Management of Drug Toxicity in Mycobacterium avium Complex Pulmonary Disease: An Expert Panel Survey.

Adverse events are frequent in nontuberculous mycobacteria pulmonary disease treatment, but evidence to support their management is scarce. An expert panel survey on management of adverse events shows consistent opinions on management of hepatoxicity, ocular toxicity, ototoxicity, tinnitus, and gastrointestinal upset. These opinions can provide assistance in individual patient management decisions.

Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline.

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.

Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline.

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.

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

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.

Species Distribution and Macrolide Susceptibility of Mycobacterium fortuitum Complex Clinical Isolates.

The understanding of species distribution and inducible macrolide resistance in the Mycobacterium fortuitum complex (MFC) is limited. Of 90 mostly respiratory MFC clinical isolates, half were M. fortuitum, followed by M. peregrinum, M. porcinum, M. septicum, and M. conceptionense Most M. fortuitum, M. porcinum, and M. septicum isolates were inducibly resistant to clarithromycin, whereas two-thirds of the M. peregrinum isolates were clarithromycin susceptible. Clarithromycin-resistant M. fortuitum isolates exhibited common mutations of erm(39), potentially involved in clarithromycin resistance.

Serodiagnosis of Mycobacterium avium complex pulmonary disease in the USA.

Diagnosis of Mycobacterium avium complex pulmonary disease (MAC-PD) can be difficult. A previous study from Japan reported the usefulness of a serodiagnostic test for MAC-PD. The objective of this study was to evaluate the usefulness of the test in similar patients in the USA. 100 patients with known or suspected MAC-PD and 52 healthy volunteers were enrolled into the study at National Jewish Health, Denver, CO, USA. Serum glycopeptidolipid core immunoglobulin A antibody levels were measured with an enzyme immunoassay (EIA) kit and routine clinical evaluations were performed. The patients were divided into two groups based on clinical evaluation: 87 patients with MAC-PD that met American Thoracic Society criteria, and 13 who did not meet the criteria. The sensitivity and specificity (cut-off point 0.3 U·mL(-1)) of the serodiagnostic test for diagnosing MAC-PD were 70.1% and 93.9%, respectively. Among the 44 patients in the MAC-PD group with two or more positive sputum cultures within the previous 6 months, sensitivity was 81.8%. The EIA kit demonstrated good sensitivity and specificity for the identification of MAC-PD, particularly in patients with two or more positive cultures, and may be useful for rapid MAC-PD diagnosis.

Management of extrapulmonary nontuberculous mycobacterial infections.

Nontuberculous mycobacteria represent a vast group of environmental organisms that have the potential to cause disease in humans. Unlike tuberculosis, these organisms are not known to be transmitted from human to human. The most common clinical presentation is pulmonary disease. Approximately 10% of infections manifest as extrapulmonary disease. The portals of entry are the respiratory tract, gastrointestinal tract, or direct inoculation via trauma or an invasive procedure. Like tuberculosis, the nontuberculous mycobacteria have the potential to infect any organ system given the opportunity in an immunocompromised host. The spectrum of disease is extensive ranging from self-limited furunculosis to life-threatening disseminated infection. Common extrapulmonary manifestations include lymphadenitis, disseminated disease, skin, soft tissue, and bone infection. Less common manifestations include keratitis, catheter-related bloodstream infections, septic arthritis, central nervous system infection, and peritonitis. The incidence of extrapulmonary infections is unknown. Outbreaks have been reported due to inadequate disinfection of surgical equipment or contamination of injected solutions or medications. A high index of suspicion is required when patients present with subacute or chronic complaints of extrapulmonary infection. This review addresses the management of the common extrapulmonary nontuberculous infections.

Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus.

RATIONALE: Mycobacterium massiliense has been recognized as a separate species from Mycobacterium abscessus; however, little is known regarding the clinical impact of this differentiation. OBJECTIVES: To compare clinical features and treatment outcomes between patients with M. abscessus lung disease and those with M. massiliense lung disease. METHODS: We performed molecular identification of stored clinical isolates of M. abscessus complex and compared clinical characteristics and treatment outcomes between 64 patients with M. abscessus lung disease and 81 patients with M. massiliense lung disease. MEASUREMENTS AND MAIN RESULTS: The clinical and radiographic manifestations of disease caused by each species were similar. Standardized combination antibiotic therapy, including a clarithromycin-containing regimen in combination with an initial 4-week course of cefoxitin and amikacin, was given to 57 patients (24 with M. abscessus and 33 with M. massiliense) for more than 12 months. The proportion of patients with sputum conversion and maintenance of negative sputum cultures was higher in patients with M. massiliense infection (88%) than in those with M. abscessus infection (25%; P < 0.001). Inducible resistance to clarithromycin (minimal inhibitory concentrations ≥ 32 µg/ml) was found in all tested M. abscessus isolates (n = 19), but in none of the M. massiliense isolates (n = 28). CONCLUSIONS: Treatment response rates to combination antibiotic therapy including clarithromycin were much higher in patients with M. massiliense lung disease than in those with M. abscessus lung disease. The inducible resistance to clarithromycin could explain the lack of efficacy of clarithromycin-containing antibiotic therapy against M. abscessus lung disease.

Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease.

BACKGROUND: Mycobacterium abscessus can produce a chronic pulmonary infection for which little is known regarding optimal treatment and long-term outcomes. METHODS: We performed a retrospective observational study (2001-2008) including all patients who met American Thoracic Society criteria for M. abscessus pulmonary disease. Our aim was the evaluation of clinical and microbiologic outcomes in patients treated with combined antibiotic and surgical therapy, compared with antibiotic therapy alone. RESULTS: A total of 107 patients were included in the analysis. Patients were predominantly female (83%) and never-smokers (60%), with a mean age of 60 years. Fifty-nine (55%) of 107 patients had coexistent or previous history of Mycobacterium avium complex pulmonary infection. High-resolution chest CT showed bronchiectasis and nodular opacities in 98% of patients and cavities in 44%. Sixty-nine (46 medical, 23 surgical) patients were followed up for a mean duration of 34 months (standard deviation, 21.1 months, range, 2-82 months). Cough, sputum production, and fatigue remained stable, improved, or resolved in 80%, 69%, and 59% of patients, respectively. Twenty (29%) of 69 patients remained culture positive, 16 (23%) converted but experienced relapse, 33 (48%) converted to negative and did not experience relapse, and 17 (16%) died during the study period. There were significantly more surgical patients than medical patients whose culture converted and remained negative for at least 1 year (57% vs 28%; P = .022). CONCLUSIONS: Patients with M. abscessus pulmonary disease who are treated with multidrug antibiotic therapy and surgery or antibiotic therapy alone had similar clinical outcomes. However, surgical resection, in addition to antibiotics, may offer a prolonged microbiologic response.

Effects of gender and age at diagnosis on disease progression in long-term survivors of cystic fibrosis.

RATIONALE: Long-term survivors of cystic fibrosis (CF) (age > 40 yr) are a growing population comprising both patients diagnosed with classic manifestations in childhood, and nonclassic phenotypes typically diagnosed as adults. Little is known concerning disease progression and outcomes in these cohorts. OBJECTIVES: Examine effects of age at diagnosis and gender on disease progression, setting of care, response to treatment, and mortality in long-term survivors of CF. METHODS: Retrospective analysis of the Colorado CF Database (1992-2008), CF Foundation Registry (1992-2007), and Multiple Cause of Death Index (1992-2005). MEASUREMENTS AND MAIN RESULTS: Patients with CF diagnosed in childhood and who survive to age 40 years have more severe CFTR genotypes and phenotypes compared with adult-diagnosed patients. However, past the age of 40 years the rate of FEV(1) decline and death from respiratory complications were not different between these cohorts. Compared with males, childhood-diagnosed females were less likely to reach age 40 years, experienced faster FEV(1) declines, and no survival advantage. Females comprised the majority of adult-diagnosed patients, and demonstrated equal FEV(1) decline and longer survival than males, despite a later age at diagnosis. Most adult-diagnosed patients were not followed at CF centers, and with increasing age a smaller percentage of CF deaths appeared in the Cystic Fibrosis Foundation Registry. However, newly diagnosed adults demonstrated sustained FEV(1) improvement in response to CF center care. CONCLUSIONS: For patients with CF older than 40 years, the adult diagnosis correlates with delayed but equally severe pulmonary disease. A gender-associated disadvantage remains for females diagnosed in childhood, but is not present for adult-diagnosed females.

Efficacy and safety of tigecycline for Mycobacterium abscessus disease.

PURPOSE: Mycobacterium abscessus disease is one of the most difficult mycobacterial infections to cure, as the bacterium is highly resistant to conventional antibiotics. The purpose of this study was to evaluate the efficacy and safety of tigecycline treatment of M. abscessus disease. PROCEDURE: We performed retrospective chart reviews of patients with M. abscessus disease receiving tigecycline-containing regimens at National Jewish Health from January 2009 to December 2017. MAIN FINDINGS: Among the 35 patients, pulmonary disease was the most common presentation of M. abscessus disease (n = 29, 82.9%). Of those receiving tigecycline treatment, 17.4% (4/23) showed microbiological improvement (≥2 consecutive negative sputum cultures), while 86.2% (25/29) and 59.3% (16/27) showed symptomatic and radiological improvements, respectively. The rate of dose reduction or discontinuation of tigecycline owing to adverse drug reactions was 57.1% (20/35) at a median of 56.5 days (IQR 10.8-122.3). The most common adverse drug reactions were gastrointestinal side effects, including nausea, vomiting, and diarrhea. CONCLUSIONS: Tigecycline-containing regimens for M. abscessus disease have a high rate of symptomatic and radiological improvement. However, considering the poor microbiological response and the common adverse effects, selection of patients for tigecycline treatment and monitoring for adverse drug reactions should be performed carefully.

Alpha-1-Antitrypsin Enhances Primary Human Macrophage Immunity Against Non-tuberculous Mycobacteria.

Rationale: The association between non-tuberculous mycobacterial lung disease and alpha-1-antitrypsin (AAT) deficiency is likely due, in part, to underlying emphysema or bronchiectasis. But there is increasing evidence that AAT itself enhances host immunity against microbial pathogens and thus deficiency could compromise host protection. Objectives: The goal of this project is to determine if AAT could augment macrophage activity against non-tuberculous mycobacteria. Methods: We compared the ability of monocyte-derived macrophages cultured in autologous plasma that were obtained immediately before and soon after AAT infusion-given to individuals with AAT deficiency-to control an ex vivo Mycobacterium intracellulare infection. Measurements and Main Results: We found that compared to pre-AAT infused monocyte-derived macrophages plus plasma, macrophages, and contemporaneous plasma obtained after a session of AAT infusion were significantly better able to control M. intracellulare infection; the reduced bacterial burden was linked with greater phagosome-lysosome fusion and increased autophagosome formation/maturation, the latter due to AAT inhibition of both M. intracellulare-induced nuclear factor-kappa B activation and A20 expression. While there was a modest increase in apoptosis in the M. intracellulare-infected post-AAT infused macrophages and plasma, inhibiting caspase-3 in THP-1 cells, monocyte-derived macrophages, and alveolar macrophages unexpectedly reduced the M. intracellulare burden, indicating that apoptosis impairs macrophage control of M. intracellulare and that the host protective effects of AAT occurred despite inducing apoptosis. Conclusion: AAT augments macrophage control of M. intracellulare infection through enhancing phagosome-lysosome fusion and autophagy.

Anxiety related to genetic testing for alpha-1 antitrypsin deficiency and cystic fibrosis in COPD and/or bronchiectasis patients.

OBJECTIVE: To describe the psychological reaction to information about diagnostic genetic testing for alpha-1 antitrypsin deficiency (Alpha-1) and cystic fibrosis (CF) in chronic obstructive pulmonary disease and/or bronchiectasis patients who were tested but did not know the results. METHODS: One hundred and three adults took the State-Trait Anxiety Inventory before and after a standardized educational intervention and responded to a questionnaire. RESULTS: Information about the limitations, risks and benefits of Alpha-1 and CF testing did not raise mean anxiety levels. Mean anxiety was slightly lower after the educational intervention than at baseline (mean pretest score 35.0, posttest score 33.7; p < 0.05). Participants whose physician preinformed them of genetic testing had slightly higher mean anxiety than other participants, both before and after the intervention, but scores were comparable to those in a normative sample of general medical and surgical patients. CONCLUSIONS: Disclosure of information regarding Alpha-1 and CF testing appears to be potentially acceptable to patients and unlikely to prevent clinicians from conducting useful diagnostic procedures. This study is a step in alleviating concerns about raising issues related to genetic testing for Alpha-1 and CF in chronic obstructive pulmonary disease patients during the informed consent process.

Extensively drug-resistant tuberculosis: are we learning from history or repeating it?

Tuberculosis (TB) is an enormous global public health problem. Cases of extensively drug-resistant TB (XDR-TB) are being reported in increasing numbers across the globe. A large outbreak of XDR-TB associated with rapid and nearly universal mortality has been reported among patients with human immunodeficiency virus infection or acquired immunodeficiency disease in South Africa who have been receiving standard TB therapy and antiretrovirals. Epidemiologic features of this outbreak make it highly suspicious for health care-associated transmission. We urge the Infectious Diseases Society of America and its members to increase involvement in ongoing international TB prevention and treatment efforts and to develop a registry of experts in infection control and laboratory and disease management. We urge advocacy for increased funding for domestic and global TB control programs, including expanded access to sputum culture and drug susceptibility testing, as well as funding for TB clinical trials and research capacity. We believe that substandard TB diagnostic tests are not acceptable for TB control in resource-poor countries. We urge the development of shorter, less toxic TB treatment and prevention regimens. Funding of TB control and research should be reassessed to prevent budget cuts at a time when the disease is killing as many as 2 million people a year.

Infections due to rapidly growing mycobacteria.

Rapidly growing mycobacteria, generally of low virulence, are capable of causing a wide spectrum of infections. Increasing reports in the literature, referral center experiences, and data from the Infectious Disease Society of America Emerging Infectious Disease Network suggest that greater numbers of infections are occurring. Epidemiological study is imperative in understanding the true incidence of these infections and preventing disease in vulnerable hosts. Especially problematic is pulmonary infection due to Mycobacterium abscessus, which is difficult to cure. New agents with enhanced activity against this group and other nontuberculous mycobacteria are needed. Here, we focus on the members of the rapidly growing mycobacteria because of their emerging importance in both sporadic infections and outbreak settings.

Proton Magnetic Resonance Imaging for Initial Assessment of Isolated Mycobacterium avium Complex Pneumonia.

RATIONALE: Computed tomographic (CT) radiography is the reference standard for imaging Mycobacterium avium complex (MAC) lung infection. Magnetic resonance imaging (MRI) has been shown to be comparable to CT for characterizing other pulmonary inflammatory conditions, but has not been rigorously tested for imaging MAC pneumonia. OBJECTIVES: To determine the feasibility of pulmonary MRI for imaging MAC pneumonia and to assess the degree of agreement between MRI and CT for assessing the anatomic features and lobar extent of MAC lung infections. METHODS: Twenty-five subjects with culture-confirmed MAC pneumonia and no identified coinfecting organisms were evaluated by thoracic MRI and then by chest CT imaging performed up to 1 week later. After deidentification, first the MRI and then the CT scans were scored 2 weeks apart by two chest radiologists working independently of one another. Discrepancies were resolved by a third chest radiologist. The scans were scored for bronchiectasis, consolidation or atelectasis, abscess or sacculation, nodules, and mucus plugging using a three-point lobar scale (absent, <50% of lobe, and >50% of lobe). Agreement analyses and ordinary least products regressions were performed. MEASUREMENTS AND MAIN RESULTS: A fixed bias was found between total CT and MRI scores, with CT scoring higher on average (median difference: 4 on a scale of 48; interquartile range: 3, 6). Fixed biases were found for bronchiectasis and consolidation or atelectasis subscale scores. Both fixed and proportional biases were found between CT and MRI mucus plugging scores. No bias was found between CT and MRI nodule scores. There was nearly perfect lobar percent agreement for more conspicuous findings such as consolidation or atelectasis and abscess or sacculation. CONCLUSIONS: In this exploratory study of 25 adult patients with culture-proven MAC lung infection, we found moderate agreement between MRI and CT for assessing the anatomic features and lobar extent of disease. Given the feasibility of chest MRI for this condition, future work is warranted to assess the clinical impact of MRI compared with CT in assessing progression of untreated MAC infection and response to treatment over time.

Nontuberculous mycobacterial infection: CT scan findings, genotype, and treatment responsiveness.

STUDY OBJECTIVE: The purpose of this study was to compare the imaging findings of nontuberculous mycobacterial (NTM) infection in patients with normal and abnormal cystic fibrosis (CF) genotypes, and normal and abnormal alpha1-antitrypsin (AAT) phenotypes. DESIGN: A retrospective review of medical records and chest CT scans from 85 patients with microbiologically proven NTM infection was performed. All patients had undergone genotype analysis for CF mutations, and phenotypic evaluation for AAT status. Patients with homozygous CF or AAT were not included. Two independent observers assessed the patterns and distribution of disease, according to a standardized score sheet. In 52 patients, follow-up CT scans were obtained 1 to 46 months (mean duration, 8 months) following the initial CT scan. The CT scan findings on the follow-up scan were visually compared with those on the initial CT scan for progression or regression of abnormalities. Statistical analysis was performed to evaluate the relationship between the dominant CT scan pattern and CF/AAT status, and between CT scan pattern and radiologic change on follow-up. RESULTS: Fifteen patients (18%) were found to carry a single CF mutation, and an abnormal AAT phenotype was seen in 13 patients (15%). Three patients (3%) were found to have both a heterozygous CF mutation and a heterozygous AAT phenotype. On the initial CT scans, bronchiectasis and nodules were the most frequent findings of NTM infection in all three groups (p > 0.05). The prevalence of nodules was slightly lower in the CF group, and the prevalence of linear scarring was greater in the AAT group than in the normal group (p < 0.05). Among the 52 patients who had a follow-up CT scan, 8 (15%) had a CF mutation and 6 (12%) had an abnormal AAT phenotype. The extent and pattern of abnormality seen on the initial CT scan did not predict change on follow-up evaluation. After treatment, 40 patients (56%) with a normal CF genotype had decrease in disease extent, compared with 4 patients (25%) with a CF mutation (p < 0.05). Bronchiectasis was improved in approximately 35% of those with normal genotype, but in none of those with a CF mutation. CONCLUSION: In patients with NTM infection, the CT scan findings show only minor differences according to phenotype and genotype. Initial CT scan findings do not predict change on follow-up CT scan evaluation. However, on follow-up CT scan, patients with CF mutations are less likely to improve, while those with AAT phenotype appear to have a radiographic outcome similar to those with normal phenotype.

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

Aminoglycoside use is limited by ototoxicity and nephrotoxicity. This study compared the incidences of toxicities associated with 2 recommended dosing regimens. Eighty-seven patients with tuberculosis or nontuberculous mycobacterial infections were prospectively randomized by drug to receive 15 mg/kg per day or 25 mg/kg 3 times per week of intravenous streptomycin, kanamycin, or amikacin. Doses were adjusted to achieve target serum concentrations. The size of the dosage and the frequency of administration were not associated with the incidences of ototoxicity (hearing loss determined by audiogram), vestibular toxicity (determined by the findings of a physical examination), or nephrotoxicity (determined by elevated serum creatinine levels). Risk of ototoxicity (found in 32 [37%] of the patients) was associated with older age and with a larger cumulative dose received. Vestibular toxicity (found in 8 [9%] of the patients) usually resolved, and nephrotoxicity (found in 13 [15%] of the patients) was mild and reversible in all cases. Subjective changes in hearing or balance did not correlate with objective findings. Streptomycin, kanamycin, and amikacin can be administered either daily or 3 times weekly without affecting the likelihood of toxicity.