RESUMO
The study aims to accurately identify differentially expressed genes (DEGs) and biological pathways in mycobacterial infections through bioinformatics for deeper disease understanding. Differentially expressed genes (DEGs) was explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Unique DEGs were submitted on least absolute shrinkage and selection operator (LASSO) regression analysis. 1,057 DEGs from two GSE datasets were identified, which were closely connected with NTM/ latent TB infection (LTBI)/active TB disease (ATB). It was demonstrated that these DEGs are mainly associated with detoxification processes, and virus and bacterial infections. Moreover, the METTL7B gene was the most informative marker for distinguishing LTBI and ATB with an area under the curve (AUC) of 0.983 (95%CI: 0.964 to 1). The significantly upregulated HBA1/2 genes were the most informative marker for distinguishing between individuals of IGRA-HC/NTM and LTBI (P < 0.001). Moreover, the upregulated HBD gene was also differ between IGRA-HC/NTM and ATB (P < 0.001). We have identified gene signatures associated with Mycobacterium infection in whole blood, which could be significant for understanding the molecular mechanisms and diagnosis of NTM, LTBI, or ATB.
Assuntos
Biologia Computacional , Mycobacterium tuberculosis , Transcriptoma , Humanos , Biologia Computacional/métodos , Mycobacterium tuberculosis/genética , Complexo Mycobacterium avium/genética , Marcadores Genéticos , Perfilação da Expressão Gênica/métodos , Infecção por Mycobacterium avium-intracellulare/genética , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Tuberculose/genética , Tuberculose/microbiologia , Tuberculose/diagnóstico , Ontologia Genética , Tuberculose Latente/genética , Tuberculose Latente/diagnóstico , Tuberculose Latente/microbiologia , Análise de Sequência de RNA/métodosRESUMO
Pulmonary Mycobacterium avium-intracellulare complex (MAC) disease is a typical non-tuberculous mycobacterial infection. The incidence of pulmonary MAC is increasing worldwide. This study aimed to clarify the pharmacokinetic parameters of anti-pulmonary MAC disease drugs in silkworms. The pharmacokinetic parameters investigated included maximum concentration, area under the concentration-time curve, total clearance, and volume of distribution at steady-state. In addition, protein-binding rates, fat body transferability, and drug-drug interactions were examined. Antibiotic concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Among the antibiotics investigated, amikacin was not eliminated from silkworms during the 48-h observation period. In contrast, dose-proportional pharmacokinetics were observed in silkworms for all antibiotics tested, except for amikacin. Protein-binding rates in hemolymph for clarithromycin, azithromycin, rifampicin, ethambutol, and amikacin were 39.6 ± 3.0%, 39.5 ± 4.3%, 76.3 ± 3.2%, 20.9 ± 4.2%, and 73.1 ± 4.7%, respectively (mean ± standard deviation). The distribution of antibiotics in the fat bodies of silkworms was related to drug lipophilicity. No drug-drug interactions were observed in the silkworms. The pharmacokinetics of these drugs in silkworms differed significantly from those in humans. Therefore, while it is challenging to predict the pharmacokinetics of these drugs in humans based on silkworm data, the silkworm infection model has facilitated a comprehensive assessment of the relationship between antibiotic exposure and efficacy.
Assuntos
Amicacina , Antibacterianos , Bombyx , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Animais , Bombyx/microbiologia , Bombyx/metabolismo , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/microbiologia , Antibacterianos/farmacocinética , Complexo Mycobacterium avium/efeitos dos fármacos , Amicacina/farmacocinética , Hemolinfa/metabolismo , Claritromicina/farmacocinética , Interações Medicamentosas , Etambutol/farmacocinética , Ligação Proteica , Rifampina/farmacocinética , Rifampina/farmacologiaRESUMO
Mycobacterium avium complex pulmonary disease (MAC-PD) has a heterogeneous clinical course. However, immune profiles associated with MAC-PD clinical course are limited. We performed single-cell RNA sequencing of peripheral blood mononuclear cells from 21 MAC-PD patients divided into three clinical courses: group A, spontaneous culture conversion; group B, stable disease without antibiotic treatment; and group C, progressive disease with antibiotic treatment. A lower proportion of NK cells and higher proportion of monocytes were noted in group C compared to combined groups A and B. The proportion of classical monocytes was higher in group C compared to groups A and B, while the proportion of non-classical monocytes decreased. EGR1, HSPA1A, HSPA1B, and CD83 were up-regulated in spontaneous culture conversion group A compared to progressive disease group C. Up-regulation of MYOM2 and LILRA4 and down-regulation of MT-ATP8, CD83, and CCL3L1 was found in progressive disease group C. PCBP1, FOS, RGCC, S100B, G0S2, AREG, and LYN were highly expressed in favorable treatment response compared to unfavorable response. Our findings may offer a comprehensive understanding of the host immune profiles that influence a particular MAC-PD clinical course and could suggest an immunological mechanism associated with the disease progression of MAC-PD.
Assuntos
Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Transcriptoma , Humanos , Masculino , Feminino , Infecção por Mycobacterium avium-intracellulare/microbiologia , Idoso , Complexo Mycobacterium avium/genética , Pessoa de Meia-Idade , Análise de Célula Única/métodos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/microbiologia , Pneumopatias/microbiologia , Pneumopatias/genética , Perfilação da Expressão Gênica , Progressão da Doença , Monócitos/metabolismo , Monócitos/imunologiaRESUMO
BACKGROUND: Mycobacterium avium complex (MAC) is an uncommon clinical pathogen, especially in the central nervous system (CNS), and carries a poor prognosis. MAC infections commonly present as immune reconstitution disease (IRD) in HIV patients. Herein, we report a case of intracranial infection caused by MAC in an AIDS patient without disseminated MAC (DMAC) and immune reconstitution inflammatory syndrome (IRIS). CASE PRESENTATION: A 31-year-old HIV-positive male presented us with progressively worsening CNS symptoms, and neuroimaging revealed ring-enhancing lesions. The intracranial lesions worsened after the empirical therapy for toxoplasma encephalitis and fungal infection. Due to the rapid progression of the disease, the patient died. Mycobacterium avium was the only pathogen in brain tissue after cultures and molecular biology tests. CONCLUSION: MAC infection in CNS is challenging to diagnose in HIV patients. Our findings emphasize that obtaining tissue samples and applying molecular biology methods is essential to help diagnose the patient as soon as possible to receive adequate treatment.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Humanos , Masculino , Adulto , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecção por Mycobacterium avium-intracellulare/complicações , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Evolução Fatal , Complexo Mycobacterium avium/isolamento & purificação , Síndrome da Imunodeficiência Adquirida/complicações , Encéfalo/patologia , Encéfalo/microbiologiaRESUMO
BACKGROUND: The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated. METHODS: Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort. RESULTS: Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04-0.28, p < 0.001 and OR 0.11 95% CI 0.02-0.4, p = 0.004, respectively) and MCH was negatively associated with fulfillment of the ATS criteria when isolated from respiratory samples (OR 0.28 95% CI 0.09-0.7, p = 0.011). With 14 out of 43 patients with available serial isolates, co-infections or co-colonizations with different strains or even species of the MAC were frequent (32.6%). CONCLUSIONS: This study demonstrates clustering and the presence of plasmids in a large proportion of MAC isolates in Europe and in a global context. Future studies need to urgently define potential ways of transmission of MAC isolates and the potential involvement of plasmids in virulence.
Assuntos
Genoma Bacteriano , Genômica , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Filogenia , Complexo Mycobacterium avium/genética , Complexo Mycobacterium avium/isolamento & purificação , Humanos , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecção por Mycobacterium avium-intracellulare/epidemiologia , Europa (Continente) , Masculino , Feminino , Genômica/métodos , Sequenciamento Completo do Genoma , Idoso , Pessoa de Meia-Idade , Plasmídeos/genética , Polimorfismo de Nucleotídeo Único , Farmacorresistência Bacteriana/genética , Adulto , Virulência/genéticaRESUMO
BACKGROUND: Non-tuberculous mycobacterial pulmonary infections (NTM-PD) are becoming increasingly common in clinical practice, and early detection and accurate determination of the infecting pathogen is crucial for subsequent treatment. We report a case of NTM-PD in a healthy middle-aged female with Mycobacterium tuberculosis complex group (MAC) infection confirmed by mNGS examination. METHODS: Appropriate laboratory tests, chest CT scan, bronchoscopic alveolar lavage fluid (BALF) examination, and macrogenomic next-generation sequencing (mNGS) were performed to establish the diagnosis. RESULTS: Chest CT showed multiple inflammatory lesions in the right middle lobe, and BALF sent for mNGS finally confirmed the diagnosis of MAC infection. After symptomatic treatment with azithromycin combined with ethambutol and rifampicin, the patient improved and was discharged from the hospital. CONCLUSIONS: In patients with pulmonary infections, pathogens should be clarified early to determine the diagnosis. mNGS of BALF samples have high specificity in detecting pathogens of infectious diseases, especially complex mixed infectious disease pathogens.
Assuntos
Líquido da Lavagem Broncoalveolar , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Humanos , Feminino , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/complicações , Complexo Mycobacterium avium/isolamento & purificação , Complexo Mycobacterium avium/genética , Líquido da Lavagem Broncoalveolar/microbiologia , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Sequenciamento de Nucleotídeos em Larga Escala , Pneumonia/microbiologia , Pneumonia/diagnóstico , Pneumonia/tratamento farmacológico , Azitromicina/uso terapêutico , Rifampina/uso terapêuticoRESUMO
Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is considered a growing health concern. The majority of NTM-PD cases in Europe are caused by slow-growing mycobacteria (SGM). However, distinct radiological features of different SGM remain largely uninvestigated. We applied a previously described radiological score to a patient cohort consisting of individuals with isolation of different SGM. Correlations between clinical data, species and computed tomography (CT) features were examined by logistic and linear regression analyses, as well as over the course of time. Overall, 135 pulmonary CT scans from 84 patients were included. The isolated NTM-species were mainly Mycobacterium avium complex (MAC, n = 49), as well as 35 patients with non-MAC-species. Patients with isolation of M. intracellulare had more extensive CT findings compared to all other SGM species (coefficient 3.53, 95% Cl - 0.37 to 7.52, p = 0.075) while patients meeting the ATS criteria and not undergoing therapy exhibited an increase in CT scores over time. This study provides insights into differential radiological features of slow-growing NTM. While M. intracellulare exhibited a tendency towards higher overall CT scores, the radiological features were similar across different SGM. The applied CT score might be a useful instrument for monitoring patients and could help to guide antimycobacterial therapy.
Assuntos
Infecções por Mycobacterium não Tuberculosas , Micobactérias não Tuberculosas , Tomografia Computadorizada por Raios X , Humanos , Masculino , Feminino , Infecções por Mycobacterium não Tuberculosas/diagnóstico por imagem , Infecções por Mycobacterium não Tuberculosas/microbiologia , Tomografia Computadorizada por Raios X/métodos , Idoso , Pessoa de Meia-Idade , Micobactérias não Tuberculosas/isolamento & purificação , Micobactérias não Tuberculosas/crescimento & desenvolvimento , Complexo Mycobacterium avium/isolamento & purificação , Pulmão/microbiologia , Pulmão/diagnóstico por imagem , Estudos Retrospectivos , Adulto , Infecção por Mycobacterium avium-intracellulare/diagnóstico por imagem , Infecção por Mycobacterium avium-intracellulare/microbiologiaRESUMO
BACKGROUND: Disease susceptibility and progression of Mycobacterium avium complex pulmonary disease (MAC-PD) is associated with multiple factors, including low body mass index (BMI). However, the specific impact of low BMI on MAC-PD progression remains poorly understood. This study aims to examine the progression of MAC-PD in the context of low BMI, utilising a disease-resistant mouse model. METHODS: We employed a MAC infection-resistant female A/J mouse model to compare the progression of MAC-PD under two dietary conditions: one group was fed a standard protein diet, representing protein-energy unrestricted conditions, and the other was fed a low protein diet (LPD), representing protein-energy restriction. FINDINGS: Our results reveal that protein-energy restriction significantly exacerbates MAC-PD progression by disrupting lipid metabolism. Mice fed an LPD showed elevated fatty acid levels and related gene expressions in lung tissues, similar to findings of increased fatty acids in the serum of patients who exhibited the MAC-PD progression. These mice also exhibited increased CD36 expression and lipid accumulation in macrophages upon MAC infection. In vitro experiments emphasised the crucial role of CD36-mediated palmitic acid uptake in bacterial proliferation. Importantly, in vivo studies demonstrated that administering anti-CD36 antibody to LPD-fed A/J mice reduced macrophage lipid accumulation and impeded bacterial growth, resulting in remarkable slowing disease progression. INTERPRETATION: Our findings indicate that the metabolic status of host immune cells critically influences MAC-PD progression. This study highlights the potential of adequate nutrient intake in preventing MAC-PD progression, suggesting that targeting CD36-mediated pathways might be a host-directed therapeutic strategy to managing MAC infection. FUNDING: This research was funded by the National Research Foundation of Korea, the Korea Research Institute of Bioscience and Biotechnology, and the Korea National Institute of Health.
Assuntos
Modelos Animais de Doenças , Progressão da Doença , Metabolismo dos Lipídeos , Infecção por Mycobacterium avium-intracellulare , Animais , Feminino , Camundongos , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecção por Mycobacterium avium-intracellulare/metabolismo , Antígenos CD36/metabolismo , Antígenos CD36/genética , Macrófagos/metabolismo , Humanos , Complexo Mycobacterium avium , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Ácidos Graxos/metabolismo , Mycobacterium avium , Suscetibilidade a DoençasRESUMO
INTRODUCTION: Exposure to Non-tuberculous Mycobacteria (NTM) varies regionally and may partly explain the disparate outcomes of BCG vaccination and tuberculosis (TB) susceptibility. METHODS: We examined NTM sputum colonization, associations with clinical characteristics, and tuberculin skin test (TST) responses in an adolescent TB prevalence survey. RESULTS: Among 5004 adolescents screened, 2281 (45.5 %) were evaluated further. TB and NTM prevalence rates were 0.3 % and 8.0 %, respectively. Among 418 NTM isolates, 103 were unidentifiable, and 315 (75 %) comprised 15 species, the most frequent being M. intracellulare (MAC) (108, 26 %), M. scrofulaceum (96, 23 %) and M. fortuitum (51, 12 %). "NTM colonized" adolescents had less frequent chronic cough and night sweats (adjusted odds ratio [aOR] 0.62, 95 % confidence interval [CI] 0.44-0.87and aOR 0.61, CI 0.42-0.89 respectively), and lower TST induration (median 11 mm (interquartile range [IQR] 0-16) vs 13 mm (IQR 6-17; p = 0.006)) when compared to "NTM not colonized" participants. MAC, but not M. scrofulaceum or M. fortuitum, was associated with decreased TST induration (median 7.5 mm (IQR 0-15) vs 13 mm (IQR 6-17) among "MAC colonized" vs "not colonized", p = 0.001). CONCLUSION: We observed high NTM prevalence rates with species-specific associations with TST induration, consistent with a model of species-dependent heterologous immunity among mycobacteria.
Assuntos
Complexo Mycobacterium avium , Escarro , Teste Tuberculínico , Humanos , Adolescente , Quênia/epidemiologia , Masculino , Feminino , Prevalência , Escarro/microbiologia , Complexo Mycobacterium avium/imunologia , Complexo Mycobacterium avium/isolamento & purificação , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/imunologia , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/imunologia , Criança , Infecção por Mycobacterium avium-intracellulare/epidemiologia , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecção por Mycobacterium avium-intracellulare/imunologia , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Valor Preditivo dos Testes , Estudos TransversaisRESUMO
Mammals are generally resistant to Mycobacterium avium complex (MAC) infections. We report here on a primary immunodeficiency disorder causing increased susceptibility to MAC infections in a canine breed. Adult Miniature Schnauzers developing progressive systemic MAC infections were related to a common founder, and pedigree analysis was consistent with an autosomal recessive trait. A genome-wide association study and homozygosity mapping using 8 infected, 9 non-infected relatives, and 160 control Miniature Schnauzers detected an associated region on chromosome 9. Whole genome sequencing of 2 MAC-infected dogs identified a codon deletion in the CARD9 gene (c.493_495del; p.Lys165del). Genotyping of Miniature Schnauzers revealed the presence of this mutant CARD9 allele worldwide, and all tested MAC-infected dogs were homozygous mutants. Peripheral blood mononuclear cells from a dog homozygous for the CARD9 variant exhibited a dysfunctional CARD9 protein with impaired TNF-α production upon stimulation with the fungal polysaccharide ß-glucan that activates the CARD9-coupled C-type lectin receptor, Dectin-1. While CARD9-deficient knockout mice are susceptible to experimental challenges by fungi and mycobacteria, Miniature Schnauzer dogs with systemic MAC susceptibility represent the first spontaneous animal model of CARD9 deficiency, which will help to further elucidate host defense mechanisms against mycobacteria and fungi and assess potential therapies for animals and humans.
Assuntos
Proteínas Adaptadoras de Sinalização CARD , Doenças do Cão , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Cães , Infecção por Mycobacterium avium-intracellulare/veterinária , Infecção por Mycobacterium avium-intracellulare/genética , Infecção por Mycobacterium avium-intracellulare/microbiologia , Complexo Mycobacterium avium/genética , Doenças do Cão/genética , Doenças do Cão/microbiologia , Deleção de Sequência , Linhagem , Feminino , Masculino , Sequenciamento Completo do Genoma , Homozigoto , Lectinas Tipo C/genéticaRESUMO
Mycobacterium avium complex (MAC) is a non-tuberculous mycobacterium widely distributed in the environment. Even though MAC infection is increasing in older women and immunocompromised patients, to our knowledge there has been no comprehensive analysis of the MAC-infected host-cell transcriptome-and particularly of long non-coding RNAs (lncRNAs). By using in vitro-cultured primary mouse bone-marrow-derived macrophages (BMDMs) and Cap analysis of gene expression, we analyzed the transcriptional and kinetic landscape of macrophage genes, with a focus on lncRNAs, during MAC infection. MAC infection of macrophages induced the expression of immune/inflammatory response genes and other genes similar to those involved in M1 macrophage activation, consistent with previous reports, although Nos2 (M1 activation) and Arg1 (M2 activation) had distinct expression profiles. We identified 31 upregulated and 30 downregulated lncRNA promoters corresponding respectively to 18 and 26 lncRNAs. Upregulated lncRNAs were clustered into two groups-early and late upregulated-predicted to be associated with immune activation and the immune response to infection, respectively. Furthermore, an Ingenuity Pathway Analysis revealed canonical pathways and upstream transcription regulators associated with differentially expressed lncRNAs. Several differentially expressed lncRNAs reported elsewhere underwent expressional changes upon M1 or M2 preactivation and subsequent MAC infection. Finally, we showed that expressional change of lncRNAs in MAC-infected BMDMs was mediated by toll-like receptor 2, although there may be other mechanisms that sense MAC infection. We identified differentially expressed lncRNAs in MAC-infected BMDMs, revealing diverse features that imply the distinct roles of these lncRNAs in MAC infection and macrophage polarization.
Assuntos
Perfilação da Expressão Gênica , Macrófagos , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , RNA Longo não Codificante , Transcriptoma , RNA Longo não Codificante/genética , Animais , Macrófagos/imunologia , Macrófagos/microbiologia , Macrófagos/metabolismo , Complexo Mycobacterium avium/imunologia , Complexo Mycobacterium avium/genética , Camundongos , Infecção por Mycobacterium avium-intracellulare/imunologia , Infecção por Mycobacterium avium-intracellulare/genética , Infecção por Mycobacterium avium-intracellulare/microbiologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Células Cultivadas , Regulação da Expressão GênicaRESUMO
ABSTRACT: Microorganisms belonging to the Mycobacterium avium complex (MAC) are ubiquitous in the environment, but only a minority of infected persons develop disease. An underlying lung disease or immune deficiency is a prerequisite for clinical manifestation. However, disseminated MAC disease primarily manifests in people living with human immunodeficiency virus (HIV) in the severe immunodeficiency stage with a whole host of clinical symptoms. We present two cases of disseminated M. avium infection in people living with HIV in the stage of severe immunodeficiency. Both patients exhibited distinct disease progression, with the absence of pulmonary symptoms being a common characteristic. The first patient predominantly experienced high fever, accompanied by diarrhea and severe anemia. The normothermia in the second patient was incongruent with the presence of marked cachexia, severe abdominal pain, and magnetic resonance imaging evidence of abdominal lymph node involvement. The causative agent was isolated from both sputum and stools. The patients underwent treatment that comprised aminoglycoside, macrolide, ethambutol, and rifampicin. Although both patients achieved optimal viral suppression of HIV, the immunologic response to antiretroviral therapy was suboptimal. The first patient died in the setting of severe immunodeficiency due to the development of decompensated liver cirrhosis, while the second patient demonstrated a slight reverse course of the disease.
Assuntos
Infecções por HIV , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Adulto , Humanos , Masculino , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Evolução Fatal , Infecções por HIV/complicações , Complexo Mycobacterium avium/isolamento & purificação , Infecção por Mycobacterium avium-intracellulare/complicações , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Escarro/microbiologiaRESUMO
OBJECTIVE: This study aims to estimate the overall in vitro activity of bedaquiline (BDQ) against clinical isolates of Mycobacterium abscessus complex (MABS) and M. avium complex (MAC), considering BDQ as a repurposed drug for non-tuberculous mycobacteria (NTM) infections. METHODS: We conducted a systematic review of publications in PubMed/ MEDLINE, Web of Science, and Embase up to 15 April 2023. Studies were included if they followed the Clinical and Laboratory Standards Institute (CLSI) criteria for drug susceptibility testing (DST). Using a random effects model, we assessed the overall in vitro BDQ resistance rate in clinical isolates of MABS and MAC. Sources of heterogeneity were analysed using Cochran's Q and the I2 statistic. All analyses were performed using CMA V3.0. RESULTS: A total of 24 publications (19 reports for MABS and 11 for MAC) were included. Using 1 µg/mL and 2 µg/mL as the breakpoint for BDQ resistance, the pooled rates of in vitro BDQ resistance in clinical isolates of MABS were found to be 1.8% (95% confidence interval [CI], 0.7-4.6%) and 1.7% (95% CI, 0.6-4.4%), respectively. In the case of MAC, the pooled rates were 1.7% (95% CI, 0.4-6.9%) and 1.6% (95% CI, 0.4-6.8%) for 1 µg/mL and 2 µg/mL, respectively. CONCLUSION: This study reports the prevalence of BDQ resistance in clinical isolates of MABS and MAC. The findings suggest that BDQ holds potential as a repurposed drug for treating MABS and MAC infections.
Assuntos
Antituberculosos , Diarilquinolinas , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Complexo Mycobacterium avium , Diarilquinolinas/farmacologia , Humanos , Mycobacterium abscessus/efeitos dos fármacos , Mycobacterium abscessus/genética , Mycobacterium abscessus/isolamento & purificação , Complexo Mycobacterium avium/efeitos dos fármacos , Complexo Mycobacterium avium/isolamento & purificação , Infecções por Mycobacterium não Tuberculosas/microbiologia , Antituberculosos/farmacologia , Farmacorresistência Bacteriana , Infecção por Mycobacterium avium-intracellulare/microbiologiaRESUMO
The latest guidelines include azithromycin as a preferred regimen for treating Mycobacterium avium complex (MAC) pulmonary disease. However, serially collected susceptibility data on clinical MAC isolates are limited, and no breakpoints have been determined. We investigated the minimum inhibitory concentrations (MICs) of azithromycin and clarithromycin for all MAC strains isolated in 2021 from a single center in Japan, excluding duplicates. The MICs were determined using a panel based on the microbroth dilution method, according to the latest Clinical and Laboratory Standards Institute recommendations. The MICs were determined for 318 MAC strains. Although there was a significant positive correlation between the MICs of azithromycin and clarithromycin, the MICs of azithromycin tended to be higher than those of clarithromycin. Among the cases in which the strains were isolated, 18 patients initiated treatment, including azithromycin treatment, after sample collection. Some patients infected with stains with relatively high azithromycin MICs achieved a microbiological cure with azithromycin-containing regimens. This study revealed a higher MIC distribution for azithromycin than clarithromycin, raising questions about the current practice of estimating azithromycin susceptibility based on the clarithromycin susceptibility test result. However, this was a single-center study that included only a limited number of cases treated with azithromycin. Therefore, further multicenter studies that include a greater number of cases treated with azithromycin are warranted to verify the distribution of azithromycin MICs and examine the correlation between azithromycin MICs and treatment effectiveness.IMPORTANCEThe macrolides serve as key drugs in the treatment of pulmonary Mycobacterium avium complex infection, and the administration of macrolide should be guided by susceptibility test results. Azithromycin is recommended as a preferred choice among macrolides, surpassing clarithromycin; however, drug susceptibility testing is often not conducted, and clarithromycin susceptibility is used as a surrogate. This study represents the first investigation into the minimum inhibitory concentration of azithromycin on a scale of several hundred clinical isolates, revealing an overall tendency for higher minimum inhibitory concentrations compared with clarithromycin. The results raise questions about the appropriateness of using clarithromycin susceptibility test outcomes for determining the administration of azithromycin. This study highlights the need for future discussions on the clinical breakpoints of azithromycin, based on large-scale clinical research correlating azithromycin susceptibility with treatment outcomes.
Assuntos
Antibacterianos , Azitromicina , Claritromicina , Testes de Sensibilidade Microbiana , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Azitromicina/farmacologia , Azitromicina/uso terapêutico , Humanos , Japão , Complexo Mycobacterium avium/efeitos dos fármacos , Complexo Mycobacterium avium/isolamento & purificação , Claritromicina/farmacologia , Antibacterianos/farmacologia , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/microbiologia , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , AdultoRESUMO
BACKGROUND: Although international nontuberculous mycobacterial pulmonary disease (NTM-PD) guidelines highlight symptom presence at diagnosis, the clinical characteristics of asymptomatic Mycobacterium avium complex pulmonary infection (MAC-PI) patients remain understudied. We clarified the clinical characteristics and course of asymptomatic MAC-PI patients. METHODS: We retrospectively analyzed 200 consecutive patients with MAC-PIs and adequate available data who newly met the microbiological and radiological criteria for NTM-PD at Fukujuji Hospital from January 2018 to June 2020. We compared the clinical characteristics and course of asymptomatic patients with symptomatic patients and evaluated factors influencing treatment initiation through multivariate analysis. RESULTS: 111 patients were symptomatic and 89 were asymptomatic at diagnosis. While the proportion was significantly lower than that in the symptomatic group (28.8 %), 15.7 % of asymptomatic group patients had cavitary lesions (P = 0.042). In the asymptomatic group, treatments were initiated in 38 (42.7 %) patients, and cavitary lesions, a positive acid-fast bacilli smear, and younger age were independent risk factors for treatment initiation. Among 22 (57.9 %) patients who experienced disease progression necessitating treatment during follow-up, 13 (34.2 %) displayed radiological progression without any worsening of symptoms. Agents used for treatment were consistent across the groups, with no significant differences in culture conversion, microbiological recurrence rates, or spontaneous culture conversion rates. CONCLUSION: Routine health checkups and radiological examinations can detect clinically important MAC-PIs even in the absence of symptoms. Considering that the clinical course of asymptomatic MAC-PI patients is largely similar to that of symptomatic patients, timely and appropriate management and intervention are essential for all MAC-PI patients.
Assuntos
Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Humanos , Masculino , Feminino , Infecção por Mycobacterium avium-intracellulare/diagnóstico por imagem , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Complexo Mycobacterium avium/isolamento & purificação , Progressão da Doença , Infecções Assintomáticas , Tomografia Computadorizada por Raios X/métodos , Idoso de 80 Anos ou mais , Fatores de Risco , Fatores EtáriosRESUMO
BACKGROUND: Mycobacterium avium complex (MAC), including Mycobacterium intracellulare is a member of slow-growing mycobacteria and contributes to a substantial proportion of nontuberculous mycobacterial lung disease in humans affecting immunocompromised and elderly populations. Adaptation of pathogens in hostile environments is crucial in establishing infection and persistence within the host. However, the sophisticated cellular and molecular mechanisms of stress response in M. intracellulare still need to be fully explored. We aimed to elucidate the transcriptional response of M. intracellulare under acidic and oxidative stress conditions. RESULTS: At the transcriptome level, 80 genes were shown [FC] ≥ 2.0 and p < 0.05 under oxidative stress with 10 mM hydrogen peroxide. Specifically, 77 genes were upregulated, while 3 genes were downregulated. In functional analysis, oxidative stress conditions activate DNA replication, nucleotide excision repair, mismatch repair, homologous recombination, and tuberculosis pathways. Additionally, our results demonstrate that DNA replication and repair system genes, such as dnaB, dinG, urvB, uvrD2, and recA, are indispensable for resistance to oxidative stress. On the contrary, 878 genes were shown [FC] ≥ 2.0 and p < 0.05 under acidic stress with pH 4.5. Among these genes, 339 were upregulated, while 539 were downregulated. Functional analysis highlighted nitrogen and sulfur metabolism pathways as the primary responses to acidic stress. Our findings provide evidence of the critical role played by nitrogen and sulfur metabolism genes in the response to acidic stress, including narGHIJ, nirBD, narU, narK3, cysND, cysC, cysH, ferredoxin 1 and 2, and formate dehydrogenase. CONCLUSION: Our results suggest the activation of several pathways potentially critical for the survival of M. intracellulare under a hostile microenvironment within the host. This study indicates the importance of stress responses in M. intracellulare infection and identifies promising therapeutic targets.
Assuntos
Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Humanos , Idoso , Complexo Mycobacterium avium/genética , Transcriptoma , Infecção por Mycobacterium avium-intracellulare/microbiologia , Perfilação da Expressão Gênica , Estresse Oxidativo , Nitrogênio , EnxofreRESUMO
INTRODUCTION: Novel therapeutic strategies are urgently needed for Mycobacterium avium complex pulmonary disease (MAC-PD). Human mesenchymal stromal cells (MSCs) can directly inhibit MAC growth, but their effect on intracellular bacilli is unknown. We investigated the ability of human MSCs to reduce bacterial replication and inflammation in MAC-infected macrophages and in a murine model of MAC-PD. METHODS: Human monocyte-derived macrophages (MDMs) were infected with M. avium Chester strain and treated with human bone marrow-derived MSCs. Intracellular and extracellular colony-forming units (CFUs) were counted at 72 hours. Six-week-old female balb/c mice were infected by nebulisation of M. avium Chester. Mice were treated with 1×106 intravenous human MSCs or saline control at 21 and 28 days post-infection. Lungs, liver and spleen were harvested 42 days post-infection for bacterial counts. Cytokines were quantified by ELISA. RESULTS: MSCs reduced intracellular bacteria in MDMs over 72 hours (median 35% reduction, p=0.027). MSC treatment increased extracellular concentrations of prostaglandin E2 (PGE2) (median 10.1-fold rise, p=0.002) and reduced tumour necrosis factor-α (median 28% reduction, p=0.025). Blocking MSC PGE2 production by cyclo-oxygenase-2 (COX-2) inhibition with celecoxib abrogated the antimicrobial effect, while this was restored by adding exogenous PGE2. MSC-treated mice had lower pulmonary CFUs (median 18% reduction, p=0.012), but no significant change in spleen or liver CFUs compared with controls. CONCLUSION: MSCs can modulate inflammation and reduce intracellular M. avium growth in human macrophages via COX-2/PGE2 signalling and inhibit pulmonary bacterial replication in a murine model of chronic MAC-PD.
Assuntos
Modelos Animais de Doenças , Células-Tronco Mesenquimais , Camundongos Endogâmicos BALB C , Infecção por Mycobacterium avium-intracellulare , Animais , Camundongos , Feminino , Humanos , Infecção por Mycobacterium avium-intracellulare/microbiologia , Complexo Mycobacterium avium , Transplante de Células-Tronco Mesenquimais/métodos , Macrófagos/microbiologia , Dinoprostona/metabolismo , Sulfonamidas/farmacologia , Mycobacterium aviumAssuntos
Obstrução Intestinal , Humanos , Lactente , Obstrução Intestinal/microbiologia , Obstrução Intestinal/etiologia , Mycobacterium avium/isolamento & purificação , Intestino Delgado/microbiologia , Intestino Delgado/patologia , Masculino , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Infecção por Mycobacterium avium-intracellulare/complicações , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Tuberculose Gastrointestinal/complicações , Tuberculose Gastrointestinal/diagnóstico , Tuberculose Gastrointestinal/tratamento farmacológico , Feminino , Complexo Mycobacterium avium/isolamento & purificaçãoRESUMO
BACKGROUND: Mycobacterium avium complex (MAC) is a group of slow-growing mycobacteria that includes Mycobacterium avium and Mycobacterium intracellulare. MAC pulmonary disease (MAC-PD) poses a threat to immunocompromised individuals and those with structural pulmonary diseases worldwide. The standard treatment regimen for MAC-PD includes a macrolide in combination with rifampicin and ethambutol. However, the treatment failure and disease recurrence rates after successful treatment remain high. RESULTS: In the present study, we investigated the unique characteristics of small colony variants (SCVs) isolated from patients with MAC-PD. Furthermore, revertant (RVT) phenotype, emerged from the SCVs after prolonged incubation on 7H10 agar. We observed that SCVs exhibited slower growth rates than wild-type (WT) strains but had higher minimum inhibitory concentrations (MICs) against multiple antibiotics. However, some antibiotics showed low MICs for the WT, SCVs, and RVT phenotypes. Additionally, the genotypes were identical among SCVs, WT, and RVT. Based on the MIC data, we conducted time-kill kinetic experiments using various antibiotic combinations. The response to antibiotics varied among the phenotypes, with RVT being the most susceptible, WT showing intermediate susceptibility, and SCVs displaying the lowest susceptibility. CONCLUSIONS: In conclusion, the emergence of the SCVs phenotype represents a survival strategy adopted by MAC to adapt to hostile environments and persist during infection within the host. Additionally, combining the current drugs in the treatment regimen with additional drugs that promote the conversion of SCVs to RVT may offer a promising strategy to improve the clinical outcomes of patients with refractory MAC-PD.
Assuntos
Pneumopatias , Infecção por Mycobacterium avium-intracellulare , Humanos , Complexo Mycobacterium avium/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/microbiologia , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Etambutol/farmacologia , Etambutol/uso terapêuticoRESUMO
BACKGROUND: Treatment of Mycobacterium avium complex pulmonary disease (MAC-PD) involves prolonged courses of multiple antibiotics that are variably tolerated and commonly cause adverse drug reactions (ADR). The purpose of this retrospective, single-center study was to identify demographic and disease-related variables associated with significant ADRs among patients treated with antibiotics against MAC-PD. METHODS: We reviewed all patients treated with antibiotic therapy for MAC-PD at a single center from 2000 to 2021. Patients were included if they met diagnostic criteria for MAC-PD, were prescribed targeted antibiotic therapy for any length of time and had their treatment course documented in their health record. We compared patients who completed antibiotics as originally prescribed (tolerant) with those whose antibiotic treatment course was modified or terminated secondary to an ADR (intolerant). RESULTS: Over the study period, 235 patients were prescribed antibiotic treatment with their clinical course documented in our center's electronic health record, and 246 treatment courses were analyzed. One hundred forty-three (57%) tolerated therapy versus 108 (43%) experienced ADRs. Among the 108 intolerant courses, 67 (63%) required treatment modification and 49 (46%) required premature treatment termination. Treatment intolerance was associated more frequently with smear positive sputum cultures (34% vs. 20%, p = 0.009), a higher Charlson Comorbidity Index (CCI) (4 vs. 6, p = 0.007), and existing liver disease (7% vs. 1%, p = 0.03). There was no between-group difference in BMI (21 vs. 22), fibrocavitary disease (24 vs. 19%), or macrolide sensitivity (94 vs. 80%). The use of daily therapy was not associated with intolerance (77 vs. 79%). Intolerant patients were more likely to be culture positive after 6 months of treatment (44 vs. 25%). CONCLUSIONS: Patients prescribed antibiotic therapy for MAC-PD are more likely to experience ADRs if they have smear positive sputum cultures at diagnosis, a higher CCI, or existing liver disease. Our study's rate of early treatment cessation due to ADR's was similar to that of other studies (20%) but is the first of its kind to evaluate patient and disease factors associated with ADR's. A systematic approach to classifying and addressing ADRs for patients undergoing treatment for MAC-PD is an area for further investigation.