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Background: Mycobacterium avium complex pulmonary disease (MAC-PD) is considered to be increasing worldwide. In Japan, the number of elderly MAC-PD patients requiring treatment is also expected to increase due to the aging society. However, reduced organ function in elderly patients makes it often difficult to continue or complete multidrug treatment due to adverse drug reactions (ADRs). Therefore, this study aimed to identify clinical factors associated with treatment tolerability, efficacy, and ADRs in elderly MAC-PD patients. Methods: We retrospectively reviewed the medical records of 102 patients with MAC-PD aged ≥ 75 years between January 2014 and March 2023. Forty-six patients were treated with multidrug regimens (treatment group), and 56 were observed without treatment (observation group). The treatment group was divided into the treatment continuation group (n = 28) who were treated without interruption for ≥ 12 months, and the treatment interruption group (n = 18). A comparative study was conducted in each group to examine tolerability, efficacy, and ADRs. Results: A two-drug regimen of ethambutol (EB) and macrolides without rifampicin (RFP) was associated with treatment continuation (p = 0.026). The treatment continuation group was superior to the observation group regarding symptoms change, sputum conversion rate, and chest computed tomography scores. The most common ADRs were gastrointestinal disorders, which may be related to RFP. Treatment efficacy of the two-drug regimen was non-inferior, and no cases of macrolide resistance were observed. Conclusions: The two-drug regimen of EB and macrolide without RFP may be a tolerable and effective treatment for elderly MAC-PD patients. [ABSTRACT FROM AUTHOR]

Background: Mycobacterium avium complex (MAC) is a common pathogen causing non-tuberculous mycobacterial infections, primarily affecting the lungs. Disseminated MAC disease occurs mainly in immunocompromised individuals, such as those with acquired immunodeficiency syndrome, hematological malignancies, or those positive for anti-interferon-γ antibodies. However, its occurrence in solid organ transplant recipients is uncommon. Herein, we report a rare case of disseminated MAC disease following liver transplantation, which led to an obstructive mass in the intestinal tract that required differentiation from a malignant tumor. Case presentation: A 76-year-old woman, who had undergone living-donor liver transplantation 15 years earlier for primary biliary cirrhosis, presented with persistent fever and vomiting three months before admission. She had a history of pulmonary MAC diagnosed five years earlier but remained untreated due to stable lung lesions. Abdominal computed tomography (CT) during her current illness revealed new thickening at the jejuno-jejunal anastomosis site and enlarged mesenteric lymph nodes. Positron emission tomography-CT indicated increased uptake at these sites, suggesting a possible malignancy. Endoscopy revealed an elevated lesion with circumferential ulcers, leading to a suspicion of primary malignant lymphoma. However, biopsies showed CD68-positive histiocyte-like cells with numerous acid-fast bacilli, confirming disseminated MAC infection. Despite ongoing antimicrobial therapy, the patient's intestinal lesions persisted, and she required prolonged hospitalization and interventions for bile drainage and enteral nutrition. Conclusion: This case underscores the importance of considering disseminated MAC as a potential complication in solid organ transplant recipients, even when a long period has passed since transplantation. Disseminated MAC can mimic malignancy, presenting with significant lesions causing intestinal obstruction. Awareness and thorough differential diagnosis are essential for timely and accurate management in such complex cases. The patient's outcome emphasizes the need for vigilance in managing long-term immunosuppressed patients, particularly when they present with atypical infections. [ABSTRACT FROM AUTHOR]

Background: Recurrent Non-Tuberculous Mycobacterial Pulmonary Disease (NTM-PD) related to treatment with Secukinumab has not been previously documented. Case presentation: Despite adherence to treatment and avoiding hot springs, a plaque psoriasis patient experienced persistent NTM-PD relapses. Conclusions: There is potential association between Secukinumab, an IL-17A inhibitor, and NTM disease, echoing anti-TNF biologics' NTM risk, indicating the urgent need for further research on pathogenic mechanisms and risk factors. [ABSTRACT FROM AUTHOR]

The Mycobacterium avium complex (MAC) is a group of closely related nontuberculous mycobacteria that can cause various diseases in humans. In this study, genome sequencing, comprehensive genomic analysis, and antimicrobial susceptibility testing of 66 MAC clinical isolates from King Chulalongkorn Memorial Hospital, Bangkok, Thailand were carried out. Whole-genome average nucleotide identity (ANI) revealed the MAC species distribution, comprising 54 (81.8%) M. intracellulare, 6 (9.1%) M. avium, 5 (7.6%) M. colombiense, and 1 (1.5%) M. timonense. Phylogenetic analysis revealed a high diversity of M. intracellulare isolates and their evolutionary relationships which could be divided into 2 subspecies: M. intracellulare subsp. intracellulare and M. intracellulare subsp. chimaera. In addition, M. intracellulare subsp. chimaera mostly clustered in the distinct clades separated from M. intracellulare strains originating from other countries. Most MAC isolates were resistant to linezolid and moxifloxacin based on phenotypic antimicrobial susceptibility testing. Mutations within rrl gene associated with clarithromycin resistance were detected in M. intracellulare and M. colombiense. The pan-genome analysis presented clade-specific proteins for M. intracellulare, such as PE and PPE protein families. This study provides valuable insights into the genomic diversity and antimicrobial resistance profiles of MAC isolates circulating in Thailand, which are useful for clinical management, guiding the development of targeted diagnostic, and treatment strategies for MAC infections. [ABSTRACT FROM AUTHOR]

Purpose: Mycobacterial liquid culturing typically requires six weeks or longer, primarily because of the slow growth rate of Mycobacterium tuberculosis. This study aimed to evaluate the potential of shortening the duration of mycobacterial liquid culturing in healthcare settings with high prevalence rates of non-tuberculous mycobacteria. Methods: We retrospectively analyzed the relationship between mycobacterial species and time to positive testing of liquid cultures from sputum samples using the Mycobacteria Growth Indicator Tube system over a 3.5-year period beginning in July 2020 at a university hospital in Japan. Results: We analyzed 15,147 sputum culture samples and found a 1.1% positivity rate for Mycobacterium tuberculosis complex, while the rates for Mycobacterium avium complex and Mycobacterium abscessus were 17.6% and 2.1%, respectively. The median time to positivity was 17 days for Mycobacterium tuberculosis complex, 9 days for Mycobacterium avium complex, and 4 days for Mycobacterium abscessus. Comparing a 4-week culture period with an eight-week period, the positivity rates for Mycobacterium avium complex and Mycobacterium abscessus were 97.0% and 99.4%, respectively. Conclusion: In settings with a high incidence of non-tuberculous mycobacteria, the basic liquid culturing period can be safely shortened to 4 weeks without significantly compromising detection sensitivity, except for the samples that are highly suspected to contain tuberculosis, extremely slow-growing mycobacteria, smear-positive, or nucleic acid amplification testing positive. [ABSTRACT FROM AUTHOR]

Background: Accurate and timely diagnosis of mycobacterial infections, including Mycobacterium tuberculosis complex (MTBC) and nontuberculous mycobacteria (NTM), is crucial for effective disease management. Methods: This study evaluated the performance of the NeoPlex TB/NTM-5 Detection Kit (NeoPlex assay, Seongnam, Republic of Korea), a multiplex real-time PCR assay that incorporates melting curve analysis, compared with the line-probe assay (LPA). The NeoPlex assay could simultaneously detect and differentiate MTBC from five other NTM species: Mycobacterium intracellulare, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium abscessus, and Mycobacterium massiliense. A total of 91 acid-fast bacillus culture-positive samples, comprising 36 MTBC and 55 NTM isolates, were collected from the Korea University Anam Hospital. Results: The NeoPlex assay successfully detected nucleic acids in 87 of the 91 isolates (95.6%). Notably, it identified additional mycobacterial nucleic acids not detected by the LPA in eight isolates. These findings were confirmed via DNA sequencing. The assay had 100% sensitivity and specificity for M. intracellulare, M. abscessus, M. massilense, NTM, and MTBC, whereas it had 100% specificity and sensitivity of 90.9% and 75.0% for M. avium and M. kansasii, respectively. Conclusions: These results highlight the potential of the NeoPlex assay to enhance rapid and accurate diagnosis of mycobacterial infections, particularly in settings in which prompt treatment initiation is essential. [ABSTRACT FROM AUTHOR]

Mycobacterium chimaera, belonging to the Mycobacterium avium complex, is an opportunistic environmental mycobacterium which has been isolated from medical device water samples such as Heater Cooler Units (HCU). Laboratories currently use culture-based diagnostic methods to detect M. chimaera, but these take a long time to obtain results. The aim of this study is to test and define the Limit of Detection (LoD) of a Real-Time Polymerase Chain Reaction test (RT-PCR) specific for M. chimaera, using a sample-to-result InGenius platform, performed on medical device water samples collected at the referral centre for the detection of mycobacteria from environmental specimens of Bologna, Italy. A total of 285 water samples were included in this study. The sensitivity and specificity of RT-PCR compared to culture were 60.5% and 98.8% respectively, with an overall agreement of 82.1% and a positive predictive value of 97.4%. The LoD calculated was approximately 2900 CFU/ml. In conclusion, this study confirmed that detection of M. chimaera with RT-PCR could support culture-based methods in reducing the time necessary to identify highly colonised HCUs, with high positive predictive values. Therefore, we suggest performing this customised RT-PCR on concentrated decontaminated water samples, shutting down and thoroughly disinfecting positive HCUs, to reduce the risk of patient infection. [ABSTRACT FROM AUTHOR]

Introduction: The incidence and prevalence of infections with non-tuberculous mycobacteria such as Mycobacterium avium (Mav) are increasing. Prolonged drug regimens, inherent antibiotic resistance, and low cure rates underscore the need for improved treatment, which may be achieved by combining standard chemotherapy with drugs targeting the host immune system. Here, we examined if the diabetes type 2 drug metformin could improve Mav-infection. Methods: Metformin was administered to C57BL/6 mice infected intranasally with Mav and C57BL/6 mice were infected intranasally with Mav and treated with metformin over 3 weeks. Organ bacterial loads and lung pathology, inflammatory cytokines and immune cell profiles were assessed. For mechanistic insight, macrophages infected with Mav were treated with metformin alone or in combination with inhibitors for mitochondrial ROS or AMPK and assessed for bacterial burden and phagosome maturation. Results and discussion: Three weeks of metformin treatment significantly reduced the lung mycobacterial burden in mice infected with Mav without major changes in the overall lung pathology or immune cell composition. Metformin treatment had no significant impact on tissue inflammation except for a tendency of increased lung IFNγ and infiltration of Mav-specific IFNγ-secreting T cells. Metformin did, however, boost the antimicrobial capacity of infected macrophages directly by modulating metabolism/activating AMPK, increasing mitochondrial ROS and phagosome maturation, and indirectly by bolstering type I immunity. Taken together, our data show that metformin improved the control of Mav-infection in mice, mainly by strengthening antimicrobial defenses in macrophages, and suggest that metformin has potential as an adjunct treatment of Mav infections. [ABSTRACT FROM AUTHOR]

In cats, mycobacteriosis tends to present in a syndromic manner, with cases either being due to tuberculosis (TB) (in countries where TB is endemic), one of the “leprosy‐like” diseases affecting the skin and subcutis, panniculitis caused by infection of subcutaneous tissues generally with rapidly growing Mycobacteria spp. or widely disseminated granulomatous disease, which is usually caused by members of the Mycobacterium avium‐intracellulare complex (MAC). Disseminated MAC disease is rare, but when it occurs, usually develops in immunocompromised hosts with defective cell‐mediated immunity. This report describes a case of widely disseminated mycobacteriosis in a 10‐year‐old American Shorthair cat with an atypical multi‐organ distribution including rarely documented thyroid gland involvement. The cat presented for a chronic history of inappetence and weight loss. Abdominal ultrasonography revealed a large mass on the left kidney, and an aspirate (FNA) from this mass showed abundant negative‐staining bacilli which were confirmed to be acid‐fast with Ziehl–Neelsen (ZN) staining. This was consistent with a mycobacterial aetiology. Necropsy revealed mycobacterial granulomas and/or granulomatous inflammation in the kidneys, thyroid gland, liver, spleen, lungs and left mandibular lymph node, with abundant intralesional acid‐fast bacilli in all these tissues. Polymerase chain reaction (PCR) and culture on samples of all affected tissues were positive for M. avium. Collectively, the findings are consistent with disseminated mycobacteriosis due to M. avium with atypical distribution of lesions. Very likely, the cat had underlying immunodeficiency of undetermined cause, exacerbated by the administration of depot corticosteroid. [ABSTRACT FROM AUTHOR]

This review of non‐tuberculous mycobacterial pulmonary disease over an 11‐year period identified 87 patients (74% women, mean age 66 years). Mycobacterium avium complex was isolated in 86% of patients. Antibiotics were commenced in 52% of patients; however, treatment was poorly tolerated with 36% terminating prematurely. Mortality was significant; death occurred in 31% of patients, with no relationship between death and treatment. [ABSTRACT FROM AUTHOR]

Background: Paratuberculosis, caused by Mycobacterium avium subspecies paratuberculosis (MAP), is a chronic granulomatous enteritis that affects domestic and wild ruminants and camelids. The disease has rarely been reported in alpacas in Germany. This publication describes epidemiologically independent cases of paratuberculosis in two alpacas in Germany. Case presentation: Two alpacas, a 26-year-old female zoo animal (case 1) and a 2.5-year-old breeding stallion from a private owner (case 2), presented with progressive emaciation, leading to death (case 2) or euthanasia (case 1) because of deteriorating general condition. In both cases typical granulomatous lesions in the intestinal mucosa and mesenteric lymph nodes were found. In case 2, other lymph nodes were severely enlarged and MAP was detected in the mandibular lymph node, lung, and liver by qPCR. The MAP isolates differed between the alpacas, with two distinct phylogenetic clades (Clade 1 and 8) within Subgroup A of the MAP-C type group and two distinct INMV profiles (INMV 2 and 1) found. These genotypes have been identified in cattle and goats in different regions in Germany. The genotype isolated from case 1 has been detected in goats from the zoo since 2011, indicating transmission between these species. Conclusions: MAP can cause severe clinical disease in alpacas of variable age and under different husbandry conditions. Therefore, paratuberculosis should be considered for differential diagnosis in alpacas with emaciation and poor general condition. Although not definitely shown, cross-species infection between ruminant species and camelids is exceedingly likely. [ABSTRACT FROM AUTHOR]

Background and Aims: Mycobacterium species cause life-threatening pulmonary and extrapulmonary diseases in humans. This study aimed to evaluate the potential antimycobacterial activity of allomaltol derivatives in the Mannich base structure in vitro and in silico. Methods: The antimycobacterial activity of each compound against Mycobacterium tuberculosis and Mycobacterium avium was tested using a resazurin microplate assay, and cytotoxicity was assessed using human MRC-5 and He-La cells. Using the SwissTarget tool, Rip1 protease, the metallo-beta-lactamase (MBL) superfamily protein, the serine protease Rv3671c, and zinc metalloprotease 1 (ZMP1) were identified as potential targets. Blind docking was performed for compound 14 using CB-Dock to identify and assess the most probable binding sites on the target proteins. Defined docking was performed with Flare to determine the best binding pose at the predicted binding pocket. The druglikeness of hit compounds, including the partition coefficient, number of hydrogen bond donors/acceptors, molecular refractivity, topological polar surface area (PSA), and gastrointestinal and blood-brain barrier absorption, were evaluated using the SwissADME tool. Results: Compounds with methyl-substituted piperidine groups were found to have antimycobacterial activity (MICs: 2 μg/mL) against M. avium, which was as potent as the clinically used drugs ethambutol and streptomycin. The predicted physicochemical properties of the four hit compounds were satisfactory. According to the docking results, the binding energies of compound 14, which showed the best overall antimycobacterial activity, ranged from -8.14 to -5.97 kcal/mol, with ZMP1 showing the lowest binding energy. Conclusion: The results of this study provide evidence that allomaltol derivatives are promising antimycobacterial agents with satisfactory drug profiles. [ABSTRACT FROM AUTHOR]

Advanced HIV disease (AHD) is increasing, with late presentation accounting for half of newly diagnosed people with HIV (PWH) in Europe. Mortality in late-presenting PWH remains high, and Mycobacterium avium complex (MAC) disease, among other opportunistic infections, presents several diagnostic and treatment challenges that lead, ultimately, to a poor clinical outcome. We aimed to provide guidance on the diagnosis and treatment of disseminated MAC disease (dMACd) in PWH. We performed a review of original articles, meta-analyses, and systematic reviews retrieved from PubMed. We reviewed and discussed the most challenging steps in the management of PWH with AHD and dMACd: the current epidemiology in the era of effective antiretroviral treatment; clinical presentation and interpretation of symptoms in the context of other opportunistic infections and immune reconstitution; diagnosis, sampling, and timing to reach a definitive diagnosis; prophylaxis, treatment options, and indications for discontinuing MAC treatment; future perspectives; and the role of rifamycins in the treatment of dMACd. Despite the widespread availability of effective antiretroviral treatment, dMACd still represents a major cause of morbidity and mortality in PWH with AHD. Residual challenges are mainly related to the difficulties and timing required to reach a definitive diagnosis, and the discussion regarding the role of rifamycins in the treatment of dMACd is still open. [ABSTRACT FROM AUTHOR]

The Mycobacterium avium complex (MAC) consists of ubiquitously present bacteria causing diseases in humans and animals. MAC infections have led to global outbreaks in recent decades. The ever-increasing MAC infections coupled with antibiotic resistance increased the economic burden on healthcare facilities, underlining the need for novel therapeutic strategies for controlling them. The purpose of the study was to examine the pangenome of MAC, understand the factors shaping the phylogeny and pathogenesis, and recognize the functionalities associated with COGs and KEGG pathways. Pangenome analysis using 90 complete genomes identified 2320 core, 1893 to 3958 accessory genes, and 6644 unique genes. While the open pangenome had an expansion rate "b" of 0.312212, the core genome remained stable. The accessory genes contributed to the variability, shaped adaptations in myriad environments, and facilitated survival within different hosts. Phylogenetic analysis demonstrated the interrelationships and depicted geographical relatedness between the strains. Besides, it reflected the ability to adapt to diverse conditions. Functional assessment of the pangenome components in COGs and KEGG disclosed the role of metabolic activities and pathogenic genes necessary for maintaining the lifestyle of these bacteria. Noteworthy genes in COGs linked to the pathogenesis of MAC included TetR/AcrR/ArC/ArsR/GntR/MerR/MarR family transcriptional regulators, MCE family proteins, Mmpl family proteins, PE/PPE family, and PPE repeat proteins, cytochrome P450, Type—II, and VII secretion system proteins, mycobactin polyketide synthetases, EmrB/QacA subfamily proteins, and virulence factor mvin family domain proteins. This study highlighted better comprehension of MAC and laid the foundation for future investigations to expand the outcomes. [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]

Background: The sexual transmissibility of enteric pathogens, including Salmonella spp., has been described in men who have sex with men (MSM). However, the factors seen in MSM with Salmonella spp. are poorly understood. Method: We aimed to systematically review the literature to explore any factors seen in MSM with Salmonella spp. (MSM). We searched six databases—Medline, PubMed, CINAHL, Embase, Emcare, and Global Health—in April 2024 for manuscripts which contained primary peer-reviewed data in English and the measurement of any risk factors observed in MSM with Salmonella spp. This review was registered on PROSPERO (CRD42023472864). Results: Eleven manuscripts were included in the final review and highlighted demographic (living with HIV), behavioural (oral–anal sex, receptive and penetrative anal sex, hand licking to stimulate their partner, group sex, non-condom use), and biological (co-infection with CMV, Mycobacterium avium complex, Strongyloides stercoralis, Blastocystis hominis, Klebsiella spp. Herpes simplex virus, Cytomegalovirus, Cryptosporidium, Histoplasmosis, Shigella spp.; previous infection with Treponema pallidum, Neisseria gonorhoeae, Chlamydia trachomatis and hepatitis B; and antimicrobial treatment failure) factors seen in MSM with Salmonella spp. Conclusion: Despite a limited number of manuscripts and individuals, this review highlighted some potential demographic, behavioural, and biological factors implicated in the transmission of Salmonella spp. in MSM. These data will provide insights for future guidelines, public health control strategies, and research. [ABSTRACT FROM AUTHOR]

Background/Objectives: In sub-Saharan Africa, there is paucity of data regarding non-tuberculous mycobacterial (NTM) infections, leading to underappreciation of disease burden. Consequently, fewer resources are allocated, leading to potential adverse outcomes. This study examines long-term mortality and risk factors of South African patients with positive NTM samples. Methods: We conducted a retrospective analysis of clinical isolates of NTMs between 1 January 2010 and 30 June 2017. We retrieved and thoroughly reviewed the corresponding medical records of patients treated at Charlotte Maxeke Johannesburg Academic Hospital. Outcomes were compared between patients who underwent different therapy regimens, including macrolide-based regimens and 'watchful waiting'. Results: A total of 123 patients were followed for a median of 1 year (interquartile range [IQR], 0.5–4.5). The median age was 39 years (IQR, 31–51) with male predominance, 58%. The common comorbid conditions were HIV (encountered in 78%) and previous TB (58%). Pulmonary disease due to Mycobacterium avium complex (MAC-PD) was found in 74% of patients, M. fortiutum in 5%, and M. gordonae in 4%. The mortality relative risk for patients on initial macrolide-containing therapy was 0.54 (95% confidence interval [CI], 0.22–1.36), p = 0.194, while that for macrolide-free antimicrobials was 1.38 (95% CI, 0.57–3.34), p = 0.471. The adjusted hazard rate for mortality with low CD4 counts < 50 cells/mm3 was 2.79 (95%, 1.20–6.50), while that for unknown CD4 counts was 4.01 (95% CI, 1.17–13.77), compared to CD4 counts > 50 cells/mm3. Conclusions: Among HIV patients, NTM-PD predominated, and not disseminated disease. MAC-PD was the most common infection. Low CD4 counts was a significant risk factor for early death, while sex, NTM species, macrolide therapy, and previous TB were not. [ABSTRACT FROM AUTHOR]

European badgers (Meles meles) play an important role in the epidemiology of bovine tuberculosis (caused by Mycobacterium bovis) in England, but little is known about the prevalence of atypical mycobacteriosis. Badgers are also known to be infected by other infectious agents, and the relationship between mycobacteriosis and concomitant infections needs further investigation. Overall, 88 badger carcasses from the Midlands of England collected between July 2016-August 2017 were selected for histopathological examination based on the degree of autolysis (mild), mycobacterial culture results and a balanced sex ratio. Mycobacteria were cultured from 44 badgers, of which 31 were mycobacteria belonging to the M. tuberculosis complex (MTBC) (based on IS6110 PCR and Hsp64 and/or rRNA PCR and sequencing) and 13 were non-tuberculous atypical mycobacteria (NTM). Mycobacteria were not cultured from the remaining 44 animals. Histologically, the most common findings were silica-laden macrophages (85%), granulomas (53%), sarcocystosis (47%), nephritis (31%), portal/periportal hepatitis (26%), ulcerative dermatitis (18%). Culturable mycobacteriosis was associated with higher prevalence of granulomas (p < 0.001) and lower prevalence of hepatitis (p = 0.003). NTM (M. nonchromogenicum, M. avium complex, M. hassiacum, M. malmoense, M. vaccae.) infections were associated with granulomatous pneumonia, and M. malmoense was associated with pyogranulomatous and ulcerative dermatitis. In conclusion, this study describes, for the first time, histological lesions associated with NTM in badgers, the histomorphology of which was similar to those caused by MTBC. In addition, the negative relationship between mycobacteriosis and periportal hepatitis may indicate a complex relationship between mycobacteriosis and other diseases, as previously observed with tuberculosis. [ABSTRACT FROM AUTHOR]

The incidence of infections caused by the Mycobacterium avium complex (MAC) has risen significantly, posing diagnostic and therapeutic challenges. This study analyzed 134 clinical isolates of the Mycobacterium avium complex from southern Spain, performing in vitro antimicrobial susceptibility testing using a commercial microdilution technique to generate additional data, refine treatment strategies, and improve patient outcomes. Phenotypic susceptibility testing revealed clarithromycin and amikacin as the most effective antibiotics, with susceptibility rates exceeding 90%, while linezolid and moxifloxacin exhibited limited activity, with resistance rates of 49.3% and 41.8%. A comparative analysis between M. avium and M. intracellulare showed significant differences in resistance to amikacin and linezolid, with M. avium exhibiting higher resistance rates. Additionally, species-specific differences were observed in MIC distributions for ethionamide, ciprofloxacin, and streptomycin. Our data reveal regional variability in resistance patterns, particularly for moxifloxacin and linezolid, which exhibit differing resistance rates compared to studies from other regions. The significant MIC differences for several antibiotics between M. avium and M. intracellulare underscore the importance of species-level identification and the heterogeneity in resistance mechanisms within MAC. [ABSTRACT FROM AUTHOR]

We present a patient with human immunodeficiency virus who developed multiple painful lesions that previously in the past had speciated as Cryptococcus neoformans cutaneously, and in the lung. Despite induction therapy for presumed re-infection, the patient did not improve so a biopsy was performed and this was speciated as Mycobacterium avium complex, with final diagnosis being disseminated Mycobacterium avium complex. This case highlights the importance of considering a broad differential diagnosis for any new lesions regardless of prior culture data.

Mycobacterium avium complex (MAC) infection is a growing public health concern worldwide, particularly affecting the elderly and immunocompromised population. The treatment of MAC lung disease relies on a combination of antibiotics in a three‐drug regimen that includes macrolides, rifamycins, and ethambutol. Therefore, the investigation of antimicrobial susceptibility is crucial for successful treatment. This study aimed to assess the antibiotic susceptibility of the most prevalent MAC species causing MAC lung disease, Mycobacterium intracellulare, in the Southwestern Gyeongsang province of South Korea using a resazurin‐based microtiter assay. A total of 97 strains of M. intracellulare were isolated and tested for antimicrobial susceptibility. The results demonstrated high susceptibility rates for two aminoglycosides (amikacin and streptomycin, 94.9% and 99%), rifampicin (90.9%), clarithromycin (98%), linezolid (100%), and moxifloxacin (94.9%) against M. intracellulare. However, notably high resistance rates were observed for ethambutol (97%) and clofazimine (98%) against M. intracellulare. In conclusion, our findings indicate relatively high susceptibility rates for these six antibiotics and significantly elevated resistance rates for clofazimine and ethambutol compared to other regions in South Korea and foreign countries. The investigated MIC data can offer valuable insights for developing an effective treatment regimen for MAC lung infection in this area. [ABSTRACT FROM AUTHOR]

Purpose: GATA2 deficiency is an autosomal dominant disease that manifests with a range of clinical symptoms, including increased susceptibility to viral, bacterial, and fungal infections. Furthermore, the increased susceptibility to infections in GATA2 deficiency can trigger hemophagocytic lymphohistiocytosis (HLH) in these patients. Our systematic review evaluates reported cases of GATA2 deficiency and HLH in the literature. Methods: A systematic review of case reports was conducted following PRISMA 2020 guidelines, encompassing studies retrieved from Ovid MEDLINE ALL, Embase via Ovid SP, Scopus, Web of Science, and Google Scholar from inception until June 14, 2024. This review included studies reporting patients diagnosed with GATA2 deficiency or having a documented history of the condition, who subsequently developed or were concurrently diagnosed with HLH. Various study types were considered, such as case reports, case series, letters to editors, original articles, correspondences, and commentaries, without any restrictions on language. Results: In our systematic review, 15 studies from 2016 to 2024 were analyzed, encompassing 23 patients with GATA2 deficiency and HLH. the mean (SD) age of patients was 23.48 (10.54) years, ranging from 7 to 57 years. These patients exhibited diverse genetic mutations and a spectrum of infections, particularly Mycobacterium avium (M. avium), Mycobacterium kansasii (M. kansasii), Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV), herpes simplex virus (HSV), and influenza A, often leading to HLH. Family histories of GATA2-deficient patients with HLH occasionally reveal confirmed GATA2 mutations or suspicious cases among first-degree relatives. Hematopoietic stem cell transplantation (HSCT) was performed in 8 patients with GATA2 deficiency and HLH. Among them, 6 patients survived post-therapy, while 2 patients died following HSCT. Currently, 1 patient is being considered for HSCT. The overall mortality rate among GATA2 deficiency patients who experienced HLH was 39.13%. Conclusions: This systematic review highlights GATA2 deficiency's association with diverse infections triggering HLH, emphasizing early infection management to mitigate mortality risks. This comprehensive analysis contributes to scientific knowledge, offering important insights for clinicians and researchers in diagnosing and managing this rare condition. [ABSTRACT FROM AUTHOR]

Background/Aims Although increased mortality has been reported among people with Mycobacterium avium complex pulmonary disease (MAC-PD), data are limited on survival associated with various antibiotic regimens used to treat MAC-PD. We conducted a comparative analysis of 3-year mortality in Medicare beneficiaries with bronchiectasis using various MAC-PD regimens. Methods We included Medicare beneficiaries aged ≥65 years with bronchiectasis (01/2006–12/2014). We limited our cohort to new MAC-PD therapy users. MAC-PD therapy was defined as ≥60-day prescriptions for a macrolide plus ≥1 other MAC-PD antibiotic. Guideline-based therapy (GBT) included a macrolide, ethambutol, and/or rifamycin. Using Cox proportional hazard models, we calculated adjusted hazard ratios (aHR) for death up to 3 years after therapy start between the following groups: (1) 2007 GBT versus non-GBT; (2) 2020 GBT versus non-GBT; and (3) macrolide-ethambutol-rifamycin (3-drug) versus macrolide-ethambutol (2-drug). Results We identified 4820 new MAC-PD therapy users, of whom 866 (17.9%) were deceased within 3 years of therapy initiation. Of 3040 (63.1%) beneficiaries prescribed 2007 GBT, 472 (15.5%) were deceased by 3 years, compared to 394 (22.1%) of 1780 (36.9%) prescribed non-GBT (aHR 0.82; 95% confidence interval [CI],.72–.94). We observed a similar trend for 2020 GBT versus non-GBT (aHR 0.81; 95% CI,.70–.94]). Three-year-mortality was similar between those starting 3-drug versus 2-drug regimens (aHR 0.89; 95% CI,.74–1.08]). Conclusions Among Medicare new MAC-PD therapy users, 3-year-mortality was higher in those prescribed non-GBT regimens compared to GBT regimens. Whether this finding suggests improved efficacy of GBT and/or differential characteristic of those using non-GBT regimens deserves further study. [ABSTRACT FROM AUTHOR]

Background: The incidence of non-tuberculous mycobacterium infection has shown a gradual increasing trend in recent years, among which cutaneous manifestations as an important aspect. This study aimed to describe the clinical features and microbiological findings in 6 cases of primary cutaneous nontuberculous mycobacterium infection. Methods: In this retrospective study from June 2021 to June 2022, the clinical data and microbiological results of six cases diagnosed with primary cutaneous non-tuberculous mycobacterium infection in department of dermatology, Hangzhou Third People's Hospital were analyzed. Results: All six cases were primary cutaneous non-tuberculous mycobacterium infections, four of which had a history of trauma or exposure, and two had an underlying disease that could lead to compromised immunity. All patients presented with erythema nodular skin lesions, four on the upper or lower extremities, one on the face, and one on the right hip. The histopathological findings of five patients who underwent biopsy were granulomatous inflammatory changes with mixed infiltration. Laboratory cultures using tissue or tissue fluid were all successful, including four Mycobacterium marinum, one Mycobacterium abscessus, and one Mycobacterium avium. Metagenomics next-generation sequencing detected results consistent with culture colonies in only two cases. With the exception of case 4, all patients responded well to oral medication, with a course of treatment ranging from 4 months to 1 year, and the prognosis was good. Conclusions: The clinical features of primary cutaneous non-tuberculous mycobacterium infection are often lacking in specificity, and the identification of related strains is difficult for a variety of reasons. Although the results of metagenomics next-generation sequencing are useful for pathogen spectrum identification, its diagnostic value should be carefully reevaluated under certain circumstances. Patients with suspected triggers who do not respond well to conventional treatments should be suspected as atypical infection and potential immunosuppression. If diagnosed and treated promptly, the prognosis of primary cutaneous non-tuberculous mycobacterium infection is generally good. [ABSTRACT FROM AUTHOR]

A 3‐year‐old male neutered Golden Retriever with nasal swelling and lymphadenopathy was diagnosed with diffuse Mycobacterium avium infection. Treatment with 9 months of enrofloxacin, clarithromycin and rifampicin was successful, but relapsed 10 months later with lymphadenopathy, skin plaques and testicular involvement. Repeat treatment for 12 months was effective but 15 months later a second relapse responded to the same therapy which is ongoing with survival from diagnosis of 82 months. A 1‐year‐old male neutered Portuguese Podengo was diagnosed with polyarthritis and M. avium infection and treated with enrofloxacin, clarithromycin and rifampicin for 4 months but relapsed, subsequently responding to combined pradofloxacin, rifampicin, doxycycline and ethambutol. After 12 months of treatment, M. avium was detected and treatment extended to 17 months before stopping when no organism was detected. Relapse occurred after 6 weeks, responding to retreatment but relapsing (polyarthropathy, lymphadenomegaly) after 15 months, with euthanasia 38 months after diagnosis. Dogs with M. avium are challenging to treat with frequent relapse; however, long‐term survival is possible. [ABSTRACT FROM AUTHOR]

Background: Edoxaban, the only factor Xa inhibitor with active metabolites, is metabolized by carboxylesterase-1 to its main active metabolite, M-4, which is a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) and is excreted in bile and urine. Because the area under the plasma concentration–time curve ratio of M-4 to parent compound is typically less than 10% in healthy subjects, M-4 is generally considered to exhibit negligible antithrombotic activity in patients treated with edoxaban. However, we identified a case in which drug interactions and kidney impairment led to a substantive increase in plasma M-4 concentrations. Case presentation: This case report involved a 68-year-old man with pancreatic cancer who was orally administered edoxaban tablets for prevention of thrombus formation in non-valvular atrial fibrillation, in addition to rifampin and clarithromycin (CAM) for treatment of mycobacterium avium complex lung disease. These medications were temporarily discontinued for a pancreaticoduodenectomy but were resumed 8 days post-surgery (POD8). On POD9, the patient developed acute kidney injury, and the trough concentrations of edoxaban and M-4 were 131.1 ng/mL and 115.8 ng/mL, respectively (M-4 ratio: 88.3%). On POD11, the M-4 trough concentration and M-4 ratio increased to 216.2 ng/mL and 186.2%, respectively. The plasma concentration of coproporphyrin-I, an endogenous biomarker of OATP1B1 activity, increased during this period. Conclusions: This case suggests that in patients with impaired renal function taking edoxaban, co-administration of carboxylesterase-1 inducers such as rifampin and/or OATP1B1 inhibitors such as rifampin or clarithromycin may increase plasma concentrations of M-4 to clinically non-negligible levels. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to develop a novel diagnostic approach using the recombinase aided amplification-lateral flow dipstick(RAA-LFD) assay for the distinction of Mycobacterium tuberculosis (MTB) and Mycobacterium avium complex (MAC), enabling rapid and convenient as well as accurate identification of them in clinical samples. Methods: Our study established a duplex RAA-LFD assay capable of discriminating between MTB and MAC. Based on the principles of RAA primer and probe design, specific primers and probes were developed targeting the MTB IS6110 and the MAC DT1 separately. Optimization of reaction time points and temperatures was conducted, followed by an evaluation of specificity, sensitivity, and reproducibility. The established detection method was then applied to clinical samples and compared with smear microscopy, liquid culture, LAMP, and Xpert/MTB RIF in terms of diagnostic performance. Results: The complete workflow allows for the effective amplification of the MTB IS6110 and MAC DT1 target sequences at constant 37°C within 20min, and the amplification products can be visually observed on the LFD test strip. This method exhibits high specificity, showing no cross-reactivity with nucleic acids from M. kansassi, M. abscessus, M. gordonae, M. chelonae, M. fortuitum, M. scrofulaceum, M. malmoense, M. chimaera, M. szulgai and common respiratory pathogens. It also demonstrates high sensitivity, with a detection limit as low as 102 CFU/mL. Additionally, the method's Coefficient of Variation (CV) is less than 5%, ensuring excellent repeatability and reliability. Furthermore, clinical performance evaluations, using Xpert/MTB RIF as the gold standard, demonstrated that the duplex RAA-LFD assay achieves a sensitivity of 92.86% and a specificity of 93.75%. It is also noteworthy that the assay exhibits considerable diagnostic efficacy in smear-negative patients. Conclusions: Our study introduces a rapid, specific, and sensitive duplex RAALFD assay for the discriminatory diagnosis of MTB and MAC. This method represents a significant advancement in the field of infectious disease diagnostics, offering a valuable tool for rapid detection and management of MTB and MAC infections. The implementation of this approach in point-of-care settings could greatly enhance TB control and prevention efforts, especially in resource-limited environments. [ABSTRACT FROM AUTHOR]

In cystic fibrosis (CF), there is abnormal translocation and function of the cystic fibrosis transmembrane conductance regulator (CFTR) and an upregulation of the epithelial sodium channel (ENaC). This leads to hyperabsorption of sodium and fluid from the airway, dehydrated mucus, and an increased risk of respiratory infections. In this study, we performed a proteomic assessment of differentially regulated proteins from CF and non-CF small airway epithelial cells (SAEC) that are sensitive to Mycobacterium avium. CF SAEC and normal non-CF SAEC were infected with M. avium before the cells were harvested for protein. Protein kinase C (PKC) activity was greater in the CF cells compared to the non-CF cells, but the activity was significantly attenuated in both cell types after infection with M. avium compared to vehicle. Western blot and densitometric analysis showed a significant increase in cathepsin B protein expression in M. avium infected CF cells. Myristoylated alanine rich C-kinase substrate (MARCKS) protein was one of several differentially expressed proteins between the groups that was identified by mass spectrometry-based proteomics. Total MARCKS protein expression was greater in CF cells compared to non-CF cells. Phosphorylation of MARCKS at serine 163 was also greater in CF cells compared to non-CF cells after treating both groups of cells with M. avium. Taken together, MARCKS protein is upregulated in CF cells and there is decreased phosphorylation of the protein due to a decrease in PKC activity and presumably increased cathepsin B mediated proteolysis of the protein after M. avium infection. [ABSTRACT FROM AUTHOR]

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]

Background: 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. Methods: 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. Results: 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. Conclusion: 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]

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]

In Europe and North America, the prevalence of pulmonary nontuberculous mycobacteria (NTM) is increasing. Most pulmonary NTM infections are caused by the Mycobacterium avium complex (MAC). Sadly, the treatment of pulmonary MAC is suboptimal with failure rates ranging from 37% to 58%. Therefore, there is a need to develop new therapeutics. Developing new immunotherapies and studying their interaction with standard or new drugs requires reliable assays. Four different assays including CFSE-based flow cytometry, in vitro protection assays, IFN-γ ELISPOT, and murine infection models were optimized using a reference strain of MAC (ATCC 700898) to help with the development of immunotherapies for MAC. Expansion of proliferating and IFN-γ producing human T cells is optimal after 7 days of stimulation with MAC at a multiplicity of infection (MOI) of 0.1, achieving a stimulation index of 26.5 ± 11.6 (mean ± SE). The in vitro protection assay for MAC works best by co-culturing T cells expanded for 7 days with MAC (MOI 1)-infected autologous macrophages. Aerosol MAC infection of mice allows measurement of the effects of the BCG vaccine and clarithromycin. IFN-γ ELISPOT assays with live MAC (MOI 3) stimulation of splenocytes from mice immunized with BCG help identify differences between unimmunized mice and mice immunized with BCG. In conclusion, multiple assays are available for use to identify MAC-specific effector T cells, which will help in the development of new therapeutics or vaccines against pulmonary MAC. [ABSTRACT FROM AUTHOR]

Background and Objectives: Intravenous amikacin, recommended for severe or recurrent M. avium complex (MAC) infections and as initial treatment for M. abscessus lung disease, is often limited by serious adverse effects such as renal and auditory toxicities. Inhaled Amikacin Liposome Inhalation Suspension (ALIS) enhances pulmonary drug deposition while minimizing systemic adverse effects, and it has recently been introduced as an add-on therapy for refractory MAC infections or when other standard treatments are inadequate. This study aims to retrospectively describe the outcomes of Greek patients with difficult-to-treat non-tuberculous mycobacterial (NTM) lung disease following the addition of ALIS to guideline-based therapy. Materials and Methods: Seventeen consecutive patients (median age: 66 years) treated with ALIS as an add-on therapy to a standard regimen at "Sotiria" General Hospital of Chest Diseases (Athens, Greece) from 2020 to 2023 were enrolled in this study. These patients had recurrent or refractory NTM lung disease and/or limited treatment options due to prior treatment-related adverse effects. Clinical, radiological, and microbiological data on treatment response and overall outcomes after ALIS initiation were recorded for each patient. Results: By the end of 2023, 14 out of 17 patients had either successfully completed or were continuing their ALIS therapy. At 6 months, 85.7% (12/14) showed clinical, microbiological, and radiological improvement. However, 25% (3/12) of treated patients, primarily those with monomicrobial or combined M. abscessus lung disease, experienced disease relapse after therapy completion. The most frequent adverse effects related to ALIS were mild and localized to the respiratory tract, with only one patient discontinuing therapy due to hypersensitivity pneumonitis. Conclusions: Adding ALIS to standard regimens was effective and safe in a small group of Greek patients with refractory or recurrent NTM lung disease, particularly those who had discontinued intravenous aminoglycosides due to significant adverse effects, with notable responses observed in MAC lung disease. Further research is needed to validate these findings in clinical practice and to investigate ALIS's role in NTM lung disease caused by other species. [ABSTRACT FROM AUTHOR]

Mycobacterial infections caused by tuberculous and non-tuberculous strains pose significant treatment challenges, especially among immunocompromised patients. Conventional antibiotic therapies often fail due to bacterial resistance, highlighting the need for alternative therapeutic strategies. Mycobacteriophages are emerging as promising candidates for the treatment of mycobacteria. This review comprehensively explores phage isolation, characterization, and clinical applications. Despite the need for more extensive in vitro and in vivo studies, existing evidence shows their efficacy against both sensitive and antibiotic-resistant mycobacterial strains, even under disease-mimicking conditions, particularly when used in cocktails to minimize resistance development. Mycobacteriophages can be engineered and evolved to overcome limitations associated with lysogeny and narrow host range. Furthermore, they exhibit activity in ex vivo and in vivo infection models, successfully targeting mycobacteria residing within macrophages. Delivery methods such as bacterial and liposomal vectors facilitate their entry into human cells. Considering the potential for phage-treatment-induced bacterial resistance, as described in this review, the combination of mycobacteriophages with antibiotics shows efficacy in countering mycobacterial growth, both in the laboratory setting and in animal models. Interestingly, phage-encoded products can potentiate the activity of relevant antibiotics. Finally, the application of phages in different compassionate cases is reported. The positive outcomes indicate that phage therapy represents a promising solution for the treatment of antibiotic-resistant mycobacteria. [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]

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]

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]

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]

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]

The aim of this study was to evaluate the relationship between seroprevalence of chronic diseases, hair cortisol concentration (HCC), and welfare of dairy goats housed throughout a productive cycle. Sixty multiparous dairy goats, over four years old, were selected. An animal welfare assessment was conducted using health indicators for goats, according to the AWIN protocol. Blood samples were also collected for haematology and determination of seroprevalence of chronic diseases, hair samples for determination of HCC, milk samples for chemical composition and somatic cell counts, and faecal samples for parasite load. Small Ruminant Lentivirus (SRLv) had a prevalence of 71.66%, Mycobacterium avium subspecies paratuberculosis (MAP) of 5%, Leptospira interrogans of 40% and Ovine Gammaherpesvirus type 2 (OvHV-2) of 50%. The percentages of goats that tested positive for one, two or three diseases were 31.67%, 50% and 11.66% respectively. Haematological alterations included hyperproteinaemia (84.94 ± 1.58 g/L) and hyperfibrinogenaemia (6.11 ± 0.65 g/L) for those with one or two diseases, with significant differences being found (P < 0.05). The welfare indicators related to health and the number of diseases were poor body condition, poor coat, poor udder conformation, and mucosal lesions (P < 0.05). However, no significant differences were observed between HCC and the number of chronic diseases in dairy goats (P > 0.05). Higher concentrations of cortisol in hair were found at 150 days of lactation (16.65 ± 1.39 pg/mg) compared to the mating season (9.55 ± 0.04 pg/mg) (P < 0.05). No associations were found (P > 0.05) between the production, composition, and somatic cell counts in milk and cortisol concentrations and diseases. It was concluded that the presence of chronic diseases in goats did not influence hair cortisol concentrations, possibly due to an effect of adaptive tolerance to diseases, as occurs in other domestic species; however, there was an effect of the productive stage. [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]

IntroductionThe incidence and prevalence of infections with non-tuberculous mycobacteria such as Mycobacterium avium (Mav) are increasing. Prolonged drug regimens, inherent antibiotic resistance, and low cure rates underscore the need for improved treatment, which may be achieved by combining standard chemotherapy with drugs targeting the host immune system. Here, we examined if the diabetes type 2 drug metformin could improve Mav-infection.MethodsMetformin was administered to C57BL/6 mice infected intranasally with Mav and C57BL/6 mice were infected intranasally with Mav and treated with metformin over 3 weeks. Organ bacterial loads and lung pathology, inflammatory cytokines and immune cell profiles were assessed. For mechanistic insight, macrophages infected with Mav were treated with metformin alone or in combination with inhibitors for mitochondrial ROS or AMPK and assessed for bacterial burden and phagosome maturation.Results and discussionThree weeks of metformin treatment significantly reduced the lung mycobacterial burden in mice infected with Mav without major changes in the overall lung pathology or immune cell composition. Metformin treatment had no significant impact on tissue inflammation except for a tendency of increased lung IFNγ and infiltration of Mav-specific IFNγ-secreting T cells. Metformin did, however, boost the antimicrobial capacity of infected macrophages directly by modulating metabolism/activating AMPK, increasing mitochondrial ROS and phagosome maturation, and indirectly by bolstering type I immunity. Taken together, our data show that metformin improved the control of Mav-infection in mice, mainly by strengthening antimicrobial defenses in macrophages, and suggest that metformin has potential as an adjunct treatment of Mav infections.