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Clinical Microbiology and Infection :... Jun 2024Mycobacterium abscessus (Mab) is considered as the most pathogenic rapid-growing mycobacteria in humans, causing pulmonary and extra-pulmonary diseases, especially in... (Review)
Review
BACKGROUND
Mycobacterium abscessus (Mab) is considered as the most pathogenic rapid-growing mycobacteria in humans, causing pulmonary and extra-pulmonary diseases, especially in patients with cystic fibrosis. Mab shows intrinsic and acquired resistance to many drugs, leaving limited treatment options that lead to a generally poor prognosis. The standard therapeutic regimen last for more than 6 months and consists of a drug cocktail that ideally includes a macrolide and amikacin. Yet, toxicity and efficacy are suboptimal due also to the high toxicity. There is a need to introduce innovative and out-of-the-box approaches to improve treatments.
OBJECTIVES
In this narrative review, we summarize the recent research on the alternative strategies proposed and discuss the importance of using appropriate experimental assays to assess their activity.
SOURCES
Included articles were identified by searching PubMed and MEDLINE until June 2023. The search terms were 'Mycobacterium abscessus', 'antimicrobial', and 'alternative therapies'. Additional relevant references were obtained from articles retrieved from the primary search.
CONTENT
Therapies against Mab including host directed therapies, repurposed drugs, phage therapy, anti-virulence strategies, essential oils, and inhalation therapies.
IMPLICATIONS
Alternative treatments may represent a valid tool to cope the burden of antimicrobial resistance in Mab-caused diseases.
Topics: Mycobacterium abscessus; Humans; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents; Complementary Therapies; Drug Repositioning; Phage Therapy
PubMed: 37820951
DOI: 10.1016/j.cmi.2023.10.001 -
The Brazilian Journal of Infectious... 2023Nocardiosis is a rare bacterial infection caused by Nocardia spp. However, an increasing incidence has been described whereby data about epidemiology and prognosis are... (Review)
Review
INTRODUCTION
Nocardiosis is a rare bacterial infection caused by Nocardia spp. However, an increasing incidence has been described whereby data about epidemiology and prognosis are essential.
METHODS
A retrospective descriptive study was conducted among patients with positive Nocardia spp. culture, from January 2019 to January 2023, at a Terciary Hospital in Portugal.
RESULTS
Nocardiosis was considered in 18 cases with a median age of 63.8-years-old. At least one immunosuppressive cause was identified in 70% of patients. Five patients had Disseminated Nocardiosis (DN). The lung was the most common site of clinical disease (77.8%) and Nocardia was most commonly identified in respiratory tract samples. The most frequently isolated species were Nocardia nova/africana (n = 7) followed by Nocardia cyriacigeorgica (n = 3) and Nocardia pseudobrasiliensis (n = 3). The majority of the patients (94.4%) received antibiotic therapy, of whom as many as 55.6% were treated with monotherapy. The most frequently prescribed antibiotic was trimethoprim-sulfamethoxazole. Selected antimicrobial agents were generally effective, with linezolid and cotrimoxazole (100% Susceptibility [S]) and amikacin (94% S) having the most activity against Nocardia species. The median (IQR) duration of treatment was 24.2 (1‒51.4) weeks for DN; The overall one-year case fatality was 33.3% (n = 6) and was higher in the DN (66.7%). No recurrence was observed.
CONCLUSION
Nocardiosis is an emerging infectious disease with a poor prognosis, particularly in DN. This review offers essential epidemiological insights and underscores the importance of gaining a better understanding of the microbiology of nocardiosis. Such knowledge can lead to the optimization of antimicrobial therapy and, when necessary, guide appropriate surgical interventions to prevent unfavorable outcomes.
Topics: Humans; Middle Aged; Retrospective Studies; Nocardia; Nocardia Infections; Anti-Bacterial Agents; Trimethoprim, Sulfamethoxazole Drug Combination; Anti-Infective Agents
PubMed: 37802128
DOI: 10.1016/j.bjid.2023.102806 -
Clinical Microbiology and Infection :... Oct 2023Mycobacterium abscessus complex is responsible for 2.6-13.0% of all non-tuberculous mycobacterial pulmonary infections and these are notoriously difficult to treat due...
OBJECTIVES
Mycobacterium abscessus complex is responsible for 2.6-13.0% of all non-tuberculous mycobacterial pulmonary infections and these are notoriously difficult to treat due to the complex regimens required, drug resistance and adverse effects. Hence, bacteriophages have been considered in clinical practice as an additional treatment option. Here, we evaluated antibiotic and phage susceptibility profiles of M. abscessus clinical isolates. Whole-genome sequencing (WGS) revealed the phylogenetic relationships, dominant circulating clones (DCCs), the likelihood of patient-to-patient transmission and the presence of prophages.
METHODS
Antibiotic susceptibility testing was performed using CLSI breakpoints (n = 95), and plaque assays were used for phage susceptibility testing (subset of n = 88, 35 rough and 53 smooth morphology). WGS was completed using the Illumina platform and analysed using Snippy/snp-dists and Discovery and Extraction of Phages Tool (DEPhT).
RESULTS
Amikacin and Tigecycline were the most active drugs (with 2 strains resistant to amikacin, and one strain with Tigecycline MIC of 4 μg/mL). Most strains were resistant to all other drugs tested, with Linezolid and Imipenem showing the least resistance, at 38% (36/95) and 55% (52/95), respectively. Rough colony morphotype strains were more phage-susceptible than smooth strains (77%-27/35 versus 48%-25/53 in the plaque assays, but smooth strains are not killed efficiently by those phages in liquid infection assay). We have also identified 100 resident prophages, some of which were propagated lytically. DCC1 (20%-18/90) and DCC4 (22%-20/90) were observed to be the major clones and WGS identified 6 events of possible patient-to-patient transmission.
DISCUSSION
Many strains of M. abscessus complex are intrinsically resistant to available antibiotics and bacteriophages represent an alternative therapeutic option, but only for strains with rough morphology. Further studies are needed to elucidate the role of hospital-borne M. abscessus transmission.
Topics: Humans; Mycobacterium abscessus; Amikacin; Tigecycline; Bacteriophages; Phylogeny; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents; Drug Resistance, Multiple; Delivery of Health Care; Microbial Sensitivity Tests
PubMed: 37364635
DOI: 10.1016/j.cmi.2023.06.026 -
PloS One 2023Tuberculosis stands as a prominent cause of mortality in developing countries. The treatment of tuberculosis involves a complex procedure requiring the administration of...
Tuberculosis stands as a prominent cause of mortality in developing countries. The treatment of tuberculosis involves a complex procedure requiring the administration of a panel of at least four antimicrobial drugs for the duration of six months. The occurrence of treatment failure after the completion of a standard treatment course presents a serious medical problem. The purpose of this study was to evaluate antimicrobial drug resistant features of Mycobacterium tuberculosis associated with treatment failure. Additionally, it aimed to evaluate the effectiveness of second line drugs such as amikacin, linezolid, moxifloxacin, and the efflux pump inhibitor verapamil against M. tuberculosis isolates associated with treatment failure. We monitored 1200 tuberculosis patients who visited TB centres in Lahore and found that 64 of them were not cured after six months of treatment. Among the M. tuberculosis isolates recovered from the sputum of these 64 patients, 46 (71.9%) isolates were simultaneously resistant to rifampicin and isoniazid (MDR), and 30 (46.9%) isolates were resistant to pyrazinamide, Resistance to amikacin was detected in 17 (26,5%) isolates whereas resistance to moxifloxacin and linezolid was detected in 1 (1.5%) and 2 (3.1%) isolates respectively. Among MDR isolates, the additional resistance to pyrazinamide, amikacin, and linezolid was detected in 15(23.4%), 4(2.6%) and 1(1.56%) isolates respectively. One isolate simultaneously resistant to rifampicin, isoniazid, amikacin, pyrazinamide, and linezolid was also identified. In our investigations, the most frequently mutated amino acid in the treatment failure group was Serine 315 in katG. Three novel mutations were detected at codons 99, 149 and 154 in pncA which were associated with pyrazinamide resistance. The effect of verapamil on the minimum inhibitory concentration of isoniazid and rifampicin was observed in drug susceptible isolates but not in drug resistant isolates. Rifampicin and isoniazid enhanced the transcription of the efflux pump gene rv1258 in drug susceptible isolates collected from the treatment failure patients. Our findings emphasize a high prevalence of MDR isolates linked primarily to drug exposure. Moreover, the use of amikacin as a second line drug may not be the most suitable choice in such cases.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; Isoniazid; Pyrazinamide; Rifampin; Linezolid; Amikacin; Moxifloxacin; Tuberculosis, Multidrug-Resistant; Microbial Sensitivity Tests; Verapamil; Mutation
PubMed: 37883448
DOI: 10.1371/journal.pone.0293194 -
Journal of Global Antimicrobial... Sep 2023Mycobacterium avium (M. avium) complex bacteria cause opportunistic infections in humans. Treatment yields cure rates of 60% and consists of a macrolide, a rifamycin,...
OBJECTIVES
Mycobacterium avium (M. avium) complex bacteria cause opportunistic infections in humans. Treatment yields cure rates of 60% and consists of a macrolide, a rifamycin, and ethambutol, and in severe cases, amikacin. Mechanisms of antibiotic tolerance remain mostly unknown. Therefore, we studied the contribution of efflux and amikacin modification to antibiotic susceptibility.
METHODS
We characterised M. avium ABC transporters and studied their expression together with other transporters following exposure to clarithromycin, amikacin, ethambutol, and rifampicin. We determined the effect of combining the efflux pump inhibitors berberine, verapamil and CCCP (carbonyl cyanide m-chlorophenyl hydrazone), to study the role of efflux on susceptibility. Finally, we studied the modification of amikacin by M. avium using metabolomic analysis.
RESULTS
Clustering shows conservation between M. avium and M. tuberculosis and transporters from most bacterial subfamilies (2-6, 7a/b, 10-12) were found. The largest number of transporter encoding genes was up-regulated after clarithromycin exposure, and the least following amikacin exposure. Only berberine increased the susceptibility to clarithromycin. Finally, because of the limited effect of amikacin on transporter expression, we studied amikacin modification and showed that M. avium, in contrast to M. abscessus, is not able to modify amikacin.
CONCLUSION
We show that M. avium carries ABC transporters from all major families important for antibiotic efflux, including homologues shown to have affinity for drugs included in treatment. Efflux inhibition in M. avium can increase susceptibility, but this effect is efflux pump inhibitor- and antibiotic-specific. Finally, the lack of amikacin modifying activity in M. avium is important for its activity.
Topics: Humans; Amikacin; Mycobacterium avium; Clarithromycin; Ethambutol; Berberine; Anti-Bacterial Agents; Mycobacterium avium Complex; Membrane Transport Proteins; Mycobacterium tuberculosis; ATP-Binding Cassette Transporters
PubMed: 37453496
DOI: 10.1016/j.jgar.2023.07.007 -
Epidemiology of Nontuberculous Mycobacteria in Tuberculosis suspects, Southwest of China, 2017-2022.Frontiers in Cellular and Infection... 2023This study summarizes the epidemiological characteristics, species distribution, and drug sensitivity of clinical nontuberculous mycobacteria (NTM) isolates at the...
OBJECTIVES
This study summarizes the epidemiological characteristics, species distribution, and drug sensitivity of clinical nontuberculous mycobacteria (NTM) isolates at the Public Health Clinical Center of Chengdu, China, from January 2017 to December 2022.
METHODS
We retrospectively analyzed data from patients with clinically isolated NTM strains. Chi-square analysis assessed the rate of strain isolation over 6 years.
RESULTS
The number of samples tested for (MTB) and/or NTM increased each year, while MTB detection decreased and NTM detection rose significantly each year (P=0.03). The average age of NTM patients was 51 ± 17.53 years, with a 14.1% HIV infection rate. The predominant isolates were (MAC) and /, with 96.4% of cases being of Han ethnicity. Amikacin, moxifloxacin, and clarithromycin were effective against and ; linezolid, amikacin, and cefoxitin were effective against /. Over 90% of NTM cases originated from the respiratory tract.
CONCLUSION
The NTM isolation rate in Southwest China has risen in recent years, primarily among elderly patients with a high HIV co-infection rate. The main NTM isolates were MAC and /. Amikacin, moxifloxacin, clarithromycin, and linezolid exhibited strong antibacterial activity against SGM, while amikacin and linezolid displayed relatively better antibacterial activity against RGM. The prevalence of NTM infection may be positively associated with regional economic development and health conditions.
Topics: Humans; Aged; Adult; Middle Aged; Nontuberculous Mycobacteria; Clarithromycin; Amikacin; Linezolid; HIV Infections; Moxifloxacin; Retrospective Studies; Anti-Bacterial Agents; Mycobacterium Infections, Nontuberculous; Tuberculosis; China; Microbial Sensitivity Tests
PubMed: 38029240
DOI: 10.3389/fcimb.2023.1282902 -
Nature Communications Aug 2023Aminoglycosides are a class of antibiotics that bind to ribosomal RNA and exert pleiotropic effects on ribosome function. Amikacin, the semisynthetic derivative of...
Aminoglycosides are a class of antibiotics that bind to ribosomal RNA and exert pleiotropic effects on ribosome function. Amikacin, the semisynthetic derivative of kanamycin, is commonly used for treating severe infections with multidrug-resistant, aerobic Gram-negative bacteria. Amikacin carries the 4-amino-2-hydroxy butyrate (AHB) moiety at the N amino group of the central 2-deoxystreptamine (2-DOS) ring, which may confer amikacin a unique ribosome inhibition profile. Here we use in vitro fast kinetics combined with X-ray crystallography and cryo-EM to dissect the mechanisms of ribosome inhibition by amikacin and the parent compound, kanamycin. Amikacin interferes with tRNA translocation, release factor-mediated peptidyl-tRNA hydrolysis, and ribosome recycling, traits attributed to the additional interactions amikacin makes with the decoding center. The binding site in the large ribosomal subunit proximal to the 3'-end of tRNA in the peptidyl (P) site lays the groundwork for rational design of amikacin derivatives with improved antibacterial properties.
Topics: Amikacin; Anti-Bacterial Agents; Models, Molecular; Ribosomes; Kanamycin; RNA, Transfer
PubMed: 37537169
DOI: 10.1038/s41467-023-40416-5