Genetic relationships between behavioral traits and feed efficiency traits in lactating Holstein cows.

The evaluation of dairy cow feed efficiency using residual feed intake accounts for known energy sinks. However, behavioral traits may also contribute to the variation in feed efficiency. Our objective was to estimate the heritability and repeatability of behavioral traits and their genetic correlations with feed efficiency and its components in lactating Holstein cows. The first data set consisted of 36,075 daily rumination and lying time records collected using a SMARTBOW ear tag accelerometer (Zoetis, Parsippany, NJ) and 6,371 weekly feed efficiency records of 728 cows from the University of Wisconsin-Madison. The second data set consisted of 59,155 daily activity records, measured as number of steps, recorded by pedometers (AfiAct; S.A.E. Afikim, Kibbutz Afikim, Israel), and 8,626 weekly feed efficiency records of 635 cows from the University of Florida. Feed efficiency and its components included dry matter intake, change in body weight, metabolic body weight, secreted milk energy, and residual feed intake. The statistical models included the fixed effect of cohort, lactation number, and days in milk, and the random effects of animal and permanent environment. Heritability estimates for behavioral traits using daily records were 0.19 ± 0.06 for rumination and activity, and 0.37 ± 0.07 for lying time. Repeatability estimates for behavioral traits using daily data ranged from 0.56 ± 0.02 for activity to 0.62 ± 0.01 for lying time. Both heritability and repeatability estimates were larger when weekly records instead of daily records were used. Rumination and activity had positive genetic correlations with residual feed intake (0.40 ± 0.19 and 0.31 ± 0.22, respectively) while lying time had a negative genetic correlation with this residual feed intake (-0.27 ± 0.11). These results indicate that more efficient cows tend to spend more time lying and less time active. Additionally, less efficient cows tend to eat more and therefore also tend to ruminate longer. Overall, sensor-based behavioral traits are heritable and genetically correlated with feed efficiency and its components and, therefore, they could be used as indicators to identify feed efficient cows within the herd.

Geographic Barriers to Indexing: Examining Appalachia.

The objective of this study was to examine the accuracy of indexing for "Appalachian Region"[Mesh]. Researchers performed a search in PubMed for articles published in 2019 using "Appalachian Region"[Mesh] or "Appalachia" or "Appalachian" in the title or abstract. Only 17.88% of the articles retrieved by the search were about Appalachia according to the ARC definition. Most articles retrieved appeared because they were indexed with state terms that were included as part of the mesh term. Database indexing and searching transparency is of growing importance as indexers rely increasingly on automated systems to catalog information and publications.

In vitro activity of gepotidacin and comparator antimicrobials against isolates of nontuberculous mycobacteria (NTM).

Novel antimicrobials are needed to treat rising nontuberculous mycobacteria (NTM) infections. Using standard broth microdilution methods, 68 NTM isolates were tested against gepotidacin, a new, first-in-class, oral triazaacenaphthylene bacterial topoisomerase inhibitor. MICs varied (0.25 to >64 µg/mL) with the lowest being M. fortuitum complex (0.25-8 µg/mL), M. mucogenicum complex (1-2 µg/mL), M. kansasii (0.25-8 µg/mL), and M. marinum (4-16 µg/mL). Testing greater numbers of some species is suggested to better understand gepotidacin activity against NTM.

A cluster of three extrapulmonary Mycobacterium abscessus infections linked to well-maintained water-based heater-cooler devices.

BACKGROUND: Various water-based heater-cooler devices (HCDs) have been implicated in nontuberculous mycobacteria outbreaks. Ongoing rigorous surveillance for healthcare-associated M. abscessus (HA-Mab) put in place following a prior institutional outbreak of M. abscessus alerted investigators to a cluster of 3 extrapulmonary M. abscessus infections among patients who had undergone cardiothoracic surgery. METHODS: Investigators convened a multidisciplinary team and launched a comprehensive investigation to identify potential sources of M. abscessus in the healthcare setting. Adherence to tap water avoidance protocols during patient care and HCD cleaning, disinfection, and maintenance practices were reviewed. Relevant environmental samples were obtained. Patient and environmental M. abscessus isolates were compared using multilocus-sequence typing and pulsed-field gel electrophoresis. Smoke testing was performed to evaluate the potential for aerosol generation and dispersion during HCD use. The entire HCD fleet was replaced to mitigate continued transmission. RESULTS: Clinical presentations of case patients and epidemiologic data supported intraoperative acquisition. M. abscessus was isolated from HCDs used on patients and molecular comparison with patient isolates demonstrated clonality. Smoke testing simulated aerosolization of M. abscessus from HCDs during device operation. Because the HCD fleet was replaced, no additional extrapulmonary HA-Mab infections due to the unique clone identified in this cluster have been detected. CONCLUSIONS: Despite adhering to HCD cleaning and disinfection strategies beyond manufacturer instructions for use, HCDs became colonized with and ultimately transmitted M. abscessus to 3 patients. Design modifications to better contain aerosols or filter exhaust during device operation are needed to prevent NTM transmission events from water-based HCDs.

Open-Label Trial of Amikacin Liposome Inhalation Suspension in Mycobacterium abscessus Lung Disease.

BACKGROUND: Mycobacterium abscessus is the second most common nontuberculous mycobacterium respiratory pathogen and shows in vitro resistance to nearly all oral antimicrobials. M abscessus treatment success is low in the presence of macrolide resistance. RESEARCH QUESTION: Does treatment with amikacin liposome inhalation suspension (ALIS) improve culture conversion in patients with M abscessus pulmonary disease who are treatment naive or who have treatment-refractory disease? STUDY DESIGN AND METHODS: In an open-label protocol, patients were given ALIS (590 mg) added to background multidrug therapy for 12 months. The primary outcome was sputum culture conversion defined as three consecutive monthly sputum cultures showing negative results. The secondary end point included development of amikacin resistance. RESULTS: Of 33 patients (36 isolates) who started ALIS with a mean age of 64 years (range, 14-81 years), 24 patients (73%) were female, 10 patients (30%) had cystic fibrosis, and nine patients (27%) had cavitary disease. Three patients (9%) could not be evaluated for the microbiologic end point because of early withdrawal. All pretreatment isolates were amikacin susceptible and only six isolates (17%) were macrolide susceptible. Eleven patients (33%) were given parenteral antibiotics. Twelve patients (40%) received clofazimine with or without azithromycin as companion therapy. Fifteen patients (50%) with evaluable longitudinal microbiologic data demonstrated culture conversion, and 10 patients (67%) sustained conversion through month 12. Six of the 33 patients (18%) demonstrated mutational amikacin resistance. All were patients using clofazimine or clofazimine plus azithromycin as companion medication(s). Few serious adverse events occurred for ALIS users; however, reduction of dosing to three times weekly was common (52%). INTERPRETATION: In a cohort of patients primarily with macrolide-resistant M abscessus, one-half of the patients using ALIS showed sputum culture conversion to negative findings. The emergence of mutational amikacin resistance was not uncommon and occurred with the use of clofazimine monotherapy. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03038178; URL: www. CLINICALTRIALS: gov.

Emergence of Inducible Macrolide Resistance in Mycobacterium chelonae Due to Broad-Host-Range Plasmid and Chromosomal Variants of the Novel 23S rRNA Methylase Gene, erm(55).

Macrolides are a mainstay of therapy for infections due to nontuberculous mycobacteria (NTM). Among rapidly growing mycobacteria (RGM), inducible macrolide resistance is associated with four chromosomal 23S rRNA methylase (erm) genes. Beginning in 2018, we detected high-level inducible clarithromycin resistance (MICs of ≥16µg/mL) in clinical isolates of Mycobacterium chelonae, an RGM species not previously known to contain erm genes. Using whole-genome sequencing, we identified a novel plasmid-mediated erm gene. This gene, designated erm(55)P, exhibits <65% amino acid identity to previously described RGM erm genes. Two additional chromosomal erm(55) alleles, with sequence identities of 81% to 86% to erm(55)P, were also identified and designated erm(55)C and erm(55)T. The erm(55)T is part of a transposon. The erm(55)P allele variant is located on a putative 137-kb conjugative plasmid, pMchErm55. Evaluation of 133 consecutive isolates from 2020 to 2022 revealed 5 (3.8%) with erm(55). The erm(55)P gene was also identified in public data sets of two emerging pathogenic pigmented RGM species: Mycobacterium iranicum and Mycobacterium obuense, dating back to 2008. In both species, the gene appeared to be present on plasmids homologous to pMchErm55. Plasmid-mediated macrolide resistance, not described previously for any NTM species, appears to have spread to multiple RGM species. This has important implications for antimicrobial susceptibility guidelines and treatment of RGM infections. Further spread could present serious consequences for treatment of other macrolide-susceptible RGM. Additional studies are needed to determine the transmissibility of pMchErm55 and the distribution of erm(55) among other RGM species.

Evolution of Mycobacterium abscessus in the human lung: Cumulative mutations and genomic rearrangement of porin genes in patient isolates.

BACKGROUND: Mycobacterium abscessus subspecies massiliense (M. massiliense) is increasingly recognized as an emerging bacterial pathogen, particularly in cystic fibrosis (CF) patients and CF centres' respiratory outbreaks. We characterized genomic and phenotypic changes in 15 serial isolates from two CF patients (1S and 2B) with chronic pulmonary M. massiliense infection leading to death, as well as four isolates from a CF centre outbreak in which patient 2B was the index case. RESULTS: Comparative genomic analysis revealed the mutations affecting growth rate, metabolism, transport, lipids (loss of glycopeptidolipids), antibiotic susceptibility (macrolides and aminoglycosides resistance), and virulence factors. Mutations in 23S rRNA, mmpL4, porin locus and tetR genes occurred in isolates from both CF patients. Interestingly, we identified two different spontaneous mutation events at the mycobacterial porin locus: a fusion of two tandem porin paralogs in patient 1S and a partial deletion of the first porin paralog in patient 2B. These genomic changes correlated with reduced porin protein expression, diminished 14C-glucose uptake, slower bacterial growth rates, and enhanced TNF-α induction in mycobacteria-infected THP-1 human cells. Porin gene complementation of porin mutants partly restored 14C-glucose uptake, growth rate and TNF-α levels to those of intact porin strains. CONCLUSIONS: We hypothesize that specific mutations accumulated and maintained over time in M. massiliense, including mutations shared among transmissible strains, collectively lead to more virulent, host adapted lineages in CF patients and other susceptible hosts.

A scoping review of barriers and facilitators to the integration of substance use treatment services into US mainstream health care.

Background: Following the national implementation of the Affordable Care Act (ACA) in 2014, barriers still exist that limit the adoption of substance use treatment (SUT) services in mainstream health care (MHC) settings in the United States. This study provides an overview of current evidence on barriers and facilitators to integrating various SUT services into MHC. Methods: A systematic search was conducted with the following databases: "PubMed including MEDLINE", "CINAHL", "Web of Science", "ABI/Inform", and "PsycINFO." We identified barriers and/or facilitators affecting patients, providers, and programs/systems. Results: Of the 540 identified citations, 36 were included. Main barriers were identified for patients (socio-demographics, finances, confidentiality, legal impact, and disinterest), providers (limited training, lack of time, patient satisfaction concerns, legal implications, lack of access to resources or evidence-based information, and lack of legal/regulatory clarity), and programs/systems (lack of leadership support, lack of staff, limited financial resources, lack of referral networks, lack of space, and lack of state-level support). Also, we recognized key facilitators pertaining to patients (trust for providers, education, and shared decision making), providers (expert supervision, use of support team, training with programs like Extension for Community Health Outcomes (ECHO), and receptivity), and programs/systems (leadership support, collaboration with external agencies, and policies e.g., those expanding the addiction workforce, improving insurance access and treatment access). Conclusions: This study identified several factors influencing the integration of SUT services in MHC. Strategies for improving SUT integration in MHC should address barriers and leverage facilitators related to patients, providers, and programs/systems.

Epidemiology, management, and clinical outcomes of extrapulmonary Mycobacterium abscessus complex infections in heart transplant and ventricular assist device recipients.

Nontuberculous mycobacteria are emerging pathogens, yet data on the epidemiology and management of extrapulmonary nontuberculous mycobacteria infections in orthotopic heart transplantation (OHT) and ventricular assist device (VAD) recipients are scarce. We retrospectively reviewed records of OHT and VAD recipients who underwent cardiac surgery at our hospital and developed Mycobacterium abscessus complex (MABC) infection from 2013 to 2016 during a hospital outbreak of MABC linked to heater-cooler units. We analyzed patient characteristics, medical and surgical management, and long-term outcomes. Ten OHT patients and 7 patients with VAD developed extrapulmonary M. abscessus subspecies abscessus infection. The median time from presumed inoculation during cardiac surgery to the first positive culture was 106 days in OHT and 29 days in VAD recipients. The most common sites of positive cultures were blood (n = 12), sternum/mediastinum (n = 8), and the VAD driveline exit site (n = 7). The 14 patients diagnosed when alive received combination antimicrobial therapy for a median of 21 weeks, developed 28 antibiotic-related adverse events, and underwent 27 surgeries. Only 8 (47%) patients survived longer than 12 weeks after diagnosis, including 2 patients with VAD who experienced long-term survival after an explantation of infected VADs and OHT. Despite aggressive medical and surgical management, OHT and VAD patients with MABC infection experienced substantial morbidity and mortality.

Decreased Interleukin-1 Family Cytokine Production in Patients with Nontuberculous Mycobacterial Lung Disease.

Nontuberculous mycobacteria (NTM) cause pulmonary disease in individuals without obvious immunodeficiency. This study was initiated to gain insight into the immunological factors that predispose persons to NTM pulmonary disease (NTMPD). Blood was obtained from 15 pairs of NTMPD patients and their healthy household contacts. Peripheral blood mononuclear cells (PBMCs) were stimulated with the Mycobacterium avium complex (MAC). A total of 34 cytokines and chemokines were evaluated in plasma and PBMC culture supernatants using multiplex immunoassays, and gene expression in the PBMCs was determined using real-time PCR. PBMCs from NTMPD patients produced significantly less interleukin-1ß (IL-1ß), IL-18, IL-1α, and IL-10 than PBMCs from their healthy household contacts in response to MAC. Although plasma RANTES levels were high in NTMPD patients, they had no effect on IL-1ß production by macrophages infected with MAC. Toll-like receptor 2 (TLR2) and TWIK2 (a two-pore domain K+ channel) were impaired in response to MAC in PBMCs of NTMPD patients. A TLR2 inhibitor decreased all four cytokines, whereas a two-pore domain K+ channel inhibitor decreased the production of IL-1ß, IL-18, and IL-1α, but not IL-10, by MAC-stimulated PBMCs and monocytes. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. A reduced monocyte ratio might contribute to the attenuated production of IL-1 family cytokines by PBMCs of NTMPD patients in response to MAC stimulations. Collectively, our findings suggest that the attenuated IL-1 response may increase susceptibility to NTM pulmonary infection through multiple factors, including impaired expression of the TLR2 and TWIK2 and reduced monocyte ratio. IMPORTANCE Upon MAC stimulation, the production of IL-1 family cytokines and IL-10 by PBMCs of NTMPD patients was attenuated compared with that of healthy household contacts. Upon MAC stimulation, the expression of TLR2 and TWIK2 (one of the two-pore domain K+ channels) was attenuated in PBMCs of NTMPD patients compared with that of healthy household contacts. The production of IL-1 family cytokines by MAC-stimulated PBMCs and MAC-infected monocytes of healthy donors was reduced by a TLR2 inhibitor and two-pore domain K+ channel inhibitor. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. Collectively, our data suggest that defects in the expression of TLR2 and TWIK2 in human PBMCs or monocytes and reduced monocyte ratio are involved in the reduced production of IL-1 family cytokines, and it may increase susceptibility to NTM pulmonary infection.

In Vitro Susceptibility Testing of Eravacycline against Nontuberculous Mycobacteria.

Nontuberculous mycobacteria (NTM) infections are increasing worldwide. Mycobacterium avium complex (MAC) and the M. abscessus species are the most commonly cultured NTM and treatment options are limited, especially for the M. abscessus species. In this study, the in vitro activity of eravacycline, a new tetracycline derivative, was tested against 110 clinical isolates of NTM. MIC testing was performed as recommended by the Clinical and Laboratory Standards Institute against 60 isolates of rapidly growing mycobacteria (RGM), of which ~70% were tetracycline resistant. These included M. abscessus subsp. abscessus (8 isolates), M. abscessus subsp. massiliense (5), M. chelonae (10), M. immunogenum (3), M. fortuitum group (20) including 12 doxycycline-resistant isolates, and M. mucogenicum group (10) including three doxycycline-resistant isolates. Due to trailing, eravacycline MICs were read at 80% and 100% inhibition. Eravacycline was active against all RGM species, with MIC50 ranges of ≤0.015 to 0.5 and ≤0.015 to 0.12 µg/mL for 100% and 80% inhibition, respectively. For M. abscessus subsp. abscessus, MIC50 values were 0.12 and 0.03 µg/mL with 100% and 80% inhibition, respectively. MICs for tigecycline were generally within 1 to 2 dilutions of the 100%-inhibition eravacycline MIC values. Fifty isolates of slowly growing mycobacteria (SGM) species, including 16 isolates of MAC, were also tested. While there was no trailing observed in most SGM, the eravacycline MICs were higher (MIC range of >8 µg/mL), except for M. kansasii and M. marinum which had MIC50 values of 1 µg/mL. This study supports further evaluation of eravacycline, including clinical trials for the development of RGM treatment regimens, especially for M. abscessus.

Early IL-17A production helps establish Mycobacterium intracellulare infection in mice.

Nontuberculous mycobacteria (NTM) infection is common in patients with structural lung damage. To address how NTM infection is established and causes lung damage, we established an NTM mouse model by intranasal inoculation of clinical isolates of M. intracellulare. During the 39-week course of infection, the bacteria persistently grew in the lung and caused progressive granulomatous and fibrotic lung damage with mortality exceeding 50%. Lung neutrophils were significantly increased at 1 week postinfection, reduced at 2 weeks postinfection and increased again at 39 weeks postinfection. IL-17A was increased in the lungs at 1-2 weeks of infection and reduced at 3 weeks postinfection. Depletion of neutrophils during early (0-2 weeks) and late (32-34 weeks) infection had no effect on mortality or lung damage in chronically infected mice. However, neutralization of IL-17A during early infection significantly reduced bacterial burden, fibrotic lung damage, and mortality in chronically infected mice. Since it is known that IL-17A regulates matrix metalloproteinases (MMPs) and that MMPs contribute to the pathogenesis of pulmonary fibrosis, we determined the levels of MMPs in the lungs of M. intracellulare-infected mice. Interestingly, MMP-3 was significantly reduced by anti-IL-17A neutralizing antibody. Moreover, in vitro data showed that exogenous IL-17A exaggerated the production of MMP-3 by lung epithelial cells upon M. intracellulare infection. Collectively, our findings suggest that early IL-17A production precedes and promotes organized pulmonary M. intracellulare infection in mice, at least in part through MMP-3 production.

Genomic Analysis of a Hospital-Associated Outbreak of Mycobacterium abscessus: Implications on Transmission.

Whole-genome sequencing (WGS) has recently been used to investigate acquisition of Mycobacterium abscessus. Investigators have reached conflicting conclusions about the meaning of genetic distances for interpretation of person-to-person transmission. Existing genomic studies were limited by a lack of WGS from environmental M. abscessus isolates. In this study, we retrospectively analyzed the core and accessory genomes of 26 M. abscessus subsp. abscessus isolates collected over 7 years. Clinical isolates (n = 22) were obtained from a large hospital-associated outbreak of M. abscessus subsp. abscessus, the outbreak hospital before or after the outbreak, a neighboring hospital, and two outside laboratories. Environmental M. abscessus subsp. abscessus isolates (n = 4) were obtained from outbreak hospital water outlets. Phylogenomic analysis of study isolates revealed three clades with pairwise genetic distances ranging from 0 to 135 single-nucleotide polymorphisms (SNPs). Compared to a reference environmental outbreak isolate, all seven clinical outbreak isolates and the remaining three environmental isolates had highly similar core and accessory genomes, differing by up to 7 SNPs and a median of 1.6% accessory genes, respectively. Although genomic comparisons of 15 nonoutbreak clinical isolates revealed greater heterogeneity, five (33%) isolates had fewer than 20 SNPs compared to the reference environmental isolate, including two unrelated outside laboratory isolates with less than 4% accessory genome variation. Detailed genomic comparisons confirmed environmental acquisition of outbreak isolates of M. abscessus subsp. abscessus. SNP distances alone, however, did not clearly differentiate the mechanism of acquisition of outbreak versus nonoutbreak isolates. We conclude that successful investigation of M. abscessus subsp. abscessus clusters requires molecular and epidemiologic components, ideally complemented by environmental sampling.

Vestibular Rehabilitation for Peripheral Vestibular Hypofunction: An Updated Clinical Practice Guideline From the Academy of Neurologic Physical Therapy of the American Physical Therapy Association.

BACKGROUND: Uncompensated vestibular hypofunction can result in symptoms of dizziness, imbalance, and/or oscillopsia, gaze and gait instability, and impaired navigation and spatial orientation; thus, may negatively impact an individual's quality of life, ability to perform activities of daily living, drive, and work. It is estimated that one-third of adults in the United States have vestibular dysfunction and the incidence increases with age. There is strong evidence supporting vestibular physical therapy for reducing symptoms, improving gaze and postural stability, and improving function in individuals with vestibular hypofunction. The purpose of this revised clinical practice guideline is to improve quality of care and outcomes for individuals with acute, subacute, and chronic unilateral and bilateral vestibular hypofunction by providing evidence-based recommendations regarding appropriate exercises. METHODS: These guidelines are a revision of the 2016 guidelines and involved a systematic review of the literature published since 2015 through June 2020 across 6 databases. Article types included meta-analyses, systematic reviews, randomized controlled trials, cohort studies, case-control series, and case series for human subjects, published in English. Sixty-seven articles were identified as relevant to this clinical practice guideline and critically appraised for level of evidence. RESULTS: Based on strong evidence, clinicians should offer vestibular rehabilitation to adults with unilateral and bilateral vestibular hypofunction who present with impairments, activity limitations, and participation restrictions related to the vestibular deficit. Based on strong evidence and a preponderance of harm over benefit, clinicians should not include voluntary saccadic or smooth-pursuit eye movements in isolation (ie, without head movement) to promote gaze stability. Based on moderate to strong evidence, clinicians may offer specific exercise techniques to target identified activity limitations and participation restrictions, including virtual reality or augmented sensory feedback. Based on strong evidence and in consideration of patient preference, clinicians should offer supervised vestibular rehabilitation. Based on moderate to weak evidence, clinicians may prescribe weekly clinic visits plus a home exercise program of gaze stabilization exercises consisting of a minimum of: (1) 3 times per day for a total of at least 12 minutes daily for individuals with acute/subacute unilateral vestibular hypofunction; (2) 3 to 5 times per day for a total of at least 20 minutes daily for 4 to 6 weeks for individuals with chronic unilateral vestibular hypofunction; (3) 3 to 5 times per day for a total of 20 to 40 minutes daily for approximately 5 to 7 weeks for individuals with bilateral vestibular hypofunction. Based on moderate evidence, clinicians may prescribe static and dynamic balance exercises for a minimum of 20 minutes daily for at least 4 to 6 weeks for individuals with chronic unilateral vestibular hypofunction and, based on expert opinion, for a minimum of 6 to 9 weeks for individuals with bilateral vestibular hypofunction. Based on moderate evidence, clinicians may use achievement of primary goals, resolution of symptoms, normalized balance and vestibular function, or plateau in progress as reasons for stopping therapy. Based on moderate to strong evidence, clinicians may evaluate factors, including time from onset of symptoms, comorbidities, cognitive function, and use of medication that could modify rehabilitation outcomes. DISCUSSION: Recent evidence supports the original recommendations from the 2016 guidelines. There is strong evidence that vestibular physical therapy provides a clear and substantial benefit to individuals with unilateral and bilateral vestibular hypofunction. LIMITATIONS: The focus of the guideline was on peripheral vestibular hypofunction; thus, the recommendations of the guideline may not apply to individuals with central vestibular disorders. One criterion for study inclusion was that vestibular hypofunction was determined based on objective vestibular function tests. This guideline may not apply to individuals who report symptoms of dizziness, imbalance, and/or oscillopsia without a diagnosis of vestibular hypofunction. DISCLAIMER: These recommendations are intended as a guide to optimize rehabilitation outcomes for individuals undergoing vestibular physical therapy. The contents of this guideline were developed with support from the American Physical Therapy Association and the Academy of Neurologic Physical Therapy using a rigorous review process. The authors declared no conflict of interest and maintained editorial independence.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A369).

Genomic characterization of sporadic isolates of the dominant clone of Mycobacterium abscessus subspecies massiliense.

Recent studies have characterized a dominant clone (Clone 1) of Mycobacterium abscessus subspecies massiliense (M. massiliense) associated with high prevalence in cystic fibrosis (CF) patients, pulmonary outbreaks in the United States (US) and United Kingdom (UK), and a Brazilian epidemic of skin infections. The prevalence of Clone 1 in non-CF patients in the US and the relationship of sporadic US isolates to outbreak clones are not known. We surveyed a reference US Mycobacteria Laboratory and a US biorepository of CF-associated Mycobacteria isolates for Clone 1. We then compared genomic variation and antimicrobial resistance (AMR) mutations between sporadic non-CF, CF, and outbreak Clone 1 isolates. Among reference lab samples, 57/147 (39%) of patients with M. massiliense had Clone 1, including pulmonary and extrapulmonary infections, compared to 11/64 (17%) in the CF isolate biorepository. Core and pan genome analyses revealed that outbreak isolates had similar numbers of single nucleotide polymorphisms (SNPs) and accessory genes as sporadic US Clone 1 isolates. However, pulmonary outbreak isolates were more likely to have AMR mutations compared to sporadic isolates. Clone 1 isolates are present among non-CF and CF patients across the US, but additional studies will be needed to resolve potential routes of transmission and spread.

Comparison of In Vitro Susceptibility of Delafloxacin with Ciprofloxacin, Moxifloxacin, and Other Comparator Antimicrobials against Isolates of Nontuberculous Mycobacteria.

Nontuberculous mycobacterial (NTM) infections are increasing globally. Mycobacterium avium complex (MAC) and M. abscessus complex are the most commonly reported NTM. Oral treatment options are limited, especially for the M. abscessus complex. We tested delafloxacin, a new oral fluoroquinolone, against 131 isolates of NTM. Delafloxacin microdilution MICs were performed as recommended by the Clinical and Laboratory Standards Institute using cation adjusted Mueller-Hinton broth. The rapidly growing mycobacteria tested included M. abscessus subsp. abscessus (n = 16) and subsp. massiliense (n = 5), M. chelonae (n = 11), M. immunogenum (n = 5), M. fortuitum group (n = 13), M. porcinum (n = 7), M. senegalense (n = 7), M. mucogenicum group (n = 5), and M. goodii (n = 1). For the slowly growing NTM (SGM), M. avium (n = 16), M. intracellulare (n = 13), M. chimaera (n = 9), M. arupense (n = 5), M. simiae (n = 5), M. lentiflavum (n = 4), M. kansasii (n = 6), and M. marinum (n = 3) were tested. Delafloxacin was most active in vitro against the M. fortuitum and M. mucogenicum groups and M. kansasii, with MIC50 values of 0.12 to 0.5 µg/ml (MIC range, 0.001 to 4 µg/ml) compared to ≤0.06 to >4 µg/ml for ciprofloxacin and ≤0.06 to >8 µg/ml for moxifloxacin. For other SGM (including MAC), and the M. abscessus/M. chelonae, the delafloxacin MIC range was 8 to >16 µg/ml compared to ciprofloxacin and moxifloxacin of 0.5 to >4 µg/ml and ≤0.06 to 8 µg/ml, respectively. To our knowledge, this is the first MIC study with delafloxacin to use Clinical and Laboratory Standards Institute (CLSI) recommended methods. This study illustrates the potential utility of delafloxacin in treatment of infections due to some NTM.

Amikacin Liposome Inhalation Suspension for Refractory Mycobacterium avium Complex Lung Disease: Sustainability and Durability of Culture Conversion and Safety of Long-term Exposure.

BACKGROUND: In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001). RESEARCH QUESTION: In patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion? STUDY DESIGN AND METHODS: Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation. RESULTS: More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment. INTERPRETATION: In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov.