A "resistance calculator": Simple stewardship intervention for refining empiric practices of antimicrobials in acute-care hospitals.

OBJECTIVE: In the era of widespread resistance, there are 2 time points at which most empiric prescription errors occur among hospitalized adults: (1) upon admission (UA) when treating patients at risk of multidrug-resistant organisms (MDROs) and (2) during hospitalization, when treating patients at risk of extensively drug-resistant organisms (XDROs). These errors adversely influence patient outcomes and the hospital's ecology. DESIGN AND SETTING: Retrospective cohort study, Shamir Medical Center, Israel, 2016. PATIENTS: Adult patients (aged >18 years) hospitalized with sepsis. METHODS: Logistic regressions were used to develop predictive models for (1) MDRO UA and (2) nosocomial XDRO. Their performances on the derivation data sets, and on 7 other validation data sets, were assessed using the area under the receiver operating characteristic curve (ROC AUC). RESULTS: In total, 4,114 patients were included: 2,472 patients with sepsis UA and 1,642 with nosocomial sepsis. The MDRO UA score included 10 parameters, and with a cutoff of ≥22 points, it had an ROC AUC of 0.85. The nosocomial XDRO score included 7 parameters, and with a cutoff of ≥36 points, it had an ROC AUC of 0.87. The range of ROC AUCs for the validation data sets was 0.7-0.88 for the MDRO UA score and was 0.66-0.75 for nosocomial XDRO score. We created a free web calculator (https://assafharofe.azurewebsites.net). CONCLUSIONS: A simple electronic calculator could aid with empiric prescription during an encounter with a septic patient. Future implementation studies are needed to evaluate its utility in improving patient outcomes and in reducing overall resistances.

Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome.

BACKGROUND: Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor excision, but underlying mechanisms are elusive. Here, we present a model of regression and latency of metastases following primary tumor excision and identify potential underlying mechanisms. RESULTS: Using MDA-MB-231HM human breast cancer cells that express highly sensitive luciferase, we monitored early development stages of spontaneous metastases in BALB/c nu/nu mice. Removal of the primary tumor caused marked regression of micro-metastases, but not of larger metastases, and in vivo supplementation of tumor secretome diminished this regression, suggesting that primary tumor-secreted factors promote early metastatic growth. Correspondingly, MDA-MB-231HM-conditioned medium increased in vitro tumor proliferation and adhesion and reduced apoptosis. To identify specific mediating factors, cytokine array and proteomic analysis of MDA-MB-231HM secretome were conducted. The results identified significant enrichment of angiogenesis, growth factor binding and activity, focal adhesion, and metalloprotease and apoptosis regulation processes. Neutralization of MDA-MB-231HM-secreted key mediators of these processes, IL-8, PDGF-AA, Serpin E1 (PAI-1), and MIF, each antagonized secretome-induced proliferation. Moreover, their in vivo simultaneous blockade in the presence of the primary tumor arrested the development of micro-metastases. Interestingly, in the METABRIC cohort of breast cancer patients, elevated expression of Serpin E1, IL-8, or the four factors combined predicted poor survival. CONCLUSIONS: These results demonstrate regression and latency of micro-metastases following primary tumor excision and a crucial role for primary tumor secretome in promoting early metastatic growth in MDA-MB-231HM xenografts. If generalized, such findings can suggest novel approaches to control micro-metastases and minimal residual disease.