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

Abstract

Whether Candida within the patient microbiome drives the pathogenesis of Staphylococcus aureus bacteremia, described as microbial hitchhiking, cannot be directly studied. Group-level observations from studies of various decontamination and non-decontamination-based ICU infection prevention interventions and studies without study interventions (observational groups) collectively enable tests of this interaction within causal models. Candidate models of the propensity for Staphylococcus aureus bacteremia to arise with versus without various antibiotic, anti-septic, and antifungal exposures, each identified as singleton exposures, were tested using generalized structural equation modelling (GSEM) techniques with Candida and Staphylococcus aureus colonization appearing as latent variables within the models. Each model was tested by confrontation against blood and respiratory isolate data, obtained from 467 groups within 284 infection prevention studies. Introducing an interaction term between Candida colonization and Staphylococcus aureus colonization substantially improved GSEM model fit. Model-derived coefficients for singular exposure to anti-septic agents (− 1.28; 95% confidence interval; − 2.05 to − 0.5), amphotericin (− 1.49; − 2.3 to − 0.67), and topical antibiotic prophylaxis (TAP; + 0.93; + 0.15 to + 1.71) as direct effects versus Candida colonization were similar in magnitude but contrary in direction. By contrast, the coefficients for singleton exposure to TAP, as with anti-septic agents, versus Staphylococcus colonization were weaker or non-significant. Topical amphotericin would be predicted to halve both candidemia and Staphylococcus aureus bacteremia incidences versus literature derived benchmarks for absolute differences of < 1 percentage point. Using ICU infection prevention data, GSEM modelling validates the postulated interaction between Candida and Staphylococcus colonization facilitating bacteremia.

Rebound Inverts the Staphylococcus aureus Bacteremia Prevention Effect of Antibiotic Based Decontamination Interventions in ICU Cohorts with Prolonged Length of Stay

“…The high S. aureus VAP and S. aureus BSI incidences within the concurrent control groups of antibiotic-BDI studies noted here as a spill-over effect, which is as previously noted for several end points [8,[17][18][19]23,43,45,46], would conflate the apparent prevention effect.…”

“…Second, at the level of the ICU population, concerns for decontamination possibly 'driving' the emergence of both antimicrobial resistance and S. aureus and other Grampositive infections with its prolonged use in the ICU, and rebound colonization and in-fection on withdrawal of antibiotic-based decontamination interventions (BDIs), remain unresolved [15][16][17][18][19][20][21][22].…”

“…Thirdly, there is the unresolved issue of spillover effects to concurrent patients within the ICU not receiving decontamination which might also 'drive' event rates [17][18][19]. This is especially concerning for high quality studies of decontamination interventions with concurrent controls [23].…”

Establishing the safety of selective digestive decontamination within the ICU population: a bridge too far?

“…The few preclinical studies that are available to be cited as a basis for the SHEET study do not provide clarity on the balance between risks versus benefits. Potentially, exposure to TAP changes the microbiome of the ICU and increases the risk for invasive infections as a result of colonization susceptibility [ 103 – 106 ].…”

Using the interquartile range in infection prevention and control research

“…In our examination of original articles published in IPC journals, it is common to encounter the median along with the IQR, represented as Q1 and Q3, instead of in a single numerical value [ [1] , [2] , [3] , [4] , [5] , [6] ]. We believe that inclusion of the term “range” in IQR may potentially mislead researchers, leading to misconceptions about its true meaning.…”