Ventilator-associated pneumonia (VAP) affects up to 20% of critically ill patients and induces significant antibiotic prescription pressure, accounting for half of all antibiotic use in the ICU. VAP significantly increases hospital length of stay and healthcare costs yet is also associated with long-term morbidity and mortality. The diagnosis of VAP continues to present challenges and pitfalls for the currently available clinical, radiological and microbiological diagnostic armamentarium. Biomarkers and artificial intelligence offer an innovative potential direction for ongoing future research. In this Review, we summarise the pathobiological heterogeneity and diagnostic challenges associated with VAP.

The optimal administration of polymyxins for treating multidrug-resistant gram-negative bacterial (MDR-GNB) pneumonia remains unclear. This study aimed to systematically assess the efficacy and safety of three polymyxin-containing regimens by conducting a comprehensive network meta-analysis.

We comprehensively searched nine databases. Overall mortality was the primary outcome, whereas the secondary outcomes encompassed microbial eradication rate, clinical success, acute kidney injury, and incidence of bronchospasm. Extracted study data were analyzed by pairwise and network meta-analyses. Version 2 of the Cochrane risk-of-bias tool and the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) assessment tool were used to assess the risk of bias in randomized trials and cohort studies, respectively.

This study included 19 observational studies and 3 randomized controlled trials (RCTs), encompassing 3318 patients. Six studies with high risk of bias were excluded from the primary analysis. In the pairwise meta-analysis, compared to the intravenous (IV) polymyxin-containing regimen, the intravenous plus inhaled (IV + IH) polymyxin-containing regimen showed a significant decrease in overall mortality, while no statistically significant difference was found in the inhaled (IH) polymyxin-containing regimen. The network meta-analysis indicated that the IV + IH polymyxin-containing regimen had significantly lower overall mortality (OR 0.67; 95% confidence interval [CI] 0.50-0.88), higher clinical success rate (OR 1.90; 95% CI 1.20-3.00), better microbial eradication rate (OR 2.70; 95% CI 1.90-3.90) than the IV polymyxin-containing regimen, and significantly better microbial eradication rate when compared with the IH polymyxin-containing regimen (OR 2.30; 95% CI 1.30-4.20). Furthermore, compared with IV + IH and IV polymyxin-containing regimens, the IH polymyxin-containing regimen showed a significant reduction in acute kidney injury.

Our study indicates that among the three administration regimens, the IV + IH polymyxin-containing regimen may be the most effective for treating MDR-GNB pneumonia, with a significantly lower overall mortality compared to the IV regimen and a considerably higher microbial eradication rate compared to the IH regimen. The IH regimen may be considered superior to the IV regimen due to its substantially lower incidence of acute kidney injury, even though the reduction in overall mortality was not significant.

Previous studies have questioned the efficacy and safety of intravenous combined with aerosolised (IV + AS) polymyxin versus intravenous (IV) polymyxin alone in the treatment of patients with multidrug-resistant gram-negative bacterial (MDR-GNB) pneumonia. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of IV + AS polymyxin in the treatment of MDR-GNB pneumonia.

We identified all relevant studies by searching the PubMed, EMBASE and Cochrane library databases from their inception to May 31, 2022. All included studies were evaluated using the Newcastle Ottawa scale (NOS) checklist. The summary relative risk (RR) and 95% confidence interval (CI) were used to determine the outcome differences between the IV + AS and the IV groups. Subgroup analysis was performed based on population, polymyxin dose and kinds of polymyxin.

A total of 16 studies were included in the meta-analysis. The IV + AS group had lower mortality (RR = 0.86, 95% CI: 0.77-0.97, P = 0.01) than the IV group. Subgroup analysis revealed that IV + AS polymyxin could reduce mortality only when used in low doses. Simultaneously, the IV + AS group outperformed the IV group in terms of clinical response rate, clinical cure rate, microbiological eradication and duration of mechanical ventilation. The duration of hospitalisation and the incidence of nephrotoxicity did not differ significantly between the two groups.

IV + AS polymyxin is beneficial in the treatment of MDR-GNB pneumonia. It could lower patient mortality and improve clinical and microbial outcomes without increasing the risk of nephrotoxicity. However, retrospective analysis in the majority of studies and heterogeneity between studies implies that our findings must be interpreted carefully.

For ventilator-associated pneumonia (VAP), the safety of short-course versus long-course antibiotic therapy is still debated, especially regarding documented VAP due to non-fermenting Gram-negative bacilli (NF-GNB). The aim of this meta-analysis was to assess the rates of recurrence and relapse of VAP in patients receiving short-course (≤8 days) and long-course (≥10-15 days) of antibiotic therapy.

The protocol for this study was registered in the PROSPERO database (ID: CRD42022365138). We performed an electronic search of the relevant literature and limited our search to data published from 2000 until September 1, 2022. We searched for randomized controlled trials (RCTs) in the United States National Library of Medicine, Cochrane Database of Systematic Reviews (CDSR) and the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, National Institutes of Health PubMed/MEDLINE, web of science and Google Scholar databases. The primary endpoint was the recurrence and relapses of VAP, secondary endpoints were 28-day mortality, mechanical ventilation duration, number of extra-pulmonary infections and length of ICU stay.

We identified five relevant studies involving 1069 patients (530 patients in the short-course group and 539 patients in the long-course group). The meta-analysis did not reveal any significant difference between short and long-course antibiotic therapy for recurrence and relapses of VAP (odd ratio "OR" = 1.48, 95% confidence intervals (CI) [0.96, 2.28], p = 0.08 and OR = 1.45, 95% CI [0.94, 2.22], p = 0.09, respectively), including those due to NF-GNB (OR = 1.90, 95% CI [0.93, 3.33], p = 0.05 and OR = 1.76, 95% CI [0.93, 3.33], p = 0.08, respectively). No difference was found for 28 days-mortality (OR = 1.24, 95% CI [0.92, 1.67], p = 0.16), mechanical ventilation duration, number of extra-pulmonary infections and length of ICU stay. However, short-course therapy significantly increased the number of antibiotic-free days.

Our meta-analysis showed that short-course antibiotic therapy did not result in increased number of recurence and relapses of VAP, suggesting that short-course should be preferred to reduce the exposure to antibiotics.

None.

Phage therapy of ventilator-associated pneumonia (VAP) is of great interest due to the rising incidence of multidrug-resistant bacterial pathogens. However, natural or therapy-induced immunity against therapeutic phages remains a potential concern. In this study, we investigated the innate and adaptive immune responses to two different phage cocktails targeting either Pseudomonas aeruginosa or Escherichia coli-two VAP-associated pathogens-in naïve mice without the confounding effects of a bacterial infection. Active or UV-inactivated phage cocktails or buffers were injected intraperitoneally daily for 7 days in C57BL/6J wild-type mice. Blood cell analysis, flow cytometry analysis, assessment of phage distribution and histopathological analysis of spleens were performed at 6 h, 10 days and 21 days after treatment start. Phages reached the lungs and although the phage cocktails were slightly immunogenic, phage injections were well tolerated without obvious adverse effects. No signs of activation of innate or adaptive immune cells were observed; however, both active phage cocktails elicited a minimal humoral response with secretion of phage-specific antibodies. Our findings show that even repetitive injections lead only to a minimal innate and adaptive immune response in naïve mice and suggest that systemic phage treatment is thus potentially suitable for treating bacterial lung infections.

Introduction: Understanding the factors associated with the development of ventilator-associated pneumonia (VAP) in critically ill patients in the intensive care unit (ICU) will allow for better prevention and control of VAP. The aim of the study was to evaluate the incidence of VAP, as well as to determine risk factors and protective factors against VAP. Design: Mixed prospective and retrospective cohort study. Methods: The cohort involved 371 critically ill patients who received standard interventions to prevent VAP. Additionally, patients in the prospective cohort were provided with continuous automatic pressure control in tapered cuffs of endotracheal or tracheostomy tubes and continuous automatic subglottic secretion suction. Logistic regression was used to assess factors affecting VAP. Results: 52 (14%) patients developed VAP, and the incidence density of VAP per 1000 ventilator days was 9.7. The median days to onset of VAP was 7 [4; 13]. Early and late onset VAP was 6.2% and 7.8%, respectively. According to multivariable logistic regression analysis, tracheotomy (OR = 1.6; CI 95%: 1.1 to 2.31), multidrug-resistant bacteria isolated in the culture of lower respiratory secretions (OR = 2.73; Cl 95%: 1.83 to 4.07) and ICU length of stay >5 days (OR = 3.32; Cl 95%: 1.53 to 7.19) were positively correlated with VAP, while continuous control of cuff pressure and subglottic secretion suction used together were negatively correlated with VAP (OR = 0.61; Cl 95%: 0.43 to 0.87). Conclusions: Tracheotomy, multidrug-resistant bacteria, and ICU length of stay >5 days were independent risk factors of VAP, whereas continuous control of cuff pressure and subglottic secretion suction used together were protective factors against VAP.