Nontuberculous Mycobacteria.

Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and 193 species of NTM have been discovered thus far. NTM species vary in virulence from benign environmental organisms to difficult-to-treat human pathogens. Pulmonary infections remain the most common manifestation of NTM disease in humans and bronchiectasis continues to be a major risk factor for NTM pulmonary disease (NTM PD). This article will provide a useful introduction and framework for clinicians involved in the management of bronchiectasis and NTM. It includes an overview of the epidemiology, pathogenesis, diagnosis, and management of NTM PD. We will address the challenges faced in the diagnosis of NTM PD and the importance of subspeciation in guiding treatment and follow-up, especially in Mycobacterium abscessus infections. The treatment of both Mycobacterium avium complex and M. abscessus, the two most common NTM species known to cause disease, will be discussed in detail. Elements of the recent ATS/ERS/ESCMID/IDSA NTM guidelines published in 2020 will also be reviewed.

Development of Drugs for Nontuberculous Mycobacterial Disease: Clinicians' Interpretation of a US Food and Drug Administration Workshop.

The US Food and Drug Administration convened a workshop to discuss clinical trial design challenges and considerations related to the treatment of nontuberculous mycobacterial pulmonary disease, to include topics such as clinical trial end points, duration, and populations. The clinicians participating in the meeting provide here their interpretation of the discussion, which included US Food and Drug Administration and industry representatives. The treatment of nontuberculous mycobacterial pulmonary disease typically includes multiple antibiotics for a prolonged period and can be difficult to tolerate; there is a great need for new treatment options. Most individuals have a microbiologic response to therapy, but data correlating decreasing bacillary load with patient-reported outcomes or measured functional improvement are lacking. Accordingly, trial designs for new therapeutic agents should incorporate both microbiologic and clinical outcome measures and select appropriate study candidates with capacity for measurable change of such outcome measures. The need for shorter study designs, early primary end points, and placebo control arms was highlighted during the workshop.

How to Leverage Collaborations Between the BME Community and Local Hospitals to Address Critical Personal Protective Equipment Shortages During the COVID-19 Pandemic.

The global COVID-19 pandemic disrupted supply chains across the world, resulting in a critical shortage of personal protective equipment (PPE) for frontline healthcare workers. To preserve PPE for healthcare providers treating COVID-19 positive patients and to reduce asymptomatic transmission, the Department of Bioengineering at the University of Colorado, Denver | Anschutz Medical Campus collaborated with National Jewish Health to design and test patterns for cloth face coverings. A public campaign to sew and donate the final pattern was launched and over 2500 face coverings have been donated as a result. Now that nearly three million cases of COVID-19 have been confirmed in the United States, many state and local governments are requiring cloth face coverings be worn in public. Here, we present the collaborative design and testing process, as well as the final pattern for non-patient facing hospital workers and community members alike.

Insights into the l,d-Transpeptidases and d,d-Carboxypeptidase of Mycobacterium abscessus: Ceftaroline, Imipenem, and Novel Diazabicyclooctane Inhibitors.

Mycobacterium abscessus is a highly drug-resistant nontuberculous mycobacterium (NTM). Efforts to discover new treatments for M. abscessus infections are accelerating, with a focus on cell wall synthesis proteins (M. abscessus l,d-transpeptidases 1 to 5 [LdtMab1 to LdtMab5] and d,d-carboxypeptidase) that are targeted by ß-lactam antibiotics. A challenge to this approach is the presence of chromosomally encoded ß-lactamase (BlaMab). Using a mechanism-based approach, we found that a novel ceftaroline-imipenem combination effectively lowered the MICs of M. abscessus isolates (MIC50 ≤ 0.25 µg/ml; MIC90 ≤ 0.5 µg/ml). Combining ceftaroline and imipenem with a ß-lactamase inhibitor, i.e., relebactam or avibactam, demonstrated only a modest effect on susceptibility compared to each of the ß-lactams alone. In steady-state kinetic assays, BlaMab exhibited a lower Ki app (0.30 ± 0.03 µM for avibactam and 136 ± 14 µM for relebactam) and a higher acylation rate for avibactam (k2/K = 3.4 × 105 ± 0.4 × 105 M-1 s-1 for avibactam and 6 × 102 ± 0.6 × 102 M-1 s-1 for relebactam). The kcat/Km was nearly 10-fold lower for ceftaroline fosamil (0.007 ± 0.001 µM-1 s-1) than for imipenem (0.056 ± 0.006 µM-1 s-1). Timed mass spectrometry captured complexes of avibactam and BlaMab, LdtMab1, LdtMab2, LdtMab4, and d,d-carboxypeptidase, whereas relebactam bound only BlaMab, LdtMab1, and LdtMab2 Interestingly, LdtMab1, LdtMab2, LdtMab4, LdtMab5, and d,d-carboxypeptidase bound only to imipenem when incubated with imipenem and ceftaroline fosamil. We next determined the binding constants of imipenem and ceftaroline fosamil for LdtMab1, LdtMab2, LdtMab4, and LdtMab5 and showed that imipenem bound >100-fold more avidly than ceftaroline fosamil to LdtMab1 and LdtMab2 (e.g., Ki app or Km of LdtMab1 = 0.01 ± 0.01 µM for imipenem versus 0.73 ± 0.08 µM for ceftaroline fosamil). Molecular modeling indicates that LdtMab2 readily accommodates imipenem, but the active site must widen to ≥8 Å for ceftaroline to enter. Our analysis demonstrates that ceftaroline and imipenem binding to multiple targets (l,d-transpeptidases and d,d-carboxypeptidase) and provides a mechanistic rationale for the effectiveness of this dual ß-lactam combination in M. abscessus infections.

Challenging scenarios in nontuberculous mycobacterial infection in cystic fibrosis.

This review summarizes the discussion of a session held during the 2018 North American Cystic Fibrosis (CF) Conference titled "Challenging Cases in Nontuberculous Mycobacterial (NTM) Management." In this session, a multidisciplinary panel of NTM experts discussed clinical challenges related to the management of NTM infection in people with CF in which decision-making falls outside of the Cystic Fibrosis Foundation/European Cystic Fibrosis Society NTM guidelines. Topics discussed included managing newly acquired NTM infection, selecting and monitoring treatment regimens, determining treatment endpoints, and caring for patients after NTM treatment.

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.

Nontuberculous Mycobacterial Musculoskeletal Infection Cases from a Tertiary Referral Center, Colorado, USA.

Nontuberculous mycobacteria represent an uncommon but important cause of infection of the musculoskeletal system. Such infections require aggressive medical and surgical treatment, and cases are often complicated by delayed diagnosis. We retrospectively reviewed all 14 nonspinal cases of nontuberculous mycobacterial musculoskeletal infections treated over 6 years by orthopedic surgeons at a university-affiliated tertiary referral center. All patients required multiple antimicrobial agents along with aggressive surgical treatment; 13 of 14 patients ultimately achieved cure. Four patients required amputation to control the infection. Half these patients were immunosuppressed by medications or other medical illness when they sought care at the referral center. Six cases involved joint prostheses; all ultimately required hardware removal and placement of an antimicrobial spacer for eradication of infection. Our findings highlight the importance of vigilance for nontuberculous mycobacterial musculoskeletal infection, particularly in patients who are immunosuppressed or have a history of musculoskeletal surgery.

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.

Nontuberculous Mycobacteria: Epidemiology and the Impact on Pulmonary and Cardiac Disease.

This article reviews the current epidemiology of nontuberculous mycobacterial pulmonary disease and the impact on thoracic disease. The prevalence of nontuberculous pulmonary disease in the United States is much higher than that of Mycobacterium tuberculosis. Estimates support an annual increase in incidence of 8% per year. Nontuberculous mycobacteria are distinguished by 2 group designations, slowly growing mycobacteria, such as Mycobacterium avium complex, and rapidly growing mycobacteria, which includes Mycobacterium abscessus. Most pulmonary infections in humans are caused by species belonging to M avium complex. This article also reviews risk factors for disease acquisition, including host and environmental risk factors.

Mycobacterium chimaera Infections Related to the Heater-Cooler Unit Outbreak: A Guide to Diagnosis and Management.

We are in the midst of a global outbreak of Mycobacterium chimaera infections related to a point source contamination of a widely used surgical device, the 3T heater-cooler unit. More than 250000 heart bypass procedures using heater-cooler devices are performed in the United States every year. It is estimated that 60% of these operations use the device associated with this outbreak. Most of the reported cases present with a disseminated infection that is striking in both the latency of presentation and the high mortality. The diagnosis can be elusive due to intermittent bacteremia and normal echocardiography. Therapy includes several months of antibiotics, and surgical intervention appears to be critical for successful outcomes. Here, we review diagnostic methods and treatment options to guide clinicians in the management of this complicated infection.

Management of Extrapulmonary Nontuberculous Mycobacterial Infections.

Extrapulmonary disease occurs in a minority of nontuberculous mycobacterial (NTM) infections. The pattern of disease tends to be multifocal in immunocompromised individuals and localized in the immunocompetent. There is increasing recognition of disseminated Mycobacterium chimaera infection, as a complication of cardiac surgery, and focal infections due to rapidly growing mycobacteria. Microbiologic diagnosis requires detection of NTM in blood or tissue samples by microscopy, culture, or molecular methods. Management of extrapulmonary NTM infection requires prolonged, targeted multiple-drug therapy and, in some cases, aggressive surgical intervention. The optimal treatment approach is often unknown. Despite combined medical and surgical therapy, outcomes may be poor. A high degree of clinical suspicion and early diagnosis are required to maximize chances of a positive outcome.

Treatment of Non-Tuberculous Mycobacterial Lung Disease.

Treatment of non-tuberculous mycobacterial lung disease (NTM-LD) is challenging for several reasons including the relative resistance of NTM to currently available drugs and the difficulty in tolerating prolonged treatment with multiple drugs. Yet-to-be-done, large, multicenter, prospective randomized studies to establish the best regimens will also be arduous because multiple NTM species are known to cause human lung disease, differences in virulence and response to treatment between different species and strains within a species will make randomization more difficult, the need to distinguish relapse from a new infection, and the difficulty in adhering to the prescribed treatment due to intolerance, toxicity, and/or drug-drug interactions, often necessitating modification of therapeutic regimens. Furthermore, the out-of-state resident status of many patients seen at the relatively few centers that care for large number of NTM-LD patients pose logistical issues in monitoring response to treatment. Thus, current treatment regimens for NTM-LD is largely based on small case series, retrospective analyses, and guidelines based on expert opinions. It has been nearly 10 years since the publication of a consensus guideline for the treatment of NTM-LD. This review is a summary of the available evidence on the treatment of the major NTM-LD until more definitive studies and guidelines become available.

The treatment of rapidly growing mycobacterial infections.

Rapidly growing mycobacteria (RGM) include a diverse group of species. We address the treatment of the most commonly isolated RGM-M abscessus complex, M fortuitum, and M chelonae. The M abscessus complex is composed of 3 closely related species: M abscessus senso stricto (hereafter M abscessus), M massiliense, and M bolletii. Most studies address treatment of M abscessus complex, which accounts for 80% of lung disease caused by RGM and is the second most common RGM to cause extrapulmonary disease (after M fortuitum). The M abscessus complex represent the most drug-resistant nontuberculous mycobacteria and are the most difficult to treat.

Analysis of a panel of rapidly growing mycobacteria for resistance to aldehyde-based disinfectants.

After several accounts across the globe of mycobacteria outbreaks associated with medical procedures and aldehyde disinfectants resistance, we undertook an analysis of mycobacteria isolated from patients seen in a hospital in the United States between 1994 and 2008 to determine prevalence of resistance to aldehyde-based disinfectants. Out of the 117 clinical isolates screened, 6 isolates belonging to the emerging Mycobacterium abscessus group were found to display significant levels of resistance to glutaraldehyde and ortho-phthalaldehyde.

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.

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.