Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.074
Filtrar
1.
Lancet Respir Med ; 8(10): 975-986, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33007285

RESUMO

BACKGROUND: Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa. METHODS: We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin. Both were combined with 12 weeks inhaled colistimethate sodium. Randomisation lists were generated by a statistician, who had no involvement in the trial, using a computer-generated list. Randomisation was stratified by centre and because of the nature of the interventions, blinding was not possible. Our primary outcome was eradication of P aeruginosa at 3 months and remaining free of infection to 15 months. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who received at least one dose of study drug. TORPEDO-CF was registered on the ISRCTN register, ISRCTN02734162, and EudraCT, 2009-012575-10. FINDINGS: Between Oct 5, 2010, and Jan 27, 2017, 286 patients were randomly assigned to treatment: 137 to intravenous antibiotics and 149 to oral antibiotics. 55 (44%) of 125 participants in the intravenous group and 68 (52%) of 130 participants in the oral group achieved the primary outcome. Participants randomly assigned to the intravenous group were less likely to achieve the primary outcome, although the difference between groups was not statistically significant (relative risk 0·84, 95% CI 0·65-1·09; p=0·18). 11 serious adverse events occurred in ten (8%) of 126 participants in the intravenous antibiotics group and 17 serious adverse events in 12 (8%) of 146 participants in the oral antibiotics group. INTERPRETATION: Compared with oral therapy, intravenous antibiotics did not achieve sustained eradication of P aeruginosa in a greater proportion of patients with cystic fibrosis and was more expensive. Although there were fewer hospitalisations in the intravenous group than the oral group during follow-up, this confers no advantage over oral treatment because intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P aeruginosa in cystic fibrosis. FUNDING: National Institute for Health Research Health Technology Assessment Programme.


Assuntos
Antibacterianos/administração & dosagem , Ceftazidima/administração & dosagem , Fibrose Cística/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa , Tobramicina/administração & dosagem , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Criança , Pré-Escolar , Fibrose Cística/tratamento farmacológico , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Infecções por Pseudomonas/complicações , Resultado do Tratamento , Adulto Jovem
2.
PLoS One ; 15(10): e0235803, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031374

RESUMO

Cystic Fibrosis (CF), caused by mutations affecting the CFTR gene, is characterised by viscid secretions in multiple organ systems. CF airways contain thick mucus, creating a gradient of hypoxia, which promotes the establishment of polymicrobial infection. Such inflammation predisposes to further infection, a self-perpetuating cycle in mediated by NF-κB. Anaerobic Gram-negative Prevotella spp. are found in sputum from healthy volunteers and CF patients and in CF lungs correlate with reduced levels of inflammation. Prevotella histicola (P. histicola) can suppress murine lung inflammation, however, no studies have examined the role of P. histicola in modulating infection and inflammation in the CF airways. We investigated innate immune signalling and NF-kB activation in CF epithelial cells CFBE41o- in response to clinical stains of P. histicola and Pseudomonas aeruginosa (P. aeruginosa). Toll-Like Receptor (TLR) expressing HEK-293 cells and siRNA assays for TLRs and IKKα were used to confirm signalling pathways. We show that P. histicola infection activated the alternative NF-kB signalling pathway in CF bronchial epithelial cells inducing HIF-1α protein. TLR5 signalling was responsible for the induction of the alternative NF-kB pathway through phosphorylation of IKKα. The induction of transcription factor HIF-1α was inversely associated with the induction of the alternative NF-kB pathway and knockdown of IKKα partially restored canonical NF-kB activation in response to P. histicola. This study demonstrates that different bacterial species in the respiratory microbiome can contribute differently to inflammation, either by activating inflammatory cascades (P. aeruginosa) or by muting the inflammatory response by modulating similar or related pathways (P. histicola). Further work is required to assess the complex interactions of the lung microbiome in response to mixed bacterial infections and their effects in people with CF.


Assuntos
Brônquios/imunologia , Fibrose Cística/imunologia , NF-kappa B/metabolismo , Prevotella/imunologia , Infecções por Pseudomonas/complicações , Pseudomonas aeruginosa/imunologia , Receptores Toll-Like/metabolismo , Brônquios/metabolismo , Brônquios/microbiologia , Brônquios/patologia , Fibrose Cística/metabolismo , Fibrose Cística/microbiologia , Fibrose Cística/patologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Humanos , Interleucina-8/metabolismo , NF-kappa B/genética , Prevotella/isolamento & purificação , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação , Transdução de Sinais , Receptores Toll-Like/imunologia
3.
Clin Ter ; 171(5): e381-e384, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32901778

RESUMO

OBJECTIVES: Evaluation of the effectiveness of home care through a telemonitoring system in reducing the incidence of new colonization by Pseudomonas Aeruginosa in a population of patients with Cystic Fibrosis (CF) followed by the CF clinic of the Bambino Gesù Hospital in Rome over a period of 36 months. MATERIALS AND METHODS: Two groups of patients were recruited, homogeneous for age, sex, BMI, FEV1, prevalence of CF-related Diabetes and CF-related Hepatopathy, access to new therapies with modulators: a) an IN group (N = 44 ) followed through a home telemonitoring system, b) an OUT control group (N = 110) followed according to the standards of care. The following parameters were detected for all patients: pulmonary colonization of the lungs, number and type of hospital admissions, respiratory function, BMI. RESULT: The OUT group had a statistically significant increase in the prevalence of Pseudomonas Aeruginosa infections during the observation period. Furthermore, a significant decrease in lung function assessed through FEV1 was also observed in the OUT group. CONCLUSION: Adolescent and adult patients belonging to the CF center who are not followed through the dedicated home telemonitoring service show, in the three-year period 2017-19, an increase in Pseudomonas Aeruginosa infections and a greater decrease in respiratory function. The use of telemedicine in CF is therefore an effective system not only in monitoring the disease but also as a treatment strategy, in the context of an evolving multidisciplinary model. As advantages, telemedicine can reduce the number of Pseudomonas Aeruginosa lung infections and the greater stability of respiratory function over time.


Assuntos
Fibrose Cística/microbiologia , Serviços de Assistência Domiciliar , Infecções por Pseudomonas/prevenção & controle , Telemedicina , Adolescente , Adulto , Estudos de Casos e Controles , Fibrose Cística/complicações , Fibrose Cística/terapia , Pesquisa Empírica , Feminino , Seguimentos , Hospitalização , Humanos , Incidência , Masculino , Monitorização Ambulatorial , Prevalência , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/microbiologia , Distribuição Aleatória , Estudos Retrospectivos
4.
PLoS One ; 15(9): e0239658, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32970760

RESUMO

BACKGROUND: Nebulization of antimicrobial drugs such as tobramycin and colistin is a cornerstone in the treatment of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa. However, nebulization has a high treatment burden. The Twincer™ is a dry powder inhaler specifically developed for the inhalation of antibiotics such as colistin. The aim of this study was to compare patient outcomes and experience with colistin dry powder by the Twincer with nebulization of colistin or tobramycin in adult CF patients in a real-life setting. METHODS: This was a retrospective study from 01-01-2015 until 01-07-2018. Effectiveness was evaluated by comparing FEV1 decline and exacerbation rate during a mean of 4.1 years of nebulization therapy prior to the initiation of the Twincer against the same values during a mean of 1.7 years of treatment with the Twincer. RESULTS: Twenty-one patients were evaluated, of whom twelve could be included in the effectiveness analysis, with a total of twenty patient years. Of all patients 71.4% preferred therapy with the Twincer over nebulization. Twincer use resulted in high treatment adherence with an average adherence rate of 92.5%. There was no significant difference in annual decline in FEV1%pred prior to and after start changing from nebulization to the use of the Twincer powder inhaler (median decline -1.56 [-5.57-5.31] and 1.35 [-8.45-6.36]) respectively, p = 0.45 (linear mixed effect model)). No significant difference was found in the number of intravenous or combined total intravenous and oral antibiotic courses during Twincer therapy compared to when using nebulization (1.68 and 2.49 courses during Twincer therapy versus 1.51 and 2.94 courses during nebulization, p = 0.88 and p = 0.63). CONCLUSION: Colistin dry powder inhalation with the Twincer is a more patient friendly alternative to nebulization, and we did not observe significant differences in the clinical outcome, regarding lung function and exacerbation rates.


Assuntos
Antibacterianos/administração & dosagem , Colistina/administração & dosagem , Fibrose Cística/microbiologia , Nebulizadores e Vaporizadores/normas , Infecções por Pseudomonas/tratamento farmacológico , Administração por Inalação , Adolescente , Adulto , Antibacterianos/uso terapêutico , Colistina/uso terapêutico , Fibrose Cística/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Pseudomonas/complicações
5.
Cochrane Database Syst Rev ; 9: CD001912, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32997797

RESUMO

BACKGROUND: Staphylococcus aureus causes pulmonary infection in young children with cystic fibrosis. Prophylactic antibiotics are prescribed hoping to prevent such infection and lung damage. Antibiotics have adverse effects and long-term use might lead to infection with Pseudomonas aeruginosa. This is an update of a previously published review. OBJECTIVES: To assess continuous oral antibiotic prophylaxis to prevent the acquisition of Staphylococcus aureus versus no prophylaxis in people with cystic fibrosis, we tested the following hypotheses to investigate whether prophylaxis: 1. improves clinical status, lung function and survival; 2. leads to fewer isolates of Staphylococcus aureus; 3. causes adverse effects (e.g. diarrhoea, skin rash, candidiasis); 4. leads to fewer isolates of other common pathogens from respiratory secretions; 5. leads to the emergence of antibiotic resistance and colonisation of the respiratory tract with Pseudomonas aeruginosa. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Companies manufacturing anti-staphylococcal antibiotics were contacted. Most recent search of the Group's Register: 27 February 2020. Online trials registries were also searched. Most recent search of online trials registries: 15 September 2020. SELECTION CRITERIA: Randomised trials of continuous oral prophylactic antibiotics (given for at least one year) compared to intermittent antibiotics given 'as required', in people with cystic fibrosis of any disease severity. DATA COLLECTION AND ANALYSIS: The authors assessed studies for eligibility and methodological quality and extracted data. The quality of the evidence was assessed using the GRADE criteria. The review's primary outcomes of interest were lung function by spirometry (forced expiratory volume in one second (FEV1)) and the number of people with one or more isolates of Staphylococcus aureus (sensitive strains). MAIN RESULTS: We included four studies, with a total of 401 randomised participants aged zero to seven years on enrolment; one study is ongoing. The two older included studies generally had a higher risk of bias across all domains, but in particular due to a lack of blinding and incomplete outcome data, than the two more recent studies. We only regarded the most recent study as being generally free of bias, although even here we were not certain of the effect of the per protocol analysis on the study results. Evidence quality was judged to be low for all outcomes assessed after being downgraded based on GRADE assessments. Downgrading decisions were due to limitations in study design (all outcomes), for imprecision and for inconsistency . Prophylactic anti-staphylococcal antibiotics probably make little or no difference to lung function measured as FEV1 % predicted after six years (mean difference (MD) -2.30, 95% confidence interval (CI) -13.59 to 8.99, one study, n = 119, low-quality evidence); but may reduce the number of children having one or more isolates of Staphylococcus aureus at two years (odds ratio (OR) 0.21, 95% CI 0.13 to 0.35, three studies, n = 315, low-quality evidence). At the same time point, there may be little or no effect on nutrition as reported using weight z score (MD 0.06, 95% CI -0.33 to 0.45, two studies, n = 140, low-quality evidence), additional courses of antibiotics (OR 0.18, 95% CI 0.01 to 3.60, one study, n = 119, low-quality evidence) or adverse effects (low-quality evidence). There was no difference in the number of isolates of Pseudomonas aeruginosa between groups at two years (OR 0.74, 95% CI 0.45 to 1.23, three studies, n = 312, low-quality evidence), though there was a trend towards a lower cumulative isolation rate of Pseudomonas aeruginosa in the prophylaxis group at two and three years and towards a higher rate from four to six years. As the studies reviewed lasted six years or less, conclusions cannot be drawn about the long-term effects of prophylaxis. AUTHORS' CONCLUSIONS: Anti-staphylococcal antibiotic prophylaxis may lead to fewer children having isolates of Staphylococcus aureus, when commenced early in infancy and continued up to six years of age. The clinical importance of this finding is uncertain. Further research may establish whether the trend towards more children with CF with Pseudomonas aeruginosa, after four to six years of prophylaxis, is a chance finding and whether choice of antibiotic or duration of treatment might influence this.


Assuntos
Antibioticoprofilaxia , Fibrose Cística/microbiologia , Infecções Respiratórias/prevenção & controle , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus , Viés , Criança , Pré-Escolar , Farmacorresistência Bacteriana , Volume Expiratório Forçado , Crescimento , Humanos , Lactente , Recém-Nascido , Pseudomonas aeruginosa/isolamento & purificação , Ensaios Clínicos Controlados Aleatórios como Assunto , Staphylococcus aureus/isolamento & purificação
6.
Zhonghua Er Ke Za Zhi ; 58(8): 646-652, 2020 Aug 02.
Artigo em Chinês | MEDLINE | ID: mdl-32842385

RESUMO

Objective: To analyze the clinical features of cystic fibrosis (CF) associated allergic bronchopulmonary aspergillosis (ABPA) in children. Methods: A retrospective study was performed in 22 children who were diagnosed with CF associated ABPA in Beijing Children's Hospital affiliated to Capital Medical University from March 2010 to March 2020. The clinical features, imaging characteristics, laboratory results and the prognosis were reviewed. Results: A total of 22 cases met the diagnostic criterion, including 12 males and 10 females. The age of diagnosis was (10.4±2.8) years and the age of onset was (5.5±4.4) years. Clinical manifestations included cough and expectoration (22 cases), recurrent wheezing (15 cases), hemoptysis (7 cases), failure to thrive (12 cases), pancreatitis (10 cases), hepatomegaly (7 cases), splenomegaly (4 cases) and steatorrhea (4 cases). CT scans of all the patients showed pulmonary infiltrates and central bronchiectasis, combined with mucoid impaction in 17 cases and high density mucus plug in 12 cases. Eosinophilia was found in 18 patients. Total IgE and serum levels of A. fumigatus-specific IgE were elevated in all 22 patients. Positive culture of sputum or bronchoalvedar lauage fluid for fungus were in 15 cases, with single Aspergillus infection in 8 cases and mixed Aspergillus infection in 3 cases. The predominant bacteria found in the airways were Pseudomonas aeruginosa (17 cases), followed by staphylococcas. aureus (6 cases) and stenotrophomonas. maltophilia (5 cases). Pulmonary function revealed obstructive ventilation dysfunction in 4 cases, mixed dysfunction in 11 cases, and small airway dysfunction in 4 cases. Regarding the treatment, 3 were treated only with systemic corticosteroid, while the remaining 19 cases also received antifungal agents.The follow up continued for 1-7 years, and 6 maintained remission, 10 had recurrent episodes, 1 died, and 5 lost to follow up. Conclusions: CF associated ABPA is extremely rare in China. The overlapping clinical, radiographic, and immunologic features of these two diseases make the diagnosis challenging. Systemic corticosteroids are considered the first-line therapy for these patients, and adjuvant antifungal agents may be helpful. Recurrence rate in our center is high.


Assuntos
Aspergilose Broncopulmonar Alérgica/complicações , Aspergillus fumigatus/isolamento & purificação , Fibrose Cística/complicações , Escarro/microbiologia , Aspergilose Broncopulmonar Alérgica/tratamento farmacológico , Criança , China , Fibrose Cística/diagnóstico , Fibrose Cística/microbiologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
7.
APMIS ; 128(12): 647-653, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32794206

RESUMO

IL-2 is a pro-inflammatory and a Th1 inducing cytokine, which is important for activation of the cell-mediated immunity. IL-2 in serum and sputum has been observed to be reduced in cystic fibrosis (CF) patients. The present IL-2 treatment study of Pseudomonas aeruginosa (PA) lung infected mice was performed in order to evaluate the effect of IL-2 supplement. One hundred-and-twenty female BALB/c mice were divided into three groups: 1) IL-2 treatment/infection (TIG), 2) non-treatment/infection (NTIG), and 3) IL-2 treatment/non-infection (TNIG). The mice were challenged intra-tracheally with PA (PAO579) embedded in seaweed alginate to resemble the biofilm mode of growth. At day 0 and 1, the treatment groups received IL-2 s.c. Mice were killed on day 1 or 2, and cytokine production, lung pathology, and quantitative lung bacteriology were estimated. IL-2 treatment of infected mice reduced the number of mice with signs of macroscopic lung pathology at day 2 (p < 0.05). The reduced macroscopic pathology was paralleled by a reduced IL-1ß and TNF-α. In contrast, an increased PMN response at day 2 was observed in the IL-2 treated mice (p < 0.01). This was preceded by a significantly higher degree of microscopic inflammation at day 1 (p < 0.02). The IL-12 levels decreased in both groups of infected mice at day 2 (p < 0.01), however, significantly more in the IL-2 treated mice (p < 0.02). In accordance, but surprisingly, IFN-γ was significantly reduced in the IL-2 treated PA infected group at day 2 (p < 0.05). The present results indicate that early IL-2 treatment prolongs the PMN response but also reduces pro-inflammatory IL-1ß and TNF-α and macroscopic signs of pathology.


Assuntos
Interleucina-2/administração & dosagem , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/fisiologia , Animais , Fibrose Cística/tratamento farmacológico , Fibrose Cística/imunologia , Fibrose Cística/microbiologia , Fibrose Cística/patologia , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/genética
8.
Thorax ; 75(9): 780-790, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32631930

RESUMO

RATIONALE: The most common antibiotic used to treat people with cystic fibrosis (PWCF) is inhaled tobramycin, administered as maintenance therapy for chronic Pseudomonas aeruginosa lung infections. While the effects of inhaled tobramycin on P. aeruginosa abundance and lung function diminish with continued therapy, this maintenance treatment is known to improve long-term outcomes, underscoring how little is known about why antibiotics work in CF infections, what their effects are on complex CF sputum microbiomes and how to improve these treatments. OBJECTIVES: To rigorously define the effect of maintenance tobramycin on CF sputum microbiome characteristics. METHODS AND MEASUREMENTS: We collected sputum from 30 PWCF at standardised times before, during and after a single month-long course of maintenance inhaled tobramycin. We used traditional culture, quantitative PCR and metagenomic sequencing to define the dynamic effects of this treatment on sputum microbiomes, including abundance changes in both clinically targeted and untargeted bacteria, as well as functional gene categories. MAIN RESULTS: CF sputum microbiota changed most markedly by 1 week of antibiotic therapy and plateaued thereafter, and this shift was largely driven by changes in non-dominant taxa. The genetically conferred functional capacities (ie, metagenomes) of subjects' sputum communities changed little with antibiotic perturbation, despite taxonomic shifts, suggesting functional redundancy within the CF sputum microbiome. CONCLUSIONS: Maintenance treatment with inhaled tobramycin, an antibiotic with demonstrated long-term mortality benefit, primarily impacted clinically untargeted bacteria in CF sputum, highlighting the importance of monitoring the non-canonical effects of antibiotics and other treatments to accurately define and improve their clinical impact.


Assuntos
Antibacterianos/farmacologia , Bactérias , Fibrose Cística/microbiologia , Microbiota/efeitos dos fármacos , Escarro/microbiologia , Tobramicina/farmacologia , Administração por Inalação , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Bactérias/genética , Bactérias/isolamento & purificação , Infecções Bacterianas/prevenção & controle , Criança , Fibrose Cística/fisiopatologia , Volume Expiratório Forçado , Humanos , Quimioterapia de Manutenção , Metagenoma/efeitos dos fármacos , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores de Tempo , Tobramicina/uso terapêutico , Adulto Jovem
10.
Rev Mal Respir ; 37(7): 561-571, 2020 Sep.
Artigo em Francês | MEDLINE | ID: mdl-32684338

RESUMO

INTRODUCTION: Common major pathogens like Pseudomonas aeruginosa are identified in the airways of patients with cystic fibrosis (CF) and non-CF bronchiectasis. However, other opportunistic bacterial pathogens like Achromobacter xylosoxidans complex, Stenotrophomonas maltophilia and non-tuberculous mycobacteria are currently emerging in CF and are also reported in non-CF bronchiectasis. BACKGROUND: The emergence of opportunistic bacterial pathogens has been recognized in CF through annual national reports of sputum microbiology data. Despite common factors driving the emergence of bacteria identified in CF and non-CF bronchiectasis patients, bronchiectasis registries have been created more recently and no longitudinal analysis of recorded microbiological data is currently available in the literature, thereby preventing the recognition of emerging bacteria in patients with non-CF bronchiectasis. OUTLOOK: A longitudinal follow-up of microbiological data is still needed in non-CF bronchiectasis to identify emerging opportunistic bacterial pathogens. Homogeneity in practice of sputum microbiological examination is also required to allow comparative analysis of data in CF and non-CF bronchiectasis. CONCLUSION: Bacterial pathogens recognized as emerging in CF have to be more carefully monitored in non-CF bronchiectasis in view of their association with deterioration of the lung disease.


Assuntos
Bronquiectasia/microbiologia , Fibrose Cística/microbiologia , Microbiologia/tendências , Fibrose Pulmonar/microbiologia , Infecções Respiratórias/microbiologia , Bronquiectasia/complicações , Bronquiectasia/epidemiologia , Bronquiectasia/terapia , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/microbiologia , Doenças Transmissíveis Emergentes/terapia , Fibrose Cística/complicações , Fibrose Cística/epidemiologia , Fibrose Cística/terapia , Humanos , Técnicas Microbiológicas/estatística & dados numéricos , Técnicas Microbiológicas/tendências , Monitorização Fisiológica/métodos , Monitorização Fisiológica/normas , Monitorização Fisiológica/tendências , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/microbiologia , Infecções Oportunistas/terapia , Fibrose Pulmonar/complicações , Fibrose Pulmonar/epidemiologia , Fibrose Pulmonar/terapia , Infecções Respiratórias/complicações , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/terapia , Escarro/microbiologia
11.
New Microbiol ; 43(3): 127-132, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32656572

RESUMO

Mycobacterium abscessus (MABS) infection represents significant management challenge in cystic fibrosis (CF) patients. This retrospective study (2005-2016) aims to determine the prevalence of the subspecies of MABS isolated from CF patients, to evaluate the persistence over the years of a single subspecies of MABS and to correlate mutations responsible for macrolides and amikacin resistance with MIC values. We investigated 314 strains (1 isolate/patient/year) isolated from the lower respiratory tract of 51 chronically infected CF patients. Sequencing of rpoB gene was performed to identify the MABS subspecies. The erm(41) gene was sequenced to differentiate the strains with and without inducible macrolide resistance. Regions of 23S and 16S rRNA were sequenced to investigate mutations responsible for constitutive resistance to macrolides and aminoglycosides, respectively. Antibiotic susceptibility, using commercial microdilution plates, was evaluated according to CLSI. M. abscessus subsp. abscessus accounted for 64% of the isolates, bolletii subspecies for 16% and massiliense subspecies for 20%. All the massiliense strains presented truncated erm(41) gene while 12 abscessus strains presented the mutation T28->C in the erm(41) gene, which makes it inactive. The 23S rRNA analysis did not show constitutive resistance to macrolides in any strain. Mutation of the 16S rRNA gene was highlighted in 2 strains out of 314, in agreement with high MIC values. The correct identification at the subspecies level and the molecular analysis of 23S rRNA, 16S rRNA and erm gene is useful to guide the treatment strategy in patients with M. abscessus lung infection.


Assuntos
Fibrose Cística , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Antibacterianos/farmacologia , Claritromicina , Fibrose Cística/microbiologia , Farmacorresistência Bacteriana , Humanos , Itália/epidemiologia , Macrolídeos/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium abscessus/genética , Mycobacterium abscessus/isolamento & purificação , RNA Ribossômico 16S/genética , Estudos Retrospectivos
12.
J Vis Exp ; (159)2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32478753

RESUMO

Antimicrobial resistance, a major consequence of diagnostic uncertainty and antimicrobial overprescription, is an increasingly recognized cause of severe infections, complications, and mortality worldwide with a huge impact on our society and on the health system. In particular, patients with compromised immune systems or pre-existing and chronic pathologies, such as cystic fibrosis (CF), are subjected to frequent antibiotic treatments to control the infections with the appearance and diffusion of multidrug resistant isolates. Therefore, there is an urgent need to address alternative therapies to counteract bacterial infections. Use of bacteriophages, the natural enemies of bacteria, can be a possible solution. The protocol detailed in this work describes the application of phage therapy against Pseudomonas aeruginosa infection in CF zebrafish embryos. Zebrafish embryos were infected with P. aeruginosa to demonstrate that phage therapy is effective against P. aeruginosa infections as it reduces lethality, bacterial burden and pro-inflammatory immune response in CF embryos.


Assuntos
Fibrose Cística/microbiologia , Fibrose Cística/terapia , Embrião não Mamífero/microbiologia , Terapia por Fagos , Infecções por Pseudomonas/terapia , Pseudomonas aeruginosa/fisiologia , Peixe-Zebra/embriologia , Peixe-Zebra/microbiologia , Animais , Antibacterianos/farmacologia , Bacteriófagos/fisiologia , Citocinas/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Proteínas de Fluorescência Verde/metabolismo , Mediadores da Inflamação/metabolismo , Microinjeções , Morfolinos/farmacologia , Terapia por Fagos/efeitos adversos , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Reprodutibilidade dos Testes
13.
Arch Oral Biol ; 116: 104772, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32474212

RESUMO

OBJECTIVE: This study aimed at assessing the oral prevalence ofCandida species in cystic fibrosis patients and the antifungal susceptibility of the isolates. DESIGN: One hundred patients aged 3-20 years old were included in the study and were divided into three groups: G1 (low severity disease): 25 cystic fibrosis patients with Shwachman-Kulczycki score (SK) between 100 and 71; G2 (high severity disease): 25 cystic fibrosis patients with SK score under 40; and G3 (control): 50 healthy patients age- and gender-matched to cystic fibrosis patients. Stimulated saliva samples were collected and the oral fungal concentrations were assessed. Isolates were identified by phenotypic and genotypic tests. Antifungal susceptibilities to amphotericin B, flucytosine and fluconazole were determined by CLSI methodology. Fungal counts were compared by Kruskal Wallis and Dunn's test (5%). RESULTS: A total of 68 % of Group 1, 80 % of Group 2, and 44 % of controls yielded positive Candida cultures. Oral concentrations of fungi were significantly higher in cystic fibrosis patients in relation to the control group (p < 0.0005). No significant difference was observed between low and high severity cystic fibrosis groups (p > 0.05). C. albicans was most frequently isolated species in all groups. Higher variability of Candida species was observed in the control group. C. dubliniensis and C. tropicalis were only detected among cystic fibrosis groups. All the isolates were susceptible to flucytosine and fluconazole. CONCLUSIONS: Patients with cystic fibrosis were more frequently colonized by Candida species and showed higher oral fungal burden. No antifungal resistant isolates were detected.


Assuntos
Antifúngicos , Fibrose Cística , Adolescente , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Criança , Pré-Escolar , Fibrose Cística/complicações , Fibrose Cística/microbiologia , Farmacorresistência Fúngica/efeitos dos fármacos , Fluconazol , Humanos , Testes de Sensibilidade Microbiana , Prevalência , Adulto Jovem
14.
Clin Sci (Lond) ; 134(14): 1911-1934, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32537652

RESUMO

Cystic fibrosis (CF) is a progressive multiorgan autosomal recessive disease with devastating impact on the lungs caused by derangements of the CF transmembrane conductance regulator (CFTR) gene. Morbidity and mortality are caused by the triad of impaired mucociliary clearance, microbial infections and chronic inflammation. Pseudomonas aeruginosa is the main respiratory pathogen in individuals with CF infecting most patients in later stages. Despite its recognized clinical impact, molecular mechanisms that underlie P. aeruginosa pathogenesis and the host response to P. aeruginosa infection remain incompletely understood. The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) γ (PPARγ), has shown to be reduced in CF airways. In the present study, we sought to investigate the upstream mechanisms repressing PPARγ expression and its impact on airway epithelial host defense. Endoplasmic reticulum-stress (ER-stress) triggered unfolded protein response (UPR) activated by misfolded CFTR and P. aeruginosa infection contributed to attenuated expression of PPARγ. Specifically, the protein kinase RNA (PKR)-like ER kinase (PERK) signaling pathway led to the enhanced expression of the CCAAT-enhancer-binding-protein homologous protein (CHOP). CHOP induction led to the repression of PPARγ expression. Mechanistically, we showed that CHOP induction mediated PPARγ attenuation, impacted the innate immune function of normal and ∆F508 primary airway epithelial cells by reducing expression of antimicrobial peptide (AMP) and paraoxanse-2 (PON-2), as well as enhancing IL-8 expression. Furthermore, mitochondrial reactive oxygen species production (mt-ROS) and ER-stress positive feedforward loop also dysregulated mitochondrial bioenergetics. Additionally, our findings implicate that PPARγ agonist pioglitazone (PIO) has beneficial effect on the host at the multicellular level ranging from host defense to mitochondrial re-energization.


Assuntos
Fibrose Cística/metabolismo , PPAR gama/metabolismo , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosa/fisiologia , Resposta a Proteínas não Dobradas , Células A549 , Arildialquilfosfatase/metabolismo , Fibrose Cística/complicações , Fibrose Cística/microbiologia , Estresse do Retículo Endoplasmático , Células Epiteliais/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Interleucina-8/metabolismo , Mitocôndrias/metabolismo , PPAR gama/agonistas , Pioglitazona , Infecções por Pseudomonas/imunologia , Fator de Transcrição CHOP/metabolismo , beta-Defensinas/metabolismo
15.
PLoS Genet ; 16(6): e1008848, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32530919

RESUMO

Pseudomonas aeruginosa colonizes the airways of cystic fibrosis (CF) patients, causing infections that can last for decades. During the course of these infections, P. aeruginosa undergoes a number of genetic adaptations. One such adaptation is the loss of swimming motility functions. Another involves the formation of the rugose small colony variant (RSCV) phenotype, which is characterized by overproduction of the exopolysaccharides Pel and Psl. Here, we provide evidence that the two adaptations are linked. Using random transposon mutagenesis, we discovered that flagellar mutations are linked to the RSCV phenotype. We found that flagellar mutants overexpressed Pel and Psl in a surface-contact dependent manner. Genetic analyses revealed that flagellar mutants were selected for at high frequencies in biofilms, and that Pel and Psl expression provided the primary fitness benefit in this environment. Suppressor mutagenesis of flagellar RSCVs indicated that Psl overexpression required the mot genes, suggesting that the flagellum stator proteins function in a surface-dependent regulatory pathway for exopolysaccharide biosynthesis. Finally, we identified flagellar mutant RSCVs among CF isolates. The CF environment has long been known to select for flagellar mutants, with the classic interpretation being that the fitness benefit gained relates to an impairment of the host immune system to target a bacterium lacking a flagellum. Our new findings lead us to propose that exopolysaccharide production is a key gain-of-function phenotype that offers a new way to interpret the fitness benefits of these mutations.


Assuntos
Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/genética , Proteínas de Bactérias/metabolismo , Biofilmes/crescimento & desenvolvimento , Vias Biossintéticas/genética , Fibrose Cística/complicações , Fibrose Cística/microbiologia , Flagelos/metabolismo , Humanos , Mutagênese Sítio-Dirigida , Mutação , Polissacarídeos Bacterianos/biossíntese , Pseudomonas aeruginosa/patogenicidade , Seleção Genética
16.
Cochrane Database Syst Rev ; 6: CD010004, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32521055

RESUMO

BACKGROUND: Nontuberculous mycobacteria are mycobacteria, other than those in the Mycobacterium tuberculosis complex, and are commonly found in the environment. Nontuberculous mycobacteria species (most commonly Mycobacterium avium complex and Mycobacterium abscessus) are isolated from the respiratory tract of approximately 5% to 40% of individuals with cystic fibrosis; they can cause lung disease in people with cystic fibrosis leading to more a rapid decline in lung function and even death in certain circumstances. Although there are guidelines for the antimicrobial treatment of nontuberculous mycobacteria lung disease, these recommendations are not specific for people with cystic fibrosis and it is not clear which antibiotic regimen may be the most effective in the treatment of these individuals. This is an update of a previous review. OBJECTIVES: The objective of our review was to compare antibiotic treatment to no antibiotic treatment, or to compare different combinations of antibiotic treatment, for nontuberculous mycobacteria lung infections in people with cystic fibrosis. The primary objective was to assess the effect of treatment on lung function and pulmonary exacerbations and to quantify adverse events. The secondary objectives were to assess treatment effects on the amount of bacteria in the sputum, quality of life, mortality, nutritional parameters, hospitalizations and use of oral antibiotics. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. Date of last search: 24 February 2020. We also searched a register of ongoing trials and the reference lists of relevant articles and reviews. Date of last search: 21 March 2019. SELECTION CRITERIA: Any randomized controlled trials comparing nontuberculous mycobacteria antibiotics to no antibiotic treatment, as well as one nontuberculous mycobacteria antibiotic regimen compared to another nontuberculous mycobacteria antibiotic regimen, in individuals with cystic fibrosis.   DATA COLLECTION AND ANALYSIS: Data were not collected because in the one trial identified by the search, data specific to individuals with cystic fibrosis could not be obtained from the pharmaceutical company. MAIN RESULTS: One completed trial was identified by the searches, but data specific to individuals with cystic fibrosis could not be obtained from the pharmaceutical company. AUTHORS' CONCLUSIONS: This review did not find any evidence for the effectiveness of different antimicrobial treatment for nontuberculous mycobacteria lung disease in people with cystic fibrosis. Until such evidence becomes available, it is reasonable for clinicians to follow published clinical practice guidelines for the diagnosis and treatment of nodular or bronchiectatic pulmonary disease due to Mycobacterium avium complex or Mycobacterium abscessus in patients with cystic fibrosis.


Assuntos
Antibacterianos/uso terapêutico , Fibrose Cística/microbiologia , Pneumopatias/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Quimioterapia Combinada/métodos , Humanos , Pneumopatias/microbiologia , Mycobacterium abscessus , Complexo Mycobacterium avium , Micobactérias não Tuberculosas
17.
Int J Infect Dis ; 96: 663-670, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32450290

RESUMO

OBJECTIVES: To study the prevalence of fungal species in cystic fibrosis (CF) patients over a 16 years period. To examine the impact of Candida albicans (C. albicans), Candida dubliniensis (C. dubliniensis) and Aspergillus fumigatus (A. fumigatus) on lung function. METHODS: Observational single-center cohort study (2000-2015) including 133 CF patients (ages 6-66 years). Linear mixed models with autoregressive covariance matrix were used. RESULTS: The most common fungus was C. albicans (prevalence 62%) followed by A. fumigatus (22%) and C. dubliniensis (11%). In the initial year of detection, there was no impact of C. albicans, C. dubliniensis or A. fumigatus on lung function. However, one and two years after detection of C. dubliniensis a reduction in percent predicted forced expiratory volume in the first second (ppFEV1) was observed of 3.8% (p = 0.022) and 4.1% (p = 0.017), respectively, compared with CF patients without these findings. Furthermore, patients with positive cultures for any of these fungal species for three consecutive years exhibited a decline in lung function: C. dubliniensis, 7.6% reduction in ppFEV1 (p = 0.001); A. fumigatus, 4.9% (p = 0.007); C. albicans, 2.6% (p = 0.014). The results were adjusted for age, CFTR genotype, chronic and intermittent P. aeruginosa colonization, and numbers of intravenous antibiotic treatments per year. Persistence of C. dubliniensis for three consecutive years was positively correlated to age and erythrocyte sedimentation rate (ESR) (both p = 0.001). CONCLUSIONS: Cystic fibrosis patients who were cultured positive for C. dubliniensis, C. albicans or A. fumigatus in sputum exhibited a decline in ppFEV1 over time. The effect was most pronounced for C. dubliniensis.


Assuntos
Candida/isolamento & purificação , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Pulmão/microbiologia , Adolescente , Adulto , Idoso , Biodiversidade , Candida/classificação , Candida/genética , Candida/fisiologia , Criança , Fibrose Cística/complicações , Feminino , Volume Expiratório Forçado , Fungos/classificação , Fungos/genética , Fungos/isolamento & purificação , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prevalência , Testes de Função Respiratória , Estudos Retrospectivos , Escarro/microbiologia , Adulto Jovem
18.
Epidemiol Infect ; 148: e149, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32450935

RESUMO

Persistent methicillin-resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis (CF) patients has been associated with a more rapid decline in lung function, increased hospitalisation and mortality. The aim of this study was to evaluate the clonal relationships among 116 MRSA isolates from 12 chronically colonised CF pediatric patients over a 6-year period in a Rio de Janeiro CF specialist centre. Isolates were characterised by antimicrobial resistance, SCCmec type, presence of Panton-Valentine Leukocidin (PVL) genes and grouped according to DNA macrorestriction profile by pulsed-field gel electrophoresis (PFGE) and spa gene type. High resistance rates were detected for erythromycin (78%) and ciprofloxacin (50%) and SCCmec IV was the most common type (72.4%). Only 8.6% of isolates were PVL positive. High genetic diversity was evident by PFGE (39 pulsotypes) and of nine that were identified spa types, t002 (53.1%) and t539 (14.8%) were the most prevalent. We conclude that the observed homogeneity of spa types within patients over the study period demonstrates the persistence of such strain lineages throughout the course of chronic lung infection.


Assuntos
Fibrose Cística/microbiologia , Staphylococcus aureus Resistente à Meticilina/genética , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Brasil/epidemiologia , Portador Sadio , Criança , Humanos , Resistência a Meticilina
19.
Cochrane Database Syst Rev ; 5: CD006961, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32412092

RESUMO

BACKGROUND: Antibiotic therapy for acute pulmonary exacerbations in people with cystic fibrosis is usually chosen based on the results of antimicrobial susceptibility testing of individual drugs. Combination antimicrobial susceptibility testing assesses the efficacy of drug combinations including two or three antibiotics in vitro and can often demonstrate antimicrobial efficacy against bacterial isolates even when individual antibiotics have little or no effect. Therefore, choosing antibiotics based on combination antimicrobial susceptibility testing could potentially improve response to treatment in people with cystic fibrosis with acute exacerbations. This is an updated version of a previously published review. OBJECTIVES: To compare antibiotic therapy based on conventional antimicrobial susceptibility testing to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis and chronic infection with Pseudomonas aeruginosa. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Cystic Fibrosis Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 19 March 2020. We also searched ongoing trials registries. Date of latest search: 07 April 2020. SELECTION CRITERIA: Randomised and quasi-randomised controlled studies of antibiotic therapy based on conventional antimicrobial susceptibility testing compared to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in cystic fibrosis due to chronic infection with Pseudomonas aeruginosa. DATA COLLECTION AND ANALYSIS: Both authors independently selected studies, assessed their quality and extracted data from eligible studies. Additionally, the authors contacted the study investigators to obtain further information. MAIN RESULTS: The search identified one multicentre study eligible for inclusion in the review. This study prospectively assessed whether the use of multiple combination bactericidal antibiotic testing improved clinical outcomes in participants with acute pulmonary exacerbations of cystic fibrosis who were infected with multiresistant bacteria. A total of 132 participants were randomised in the study. The study investigators provided data specific to the 82 participants who were only infected with Pseudomonas aeruginosa for their primary outcome of time until next pulmonary exacerbation. For participants specifically infected with only Pseudomonas aeruginosa, the hazard ratio of a subsequent exacerbation was 0.82, favouring the control group (95% confidence interval 0.44 to 1.51) (P = 0.52). No further data for any of this review's outcomes specific to participants infected with Pseudomonas aeruginosa were available. The risk of bias for the included study was deemed to be low. The quality of the evidence was moderate for the only outcome providing data solely for individuals with infection due to Pseudomonas aeruginosa. For other outcomes, we were unable to judge the quality of the evidence as no data were available for the relevant subset of participants. AUTHORS' CONCLUSIONS: The current evidence, limited to one study, shows that there is insufficient evidence to determine effect of choosing antibiotics based on combination antimicrobial susceptibility testing compared to choosing antibiotics based on conventional antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis with chronic Pseudomonas aeruginosa infection. A large international and multicentre study is needed to further investigate this issue. The only study included in the review was published in 2005, and we have not identified any further relevant studies up to March 2017. We therefore do not plan to update this review until new studies are published.


Assuntos
Antibacterianos/uso terapêutico , Fibrose Cística/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa , Doença Crônica , Progressão da Doença , Quimioterapia Combinada , Humanos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Nat Commun ; 11(1): 2287, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385294

RESUMO

Culture-independent studies of cystic fibrosis lung microbiota have provided few mechanistic insights into the polymicrobial basis of disease. Deciphering the specific contributions of individual taxa to CF pathogenesis requires comprehensive understanding of their ecophysiology at the site of infection. We hypothesize that only a subset of CF microbiota are translationally active and that these activities vary between subjects. Here, we apply bioorthogonal non-canonical amino acid tagging (BONCAT) to visualize and quantify bacterial translational activity in expectorated sputum. We report that the percentage of BONCAT-labeled (i.e. active) bacterial cells varies substantially between subjects (6-56%). We use fluorescence-activated cell sorting (FACS) and genomic sequencing to assign taxonomy to BONCAT-labeled cells. While many abundant taxa are indeed active, most bacterial species detected by conventional molecular profiling show a mixed population of both BONCAT-labeled and unlabeled cells, suggesting heterogeneous growth rates in sputum. Differentiating translationally active subpopulations adds to our evolving understanding of CF lung disease and may help guide antibiotic therapies targeting bacteria most likely to be susceptible.


Assuntos
Aminoácidos/metabolismo , Fibrose Cística/microbiologia , Pulmão/microbiologia , Microbiota , Biossíntese de Proteínas , Bactérias/classificação , Humanos , Pseudomonas aeruginosa/fisiologia , Escarro/microbiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA