Empiric combination therapy for gram-negative bacteremia.

BACKGROUND: Empirical combination antibiotic regimens consisting of a ß-lactam and an aminoglycoside are frequently employed in the pediatric population. Data to demonstrate the comparative benefit of empirical ß-lactam combination therapy relative to monotherapy for culture-proven Gram-negative bacteremia are lacking in the pediatric population. METHODS: We conducted a retrospective cohort study of children treated for Gram-negative bacteremia at The Johns Hopkins Hospital from 2004 through 2012. We compared the estimated odds of 10-day mortality and the relative duration of bacteremia for children receiving empirical combination therapy versus empirical monotherapy using 1:1 nearest-neighbor propensity-score matching without replacement, before performing regression analysis. RESULTS: We identified 226 matched pairs of patients well balanced on baseline covariates. Ten-day mortality was similar between the groups (odds ratio, 0.84; 95% confidence interval [CI], 0.28 to 1.71). Use of empirical combination therapy was not associated with a decrease in the duration of bacteremia (-0.51 days; 95% CI, -2.22 to 1.48 days). There was no survival benefit when evaluating 10-day mortality for the severely ill (pediatric risk of mortality III score ≥15) or profoundly neutropenic patients (absolute neutrophil count ≤100 cells/mL) receiving combination therapy. However, a survival benefit was observed when empirical combination therapy was prescribed for children growing multidrug-resistant Gram-negative organisms from the bloodstream (odds ratio, 0.70; 95% CI, 0.51 to 0.84). CONCLUSIONS: Although there appears to be no advantage to the routine addition of an aminoglycoside to a ß-lactam as empirical therapy for children who have Gram-negative bacteremia, children who have risk factors for MDRGN organisms appear to benefit from this practice.

Sustained savings from a longitudinal cost analysis of an internet-based preapproval antimicrobial stewardship program.

OBJECTIVE: To evaluate an internet-based preapproval antimicrobial stewardship program for sustained reduction in antimicrobial prescribing and resulting cost savings. DESIGN: Retrospective cohort study and cost analysis. METHODS: Review of all doses and charges of antimicrobials dispensed to patients over 6 years (July 1, 2005-June 30, 2011) at a tertiary care pediatric hospital. RESULTS: Restricted antimicrobials account for 26% of total doses but 81% of total antimicrobial charges. Winter months (November-February) and the oncology and infant and toddler units were associated with the highest antimicrobial charges. Five restricted drugs accounted for the majority (54%) of charges but only 6% of doses. With an average approval rate of 91.5% (95% confidence interval [CI], 91.1%-91.9%), the preapproval antibiotic stewardship program saved $103,787 (95% CI, $98,583-$109,172) per year, or $14,156 (95% CI, $13,446-$14,890) per 1,000 patient-days. CONCLUSIONS: A preapproval antimicrobial stewardship program effectively reduces the number of doses and subsequent charges due to restricted antimicrobials years after implementation. Hospitals with reduced resources for implementing postprescription review may benefit from a preapproval antimicrobial stewardship program. Targeting specific units, drugs, and seasons may optimize preapproval programs for additional cost savings.

Oxidative stress modulates complement factor H expression in retinal pigmented epithelial cells by acetylation of FOXO3.

Age-related macular degeneration (AMD), the leading cause of severe vision loss in the elderly, is a complex disease that results from genetic modifications that increase susceptibility to environmental exposures. Smoking, a major source of oxidative stress, increases the incidence and severity of AMD, and antioxidants slow progression, suggesting that oxidative stress plays a major role. Polymorphisms in the complement factor H (CFH) gene that reduce activity of CFH increase the risk of AMD. In this study we demonstrate an interaction between these two risk factors, because oxidative stress reduces the ability of an inflammatory cytokine, interferon-gamma, to increase CFH expression in retinal pigmented epithelial cells. The interferon-gamma-induced increase in CFH is mediated by transcriptional activation by STAT1, and its suppression by oxidative stress is mediated by acetylation of FOXO3, which enhances FOXO3 binding to the CFH promoter, reduces its binding to STAT1, inhibits STAT1 interaction with the CFH promoter, and reduces expression of CFH. Expression of SIRT1, a mammalian homolog of NAD-dependent protein deacetylase sir2, attenuated FOXO3 recruitment to the CFH regulatory region and reversed the H(2)O(2)-induced repression of CFH gene expression. These data suggest an important interaction between environmental exposure and genetic susceptibility in the pathogenesis of AMD and, by elucidating molecular signaling involved in the interaction, provide potential targets for therapeutic intervention.

Reduction of p66Shc suppresses oxidative damage in retinal pigmented epithelial cells and retina.

The largest isoform of the Shc adapter protein, p66Shc, has been implicated in oxidative damage-induced apoptosis in vital organs, because mice deficient in p66Shc have a 30% increase in life span and are resistant to the lethal effects of systemically administered paraquat, a source of severe oxidative damage. In this study, we utilized siRNA directed against the CH2 domain of Shc, to reduce p66Shc, but not p52Shc nor p46Shc in retinal pigmented epithelial (RPE) cells. RPE cells deficient in p66Shc had reduced susceptibility to oxidative stress-induced apoptosis. Compared to control cells, those with reduced p66Shc had increased basal and oxidative stress-induced NF-kappaB transcriptional activity, increased levels of antioxidant enzymes, and less generation of reactive oxygen species when challenged with H(2)O(2). The increase in oxidative stress-induced NF-kappaB activity was mediated by activation of ERK. Compared to eyes injected with GFP siRNA, those injected with p66Shc siRNA showed less loss of retinal function as assessed by electroretinograms from paraquat-induced oxidative stress. These data suggest that p66Shc and molecular signals involved in its regulation provide therapeutic targets for retinal degenerations in which oxidative-damage plays a major role, including age-related macular degeneration and cone cell death in retinitis pigmentosa.