Activity of Pulmonary Vancomycin Exposures versus Planktonic and Biofilm Methicillin-Resistant Staphylococcus aureus Isolated from Cystic Fibrosis Sputum.
- 作者列表："Britt NS","Hazlett DS","Horvat RT","Liesman RM","Steed ME
:Vancomycin is commonly used to treat methicillin-resistant Staphylococcus aureus (MRSA) infection in patients with cystic fibrosis (CF) lung disease; however, there are limited data to support the in vitro activity of this agent against MRSA isolated from CF sputum. The primary objective of this study was to evaluate the activity of vancomycin at pulmonary concentrations (intravenous and inhaled) against 4 clinical MRSA CF sputum isolates in planktonic and biofilm time-kill (TK) experiments. Vancomycin minimum inhibitory concentrations (MICs) were determined for these isolates at standard inoculum (SI; ∼106 colony-forming units [CFU]/mL) and high inoculum (HI; ∼108 CFU/mL), and in biofilms cultivated using physiologic media recapitulating the microenvironment of the CF lung. Vancomycin concentrations of 10, 25, 100, and 275 µg/mL were evaluated in TK experiments against planktonic MRSA at varying inocula and versus biofilm MRSA. Vancomycin MICs increased from 0.5 µg/mL at SI to 8-16 µg/mL when tested at HI. Vancomycin MICs were further increased to 16-32 µg/mL in biofilm studies. In TK experiments, vancomycin displayed bactericidal activity (≥ 3 log10 killing at 24 h) against 1/4 and 0/4 planktonic MRSA isolates at SI and HI, respectively. Against MRSA biofilms, vancomycin was bactericidal against 0/4 isolates. Based on these findings, vancomycin monotherapy appears unlikely to eradicate MRSA from the respiratory tract of patients with CF, even at high concentrations similar to those observed with inhaled therapy. Novel vancomycin formulations with enhanced biofilm penetration or combination therapy with other potentially synergistic agents should be explored.
: 万古霉素常用于治疗囊性纤维化 (CF) 肺病患者的耐甲氧西林金黄色葡萄球菌 (MRSA) 感染; 然而, 支持该药物对 CF 痰中分离的 MRSA 的体外活性的数据有限。本研究的主要目的是在浮游和生物膜时间杀伤 (TK) 实验中评价万古霉素在肺部浓度 (静脉和吸入) 下对 4 株临床 MRSA CF 痰液分离株的活性。在标准接种物 (SI; 106 菌落形成单位 [CFU]/mL) 和高接种物 (HI; 108 CFU/mL)，并在使用生理培养基培养的生物膜中概括了 CF 肺的微环境。万古霉素浓度为 10 、 25 、 100 和 275 µ g/mL 在 TK 实验中对不同接种物和生物膜 MRSA 的浮游 MRSA 进行了评价。HI 测试时，万古霉素 mic 从 SI 时的 0.5 µ g/mL 增加到 8-16 µ g/mL。在生物膜研究中，万古霉素 mic 进一步增加至 16-32 µ g/mL。在 TK 实验中，万古霉素在 SI 和 HI 分别对 1/4 和 0/4 株浮游 MRSA 分离株表现出杀菌活性 (24 h 时 ≥ 3 log10 杀灭)。针对 MRSA 生物膜，万古霉素对 0/4 株分离株具有杀菌作用。基于这些发现，万古霉素单药治疗似乎不太可能从 CF 患者的呼吸道根除 MRSA，即使在与吸入治疗观察到的高浓度下也是如此。应探索生物膜渗透增强或与其他潜在增效剂联合治疗的新型万古霉素制剂。
METHODS:OBJECTIVES:To asses the clinical course in RA-related interstitial lung disease (RA-ILD) patients with and without rituximab (RTX). The influence of other variables was also evaluated. METHODS:A longitudinal multicentre study was conducted in RA diagnosed with ILD from 2007 until 2018 in Madrid. Patients were included in a registry [pNEumology RhEumatology Autoinmune diseases (NEREA)] from the time of ILD diagnosis. The main endpoint was functional respiratory impairment (FI), when there was a decline ≥5% in the predicted forced vital capacity compared with the previous one. Pulmonary function was measured at baseline and in follow-up visits every 6-12 months. The independent variable was therapy with RTX. Covariables included sociodemographic, clinical, radiological and other therapies. Survival techniques were used to estimate the incidence rate (IR) and 95% CI of functional impairment, expressed per 100 patient-semesters. Cox multivariate regression models were run to examine the influence of RTX and other covariates on FI. Results were expressed as the hazard ratio (HR) and CI. RESULTS:A total of 68 patients were included. FI occurred in 42 patients [IR 23.5 (95% CI 19, 29.1)] and 50% of them had FI within 1.75 years of an ILD diagnosis. A multivariate analysis showed that RTX exposure resulted in a lower risk of FI compared with non-exposure [HR 0.51 (95% CI 0.31, 0.85)]. Interstitial pneumonia, glucocorticoids, disease activity and duration also influenced FI. CONCLUSION:RA-ILD patients deteriorate over time, with the median time free of impairment being <2 years. Patients exposed to RTX had a higher probability of remaining free of FI compared with other therapies. Other factors have also been identified. Key words: rheumatoid arthritis, interstitial lung disease, observational study, rituximab and prognosis
METHODS:The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3–2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2–14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.
METHODS::Bacteria of the Burkholderia cepacia complex (Bcc) are ubiquitous multidrug resistant organisms and opportunistic pathogens capable of causing life threatening lung infections among cystic fibrosis (CF) patients. No effective therapies are currently available to eradicate Bcc bacteria from CF patients, as these organisms are inherently resistant to the majority of clinically available antimicrobials. An immunoproteomics approach was used to identify Bcc proteins that stimulate the humoral immune response of the CF host, using bacterial cells grown under conditions mimicking the CF lung environment and serum samples from CF patients with a clinical record of Bcc infection. 24 proteins of the Bcc strain B. cenocepacia J2315 were identified as immunoreactive, 19 here reported as immunogenic for the first time. Ten proteins were predicted as extracytoplasmic, 9 of them being conserved in Bcc genomes. The immunogenic Bcc extracytoplasmic proteins are potential targets for development of novel therapeutic strategies and diagnostic tools to protect patients against the onset of chronic Bcc lung infections.