Rigorous antibiotic stewardship in the hospitalized elderly population: saving lives and decreasing cost of inpatient care.

BACKGROUND: There is limited literature evaluating the effect of antibiotic stewardship programmes (ASPs) in hospitalized geriatric patients, who are at higher risk for readmissions, developing Clostridioides difficile infection (CDI) or other adverse outcomes secondary to antibiotic treatments. METHODS: In this cohort study we compare the rates of 30 day hospital readmissions because of reinfection or development of CDI in patients 65 years and older who received ASP interventions between January and June 2017. We also assessed their mortality rates and length of stay. Patients were included if they received antibiotics for pneumonia, urinary tract infection, acute bacterial skin and skin structure infection or complicated intra-abdominal infection. The ASP team reviewed patients on antibiotics daily. ASP interventions included de-escalation of empirical or definitive therapy, change in duration of therapy or discontinuation of therapy. Treatment failure was defined as readmission because of reinfection or a new infection. A control group of patients 65 years and older who received antibiotics between January and June 2015 (pre-ASP) was analysed for comparison. RESULTS: We demonstrated that the 30 day hospital readmission rate for all infection types decreased during the ASP intervention period from 24.9% to 9.3%, P < 0.001. The rate of 30 day readmissions because of CDI decreased during the intervention period from 2.4% to 0.30%, P = 0.02. Mortality in the cohort that underwent ASP interventions decreased from 9.6% to 5.4%, P = 0.03. Lastly, antibiotic expenditure decreased after implementation of the ASP from $23.3 to $4.3 per adjusted patient day, in just 6 months. CONCLUSIONS: Rigorous de-escalation and curtailing of antibiotic therapies were beneficial and without risk for the hospitalized patients 65 years and over.

Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study.

BACKGROUND: Tocilizumab, a monoclonal antibody directed against the interleukin-6 receptor, has been proposed to mitigate the cytokine storm syndrome associated with severe COVID-19. We aimed to investigate the association between tocilizumab exposure and hospital-related mortality among patients requiring intensive care unit (ICU) support for COVID-19. METHODS: We did a retrospective observational cohort study at 13 hospitals within the Hackensack Meridian Health network (NJ, USA). We included patients (aged ≥18 years) with laboratory-confirmed COVID-19 who needed support in the ICU. We obtained data from a prospective observational database and compared outcomes in patients who received tocilizumab with those who did not. We applied a multivariable Cox model with propensity score matching to reduce confounding effects. The primary endpoint was hospital-related mortality. The prospective observational database is registered on ClinicalTrials.gov, NCT04347993. FINDINGS: Between March 1 and April 22, 2020, 764 patients with COVID-19 required support in the ICU, of whom 210 (27%) received tocilizumab. Factors associated with receiving tocilizumab were patients' age, gender, renal function, and treatment location. 630 patients were included in the propensity score-matched population, of whom 210 received tocilizumab and 420 did not receive tocilizumab. 358 (57%) of 630 patients died, 102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. Overall median survival from time of admission was not reached (95% CI 23 days-not reached) among patients receiving tocilizumab and was 19 days (16-26) for those who did not receive tocilizumab (hazard ratio [HR] 0·71, 95% CI 0·56-0·89; p=0·0027). In the primary multivariable Cox regression analysis with propensity matching, an association was noted between receiving tocilizumab and decreased hospital-related mortality (HR 0·64, 95% CI 0·47-0·87; p=0·0040). Similar associations with tocilizumab were noted among subgroups requiring mechanical ventilatory support and with baseline C-reactive protein of 15 mg/dL or higher. INTERPRETATION: In this observational study, patients with COVID-19 requiring ICU support who received tocilizumab had reduced mortality. Results of ongoing randomised controlled trials are awaited. FUNDING: None.

Rescue of CD8 T cell-mediated antimicrobial immunity with a nonspecific inflammatory stimulus.

Reconstitution of protective immunity by adoptive transfer of pathogen-specific T cells has been successful in patients with compromised cellular immunity. The in vivo effectiveness of in vitro-expanded CD8 CTLs is variable, however. For example, adoptively transferred Listeria monocytogenes-specific CD8 CTLs only confer protective immunity if challenge infection occurs within 48 hours of T cell infusion. Herein we show that transferred CTLs persist in lymphoid compartments for many weeks, but that their response to bacterial challenge decreases during the first week following transfer. While T cells transferred less than 48 hours before infection proliferate, those transferred 7 days before infection die. Remarkably, treatment of mice with anti-CD40 at the time of T cell infusion reprograms transferred T cells, allowing them to proliferate and confer protective immunity upon bacterial challenge 7 days later. Our study demonstrates, for the first time to our knowledge that CD40-mediated stimuli can influence CD8 T cell activation independent of concurrent antigen exposure. The ability to modulate long-term responsiveness of CD8 T cells with a transient, nonspecific inflammatory stimulus has importation implications for adoptive immunotherapy.

Homeostasis of naïve, effector and memory CD8 T cells.

Homeostatic control of CD8 T cell populations is essential for defense against infectious pathogens. Our understanding of the mechanisms that control naïve, effector and memory T cell populations in the intact animal has increased significantly over the last several years. There have been some surprises. For example, peripheral tissues have been found to harbor unexpectedly large numbers of effector memory T cells. Also unexpected was the finding of programmed T cell proliferation following very brief exposure to antigen. These and other recent advances are summarized in the following review.