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Neurology India 2023Mycobacterium abscessus complex (MabC) has emerged as an important cause of human infections, including meningitis. In the absence of correct microbiological... (Review)
Review
BACKGROUND
Mycobacterium abscessus complex (MabC) has emerged as an important cause of human infections, including meningitis. In the absence of correct microbiological identification, cases of MabC meningitis are treated with conventional anti-tubercular therapy, thereby worsening the outcome.
OBJECTIVE
The current study was conducted to determine the clinical features, antimicrobial susceptibility, and outcome of patients with MabC meningitis.
MATERIAL AND METHODS
Cerebrospinal fluid specimens processed between 2011 and 2021 were subjected to smear, culture, MALDI TOF identification, hsp65 gene sequencing, and susceptibility testing using Sensititre™ RAPMYCOI plates along with a literature review.
RESULTS
12 cases of MabC meningitis were identified between 2011 and 2021, 11 of which were M. abscessus subspecies abscessus on hsp65 gene sequencing. A pioneer case of meningitis with M. abscessus subspecies bolletii was also identified. The common predispositions were TB elsewhere, HIV positivity, and head injury. Two patients had dual infections, both MabC and TB. Ten patients succumbed to infection with a mean survival of 11 months. All isolates were susceptible to amikacin and tigecycline and subspecies bolletii had a higher minimum inhibitory concentration (MIC) than subspecies abscessus. A combined analysis with the available literature, reporting 19 more cases, revealed that the overall mortality of MabC meningitis was 61.3% (19/31) and that of shunt-associated/neurosurgical intervention-related MabC meningitis was 66.7% (12/20). To date, out of 20 MabC meningitis isolates in which subspecies identification was carried, 13 were M. abscessus, six were M. massiliense, and one was M. bolletii.
CONCLUSION
MabC is an important differential diagnosis of chronic meningitis. Prompt identification and speciation are imperative for targeted therapy, thus improving the overall patient outcome.
Topics: Humans; Mycobacterium abscessus; Tigecycline; Tuberculosis; Meningitis; Anti-Bacterial Agents
PubMed: 37929432
DOI: 10.4103/0028-3886.388095 -
Transplantation Reviews (Orlando, Fla.) Dec 2023There is lack of consensus on non-tuberculous mycobacteria pulmonary disease (NTM-PD) treatment regimen and duration in patient listed for lung transplantation (LTx). We... (Review)
Review
BACKGROUND
There is lack of consensus on non-tuberculous mycobacteria pulmonary disease (NTM-PD) treatment regimen and duration in patient listed for lung transplantation (LTx). We conducted a systematic review on treatment regimen and duration pre- and directly post-LTx, for patients with known NTM-PD pre-LTx. Additionally, we searched for risk factors for NTM disease development post-LTx and for mortality.
METHODS
Literature was reviewed on PubMed, Embase and the Cochrane Library, for articles published from inception to January 2022. Individual patient data were sought.
RESULTS
Sixteen studies were included reporting 92 patients. Most frequent used agents were aminoglycosides and macrolides for Mycobacterium abscessus (M. abscessus) and macrolides and tuberculostatic agents for Mycobacterium avium complex (M. avium complex). The median treatment duration pre-LTx was 10 months (IQR 6-17) and 2 months (IQR 2-8) directly post-LTx. Longer treatment duration pre-LTx was observed in children and in patients with M. abscessus. 46% of the patients with NTM-PD pre-LTx developed NTM disease post-LTx, related mortality rate was 10%. Longer treatment duration pre-LTx (p < 0.001) and sputum non-conversion pre-LTx (p = 0.003) were significantly associated with development of NTM-disease post-LTx. Longer treatment duration pre-LTx (p = 0.004), younger age (p < 0.001) and sputum non-conversion (p = 0.044) were risk factors for NTM related death.
CONCLUSIONS
The median treatment duration pre-LTx was 10 months (IQR 6-17) and 2 months (IQR 2-8) directly post-LTx. Patients with longer treatment duration for NTM-PD pre-LTx and with sputum non-conversion are at risk for NTM disease post-LTx and for NTM-related death. Children were particularly at risk for NTM related death.
Topics: Child; Humans; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Lung Diseases; Lung Transplantation; Anti-Bacterial Agents; Macrolides
PubMed: 37832509
DOI: 10.1016/j.trre.2023.100800 -
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 -
Frontiers in Cellular and Infection... 2023Non-tuberculous mycobacteria (NTM) are opportunistic pathogens that can infect all body tissues and organs. In particular, the lungs are the most commonly involved... (Review)
Review
Non-tuberculous mycobacteria (NTM) are opportunistic pathogens that can infect all body tissues and organs. In particular, the lungs are the most commonly involved organ, with NTM pulmonary diseases causing serious health issues in patients with underlying lung disease. Moreover, NTM infections have been steadily increasing worldwide in recent years. NTM are also naturally resistant to many antibiotics, specifically anti-tuberculosis (anti-TB) drugs. The lack of drugs targeting NTM infections and the increasing drug resistance of NTM have further made treating these mycobacterial diseases extremely difficult. The currently recommended NTM treatments rely on the extended indications of existing drugs, which underlines the difficulties of new antibiotic discovery against NTM. Another challenge is determining which drug combinations are most effective against NTM infection. To a certain extent, anti-NTM drug development depends on using already available antibiotics and compounds. Here, we aimed to review new antibiotics or compounds with good antibacterial activity against NTM, focusing on their mechanisms of action, and antibacterial activities.
Topics: Humans; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Lung Diseases; Antitubercular Agents; Lung
PubMed: 37850054
DOI: 10.3389/fcimb.2023.1243457 -
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 -
Antimicrobial Agents and Chemotherapy Jul 2023Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of...
Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of the bacteria, combination therapy of three or more antibiotics is recommended. A major challenge in treating M. abscessus infections is the absence of a universal combination therapy with satisfying clinical success rates, leaving clinicians to treat infections using antibiotics lacking efficacy data. We systematically measured drug combinations in M. abscessus to establish a resource of drug interaction data and identify patterns of synergy to help design optimized combination therapies. We measured 191 pairwise drug combination effects among 22 antibacterials and identified 71 synergistic pairs, 54 antagonistic pairs, and 66 potentiator-antibiotic pairs. We found that commonly used drug combinations in the clinic, such as azithromycin and amikacin, are antagonistic in the lab reference strain ATCC 19977, whereas novel combinations, such as azithromycin and rifampicin, are synergistic. Another challenge in developing universally effective multidrug therapies for M. abscessus is the significant variation in drug response between isolates. We measured drug interactions in a focused set of 36 drug pairs across a small panel of clinical isolates with rough and smooth morphotypes. We observed strain-dependent drug interactions that cannot be predicted from single-drug susceptibility profiles or known drug mechanisms of action. Our study demonstrates the immense potential to identify synergistic drug combinations in the vast drug combination space and emphasizes the importance of strain-specific combination measurements for designing improved therapeutic interventions.
Topics: Humans; Mycobacterium abscessus; Azithromycin; Anti-Bacterial Agents; Amikacin; Mycobacterium Infections, Nontuberculous; Drug Interactions; Microbial Sensitivity Tests
PubMed: 37278639
DOI: 10.1128/aac.00090-23 -
Microbiology Spectrum Aug 2023Among the numerous pathogenic nontuberculous mycobacteria (NTM), which may cause disease in both poikilothermic and homoeothermic organisms, members of the unique clade...
Among the numerous pathogenic nontuberculous mycobacteria (NTM), which may cause disease in both poikilothermic and homoeothermic organisms, members of the unique clade Mycobacterium ulcerans/Mycobacterium marinum (MuMC) may cause disease in both fish and humans. Here, we describe the emergence of Mycobacterium pseudoshottsii, one of the four MuMC members, in Israel. For many years, M. marinum was the dominant NTM that was diagnosed in Israel as a fish pathogen. To the best of our knowledge, this is the first isolation and genomic characterization of infecting edible fish from two different fish species farmed in offshore sea cages in the eastern Mediterranean as well as in a recirculating aquaculture system in Israel. We compared the whole-genome sequences to all available genomic sequences of MuMC in free, publicly accessible databases. Mycobacterium pseudoshottsii was first detected in 1997 in the USA, infecting wild striped bass (Morone saxatilis). Since then, several reports from different countries worldwide have shown its capacity to become established in new regions as well as its pathogenicity to saltwater and euryhaline finfish of different genera. Our phylogenetic analysis revealed that the Mycobacterium ulcerans/Mycobacterium marinum clade (MuMC) is divided into two main branches: one that includes M. marinum and , and the second, which includes other M. marinum isolates as well as two isolates of M. shottsii. Our results reinforce the proposition that the geographical distribution of is much more extensive than is commonly believed. The emergence of in different parts of the world and its pathogenic traits that affect finfish of different genera may be a cause for concern among fish farmers, researchers, and environmental organizations.
Topics: Humans; Animals; Phylogeny; Mycobacterium; Bass; Phenotype; Mycobacterium marinum; Mycobacterium Infections, Nontuberculous; Fish Diseases
PubMed: 37272844
DOI: 10.1128/spectrum.00856-23 -
Microbiology Spectrum Aug 2023Single-step selection of Mycobacterium abscessus mutants resistant to linezolid yielded high-level resistance at a low frequency that was associated with mutations in...
Single-step selection of Mycobacterium abscessus mutants resistant to linezolid yielded high-level resistance at a low frequency that was associated with mutations in 23S rRNA or the ribosomal protein L3. Surprisingly, linezolid-resistant rRNA mutations conferred cross-resistance to several unrelated antibiotics. Low-level linezolid-resistant mutants were isolated at a higher frequency and were due to loss-of-function mutations in the transcriptional regulator MAB_4384, the repressor of the drug efflux pump MmpL5-MmpS5. The protein synthesis inhibitor linezolid is used for the treatment of lung disease caused by Mycobacterium abscessus. However, many strains of the bacterium show poor susceptibility to the antibiotic. For most clinical isolates, resistance is not due to mutations in the target of the drug, the ribosome. The mechanism responsible for non-target-related, indirect linezolid resistance is unknown. Here, we analyzed the development of linezolid resistance in the M. abscessus reference strain . We found, as expected, resistance mutations in the ribosome. In addition, we identified mutations in a system that involves a drug pump, suggesting drug efflux as a mechanism of resistance to linezolid. This finding may inform the analysis of clinical resistance to linezolid. Surprisingly, a subset of linezolid-resistant ribosome mutations conferred cross-resistance to several structurally and mechanistically unrelated drugs, uncovering a novel multidrug resistance mechanism.
Topics: Humans; Linezolid; Mycobacterium abscessus; Drug Resistance, Bacterial; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mutation
PubMed: 37458588
DOI: 10.1128/spectrum.02199-23 -
BMC Infectious Diseases Mar 2024Nontuberculous mycobacteria (NTM) are environmental bacteria which may cause chronic lung disease. The prevalence of NTM pulmonary infection and disease has been...
BACKGROUND
Nontuberculous mycobacteria (NTM) are environmental bacteria which may cause chronic lung disease. The prevalence of NTM pulmonary infection and disease has been increasing in the United States and globally. The predominant clinically relevant species of NTM in the United States are Mycobacterium avium complex (MAC) species and Mycobacterium abscessus. With the development of rapid species identification methods for NTM (e.g. PCR probes), more testing for NTM is being conducted through commercial labs, such as Laboratory Corporation of America (Labcorp), which provides deidentified real-time testing data to the Centers for Disease Control (CDC) pursuant to a data sharing agreement. Because NTM lung infections are not reportable in most states, other data sources are key to understanding NTM testing patterns, positivity rates, and species distributions to track infection trends and identify clinical care needs.
METHODS
We obtained national Labcorp data for the period January 2019 through mid-April 2022. We subset the data to only respiratory samples sent for Acid Fast Bacilli (AFB) cultures. NTM positive results were defined as those which identified an NTM species and are not Mycobacterium tuberculosis, Mycobacterium bovis, or Mycobacterium gordonae.
RESULTS
Overall, 112,528 respiratory samples were sent for AFB testing during the study period; 26.3% were from the Southeast U.S., identified as HSS Region IV in the Labcorp dataset, and 23.0% were from the Pacific and South Pacific region (Region IX). The culture positive prevalence ranged from 20.2% in the Southeast to 9.2% in the East North Central region (Region V). In the Southeast US, M. abscessus prevalence was 4.0%. For MAC, the highest prevalence was observed in the Mountain region (Region VII) (13.5%) and the lowest proportion was in the East South Central region (7.3%, Region III). Among positive tests, the proportion which was MAC varied from 61.8% to 88.9% and was highest in the Northeast U.S. The proportion of positive samples which were M. abscessus ranged from 3.8% to 19.7% and was highest in the Southeast.
CONCLUSIONS
The Southeastern region of the U.S. has the highest rate of culture positivity in Labcorp tests for total NTM and, of all positive tests, the highest proportion of M. abscessus. These estimates may underrepresent the true number of M. abscessus infections because M. absesscus-specific probes are not commercially available and not all NTM testing in the United States is done by Labcorp. Analysis of real-time testing data from commercial laboratories may provide insights into risk factors for NTM culture positivity in 'hotspot' areas.
Topics: United States; Humans; Nontuberculous Mycobacteria; Mycobacterium avium Complex; Mycobacterium abscessus; Laboratories; Mycobacterium bovis; Opportunistic Infections
PubMed: 38448840
DOI: 10.1186/s12879-024-09059-9 -
Nature Communications Mar 2024Antimicrobial resistance is a global health threat that requires the development of new treatment concepts. These should not only overcome existing resistance but be...
Antimicrobial resistance is a global health threat that requires the development of new treatment concepts. These should not only overcome existing resistance but be designed to slow down the emergence of new resistance mechanisms. Targeted protein degradation, whereby a drug redirects cellular proteolytic machinery towards degrading a specific target, is an emerging concept in drug discovery. We are extending this concept by developing proteolysis targeting chimeras active in bacteria (BacPROTACs) that bind to ClpC1, a component of the mycobacterial protein degradation machinery. The anti-Mycobacterium tuberculosis (Mtb) BacPROTACs are derived from cyclomarins which, when dimerized, generate compounds that recruit and degrade ClpC1. The resulting Homo-BacPROTACs reduce levels of endogenous ClpC1 in Mycobacterium smegmatis and display minimum inhibitory concentrations in the low micro- to nanomolar range in mycobacterial strains, including multiple drug-resistant Mtb isolates. The compounds also kill Mtb residing in macrophages. Thus, Homo-BacPROTACs that degrade ClpC1 represent a different strategy for targeting Mtb and overcoming drug resistance.
Topics: Mycobacterium smegmatis; Mycobacterium tuberculosis; Proteolysis; Dimerization; Drug Discovery
PubMed: 38443338
DOI: 10.1038/s41467-024-46218-7