Amikacin nebulization for the adjunctive therapy of gram-negative pneumonia in mechanically ventilated patients: a systematic review and meta-analysis of randomized controlled trials.
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SUBMITTER: Qin JP
PROVIDER: S-EPMC7997905 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionAminoglycosides aerosolization might achieve better diffusion into the alveolar compartment than intravenous use. The objective of this multicenter study was to evaluate aerosol-delivered amikacin penetration into the alveolar epithelial lining fluid (ELF) using a new vibrating mesh nebulizer (Pulmonary Drug Delivery System (PDDS), Nektar Therapeutics), which delivers high doses to the lungs.MethodsNebulized amikacin (400 mg bid) was delivered to the lungs of 28 mechanically ventilated patients with Gram-negative VAP for 7-14 days, adjunctive to intravenous therapy. On treatment day 3, 30 minutes after completing aerosol delivery, all the patients underwent bronchoalveolar lavage in the infection-involved area and the ELF amikacin concentration was determined. The same day, urine and serum amikacin concentrations were determined at different time points.ResultsMedian (range) ELF amikacin and maximum serum amikacin concentrations were 976.1 (135.7-16127.6) and 0.9 (0.62-1.73) microg/mL, respectively. The median total amount of amikacin excreted in urine during the first and second 12-hour collection on day 3 were 19 (12.21-28) and 21.2 (14.1-29.98) microg, respectively. During the study period, daily through amikacin measurements were below the level of nephrotoxicity. Sixty-four unexpected adverse events were reported, among which 2 were deemed possibly due to nebulized amikacin: one episode of worsening renal failure, and one episode of bronchospasm.ConclusionsPDDS delivery of aerosolized amikacin achieved very high aminoglycoside concentrations in ELF from radiography-controlled infection-involved zones, while maintaining safe serum amikacin concentrations. The ELF concentrations always exceeded the amikacin minimum inhibitory concentrations for Gram-negative microorganisms usually responsible for these pneumonias. The clinical impact of amikacin delivery with this system remains to be determined.Trial registrationClinicalTrials.gov Identifier: NCT01021436.
| S-EPMC2811890 | biostudies-literature
Project description:Rationale: Patients in the intensive care unit (ICU) are frequently exposed to unnecessary antibiotics. Markers of the host response to infection may aid pneumonia diagnosis and avoid antibiotic-induced complications. Objective: To assess the host response to suspected bacterial pneumonia through assessment of alveolar neutrophilia and transcriptomic profiling of alveolar macrophages. Methods: We determined the test characteristics of BAL neutrophilia for the diagnosis of bacterial pneumonia in 3 cohorts of mechanically ventilated patients. In one cohort, we also isolated alveolar macrophages from BAL fluid and used the transcriptome to identify signatures of bacterial pneumonia. Finally, we developed a humanized mouse model of Pseudomonas aeruginosa pneumonia to determine if pathogen-specific signatures can be identified in human alveolar macrophages. Measurements and Main Results: BAL neutrophilia was highly sensitive for bacterial pneumonia in both the retrospective (N = 851) and validation cohorts (N = 76 and N = 79) with a negative predictive value of over 90% when BAL neutrophil percentage was less than 50%. A transcriptional signature of bacterial pneumonia was present in both resident and recruited macrophages. Gene signatures from both cell types identified patients with bacterial pneumonia with test characteristics similar to BAL neutrophilia. Conclusions: A BAL neutrophil percentage of less than 50% is highly sensitive for bacterial pneumonia. Informative transcriptomic signatures can be generated from BAL fluid obtained during routine clinical care in the ICU. The identification of novel host response biomarkers is a promising approach to aid the diagnosis and treatment of pneumonia.
2018-11-06 | GSE121871 | GEO
Project description:OBJECTIVE: To evaluate the effect of oral decontamination on the incidence of ventilator associated pneumonia and mortality in mechanically ventilated adults. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, CINAHL, the Cochrane Library, trials registers, reference lists, conference proceedings, and investigators in the specialty. REVIEW METHODS: Two independent reviewers screened studies for inclusion, assessed trial quality, and extracted data. Eligible trials were randomised controlled trials enrolling mechanically ventilated adults that compared the effects of daily oral application of antibiotics or antiseptics with no prophylaxis. RESULTS: 11 trials totalling 3242 patients met the inclusion criteria. Among four trials with 1098 patients, oral application of antibiotics did not significantly reduce the incidence of ventilator associated pneumonia (relative risk 0.69, 95% confidence interval 0.41 to 1.18). In seven trials with 2144 patients, however, oral application of antiseptics significantly reduced the incidence of ventilator associated pneumonia (0.56, 0.39 to 0.81). When the results of the 11 trials were pooled, rates of ventilator associated pneumonia were lower among patients receiving either method of oral decontamination (0.61, 0.45 to 0.82). Mortality was not influenced by prophylaxis with either antibiotics (0.94, 0.73 to 1.21) or antiseptics (0.96, 0.69 to 1.33) nor was duration of mechanical ventilation or stay in the intensive care unit. CONCLUSIONS: Oral decontamination of mechanically ventilated adults using antiseptics is associated with a lower risk of ventilator associated pneumonia. Neither antiseptic nor antibiotic oral decontamination reduced mortality or duration of mechanical ventilation or stay in the intensive care unit.
| S-EPMC1857782 | biostudies-literature
Project description:Background and Objective: Ventilator-associated pneumonia (VAP) is still an important cause of morbidity and mortality in mechanically ventilated patients. The efficacy of the probiotics for preventing VAP is still controversial. Present study was conducted to comprehensively evaluate the effect of probiotics on VAP prevention in mechanically ventilated patients. Methods: PubMed, Embase, and CENTRAL were searched up to September 2016. Eligible trials designed with randomized controlled trials (RCTs) comparing probiotics with control in mechanically ventilated patients were included. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were estimated with fixed or random effects models. Trial sequential analysis (TSA) was performed using TSA 0.9beta software. Results: Thirteen RCTs (N = 1969) were included. Overall, probiotics were associated with reduced incidence of VAP (RR = 0.73, 95% CI = 0.60-0.89; P = 0.002), which was confirmed by TSA (TSA adjusted 95% CI = 0.55-0.96). However, no significant difference was observed in 90-day mortality (RR = 1.00, 95% CI = 0.72-1.37; P = 0.99), overall mortality (RR = 0.84, 95% CI = 0.70-1.02; P = 0.09), 28-day mortality (RR = 1.06, 95% CI = 0.72-1.57; P = 0.99), intensive care unit (ICU) mortality (RR = 0.97, 95% CI = 0.74-1.27; P = 0.82), hospital mortality (RR = 0.81, 95% CI = 0.65-1.02; P = 0.07), diarrhea (RR = 0.99, 95% CI = 0.83-1.19; P = 0.92), length of ICU stay (MD = -2.40 days, 95% CI = -6.75 to 1.95; P = 0.28), length of hospital stay (MD = -1.34 days, 95% CI = -6.21 to 3.54; P = 0.59), and duration of mechanical ventilation (MD = -3.32 days, 95% CI = -6.74 to 0.09; P = 0.06). Conclusions: In this meta-analysis, we found that probiotics could reduce the incidence of VAP in mechanically ventilated patients. It seems likely that probiotics provide clinical benefits for mechanically ventilated patients.
| S-EPMC5640711 | biostudies-literature
Project description:IntroductionNosocomial pneumonia is the most important infectious complication in patients admitted to intensive care units. Kinetic bed therapy may reduce the incidence of nosocomial pneumonia in mechanically ventilated patients. The objective of this study was to investigate whether kinetic bed therapy reduces the incidence of nosocomial pneumonia and improves outcomes in critically ill mechanically ventilated patients.MethodsWe searched Medline, EMBASE, CINAHL, CENTRAL, and AMED for studies, as well as reviewed abstracts of conference proceedings, bibliographies of included studies and review articles and contacted the manufacturers of medical beds. Studies included were randomized or pseudo-randomized clinical trials of kinetic bed therapy compared to standard manual turning in critically ill mechanically ventilated adult patients. Two reviewers independently applied the study selection criteria and extracted data regarding study validity, type of bed used, intensity of kinetic therapy, and population under investigation. Outcomes assessed included the incidence of nosocomial pneumonia, mortality, duration of ventilation, and intensive care unit and hospital length of stay.ResultsFifteen prospective clinical trials were identified, which included a total of 1,169 participants. No trial met all the validity criteria. There was a significant reduction in the incidence of nosocomial pneumonia (pooled odds ratio (OR) 0.38, 95% confidence interval (CI) 0.28 to 0.53), but no reduction in mortality (pooled OR 0.96, 95%CI 0.66 to 1.14), duration of mechanical ventilation (pooled standardized mean difference (SMD) -0.14 days, 95%CI, -0.29 to 0.02), duration of intensive care unit stay (pooled SMD -0.064 days, 95% CI, -0.21 to 0.086) or duration of hospital stay (pooled SMD 0.05 days, 95% CI -0.18 to 0.27).ConclusionWhile kinetic bed therapy has been purported to reduce the incidence of nosocomial pneumonia in mechanically ventilated patients, the overall body of evidence is insufficient to support this conclusion. There appears to be a reduction in the incidence of nosocomial pneumonia, but no effect on mortality, duration of mechanical ventilation, or intensive care or hospital length of stay. Given the lack of consistent benefit and the poor methodological quality of the trials included in this analysis, definitive recommendations regarding the use of this therapy cannot be made at this time.
| S-EPMC1550950 | biostudies-literature
Project description:ObjectivesLung penetration of cefiderocol, a novel siderophore cephalosporin approved for treatment of nosocomial pneumonia, has previously been evaluated in healthy subjects. This study assessed the intrapulmonary pharmacokinetic profile of cefiderocol at steady state in hospitalized, mechanically ventilated pneumonia patients.MethodsPatients received cefiderocol 2 g (or ≤1.5 g if renally impaired), administered IV q8h as a 3 h infusion, or 2 g q6h if patients had augmented renal function (estimated CLCR > 120 mL/min). After multiple doses, each patient underwent a single bronchoalveolar lavage (BAL) procedure either at the end of the infusion or at 2 h after the end of infusion. Plasma samples were collected at 1, 3, 5 and 7 h after the start of infusion. After correcting for BAL dilution, cefiderocol concentrations in epithelial lining fluid (ELF) for each patient and the ELF/unbound plasma concentration ratio (RC, E/P) were calculated. Safety was assessed up to 7 days after the last cefiderocol dose.ResultsSeven patients received cefiderocol. Geometric mean ELF concentration of cefiderocol was 7.63 mg/L at the end of infusion and 10.40 mg/L at 2 h after the end of infusion. RC, E/P was 0.212 at the end of infusion and 0.547 at 2 h after the end of infusion, suggesting delayed lung distribution. There were no adverse drug reactions.ConclusionsThe results suggest that cefiderocol penetrates the ELF in critically ill pneumonia patients with concentrations that are sufficient to treat Gram-negative bacteria with an MIC of ≤4 mg/L.
| S-EPMC8521398 | biostudies-literature
Project description:BackgroundVentilator-associated pneumonia (VAP) is one of the common critical complications of nosocomial infection (NI) in invasive mechanically ventilated intensive care unit (ICU) patients. The efficacy of total parenteral nutrition (TPN), enteral nutrition and/or adjuvant peripheral parenteral nutrition (EPN) supplemented with or without probiotic, prebiotic, and synbiotic therapies in preventing VAP among these patients has been questioned. We aimed to systematically and comprehensively summarize all available studies to generate the best evidence of VAP prevention for invasive mechanically ventilated ICU patients.MethodsRandomized controlled trials (RCTs) for the administration of TPN, EPN, probiotics-supplemented EPN, prebiotics-supplemented EPN, and synbiotics-supplemented EPN for VAP prevention in invasive mechanically ventilated ICU patients were systematically retrieved from four electronic databases. The incidence of VAP was the primary outcome and was determined by the random-effects model of a Bayesian framework. The secondary outcomes were NI, ICU and hospital mortality, ICU and hospital length of stay, and mechanical ventilation duration. The registration number of Prospero is CRD42020195773.ResultsA total of 8339 patients from 31 RCTs were finally included in network meta-analysis. The primary outcome showed that probiotic-supplemented EPN had a higher correlation with the alleviation of VAP than EPN in critically invasive mechanically ventilated patients (odds ratio [OR] 0.75; 95% credible intervals [CrI] 0.58-0.95). Subgroup analyses showed that probiotic-supplemented EPN prevented VAP in trauma patients (OR 0.30; 95% CrI 0.13-0.83), mixed probiotic strain therapy was more effective in preventing VAP than EPN therapy (OR 0.55; 95% CrI 0.31-0.97), and low-dose probiotic therapy (less than 1010 CFU per day) was more associated with lowered incidence of VAP than EPN therapy (OR 0.16; 95% CrI 0.04-0.64). Secondary outcomes indicated that synbiotic-supplemented EPN therapy was more significantly related to decreased incidence of NI than EPN therapy (OR 0.34; 95% CrI 0.11-0.85). Prebiotic-supplemented EPN administration was the most effective in preventing diarrhea (OR 0.05; 95% CrI 0.00-0.71).ConclusionProbiotic supplementation shows promise in reducing the incidence of VAP in critically invasive mechanically ventilated patients. Currently, low quality of evidence reduces strong clinical recommendations. Further high-quality RCTs are needed to conclusively prove these findings.Systamatic review registration[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020195773], identifier [CRD42020195773].
| S-EPMC9307490 | biostudies-literature
Project description:Etiologic diagnosis of bacterial pneumonia relies on identification of causative pathogens by cultures, which require extended incubation periods and have limited sensitivity. Next-generation sequencing of microbial DNA directly from patient samples may improve diagnostic accuracy for guiding antibiotic prescriptions. In this study, we hypothesized that enhanced pathogen detection using sequencing can improve upon culture-based diagnosis and that certain sequencing profiles correlate with host response. We prospectively collected endotracheal aspirates and plasma within 72 h of intubation from patients with acute respiratory failure. We performed 16S rRNA gene sequencing to determine pathogen abundance in lung samples and measured plasma biomarkers to assess host responses to detected pathogens. Among 56 patients, 12 patients (21%) had positive respiratory cultures. Sequencing revealed lung communities with low diversity (p < 0.02) dominated by taxa (>50% relative abundance) corresponding to clinically isolated pathogens (concordance p = 0.009). Importantly, sequencing detected dominant pathogens in 20% of the culture-negative patients exposed to broad-spectrum empiric antibiotics. Regardless of culture results, pathogen dominance correlated with increased plasma markers of host injury (receptor of advanced glycation end-products-RAGE) and inflammation (interleukin-6, tumor necrosis factor receptor 1-TNFR1) (p < 0.05), compared to subjects without dominant pathogens in their lung communities. Machine-learning algorithms identified pathogen abundance by sequencing as the most informative predictor of culture positivity. Thus, enhanced detection of pathogenic bacteria by sequencing improves etiologic diagnosis of pneumonia, correlates with host responses, and offers substantial opportunity for individualized therapeutic targeting and antimicrobial stewardship. Clinical translation will require validation with rapid whole meta-genome sequencing approaches to guide real-time antibiotic prescriptions.
| S-EPMC6048198 | biostudies-literature
Project description:Purpose: A systematic review was conducted to investigate the effect of respiratory physiotherapy on mortality, quality of life, functional recovery, intensive care length of stay, duration of ventilation, oxygenation, secretion clearance, and pulmonary mechanics for invasively ventilated adults with pneumonia. Method: Five databases were searched for randomized trials published between January 1995 and November 2018. Study quality was assessed using a standardized Joanna Briggs Institute critical appraisal tool, and Review Manager software was used to pool the studies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate the level of certainty of the evidence. Results: A total of 14 studies of moderate quality included 251 subjects with pneumonia. Eight studies were pooled for meta-analysis. Interventions that increased inspiratory volume appeared to benefit secretion clearance by nearly 2 grams (mean difference [MD] 1.97; 95% CI: 0.80, 3.14; very low GRADE evidence) and increase static lung compliance immediately after treatment by more than 5 millilitres/centimetre H20 (MD 5.40 mL/cm H2O; 95% CI: 2.37, 8.43; very low GRADE evidence) or by more than 6 millilitres/centimetre H2O after a 20- to 30-minute delay (MD 6.86 mL/cm H2O; 95% CI: 2.86, 10.86; very low GRADE evidence). No adverse events were found. Conclusions: Respiratory physiotherapy that increases tidal volume may benefit secretion clearance and lung compliance in invasively ventilated adults with pneumonia, but its impact on other outcomes, including mortality, length of stay, and other patient-centred outcomes, is unclear, and further research is required.
| S-EPMC8774958 | biostudies-literature
Project description:Improving the outcome of patients with community-acquired pneumonia (CAP) is an ongoing challenge, even in the setting of significant advances in antimicrobial chemotherapy and critical care. Recognition of the underlying involvement of inflammation-mediated organ dysfunction as a determinant of adverse outcomes in CAP has aroused intense interest in the protective potential of adjunctive anti-inflammatory therapies in CAP, particularly the role of corticosteroids (CS). This is the primary topic of the current review which is focused on an evaluation of the latest meta-analyses encompassing both recent and earlier clinical trials, with particular emphasis on the stringent meta-analysis undertaken by Siemieniuk and colleagues (Ann Intern Med 2015;163:519-528). The review highlights the findings and recommendations of these and related published commentaries/critiques, while providing a brief description of those sub-groups of patients who seemingly stand to benefit most from CS therapy. This is preceded by an overview of the mechanisms of the anti-inflammatory activities of CS, the interactions of these agents with macrolide antibiotics, and the potential benefits and risks of short-term administration of CS, concluding with a succinct appraisal of priority issues for ongoing and future research.
| S-EPMC4805802 | biostudies-other