Genomic and epidemiologic investigation of Mycobacterium abscessus isolates in a cystic fibrosis center to determine potential routes of transmission.

Background: Cystic Fibrosis (CF) Centers worldwide have reported healthcare-associated outbreaks of nontuberculous mycobacteria (NTM). We report a retrospective investigation of shared Mycobacterium abscessus strains among people with cystic fibrosis (pwCF) receiving care at Dell Children's/Ascension combined Pediatric and Adult CF Program (DCMC).

Methods: Whole genome sequencing (WGS) was used to identify genetically similar isolates among 167 NTM isolates from 57 pwCF.

Trial design of bacteriophage therapy for nontuberculous mycobacteria pulmonary disease in cystic fibrosis: The POSTSTAMP study.

Bacteriophages (phages) are viruses that selectively infect bacteria and have been utilized to treat Mycobacterium abscessus (Mab) with varying success. The POSTSTAMP study is an ongoing, multi-site phage therapy protocol for treatment-refractory pulmonary Mab disease in people with cystic fibrosis (pwCF). Participants (n = 10) are prospectively assessed while utilizing FDA investigational new drug (IND) approval for compassionate use.

Divergent host humoral innate immune response to the smooth-to-rough adaptation of in chronic infection.

is a nontuberculous mycobacterium emerging as a significant pathogen in individuals with chronic lung diseases, including cystic fibrosis and chronic obstructive pulmonary disease. Current therapeutics have poor efficacy. Strategies of bacterial control based on host defenses are appealing; however, antimycobacterial immunity remains poorly understood and is further complicated by the appearance of smooth and rough morphotypes, which elicit distinct host responses.

Prospective Analysis of urINe LAM to Eliminate NTM Sputum Screening (PAINLESS) study: Rationale and trial design for testing urine lipoarabinomannan as a marker of NTM lung infection in cystic fibrosis.

Background: Routine screening for nontuberculous mycobacterial (NTM) lung disease is dependent on sputum cultures. This is particularly challenging in the cystic fibrosis (CF) population due to reduced sputum production and low culture sensitivity. Biomarkers of infection that do not rely on sputum may lead to earlier diagnosis, but validation trials require a unique prospective design.

Modeling cystic fibrosis patient prognosis: Nomograms to predict lung transplantation and survival prior to highly effective modular therapy.

Background: The duration of time a person with cystic fibrosis (pwCF) spends on the lung transplant waitlist is dependent on waitlist and post-transplant survival probabilities and can extend up to 2 years. Understanding the characteristics involved with lung transplant and survival prognoses may help guide decision making by the patient, the referring CF Center and the transplant team.

Methods: This study seeks to identify clinical predictors of lung transplant and survival of individuals with CF using 29,847 subjects from 2003-2014 entered in the Cystic Fibrosis Foundation Patient Registry (CFFPR).

Prospective Analysis of urINe LAM to Eliminate NTM Sputum Screening (PAINLESS) study: Rationale and trial design for testing urine lipoarabinomannan as a marker of NTM lung infection in cystic fibrosis.

Background: Routine screening for nontuberculous mycobacterial (NTM) lung disease is dependent on sputum cultures. This is particularly challenging in the cystic fibrosis (CF) population due to reduced sputum production and low culture sensitivity. Biomarkers of infection that do not rely on sputum may lead to earlier diagnosis, but validation trials require a unique prospective design.

Prospective evaluation of nontuberculous mycobacteria disease in cystic fibrosis: The design of the PREDICT study.

Background: Nontuberculous mycobacteria (NTM) are an important cause of airway infections in people with cystic fibrosis (pwCF). Isolation of NTM from respiratory specimens of pwCF do not mandate treatment in the absence of clinical and radiologic features of NTM pulmonary disease (NTM-PD), as some pwCF clear the infection without treatment and others do not appear to progress to NTM-PD despite persistent infection. An evidence-based protocol to standardize diagnosis of NTM-PD is needed to systematically identify pwCF who may benefit from treatment.

Dectin-1-Independent Macrophage Phagocytosis of .

, a species of nontuberculous mycobacteria (NTM), is an opportunistic pathogen that is readily cleared by healthy lungs but can cause pulmonary infections in people with chronic airway diseases. Although knowledge pertaining to molecular mechanisms of host defense against NTM is increasing, macrophage receptors that recognize remain poorly defined. Dectin-1, a C-type lectin receptor identified as a fungal receptor, has been shown to be a pathogen recognition receptor (PRR) for both and NTM.

Divergent host innate immune response to the smooth-to-rough adaptation to chronic infection.

is a nontuberculous mycobacterium emerging as a significant pathogen for individuals with chronic lung disease, including cystic fibrosis and chronic obstructive pulmonary disease. Current therapeutics have poor efficacy. New strategies of bacterial control based on host defenses are appealing, but anti-mycobacterial immune mechanisms are poorly understood and are complicated by the appearance of smooth and rough morphotypes with distinct host responses.

Molecular Epidemiologic Investigation of Subspecies Lung Infections at an Adult Cystic Fibrosis Program.

Outbreaks of nontuberculous mycobacteria (NTM) among people with cystic fibrosis (pwCF) have been reported at CF centers with conflicting conclusions. The occurrence of NTM at the UVMC (University of Vermont Medical Center) adult CF program was investigated. Use the HALT NTM (Healthcare-associated Links in Transmission of NTM) toolkit to investigate the healthcare-associated transmission and/or acquisition of NTM among pwCF having genetically similar NTM isolates.

Deficient Complement Opsonization Impairs Mycobacterium avium Killing by Neutrophils in Cystic Fibrosis.

Nontuberculous mycobacteria (NTM), including Mycobacterium avium, are clinically important pathogens in cystic fibrosis (CF). The innate immune response to M. avium remains incompletely understood.

Culture independent markers of nontuberculous mycobacterial (NTM) lung infection and disease in the cystic fibrosis airway.

Nontuberculous mycobacteria (NTM) are opportunistic pathogens that affect a relatively small but significant portion of the people with cystic fibrosis (CF), and may cause increased morbidity and mortality in this population. Cultures from the airway are the only test currently in clinical use for detecting NTM. Culture techniques used in clinical laboratories are insensitive and poorly suited for population screening or to follow progression of disease or treatment response.

Nontuberculous Mycobacterial Infections in Cystic Fibrosis.

Nontuberculous mycobacteria (NTM) are important pathogens, with a longitudinal prevalence of up to 20% within the cystic fibrosis (CF) population. Diagnosis of NTM pulmonary disease in people with CF (pwCF) is challenging, as a majority have NTM infection that is transient or indolent, without evidence of clinical consequence. In addition, the radiographic and clinical manifestations of chronic coinfections with typical CF pathogens can overlap those of NTM, making diagnosis difficult.

Specificity of Immunoglobulin Response to Nontuberculous Mycobacteria Infection in People with Cystic Fibrosis.

Nontuberculous mycobacteria (NTM) infections are increasingly prevalent in chronic lung diseases, including cystic fibrosis (CF). Mycobacterium abscessus is of particular concern due to relatively greater virulence and intrinsic antimicrobial resistance. Airway culture identification, the standard method for detecting pulmonary infection, is hindered by low sensitivity, long culture times, and reliance on sputum production or lavage.

Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease.

Background: Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach.

Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection.

Two mycobacteriophages were administered intravenously to a male with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. The phages were engineered to enhance their capacity to lyse M. abscessus and were selected specifically as the most effective against the subject's bacterial isolate.

Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in .

A search for alternative treatments led to our interest in the two-component regulator DosRS, which, in , is required for the bacterium to establish a state of nonreplicating, drug-tolerant persistence in response to a variety of host stresses. We show here that the genetic disruption of impairs the adaptation of to hypoxia, resulting in decreased bacterial survival after oxygen depletion, reduced tolerance to a number of antibiotics in vitro and in vivo, and the inhibition of biofilm formation. We determined that three antimalarial drugs or drug candidates, artemisinin, OZ277, and OZ439, can target DosS-mediated hypoxic signaling in and recapitulate the phenotypic effects of genetically disrupting .

Investigating Nontuberculous Mycobacteria Transmission at the Colorado Adult Cystic Fibrosis Program.

Healthcare-associated transmission of nontuberculous mycobacteria (NTM) among people with cystic fibrosis (pwCF) has been investigated at CF centers worldwide, with conflicting conclusions. We investigated transmission at the Colorado Adult CF Program. To systematically investigate healthcare-associated transmission and/or acquisition of NTM to determine similarity among respiratory and environmental isolates, and to compare home residence watershed mapping among pwCF having genetically similar NTM isolates.

Healthcare-associated links in transmission of nontuberculous mycobacteria among people with cystic fibrosis (HALT NTM) study: Rationale and study design.

Background: Healthcare-associated transmission of nontuberculous mycobacteria (NTM) among people with cystic fibrosis (pwCF) has been reported and is of increasing concern. No standardized epidemiologic investigation tool has been published for healthcare-associated NTM outbreak investigations. This report describes the design of an ongoing observational study to standardize the approach to NTM outbreak investigation among pwCF.