Prospective Validation of the "Shamir Resistance Calculator": an Interventional Crossover Trial to Improve Empiric Prescription of Antimicrobials in Acute Care Hospitals.

2.1 List the clinical hypotheses.

• Primary hypothesis: The "Shamir Resistance Calculator" will shorten the time to initiation of appropriate antimicrobials among hospitalized septic patients.
• Secondary hypotheses: The "Shamir Resistance Calculator" will reduce the rate of new MDRO acquisitions, will reduce the empiric usage of broad-spectrum agents, will reduce the incidences of acute Clostridiodes difficile infections, and will reduce the in-hospital mortality rates among hospitalized septic patients.

2.2 Background & Rationale, Significance of Selected Topic & Preliminary Data

The world health organization (WHO) had declared that the issue of resistance to multiple antimicrobials, is one of the current and future biggest challenges and threats to human health.

• Multi-drug resistant organisms (MDRO) and extensively drug resistant organisms (XDRO) are prevalent in hospitals, in acute care settings, and also in the community.2
• The outcomes of infections caused by MDROs and XDROs are worse in comparison to susceptible organisms, mainly due to delay in initiation of appropriate antimicrobial therapy (DAAT) in those infections.3
• DAAT is the strongest independent modifiable predictor for mortality among patients with severe infections.3
• Therefore, it is of paramount importance to avoid and shorten DAAT among hospitalized septic patients.
• However, empirically prescribing unnecessary broad-spectrum agents, to patients with infections resulting from susceptible organisms, increases the burden of resistances and costs to the facility.
• Moreover, narrow-spectrum agents are frequently more potent vs. susceptible organisms (e.g., cefazolin vs. vancomycin for methicillin-susceptible Staphylococcus aureus infection4), and are frequently less toxic (e.g., colistin, vancomycin).4-6
• There are two time points, where the majority of empiric prescription errors and DAAT frequently occurs among hospitalized adults: 1) upon admission (UA) while attending patients at risk of MDRO infection, and 2) during hospitalization, while attending patients at risk of XDRO infection (MDRO are usually covered empirically in nosocomial sepsis).6
• At the first encounter with a septic patient, the primary physician needs a simple and reliable tool to be used bedside, in order to tailor an appropriate empiric antimicrobial regimen.
• Many previous attempts to develop such scores, failed to become a standard of practice, for multiple and various reasons,7-10 lacking the size and the comprehensiveness to address the whole spectrum of clinical issues and decisions.
• We developed an on-line calculator (https://assafharofe.azurewebsites.net), which is free and accessible from all devices, in order to predict the risk of MDRO infection upon admission, and the risk of nosocomial XDRO infection during the hospitalization.11
• The calculator contains only parameters that could be extracted bedside, at the first presentation of a septic patient, including the ability to conduct a complete assessment also among patients with reduced consciousness and/or cognition.
• The study that was executed in order to develop the "Shamir Resistance Calculator", which was recently published in Infection Control and Hospital Epidemiology,11 was a large study that included 4,114 patients: 2,472 patients with sepsis upon admission and 1,642 patients with nosocomial sepsis. This as far as we know, is the largest trial ever published in this field of research.
• Moreover, the calculator performances were very encouraging. The MDRO upon admission score included 10 parameters, and with a cutoff of ≥22 points, it had a ROC AUC of 0.85. The nosocomial XDRO score included 7 parameters, and with a cutoff of ≥36 points, it had a ROC AUC of 0.87.
• However, the main limitation of the on-line calculator, remains the lack of prospective data that trialed the performances of the calculator prospectively, on hard hospitalization's outcomes.
• Therefore, our goal is to trial the calculator prospectively, using the cluster randomized crossover design, which is considered today the gold standard methodology in terms of interventional studies in the field of hospital epidemiology.12