Pulmonary Mycobacterium avium complex infection with vascular Ehlers-Danlos syndrome: A case report.

A female patient developed multiple intestinal perforations at 31 and 43 years of age. Because of her family history of pneumothorax and intestinal perforation, Ehlers-Danlos syndrome (EDS) was suspected when she visited our hospital at 52 years. She was diagnosed with vascular Ehlers-Danlos syndrome (vEDS) and developed bilateral external iliac artery dissection. A CT scan at the time of admission revealed granular and infiltrative shadows in both lungs with bronchiectasis. The patient was also diagnosed with Mycobacterium avium complex (MAC) pulmonary disease, and drug susceptibility to clarithromycin was confirmed. After treatments with rifampicin, ethambutol, and clarithromycin were started, the acid-fast bacilli cultures taken from sputum were negative, and respiratory symptoms partially improved after about 1 month. vEDS is reportedly associated with lung diseases, such as pneumothorax and cystic lung lesions, but there are few reports of respiratory infections with vEDS. Moreover, there are no reports of complications associated with MAC disease. We report a case of vEDS with rare complications and suggest the possible mechanism of infection.

Disseminated Mycobacterium avium Complex Infection Following CD3/CD20 Bispecific Antibody Therapy in a Patient With Follicular Lymphoma.

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.

Rifabutin-Induced Thrombocytopenia in a Patient With Uncontrolled HIV: A Case Report.

Uncontrolled HIV is associated with a wide range of hematologic abnormalities through direct suppressive effects, opportunistic infections, tumor marrow infiltration, or antiretroviral, antimicrobial, or antitumor therapy. We present a patient with a history of uncontrolled HIV presenting with acute severe thrombocytopenia shortly after starting treatment for disseminated Mycobacterium avium complex (MAC). While the thrombocytopenia was resistant to transfusion and intravenous immunoglobulin (IVIG), it mildly improved with dexamethasone after holding home medications. Etiologies for this patient's thrombocytopenia include uncontrolled HIV infection and medication-induced, likely secondary to rifabutin. We propose a possible combined effect of both factors. Clinicians should be aware of the increased risk of severe, acute medication-induced thrombocytopenia in patients with uncontrolled HIV, given their baseline susceptibility to hematologic abnormalities.

Pneumatosis Cystoides Intestinalis Which Developed During Treatment for Mycobacterium avium Complex Lung Disease: A Case Series of 3 Patients.

Pneumatosis cystoides intestinalis (PCI) is an uncommon condition characterized by the presence of a collection of individual gas cysts in the submucosa and subserosa of the intestine. The etiology of PCI is still unclear. We experienced 3 cases with PCI during treatment for pulmonary Mycobacterium avium complex (MAC) infection. Each case was treated conservatively. We believe our case series will highlight the importance of examining the gastrointestinal tract of patients with MAC infection and hopefully elucidate the clinical characteristics of PCI which developed during MAC treatment.

Pulmonary Mycobacterium avium Complex With Adenocarcinoma of the Lung: A Case Report.

Nontuberculous mycobacteria are responsible for causing pulmonary as well as extrapulmonary diseases. These organisms are often multidrug resistant and management of these cases poses a therapeutic challenge. Lung cancer has been a prevalent challenge globally with a high mortality rate in affected individuals. Adenocarcinoma poses debilitating outcomes in most patients by inflicting a diagnostic and therapeutic challenge. The concomitant association of adenocarcinoma and Mycobacterium avium complex worsens the prognosis causing a challenge in managing such cases. We present a rare association between adenocarcinoma and pulmonary Mycobacterium avium complex complicating the traditional therapeutic regime. A different approach in the administration of therapy for this unique concomitant association between two debilitating diseases is outlined in the presented report.

Evaluation of the GenoType NTM-DR line probe assay for nontuberculous mycobacteria using whole genome sequences as reference standard.

Pulmonary nontuberculous mycobacteria (NTM) disease is an emerging public health challenge that is especially problematic in people with cystic fibrosis (CF). Effective treatment depends on accurate species and subspecies identification and antimicrobial susceptibility status. We evaluated the GenoType NTM-DR VER 1.0 assay using biobanked NTM isolates with whole genome sequence (WGS) data and control isolates (total n=285). Species and subspecies detection sensitivity and specificity were 100 % for all species and subspecies except for two subspecies of M. intracellulare, that demonstrated a small degree of discrepant identification between M. intracellulare subspecies intracellulare and subspecies chimaera. All antimicrobial resistance markers were identified with 100 % sensitivity and specificity. We conclude that the GenoType NTM-DR assay offers a rapid and accurate option for identifying the most frequently encountered pathogenic NTM taxa and drug resistance markers. SUPPORT: Colorado CF Research Development Program and Colorado CF National Resource Centers funded by the Cystic Fibrosis Foundation, NJH Advanced Diagnostics Laboratories, Colorado Advanced Industries Accelerator Grant.

Navigating Middle Lobe Syndrome: Exploring the Impact of Mycobacterium avium.

Middle lobe syndrome (MLS) is characterized by recurrent or chronic collapse (atelectasis) of the middle lobe of the right lung. Despite its clinical significance, MLS often goes unnoticed in medical practice. It manifests with obstructive symptoms, either due to external compression or internal causes, commonly stemming from infectious agents such as Mycobacterium avium complex (MAC) or occasionally from tumors. We present a unique case of MLS induced by MAC in an immunocompetent 74-year-old female patient with a history of bronchiectasis. Imaging revealed typical findings associated with MLS. Additional testing confirmed the diagnosis, and the patient was successfully treated. This case presents the opportunity to recognize and correctly treat cases of MLS with infectious etiology.

Chemical optimization and derivatization of micrococcin p2 to target multiple bacterial infections: new antibiotics from thiopeptides.

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.

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

Background: Routine screening for nontuberculous mycobacterial (NTM) lung disease is dependent on sputum cultures. This is particularly challenging in the cystic fibrosis (CF) population due to reduced sputum production and low culture sensitivity. Biomarkers of infection that do not rely on sputum may lead to earlier diagnosis, but validation trials require a unique prospective design. Purpose: The rationale of this trial is to investigate the utility of urine lipoarabinomannan (LAM) as a test to identify people with CF with a new positive NTM culture. We hypothesize that urine LAM is a sensitive, non-invasive screening test with a high negative predictive value to identify individuals with a relatively low risk of having positive NTM sputum culture. Study design: This is a prospective, single-center, non-randomized observational study in adults with CF, 3 years of negative NTM cultures, and no known history of NTM positive cultures. Patients are followed for two year-long observational periods with the primary endpoint being a positive NTM sputum culture within a year of a positive urine LAM result and a secondary endpoint of a positive NTM sputum culture within 3 years of a positive urine LAM result. Study implementation includes remote consent and sample collection to accommodate changes from the COVID-19 pandemic. Conclusions: This report describes the study design of an observational study aimed at using a urine biomarker to assist in the diagnosis of NTM lung infection in pwCF. If successful, urine LAM could be used as an adjunct to traditional sputum cultures for routine NTM screening.

Clinical outcomes of lung transplant recipients with pre-transplant Mycobacterium avium complex infection.

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.

Long-term Outcomes of Adjunctive Lung Resection for Nontuberculous Mycobacteria Pulmonary Disease.

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.

Bacillary Angiomatosis in a Patient With HIV and Disseminated Mycobacterium avium Complex Infection.

Bartonella is a genus of arthropod-borne bacterial pathogens that typically cause persistent infections of erythrocytes and endothelial cells in mammalian hosts. The species that primarily infect humans are Bartonella henselae and Bartonella quintana. Depending on immune status, the clinical presentation of B. henselae may differ, manifesting as cat-scratch disease in immunocompetent individuals or bacillary angiomatosis (BA) and peliosis in immunocompromised patients. The cutaneous manifestations of BA are typically characterized by occasionally painful, angiomatous papules and nodules, often with a chronic, persistent course. Herein, we present a case of biopsy-confirmed B. henselae infection in a 32-year-old HIV-positive female with acquired immunodeficiency syndrome in the setting of disseminated Mycobacterium avium complex infection, an association that has been less frequently described. This case serves as an important reminder to consider uncommon opportunistic infectious etiologies when examining immunocompromised patients, as prompt diagnosis and treatment are essential in this patient population.

Opportunistic Infections and Malignancies in a Patient With HIV/AIDS and a Critically Low CD4 Count of 1 Cell/µL.

We present a 45-year-old African American male with a medical history of advanced-stage HIV/AIDS (CD4 count: 1 cell/µL) and poor adherence to highly active antiretroviral therapy (HAART), who presented with symptoms of diarrhea, weakness, and respiratory distress. Upon admission, duodenal and colonic biopsies revealed a diffuse histiocytic infiltrate consistent with Mycobacterium avium complex (MAC), and a cecal biopsy was positive for Kaposi sarcoma (KS). Further workup showed consolidation and a right pleural effusion on chest X-ray, suggesting a pneumonia infection. The patient's hypoglycemic state and lung consolidation raised concerns for sepsis, despite negative blood cultures for the first 24 hours. The patient was initiated on HAART and treated with azithromycin, rifabutin, and ethambutol for disseminated MAC. Despite the aggressive immunotherapy, the patient's condition did not improve, and he eventually expired. This case uniquely highlights the wide range of opportunistic infections and malignancies that can present in individuals with advanced-stage HIV/AIDS, underscoring the importance of early recognition and treatment. This susceptible demographic warrants further research due to the non-solidified prognosis of individuals with severe immunodeficiency.

Protein-energy restriction-induced lipid metabolism disruption causes stable-to-progressive disease shift in Mycobacterium avium-infected female mice.

BACKGROUND: Disease susceptibility and progression of Mycobacterium avium complex pulmonary disease (MAC-PD) is associated with multiple factors, including low body mass index (BMI). However, the specific impact of low BMI on MAC-PD progression remains poorly understood. This study aims to examine the progression of MAC-PD in the context of low BMI, utilising a disease-resistant mouse model. METHODS: We employed a MAC infection-resistant female A/J mouse model to compare the progression of MAC-PD under two dietary conditions: one group was fed a standard protein diet, representing protein-energy unrestricted conditions, and the other was fed a low protein diet (LPD), representing protein-energy restriction. FINDINGS: Our results reveal that protein-energy restriction significantly exacerbates MAC-PD progression by disrupting lipid metabolism. Mice fed an LPD showed elevated fatty acid levels and related gene expressions in lung tissues, similar to findings of increased fatty acids in the serum of patients who exhibited the MAC-PD progression. These mice also exhibited increased CD36 expression and lipid accumulation in macrophages upon MAC infection. In vitro experiments emphasised the crucial role of CD36-mediated palmitic acid uptake in bacterial proliferation. Importantly, in vivo studies demonstrated that administering anti-CD36 antibody to LPD-fed A/J mice reduced macrophage lipid accumulation and impeded bacterial growth, resulting in remarkable slowing disease progression. INTERPRETATION: Our findings indicate that the metabolic status of host immune cells critically influences MAC-PD progression. This study highlights the potential of adequate nutrient intake in preventing MAC-PD progression, suggesting that targeting CD36-mediated pathways might be a host-directed therapeutic strategy to managing MAC infection. FUNDING: This research was funded by the National Research Foundation of Korea, the Korea Research Institute of Bioscience and Biotechnology, and the Korea National Institute of Health.

Disinfection and monitoring of Mycobacterium avium complex in the environment: A novel approach to the management of hot tub lung.

A 45-year-old man visited our hospital with a chronic cough and breathing difficulties. Chest computed tomography revealed diffuse granular shadows. Mycobacterium avium (M. avium) was cultured from bronchoalveolar lavage fluid (BALF). Surgical lung biopsy revealed non-necrotizing granulomas, and M. avium-specific PCR was positive in the tissue. M. avium was also cultured in a sample from the inlet of the patient's bathtub. Mycobacterium avium tandem repeat variable-number tandem-repeat loci (MATR-VNTR) analysis confirmed that the M. avium cultured from BALF and the bathtub inlet had identical allele profiles. The patient's symptoms and oxygenation improved while the patient was in hospital, presumably because of lack of ongoing exposure to M. avium. He was diagnosed with hot tub lung. We advised the patient to avoid bathing to avoid re-exposure. However, the patient was unwilling to follow this advice. Therefore, his bathtub and pipework were disinfected by heating them to over 70 °C. We confirmed that the disinfection has been successful by repeated culture of environmental samples. Three months after resuming bathtub use, the patient's symptoms resolved, and the pulmonary shadows seen on the initial radiography did not recur. For the treatment of hot tub lung, disinfection of M. avium complex in the environment should be considered and the environment should be monitored to confirm eradication.

Amikacin Liposome Inhalation Suspension in the Real-World Management of Refractory Mycobacterium avium Complex Pulmonary Disease.

The increasing prevalence of Mycobacterium avium complex (MAC) pulmonary disease poses a significant therapeutic challenge, particularly due to the limited efficacy and systemic toxicity associated with conventional guideline-based therapy. Amikacin liposome inhalation suspension (ALIS) has been developed, yet its real-world application remains underreported. This retrospective analysis, conducted from March 2021 to February 2024, examined ALIS's clinical use in patients aged 20 years or older with refractory MAC pulmonary disease at our institution. The primary objective of this study is to describe the patient characteristics and clinical trajectories associated with the initiation of ALIS therapy in real-world settings for individuals diagnosed with MAC pulmonary disease. Of 11 patients initiated on ALIS, one was excluded due to financial constraints impacting continuation. The analysis proceeded with the remaining 10 subjects. The mean age of participants was 70.2 years, with a predominance of female patients (n = 7, 70%) and a higher incidence of M. avium infections (n = 6, 60%). Forty percent of the cohort (n = 4) had a history of ethambutol-induced optic neuritis leading to the cessation of the drug. The average interval from the initiation of guideline-based therapy to the start of ALIS was 8.5 ± 6.9 years (mean ± standard deviation). The majority (80%) presented with positive Gaffky scores at ALIS initiation, and a significant proportion exhibited resistance to clarithromycin and ethambutol. Comorbid conditions, including diabetes and previous cancer, were noted. The study also observed elevated anti-MAC antibody levels. Treatment duration varied, with fatigue leading to discontinuation in two cases. Treatment-emergent adverse events were documented in individual patients, each presenting with grade 1 severity: hemoptysis (n = 1, 10%), elevated creatinine levels (n = 1, 10%), and dysphonia (n = 2, 20%) were observed, respectively. Correlation analysis revealed a significant inverse relationship between body mass index (BMI) and ALIS discontinuation due to fatigue, and a positive correlation between Gaffky scores and C-reactive protein (CRP) levels. These results underscore the potential benefits and limitations of ALIS, suggesting that timely intervention and comprehensive healthcare support are crucial for optimal outcomes in the treatment of advanced MAC pulmonary disease.

Anticancer and Antibacterial Properties of Curcumin-Loaded Mannosylated Solid Lipid Nanoparticles for the Treatment of Lung Diseases.

Lung cancer and Mycobacterium avium complex infection are lung diseases associated with high incidence and mortality rates. Most conventional anticancer drugs and antibiotics have certain limitations, including high drug resistance rates and adverse effects. Herein, we aimed to synthesize mannose surface-modified solid lipid nanoparticles (SLNs) loaded with curcumin (Man-CUR SLN) for the effective treatment of lung disease. The synthesized Man-CUR SLNs were analyzed using various instrumental techniques for structural and physicochemical characterization. Loading curcumin into SLNs improved the encapsulation efficiency and drug release capacity, as demonstrated by high-performance liquid chromatography analysis. Furthermore, we characterized the anticancer effect of curcumin using the A549 lung cancer cell line. Cells treated with Man-CUR SLN exhibited an increased cellular uptake and cytotoxicity. Moreover, treatment with free CUR could more effectively reduce cancer migration than treatment with Man-CUR SLNs. Similarly, free curcumin elicited a stronger apoptosis-inducing effect than that of Man-CUR SLNs, as demonstrated by reverse transcription-quantitative PCR analysis. Finally, we examined the antibacterial effects of free curcumin and Man-CUR SLNs against Mycobacterium intracellulare (M.i.) and M.i.-infected macrophages, revealing that Man-CUR SLNs exerted the strongest antibacterial effect. Collectively, these findings indicate that mannose-receptor-targeted curcumin delivery using lipid nanoparticles could be effective in treating lung diseases. Accordingly, this drug delivery system can be used to target a variety of cancers and immune cells.

Rare Case of Mycobacterium Avium Complex Peritonitis in a Patient with Multiple Myeloma Undergoing Peritoneal Dialysis.

Mycobacterium avium complex (MAC) infections can present as a variety of severe diseases. While it has a predilection for immunocompromised patients such as those with Human immunodeficiency virus (HIV), it can also affect immunocompetent patients as well. One of the rare yet severe diseases that MAC infections can present is MAC peritonitis. Often hard to distinguish from other causes of peritonitis, high clinical suspicion should be maintained for those who are susceptible. Here we present an 85-year-old female with a past medical history of end-stage renal disease on peritoneal dialysis who presented with nausea and vomiting. She was found to have tenderness around her peritoneal dialysis site and was noted to have mild ascites. Her labs were significant for several electrolyte abnormalities, leukocytosis, and ascitic fluid obtained during a previous admission, and serology was positive for acid-fast bacilli. It was further revealed that the species was Mycobacterium avium complex. Initially, she started on rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE), subsequently antibiotics were changed to azithromycin, ethambutol, and rifampin after MAC identification in acid-fast bacilli culture. We aim to highlight this rare presentation of peritonitis secondary to MAC.

Tackling Nontuberculous Mycobacteria by Repurposable Drugs and Potential Leads from Natural Products.

Nontuberculous Mycobacteria (NTM) refer to bacteria other than all Mycobacterium species that do not cause tuberculosis or leprosy, excluding the species of the Mycobacterium tuberculosis complex, M. leprae and M. lepromatosis. NTM are ubiquitous and present in soils and natural waters. NTM can survive in a wide range of environmental conditions. The direct inoculum of the NTM from water or other materials is most likely a source of infections. NTMs are responsible for several illnesses, including pulmonary alveolar proteinosis, cystic fibrosis, bronchiectasis, chronic obstructive pneumoconiosis, and pulmonary disease. Recent reports suggest that NTM species have become insensitive to sterilizing agents, antiseptics, and disinfectants. The efficacy of existing anti-NTM regimens is diminishing and has been compromised due to drug resistance. New and recurring cases of multidrug-resistant NTM strains are increasing. Thus, there is an urgent need for ant-NTM regimens with novel modes of action. This review sheds light on the mode of antimicrobial resistance in the NTM species. Then, we discussed the repurposable drugs (antibiotics) that have shown new indications (activity against NTM strains) that could be developed for treating NTM infections. Also, we have summarised recently identified natural leads acting against NTM, which have the potential for treating NTM-associated infections.

Cystic Fibrosis-Related Nontuberculous Mycobacterial Pulmonary Disease.

Non-tuberculous mycobacteria (NTM) infection is a major cause of morbidity in people with cystic fibrosis (pwCF) with rates of infection increasing worldwide. Accurate diagnosis and decisions surrounding best management remain challenging. Treatment guidelines have been developed to assist physicians in managing NTM in pwCF, but involve prolonged and complex mycobacterial regimens, often associated with significant toxicity. Fortunately, current management and outcomes of NTM in CF are likely to evolve due to improved understanding of disease acquisition, better diagnostics, emerging antimycobacterial therapies, and the widespread uptake of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies.