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BACKGROUND: Disseminated non-tuberculous mycobacteria (dNTM) infections are mostly reported among individuals with an underlying congenital or acquired immunodeficiency or receiving immunosuppressive treatment, but are rarely documented in otherwise healthy subjects. CASE PRESENTATION: We describe a case of recurrent disseminated mycobacterial infection in an apparently immunocompetent Chinese woman. Mycobacterium szulgai and Mycobacterium avium-complex were identified in distinct episodes. Long-term antimycobacterial therapy was administered given the occurrence of recurrent events when off-treatment. Successful management over more than 10 years and immunologic data are reported. CONCLUSIONS: This case-report highlights that dNTM should be suspected also among apparently immunocompetent hosts and that thorough assessment of underling immune-impairments is helpful to define patients' management. Long-term antimycobacterial therapy and close monitoring is required to grant successful outcomes in case of recurrent dNTM infections.
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Infecciones por Mycobacterium no Tuberculosas , Micobacterias no Tuberculosas , Recurrencia , Humanos , Femenino , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no Tuberculosas/efectos de los fármacos , Antibacterianos/uso terapéutico , Complejo Mycobacterium avium/efectos de los fármacos , China , Adulto , Resultado del Tratamiento , Persona de Mediana Edad , Pueblos del Este de AsiaRESUMEN
Nontuberculous mycobacteria (NTM) are important opportunistic pathogens in humans, mostly affecting the lungs, and potentially causing progressive disease in individuals with underlying diseases. The prevalence of NTM infections is increasing worldwide. However, Mycobacterium iranicum (M. iranicum) infections are less common. Here we report a 65-year-old female who developed pneumonia caused by Mycobacterium iranicum, which was detected in bronchoalveolar lavage fluid (BALF) through metagenomic next-generation sequencing (mNGS). The patient was treated with moxifloxacin, doxycycline, and sulfamethoxazole/trimethoprim. Symptoms were relieved and lung abnormalities were shown to be partially absorbed on the follow-up chest computed tomography (CT) scans. As we know, this is the first case of Mycobacterium iranicum pulmonary infection identified by mNGS in BALF.
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Líquido del Lavado Bronquioalveolar , Secuenciación de Nucleótidos de Alto Rendimiento , Metagenómica , Infecciones por Mycobacterium no Tuberculosas , Humanos , Femenino , Anciano , Líquido del Lavado Bronquioalveolar/microbiología , Metagenómica/métodos , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Antibacterianos/uso terapéutico , Micobacterias no Tuberculosas/genética , Micobacterias no Tuberculosas/aislamiento & purificación , Micobacterias no Tuberculosas/efectos de los fármacos , Tomografía Computarizada por Rayos X , Moxifloxacino/uso terapéutico , Doxiciclina/uso terapéuticoRESUMEN
INTRODUCTION: The clinical relevance of Mycobacterium malmoense isolation from pulmonary specimens has been considered high compared with other non-tuberculous mycobacteria. In this study, we aimed to analyse all published clinical data of patients with M. malmoense isolation to investigate the clinical spectrum, relevance, and outcomes of infections with this uncommon mycobacterium. METHODS: A systematic review of PubMed, Web of Science, Embase, and Scopus was performed to identify all clinical data about M. malmoense. Random effects meta-analyses of proportions were calculated for clinical relevance, treatment success, and mortality, as well as for other clinical characteristics. A logistic regression analysis, investigating predictors of mortality, as well as Kaplan-Meier survival analyses, were performed. RESULTS: One hundred and eighty eight patients with individual data from 112 articles and 671 patients with pooled data from 12 articles were included in the meta-analyses. Of patients with individual data, pulmonary infection was the most common manifestation (n = 106/188, 56.4%). One third (n = 61/188, 32.4%) suffered from isolated extra-pulmonary and 21/188 (11.2%) from disseminated disease. In 288 patients with pooled data and pulmonary affection, clinical relevance was high with 68% (95% CI 44-85%) of patients fulfilling criteria for clinical disease. Macrolide and rifamycin-containing regimens were associated with improved survival (adjusted OR 0.12, 95% CI 0.03-0.42, p = 0.002, and 0.23, 95% CI 0.04-0.86, p = 0.03, for lethal events, respectively). CONCLUSION: In this study, we provide a detailed clinical description of M. malmoense infections. The pathogen is of high clinical relevance for the individual patient with more than 2 out of 3 patients having relevant disease and >40% of manifestations being extra-pulmonary or disseminated. Macrolide and rifamycin-containing regimens are associated with improved survival.
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Infecciones por Mycobacterium no Tuberculosas , Humanos , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/mortalidad , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Antibacterianos/uso terapéutico , Masculino , Femenino , Micobacterias no Tuberculosas/aislamiento & purificación , Micobacterias no Tuberculosas/efectos de los fármacos , Adulto , Persona de Mediana Edad , Anciano , Mycobacterium/aislamiento & purificación , Mycobacterium/efectos de los fármacos , Mycobacterium/clasificaciónRESUMEN
Non-tuberculosis infections in immunocompromised patients represent a cause for concern, given the increased risks of infection, and limited treatments available. Herein, we report that molecules for binding to the catalytic site of histone deacetylase (HDAC) inhibit its activity, thus increasing the innate immune response against environmental mycobacteria. The action of HDAC inhibitors (iHDACs) was explored in a model of type II pneumocytes and macrophages infection by Mycobacterium aurum. The results show that the use of 1,3-diphenylurea increases the expression of the TLR-4 in M. aurum infected MDMs, as well as the production of defb4, IL-1ß, IL-12, and IL-6. Moreover, we observed that aminoacetanilide upregulates the expression of TLR-4 together with TLR-9, defb4, CAMP, RNase 6, RNase 7, IL-1ß, IL-12, and IL-6 in T2P. Results conclude that the tested iHDACs selectively modulate the expression of cytokines and antimicrobial peptides that are associated with reduction of non-tuberculous mycobacteria infection.
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Citocinas , Reposicionamiento de Medicamentos , Inhibidores de Histona Desacetilasas , Inmunidad Innata , Infecciones por Mycobacterium no Tuberculosas , Inmunidad Innata/efectos de los fármacos , Humanos , Infecciones por Mycobacterium no Tuberculosas/inmunología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Inhibidores de Histona Desacetilasas/farmacología , Citocinas/metabolismo , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Micobacterias no Tuberculosas/efectos de los fármacos , Micobacterias no Tuberculosas/inmunología , Mycobacterium/inmunología , Mycobacterium/efectos de los fármacosRESUMEN
BACKGROUND: From June 2021 to July 2021, our hospital confirmed 3 cases of Mycobacterium infection in skin abscesses. All 3 patients underwent thread embedding and weight loss surgery at the same informal beauty institution, with a history of silk protein injection. None of the patients had any other underlying diseases or surgical history. Symptoms and signs show that the disease is acute and the course of the disease is short. All patients have found subcutaneous masses in different parts of the body. In most cases, the masses show redness and swelling, and some of the masses are accompanied by tenderness, wave sensation, and rupture. After some of the masses rupture, purulent secretions can be seen. METHODS: The pus secreted by the skin lesions of the three patients were cultured to a single bacterium, which was identified by MALDI-TOF MS. Multiple locus sequence typing (MLST) was performed using three specific genes (hsp65, rpoB, and secA1) and seven housekeeping genes (argH, cya, glpK, gnd, murC, pta, and purH). The results were queried through the MLST database of Mycobacterium abscess. RESULTS: All three strains of bacteria were Mycobacterium abscess type ST279 massiliense subtype. Three antibacterial drugs including cefmetazole, amikacin, and clarithromycin were administered in combination with 5-aminolevulinic acid photodynamic therapy (ALA-PDT). After 3 - 6 months, there was no obvious redness or swelling in the surrounding tissues of the wound, and no obvious purulent secretions were observed. All patients were cured and discharged from the hospital. After a follow-up of six months, there was no recurrence of the lesions. CONCLUSIONS: Medical institutions must strictly follow infection control guidelines and take preventive measures to prevent such incidents from happening again. ALA-PDT as a combination therapy for nontuberculous Mycobacterium (NTM) skin infections can improve treatment efficacy and shorten antibiotic usage time.
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Antibacterianos , Brotes de Enfermedades , Infecciones por Mycobacterium no Tuberculosas , Humanos , Femenino , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Adulto , Antibacterianos/uso terapéutico , Enfermedades Cutáneas Bacterianas/epidemiología , Enfermedades Cutáneas Bacterianas/microbiología , Enfermedades Cutáneas Bacterianas/diagnóstico , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Absceso/microbiología , Absceso/epidemiología , Absceso/diagnóstico , Mycobacterium abscessus/aislamiento & purificación , Mycobacterium abscessus/genética , Micobacterias no Tuberculosas/aislamiento & purificación , Micobacterias no Tuberculosas/genética , Micobacterias no Tuberculosas/efectos de los fármacosRESUMEN
INTRODUCTION: Although nontuberculous mycobacterial (NTM) infection is a common cause of pulmonary disease worldwide, few studies have focused on epidemiological and therapeutic factors related to NTM cases in Anhui Province, China. This retrospective study aimed to identify aetiological and clinical factors, and treatment outcomes of patients with NTM pulmonary disease (NTMPD) in Anhui. METHODOLOGY: Retrospective clinical data obtained from medical records of NTMPD patients seeking care at Anhui Chest Hospital from July 2019 to June 2022 were analyzed. Treatment outcomes were compared between two patient groups: one receiving a standardised NTM treatment regimen and the other receiving precision treatment regimens. RESULTS: Genotypic analysis of 672 clinical NTMPD-associated isolates revealed that most were Mycobacterium intracellulare, while drug-susceptibility test results demonstrated diverse antibiotic resistance profiles for these isolates. Cough was the most common symptom for 101 NTMPD patients. After patients of both groups received treatment, symptoms improved, sputum culture conversion was observed for some patients, imaging findings stabilised; however, no statistically significant intergroup differences in treatment outcomes were found. CONCLUSIONS: In this study, M. intracellulare was the predominant NTM species identified in isolates obtained from NTMPD patients. Drug resistance profiles of our patient isolates were complex, highlighting the need for administration of timely, more effective, standardised treatments for patients with NTMPD in Anhui Province, China.
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Antibacterianos , Infecciones por Mycobacterium no Tuberculosas , Humanos , China/epidemiología , Estudios Retrospectivos , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Antibacterianos/uso terapéutico , Resultado del Tratamiento , Micobacterias no Tuberculosas/aislamiento & purificación , Micobacterias no Tuberculosas/efectos de los fármacos , Micobacterias no Tuberculosas/genética , Adulto , Pruebas de Sensibilidad Microbiana , Enfermedades Pulmonares/microbiología , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/epidemiología , Esputo/microbiologíaRESUMEN
OBJECTIVE: GeneXpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) is a conceptually helpful tool for establishing tuberculosis (TB) disease. Negative results from the GeneXpert test do not exclude the possibility of diagnosing non-tuberculous mycobacteria lung disease (NTMLD) as a chronic pulmonary disease. When a patient is diagnosed on a clinical basis, and there is no bacteriological evidence of TB, it is necessary to consider NTM as one of the causes of disease with TB-like symptoms. The prevalence of non-tuberculous mycobacteria (NTM) disease is rising globally, but its diagnosis is still delayed and often misdiagnosed as multidrug-resistant TB (MDR-TB). This study highlights the implication of negative GeneXpert MTB/RIF results in suspected TB patients who conducted mycobacteria culture and detected the incidence of NTMLD. METHODS: In this experimental study, the performance of GeneXpert MTB/RIF-negative results with those of mycobacteria cultures and lung abnormalities among suspected TB patients in a referral hospital in Indonesia were evaluated. From January to August 2022, 100 sputum samples from suspected chronic pulmonary TB patients with GeneXpert MTB/RIF assay-negative results were cultured in Lowenstein-Jensen medium, and the implication among negative GeneXpert result MTB/RIF assay. RESULTS: 7% were confirmed to have MTB and 1% had NTM by culture assay. Moreover, 34% were diagnosed with clinical TB and treated with anti-TB drugs. CONCLUSION: For patients with negative assay results of GeneXpert MTB/RIF regarding clinically suspected chronic TB infection, further diagnostic tests to determine the causative agents of the lung abnormalities should be carried out.
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Mycobacterium tuberculosis , Rifampin , Esputo , Tuberculosis Pulmonar , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Rifampin/farmacología , Masculino , Esputo/microbiología , Femenino , Adulto , Persona de Mediana Edad , Indonesia , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/microbiología , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Micobacterias no Tuberculosas/genética , Micobacterias no Tuberculosas/aislamiento & purificación , Micobacterias no Tuberculosas/efectos de los fármacos , Anciano , Adulto JovenRESUMEN
Four species of non-tuberculous mycobacteria (NTM) rated as biosafety level 1 or 2 (BSL-1/BSL-2) organisms and showing higher genomic similarity with Mycobacterium tuberculosis (Mtb) than previous comparator species Mycobacterium kansasii and Mycobacterium marinum were subjected to genomic and phenotypic characterization. These species named Mycobacterium decipiens, Mycobacterium lacus, Mycobacterium riyadhense, and Mycobacterium shinjukuense might represent "missing links" between low-virulent mycobacterial opportunists and the highly virulent obligate pathogen Mtb. We confirmed that M. decipiens is the closest NTM species to Mtb currently known and found that it has an optimal growth temperature of 32°C-35°C and not 37°C. M. decipiens showed resistance to rifampicin, isoniazid, and ethambutol, whereas M. lacus and M. riyadhense showed resistance to isoniazid and ethambutol. M. shinjukuense was sensitive to all three first-line TB drugs, and all four species were sensitive to bedaquiline, a third-generation anti-TB drug. Our results suggest these four NTM may be useful models for the identification and study of new anti-TB molecules, facilitated by their culture under non-BSL-3 conditions as compared to Mtb. M. riyadhense was the most virulent of the four species in cellular and mouse infection models. M. decipiens also multiplied in THP-1 cells at 35°C but was growth impaired at 37°C. Genomic comparisons showed that the espACD locus, essential for the secretion of ESX-1 proteins in Mtb, was present only in M. decipiens, which was able to secrete ESAT-6 and CFP-10, whereas secretion of these antigens varied in the other species, making the four species interesting examples for studying ESX-1 secretion mechanisms.IMPORTANCEIn this work, we investigated recently identified opportunistic mycobacterial pathogens that are genomically more closely related to Mycobacterium tuberculosis (Mtb) than previously used comparator species Mycobacterium kansasii and Mycobacterium marinum. We confirmed that Mycobacterium decipiens is the currently closest known species to the tubercle bacilli, represented by Mycobacterium canettii and Mtb strains. Surprisingly, the reference strain of Mycobacterium riyadhense (DSM 45176), which was purchased as a biosafety level 1 (BSL-1)-rated organism, was the most virulent of the four species in the tested cellular and mouse infection models, suggesting that a BSL-2 rating might be more appropriate for this strain than the current BSL-1 rating. Our work establishes the four NTM species as interesting study models to obtain new insights into the evolutionary mechanisms and phenotypic particularities of mycobacterial pathogens that likely have also impacted the evolution of the key pathogen Mtb.
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Antituberculosos , Mycobacterium tuberculosis , Micobacterias no Tuberculosas , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/farmacología , Micobacterias no Tuberculosas/genética , Micobacterias no Tuberculosas/efectos de los fármacos , Micobacterias no Tuberculosas/clasificación , Micobacterias no Tuberculosas/crecimiento & desarrollo , Humanos , Genoma Bacteriano/genética , Genómica , Fenotipo , Pruebas de Sensibilidad Microbiana , Infecciones por Mycobacterium no Tuberculosas/microbiología , Filogenia , Animales , Tuberculosis/microbiología , Farmacorresistencia Bacteriana/genética , RatonesRESUMEN
BACKGROUND: Drug susceptibility testing (DST) protocol of omadacycline against non-tuberculous mycobacteria has not yet been established. We developed a method to accurately determine MIC omadacycline MIC against Mycobacterium abscessus (Mab), Mycobacterium avium-complex (MAC), and Mycobacterium kansasii (Mkn). METHODS: First, we identified the oxyrase concentration not affecting Mab, MAC, and Mkn growth followed by omadacycline MIC experiments with and without oxyrase using reference and clinical strains. RESULTS: Oxyrase 0.5 % (v/v) stabilized omadacycline in the culture medium. The median omadacycline MIC was 1 mg/L for Mab and 8 mg/L for Mkn. For MAC, the median omadacycline MIC was 2 mg/L for M. avium, 256 mg/L for M. intracellulare, and 4 mg/L for M. chimaera (p < 0.0001). Wilcoxon matched-pairs signed rank test revealed statistically lower MICs with oxyrase for all MAC subspecies (p < 0.0001), all Mab subspecies (p < 0.0001), and Mkn (p = 0.0002). The decrease in MICs with oxyrase was 17/18 of Mab, 14/19 of Mkn, 8/8 of M. avium, 4/5 M. chimera, but only 11/18 of M. intracellulare (p < 0.013). CONCLUSION: Use of 0.5 % oxyrase could be a potential solution to reliable and reproducible omadacycline MIC of Mab. However, oxyrase demonstrated a variable effect in reducing MICs against MAC and Mkn.
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Antituberculosos , Pruebas de Sensibilidad Microbiana , Mycobacterium abscessus , Tetraciclinas , Pruebas de Sensibilidad Microbiana/métodos , Humanos , Antituberculosos/farmacología , Tetraciclinas/farmacología , Mycobacterium abscessus/efectos de los fármacos , Mycobacterium abscessus/enzimología , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium kansasii/enzimología , Complejo Mycobacterium avium/efectos de los fármacos , Complejo Mycobacterium avium/enzimología , Micobacterias no Tuberculosas/efectos de los fármacos , Micobacterias no Tuberculosas/enzimología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológicoAsunto(s)
Azitromicina , Rifampin , Rifampin/uso terapéutico , Humanos , Azitromicina/uso terapéutico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no Tuberculosas/efectos de los fármacos , Antibacterianos/uso terapéutico , Masculino , Femenino , Pruebas de Sensibilidad Microbiana , Persona de Mediana EdadRESUMEN
Increasingly prevalent, nontuberculous mycobacteria (NTM) infections affect approximately 20% of people with cystic fibrosis (CF). Previous studies of CF sputum identified lower levels of the host metabolite itaconate in those infected with NTM. Itaconate can inhibit the growth of M. tuberculosis (MTB) in vitro via the inhibition of the glyoxylate cycle enzyme (ICL), but its impact on NTM is unclear. To test itaconic acid's (IA) effect on NTM growth, laboratory and CF clinical strains of Mycobacterium abscessus and Mycobacterium avium were cultured in 7H9 minimal media supplemented with 1-10 mM of IA and short-chain fatty acids (SCFA). M. avium and M. abscessus grew when supplemented with SCFAs, whereas the addition of IA (≥ 10 mM) completely inhibited NTM growth. NTM supplemented with acetate or propionate and 5 mM IA displayed slower growth than NTM cultured with SCFA and ≤ 1 mM of IA. However, IA's inhibition of NTM was pH dependent; as similar and higher quantities (100 mM) of pH adjusted IA (pH 7) did not inhibit growth in vitro, while in an acidic minimal media (pH 6.1), 1 to 5 mM of non-pH adjusted IA inhibited growth. None of the examined isolates displayed the ability to utilize IA as a carbon source, and IA added to M. abscessus isocitrate lyase (ICL) decreased enzymatic activity. Lastly, the addition of cell-permeable 4-octyl itaconate (4-OI) to THP-1 cells enhanced NTM clearance, demonstrating a potential role for IA/itaconate in host defense against NTM infections.
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Succinatos , Succinatos/farmacología , Succinatos/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Micobacterias no Tuberculosas/efectos de los fármacos , Micobacterias no Tuberculosas/crecimiento & desarrollo , Células THP-1 , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Mycobacterium avium/efectos de los fármacos , Mycobacterium avium/crecimiento & desarrollo , Mycobacterium abscessus/efectos de los fármacos , Mycobacterium abscessus/crecimiento & desarrollo , Mycobacterium abscessus/metabolismoRESUMEN
BACKGROUND: We evaluated whether the sputum bacterial microbiome differs between nontuberculous mycobacteria pulmonary disease (NTM-PD) patients with stable disease not requiring antibiotic treatment and those requiring antibiotics. METHODS: We collected sputum samples from 21 clinically stable NTM-PD patients (stable group) and 14 NTM-PD patients needing antibiotic treatment (treatment group). We also obtained 13 follow-up samples from the stable group. We analyzed the 48 samples using 16S rRNA gene sequencing (V3-V4 region) and compared the groups. RESULTS: In the linear discriminant analysis effect size (LEfSe) analysis, the species Porphyromonas pasteri, Haemophilus parahaemolyticus, Prevotella nanceiensis, and Gemella haemolysans were significantly more prevalent in the sputum of the stable group compared to the treatment group. No taxa showed significant differences in alpha-/beta-diversity or LEfSe between the 21 baseline and 13 follow-up sputum samples in the stable group. In the stable group, the genus Bergeyella and species Prevotella oris were less common in patients who achieved spontaneous culture conversion (n = 9) compared to those with persistent NTM positivity (n = 12) (effect size 3.04, p = 0.039 for Bergeyella; effect size 3.64, p = 0.033 for P. oris). In the treatment group, H. parainfluenzae was more common in patients with treatment success (n = 7) than in treatment-refractory patients (n = 7) (effect size 4.74, p = 0.013). CONCLUSIONS: Our study identified distinct bacterial taxa in the sputum of NTM-PD patients based on disease status. These results suggest the presence of a microbial environment that helps maintain disease stability.
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Microbiota , Infecciones por Mycobacterium no Tuberculosas , ARN Ribosómico 16S , Esputo , Humanos , Esputo/microbiología , Masculino , Femenino , Microbiota/genética , Microbiota/efectos de los fármacos , Anciano , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , ARN Ribosómico 16S/genética , Persona de Mediana Edad , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Micobacterias no Tuberculosas/aislamiento & purificación , Micobacterias no Tuberculosas/genética , Micobacterias no Tuberculosas/clasificación , Micobacterias no Tuberculosas/efectos de los fármacos , ADN Bacteriano/genética , Enfermedades Pulmonares/microbiología , Enfermedades Pulmonares/tratamiento farmacológicoRESUMEN
BACKGROUND: Improving health-related quality of life (HRQOL) has emerged as a priority in the management of nontuberculous mycobacterial pulmonary disease (NTM-PD). We aimed to evaluate HRQOL and its changes after 6 months' treatment in patients with NTM-PD. METHODS: The NTM-KOREA is a nationwide prospective cohort enrolling patients initiating treatment for NTM-PD in 8 institutions across South Korea. We conducted the Quality of Life-Bronchiectasis (QOL-B) at 6-month intervals and evaluated baseline scores (higher scores indicate better quality of life) and changes after 6 months' treatment. Multivariate logistic regression was performed to identify factors associated with improvement in the QOL-B physical functioning and respiratory symptoms domains. RESULTS: Between February 2022 and August 2023, 411 patients were included in the analysis. Baseline scores (95% confidence interval [CI]) for physical functioning and respiratory symptoms were 66.7 (46.7-86.7) and 81.5 (70.4-92.6), respectively. Among 228 patients who completed the QOL-B after 6 months' treatment, improvements in physical functioning and respiratory symptoms were observed in 61 (26.8%) and 71 (31.1%) patients, respectively. A lower score (adjusted odds ratio; 95% CI) for physical functioning (0.93; 0.91-0.96) and respiratory symptoms (0.92; 0.89-0.95) at treatment initiation was associated with a greater likelihood of physical functioning and respiratory symptom improvement, respectively; achieving culture conversion was not associated with improvement in physical functioning (0.62; 0.28-1.39) or respiratory symptoms (1.30; 0.62-2.74). CONCLUSIONS: After 6 months of antibiotic treatment for NTM-PD, HRQOL improved in almost one-third, especially in patients with severe initial symptoms, regardless of culture conversion. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT03934034.
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Antibacterianos , Infecciones por Mycobacterium no Tuberculosas , Calidad de Vida , Humanos , Masculino , Femenino , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , República de Corea , Antibacterianos/uso terapéutico , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Micobacterias no Tuberculosas/efectos de los fármacos , Resultado del TratamientoRESUMEN
OBJECTIVE: Mycobacterium avium complex (MAC) and Mycobacterium abscessus are a group of nontuberculous mycobacteria (NTM) that have been described as human pathogens. Their ability to develop biofilms in tissues and medical devices is one of the most important pathogenicity factors, with important implications in diagnosis and treatment. Macrolides are usually considered one of the bases of this treatment. METHODS: Here we have studied the biofilm prevention concentration (BPC) of 16 strains (n=16) with clarithromycin to avoid the biofilm development by these NTM. RESULTS: In this study, all M. abscessus strains have similar BPC, while MAC strains showed different values. For MAC the concentrations ranged between 1-16 mg/L, while for M. abscessus the concentration was 32 mg/L for all strains except one that was 64 mg/L. CONCLUSIONS: These results open the possibility of using macrolides for the prevention of biofilm development in patients with a risk of developing NTM disease.
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Antibacterianos , Biopelículas , Claritromicina , Pruebas de Sensibilidad Microbiana , Micobacterias no Tuberculosas , Claritromicina/farmacología , Biopelículas/efectos de los fármacos , Antibacterianos/farmacología , Micobacterias no Tuberculosas/efectos de los fármacos , Humanos , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/prevención & control , Complejo Mycobacterium avium/efectos de los fármacos , Mycobacterium abscessus/efectos de los fármacosRESUMEN
The prevalence of Non-tuberculous Mycobacterial Pulmonary Disease (NTM-PD) is increasing worldwide. The advancement in molecular diagnostic technology has greatly promoted the rapid diagnosis of NTM-PD clinically, and the pathogenic strains can be identified to the species level through molecular typing, which provides a reliable basis for treatment. In addition to the well-known PCR and mNGS methods, there are numerous alternative methods to identify NTM to the species level. The treatment of NTM-PD remains a challenging problem. Although clinical guidelines outline several treatment options for common NTM species infections, in most cases, the therapeutic outcomes of these drugs for NTM-PD often fall short of expectations. At present, the focus of research is to find more effective and more tolerable NTM-PD therapeutic drugs and regimens. In this paper, the latest diagnostic techniques, therapeutic drugs and methods, and prevention of NTM-PD are reviewed.
Asunto(s)
Infecciones por Mycobacterium no Tuberculosas , Micobacterias no Tuberculosas , Humanos , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no Tuberculosas/genética , Micobacterias no Tuberculosas/efectos de los fármacos , Micobacterias no Tuberculosas/aislamiento & purificación , Micobacterias no Tuberculosas/clasificación , Antibacterianos/uso terapéutico , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/microbiología , Enfermedades Pulmonares/tratamiento farmacológico , Técnicas de Diagnóstico Molecular/métodosRESUMEN
To address intracellular mycobacterial infections, we developed a cocktail of four enzymes that catalytically attack three layers of the mycobacterial envelope. This cocktail is delivered to macrophages, through a targeted liposome presented here as ENTX_001. Endolytix Cocktail 1 (EC1) leverages mycobacteriophage lysin enzymes LysA and LysB, while also including α-amylase and isoamylase for degradation of the mycobacterial envelope from outside of the cell. The LysA family of proteins from mycobacteriophages has been shown to cleave the peptidoglycan layer, whereas LysB is an esterase that hydrolyzes the linkage between arabinogalactan and mycolic acids of the mycomembrane. The challenge of gaining access to the substrates of LysA and LysB provided exogenously was addressed by adding amylase enzymes that degrade the extracellular capsule shown to be present in Mycobacterium tuberculosis. This enzybiotic approach avoids antimicrobial resistance, specific receptor-mediated binding, and intracellular DNA surveillance pathways that limit many bacteriophage applications. We show this cocktail of enzymes is bactericidal in vitro against both rapid- and slow-growing nontuberculous mycobacteria (NTM) as well as M. tuberculosis strains. The EC1 cocktail shows superior killing activity when compared to previously characterized LysB alone. EC1 is also powerfully synergistic with standard-of-care antibiotics. In addition to in vitro killing of NTM, ENTX_001 demonstrates the rescue of infected macrophages from necrotic death by Mycobacteroides abscessus and Mycobacterium avium. Here, we demonstrate shredding of mycobacterial cells by EC1 into cellular debris as a mechanism of bactericide.IMPORTANCEThe world needs entirely new forms of antibiotics as resistance to chemical antibiotics is a critical problem facing society. We addressed this need by developing a targeted enzyme therapy for a broad range of species and strains within mycobacteria and highly related genera including nontuberculous mycobacteria such as Mycobacteroides abscessus, Mycobacterium avium, Mycobacterium intracellulare, as well as Mycobacterium tuberculosis. One advantage of this approach is the ability to drive our lytic enzymes through encapsulation into macrophage-targeted liposomes resulting in attack of mycobacteria in the cells that harbor them where they hide from the adaptive immune system and grow. Furthermore, this approach shreds mycobacteria independent of cell physiology as the drug targets the mycobacterial envelope while sidestepping the host range limitations observed with phage therapy and resistance to chemical antibiotics.
Asunto(s)
Galactanos , Macrófagos , Micobacteriófagos , Mycobacterium tuberculosis , Micobacterias no Tuberculosas , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/enzimología , Micobacteriófagos/genética , Micobacteriófagos/enzimología , Macrófagos/microbiología , Macrófagos/virología , Humanos , Micobacterias no Tuberculosas/efectos de los fármacos , Liposomas/química , Antibacterianos/farmacología , Peptidoglicano/metabolismo , Pruebas de Sensibilidad Microbiana , Endopeptidasas/metabolismo , Endopeptidasas/farmacología , Endopeptidasas/genéticaRESUMEN
Antimicrobial resistance is a global health problem. In 2021, it was estimated almost half a million of multidrug-resistant tuberculosis (MDR-TB) cases. Besides, non-tuberculous mycobacteria (NTM) are highly resistant to several drugs and the emergence of fluoroquinolone (FQ) resistant M. tuberculosis (Mtb) is also a global concern making treatments difficult and with variable outcome. The aim of this study was to evaluate the activity of the FQ, DC-159a, against Mtb and NTM and to explore the cross-resistance with the currently used FQs.A total of 12 pre-extensively drug-resistant (XDR) Mtb, 2 XDR, 36 fully drug susceptible strains and 41 NTM isolates were included to estimate the in vitro activity of DC-159a, moxifloxacin (MOX) and levofloxacin (LX), using minimal inhibitory and bactericidal concentration (MIC and MBC). The activity inside the human macrophages and pulmonary epithelial cells were also determined.DC-159a was active in vitro and ex vivo against mycobacteria. Besides, it was more active than MOX/LX. Moreover, no cross-resistance was evidenced between DC-159a and LX/MOX as DC-159a could inhibit Mtb and MAC strains that were already resistant to LX/MOX.DC-159a could be a possible candidate in new therapeutic regimens for MDR/ XDR-TB and mycobacterioses cases.
Asunto(s)
Aminopiridinas , Fluoroquinolonas , Pruebas de Sensibilidad Microbiana , Moxifloxacino , Mycobacterium tuberculosis , Fluoroquinolonas/farmacología , Humanos , Mycobacterium tuberculosis/efectos de los fármacos , Moxifloxacino/farmacología , Antituberculosos/farmacología , Micobacterias no Tuberculosas/efectos de los fármacos , Levofloxacino/farmacología , Macrófagos/efectos de los fármacos , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacosRESUMEN
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.
Asunto(s)
Antituberculosos , Infecciones por Mycobacterium no Tuberculosas , Humanos , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Antituberculosos/uso terapéutico , Antituberculosos/farmacología , Animales , Desarrollo de Medicamentos/métodos , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Micobacterias no Tuberculosas/efectos de los fármacos , Descubrimiento de Drogas , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/microbiologíaRESUMEN
BACKGROUND: Non-tuberculous mycobacteria (NTM) are generally free-living organism, widely distributed in the environment, with sporadic potential to infect. In recent years, there has been a significant increase in the global incidence of NTM-related disease, spanning across all continents and an increased mortality after the diagnosis has been reported. The decisions on whether to treat or not and which drugs to use are complex and require a multidisciplinary approach as well as patients' involvement in the decision process. METHODS AND RESULTS: This review aims at describing the drugs used for treating NTM-associated diseases emphasizing the efficacy, tolerability, optimization strategies as well as possible drugs that might be used in case of intolerance or resistance. We also reviewed data on newer compounds highlighting the lack of randomised clinical trials for many drugs but also encouraging preliminary data for others. We also focused on non-pharmacological interventions that need to be adopted during care of individuals with NTM-associated diseases CONCLUSIONS: Despite insufficient efficacy and poor tolerability this review emphasizes the improvement in patients' care and the needs for future studies in the field of anti-NTM treatments.
Asunto(s)
Antibacterianos , Infecciones por Mycobacterium no Tuberculosas , Micobacterias no Tuberculosas , Humanos , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no Tuberculosas/efectos de los fármacos , Antibacterianos/uso terapéutico , ItaliaRESUMEN
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.