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Background: Non-tuberculous mycobacteria (NTM) are common opportunistic pathogens, and the most common infection site is lung. NTM are found commonly in the environment. Many patients have NTM lung colonization (NTM-Col). NTM lung disease (NTM-LD) have no specific sympotms, though it is hard to differentiate NTM-LD and NTM-Col under this circumstance. The aim of this study is to explore the differences between NTM-LD and NTM-Col for future clinical diagnosis and treatment. Methods: We retrospectively enrolled patients who had a history of NTM isolated from respiratory specimens in Peking Union Medical College Hospital (PUMCH) from January 1st, 2013 to December 31st, 2022. Patients were classified into NTM-LD group and NTM-Col group. Demographic characteristics, clinical manifestations, laboratory tests and imaging findings of the two groups were compared. Comparative analysis was also performed in peripheral blood lymphocyte subsets among three groups. Results: A total of 127 NTM-LD patients and 37 NTM-Col patients were enrolled. Proportion of patients with bronchiectasis was higher in NTM-LD group than in NTM-Col group (P = 0.026). Predominant NTM isolates were Mycobacterium avium complex (MAC). NTM-LD group had a higher proportion of Mycobacterium intracellulare (P = 0.004). CD4+ T cells counts was lower in NTM-LD group (P = 0.041) than in NTM-Col group. Imaging finding of bronchiectasis (P = 0.006) was higher in NTM-LD group than in NTM-Col group. Imaging findings of bronchiectasis (OR = 6.282, P = 0.016), and CD4+ T cell count (OR = 0.997, P = 0.012) were independent associated factors for differential diagnosis between NTM-LD and NTM-Col. Conclusion: NTM isolates from both NTM-LD and NTM-Col patients were predominantly MAC, with a higher Mycobacterium intracellulare isolation rate in NTM-LD group. Imaging findings of bronchiectasis and lower peripheral blood CD4+ T cell count may be helpful to separate the diagnosis of NTM-LD from NTM-Col. [ABSTRACT FROM AUTHOR]

Background: Cutaneous infections caused by non-tuberculous mycobacteria (NTM) are extremely rare, particularly when they are localized to the facial area. This condition presents significant diagnostic challenges due to its unusual presentation and the need for precise microbiological identification. Case Presentation: A two-year-old male patient presented with a progressively enlarging reddish-brown mass on the left side of his face. Despite the absence of systemic symptoms, the lesion's growth warranted investigation due to its growth. Ultrasonography showed a hypoechoic mass in the dermis, indicating an underlying abscess. The subsequent aspiration resulted in pale yellow pus, which upon testing and culture, confirmed the presence of Mycobacterium avium complex infection, a species of NTM. This case exemplifies the synergy between imaging modalities and microbiological analysis, highlighting the crucial role of both in achieving favorable clinical outcomes in patients with suspected cutaneous NTM infections. Ultrasound can expedite diagnosis, improve treatment planning, and enhance patient care by enabling targeted interventions and monitoring response to therapy in these scenarios. However, it is the combination of pathogen-specific diagnostics that ensures accurate etiological attribution and appropriate antimicrobial stewardship. Conclusion: Although rare, facial cutaneous infections caused by NTM still deserve thorough investigation to determine the exact cause. Ultrasound is used to identify cutaneous lesions, measure their extent, and guide surgical procedures. The ultimate diagnosis is based on microbiological confirmation. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance poses a significant threat to humanity, and the development of new antibiotics is urgently needed. Our research has focused on thiopeptide antibiotics such as micrococcin P2 (MP2) and derivatives thereof as new anti-infective agents. Thiopeptides are sulfur-rich, structurally complex substances that exhibit potent activity against Gram-positive pathogens and Mycobacteria species, including clinically resistant strains. The clinical development of thiopeptides has been hampered by the lack of efficient synthetic platforms to conduct detailed structure-activity relationship studies of these natural products. The present contribution touches upon efficient synthetic routes to MP2 that laid the groundwork for clinical translation. The medicinal chemistry campaign on MP2 has been guided by computational molecular dynamic simulations and parallel investigations to improve drug-like properties, such as enhancing the aqueous solubility and optimizing antibacterial activity. Such endeavors have enabled identification of promising lead compounds, AJ-037 and AJ-206, against Mycobacterium avium complex (MAC). Extensive in vitro studies revealed that these compounds exert potent activity against MAC species, a subspecies of non-tuberculous mycobacteria (NTM) that proliferate inside macrophages. Two additional pre-clinical candidates have been identified: AJ-024, for the treatment of Clostridioides difficile infections, and AJ-147, for methicillin-resistant Staphylococcus aureus impetigo. Both compounds compare quite favorably with current first-line treatments. In particular, the ability of AJ-147 to downregulate pro-inflammatory cytokines adds a valuable dimension to its clinical use. In light of above, these new thiopeptide derivatives are well-poised for further clinical development. [ABSTRACT FROM AUTHOR]

The treatment of Mycobacterium avium infections is still long, complex, and often poorly tolerated, besides emergence of resistances. New active molecules that are more effective and better tolerated are deeply needed. Mefloquine and its enantiomers ((+) Erythro-mefloquine ((+)-EMQ) and (-)-Erythro-mefloquine ((-)-EMQ)) have shown efficacy in both in vitro and in vivo, in a mouse model of M. avium intraveinous infection. However, no study reports aerosol model of infection or combination with gold standard treatment. That was the aim of our study. In an aerosol model of M. avium infection in BALB/c mice, we used five treatment groups as followed: Clarithromycin-Ethambutol-Rifampicin (CLR-EMB-RIF, standard of care, n = 15), CLR-EMB-MFQ (n = 15), CLR-EMB-(+)-EMQ (n = 15), CLR-EMB-(-)-EMQ (n = 15) and an untreated group (n = 25). To evaluate drug efficacy, we sacrificed each month over 3 months, 5 mice from each group. Lung homogenates were diluted and plated for colony forming unit count (CFU) expressed in Log10. At each time point, we found a significant difference between the untreated group and each of the treatment groups (p<0.005). The (+)-EMQ-CLR-EMB group was the group with the lowest CFU count at each time point but never reached statistical significance. The results of each group 3 months after treatment are: (+)-EMQ-CLR-EMB (4.43 ± 0.26), RIF-CLR-EMB (4.83 ± 0.37), (-)-EMQ-CLR-EMB (4.82 ± 0.18), MFQ-CLR-EMB (4.70 ± 0.21). In conclusion, MFQ and its enantiomers appear to be as effective as rifampicin in combination therapy. Further studies are needed to evaluate the ability of these drugs to prevent selection of clarithromycin resistant strains and potential for lung sterilization. [ABSTRACT FROM AUTHOR]

Background: It remains unclear whether erythrocyte sedimentation rate (ESR) accurately predicts prognosis during treatment and how ESR changes. Objectives: We aimed to assess the predictive values of ESR as a prognostic factor of Mycobacterium avium complex pulmonary disease (MAC-PD) while on anti-mycobacterial treatment and its changes according to the treatment responses. Design: This study is a retrospective cohort study. Methods: This study included patients aged 18 years or older who initiated anti-mycobacterial treatment for MAC-PD at Seoul National University Hospital between January 1, 2009 and March 31, 2022. ESR should be measured at least twice, with a minimum interval of 3 months, during the initial 12 months from the commencement of antibiotic treatment. A mixed linear regression and Cox proportional-hazards models were used to analyze repeated ESR data and the association with patient survival. Results: Of a total of 825 patients who initiated antibiotic treatment for MAC-PD, 369 patients were included in the analysis. Increased levels of ESR during the treatment process were associated with a higher risk of mortality (adjusted hazard ratio 1.03; 95% confidence interval, 1.02–1.03) after adjusting age, sex, comorbidities, presence of cavity, acid-fast bacilli smear positivity, and culture conversion at 12 months. During the treatment, ESR at 12 months of treatment significantly decreased compared to baseline ESR in both the culture-converted and not-converted groups, which was categorized based on whether the culture conversion was achieved within the 12 months after treatment initiation. Conclusion: ESR predicted mortality during treatment and decreased over time, regardless of treatment outcomes. Our results underscore the importance of administering anti-mycobacterial treatment even in patients who did not achieve a microbiological cure. [ABSTRACT FROM AUTHOR]

Cavities are characteristic radiological features related to increased mycobacterial burden and poor prognosis in Mycobacterium avium complex pulmonary disease (MAC-PD). However, cavity changes following treatment and their clinical implications remain unknown. We aimed to elucidate whether cavity obliteration or reduction in cavity size or wall thickness correlates with microbiological cure. In total, 136 adult patients with cavitary MAC-PD treated for ≥ 6 months between January 1st, 2009, and December 31st, 2021, in a tertiary referral centre in South Korea were enrolled. The cavity with the largest diameter at treatment initiation was tracked for size and thickness changes. Following median treatment of 20.0 months, 74 (54.4%) patients achieved microbiological cure. Cavity obliteration, achieved in 58 (42.6%) patients at treatment completion, was independently associated with microbiological cure. In patients with persistent cavities, size reduction of ≥ 10% was significantly associated with microbiological cure, whereas thickness reduction was not. Five-year mortality rates in patients with cavity obliteration, persistent but reduced cavity, and persistent cavity without shrinkage were 95.6%, 72.1%, and 65.3%, respectively (P < 0.001). In conclusion, cavity obliteration or shrinkage at treatment completion is associated with microbiological cure and reduced mortality in MAC-PD, suggesting that cavity changes could serve as a proxy indicator for treatment response. [ABSTRACT FROM AUTHOR]

Background: Amikacin liposome inhalation suspension (ALIS) improved sputum culture conversion rate at 6 months for patients with refractory Mycobacterium avium complex pulmonary disease (MAC-PD) in an international phase 3 trial. Patient characteristics and chest high-resolution CT (HRCT) findings associated with ALIS effectiveness are poorly documented. Objective: We aimed to clarify ALIS effectiveness for refractory MAC-PD at 6 months, elucidating associated patient characteristics and chest CT findings. Methods: We reviewed medical records of 12 patients with refractory MAC-PD for whom ALIS treatment was initiated at Toho University Omori Medical Center from November 2021 through September 2022. All patients demonstrated treatment persistence for at least 3 months. They were divided into culture conversion and non-conversion groups using sputum culture conversion status after 6-month ALIS treatment initiation. Clinical and radiological characteristics were compared. Results: Seven of the 12 patients (58.3%) achieved sputum culture conversion within 6 months. The culture conversion group had shorter pre-ALIS initiation treatment duration [21 months (16–25) vs. 62 months (32–69); p = 0.045]; lower cavitary lesion incidence on HRCT (28.6% vs. 100%; p = 0.028); and fewer clarithromycin (CLA)-resistant strains [0/7 (0%) vs. 3/5 (60%); p = 0.045]. Chest HRCT findings improved in 4 of 7 (57.1%) and 1 of 5 (20%) patients in the culture conversion and non-conversion groups, respectively. Conclusion: ALIS facilitated sputum culture conversion within 6 months in 58.3% of patients with refractory MAC-PD. Sputum culture conversion was significantly more frequent for CLA-susceptible strains and patients with fewer cavitary lesions. Improved CT findings after ALIS did not always correspond to sputum culture conversion. [ABSTRACT FROM AUTHOR]

Nontuberculous mycobacteria (NTM) in drinking water are a significant public health concern. However, an incomplete understanding of the factors that influence the occurrence of NTM in drinking water limits our ability to characterize risk and prevent infection. This study sought to evaluate the influence of season and water treatment, distribution, and stagnation on NTM in drinking water. Samples were collected source-to-tap in a full-scale, chloraminated drinking water system approximately monthly from December 2019 to November 2020. NTM were characterized using culture-dependent (plate culture with matrix-assisted laser desorption ionization-timeof- flight mass spectrometry [MALDI-TOF MS] isolate analysis) and culture-independent methods (quantitative PCR and genome-resolved metagenomics). Sampling locations included source waters, three locations within the treatment plant, and five buildings receiving water from the distribution system. Building plumbing samples consisted of first draw, 5-min flush, and full flush cold-water samples. As the study took place during the COVID-19 pandemic, the influence of reduced water usage in three of the five buildings was also investigated. The highest NTM densities source-to-tap were found in the summer first draw building water samples (107 gene copies/L), which also had the lowest monochloramine concentrations. Flushing was found to be effective for reducing NTM and restoring disinfectant residuals, though flush times necessary to improve water quality varied by building. Clinically relevant NTM species, including Mycobacterium avium, were recovered via plate culture, with increased occurrence observed in buildings with higher water age. Four of five NTM metagenome-assembled genomes were identified to the species level and matched identified isolates. [ABSTRACT FROM AUTHOR]

Infections remain a major concern following bispecific antibody therapy but are not well described in pivotal trials. We present the first well-documented case of a classic but rare opportunistic infection, disseminated Mycobacterium avium complex, in a patient receiving bispecific antibody therapy. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. Mycobacterium avium ssp. paratuberculosis (MAP) is the bacterium responsible for causing Johne's disease (JD), which is endemic to dairy cattle and also implicated in the etiology of Crohn's disease. The difficulty in diagnosing asymptomatic cows for JD makes this disease hard to control. Johne's disease is considered a priority under the One Health approach to prevent the spread of the causative agent to humans. Environmental screening is a strategic approach aimed at identifying dairy herds with animals infected with MAP. It serves as the initial step toward implementing more intensive actions to control the disease. Quantitative PCR (qPCR) technology is widely used for diagnosis. Given that genome sequencing is now much more accessible than ever before, it is possible to target regions of the MAP genome that allow for the greatest diagnostic sensitivity and specificity. The aim of this study was to identify among the published qPCR assays targeting IS 900 the more cost-effective options to detect MAP and to validate them in the diagnostic context of JD. Mycobacterium avium ssp. paratuberculosis IS 900 is a prime target because it is a multicopy genetic element. A total of 136 publications have reported on the use of IS 900 qPCR assays over the past 3 decades. Among these records, 29 used the SYBR Green chemistry, and 107 used TaqMan technology. Aside from the 9 reports using commercial assays, 72 TaqMan reports cited previously published work, leaving us with 27 TaqMan qPCR designs. Upon closer examination, 5 TaqMan designs contained mismatches in primer or probe sequences. Additionally, others exhibited high similarity to environmental microorganisms or non-MAP mycobacteria. We assessed the performance of 6 IS 900 qPCR designs and their sensitivity when applied to clinical or environmental samples, which varied from 4 to 56 fold overall. Additionally, we provide recommendations for testing clinical and environmental samples, as certain strategies used previously should be avoided due to poor qPCR design (e.g., the presence of mismatches) or a lack of specificity. [ABSTRACT FROM AUTHOR]

The association between treatment outcome and the mortality of patients with Mycobacterium avium complex pulmonary disease (MAC-PD) with cavitary lesions is unclear. This article assessed the impact of culture conversion on mortality in patients with cavitary MAC-PD. Is the achievement of sputum culture conversion in patients with MAC-PD with cavitary lesions associated with the prognosis? From 2002 to 2020, a total of 351 patients with cavitary MAC-PD (105 with the fibrocavitary type and 246 with the cavitary nodular bronchiectatic type), who had been treated with a ≥ 6-month macrolide-containing regimen at a tertiary referral center in South Korea, were retrospectively enrolled in this study. All-cause mortality during the follow-up period was analyzed based on culture conversion at the time of treatment completion. The cohort had a median treatment duration of 14.7 months (interquartile range [IQR], 13.4-16.8 months). Of the 351 patients, 69.8% (245 of 351) achieved culture conversion, and 30.2% (106 of 351) did not. The median follow-up was 4.4 years (IQR, 2.3-8.3 years) in patients with culture conversion and 3.1 years (IQR, 2.1-4.8 years) in those without. For the patients with and without culture conversion, all-cause mortality was 5.3% vs 35.8% (P <.001), and the 5-year cumulative mortality was 20.0% vs 38.4%, respectively. Cox analysis found that a lack of culture conversion was significantly associated with higher mortality (adjusted hazard ratio, 5.73; 95% CI, 2.86-11.50). Moreover, the 2-year landmark analysis revealed a distinct impact of treatment outcome on mortality. The mortality rate of patients with cavitary MAC-PD who did not achieve culture conversion was significantly higher than that of those with culture conversion. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to gain insight from patients with refractory Mycobacterium avium complex lung disease (MAC-LD) into strategies used to manage adverse events (AEs) associated with amikacin liposome inhalation suspension (ALIS). Methods: We conducted semi-structured interviews with US patients with refractory MAC-LD prescribed ALIS in a real-world setting. Interview transcripts were analyzed and coded to identify patterns in participants' descriptions of their ALIS treatment experiences, including AEs and their disruptiveness, and AE mitigation strategies, including participants' ratings of strategies' effectiveness. Concept saturation was also assessed. Results: Twenty participants (mean age 48.7 years; 80% women; mean ALIS duration 5.45 months) were interviewed. At the time of the interview, 15 participants (75%) had received ALIS for > 1 month and 13 (65%) were currently receiving ALIS. Participants described 44 unique AE mitigation strategies, which can be categorized into three groups: prepare for treatment; prevent increased emergence of AEs; and persist on treatment by mitigating AEs. Common strategies (reported by ≥ 50% of participants) included use of educational materials from the patient support program, localized management of throat irritation, and symptom management to reduce fatigue. Evidence of concept saturation was observed: no new strategies were identified in the last five interviews, which suggests the sample was robust enough to identify all mitigation strategies likely to be used by the broader patient population. Conclusions: This real-world study identified a diverse set of potential AE mitigation strategies intended to help individual patients prepare for ALIS treatment, prevent the increased emergence of certain AEs, and mitigate the impact of AEs on treatment persistence. Developing a comprehensive accounting of the types of mitigation strategies in use among patients in real-world settings can inform future investigation of the effectiveness of such strategies, and support evidence-based recommendations for treatment management. [ABSTRACT FROM AUTHOR]

We retrospectively review consecutive patients with nontuberculous mycobacterium (NTM) pulmonary disease reported from a designated hospital for infectious diseases in the Fuyang district of China to determine the clinical characteristics of these patients. Methods: This research enrolled 234 patients with NTM pulmonary disease between January 2018 and May 2023 in the Fuyang district of China. Data were collected from the electronic medical records. The NTM strain composition and clinical characteristics of NTM pulmonary disease were retrospectively analyzed. Results: 73 (31.20%) patients had previous tuberculosis (TB) or TB exposure history and bronchiectasis. Mixed NTM infection accounted for 12.39%. Mycobacterium intracellulare strain was detected in 132 patients (49.62%). Women were found to be more affected by Mycobacterium avium infection, and men by Mycobacterium abscessus infection. Mycobacterium avium (34.21%) and Mycobacterium abscessus (33.33%) strains were most common in people with previous TB or TB exposure history. Among respiratory tract-related diseases, patients with bronchiectasis had the highest isolation rate of Mycobacterium avium (55.36%). Women were susceptible to bronchiectasis (P < 0.01). The median of mononuclear-to-lymphocyte ratio (MLR) was higher in men than in women (P < 0.01). The serum albumin (ALB) level was lower in patients with TB or TB exposure history than in those without TB history (P = 0.034). The prognostic nutritional index (PNI) was lower in patients with TB or TB exposure history than in those without tuberculosis history (P = 0.021). Patients with NTM lung disease were poorly treated. Conclusion: Clinical symptoms of the disease were not species-specific. Mycobacterium intracellulare and Mycobacterium avium strains were predominant in the Fuyang district of China. Previous TB or TB exposure history immensely enhanced the risk of NTM disease. [ABSTRACT FROM AUTHOR]

Background: The prevalence of nontuberculous mycobacteria pulmonary disease (NTM-PD), particularly caused by Mycobacterium avium complex (MAC), is rising due to improved diagnostics, increased awareness, and more susceptible populations. NTM-PD significantly affects quality of life and imposes substantial economic costs. Understanding its clinical features, risk factors, and treatment challenges is vital for enhancing patient outcomes. Patients and methods: A convenience sample from the University of Connecticut Health Center and Wayne State University involving patients with NTM-PD from 2021 to 2024 was studied retrospectively. Cases were selected to demonstrate typical diagnostic and treatment challenges, followed by a multidisciplinary roundtable discussion to examine patient-centered care strategies. Results: Analysis of six cases pinpointed chronic lung conditions and immunomodulatory therapy as key risk factors. Standard treatment, involving extensive multi-drug regimens, frequently results in poor adherence due to side effects and complex management requirements. The discussions underlined the importance of a customized, interdisciplinary approach to improve treatment effectiveness and patient quality of life. Conclusions: NTM-PD is an escalating public health issue with notable clinical and economic consequences. Managing this disease effectively demands a comprehensive, patient-centered strategy that includes precise diagnosis, flexible treatment plans, and collaborative care. Plain Language Summary: This paper focuses on a type of lung disease caused by nontuberculous mycobacteria (NTM), which are bacteria found in the environment. NTM pulmonary disease has become more common due to better diagnostic methods, increased awareness, and a growing number of people with conditions that make them more vulnerable to infections. This disease can seriously affect a person's quality of life and is challenging to treat because it often requires long and complex antibiotic regimens. The authors, who have expertise in pulmonary diseases and infectious diseases, reviewed the medical records of six patients treated for NTM disease at the University of Connecticut Health Center and Wayne State University between 2021 and 2024. Following the submission of case synopses, the authors engaged in a discussion to explore the challenges of managing NTM infections. The discussion focused on identifying the best practices for diagnosis and treatment, emphasizing a patient-centered approach to care. Patients with preexisting lung conditions or those undergoing certain medical treatments are more susceptible to developing NTM lung disease. The treatment often involved multiple drugs, which posed challenges for patients due to side effects and the complexity of the regimen. The findings underscored the importance of a personalized, collaborative approach in treating NTM lung disease to improve patient outcomes and quality of life. [ABSTRACT FROM AUTHOR]

Mycobacterium chimaera (MC), a member of the Mycobacterium avium complex, can cause infections in patients after open-heart surgery due to contaminated heater–cooler units (HCUs). The transmission route of HCU-related MC infection is non-inhalational, and infection can occur in patients without previously known immune deficiency. Patients may develop endocarditis of the prosthetic valve, infection of the vascular graft, and/or manifestations of disseminated mycobacterial infection (splenomegaly, arthritis, hepatitis, nephritis, myocarditis, etc.). MC infections have serious outcomes (30–50% recurrence rate, 20–67% mortality rate). In 2015, an international outbreak of M. chimaera infections among patients undergoing cardiothoracic surgeries was associated with exposure to contaminated LivaNova 3T HCUs (formerly Stöckert 3T heater–cooler system, London, United Kingdom). In response to the global outbreak, many international agencies have issued directives and recommendations in order to reduce the risk of MC infection in cardiac surgery. Whole-genome sequencing (WGS) technology can be used to describe the global spread and dynamics of MC infections, to characterize local outbreaks, and also to identify sources of infection in hospital settings. In order to minimize the risk of contamination of HCUs and reduce the risk of patient infection, it is imperative that healthcare facilities establish a program of regular cleaning and disinfection maintenance procedures as well as monitoring of the water used and the air in the operating room, in accordance with the manufacturer's procedure. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Lung transplant recipients (LTRs) are at risk for Mycobacterium avium complex (MAC) infections, in part due to the presence of structural lung disease pre‐transplant and relatively higher levels of immunosuppression post‐transplant. There is a lack of data regarding outcomes of LTR with MAC infections pre‐transplant.This is a single‐center retrospective analysis of patients who received lung transplants (LTs) from 2013 to 2020 with 1) evidence of MAC on culture or polymerase chain reaction before or at the time of transplant or 2) granulomas on explant pathology and positive acid‐fast bacillus stains with no other mycobacteria identified. Patients were deemed to have MAC pulmonary disease (MAC‐PD) if they met the American Thoracic Society/Infectious Disease Society of America criteria.Fourteen patients (14/882, 2%) met inclusion criteria. Seven patients (7/14, 50%) had pre‐transplant MAC‐PD, four of whom had cavitary disease. None of the 14 patients had smear‐positive cultures at the time of transplant. Two patients in our cohort received treatment for MAC before transplant. Thirteen patients were bilateral LTR (13/14, 93%). One single LTR was the sole patient to receive MAC treatment post‐transplant. No patients developed MAC‐PD after transplant.The bilateral LTR in our cohort did not develop MAC‐PD despite not receiving MAC treatment post‐transplant. It is possible source control was achieved with native lung explantation. Our observations suggest patients may not uniformly require pre‐ or post‐transplant MAC treatment if they are smear‐negative and undergo bilateral LT. [ABSTRACT FROM AUTHOR]

Cure rates for pulmonary disease caused by the Mycobacterium avium complex (MAC) are poor. While β-lactam are front line antibiotics against Mycobacterium abscessus pulmonary disease, they have not been used or recommended to treat MAC lung infections. Through a comprehensive screen of oral β-lactams, we have discovered that selected pairs combining either a penem/carbapenem or penicillin with a cephalosporin are strongly bactericidal at clinically achieved concentrations. These dual β-lactam combinations include tebipenem and sulopenem, both in phase 3, and Food and Drug Administration-approved amoxicillin and cefuroxime. They could therefore immediately enter clinical trials or clinical practice. [ABSTRACT FROM AUTHOR]

Background Only 35.6%–50.8% of patients with Mycobacterium avium complex (MAC) pulmonary disease achieve sustained sputum culture conversion (SSCC) on treatment with the azithromycin-ethambutol-rifabutin standard of care (SOC). We tested the efficacy of ceftriaxone, a β-lactam with a lung-to-serum penetration ratio of 12.18-fold. Methods We mimicked lung concentration-time profiles of 7 ceftriaxone once-daily doses for 28 days in the hollow fiber system model of intracellular MAC (HFS-MAC). Monte Carlo experiments were used for dose selection. We also compared once-daily ceftriaxone monotherapy to 3-drug SOC against 5 MAC clinical isolates in HFS-MAC using γ (kill) slopes, and translated to SSCC rates. Results Ceftriaxone killed 1.02–3.82 log10 colony-forming units (CFU)/mL, at optimal dose of 2 g once-daily. Ceftriaxone killed all 5 strains below day 0 versus 2 of 5 for SOC. The median γ (95% confidence interval [CI]) was 0.49 (.47–.52) log10 CFU/mL/day for ceftriaxone and 0.38 (.34–.43) log10 CFU/mL/day for SOC. In patients, the SOC was predicted to achieve SSCC rates (CI) of 39.3% (36%–42%) at 6 months. The SOC SSCC was 50% at 8.18 (3.64–27.66) months versus 3.58 (2.20–7.23) months for ceftriaxone, shortening time to SSCC 2.35-fold. Conclusions Ceftriaxone is a promising agent for creation of short-course chemotherapy. [ABSTRACT FROM AUTHOR]

Mycobacterium avium is associated with pulmonary disease in otherwise healthy adults. Several clarithromycin-refractory cases have been reported, including some cases caused by clarithromycin-susceptible strains. To characterize the reason for the discrepancy between clinical response and antibiotic susceptibility results. We conducted population analysis of clarithromycin-tolerant and heteroresistant subpopulations of M. avium cultured in vitro and in homogenates of infected lungs of mice. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined for 28 M. avium and two M. kansasii strains. Mice were intranasally infected with M. avium and treated with or without clarithromycin (100 mg/kg) thrice weekly. They were sacrificed on day 35 and the bacteria in lung homogenates were tested for clarithromycin resistance. Population analysis assays were performed based on colony growth on plates containing two-fold dilutions of clarithromycin. The MBC/MIC ratios were ≥8 in all 28 strains of M. avium tested. In the population analysis assay, several colonies were observed on the plates containing clarithromycin concentrations above the MIC (2–64 mg/L). No growth of M. kansasii colonies was observed on the plates containing clarithromycin concentrations ≥2 mg/L. M. avium in the homogenates of infected lungs showed clearer clarithromycin-resistant subpopulations than in vitro , regardless of clarithromycin exposure. M. avium shows intrinsic heterogeneous resistance (heteroresistance) to clarithromycin. This may explain the observed discrepancies between clarithromycin susceptibility testing results and clinical response to clarithromycin treatment. Further studies are needed to confirm a link between heteroresistance and clinical outcomes. [ABSTRACT FROM AUTHOR]

Mycobacterium abscessus species (MABS) is now a most virulent rapidly growing mycobacteria (RGM), and the rapid increase of MABS was recently observed worldwide, including in Japan. Thus, we gathered evidences of the presence of pulmonary MABS in Japanese population from Japanese articles. we searched studies that addressed the isolation of pulmonary non-tuberculous Mycobacteria (NTM) or MABS from clinical respiratory specimens in Japan. the ratio of MABS to NTM was 3.04% (95% confidence interval [CI]: 2.51–3.68), found using the meta-analysis of single proportions. The estimated mean age of patients infected with MABS was 67.72 years (95% CI: 65.41–70.02), found using the meta-analysis of single means. The estimated proportion of females, never smoker, and the co-infection with Mycobacterium avium complex (MAC) was 66.75% (95% CI: 59.23–73.50), 67.57% (95% CI: 62.43–72.32), and 36.74% (95% CI: 25.30–49.90), respectively. The characteristics of MABS in Japan were considerably different from that in Europe and United States from the perspective of age, gender, and complications, wherein the patients in these countries tended to be younger, had lower number of females, and had more occurrences of hereditary diseases, including cystic fibrosis (CF). we hypothesized that the characteristics of MABS in the Japanese were involved in those of non-CF MABS, and the distribution of gender and age of MABS were similar to that of MAC in the Japanese. [ABSTRACT FROM AUTHOR]

Patients with Mycobacterium avium complex pulmonary disease (MAC-PD) often suffer from chronic symptoms such as sputum production, which reduces quality of life. Oscillatory positive expiratory pressure (OPEP) devices are used in physiotherapy to promote the clearance of respiratory secretions. We report two cases of improved lung function and improved scores on the Leicester Cough Questionnaire (LCQ) and the Breathlessness, Cough and Sputum Scale (BCSS) after the use of OPEP in patients with MAC-PD where treatment with guideline-based therapy, including amikacin liposome inhalation suspension, had proved ineffective for symptoms. Use of OPEP might maximize the efficacy of therapy and thereby improves outcomes in patients with MAC-PD. It is important to use both guideline-based therapy and OPEP, especially in patients whose health-related quality of life is affected by sputum symptoms. Further prospective studies are warranted to assess the benefit of adding OPEP to guidelines concerning therapy for patients with MAC-PD and sputum symptoms. [ABSTRACT FROM AUTHOR]

Introduction: The incidence and prevalence of nontuberculous mycobacterial pulmonary disease (NTM-PD) are increasing globally. Approximately 80% of NTM-PD cases in Japan and five countries within Europe (Eur5; France, Germany, Italy, Spain, and the UK) are caused by Mycobacterium avium complex (MAC). This study describes the clinical decision-making process associated with the management of patients with NTM-PD in Japan and the Eur5. Methods: We analyzed data from a survey conducted between July 2013 and October 2013 among physicians treating patients with NTM-PD in clinical practice to compare the healthcare settings, clinical presentation, and patient management in Japan and the Eur5. Results: Overall, 619 physicians (Japan, 173; Eur5, 446) participated in the survey. Most patients in Japan (85%) and the Eur5 (79%) were diagnosed with MAC-PD. Patients were managed generally in hospital-based outpatient clinics (117/173, 68%) in Japan and research/teaching hospitals affiliated with medical schools (140/446, 31%) in the Eur5. The most common reason for delaying treatment was the patient's symptoms not being considered serious enough for treatment (55/128, 43%) in Japan and awaiting results of antimicrobial susceptibility testing (44/151, 29%) in the Eur5. Culture negativity was less commonly achieved after treatment in patients in Japan versus those in the Eur5 (31% [73/238] vs. 70% [300/426], p < 0.0001). In treatment phases that were either completed or discontinued, the primary goal was symptomatic improvement, followed by achieving culture conversion, in both Japan and the Eur5. Overall, 19% (16/85) of physicians in Japan and 43% (220/511) in the Eur5 were "entirely satisfied" with their patients' treatment outcomes. Conclusions: Similarities and differences exist in the healthcare settings, clinical presentation, and management of patients with NTM-PD in Japan and the Eur5. Insufficient consideration of culture status by physicians, delayed treatment initiation, and symptom-based cessation emphasize the need for educational efforts on the guideline-based strategies. Plain Language Summary: Mycobacteria are microorganisms that cause a disease in the lungs known as nontuberculous mycobacterial pulmonary disease (NTM-PD). The number of people with NTM-PD is increasing globally. This study was a survey of doctors who treated people with NTM-PD in Japan and Europe and aimed to understand geographical similarities and differences in the management, treatment, and health of people with NTM-PD. In the survey, treatment for NTM-PD was found to be often delayed or not started. In Japan, this was most commonly because the individual's symptoms were not thought to be serious enough and in Europe because of delays in laboratory testing needed to decide which antibiotic treatment should be used. The most common treatment goal in both Japan and Europe was improvement in the individual's symptoms. Clinical guidelines recommend continuing treatment for at least 12 months after the person with NTM-PD has tested negative for mycobacteria. There were similarities and differences in the healthcare settings, clinical presentation, and management of people with NTM-PD between Japan and Europe. It is important to ensure uniform implementation of the treatment guidelines for NTM-PD in each clinical setting so that people with NTM-PD experience better health outcomes. [ABSTRACT FROM AUTHOR]

Background: The treatment of non-tuberculous mycobacterial (NTM) infections is challenging because of the difficulty in obtaining phenotypic (pDST) and/or molecular (mDST) drug susceptibility testing and the need of a multi-drug regimen. Objectives: The objective was to describe the in vitro susceptibility patterns of various NTM species through an analysis of susceptibility results obtained on isolates collected between 2018 and 2023. Methods: Species identification and mutations in rrs or rrl genes (mDST) were identified by a line probe assay, while the pDST was performed by broth microdilution and interpreted according to CLSI criteria. Results: We analysed 337 isolates of NTM belonging to 15 species/subspecies. The Mycobacterium avium complex (MAC) was the most common (62%); other species identified included M. gordonae (11%), M. kansasii (5%), the M. abscessus complex (8%), M. chelonae (6%), and M. fortuitum (2%). The results of pDST (claritromycin and amikacin) and mDST (rrl and rrs genes) on 66 NTM strains showed that while wild-type rrl and rrs occurred in 86.3% and 94% strains, respectively, the pDST showed 88% sensitivity for clarithromycin and 57.5% for amikacin. The main incongruity was observed for macrolides. Conclusions: Most NTM are likely to be susceptible to macrolides and aminoglycosides. The molecular identification of resistant genotypes is accurate and strongly recommended for optimal patient management. [ABSTRACT FROM AUTHOR]

Nontuberculous mycobacterial pulmonary disease (NTM-PD) results from opportunistic lung infections by mycobacteria other than Mycobacterium tuberculosis or Mycobacterium leprae species. Similar to many other countries, the incidence of NTM-PD in the United Kingdom (UK) is on the rise for reasons that are yet to be determined. Despite guidelines established by the American Thoracic Society (ATS), the Infectious Diseases Society of America, and the British Thoracic Society, NTM-PD diagnosis and management remain a significant clinical challenge. In this review article, we comprehensively discuss key challenges in NTM-PD diagnosis and management, focusing on the UK healthcare setting. We also propose countermeasures to overcome these challenges and improve the detection and treatment of patients with NTM-PD. [ABSTRACT FROM AUTHOR]

The impact of residential villages on the nontuberculous mycobacteria (NTM) in streams flowing through them has not been studied in detail. Water and sediments of streams are highly susceptible to anthropogenic inputs such as surface water flows. This study investigated the impact of seven residential villages in a karst watershed on the prevalence and species spectrum of NTM in water and sediments. Higher NTM species diversity (i.e., 19 out of 28 detected) was recorded downstream of the villages and wastewater treatment plants (WWTPs) compared to sampling sites upstream (i.e., 5). Significantly, higher Zn and lower silicon concentrations were detected in sediments inside the village and downstream of the WWTP’s effluents. Higher phosphorus concentration in sediment was downstream of WWTPs compared to other sampling sites. The effluent from the WWTPs had a substantial impact on water quality parameters with significant increases in total phosphorus, anions (Cl–and N-NH3–), and cations (Na+ and K+). The results provide insights into NTM numbers and species diversity distribution in a karst watershed and the impact of urban areas. Although in this report the focus is on the NTM, it is likely that other water and sediment microbes will be influenced as well. [ABSTRACT FROM AUTHOR]

Abstract Background Mycobacterium avium complex (MAC) is an uncommon clinical pathogen, especially in the central nervous system (CNS), and carries a poor prognosis. MAC infections commonly present as immune reconstitution disease (IRD) in HIV patients. Herein, we report a case of intracranial infection caused by MAC in an AIDS patient without disseminated MAC (DMAC) and immune reconstitution inflammatory syndrome (IRIS). Case presentation A 31-year-old HIV-positive male presented us with progressively worsening CNS symptoms, and neuroimaging revealed ring-enhancing lesions. The intracranial lesions worsened after the empirical therapy for toxoplasma encephalitis and fungal infection. Due to the rapid progression of the disease, the patient died. Mycobacterium avium was the only pathogen in brain tissue after cultures and molecular biology tests. Conclusion MAC infection in CNS is challenging to diagnose in HIV patients. Our findings emphasize that obtaining tissue samples and applying molecular biology methods is essential to help diagnose the patient as soon as possible to receive adequate treatment.

Abstract Background The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated. Methods Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort. Results Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04–0.28, p

Introducción. Mycobacterium chelonae y los complejos Mycobacterium avium y M. abscessus, son agentes patógenos emergentes causantes de micobacteriosis. El tratamiento de esta infección depende de la especie y la subespecie identificadas. Los fármacos de elección son los macrólidos y aminoglucósidos, contra los cuales se ha reportado resistencia; por esta razón, el determinar el perfil de sensibilidad le permite al médico tratante comprender mejor el pronóstico y la evolución de estas infecciones. Objetivo. Describir los perfiles de sensibilidad ante macrólidos y aminoglucósidos, de los cultivos identificados como complejo Mycobacterium avium, complejo M. abscessus o especie M. chelonae, en el Laboratorio Nacional de Referencia de Micobacterias durante los años 2018 a 2022. Materiales y métodos. Se llevó a cabo un estudio descriptivo del perfil de sensibilidad a macrólidos y aminoglucósidos, de los cultivos identificados como complejo M. avium, complejo M. abscessus o M. chelonae, mediante la metodología GenoType® NTM-DR. Resultados. Los cultivos del complejo M. avium fueron 159 (47,3 %), de los cuales, 154 (96,9 %) fueron sensibles y 5 (3,1 %) resistentes a los macrólidos; todos fueron sensibles a los aminoglucósidos. Del complejo M. abscessus se estudiaron 125 (37,2 %) cultivos, 68 (54,4 %) resultaron sensibles y 57 (45,6 %) resistentes a los macrólidos; solo un cultivo (0,8 %) fue resistente a los aminoglucósidos. De M. chelonae se analizaron 52 cultivos (15,5 %), todos sensibles a los macrólidos y aminoglucósidos. Conclusiones. En las tres especies de micobacterias estudiadas, la resistencia contra la amikacina fue la menos frecuente. La identificación de las subespecies y los perfiles de sensibilidad permiten instaurar esquemas de tratamiento adecuados, especialmente en las micobacteriosis causadas por M. abscessus.

The study aims to accurately identify differentially expressed genes (DEGs) and biological pathways in mycobacterial infections through bioinformatics for deeper disease understanding. Differentially expressed genes (DEGs) was explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Unique DEGs were submitted on least absolute shrinkage and selection operator (LASSO) regression analysis. 1,057 DEGs from two GSE datasets were identified, which were closely connected with NTM/ latent TB infection (LTBI)/active TB disease (ATB). It was demonstrated that these DEGs are mainly associated with detoxification processes, and virus and bacterial infections. Moreover, the METTL7B gene was the most informative marker for distinguishing LTBI and ATB with an area under the curve (AUC) of 0.983 (95%CI: 0.964 to 1). The significantly upregulated HBA1/2 genes were the most informative marker for distinguishing between individuals of IGRA-HC/NTM and LTBI (P < 0.001). Moreover, the upregulated HBD gene was also differ between IGRA-HC/NTM and ATB (P < 0.001). We have identified gene signatures associated with Mycobacterium infection in whole blood, which could be significant for understanding the molecular mechanisms and diagnosis of NTM, LTBI, or ATB. [ABSTRACT FROM AUTHOR]

Background: The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated. Methods: Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort. Results: Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04–0.28, p < 0.001 and OR 0.11 95% CI 0.02–0.4, p = 0.004, respectively) and MCH was negatively associated with fulfillment of the ATS criteria when isolated from respiratory samples (OR 0.28 95% CI 0.09-0.7, p = 0.011). With 14 out of 43 patients with available serial isolates, co-infections or co-colonizations with different strains or even species of the MAC were frequent (32.6%). Conclusions: This study demonstrates clustering and the presence of plasmids in a large proportion of MAC isolates in Europe and in a global context. Future studies need to urgently define potential ways of transmission of MAC isolates and the potential involvement of plasmids in virulence. [ABSTRACT FROM AUTHOR]

Background: Mycobacterium avium complex (MAC) is an uncommon clinical pathogen, especially in the central nervous system (CNS), and carries a poor prognosis. MAC infections commonly present as immune reconstitution disease (IRD) in HIV patients. Herein, we report a case of intracranial infection caused by MAC in an AIDS patient without disseminated MAC (DMAC) and immune reconstitution inflammatory syndrome (IRIS). Case presentation: A 31-year-old HIV-positive male presented us with progressively worsening CNS symptoms, and neuroimaging revealed ring-enhancing lesions. The intracranial lesions worsened after the empirical therapy for toxoplasma encephalitis and fungal infection. Due to the rapid progression of the disease, the patient died. Mycobacterium avium was the only pathogen in brain tissue after cultures and molecular biology tests. Conclusion: MAC infection in CNS is challenging to diagnose in HIV patients. Our findings emphasize that obtaining tissue samples and applying molecular biology methods is essential to help diagnose the patient as soon as possible to receive adequate treatment. [ABSTRACT FROM AUTHOR]

Background Adjunctive lung resection is recommended for select patients with nontuberculous mycobacteria (NTM) pulmonary disease (PD). However, data are limited on long-term recurrence rates in patients infected with major pathogens, including Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MABC). Methods In this prospective observational study, we retrospectively analyzed data from 125 patients with MAC-PD (n = 90) or MABC-PD (n = 35) who underwent adjunctive lung resection. We evaluated microbiological response, postoperative complications, recurrence, and all-cause mortality over a median 80-month follow-up. Results Persistent culture positivity (64%) was the most common indication for surgery, followed by hemoptysis, recurrent pneumonia, or radiologic deterioration. Postoperative complications occurred in 18 (14%) patients, with no surgery-related deaths. Treatment outcomes did not significantly differ between the MAC- and MABC-PD groups. Cure with culture conversion was achieved in 112 (90%) patients. Recurrence occurred in 37 (33%) of 112 patients, of which 18 (49%) cases were attributed to reinfection by different NTM species or subspecies. The MAC group had higher recurrence rates than the MABC group (Kaplan-Meier curve, log-rank test, P =.043) and was significantly associated with recurrence in the multivariable analysis (adjusted hazard ratio, 2.71; 95% CI, 1.23–5.99). However, mortality was higher in the MABC-PD group than the MAC-PD group (7/35 vs 4/90, P =.006). Conclusions Adjunctive lung resection with antibiotics helps to reduce bacterial burden and manage symptoms in patients with NTM-PD. However, it does not prevent recurrence, which is mostly caused by reinfection. [ABSTRACT FROM AUTHOR]

We investigated the prevalence and spatial distribution of selected pathogens associated with infectious diseases of dairy cattle in Ontario, Canada. The cross-sectional study surveyed bulk tank milk for antibodies against bovine leukemia virus (BLV), Mycobacterium avium ssp. paratuberculosis (MAP), and Salmonella Dublin, and for the presence of mastitis pathogens (Staphylococcus aureus , Streptococcus agalactiae , Mycoplasma bovis). Between October 2021 and June 2022, bulk tank milk samples were obtained from every commercial dairy farm in Ontario (n = 3,286). Samples underwent ELISA testing for the presence of BLV, MAP, and S. Dublin antibodies, and quantitative PCR testing for the detection of specific antigens of pathogens associated with mastitis. Bayesian models were used to estimate prevalence, and spatial analysis was carried out to identify regional clusters of high pathogen prevalence. Prevalence varied for different pathogens, and BLV was widespread across dairy farms in Ontario, with an estimated prevalence of 88.3%. The prevalence of MAP, Staph. aureus and S. Dublin in Ontario dairy herds was 39.8%, 31.5%, and 5.1%, respectively. The vast majority of dairy herds in Ontario were free of intramammary infections caused by Strep. agalactiae and M. bovis. Clusters of increased positive test rates were detected for S. Dublin, MAP, and Staph. aureus , indicating potential geographic risk factors for pathogen transmission. For S. Dublin, an area of increased test positivity rates was detected in southwestern Ontario, close to the Canada-United States border where most of the dairy herds in Ontario are located. Conversely, a localized cluster of positive test outcomes involving 14 subdivisions located in the southeastern region of Ontario was detected for Staph. aureus. Findings from our survey highlight the importance of the testing of aggregated samples and conducting spatial analysis as part of disease surveillance programs, and for implementing risk-based trading approaches among dairy producers. [ABSTRACT FROM AUTHOR]

Background: Mycobacterium abscessus is a new pathogen in recent years, which belongs to non-tuberculosis mycobacterium. Mycobacterium abscessus is widely involved in many nosocomial infections and secondary aggravation of genetic respiratory diseases. Mycobacterium abscessus is naturally resistant to most antibiotics and is difficult to treat. We report a case of mycobacterium abscessus infection with hemoptysis as the first manifestation. Methods: Bronchoscopy, next-generation sequencing (NGS). Results: Acid-fast staining of bronchoscopic lavage fluid showed that a small amount of acid-fast bacilli could be seen. NGS test showed the presence of Mycobacterium abscess, sequence number 137 (reference range ≥ 0), and symptomatic treatment against non-tuberculosis mycobacteria. Conclusions: For the follow-up infection of patients with hemoptysis, the treatment effect of antibiotics is not good, so the pathological tissue should be obtained by bronchoscopy or percutaneous lung biopsy in time, and the diagnosis should be confirmed by NGS if necessary. [ABSTRACT FROM AUTHOR]

Caprine paratuberculosis (PTB) is a progressive, debilitating and production-limiting disease that causes significant economic losses and raises public health concerns. The goal was to study active surveillance and associated epidemiological risk factors of caprine PTB in selected district of Odisha, India. The 818 goats of various ages, sexes and breeds were randomly screened in ten different districts for a year based on history, clinical signs and fecal smear examination using the Ziehl-Neelsen stain, yielding an overall prevalence of 38.75%, with clinical and sub-clinical PTB at 8.06 and 30.68%, respectively. A molecular tool, IS900 polymerase chain reaction, was also used to confirm the disease. With Mycobacterium avium subsp. paratuberculosis (MAP) bacilli and endoparasite infections, the majority of affected goats (69.08%) were low shedders. Puri coastal district had the highest prevalence (52.29%) followed by Sambalpur (48.61%), while Khordha had the lowest prevalence (26.41%). Caprine PTB was more common in goats over 2 years old (51.23%), in the Ganjam breed (42.30%), in females (39.17%) and in goats housed on earthen floors (55.83%) according to chi-square analysis. The current study concluded that higher (30.68%) observations of subclinical PTB were cause of real concern due to its insidious spread as well as its zoonotic significance with potential human consequences, which requires immediate attention at all levels. Because of the public health importance of this hidden killer disease, the current findings would be useful in developing a roadmap for implementing prevention and control policies, prompting provision for adequate funding with elaborative research. [ABSTRACT FROM AUTHOR]

Rationale: The clinical implications of trehalose 6,6′-dimycolate (TDM) in nontuberculous mycobacterial pulmonary disease have not been studied. Objectives: To examine the presence of TDM in clinical isolates obtained from patients with Mycobacterium avium complex (MAC) pulmonary disease (PD) and its impact on disease severity and treatment outcomes. Methods: We analyzed clinical isolates from patients with diagnoses of MAC PD at Seoul National University Hospital between January 1, 2019, and December 31, 2021. The lipids were extracted from clinical isolates obtained at the time of diagnosis using mass spectrometry. Mass peaks between 300 and 3,500 m/z were obtained, and the peak patterns of the total lipids were analyzed. Results: TDM was identified in clinical isolates from 176 of 343 patients. Cavities were more prevalent in patients with TDM-negative isolates (19.8%) than in those with TDM-positive isolates (10.2%) (P = 0.015). The time to antibiotic treatment was shorter in patients with TDM-negative isolates (4 mo [interquartile range, 2–10 mo]) than in those with TDM-positive isolates (7 mo [interquartile range, 3–16 mo]) (P = 0.032). Patients with TDM-negative isolates had a significantly lower proportion of culture conversions (P = 0.012). TDM was associated with higher likelihood of culture conversion (adjusted hazard ratio, 2.29; P = 0.035). Conclusions: TDM-negative isolates were linked to a higher occurrence of cavities, earlier initiation of treatment, and worse treatment outcome in patients with MAC PD. [ABSTRACT FROM AUTHOR]

Mycobacterium avium subsp. avium is pathogenic mainly to birds, although cases of mycobacteriosis caused by these bacteria have also been reported in other animals and humans. Not much is known about the effects of this pathogen on otters. The aim of this study was to report for the first time the isolation of M. avium subsp. avium in wild otter and to describe its multidrug resistance profile. A female otter injured in a car accident was found dead and subjected to postmortem examination. Apart from the trauma changes, no other macroscopic pathological changes were detected. Bacteriologic examination revealed the presence of acid-fast bacilli in the lymph nodes, which were confirmed by molecular methods as M. avium subsp. avium. Antimicrobial susceptibility testing revealed susceptibility to clarithromycin and amikacin, but resistance to linezolid, moxifloxacin, streptomycin, isoniazid, trimethoprim/sulfamethoxazole, ciprofloxacin, doxycycline, and ethionamide. This is unusual for wild species, which generally should not come into contact with antimicrobials, and may suggest that multidrug-resistant MAC strains are circulating between wild and domestic animals. These results emphasise the need for additional epidemiological studies on non-tuberculous mycobacteria in wildlife and their implications for one health. [ABSTRACT FROM AUTHOR]

Bronchiectasis and nontuberculous mycobacteria (NTM) are intricately intertwined, with NTM capable of being both a cause and consequence of bronchiectatic disease. This narrative review focuses on the common ground of bronchiectasis and NTM pulmonary disease (NTM-PD) in terms of diagnostic approach, underlying risk factors and treatment strategies. NTM-PD diagnosis relies on a combination of clinical, radiological and microbiological criteria. Although their epidemiology is complicated by detection and reporting biases, the prevalence and pathogenicity of NTM species vary geographically, with Mycobacterium avium complex and Mycobacterium abscessus subspecies most frequently isolated in bronchiectasis-associated NTM-PD. Diagnosis of nodular bronchiectatic NTM-PD should prompt investigation of host factors, including disorders of mucociliary clearance, connective tissue diseases and immunodeficiencies, either genetic or acquired. Treatment of NTM-PD in bronchiectasis involves a multidisciplinary approach and considers the (sub)species involved, disease severity and comorbidities. Current guideline-based antimicrobial treatment of NTM-PD is considered long, cumbersome and unsatisfying in terms of outcomes. Novel treatment regimens and strategies are being explored, including rifampicin-free regimens and inclusion of clofazimine and inhaled antibiotics. Host-directed therapies, such as immunomodulators and cytokine-based therapies, might enhance antimycobacterial immune responses. Optimising supportive care, as well as pathogen- and host-directed strategies, is crucial, highlighting the need for personalised approaches tailored to individual patient needs. Further research is warranted to elucidate the complex interplay between host and mycobacterial factors, informing more effective management strategies. [ABSTRACT FROM AUTHOR]

Non-Tuberculous mycobacteria (NTM) are opportunistic environmental bacteria. Globally, NTM incidence is increasing and modeling suggests that, without new interventions, numbers will continue to rise. Effective treatments for NTM infections remain suboptimal. Standard therapy for Mycobacterium avium complex, the most commonly isolated NTM, requires a 3-drug regime taken for approximately 18 months, with rates of culture conversion reported between 45 and 70%, and high rates of relapse or reinfection at up to 60%. New therapeutic options for NTM treatment are urgently required. A survey of ongoing clinical trials for new NTM therapy listed on ClinicalTrials.Gov using the terms 'Mycobacterium avium', 'Mycobacterium abscessus', 'Mycobacterium intracellulare', 'Non tuberculous Mycobacteria' and 'Nontuberculous Mycobacteria' and a selection criterion of interventional studies using antibiotics demonstrates that most trials involve dose and combination therapy of the guideline based therapy or including one or more of; Amikacin, Clofazimine, Azithromycin and the anti-TB drugs Bedaquiline and Linezolid. The propensity of NTMs to form biofilms, their unique cell wall and expression of both acquired and intrinsic resistance, are all hampering the development of new anti-NTM therapy. Increased investment in developing targeted treatments, specifically for NTM infections is urgently required. [ABSTRACT FROM AUTHOR]

Mycobacterium abscessus belongs to the largest group of mycobacteria, the rapid-growing saprophytic mycobacteria, and is one of the most difficult-to-treat opportunistic pathogen. Several features pertain to the high adaptability of M. abscessus to the host. These include the capacity to survive and persist within amoebae, to transition from a smooth to a rough morphotype that occurs during the course of the disease and to express of a wide array of virulence factors. The main objective of this narrative review consists to report major assets of M. abscessus that contribute to the virulence of these rapid-growing saprophytic mycobacteria. Strikingly, many of these determinants, whether they are from a mycobacterial origin or acquired by horizontal gene transfer, are known virulence factors found in slow-growing and strict pathogens for humans and animals. In the light of recent published work in the field we attempted to highlight major features characterizing M. abscessus pathogenicity and to explain why this led to the emergence of this mycobacterial species in patients with cystic fibrosis. M. abscessus genome plasticity, the smooth-to-rough transition, and the expression of a panel of enzymes associated with virulence in other bacteria are key players in M. abscessus virulence. In addition, the very large repertoire of lipid transporters, known as mycobacterial membrane protein large and small (MmpL and MmpS respectively), deeply influences the pathogenicity of M. abscessus , as exemplified here for some of them. All these traits largely contribute to make M. abscessus a unique mycobacterium regarding to its pathophysiological processes, ranging from the early colonization steps to the establishment of severe and chronic pulmonary diseases. [ABSTRACT FROM AUTHOR]

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Copyright of Revista Española de Quimioterapia is the property of Sociedad Espanola de Quimioterapia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Non-tuberculous mycobacterial pulmonary infections (NTM-PD) are becoming increasingly common in clinical practice, and early detection and accurate determination of the infecting pathogen is crucial for subsequent treatment. We report a case of NTM-PD in a healthy middle-aged female with Mycobacterium tuberculosis complex group (MAC) infection confirmed by mNGS examination. Methods: Appropriate laboratory tests, chest CT scan, bronchoscopic alveolar lavage fluid (BALF) examination, and macrogenomic next-generation sequencing (mNGS) were performed to establish the diagnosis. Results: Chest CT showed multiple inflammatory lesions in the right middle lobe, and BALF sent for mNGS finally confirmed the diagnosis of MAC infection. After symptomatic treatment with azithromycin combined with ethambutol and rifampicin, the patient improved and was discharged from the hospital. Conclusions: In patients with pulmonary infections, pathogens should be clarified early to determine the diagnosis. mNGS of BALF samples have high specificity in detecting pathogens of infectious diseases, especially complex mixed infectious disease pathogens. [ABSTRACT FROM AUTHOR]

Objectives: Slow-growing nontuberculous mycobacteria (NTMs) are highly prevalent and routinely cause opportunistic intracellular infectious disease in immunocompromised hosts. Methods: The activity of the triple combination of antibiotics, clarithromycin (CLR), rifabutin (RFB), and clofazimine (CFZ), was evaluated and compared with the activity of single antibiotics as well as with double combinations in an in vitro biofilm assay and an in vivo murine model of Mycobacterium avium subsp. hominissuis (M. avium) lung infection. Results: Treatment of 1-week-old biofilms with the triple combination exerted the strongest effect of all (0.12 ± 0.5 × 107 CFU/mL) in reducing bacterial growth as compared to the untreated (5.20 ± 0.5 × 107/mL) or any other combination (≥0.75 ± 0.6 × 107/mL) by 7 days. The treatment of mice intranasally infected with M. avium with either CLR and CFZ or the triple combination provided the greatest reduction in CLR-sensitive M. avium bacterial counts in both the lung and spleen compared to any single antibiotic or remaining double combination by 4 weeks posttreatment. After 4 weeks of treatment with the triple combination, there were no resistant colonies detected in mice infected with a CLR-resistant strain. No clear relationships between treatment and spleen or lung organ weights were apparent after triple combination treatment. Conclusions: The biofilm assay data and mouse disease model efficacy results support the further investigation of the triple-antibiotic combination. [ABSTRACT FROM AUTHOR]

Rationale:Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial (NTM) pulmonary disease (PD), which exhibits increasing global incidence. Current microbiologic methods routinely used in clinical practice lack sensitivity and have long latencies, leading to delays in diagnosis and treatment initiation and evaluation. A clustered regularly interspaced short palindromic repeats (CRISPR)–based assay that measures MAC cell-free DNA (cfDNA) concentrations in serum could provide a rapid means to detect MAC infection and monitor response to antimicrobial treatment. Objectives: To develop and optimize a CRISPR MAC assay for MAC infection detection and to evaluate its diagnostic and prognostic performance in two MAC disease cohorts. Methods: MAC cfDNA serum concentrations were measured in individuals with diagnoses of MAC disease or who had bronchiectasis or chronic obstructive pulmonary disease diagnoses without histories of NTM PD or NTM-positive sputum cultures. Diagnostic performance was analyzed using pretreatment serum from two cohorts. Serum MAC cfDNA changes during MAC PD treatment were evaluated in a subset of patients with MAC PD who received macrolide-based multidrug regimens. Measurements and Main Results: The CRISPR MAC assay detected MAC cfDNA in MAC PD with 97.6% (91.6–99.7%) sensitivity and 97.6% (91.5–99.7%) specificity overall. Serum MAC cfDNA concentrations markedly decreased after MAC-directed treatment initiation in patients with MAC PD who demonstrated MAC culture conversion. Conclusions: This study provides preliminary evidence for the utility of a serum-based CRISPR MAC assay to rapidly detect MAC infection and monitor the response to treatment. [ABSTRACT FROM AUTHOR]

Increasingly prevalent, nontuberculous mycobacteria (NTM) infections affect approximately 20% of people with cystic fibrosis (CF). Previous studies of CF sputum identified lower levels of the host metabolite itaconate in those infected with NTM. Itaconate can inhibit the growth of M. tuberculosis (MTB) in vitro via the inhibition of the glyoxylate cycle enzyme (ICL), but its impact on NTM is unclear. To test itaconic acid's (IA) effect on NTM growth, laboratory and CF clinical strains of Mycobacterium abscessus and Mycobacterium avium were cultured in 7H9 minimal media supplemented with 1–10 mM of IA and short-chain fatty acids (SCFA). M. avium and M. abscessus grew when supplemented with SCFAs, whereas the addition of IA (≥ 10 mM) completely inhibited NTM growth. NTM supplemented with acetate or propionate and 5 mM IA displayed slower growth than NTM cultured with SCFA and ≤ 1 mM of IA. However, IA's inhibition of NTM was pH dependent; as similar and higher quantities (100 mM) of pH adjusted IA (pH 7) did not inhibit growth in vitro, while in an acidic minimal media (pH 6.1), 1 to 5 mM of non-pH adjusted IA inhibited growth. None of the examined isolates displayed the ability to utilize IA as a carbon source, and IA added to M. abscessus isocitrate lyase (ICL) decreased enzymatic activity. Lastly, the addition of cell-permeable 4-octyl itaconate (4-OI) to THP-1 cells enhanced NTM clearance, demonstrating a potential role for IA/itaconate in host defense against NTM infections. [ABSTRACT FROM AUTHOR]

Introduction: Nontuberculous mycobacteria (NTM) mediated infections are important to consider in cases with neuroinflammatory presentations. We aimed to characterize cases of NTM with neurological manifestations at the National Institutes of Health (NIH) Clinical Center and review the relevant literature. Materials and methods: Between January 1995 and December 2020, six cases were identified. Records were reviewed for demographic, clinical, and radiological characteristics. A MEDLINE search found previously reported cases. Data were extracted, followed by statistical analysis to compare two groups [cases with slow-growing mycobacteria (SGM) vs. those with rapidly growing mycobacteria (RGM)] and evaluate for predictors of survival. NIH cases were evaluated for clinical and radiological characteristics. Cases from the literature were reviewed to determine the differences between SGM and RGM cases and to identify predictors of survival. Results: Six cases from NIH were identified (age 41 ± 13, 83% male). Five cases were caused by SGM [Mycobacterium avium complex (MAC) n = 4; Mycobacterium haemophilum n = 1] and one due to RGM (Mycobacterium abscessus). Underlying immune disorders were identified only in the SGM cases [genetic (n = 2), HIV (n = 1), sarcoidosis (n = 1), and anti-interferongamma antibodies (n = 1)]. All cases were diagnosed using tissue analysis. A literature review found 81 reports on 125 cases (SGM n = 85, RGM n = 38, nonidentified n = 2). No immune disorder was reported in 26 cases (21%). Within SGM cases, the most common underlying disease was HIV infection (n = 55, 65%), and seizures and focal lesions were more common. In RGM cases, the most common underlying condition was neurosurgical intervention or implants (55%), and headaches and meningeal signs were common. Tissue-based diagnosis was used more for SGM than RGM (39% vs. 13%, p = 0.04). Survival rates were similar in both groups (48% SGM and 55% in RGM). Factors associated with better survival were a solitary CNS lesion (OR 5.9, p = 0.01) and a diagnosis made by CSF sampling only (OR 9.9, p = 0.04). Discussion: NTM infections cause diverse neurological manifestations, with some distinctions between SGM and RGM infections. Tissue sampling may be necessary to establish the diagnosis, and an effort should be made to identify an underlying immune disorder. [ABSTRACT FROM AUTHOR]

Mycobacterium avium complex (MAC) is a non-tuberculous mycobacterium widely distributed in the environment. Even though MAC infection is increasing in older women and immunocompromised patients, to our knowledge there has been no comprehensive analysis of the MAC-infected host-cell transcriptome--and particularly of long non-coding RNAs (lncRNAs). By using in vitro-cultured primary mouse bone-marrow-derived macrophages (BMDMs) and Cap analysis of gene expression, we analyzed the transcriptional and kinetic landscape of macrophage genes, with a focus on lncRNAs, during MAC infection. MAC infection of macrophages induced the expression of immune/inflammatory response genes and other genes similar to those involved in M1 macrophage activation, consistent with previous reports, although Nos2 (M1 activation) and Arg1 (M2 activation) had distinct expression profiles. We identified 31 upregulated and 30 downregulated lncRNA promoters corresponding respectively to 18 and 26 lncRNAs. Upregulated lncRNAs were clustered into two groups--early and late upregulated--predicted to be associated with immune activation and the immune response to infection, respectively. Furthermore, an Ingenuity Pathway Analysis revealed canonical pathways and upstream transcription regulators associated with differentially expressed lncRNAs. Several differentially expressed lncRNAs reported elsewhere underwent expressional changes upon M1 or M2 preactivation and subsequent MAC infection. Finally, we showed that expressional change of lncRNAs in MAC-infected BMDMs was mediated by toll-like receptor 2, although there may be other mechanisms that sense MAC infection. We identified differentially expressed lncRNAs in MAC-infected BMDMs, revealing diverse features that imply the distinct roles of these lncRNAs in MAC infection and macrophage polarization. [ABSTRACT FROM AUTHOR]

In non-human primates (NHPs), Mycobacterium avium complex (MAC) species are the major source of non-tuberculous mycobacteriosis, causing tuberculous-like lesions in lymph nodes and parenchymatous organs in zoo and wildlife animals. Poor species-specific detection by serological diagnosis has negatively impacted the surveillance of MAC on non-human primates. Serum was collected from suspected twelve (n = 12) NHPs with no record of health monitoring, including gibbon (n = 5), capuchins (n = 2), siamang (n = 2), mandrill (n = 1), and orangutan (n = 2). An in-house avian purified protein derivative (aPPD) enzyme-linked immunosorbent assays (ELISA) antibody detection was developed and modified based on the established protocols. The aPPD ELISA for MAC antibodies detection at serum and Protein-G dilutions of 1:200-0.5µg/ml, respectively, detected 3/12 (25%) positive serum. At both serum and Protein-G dilutions of 1:100-0.05 and 1:300-1 µg/ml, the aPPD ELISA detected 12/12 (100%), respectively. The antibody was not detected for an in-house aPPD ELISA with serum and anti-monkey immunoglobulin G (IgG) dilutions at 1:100- 0.5 and 1:300-1 µg/ml. However, 2/12 (16%) was detected using serum and anti-monkey IgG dilutions at 1:200-0.05 µg/ml. An in-house aPPD ELISA procedure for MAC antibodies detection in primates, at serum and Protein-G dilutions of 1:100-0.05 and 1:300-1 µg/ml, both have shown sensitivity and specificity of 100%, positive predictive value and negative predictive value of 100%, respectively. The serum and anti-monkey IgG have shown extremely low sensitivity and specificity. In conclusion, the performance of an in-house aPPD ELISA using three different dilutions on serum and conjugates in detecting MAC in a primate has shown that Protein-G horseradish peroxidase, as secondary conjugates were able to detect MAC antibodies. [ABSTRACT FROM AUTHOR]

Nontuberculous mycobacteria are environmental organisms that are increasingly causing chronic and debilitating pulmonary infections, of which Mycobacterium avium complex (MAC) is the most common pathogen. MAC pulmonary disease (MAC-PD) is often difficult to treat, often requiring long-term multidrug antibiotic therapy. Is there an association between various guideline-based three-drug therapy (GBT) regimens and (1) therapy-associated adverse events or (2) regimen change/discontinuation, within 12 months of therapy initiation? In a retrospective cohort study, we examined tolerability outcomes of GBT regimens for MAC-PD in 4,626 US Medicare beneficiaries with bronchiectasis, who were prescribed a GBT as initial antibiotic treatment for presumed MAC-PD during 2006 to 2014. Using multivariable Cox proportional hazard regression, we estimated adjusted hazard ratios (aHRs) to compare the risk of adverse events and regimen change/discontinuations within 12 months of therapy initiation in various GBT regimens. The cohort had a mean age ± SD of 77.9 ± 6.1 years at treatment start, were mostly female (77.7%), and were mostly non-Hispanic White (87.2%). The risk of regimen change/discontinuation within 12 months of therapy was higher for clarithromycin-based regimens than azithromycin-based regimens (aHR, 1.12; 95% CI, 1.04-1.20 with rifampin; aHR, 1.11; 95% CI, 0.93-1.32 with rifabutin as the companion rifamycin), and for rifabutin-containing regimens than rifampin-containing regimens (aHR, 1.49; 95% CI, 1.33-1.68 with azithromycin; aHR, 1.47; 95% CI, 1.27-1.70 with clarithromycin as the companion macrolide). The aHR comparing regimen change/discontinuation with clarithromycin-ethambutol-rifabutin and azithromycin-ethambutol-rifampin was 1.64 (95% CI, 1.43-1.64). Overall, an azithromycin-based regimen was less likely to be changed or discontinued than a clarithromycin-based regimen, and a rifampin-containing regimen was less likely to be changed or discontinued than a rifabutin-containing regimen within 12 months of therapy start. Our work provides a population-based assessment on the tolerability of multidrug antibiotic regimens used for the treatment of MAC-PD. [Display omitted] [ABSTRACT FROM AUTHOR]