CF. Individuals should have two or more positive sputum cultures for the same NTM species. An exception is that a positive culture from a single bronchial wash or lavage, or from transbronchial or other lung tissue biopsy, can be sufficient if NTM is highly suspected. Expert consultation should be obtained when NTM that are either infrequently encountered or that usually represent environmental contamination are recovered from culture. Patients who are suspected of having NTM lung disease, but who do not meet the diagnostic criteria, should be followed closely with increased surveillance of sputum acid-fast bacilli (AFB) smears and cultures until the diagnosis is firmly established or excluded. Importantly, making the diagnosis of NTM pulmonary disease does not necessarily require initiation of treatment. Due to the burden of treatment, risk of emergence of resistance with partial treatment, and potential treatment-related side effects, the risks and benefits of therapy for the individual patient must be considered and discussed prior to initiating therapy.
Extrapulmonary Nontuberculous Mycobacteria Disease
Extrapulmonary NTM disease in children most commonly occurs as lymphadenitis, typically in the cervical lymph nodes. Localized disease can happen in both immunocompetent and immunocompromised children and presents with fever, leukocytosis, and focal inflammation in a lymph node (cervical, intraabdominal, or mediastinal). The diagnosis is confirmed by AFB culture from an aspirate of the node. Less common are skin and soft-tissue infections due to NTM. A high level of suspicion when evaluating a nonhealing wound should prompt collection of AFB cultures. Disseminated NTM disease is uncommon in children, most typically occurring in an immunocompromised child. Disseminated MAC presents as fever, night sweats, abdominal pain, diarrhea, and weight loss, with the diagnosis confirmed through isolation of MAC from blood cultures. M. kansasii can present similarly with features that resemble M. tuberculosis. Notably, in extrapulmonary or disseminated disease, a single culture from a wound or blood is sufficient for diagnosis, and treatment should be initiated.
Management and Treatment
Treatment of NTM disease depends on the location and extent of disease, the species causing infection, and the drug resistance pattern of the organism. Precise speciation is critical for directing antimicrobial therapy as treatment outcomes vary depending on the causative species. Unfortunately, drug susceptibility test results do not correlate well with treatment outcomes, except for the macrolides and amikacin in pulmonary MAC, rifampin in pulmonary M. kansasii, and macrolides in MABSC.
The drugs most commonly used to treat NTM infections are listed in Table 30.3 . Multiple-drug therapy is used for all mycobacterial infections because of the propensity of these organisms to develop resistance. The treatment regimens for children with NTM disease are based on either limited clinical trials in adults or anecdotal evidence from small series or case reports. Standard treatment regimens typically include at least three drugs directed against the specific NTM pathogen, in the oral, inhaled, and/or intravenous forms. Empirical therapy is not advised in most settings as treatment varies significantly between species. However, in settings where tuberculosis is endemic or clinically suspected, empirical therapy for tuberculosis is recommended pending the results of diagnostic studies.
| Drug | Route of Administration | Pediatric Dosage | Adverse Reactions | Suggested Monitoring |
|---|---|---|---|---|
| Amikacin | Intravenous | Children: 15–30 mg/kg per dose once daily Adolescents:10–15 mg/kg per dose once daily (maximum dose 1500 mg daily) | Nephrotoxicity, auditory-vestibular toxicity | Creatinine Serum amikacin levels Hearing exams Clinical symptoms |
| Amikacin | Nebulized | 250–500 mg/dose once or twice daily | Auditory-vestibular toxicity | Hearing exams Clinical symptoms |
| Azithromycin | Oral | Children: 10–12 mg/kg per dose once daily (maximum dose 500 mg daily) Adolescents: 250–500 mg daily | Nausea, vomiting, diarrhea, auditory-vestibular toxicity, prolonged QT | Clinical symptoms Hearing exams EKG |
| Cefoxitin | Intravenous | 50 mg/kg per dose three times daily (maximum dose 12 g/day) | Fever, rash, cytopenias, eosinophilia | Complete blood count Clinical symptoms |
| Clarithromycin | Oral | 7.5 mg/kg per dose twice daily (maximum dose 500 mg daily) | Hepatitis, taste disturbance, inhibits metabolism of rifabutin | Clinical symptoms |
| Clofazimine | Oral | 1–2 mg/kg per dose once daily (maximum dose 100 mg daily) | Discoloration of skin, enteropathy, nausea, vomiting, prolonged QT | Liver function tests Clinical symptoms EKG |
| Ethambutol | Oral | 15 mg/kg per dose once daily | Optic neuritis, peripheral neuropathy | Liver function tests Eye exams Clinical symptoms |
| Imipenem | Intravenous | 15–20 mg/kg per dose twice daily (maximum 1000 mg per dose) | Nausea, vomiting, diarrhea, hepatitis, fever, rash | Liver function tests Complete blood count Clinical symptoms |
| Isoniazid | Oral | 5 mg/kg per dose once daily | Hepatitis, peripheral neuropathy | Liver function tests Clinical symptoms |
| Linezolid | Oral, intravenous | <12 years: 10 mg/kg per dose three times daily ≥12 years: 10 mg/kg per dose once or twice daily (maximum 600 mg per dose) | Cytopenias, peripheral neuropathy, optic neuritis | Complete blood count Eye exams Clinical symptoms |
| Minocycline | Oral | 2 mg/kg per dose once daily (maximum dose 200 mg) | Photosensitivity, nausea, vomiting, diarrhea, vertigo, tooth discoloration | Clinical symptoms |
| Moxifloxacin | Oral | 7.5–10 mg/kg per dose once daily (maximum dose 400 mg) | Nausea, vomiting, diarrhea, insomnia, agitation, anxiety, tendonitis, photosensitivity, prolonged QT | Clinical symptoms EKG |
| Rifabutin | Oral | 5–10 mg/kg per dose once daily (maximum dose 300 mg) | Cytopenias, orange discoloration of fluids, hepatitis, nausea, vomiting, diarrhea, hypersensitivity/flulike syndrome, increased metabolism of many drugs, uveitis | Liver function tests Complete blood count Clinical symptoms |
| Rifampin | Oral | 10–20 mg/kg per dose once daily (maximum dose 600 mg) | Cytopenias, orange discoloration of fluids, hepatitis, nausea, vomiting, diarrhea, fever, chills, increased metabolism of many drugs, renal failure | Liver function tests Complete blood count Clinical symptoms |
| Tigecycline | Intravenous | 8–11 years: 1.2 mg/kg per dose twice daily (maximum 50 mg per dose) ≥12 years: 50 mg once or twice daily | Nausea, vomiting, diarrhea, pancreatitis, hypoproteinemia, hepatitis | Liver function tests Complete blood count Clinical symptoms |
| Trimethoprim-sulfamethoxazole | Oral | 10–20 mg/kg per dose twice daily | Nausea, vomiting, diarrhea, cytopenias, fever, rash | Complete blood count Clinical symptoms |
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