Background There is a paucity of data on the effect of early de-escalation of antimicrobial therapy on rates of Clostridioides difficile infection (CDI). This retrospective cohort study evaluated impact of de-escalation from antipseudomonal β-lactam (APBL) therapy within 48 hours of Enterobacteriaceae bloodstream infections (BSIs) on 90-day risk of CDI. Methods Adult patients hospitalized for >48 hours for treatment of Enterobacteriaceae BSI at Palmetto Health hospitals in Columbia, South Carolina, from 1 January 2011 through 30 June 2015 were identified. Multivariable Cox proportional hazards regression was used to examine time to CDI in patients who received >48 hours or ≤48 hours of APBL for empirical therapy of Enterobacteriaceae BSI after adjustment for the propensity to receive >48 hours of APBL. Results Among 808 patients with Enterobacteriaceae BSI, 414 and 394 received >48 and ≤48 hours of APBL, respectively. Incidence of CDI was higher in patients who received >48 hours than those who received ≤48 hours of APBL (7.0% vs 1.8%; log-rank P = .002). After adjustment for propensity to receive >48 hours of APBL and other variables in the multivariable model, receipt of >48 hours of APBL (hazard ratio [HR], 3.56 [95% confidence interval {CI}, 1.48–9.92]; P = .004) and end-stage renal disease (HR, 4.27 [95% CI, 1.89–9.11]; P = .001) were independently associated with higher risk of CDI. Conclusions The empirical use of APBL for >48 hours was an independent risk factor for CDI. Early de-escalation of APBL using clinical risk assessment tools or rapid diagnostic testing may reduce the incidence of CDI in hospitalized adults with Enterobacteriaceae BSIs.
All-trans-retinoic acid (ATRA) induces growth arrest of many cell types. Previous studies have reported that ATRA can modulate cellular sphingolipids, but the role of sphingolipids in the ATRA response is not clear. Using MCF-7 cells as a model system, we show that ATRA stimulates an increase in ceramide levels followed by G 0 /G 1 growth arrest. Notably, induction of nSMase2 was the primary effect of ATRA on the sphingolipid network and was both time-and dose-dependent. Importantly, pretreatment with nSMase2 siRNA significantly inhibited ATRA effects on ceramide levels and growth arrest. In contrast, nSMase2 overexpression was sufficient to increase ceramide levels and induce G 0 /G 1 growth arrest of asynchronous MCF-7 cells. Surprisingly, neither ATRA stimulation nor nSMase2 overexpression had significant effects on classical cell cycle regulators such as p21/WAF1 or retinoblastoma. In contrast, ATRA suppressed phosphorylation of ribosomal S6 kinase (S6K) and its downstream targets S6 and eIF4B. Importantly, these effects were significantly inhibited by nSMase2 siRNA. Reciprocally, nSMase2 overexpression was sufficient to suppress S6K phosphorylation and signaling. Notably, neither ATRA effects nor nSMase2 effects on S6K phosphorylation required the ceramide-activated protein phosphatase PP2A, previously identified as important for S6K regulation. Finally, nSMase2 overexpression was sufficient to decrease translation as measured by methionine incorporation and analysis of polyribosome profiles. Taken together, these results implicate nSMase2 as a major component of ATRA-induced growth arrest of MCF-7 cells and identify S6K as a novel downstream target of nSMase2.Sphingolipids such as ceramide (Cer) 2 are a class of bioactive lipids implicated in a variety of physiological processes. In particular, Cer is thought to be involved in apoptosis, inflammation, and the cellular response to cytokines and other stresses (1). Cer production can occur through multiple pathways and is under tight control within the cell. Sphingomyelinases (SMases) produce Cer through hydrolysis of sphingomyelin and are considered important mediators of stress-induced Cer production (2). Currently, three families of SMases have been identified and are classified by the pH optima of their activity. Of these, both acid and neutral SMases (N-SMases) have been reported to contribute to stress and cytokine-induced Cer production (2, 3).Currently, four mammalian N-SMases have been cloned and characterized: nSMase1, nSMase2, nSMase3, and the recently identified mitochondria-associated nSMase. Of these, studies have implicated nSMase2 in the acute responses to cytokines, chemotherapeutic drugs, and oxidative stress (2). Importantly, emerging evidence is beginning to suggest a more protracted mode of nSMase2 regulation involving changes in nSMase2 gene expression. For example, increased nSMase2 expression has been demonstrated in confluence-induced growth arrest of MCF-7 cells (4) and in rat 3Y1 cells where the CCA1 gene (for cell confluence arr...
Objective: To review the use of antibiotic stewardship interventions in the adult oncology and hematopoietic cell transplantation (HCT) populations. Data Sources: A literature search of PubMed was performed from inception to October 31, 2019. The general search terms used were oncology, cancer, hematologic malignancy, antimicrobial stewardship, antibiotic stewardship, febrile neutropenia, neutropenic fever, de-escalation, discontinuation, prophylaxis, practice guidelines, clinical pathway, rapid diagnostics, Filmarray, Verigene, MALDI-TOF, antibiotic allergy, and antimicrobial resistance. Study Selection and Data Extraction: Relevant English-language studies describing interventions supported by the Infectious Diseases Society of America guidelines on “Implementing an Antibiotic Stewardship Program” were included. Data Synthesis: Antibiotic stewardship publications in the oncology population have increased in recent years. Studies have described the impact of stewardship interventions, including preauthorization, prospective audit and feedback, implementation of clinical pathways, de-escalation of empirical antibiotics for febrile neutropenia (FN) prior to neutrophil recovery, allergy assessments, and use of rapid diagnostic testing. Many of these interventions have been shown to decrease antibiotic use without increased negative consequences, such as affecting length of stay or mortality. Relevance to Patient Care and Clinical Practice: This review synthesizes available evidence for implementing antibiotic stewardship interventions, particularly de-escalation of antibiotics for FN and implementation of clinical pathways for FN and sepsis, in oncology patients and HCT recipients. Summary tables highlight studies and specific research needs for clinicians. Conclusions: Immunocompromised populations, including oncology patients, have often been excluded from stewardship studies. Antibiotic stewardship is effective in reducing antibiotic consumption and improving outcomes in this patient population, although more quality data are needed.
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