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Biofilm Dec 2023Structural or mucus hypersecretory pulmonary diseases such as cystic fibrosis (CF), wherein viscous mucus accumulates and clearance functions are impaired, predispose...
OBJECTIVES
Structural or mucus hypersecretory pulmonary diseases such as cystic fibrosis (CF), wherein viscous mucus accumulates and clearance functions are impaired, predispose people to lung infection by inhaled bacteria that form biofilm aggregates. Nontuberculous mycobacteria (NTM), primarily and are the growing cause of these lung infections and are extremely challenging to treat due to antibiotic recalcitrance. Better therapeutic approaches are urgently needed. We developed a humanized monoclonal antibody (HuTipMab) directed against a biofilm structural linchpin, the bacterial DNABII proteins, that rapidly disrupts biofilms and generates highly vulnerable newly released bacteria (NRel).
METHODS
HuTipMab's ability to recognize HupB, NTM's DNABII homologue was determined by ELISA. Relative ability of HuTipMab to disrupt biofilms formed by lab-passaged and clinical isolates of NTM was assessed by CLSM. Relative sensitivity of NTM NRel to antibiotic killing compared to when grown planktonically was evaluated by plate count.
RESULTS
HuTipMab recognized HupB and significantly disrupted NTM biofilms in a time- and dose-dependent manner. Importantly, NTM NRel of lab-passaged and clinical isolates were now highly sensitive to killing by amikacin and azithromycin.
CONCLUSIONS
If successful, this combinatorial treatment strategy would empower existing antibiotics to more effectively kill NTM newly released from a biofilm by HuTipMab and thereby both improve clinical outcomes and perhaps decrease length of antibiotic treatment for people that are NTM culture-positive.
PubMed: 38078059
DOI: 10.1016/j.bioflm.2023.100166 -
Animals : An Open Access Journal From... Apr 2024While paratuberculosis control has been studied for over a century, knowledge gaps still exist regarding the uptake and efficacy of control programmes. This narrative... (Review)
Review
While paratuberculosis control has been studied for over a century, knowledge gaps still exist regarding the uptake and efficacy of control programmes. This narrative review aims to summarise studies on control programmes presented at the IDF ParaTB Fora in 2021 and 2022 and the International Colloquium on Paratuberculosis in 2022. Studies were grouped by topic as follows: successful control, field studies, education and extension, voluntary and compulsory control programmes, and surveillance. Various Map control programmes resulted in a decreasing animal and herd level Map prevalence. Long-term stakeholder commitment, stable funding, involvement of herd veterinarians and incentives for farmers to participate were shown to be pivotal for long-term success. Control measures focused on vertical and calf-to-calf transmission may improve Map control in infected herds. Easy-to-capture visualisation of surveillance test results to inform participants on the progress of Map control in their herds was developed. The probability of freedom from disease and estimated within-herd prevalence were identified as good candidates for categorisation of herds to support low-risk trade of cattle. Results of the surveillance schemes may inform genetic selection for resistance to Map infection. In conclusion, successful paratuberculosis control is feasible at both the herd and country level provided that crucial prerequisites are met.
PubMed: 38612366
DOI: 10.3390/ani14071127 -
Pathogens (Basel, Switzerland) Aug 2023(), a type of nontuberculous mycobacteria (NTM), poses a risk for pulmonary infections and disseminated infections in immunocompromised individuals. Conventional...
(), a type of nontuberculous mycobacteria (NTM), poses a risk for pulmonary infections and disseminated infections in immunocompromised individuals. Conventional treatment consists of a 12-month regimen of the first-line antibiotics rifampicin and azithromycin. However, the treatment duration and low antibiotic tolerability present challenges in the treatment of infection. Furthermore, the emergence of multidrug-resistant mycobacterium strains prompts a need for novel treatments against infection. This study aims to test the efficacy of a novel antimicrobial peptide, cyclic [R4W4], alongside the first-line antibiotics azithromycin and rifampicin in reducing survival. Colony-forming unit (CFU) counts were assessed after treating cultures with varying concentrations of cyclic [R4W4] alone or in conjunction with azithromycin or rifampicin 3 h and 4 days post-treatment. growth was significantly reduced 4 days after cyclic [R4W4] single treatment. Additionally, cyclic [R4W4]-azithromycin and cyclic [R4W4]-rifampicin combination treatments at specific concentrations significantly reduced survival 3 h and 4 days post-treatment compared with single antibiotic treatment alone. These findings demonstrate cyclic [R4W4] as a potent treatment method against and provide insight into novel therapeutic approaches against mycobacterium infections.
PubMed: 37624017
DOI: 10.3390/pathogens12081057 -
Microbiology Spectrum May 2024Tuberculostearic acid (TBSA) is a fatty acid unique to mycobacteria and some corynebacteria and has been studied due to its diagnostic value, biofuel properties, and...
Tuberculostearic acid (TBSA) is a fatty acid unique to mycobacteria and some corynebacteria and has been studied due to its diagnostic value, biofuel properties, and role in membrane dynamics. In this study, we demonstrate that TBSA production can be abrogated either by addition of pivalic acid to mycobacterial growth cultures or by a gene knockout encoding a flavin adenine dinucleotide (FAD)-binding oxidoreductase. subspecies () growth and TBSA production were inhibited in 0.5-mg/mL pivalic acid-supplemented cultures, but higher concentrations were needed to have a similar effect in other mycobacteria, including . While C-type strains, isolated from cattle and other ruminants, will produce TBSA in the absence of pivalic acid, the S-type strains, typically isolated from sheep, do not produce TBSA in any condition. A SAM-dependent methyltransferase encoded by and FAD-binding oxidoreductase are both required in the two-step biosynthesis of TBSA. However, S-type strains contain a single-nucleotide polymorphism in the gene, rendering the oxidoreductase enzyme vestigial. This results in the production of an intermediate, termed 10-methylene stearate, which is detected only in S-type strains. Fatty acid methyl ester analysis of a C-type knockout revealed the loss of TBSA production, but the intermediate was present, similar to the S-type strains. Collectively, these results demonstrate the subtle biochemical differences between two primary genetic lineages of and other mycobacteria as well as explain the resulting phenotype at the genetic level. These data also suggest that TBSA should not be used as a diagnostic marker for .IMPORTANCEBranched-chain fatty acids are a predominant cell wall component among species belonging to the genus. One of these is TBSA, which is a long-chain middle-branched fatty acid used as a diagnostic marker for . This fatty acid is also an excellent biolubricant. Control of its production is important for industrial purposes as well as understanding the biology of mycobacteria. In this study, we discovered that a carboxylic acid compound termed pivalic acid inhibits TBSA production in mycobacteria. Furthermore, strains from two separate genetic lineages (C-type and S-type) showed differential production of TBSA. Cattle-type strains of subspecies produce TBSA, while the sheep-type strains do not. This important phenotypic difference is attributed to a single-nucleotide deletion in sheep-type strains of . This work sheds further light on the mechanism used by mycobacteria to produce tuberculostearic acid.
Topics: Mycobacterium avium subsp. paratuberculosis; Animals; Paratuberculosis; Cattle; Bacterial Proteins; Sheep; Fatty Acids; Polymorphism, Single Nucleotide; Methyltransferases; Stearic Acids
PubMed: 38501867
DOI: 10.1128/spectrum.00508-24 -
Pathogens (Basel, Switzerland) Nov 2023As the number of patients with complex lung disease is significantly increasing worldwide, several studies have focused on the prognostic factors associated with the... (Review)
Review
PURPOSE
As the number of patients with complex lung disease is significantly increasing worldwide, several studies have focused on the prognostic factors associated with the disease. This systematic review investigated the factors associated with mortality among patients with complex lung disease.
METHODS
Two investigators independently identified studies that were designed to determine risk factors for mortality in patients with complex lung disease from PubMed, the Cochrane Register of Control Trial database, and EMBASE (accessed on 25 November 2022).
RESULTS
Of the 1133 titles and abstracts screened, 54 full texts were selected for review, and 15 studies were finally included in this systematic review. The most commonly studied risk factors were advanced age and low body mass index (11 studies for each), followed by male sex (8 studies), hypoalbuminemia (5 studies), and cavity (5 studies). In each study, these factors were mostly associated with increased all-cause mortality among patients with complex lung disease as confirmed via multivariate analysis.
CONCLUSIONS
Advanced age, male sex, low body mass index, hypoalbuminemia, and cavity are likely to be the common risk factors for all-cause mortality among patients with complex lung disease, suggesting that patients with these factors need to be carefully monitored.
PubMed: 38003795
DOI: 10.3390/pathogens12111331 -
Respiratory Investigation Mar 2024CONVERT, a randomized, active-controlled, global, Phase 3 trial demonstrated that patients with treatment-refractory Mycobacterium avium complex (MAC) pulmonary disease... (Randomized Controlled Trial)
Randomized Controlled Trial
Amikacin liposome inhalation suspension for Mycobacterium avium complex pulmonary disease: A subgroup analysis of Japanese patients in the randomized, phase 3, CONVERT study.
BACKGROUND
CONVERT, a randomized, active-controlled, global, Phase 3 trial demonstrated that patients with treatment-refractory Mycobacterium avium complex (MAC) pulmonary disease were more likely to achieve culture conversion with amikacin liposome inhalation suspension (ALIS) plus guideline-based therapy (GBT) versus those continuing on GBT alone. This subgroup analysis reports the efficacy and safety of ALIS in Japanese patients enrolled in CONVERT.
METHODS
Japanese patients aged ≥20 years with treatment-refractory MAC pulmonary disease from Japanese sites were included. Patients were randomized to receive once-daily 590 mg ALIS + GBT or GBT alone; patients converting by Month 6 remained in the study to complete 12-month treatment followed by a 12-month off-treatment period. Nonconverters exited the study at Month 8. The primary endpoint was the proportion of patients achieving culture conversion by Month 6.
RESULTS
Of the 59 Japanese patients screened, 48 were randomized to receive ALIS + GBT (n = 34) or GBT alone (n = 14), and 41/48 (85.4 %) were women. The mean (standard deviation) age of patients was 64.5 (8.6) years, and 83.3 % of patients had bronchiectasis at baseline. By Month 6, sputum culture conversion was cumulatively achieved in 9/34 (26.5 %) patients receiving ALIS + GBT versus none receiving GBT alone. Treatment-emergent adverse events were reported in 94.1 % and 100.0 % of patients receiving ALIS + GBT and GBT alone, respectively. No deaths were reported.
CONCLUSIONS
The efficacy observed in the Japanese subpopulation was largely consistent with that in the overall CONVERT study population, with more patients achieving culture conversion with ALIS + GBT versus GBT alone. Safety profiles were similar between the overall population and the Japanese subpopulation.
CLINICAL TRIAL REGISTRATION
NCT02344004.
Topics: Female; Humans; Male; Amikacin; Anti-Bacterial Agents; Japan; Liposomes; Lung Diseases; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Middle Aged; Aged
PubMed: 38277865
DOI: 10.1016/j.resinv.2023.12.012 -
Journal of Thoracic Disease May 2024() is a species of nontuberculous mycobacteria (NTM) that rarely causes infection. It has previously been labeled the most common NTM contaminant. Bronchiectasis is a...
() is a species of nontuberculous mycobacteria (NTM) that rarely causes infection. It has previously been labeled the most common NTM contaminant. Bronchiectasis is a disease characterized by abnormal airway dilation leading to chronic cough, sputum production and pulmonary infections. Patients with bronchiectasis are at higher risk of NTM-lung disease with more pathogenic NTM species including complex (MAC) and (). The relationship between bronchiectasis and less-pathogenic NTM species such as is less well understood. We performed a retrospective study on patients who had isolated from respiratory specimens at UConn Health between May 2, 2010 and October 18, 2022. was isolated 74 times from 56 patients. It was isolated 35 (47.3%) times from 31 patients with bronchiectasis and 39 (52.7%) times from 26 patients without bronchiectasis. Data was available on all mycobacterial cultures sent from May 2 2018 to October 18 2022. Mycobacterial cultures sent from patients with bronchiectasis were significantly more likely to grow than patients without bronchiectasis (4.3% . 1.6%, P=0.007). Furthermore, when considered at the patient level, there remained a significant increased rate of isolation among patients with bronchiectasis (7.1% . 2.2%, P<0.001). We then looked at past and future isolation of more pathogenic NTM species and found a non-statistically increased rate of isolation of more pathogenic NTM species including MAC and in patients with bronchiectasis (45.2% . 29%, P=0.09). Based on our results, isolation of should raise suspicion of chronic airway disease and defects in host immune response, such as those seen in bronchiectasis. Furthermore, isolation of may suggest increased risk of infection with more pathogenic NTM species such as MAC and .
PubMed: 38883635
DOI: 10.21037/jtd-23-1648 -
BMC Infectious Diseases Jul 2023Nontuberculous mycobacteria (NTM) are ubiquitous, environmental bacteria that can cause chronic lung disease. Persons with cystic fibrosis (pwCF) are at high risk for...
BACKGROUND
Nontuberculous mycobacteria (NTM) are ubiquitous, environmental bacteria that can cause chronic lung disease. Persons with cystic fibrosis (pwCF) are at high risk for NTM. Approximately 1 in 5 pwCF in the United States (U.S.) is affected by pathogenic NTM species, and incidence rates of NTM have been increasing among pwCF as well as in the general population. Prevalence of NTM pulmonary infections (PI) varies widely across the United States because of geographic variation in environmental exposures. This study will present updated region-level incidence of NTM infections in the cystic fibrosis (CF) population in the U.S.
METHODS
We used the Cystic Fibrosis Foundation Patient Registry (CFFPR) data for the period 2010 through 2019. Our study population comprised persons with CF ≥ 12 years of age who had been tested for NTM PI. We included only registry participants with NTM culture results. We defined incident cases as persons with one positive mycobacterial culture preceded by ≥ two negative mycobacterial cultures. We defined non-cases as persons with ≥ two negative mycobacterial cultures. We estimated average annual NTM PI incidence by region. Using quasi-Poisson models, we calculated annual percent change in incidence by region.
RESULTS
We identified 3,771 incident NTM infections. Of these cases, 1,816 (48.2%) were Mycobacterium avium complex (MAC) infections and 960 (25.5%) were Mycobacterium abscessus infections. The average annual incidence of NTM PI among pwCF in the U.S. was 58.0 cases per 1,000 persons. The Northeast had the highest incidence of MAC (33.5/1,000 persons tested) and the South had the highest incidence of M. abscessus (20.3/1,000 persons tested). From 2010 to 2019, the annual incidence of total NTM PI increased significantly by 3.5% per year in the U.S.
CONCLUSIONS
NTM PI incidence is increasing among pwCF. Identifying high risk areas and increasing trends is important for allocating public health and clinical resources as well as evaluating interventions.
Topics: Humans; United States; Cystic Fibrosis; Incidence; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Mycobacterium avium Complex
PubMed: 37488500
DOI: 10.1186/s12879-023-08468-6 -
Frontiers in Microbiology 2023complex (MAC) bacteria are the most prominent etiological agents of lymphadenitis in pigs. subspecies (MAH) is a member of MAC and has been reported in many parts of...
INTRODUCTION
complex (MAC) bacteria are the most prominent etiological agents of lymphadenitis in pigs. subspecies (MAH) is a member of MAC and has been reported in many parts of the world to be the most prevalent non-tuberculous mycobacteria (NTM) to cause mycobacteriosis in humans, mainly in children. Thus, the economic and zoonotic impact of MAC species are increasingly being recognized. In South Africa, little is known about the distribution of NTM and the molecular epidemiology of in pigs.
MATERIALS AND METHODS
In this study, lymph nodes including mandibular, mesenteric, submandibular, and retropharyngeal, with tuberculosis-like lesions were collected during routine meat inspection of slaughter pigs with no disease symptoms ( = 132), between 1991 and 2002. These pigs were slaughtered at 44 abattoirs distributed across seven of the nine South African provinces. Mycobacterial culture, polymerase chain reaction (PCR), and sequencing of the specific 577 bp 16S rRNA gene fragment were performed for species and subspecies identification.
RESULTS
The majority of the isolates (each per sample); 114 (86.4%) were identified as MAH, 8 (6%) as MAA subsp. , 4 (3%) were , 2 (1.5%) as , and 1 (0.75%) as The other isolates were identified as (0.75%), (0.75%), and a spp. (0.75%). Using an eight-marker MLVA typing tool, we deciphered at least nine MIRU VNTR INMV types of MAH and MAA.
DISCUSSION
Identification of known zoonotic mycobacteria, including MAH, MAA, , and , from slaughter pigs has a potential public health impact and also strengthens recognition of the potential economic impact of MAC. This study has also for the first time in South Africa, revealed MAC MIRU VNTR INMV genotypes which will aid in the future epidemiological investigation of MAC in South Africa.
PubMed: 38033580
DOI: 10.3389/fmicb.2023.1284906 -
Journal of Rural Medicine : JRM Jul 2023To identify the prevalence of risk factors for pulmonary non-tuberculous mycobacterial (NTM) disease in a Japanese population. We reviewed 337 consecutive Japanese...
To identify the prevalence of risk factors for pulmonary non-tuberculous mycobacterial (NTM) disease in a Japanese population. We reviewed 337 consecutive Japanese patients (210 women) with pulmonary NTM disease, including 225 patients with Mycobacterium avium complex (MAC) disease (95.8%) at our hospital during 2006-2017. We calculated the prevalence of risk factors reported in Western countries among mycobacterial species. Pulmonary MAC disease cases comprised 78.2% of pulmonary NTM patients in their 40s, increasing to 100% at age ≥80 years. Body mass index (BMI) was <18.5 in approximately 40% of patients, which was significantly higher than the prevalence of underweight in the Japanese population. The percentage of male heavy smokers (Brinkman index ≥600) was 58.2% of pulmonary NTM disease and was high for all mycobacterial species. In pulmonary MAC disease, systemic factors were observed in the order of malignant tumors (other than lung cancer), diabetes, rheumatoid arthritis, and tuberculosis. Local factors were observed in the order of bronchiectasis, chronic obstructive pulmonary disease, lung cancer, and bronchial asthma. The risk factors reported in Western countries were relatively highly prevalent among Japanese pulmonary NTM disease patients. This observation may help elucidate disease onset mechanisms.
PubMed: 37448701
DOI: 10.2185/jrm.2023-001