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Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia.

ABSTRACT: Aminoglycosides 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.Nebulized 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.Median (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.PDDS 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.ClinicalTrials.gov Identifier: NCT01021436.

SUBMITTER: Luyt CE

PROVIDER: S-EPMC2811890 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia.

Luyt Charles-Edouard CE Clavel Marc M Guntupalli Kalpalatha K Johannigman Jay J Kennedy John I JI Wood Christopher C Corkery Kevin K Gribben Dennis D Chastre Jean J

Critical care (London, England) 20091210 6

<h4>Introduction</h4>Aminoglycosides 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.<h4>Methods</h4>Nebulized amikacin (400 mg bid) was delivered to the lungs of 28 mec ...[more]

PMID: 20003269

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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.

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.

Project description:BackgroundLimited data are available on the use of prone position in intubated, invasively ventilated patients with Coronavirus disease-19 (COVID-19). Aim of this study is to investigate the use and effect of prone position in this population during the first 2020 pandemic wave.MethodsRetrospective, multicentre, national cohort study conducted between February 24 and June 14, 2020, in 24 Italian Intensive Care Units (ICU) on adult patients needing invasive mechanical ventilation for respiratory failure caused by COVID-19. Clinical data were collected on the day of ICU admission. Information regarding the use of prone position was collected daily. Follow-up for patient outcomes was performed on July 15, 2020. The respiratory effects of the first prone position were studied in a subset of 78 patients. Patients were classified as Oxygen Responders if the PaO2/FiO2 ratio increased ≥ 20 mmHg during prone position and as Carbon Dioxide Responders if the ventilatory ratio was reduced during prone position.ResultsOf 1057 included patients, mild, moderate and severe ARDS was present in 15, 50 and 35% of patients, respectively, and had a resulting mortality of 25, 33 and 41%. Prone position was applied in 61% of the patients. Patients placed prone had a more severe disease and died significantly more (45% vs. 33%, p < 0.001). Overall, prone position induced a significant increase in PaO2/FiO2 ratio, while no change in respiratory system compliance or ventilatory ratio was observed. Seventy-eight % of the subset of 78 patients were Oxygen Responders. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p = 0.047). Forty-seven % of patients were defined as Carbon Dioxide Responders. These patients were older and had more comorbidities; however, no difference in terms of ICU mortality was observed (51% vs. 37%, p = 0.189 for Carbon Dioxide Responders and Non-Responders, respectively).ConclusionsDuring the COVID-19 pandemic, prone position has been widely adopted to treat mechanically ventilated patients with respiratory failure. The majority of patients improved their oxygenation during prone position, most likely due to a better ventilation perfusion matching.Trial registrationclinicaltrials.gov number: NCT04388670.

Project description:BACKGROUND:Antibiotics are commonly administered to hospitalized patients with infiltrates for possible bacterial pneumonia, often leading to unnecessary treatment and increasing the risk for resistance emergence. Therefore, we performed a study to determine if an enhanced antibiotic de-escalation practice could improve antibiotic utilization in mechanically ventilated patients with suspected pneumonia cared for in an academic closed intensive care unit (ICU). METHODS:This was a prospective cross-over trial comparing routine antibiotic management (RAM) and enhanced antimicrobial de-escalation (EAD) performed within two medical ICUs (total 34 beds) at Barnes-Jewish Hospital, an academic referral center. Patients in the EAD group had their antibiotic orders and microbiology results reviewed daily by a dedicated team comprised of a second-year critical care fellow, an ICU attending physician and an ICU pharmacist. Antibiotic de-escalation recommendations were made when appropriate based on microbiologic test results and clinical response to therapy. RESULTS:There were 283 patients evaluable, with suspected pneumonia requiring mechanical ventilation: 139 (49.1%) patients in the RAM group and 144 (50.9%) in the EAD group. Early treatment failure based on clinical deterioration occurred in 33 (23.7%) and 40 (27.8%) patients, respectively (P?=?0.438). In the remaining patients, antimicrobial de-escalation occurred in 70 (66.0%) and 70 (67.3%), respectively (P?=?0.845). There was no difference between groups in total antibiotic days ((median (interquartile range)) 7.0 days (4.0, 9.0) versus 7.0 days (4.0, 8.8) (P?=?0.616)); hospital mortality (25.2% versus 35.4% (P?=?0.061)); or hospital duration (12.0 days (6.0, 20.0) versus 11.0 days (6.0, 22.0) (P?=?0.918). CONCLUSIONS:The addition of an EAD program to a high-intensity daytime staffing model already practicing a high-level of antibiotic stewardship in an academic ICU was not associated with greater antibiotic de-escalation or a reduction in the overall duration of antibiotic therapy. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02685930 . Registered on 26 January 2016.

Dataset Information

Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia.

Publications

Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia.

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