Pneumonia can be acquired in the community such as COVID-19 or flu, or during hospitalization for a different medical condition.
The significant burden of CAP is set to increase with ageing populations and growing rates of comorbidity. CAP was the leading cause of communicable diseases and the second cause of disability-adjusted life-years loss in the world in 2019, even before the COVID-19 pandemic (GBD 2019 Adolescent Mortality Collaborators 2021; GBD 2019 Diseases and Injuries Collaborators 2020). CAP is classically induced by virulent bacteria (such as Streptococcus pneumoniae) or viruses (influenza), but also new pathogenic viruses such as SARS-CoV-2 (COVID-19).
Incidence of VAP ranges from 5% to 67% depending on case mix and diagnostic criteria. In the US, the incidence of VAP ranges from 2 to 16 episodes per 1,000 ventilator-day. The estimated risk of VAP is initially high and decreases to less than 0.5% per day after 14 days of mechanical ventilation. VAP increases the duration of hospitalization by 7 days and health-care costs by approximately $40,000 USD per episode (Safdar et al. 2005; Eber et al. 2010). Antimicrobial resistance is rising, leading to increased durations of hospital stay and excess deaths in septic patients worldwide. The World Health Organization considers antibiotic resistance to be one of the biggest global health threats we are currently facing. AMR, including malaria, tuberculosis and bacterial infections, may increase to 10 million fatalities worldwide by 2050. While some resistance is intrinsic in some bacterial taxa, the main issue is acquired resistance, as bacteria can exchange genetic material and thereby spread antibiotic resistance genes (ARG).
Previous carriage of extended-spectrum beta-lactamases-producing Enterobacterales (ESBL-E) is found in 5 to 25% of ICU patients. Although a previous carriage is the major risk factor associated with VAP related to ESBL-E, only 5% to 20% of the ESBL-E carriers will develop a VAP related to ESBL-E. Carriage status therefore has a high negative predictive value for ESBL-E-associated VAP, whereas positive predictive value, i.e., the probability of having an ESBL-E infection in case of ESBL-E carriage, is less than 50%.
When caring for patients with VAP, recent studies have shown that the adequacy of the initial antimicrobial therapy is not associated with a significant improvement of VAP prognosis, especially if a multidrug-resistant (MDR) Gram-negative bacterium is involved (Sommer et al. 2018; Titov et al. 2021). One likely explanation of the absence of benefit of adequate therapy within 24h is the rapid diffusion and expression of ARGs within the microbiome during treatment. It has been demonstrated the feasibility of characterizing lung microbiota by producing preliminary data from 174 respiratory samples collected in 65 patients included in the IBIS biobank within the IBIS cohort. These preliminary analyses have also confirmed that the respiratory microbiome of hospitalized patients shifts from a normal composition (day 1) to a specific pattern poor in Streptococcus and enriched in Haemophilus (day 7). Recently, it was observed in a randomized clinical trial that probiotics increase the ARG richness of the gut microbiome during antimicrobial treatment (Figure 2) (Montassier et al. 2021). These data demonstrated the ability to investigate the time course of ARG during treatment in human samples, and reinforce the hypothesis of rapid modifications of the ARG during treatment.
In summary, treatment failures are common in patients with CAP and HAP, even in cases of adequate antimicrobial therapy. Some specific antimicrobial therapies result in better outcomes than standard of cares and classical microbiology fail to explain this outcome.
Recent data demonstrated that the microbiome is a significant source of antibiotic resistance genes (ARG) which can rapidly be diffused between species during treatment.
In light of these preliminary results, we intend
1. to define VAP and CAP sub-phenotypes based on the real-time course of the load of ARG in vivo
2. to demonstrate in vivo that specific microbiome editing based on these phenotypes can enhance pneumonia outcomes.
The definition of these phenotypes of pneumonia is likely to impact the way patients are treated in daily practice, shifting the antimicrobial treatment from in vitro functional tests to in vivo prediction of response to treatment.
