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The Journal of Biological Chemistry Aug 2023Mycobacterium abscessus causes severe lung infections. Clinical isolates can have either smooth (S) or rough (R) colony morphotypes; of these, S but not R variants have...
Mycobacterium abscessus causes severe lung infections. Clinical isolates can have either smooth (S) or rough (R) colony morphotypes; of these, S but not R variants have abundant cell wall glycopeptidolipids (GPL) consisting of a peptidolipid core substituted by a 6-deoxy-α-L-talose (6-dTal) and rhamnose residues. Deletion of gtf1, encoding the 6-dTal transferase, results in the S-to-R transition, mycobacterial cord formation, and increased virulence, underscoring the importance of 6-dTal in infection outcomes. However, since 6-dTal is di-O-acetylated, it is unclear whether the gtf1 mutant phenotypes are related to the loss of the 6-dTal or the result of the absence of acetylation. Here, we addressed whether M. abscessus atf1 and atf2, encoding two putative O-acetyltransferases located within the gpl biosynthetic locus, transfer acetyl groups to 6-dTal. We found deletion of atf1 and/or atf2 did not drastically alter the GPL acetylation profile, suggesting there are additional enzymes with redundant functions. We subsequently identified two paralogs of atf1 and atf2, MAB_1725c and MAB_3448. While deletion of MAB_1725c and MAB_3448 had no effect on GPL acetylation, the triple atf1-atf2-MAB_1725c mutant did not synthetize fully acetylated GPL, and the quadruple mutant was totally devoid of acetylated GPL. Moreover, both triple and quadruple mutants accumulated hyper-methylated GPL. Finally, we show deletion of atf genes resulted in subtle changes in colony morphology but had no effect on M. abscessus internalization by macrophages. Overall, these findings reveal the existence of functionally redundant O-acetyltransferases and suggest that O-acetylation influences the glycan moiety of GPL by deflecting biosynthetic flux in M. abscessus.
Topics: Humans; Acetyltransferases; Macrophages; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous
PubMed: 37390990
DOI: 10.1016/j.jbc.2023.104979 -
Clinical Microbiology and Infection :... Aug 2023Since 2013, heater-cooler unit (HCU) associated Mycobacterium chimaera infections linked to a global outbreak have been described. These infections were characterised by... (Meta-Analysis)
Meta-Analysis Review
Clinical characteristics and outcome of Mycobacterium chimaera infections after cardiac surgery: systematic review and meta-analysis of 180 heater-cooler unit-associated cases.
OBJECTIVES
Since 2013, heater-cooler unit (HCU) associated Mycobacterium chimaera infections linked to a global outbreak have been described. These infections were characterised by high morbidity and mortality due to delayed diagnosis, as well as challenges in antimycobacterial and surgical therapy. This study aimed to investigate the clinical characteristics and outcome of published cases of HCU-associated M. chimaera infections.
METHODS
We searched PubMed and the Web of Science until 15 June 2022 for case reports, case series, and cohort studies, without language restriction, on patients with M. chimaera infection and a prior history of cardiac surgery. In this systematic review of case reports, no risk of bias assessment could be performed. Clinical, microbiological, and radiological features were recorded. Logistic regression and time-to-event analyses were performed to identify the potential factors associated with better survival.
RESULTS
One hundred eighty patients from 54 publications were included. Most patients underwent surgical aortic valve (67.0%; 118/176 of patients with available data) or combined aortic valve and root replacement (15.3%; 27/176). The median period between the time point of surgery and the first symptoms was 17 months (interquartile range 13-26 months). The overall case fatality rate was 45.5% (80/176), with a median survival of 24 months after the initiation of antimycobacterial therapy or diagnosis. A reoperation (including the removal or exchange of foreign material) was associated with better survival in multivariate logistic regression (OR 0.32 for lethal events; 95% CI 0.12-0.79; p 0.015) and in time-to-event analysis (p 0.0094).
DISCUSSION
This systematic review and meta-analysis confirm the high overall mortality of HCU -associated disseminated M. chimaera infections after cardiac surgery. A reoperation seems to be associated with better survival. Physicians have to stay aware of this infection, as patients might still be present today due to the long latency period.
Topics: Humans; Mycobacterium Infections; Mycobacterium; Cardiac Surgical Procedures; Mycobacterium avium Complex; Equipment Contamination; Mycobacterium Infections, Nontuberculous
PubMed: 36918144
DOI: 10.1016/j.cmi.2023.03.005 -
Nature Reviews. Drug Discovery May 2024Tuberculosis (TB) drug discovery and development has undergone nothing short of a revolution over the past 20 years. Successful public-private partnerships and sustained... (Review)
Review
Tuberculosis (TB) drug discovery and development has undergone nothing short of a revolution over the past 20 years. Successful public-private partnerships and sustained funding have delivered a much-improved understanding of mycobacterial disease biology and pharmacology and a healthy pipeline that can tolerate inevitable attrition. Preclinical and clinical development has evolved from decade-old concepts to adaptive designs that permit rapid evaluation of regimens that might greatly shorten treatment duration over the next decade. But the past 20 years also saw the rise of a fatal and difficult-to-cure lung disease caused by nontuberculous mycobacteria (NTM), for which the drug development pipeline is nearly empty. Here, we discuss the similarities and differences between TB and NTM lung diseases, compare the preclinical and clinical advances, and identify major knowledge gaps and areas of cross-fertilization. We argue that applying paradigms and networks that have proved successful for TB, from basic research to clinical trials, will help to populate the pipeline and accelerate curative regimen development for NTM disease.
Topics: Humans; Mycobacterium Infections, Nontuberculous; Antitubercular Agents; Animals; Drug Development; Tuberculosis; Nontuberculous Mycobacteria; Drug Discovery; Lung Diseases
PubMed: 38418662
DOI: 10.1038/s41573-024-00897-5 -
Journal of Infection in Developing... Jul 2023Although non-tuberculous mycobacterium (NTM) infection accounts for only a small proportion of fever of unknown origin (FUO) cases, it has become a more common etiology... (Review)
Review
INTRODUCTION
Although non-tuberculous mycobacterium (NTM) infection accounts for only a small proportion of fever of unknown origin (FUO) cases, it has become a more common etiology in recent years. Therefore, we reviewed FUO patients with underlying NTM infection to better understand its clinical features.
METHODOLOGY
The medical records of patients presenting with FUO and diagnosed with NTM infection admitted to Peking Union Medical College Hospital between January 2016 and June 2021 were reviewed. The clinical information of patients whose follow-up data were available were summarized. Specimens submitted for pathogenic identification were processed by mycobacterial culture, acid-fast staining, and mycobacterial nucleic acid detection. IBM SPSS Statistics v22.0 (SPSS, Inc., Chicago, IL, USA) was used for data analysis.
RESULTS
Fifty-five FUO patients were diagnosed with NTM infection (55/785; 7.0% of FUO cases). Patients were mostly middle-aged men and had a relatively long disease course. Seven, 29, and 54 patients had previously no respondence to glucocorticoids, immunosuppressants, and multiple antibiotics, respectively; their inflammatory indexes were significantly increased; and there was no obvious risk of immunosuppression in this group, who were likely to be T.SPOT-TB negative (33/41; 80.5%). The most commonly identified NTM was Mycobacterium intracellulare followed by Mycobacterium chelonae/abscessus, Mycobacterium kansasii, and Mycobacterium avium.
CONCLUSIONS
Microbiological investigations including culture, acid-fast staining, NTM nucleic acid examination, and next-generation sequencing were performed to confirm the diagnosis of NTM in FUO patients. FUO patients should screen for NTM infections so that this important etiology can be recognized, targeted treatments administered early, and outcomes improved.
Topics: Male; Middle Aged; Humans; Mycobacterium Infections, Nontuberculous; Fever of Unknown Origin; Mycobacterium avium Complex; Mycobacterium; Tuberculosis; Nontuberculous Mycobacteria; Retrospective Studies
PubMed: 37515806
DOI: 10.3855/jidc.17610 -
Clinics in Chest Medicine Dec 2023Standard treatment of nontuberculous mycobacterial pulmonary disease (NTM-PD) infection involves a multi-drug antimicrobial regimen for at least 12 months. The length,... (Review)
Review
Standard treatment of nontuberculous mycobacterial pulmonary disease (NTM-PD) infection involves a multi-drug antimicrobial regimen for at least 12 months. The length, complexity, and side effect profile of antibiotic therapy for NTM-PD pose significant difficulties for maintaining patient adherence. Furthermore, physician adherence to NTM guidelines suffers for similar reasons to the extent that a study evaluating treatment approaches across multiple specialties found that only 13% of antibiotic regimens met ATS/IDSA guidelines. For this reason, a great need exists for therapy that augments the current armamentarium of antimicrobial chemotherapeutics or provides an alternative approach for decreasing host mycobacterial burden. As our knowledge of the mechanisms driving protective responses to NTM-PD infections by mammalian hosts expand, these processes provide novel therapeutic targets. These agents, which are commonly referred to as host-directed therapies (HDTs) have the potential of providing the much-needed boost to the nontuberculous mycobacterial therapeutic pipeline. In this review, we will focus on translational research and clinical trial data that detail the creation of therapeutic modalities developed to improve host mechanical protection and immunologic responses to PNTM infection.
Topics: Animals; Humans; Mycobacterium Infections, Nontuberculous; Lung; Nontuberculous Mycobacteria; Lung Diseases; Anti-Bacterial Agents; Mammals
PubMed: 37890920
DOI: 10.1016/j.ccm.2023.07.004 -
Scientific Reports Oct 2023Non-tuberculosis mycobacterial (NTM) diseases are steadily increasing in prevalence and mortality worldwide. Mycobacterium avium and M. intracellulare, the two major...
Non-tuberculosis mycobacterial (NTM) diseases are steadily increasing in prevalence and mortality worldwide. Mycobacterium avium and M. intracellulare, the two major pathogens of NTM diseases, are resistant to antibiotics, and chlorine, necessitating their capacity to survive in natural environments (e.g. soil and rivers) and disinfected municipal water. They can also form biofilms on artificial surfaces to provide a protective barrier and habitat for bacilli, which can cause refractory systemic disseminated NTM disease. Therefore, preventing biofilm formation by these pathogens is crucial; however, not many in vivo experimental systems and studies on NTM biofilm infection are available. This study develops a mouse model of catheter-associated systemic disseminated disease caused by M. intracellulare that reproduces the pathophysiology of catheter-associated infections observed in patients undergoing peritoneal dialysis. In addition, the bioluminescence system enabled noninvasive visualization of the amount and distribution of bacilli in vivo and conveniently examine the efficacy of antimicrobials. Furthermore, the cellulose-based biofilms, which were extensively formed in the tissue surrounding the catheter insertion site, reduced drug therapy effectiveness. Overall, this study provides insights into the cause of the drug resistance of NTM and may guide the development of new therapies for NTM diseases.
Topics: Humans; Mice; Animals; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Mice, Inbred Strains; Catheters; Biofilms; Bacillus
PubMed: 37816786
DOI: 10.1038/s41598-023-44403-0 -
Epidemiologie, Mikrobiologie,... 2023The annual number of diagnosed diseases caused by non-tuberculous mycobacteria in predisposed individuals remains constant in the Czech Republic. Their clinical...
The annual number of diagnosed diseases caused by non-tuberculous mycobacteria in predisposed individuals remains constant in the Czech Republic. Their clinical characteristics vary depending on the properties of the causative species and its presence and quantity in the immediate environment of the patient. The most common clinically relevant species are Mycobacterium avium, M. kansasii, and M. xenopi. The most important source of M. avium is peat and products derived from it. M. avium may colonise warm water systems, posing a high risk of exposure to users (jacuzzi users in particular). M. kansasii is still present in waters of areas affected by industrial and mining activities. Its recently isolated genetic variants are mostly of no clinical significance but may be present as contaminants in medical preparations. M. xenopi permanently colonises most warm water systems, and its practical ubiquity makes difficult the interpretation of ambiguous findings on imaging. The antibiotic treatment, which may not always be successful, should be initiated after a comprehensive assessment of the patient's condition, imaging data, and disease progression. Similarly, the results of laboratory tests may not always be authoritative in decision making.
Topics: Humans; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Czech Republic; Anti-Bacterial Agents; Water
PubMed: 37871989
DOI: No ID Found -
Journal of Orthopaedic Surgery (Hong... 2023(MAC) prosthetic joint infection (PJI) has been rarely reported.
BACKGROUND
(MAC) prosthetic joint infection (PJI) has been rarely reported.
METHODS
This study aimed to investigate the epidemiology and outcomes of MAC PJI. A systematic review of the literature regarding the MAC infection following total joint arthroplasty including hip and knee joint was performed. Multiple databases were searched for published English-written articles up to May 2023. Studies that reported cases of PJI by MAC were reviewed.
RESULTS
A total of 17 patients were identified and analyzed from 11 published studies. All patients presented with joint symptom of pain or swelling prior to the diagnosis and MAC was confirmed by culture. The most of the patients (16/17 patients, 94.1%) were noted to have underlying medical condition(s) that might have affected immunity. Treatment consisted of anti-MAC medication therapy only in two patients and anti-MAC medication therapy plus surgery in 15 patients. Among the patients who underwent surgery, 14 patients (82.3%) had removal of the prosthesis including seven patients who had two-stage surgery to have reimplantation of the prosthesis. No relapse of MAC infection was reported despite of one case of relapse of infection caused by different pyogenic bacteria. The rate of overall mortality was 29.4%, however, identified attributable mortality due to MAC infection was low (5.9%).
CONCLUSION
PJI by MAC is a rare disease. However, MAC needs to be considered in the differential diagnosis in immunocompromised patients presenting with symptoms of PJI. Two-stage exchange arthroplasty may result in successful treatment outcomes without higher risks of relapse of infection if undertaken in association with appropriate active anti-MAC antibiotic therapy.
Topics: Humans; Mycobacterium avium Complex; Arthroplasty, Replacement, Knee; Arthroplasty, Replacement, Hip; Mycobacterium avium-intracellulare Infection; Prostheses and Implants; Anti-Bacterial Agents; Arthritis, Infectious; Recurrence; Prosthesis-Related Infections; Retrospective Studies
PubMed: 37878458
DOI: 10.1177/10225536231199392 -
Frontiers in Cellular and Infection... 2023The epidemiology of complex (MTBC) lineage 5 (L5) infections in Ghana revealed a significantly increased prevalence in Ewes compared to other self-reported ethnic...
BACKGROUND
The epidemiology of complex (MTBC) lineage 5 (L5) infections in Ghana revealed a significantly increased prevalence in Ewes compared to other self-reported ethnic groups. In that context, we sought to investigate the early phase of tuberculosis (TB) infection using infection of macrophages derived from the blood of Ewe and Akan ethnic group volunteers with MTBC L4 and L5 strains.
METHODS
The study participants consisted of 16 controls, among which self-reported Akan and Ewe ethnicity was equally represented, as well as 20 cured TB cases consisting of 11 Akans and 9 Ewes. Peripheral blood mononuclear cells were isolated from both healthy controls and cured TB cases. CD14 monocytes were isolated and differentiated into monocyte-derived macrophages (MDMs) before infection with L4 or L5 endemic strains. The bacterial load was assessed after 2 hours (uptake) as well as 3 and 7 days post-infection.
RESULTS
We observed a higher capacity of MDMs from Ewes to phagocytose L4 strains (p < 0.001), translating into a higher bacillary load on day 7 (p < 0.001) compared to L5, despite the higher replication rate of L5 in Ewe MDMs (fold change: 1.4 1.2, p = 0.03) among the controls. On the contrary, within macrophages from Akans, we observed a significantly higher phagocytic uptake of L5 (p < 0.001) compared to L4, also translating into a higher load on day 7 (p = 0.04). However, the replication rate of L4 in Akan MDMs was higher than that of L5 (fold change: L4 = 1.2, L4 = 1.1, p = 0.04). Although there was no significant difference in the uptake of L4 and L5 among cured TB cases, there was a higher bacterial load of both L4 (p = 0.02) and L5 (p = 0.02) on day 7 in Ewe MDMs.
CONCLUSION
Our results suggest that host ethnicity (driven by host genetic diversity), MTBC genetic diversity, and individual TB infection history are all acting together to modulate the outcome of macrophage infections by MTBC.
Topics: Humans; Animals; Female; Sheep; Ethnicity; Ghana; Mycobacterium tuberculosis; Self Report; Leukocytes, Mononuclear; Macrophages; Latent Tuberculosis
PubMed: 37645380
DOI: 10.3389/fcimb.2023.1163993 -
BMJ Case Reports Apr 2024Catheter-related bloodstream infection (CRBSI) is one of the common healthcare-acquired infections imposing a high burden of morbidity and mortality on the patients....
Catheter-related bloodstream infection (CRBSI) is one of the common healthcare-acquired infections imposing a high burden of morbidity and mortality on the patients. Non-tuberculous mycobacterium is a rare aetiology for CRBSI and poses challenges in laboratory diagnosis and clinical management. This is a case of a woman in her early 60s with underlying end-stage renal failure, diabetes mellitus and hypertension presented with a 2-week history of high-grade fever postregular haemodialysis, vomiting, lethargy and altered mental status.Blood cultures from a permanent catheter and peripheral taken concurrently yielded , identified by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry, which established the diagnosis of CRBSI atypically presented with concurrent acute intracranial bleeding and cerebrovascular infarction at initial presentation. She was started on a combination of oral azithromycin, oral amikacin and intravenous imipenem, and the permanent catheter was removed. Despite the treatments instituted, she developed septicaemia, acute myocardial infarction and macrophage activation-like syndrome, causing the patient's death.
Topics: Humans; Female; Catheter-Related Infections; Mycobacterium Infections, Nontuberculous; Middle Aged; Anti-Bacterial Agents; Fatal Outcome; Bacteremia; Renal Dialysis; Kidney Failure, Chronic; Amikacin
PubMed: 38688568
DOI: 10.1136/bcr-2024-259761