Structural equation modelling the relationship between anti-fungal prophylaxis and Pseudomonas bacteremia in ICU patients

Abstract

Purpose Animal models implicate candida colonization facilitating invasive bacterial infections. The clinical relevance of this microbial interaction remains undefined and difficult to study directly. Observations from studies of anti-septic, antibiotic, anti-fungal, and non-decontamination-based interventions to prevent ICU acquired infection collectively serve as a natural experiment. Methods Three candidate generalized structural equation models (GSEM), with Candida and Pseudomonas colonization as latent variables, were confronted with blood culture and respiratory tract isolate data derived from 464 groups from 279 studies including studies of combined antibiotic and antifungal exposures within selective digestive decontamination (SDD) interventions. Results Introducing an interaction term between Candida colonization and Pseudomonas colonization substantially improved GSEM model fit. Model derived coefficients for singular exposure to anti-septic agents (− 1.23; − 2.1 to − 0.32), amphotericin (− 1.78; − 2.79 to − 0.78) and topical antibiotic prophylaxis (TAP; + 1.02; + 0.11 to + 1.93) versus Candida colonization were similar in magnitude but contrary in direction. By contrast, the model-derived coefficients for singular exposure to TAP, as with anti-septic agents, versus Pseudomonas colonization were weaker or non-significant. Singular exposure to amphotericin would be predicted to more than halve candidemia and Pseudomonas bacteremia incidences versus literature benchmarks for absolute differences of approximately one percentage point or less. Conclusion GSEM modelling of published data supports the postulated interaction between Candida and Pseudomonas colonization towards promoting bacteremia among ICU patients. This would be difficult to detect without GSEM modelling. The model indicates that anti-fungal agents have greater impact in preventing Pseudomonas bacteremia than TAP, which has no impact.

Staphylococcus aureus hitchhiking from colonization to bacteremia via Candida within ICU infection prevention studies: a proof of concept modelling

“…The literature search and study decant used here is as described previously [14] and is detailed in electronic supplementary material (ESM) Fig S1 Studies without ICU infection prevention interventions (observational studies) were sourced to provide incidence proportion data from which to derive external benchmarks. Most of the studies had been cited in systematic reviews with additional studies being found by snowball sampling using the "Related articles" function within Google Scholar.…”

“…The postulated "hitchhiking" and contextual exposures within the ICU environment as facilitators of Staphylococcal bacteremia could be posed as research questions versus other drivers of bacteremia within a causal model (Fig. 1) as has recently been demonstrated in the case of Candida facilitating Pseudomonas bacteremia [14]. Structural equation modelling (SEM) is an emerging method to test for potential causal relationships between multiple simultaneously observed variables mediated through latent variables [15][16][17].…”

Candida and the Gram-positive trio: testing the vibe in the ICU patient microbiome using structural equation modelling of literature derived data

“…For example, using an SEM approach, the interaction between Candida colonization emerges as a key driver of Pseudomonas invasive infections among 279 studies of infection prevention methods among ICU patients. Moreover, the relative impacts of specific anti-fungal agents on Pseudomonas bacteraemia can be estimated and compared [ 21 ].…”

“…The snowball sampling also identified additional eligible studies. The study decant used here is as described previously [ 21 ] and is detailed in Fig. 2 .…”

“…Of note, Topical antibiotic prophylaxis (TAP) based methods appear to be the most effective but these are always used in combination regimens together with an antifungal (termed selective digestive decontamination; SDD) due to their broad microbiome effects [ 12 , 16 ]. Yet surprisingly, the incidences of candidemia, VAP and bacteremia with Staphylococcus aureus, coagulase negative Staphylococci (CNS) and Enterococci are unusually high among studies of methods using TAP and moreso among the concurrent control groups of these studies [ 17 – 21 ]. These paradoxically high incidences are unexplained.…”