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  1. Article: Eradication of Drug-Tolerant

    Lanni, Alessio / Iacobino, Angelo / Fattorini, Lanfranco / Giannoni, Federico

    Microorganisms

    2023  Volume 11, Issue 6

    Abstract: The lungs of tuberculosis (TB) patients contain a spectrum of granulomatous lesions, ranging from solid and well-vascularized cellular granulomas to avascular caseous granulomas. In solid granulomas, current therapy kills actively replicating (AR) ... ...

    Abstract The lungs of tuberculosis (TB) patients contain a spectrum of granulomatous lesions, ranging from solid and well-vascularized cellular granulomas to avascular caseous granulomas. In solid granulomas, current therapy kills actively replicating (AR) intracellular bacilli, while in low-vascularized caseous granulomas the low-oxygen tension stimulates aerobic and microaerophilic AR bacilli to transit into non-replicating (NR), drug-tolerant and extracellular stages. These stages, which do not have genetic mutations and are often referred to as persisters, are difficult to eradicate due to low drug penetration inside the caseum and mycobacterial cell walls. The sputum of TB patients also contains viable bacilli called differentially detectable (DD) cells that, unlike persisters, grow in liquid, but not in solid media. This review provides a comprehensive update on drug combinations killing in vitro AR and drug-tolerant bacilli (persisters and DD cells), and sterilizing
    Language English
    Publishing date 2023-06-06
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2720891-6
    ISSN 2076-2607
    ISSN 2076-2607
    DOI 10.3390/microorganisms11061511
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Epidemiology and drug susceptibility of nontuberculous mycobacteria (NTM) in Italy in 2016-2020.

    Giannoni, Federico / Lanni, Alessio / Iacobino, Angelo / Fattorini, Lanfranco

    Annali dell'Istituto superiore di sanita

    2023  Volume 59, Issue 2, Page(s) 132–138

    Abstract: Introduction: Nontuberculous mycobacteria (NTM) are environmental mycobacteria which may cause pulmonary and extrapulmonary diseases. These organisms are difficult to treat due to their intrinsic drug-resistance. In Italy, no major nationwide study on ... ...

    Abstract Introduction: Nontuberculous mycobacteria (NTM) are environmental mycobacteria which may cause pulmonary and extrapulmonary diseases. These organisms are difficult to treat due to their intrinsic drug-resistance. In Italy, no major nationwide study on NTM epidemiology and drug susceptibility was performed.
    Methods: Data on the epidemiology of 7,469 NTM clinical isolates identified in Italy in 2016-2020 and on the minimum inhibitory concentrations (MICs) of 1,506 of these strains were analysed.
    Results: Overall, 63 species were identified in 42 hospital laboratories located in 16 out of 20 regions, with Mycobacterium avium complex (MAC) being the most frequently isolated, followed by M. gordonae, M. xenopi, M. abscessus. The MICs of 12 drugs for MAC, M. xenopi, M. kansasii, M. abscessus, M. fortuitum and M. chelonae were interpreted for clinical significance (susceptible, intermediate, resistant) based on the guidelines published by the Clinical and Laboratory Standards Institute in November 2018.
    Conclusions: Our data are in line with other nationwide studies and may be of value for further update of microbiological and clinical guidelines.
    MeSH term(s) Humans ; Nontuberculous Mycobacteria ; Mycobacterium Infections, Nontuberculous/epidemiology ; Mycobacterium Infections, Nontuberculous/microbiology ; Microbial Sensitivity Tests ; Italy/epidemiology
    Language English
    Publishing date 2023-02-17
    Publishing country Italy
    Document type Journal Article
    ZDB-ID 950344-4
    ISSN 2384-8553 ; 0021-2571
    ISSN (online) 2384-8553
    ISSN 0021-2571
    DOI 10.4415/ANN_23_02_06
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Eradication of Drug-Tolerant Mycobacterium tuberculosis 2022

    Alessio Lanni / Angelo Iacobino / Lanfranco Fattorini / Federico Giannoni

    Microorganisms, Vol 11, Iss 1511, p

    Where We Stand

    2023  Volume 1511

    Abstract: The lungs of tuberculosis (TB) patients contain a spectrum of granulomatous lesions, ranging from solid and well-vascularized cellular granulomas to avascular caseous granulomas. In solid granulomas, current therapy kills actively replicating (AR) ... ...

    Abstract The lungs of tuberculosis (TB) patients contain a spectrum of granulomatous lesions, ranging from solid and well-vascularized cellular granulomas to avascular caseous granulomas. In solid granulomas, current therapy kills actively replicating (AR) intracellular bacilli, while in low-vascularized caseous granulomas the low-oxygen tension stimulates aerobic and microaerophilic AR bacilli to transit into non-replicating (NR), drug-tolerant and extracellular stages. These stages, which do not have genetic mutations and are often referred to as persisters, are difficult to eradicate due to low drug penetration inside the caseum and mycobacterial cell walls. The sputum of TB patients also contains viable bacilli called differentially detectable (DD) cells that, unlike persisters, grow in liquid, but not in solid media. This review provides a comprehensive update on drug combinations killing in vitro AR and drug-tolerant bacilli (persisters and DD cells), and sterilizing Mycobacterium tuberculosis -infected BALB/c and caseum-forming C3HeB/FeJ mice. These observations have been important for testing new drug combinations in noninferiority clinical trials, in order to shorten the duration of current regimens against TB. In 2022, the World Health Organization, following the results of one of these trials, supported the use of a 4-month regimen for the treatment of drug-susceptible TB as a possible alternative to the current 6-month regimen.
    Keywords Mycobacterium tuberculosis ; tuberculosis ; drug-resistance ; drug combinations ; drug-tolerance ; persisters ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article: Moxifloxacin Activates the SOS Response in

    Iacobino, Angelo / Piccaro, Giovanni / Pardini, Manuela / Fattorini, Lanfranco / Giannoni, Federico

    Microorganisms

    2021  Volume 9, Issue 2

    Abstract: Previous studies ... ...

    Abstract Previous studies on
    Language English
    Publishing date 2021-01-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2720891-6
    ISSN 2076-2607
    ISSN 2076-2607
    DOI 10.3390/microorganisms9020255
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Bacterial coinfections in COVID-19: an underestimated adversary.

    Fattorini, Lanfranco / Creti, Roberta / Palma, Carla / Pantosti, Annalisa

    Annali dell'Istituto superiore di sanita

    2020  Volume 56, Issue 3, Page(s) 359–364

    Abstract: Current literature shows that secondary bacterial infections, although less frequent than in previous influenza pandemics, affect COVID-19 patients. Mycoplasma pneumoniae, Staphylococcus aureus, Legionella pneumophila, Streptococcus pneumoniae, ... ...

    Abstract Current literature shows that secondary bacterial infections, although less frequent than in previous influenza pandemics, affect COVID-19 patients. Mycoplasma pneumoniae, Staphylococcus aureus, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus and Klebsiella spp. are the main species isolated. Of note, Mycobacterium tuberculosis-COVID-19 coinfections are also reported. However, bacterial coinfection rates increase in patients admitted in the intensive care units, and those diseases can be due to super-infections by nosocomial antibiotic-resistant bacteria. This highlights the urgency to revise frequent and empiric prescription of broad-spectrum antibiotics in COVID-19 patients, with more attention to evidence-based studies and respect for the antimicrobial stewardship principles.
    MeSH term(s) Antimicrobial Stewardship ; Bacterial Infections/drug therapy ; Bacterial Infections/epidemiology ; Bacterial Infections/microbiology ; Bacterial Infections/transmission ; Betacoronavirus ; COVID-19 ; Coinfection/epidemiology ; Coronavirus Infections/epidemiology ; Cross Infection/epidemiology ; Cross Infection/transmission ; Drug Resistance, Microbial ; Early Diagnosis ; Humans ; Intensive Care Units ; Italy/epidemiology ; Mycoses/epidemiology ; Pandemics ; Pneumonia, Viral/epidemiology ; Respiratory Tract Infections/epidemiology ; Respiratory Tract Infections/microbiology ; SARS-CoV-2 ; Species Specificity ; Tuberculosis/epidemiology
    Keywords covid19
    Language English
    Publishing date 2020-09-22
    Publishing country Italy
    Document type Journal Article
    ZDB-ID 950344-4
    ISSN 2384-8553 ; 0021-2571
    ISSN (online) 2384-8553
    ISSN 0021-2571
    DOI 10.4415/ANN_20_03_14
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Activity of Drug Combinations against

    Lanni, Alessio / Borroni, Emanuele / Iacobino, Angelo / Russo, Cristina / Gentile, Leonarda / Fattorini, Lanfranco / Giannoni, Federico

    Microorganisms

    2022  Volume 10, Issue 7

    Abstract: Infections caused by Mycobacterium abscessus (Mab), an environmental non-tuberculous mycobacterium, are difficult to eradicate from patients with pulmonary diseases such as cystic fibrosis and bronchiectasis even after years of antibiotic treatments. In ... ...

    Abstract Infections caused by Mycobacterium abscessus (Mab), an environmental non-tuberculous mycobacterium, are difficult to eradicate from patients with pulmonary diseases such as cystic fibrosis and bronchiectasis even after years of antibiotic treatments. In these people, the low oxygen pressure in mucus and biofilm may restrict Mab growth from actively replicating aerobic (A) to non-replicating hypoxic (H) stages, which are known to be extremely drug-tolerant. After the exposure of Mab A and H cells to drugs, killing was monitored by measuring colony-forming units (CFU) and regrowth in liquid medium (MGIT 960) of 1-day-old A cells (A1) and 5-day-old H cells (H5). Mab killing was defined as a lack of regrowth of drug-exposed cells in MGIT tubes after >50 days of incubation. Out of 18 drugs tested, 14-day treatments with bedaquiline-amikacin (BDQ-AMK)-containing three-drug combinations were very active against A1 + H5 cells. However, drug-tolerant cells (persisters) were not killed, as shown by CFU curves with typical bimodal trends. Instead, 56-day treatments with the nitrocompounds containing combinations BDQ-AMK-rifabutin-clarithromycin-nimorazole and BDQ-AMK-rifabutin-clarithromycin-metronidazole-colistin killed all A1 + H5 Mab cells in 42 and 56 days, respectively, as shown by lack of regrowth in agar and MGIT medium. Overall, these data indicated that Mab persisters may be killed by appropriate drug combinations.
    Language English
    Publishing date 2022-07-14
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2720891-6
    ISSN 2076-2607
    ISSN 2076-2607
    DOI 10.3390/microorganisms10071421
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Mycobacterium tuberculosis

    Bostanghadiri, Narjess / Jazi, Faramarz Masjedian / Razavi, Shabnam / Fattorini, Lanfranco / Darban-Sarokhalil, Davood

    Frontiers in microbiology

    2022  Volume 12, Page(s) 747827

    Abstract: Background: Tuberculosis (TB) is still one of the most important causes of death worldwide. The lack of timely attention on TB diagnosis and treatment during the coronavirus disease 2019 (COVID-19) pandemic is a potential threat to health issues and may ...

    Abstract Background: Tuberculosis (TB) is still one of the most important causes of death worldwide. The lack of timely attention on TB diagnosis and treatment during the coronavirus disease 2019 (COVID-19) pandemic is a potential threat to health issues and may have severe consequences for patients and health systems. There is not much information on the management of TB during this period. Here, we reviewed the current literature to evaluate the rate of
    Methods: Several databases, including Web of Science, Scopus, and MEDLINE (via PubMed), were searched for original articles addressing TB and COVID-19 diseases published from December 2019 to April 2021.
    Results: Of 3,879 articles, 57 articles were included in this study, and among 106,033 patients affected by COVID-19, 891 also had TB. Overall, investigators found a consistent increase in C-reactive protein, D-dimer (especially in patients with severe clinical manifestation), erythrocyte sedimentation rate, lactate dehydrogenase, alanine aminotransferase, and a reduction of lymphocytes. The respiratory symptoms of TB/COVID-19 patients were similar to those of TB patients, but the risk of developing pulmonary TB increased in COVID-19 patients. Also, the mortality rate in TB/COVID-19 patients was higher than that in patients affected only by COVID-19 or TB.
    Conclusion: Some reports indicated worsening respiratory symptoms and even activation of latent TB after COVID-19 or vice versa. It seems that both active and previously treated TB constituted a risk factor for COVID-19 in terms of severity and mortality, regardless of other underlying diseases and patient status. Health systems should not neglect TB during this era of the ongoing COVID-19 pandemic by setting up appropriate diagnostic and clinical management algorithms.
    Language English
    Publishing date 2022-02-03
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2587354-4
    ISSN 1664-302X
    ISSN 1664-302X
    DOI 10.3389/fmicb.2021.747827
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Drug-Resistant Tuberculosis 2020

    Angelo Iacobino / Lanfranco Fattorini / Federico Giannoni

    Applied Sciences, Vol 10, Iss 6, p

    Where We Stand

    2020  Volume 2153

    Abstract: The control of tuberculosis (TB) is hampered by the emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, defined as resistant to at least isoniazid and rifampin, the two bactericidal drugs essential for the treatment of the ... ...

    Abstract The control of tuberculosis (TB) is hampered by the emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, defined as resistant to at least isoniazid and rifampin, the two bactericidal drugs essential for the treatment of the disease. Due to the worldwide estimate of almost half a million incident cases of MDR/rifampin-resistant TB, it is important to continuously update the knowledge on the mechanisms involved in the development of this phenomenon. Clinical, biological and microbiological reasons account for the generation of resistance, including: (i) nonadherence of patients to their therapy, and/or errors of physicians in therapy management, (ii) complexity and poor vascularization of granulomatous lesions, which obstruct drug distribution to some sites, resulting in resistance development, (iii) intrinsic drug resistance of tubercle bacilli, (iv) formation of non-replicating, drug-tolerant bacilli inside the granulomas, (v) development of mutations in Mtb genes, which are the most important molecular mechanisms of resistance. This review provides a comprehensive overview of these issues, and releases up-dated information on the therapeutic strategies recently endorsed and recommended by the World Health Organization to facilitate the clinical and microbiological management of drug-resistant TB at the global level, with attention also to the most recent diagnostic methods.
    Keywords tuberculosis ; mycobacterium tuberculosis ; rifampin ; isoniazid ; mechanisms of resistance ; mutations ; granulomas ; caseum ; cell envelope ; dormancy ; Technology ; T ; Engineering (General). Civil engineering (General) ; TA1-2040 ; Biology (General) ; QH301-705.5 ; Physics ; QC1-999 ; Chemistry ; QD1-999
    Subject code 610
    Language English
    Publishing date 2020-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Moxifloxacin Activates the SOS Response in Mycobacterium tuberculosis in a Dose- and Time-Dependent Manner

    Angelo Iacobino / Giovanni Piccaro / Manuela Pardini / Lanfranco Fattorini / Federico Giannoni

    Microorganisms, Vol 9, Iss 2, p

    2021  Volume 255

    Abstract: Previous studies on Escherichia coli demonstrated that sub-minimum inhibitory concentration (MIC) of fluoroquinolones induced the SOS response, increasing drug tolerance. We characterized the transcriptional response to moxifloxacin in Mycobacterium ... ...

    Abstract Previous studies on Escherichia coli demonstrated that sub-minimum inhibitory concentration (MIC) of fluoroquinolones induced the SOS response, increasing drug tolerance. We characterized the transcriptional response to moxifloxacin in Mycobacterium tuberculosis . Reference strain H37Rv was treated with moxifloxacin and gene expression studied by qRT-PCR. Five SOS regulon genes, recA , lexA , dnaE2 , Rv3074 and Rv3776, were induced in a dose- and time-dependent manner. A range of moxifloxacin concentrations induced recA , with a peak observed at 2 × MIC (0.25 μg/mL) after 16 h. Another seven SOS responses and three DNA repair genes were significantly induced by moxifloxacin. Induction of recA by moxifloxacin was higher in log-phase than in early- and stationary-phase cells, and absent in dormant bacilli. Furthermore, in an H37Rv fluoroquinolone-resistant mutant carrying the D94G mutation in the gyrA gene, the SOS response was induced at drug concentrations higher than the mutant MIC value. The 2 × MIC of moxifloxacin determined no significant changes in gene expression in a panel of 32 genes, except for up-regulation of the relK toxin and of Rv3290c and Rv2517c , two persistence-related genes. Overall, our data show that activation of the SOS response by moxifloxacin, a likely link to increased mutation rate and persister formation, is time, dose, physiological state and, possibly, MIC dependent.
    Keywords Mycobacterium tuberculosis ; SOS response ; DNA repair ; fluoroquinolone ; moxifloxacin ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Activity of Drug Combinations against Mycobacterium abscessus Grown in Aerobic and Hypoxic Conditions

    Alessio Lanni / Emanuele Borroni / Angelo Iacobino / Cristina Russo / Leonarda Gentile / Lanfranco Fattorini / Federico Giannoni

    Microorganisms, Vol 10, Iss 7, p

    2022  Volume 1421

    Abstract: Infections caused by Mycobacterium abscessus (Mab), an environmental non-tuberculous mycobacterium, are difficult to eradicate from patients with pulmonary diseases such as cystic fibrosis and bronchiectasis even after years of antibiotic treatments. In ... ...

    Abstract Infections caused by Mycobacterium abscessus (Mab), an environmental non-tuberculous mycobacterium, are difficult to eradicate from patients with pulmonary diseases such as cystic fibrosis and bronchiectasis even after years of antibiotic treatments. In these people, the low oxygen pressure in mucus and biofilm may restrict Mab growth from actively replicating aerobic (A) to non-replicating hypoxic (H) stages, which are known to be extremely drug-tolerant. After the exposure of Mab A and H cells to drugs, killing was monitored by measuring colony-forming units (CFU) and regrowth in liquid medium (MGIT 960) of 1-day-old A cells (A1) and 5-day-old H cells (H5). Mab killing was defined as a lack of regrowth of drug-exposed cells in MGIT tubes after >50 days of incubation. Out of 18 drugs tested, 14-day treatments with bedaquiline-amikacin (BDQ-AMK)-containing three-drug combinations were very active against A1 + H5 cells. However, drug-tolerant cells (persisters) were not killed, as shown by CFU curves with typical bimodal trends. Instead, 56-day treatments with the nitrocompounds containing combinations BDQ-AMK-rifabutin-clarithromycin-nimorazole and BDQ-AMK-rifabutin-clarithromycin-metronidazole-colistin killed all A1 + H5 Mab cells in 42 and 56 days, respectively, as shown by lack of regrowth in agar and MGIT medium. Overall, these data indicated that Mab persisters may be killed by appropriate drug combinations.
    Keywords Mycobacterium abscessus ; cystic fibrosis ; aerobiosis ; anaerobiosis ; nitrocompounds ; colistin ; Biology (General) ; QH301-705.5
    Subject code 630
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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