Urinary Tract Infections in Long-term Care: Evaluation of Uropathogens, Antibiotic Susceptibility, and Empiric Treatment.

Objective To devise a residential empiric treatment algorithm, describe common uropathogens associated with urinary tract infections (UTIs) in residential care, assess all-pathogen and non-ESBL (extended-spectrum beta-lactamase) Escherichia coli antibiotic susceptibilities, and report the percentage of antibiotic use. Design A retrospective chart review of 198 residents with positive urine cultures from September 2019 to September 2020. Setting Institutional long-term care facility. Participants The exclusion criteria were negative urine culture, mixed organisms on urine culture, no antibiotic treatment, signs and symptoms of systemic infection, hospitalization because of systemic infection, and intravenous antibiotic treatment. The entire population was screened. Results The most prevalent pathogens were non-ESBL E. coli (29%), Proteus mirabilis (12%), Klebsiella pneumoniae (8%), and ESBL E. coli (8%). All-pathogen susceptibilities were 79.6% (amoxicillin/clavulanate), 64.1% (nitrofurantoin), 50.5% (sulfamethoxazole/trimethoprim), 43.7% (cephalexin), 42.7% (amoxicillin), and 41.8% (ciprofloxacin). Amoxicillin/clavulanate (96.7%), nitrofurantoin (90.0%) and sulfamethoxazole/trimethoprim (83.3%) demonstrated the highest non-ESBL E. coli susceptibilities. Nitrofurantoin was the most prescribed antibiotic (21%), followed by amoxicillin/clavulanate (19%) and ciprofloxacin (17%). Conclusion Based on the data, amoxicillin/clavulanate and nitrofurantoin are appropriate first-line options for empiric treatment of symptomatic cystitis in this long-term care facility, with sulfamethoxazole/trimethoprim as an alternative. Ciprofloxacin was overprescribed despite its low susceptibilities to commonly encountered pathogens, which emphasizes the need for a UTI empiric treatment algorithm tailored towards residential care.

Immunisation with the BCG and DTPw vaccines induces different programs of trained immunity in mice.

In addition to providing pathogen-specific immunity, vaccines can also confer nonspecific effects (NSEs) on mortality and morbidity unrelated to the targeted disease. Immunisation with live vaccines, such as the BCG vaccine, has generally been associated with significantly reduced all-cause infant mortality. In contrast, some inactivated vaccines, such as the diphtheria, tetanus, whole-cell pertussis (DTPw) vaccine, have been controversially associated with increased all-cause mortality especially in female infants in high-mortality settings. The NSEs associated with BCG have been attributed, in part, to the induction of trained immunity, an epigenetic and metabolic reprograming of innate immune cells, increasing their responsiveness to subsequent microbial encounters. Whether non-live vaccines such as DTPw induce trained immunity is currently poorly understood. Here, we report that immunisation of mice with DTPw induced a unique program of trained immunity in comparison to BCG immunised mice. Altered monocyte and DC cytokine responses were evident in DTPw immunised mice even months after vaccination. Furthermore, splenic cDCs from DTPw immunised mice had altered chromatin accessibility at loci involved in immunity and metabolism, suggesting that these changes were epigenetically mediated. Interestingly, changing the order in which the BCG and DTPw vaccines were co-administered to mice altered subsequent trained immune responses. Given these differences in trained immunity, we also assessed whether administration of these vaccines altered susceptibility to sepsis in two different mouse models. Immunisation with either BCG or a DTPw-containing vaccine prior to the induction of sepsis did not significantly alter survival. Further studies are now needed to more fully investigate the potential consequences of DTPw induced trained immunity in different contexts and to assess whether other non-live vaccines also induce similar changes.

BCG vaccination-induced emergency granulopoiesis provides rapid protection from neonatal sepsis.

Death from sepsis in the neonatal period remains a serious threat for millions. Within 3 days of administration, bacille Calmette-Guérin (BCG) vaccination can reduce mortality from neonatal sepsis in human newborns, but the underlying mechanism for this rapid protection is unknown. We found that BCG was also protective in a mouse model of neonatal polymicrobial sepsis, where it induced granulocyte colony-stimulating factor (G-CSF) within hours of administration. This was necessary and sufficient to drive emergency granulopoiesis (EG), resulting in a marked increase in neutrophils. This increase in neutrophils was directly and quantitatively responsible for protection from sepsis. Rapid induction of EG after BCG administration also occurred in three independent cohorts of human neonates.

Energy Demands of Early Life Drive a Disease Tolerant Phenotype and Dictate Outcome in Neonatal Bacterial Sepsis.

Bacterial sepsis is one of the leading causes of death in newborns. In the face of growing antibiotic resistance, it is crucial to understand the pathology behind the disease in order to develop effective interventions. Neonatal susceptibility to sepsis can no longer be attributed to simple immune immaturity in the face of mounting evidence that the neonatal immune system is tightly regulated and well controlled. The neonatal immune response is consistent with a "disease tolerance" defense strategy (minimizing harm from immunopathology) whereas adults tend toward a "disease resistance" strategy (minimizing harm from pathogens). One major advantage of disease tolerance is that is less energetically demanding than disease resistance, consistent with the energetic limitations of early life. Immune effector cells enacting disease resistance responses switch to aerobic glycolysis upon TLR stimulation and require steady glycolytic flux to maintain the inflammatory phenotype. Rapid and intense upregulation of glucose uptake by immune cells necessitates an increased reliance on fatty acid metabolism to (a) fuel vital tissue function and (b) produce immunoregulatory intermediates which help control the magnitude of inflammation. Increasing disease resistance requires more energy: while adults have fat and protein stores to catabolize, neonates must reallocate resources away from critical growth and development. This understanding of sepsis pathology helps to explain many of the differences between neonatal and adult immune responses. Taking into account the central role of metabolism in the host response to infection and the severe metabolic demands of early life, it emerges that the striking clinical susceptibility to bacterial infection of the newborn is at its core a problem of metabolism. The evidence supporting this novel hypothesis, which has profound implications for interventions, is presented in this review.