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Pre-exposure to mechanical ventilation and endotoxemia increases Pseudomonas aeruginosa growth in lung tissue during experimental porcine pneumonia.

ABSTRACT: BACKGROUND:Immune system suppression during critical care contributes to the risk of acquired bacterial infections with Pseudomonas (P.) aeruginosa. Repeated exposure to endotoxin can attenuate systemic inflammatory cytokine responses. Mechanical ventilation affects the systemic inflammatory response to various stimuli. AIM:To study the effect of pre-exposure to mechanical ventilation with and without endotoxin-induced systemic inflammation on P. aeruginosa growth and wet-to-dry weight measurements on lung tissue and plasma and bronchoalveolar lavage levels of tumor necrosis factor alpha, interleukins 6 and 10. METHODS:Two groups of pigs were exposed to mechanical ventilation for 24 hours before bacterial inoculation and six h of experimental pneumonia (total experimental time 30 h): A30h+Etx (n = 6, endotoxin 0.063 ?g x kg-1 x h-1) and B30h (n = 6, saline). A third group, C6h (n = 8), started the experiment at the bacterial inoculation unexposed to endotoxin or mechanical ventilation (total experimental time 6 h). Bacterial inoculation was performed by tracheal instillation of 1x1011 colony-forming units of P. aeruginosa. Bacterial cultures and wet-to-dry weight ratio analyses were done on lung tissue samples postmortem. Separate group comparisons were done between A30h+Etx vs.B30h (Inflammation) and B30h vs. C6h (Ventilation Time) during the bacterial phase of 6 h. RESULTS:P. aeruginosa growth was highest in A30h+Etx, and lowest in C6h (Inflammation and Ventilation Time both p<0.05). Lung wet-to-dry weight ratios were highest in A30h+Etx and lowest in B30h (Inflammation p<0.01, Ventilation Time p<0.05). C6h had the highest TNF-? levels in plasma (Ventilation Time p<0.01). No differences in bronchoalveolar lavage variables between the groups were observed. CONCLUSIONS:Mechanical ventilation and systemic inflammation before the onset of pneumonia increase the growth of P. aeruginosa in lung tissue. The attenuated growth of P. aeruginosa in the non-pre-exposed animals (C6h) was associated with a higher systemic TNF-? production elicited from the bacterial challenge.

SUBMITTER: Sperber J

PROVIDER: S-EPMC7591049 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Pre-exposure to mechanical ventilation and endotoxemia increases Pseudomonas aeruginosa growth in lung tissue during experimental porcine pneumonia.

Sperber Jesper J Nyberg Axel A Krifors Anders A Skorup Paul P Lipcsey Miklós M Castegren Markus M

PloS one 20201027 10

<h4>Background</h4>Immune system suppression during critical care contributes to the risk of acquired bacterial infections with Pseudomonas (P.) aeruginosa. Repeated exposure to endotoxin can attenuate systemic inflammatory cytokine responses. Mechanical ventilation affects the systemic inflammatory response to various stimuli.<h4>Aim</h4>To study the effect of pre-exposure to mechanical ventilation with and without endotoxin-induced systemic inflammation on P. aeruginosa growth and wet-to-dry w ...[more]

PMID: 33108383

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Project description:BackgroundPseudomonas aeruginosa pneumonia is commonly treated with systemic antibiotics to ensure adequate treatment of multidrug resistant (MDR) bacteria. However, intravenous (IV) antibiotics often achieve suboptimal pulmonary concentrations. We therefore aimed to evaluate the effect of inhaled amikacin (AMK) plus IV meropenem (MEM) on bactericidal efficacy in a swine model of monolateral MDR P. aeruginosa pneumonia.MethodsWe ventilated 18 pigs with monolateral MDR P. aeruginosa pneumonia for up to 102 h. At 24 h after the bacterial challenge, the animals were randomized to receive 72 h of treatment with either inhaled saline (control), IV MEM only, or IV-MEM plus inhaled AMK (MEM + AMK). We dosed IV MEM at 25 mg/kg every 8 h and inhaled AMK at 400 mg every 12 h. The primary outcomes were the P. aeruginosa burden and histopathological injury in lung tissue. Secondary outcomes included the P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage fluid, the development of antibiotic resistance, the antibiotic distribution, and the levels of inflammatory markers.ResultsThe median (25-75th percentile) P. aeruginosa lung burden for animals in the control, MEM only, and MEM + AMK groups was 2.91 (1.75-5.69), 0.72 (0.12-3.35), and 0.90 (0-4.55) log10 CFU/g (p = 0.009). Inhaled therapy had no effect on preventing dissemination compared to systemic monotherapy, but it did have significantly higher bactericidal efficacy in tracheal secretions only. Remarkably, the minimum inhibitory concentration of MEM increased to > 32 mg/L after 72-h exposure to monotherapy in 83% of animals, while the addition of AMK prevented this increase (p = 0.037). Adjunctive therapy also slightly affected interleukin-1β downregulation. Despite finding high AMK concentrations in pulmonary samples, we found no paired differences in the epithelial lining fluid concentration between infected and non-infected lungs. Finally, a non-significant trend was observed for higher amikacin penetration in low-affected lung areas.ConclusionsIn a swine model of monolateral MDR P. aeruginosa pneumonia, resistant to the inhaled AMK and susceptible to the IV antibiotic, the use of AMK as an adjuvant treatment offered no benefits for either the colonization of pulmonary tissue or the prevention of pathogen dissemination. However, inhaled AMK improved bacterial eradication in the proximal airways and hindered antibiotic resistance.

Project description:BackgroundProtective ventilation with lower tidal volumes reduces systemic and organ-specific inflammation. In sepsis-induced encephalopathy or acute brain injury the use of protective ventilation has not been widely investigated (experimentally or clinically). We hypothesized that protective ventilation would attenuate cerebral inflammation in a porcine endotoxemic sepsis model. The aim of the study was to study the effect of tidal volume on cerebral inflammatory response, cerebral metabolism and brain injury. Nine animals received protective mechanical ventilation with a tidal volume of 6 mL × kg-1 and nine animals were ventilated with a tidal volume of 10 mL × kg-1. During a 6-h experiment, the pigs received an endotoxin intravenous infusion of 0.25 µg × kg-1 × h-1. Systemic, superior sagittal sinus and jugular vein blood samples were analysed for inflammatory cytokines and S100B. Intracranial pressure, brain tissue oxygenation and brain microdialysis were sampled every hour.ResultsNo differences in systemic or sagittal sinus levels of TNF-α or IL-6 were seen between the groups. The low tidal volume group had increased cerebral blood flow (p < 0.001) and cerebral oxygen delivery (p < 0.001), lower cerebral vascular resistance (p < 0.05), higher cerebral metabolic rate (p < 0.05) along with higher cerebral glucose consumption (p < 0.05) and lactate production (p < 0.05). Moreover, low tidal volume ventilation increased the levels of glutamate (p < 0.01), glycerol (p < 0.05) and showed a trend towards higher lactate to pyruvate ratio (p = 0.08) in cerebral microdialysate as well as higher levels of S-100B (p < 0.05) in jugular venous plasma compared with medium-high tidal volume ventilation.ConclusionsContrary to the hypothesis, protective ventilation did not affect inflammatory cytokines. The low tidal volume group had increased cerebral blood flow, cerebral oxygen delivery and cerebral metabolism together with increased levels of markers of brain injury compared with medium-high tidal volume ventilation.

Project description:BACKGROUND:The emergence of multi-drug resistant pathogens is an urgent health-related problem, and the appropriate use of antibiotics is imperative. It is often difficult to identify the causative bacteria in patients with aspiration pneumonia because tracheal aspirate contains contaminants of oral bacteria. We investigated the dynamics of microbiota in mechanically ventilated patients with aspiration pneumonia to develop a treatment strategy. METHODS:Twenty-two intubated patients with aspiration pneumonia were recruited. Saliva and tracheal aspirate of the subjects were collected at three time points: (A) within 2?h after intubation, (B) just before administration of antibiotics, and (C) 48-72?h after administration of antibiotics. The microbiota in each specimen was analyzed by using the 16S rRNA gene clone library sequencing method. Bacterial floras of the samples were analyzed by principal component analysis. RESULTS:Principal component analysis based on the composition of genus revealed that although the changes of microbiota in the saliva from (A) to (B) were not clear, the composition of anaerobes in the tracheal aspirate (B) was lower than (A). In fact, the reduction of anaerobes, not in the saliva but in the tracheal aspirate from (A) to (B), was confirmed by incident rate ratios estimated by a multilevel Poisson regression model (p?<?0.001). The extent of decrease in anaerobes was fully dependent on the time difference between the sampling of tracheal aspirate (A) and (B)-in particular, over 3?h of mechanical ventilation. This indicates that the alterations of microbiota (involving the reduction of anaerobes in the lower respiratory tract) occurred during mechanical ventilation prior to the administration of antibiotics. After the administration of antibiotics, Enterobacter spp., Corynebacterium spp., Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, and Granulicatera adiacens were predominantly detected in the tracheal aspirate (C). CONCLUSION:The microbiota of the lower respiratory tract changes dynamically during mechanical ventilation and during the administration of antibiotics in intubated patients with aspiration pneumonia. Antibiotics should be selected on the premise that dynamic changes in microbiota (involved in the reduction of anaerobes) may occur during the mechanical ventilation in these patients.

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Pre-exposure to mechanical ventilation and endotoxemia increases Pseudomonas aeruginosa growth in lung tissue during experimental porcine pneumonia.

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Pre-exposure to mechanical ventilation and endotoxemia increases Pseudomonas aeruginosa growth in lung tissue during experimental porcine pneumonia.

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