Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis.
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ABSTRACT:
SUBMITTER: Smith S
PROVIDER: S-EPMC8407188 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC9662285 | biostudies-literature
Project description:BackgroundThe choice of antibiotic, and the use of single or combined therapy are controversial areas in the treatment of respiratory infection due to Pseudomonas aeruginosa in cystic fibrosis (CF). Advantages of combination therapy include wider range of modes of action, possible synergy and reduction of resistant organisms; advantages of monotherapy include lower cost, ease of administration and reduction of drug-related toxicity. Current evidence does not provide a clear answer and the use of intravenous antibiotic therapy in CF requires further evaluation. This is an update of a previously published review.ObjectivesTo assess the effectiveness of single compared to combination intravenous anti-pseudomonal antibiotic therapy for treating people with CF.Search methodsWe searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search of the Group's Trials Register: 07 October 2020. We also searched online trials registries on 16 November 2020.Selection criteriaRandomised controlled trials (RCTs) comparing a single intravenous anti-pseudomonal antibiotic with a combination of that antibiotic plus a second anti-pseudomonal antibiotic in people with CF.Data collection and analysisTwo authors independently assessed trial quality and extracted data. We assessed the certainty of the data using GRADE.Main resultsWe identified 59 trials, of which we included eight trials (356 participants) comparing a single anti-pseudomonal agent to a combination of the same antibiotic and one other. There was a wide variation in the individual antibiotics used in each trial. In total, the trials included seven comparisons of a beta-lactam antibiotic (penicillin-related or third generation cephalosporin) with a beta-lactam-aminoglycoside combination and three comparisons of an aminoglycoside with a beta-lactam-aminoglycoside combination. There was considerable heterogeneity amongst these trials, leading to difficulties in performing the review and interpreting the results. These results should be interpreted cautiously. Six of the included trials were published between 1977 and 1988; these were single-centre trials with flaws in the randomisation process and small sample size. Overall, the methodological quality was poor and the certainty of the evidence ranged from low to moderate. The review did not find any differences between monotherapy and combination therapy in either the short term or in the long term for the outcomes of different lung function measures, bacteriological outcome measures, need for additional treatment, adverse effects, quality of life or symptom scores.Authors' conclusionsThe results of this review are inconclusive. The review raises important methodological issues. There is a need for an RCT which needs to be well-designed in terms of adequate randomisation allocation, blinding, power and long-term follow-up. Results need to be standardised to a consistent method of reporting, in order to validate the pooling of results from multiple trials.
| S-EPMC8220369 | biostudies-literature
Project description:BackgroundThe optimum antibiotic therapy for non-cystic fibrosis bronchiectasis (NCFB) has yet to be determined. A meta-analysis was conducted to evaluate the efficacy and safety of inhaled antibiotics in adults with stable NCFB.MethodsPubMed, EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials were searched through November 2019.ResultsA total of 16 randomized controlled trials (RCTs), recruiting 2748 NCFB patients, were finally included. Inhaled antibiotics treatment significantly reduced the sputum bacterial load [standard mean difference (SMD) = -0.74, 95% CI: -1.16-0.32, p < 0.001, I2 = 68.1%], prolonged median time [hazard risk (HR) = 0.73, 95% confidence interval (CI): 0.57-0.93, p < 0.001, I2 = 53.6%] and reduced frequency [incidence rate ratio (IRR) = 0.74, 95% CI 0.63-0.87, p < 0.001, I2 = 20.5%] of exacerbations, with good tolerance. However, it failed to improve Pseudomonas aeruginosa eradication, [forced expiratory volume in 1 s (FEV1)] % predicted, quality of life questionnaire (QoL-B) and St. George's respiratory questionnaire (SGRQ) scores, and may induce higher risk of P. aeruginosa resistance. Subgroup analysis showed Ciprofloxacin was more effective than other antibiotics in reducing bacterial load (SMD = -1.35, 95% CI: -1.85-0.85, I2 = 63.4%, p = 0.042).ConclusionInhaled antibiotics therapy holds great promise for stable NCFB as it is effective in reducing sputum bacterial load and the risk of acute attack, delaying disease progression, and is well tolerated. Although this study brings some constructive ideas in the field of clinical medication, further clinical trials should be carried out, particularly in solving drug-resistance and improving health-related quality of life (HRQoL), which we believe will finally provide benefits for patients suffering from bronchiectasis. The reviews of this paper are available via the supplemental material section.
| S-EPMC7336831 | biostudies-literature
Project description: Not available
| S-EPMC9342853 | biostudies-literature
Project description:Rationale: Chronic azithromycin is commonly used in cystic fibrosis based on short controlled clinical trials showing reductions in pulmonary exacerbations and improved FEV1. Long-term effects are unknown.Objectives: Examine pulmonary outcomes among chronic azithromycin users compared with matched controls over years of use and consider combined azithromycin use in cohorts using chronic inhaled tobramycin or aztreonam.Methods: This retrospective cohort study used the U.S. cystic fibrosis Foundation Patient Registry. Incident chronic azithromycin users were compared with matched controls by FEV1% predicted rate of decline and rates of intravenous antibiotic use to treat pulmonary exacerbations. Propensity score methods were utilized to address confounding by indication. Predefined sensitivity analyses based on lung function, Pseudomonas aeruginosa (PA) status, and follow-up time intervals were conducted.Measurements and Main Results: Across 3 years, FEV1% predicted per-year decline was nearly 40% less in those with PA using azithromycin compared with matched controls (slopes, -1.53 versus -2.41% predicted per yr; difference: 0.88; 95% confidence interval [CI], 0.30-1.47). This rate of decline did not differ based on azithromycin use in those without PA. Among all cohorts, use of intravenous antibiotics was no different between azithromycin users and controls. Users of inhaled tobramycin and azithromycin had FEV1% predicted per-year decline of -0.16 versus nonusers (95% CI, -0.44 to 0.13), whereas users of inhaled aztreonam lysine and azithromycin experienced a mean 0.49% predicted per year slower decline than matched controls (95% CI, -0.11 to 1.10).Conclusions: Results from this study provide additional rationale for chronic azithromycin use in PA-positive patients to reduce lung function decline.
| S-EPMC7049934 | biostudies-literature
Project description:BACKGROUND:Inhaled alpha1-proteinase inhibitor (PI) is known to reduce neutrophil elastase burden in some patients with CF. This phase 2a study was designed to test inhaled Alpha-1 HC, a new aerosolized alpha1-PI formulation, in CF patients. METHODS:We performed a randomized, double-blind, placebo-controlled study and evaluated the safety of 100 or 200mg of inhaled Alpha-1 HC once daily for 3 weeks in subjects with CF. Thirty adult subjects were randomized in a 2:1 ratio to receive Alpha-1 HC or placebo. RESULTS:Drug delivery was confirmed by a dose-dependent increase in the sputum alpha1-PI. Seven (20.0%) of the 35 adverse events in the 100-mg dose group, 3 (13.0%) of 23 in the 200-mg dose group, and 4 (14.3%) of 28 in the placebo group were drug-related in these subjects. One serious adverse event occurred in 1 subject within each group. CONCLUSIONS:Alpha-1 HC inhalation was safe and well tolerated.
| S-EPMC4993024 | biostudies-literature
Project description:Most Cystic Fibrosis (CF) patients succumb to airway inflammation and pulmonary infections due to Pseudomonas aeruginosa. D-BMAP18, a membrane-permeabilizing antimicrobial peptide composed of D-amino acids, was evaluated as a possible antibacterial aimed to address this issue. The antipseudomonal activity of D-BMAP18 was tested in a pathophysiological context. The peptide displayed activity against CF isolates of Pseudomonas aeruginosa in the presence of CF sputum when combined with sodium chloride and DNase I. In combination with DNase I, D-BMAP18 discouraged the deposition of new biofilm and eradicated preformed biofilms of some P. aeruginosa strains. In addition, D-BMAP18 down regulated the production of TNF-α, IL1-β, and TGF-β in LPS-stimulated or IFN-γ macrophages derived from THP-1 cells indicating an anti-inflammatory activity. The biocompatibility of D-BMAP18 was assessed using four different cell lines, showing that residual cell-specific cytotoxicity at bactericidal concentrations could be abolished by the presence of CF sputum. Overall, this study suggests that D-BMAP18 may be an interesting molecule as a starting point to develop a novel therapeutic agent to simultaneously contrast lung infections and inflammation in CF patients.
| S-EPMC7565916 | biostudies-literature
Project description: Not available
| S-EPMC7195814 | biostudies-literature
Project description:The genetic disorder cystic fibrosis is a life-limiting condition affecting ∼70,000 people worldwide. Targeted, early, treatment of the dominant infecting species, Pseudomonas aeruginosa, has improved patient outcomes; however, there is concern that other species are now stepping in to take its place. In addition, the necessarily long-term antibiotic therapy received by these patients may be providing a suitable environment for the emergence of antibiotic resistance. To investigate these issues, we employed whole-genome sequencing of 28 non-Pseudomonas bacterial strains isolated from three paediatric patients. We did not find any trend of increasing antibiotic resistance (either by mutation or lateral gene transfer) in these isolates in comparison with other examples of the same species. In addition, each isolate contained a virulence gene repertoire that was similar to other examples of the relevant species. These results support the impaired clearance of the CF lung not demanding extensive virulence for survival in this habitat. By analysing serial isolates of the same species we uncovered several examples of strain persistence. The same strain of Staphylococcus aureus persisted for nearly a year, despite administration of antibiotics to which it was shown to be sensitive. This is consistent with previous studies showing antibiotic therapy to be inadequate in cystic fibrosis patients, which may also explain the lack of increasing antibiotic resistance over time. Serial isolates of two naturally multi-drug resistant organisms, Achromobacter xylosoxidans and Stenotrophomonas maltophilia, revealed that while all S. maltophilia strains were unique, A. xylosoxidans persisted for nearly five years, making this a species of particular concern. The data generated by this study will assist in developing an understanding of the non-Pseudomonas species associated with cystic fibrosis.
| S-EPMC4579023 | biostudies-literature
Project description: Not available
| S-EPMC9231652 | biostudies-literature