Multidisciplinary Tool Kit for Febrile Neutropenia: Stewardship Guidelines, Staphylococcus aureus Epidemiology, and Antibiotic Use Ratios.

PURPOSE: Inappropriate vancomycin for febrile neutropenia (FN) is an ideal antimicrobial stewardship target. To improve vancomycin prescribing, we instituted a multifaceted intervention, including an educational guideline with audit for compliance; an antibiotic use audit; and an assessment of local burden of methicillin-resistant Staphylococcus aureus (MRSA) colonization and infection. MATERIALS AND METHODS: We conducted a quasi-experimental pre-post intervention review of vancomycin initiation for FN on a 32-bed hematology/oncology unit. A retrospective chart review was conducted from November 2015 to May 2016 (preintervention period). In January 2017, we implemented an institutional FN guideline emphasizing criteria for appropriate use. Vancomycin audit was conducted from February 2017 to October 2017 (postintervention period). The primary outcome was appropriateness of vancomycin initiation. We then compared average antibiotic use (days of therapy per 1,000 patient days) for vancomycin and cefepime before and after intervention. Finally, unit-wide MRSA screening cultures were obtained upon admission and bimonthly for 6 weeks (October 2, 2017, to November 9, 2017). Screened patients were followed for 12 months for clinical MRSA infection. RESULTS: Forty-three (49%) of 88 preintervention patients were started on empiric vancomycin appropriately, compared with 59 (66%) of 90 postintervention patients (P = .02). There was a significant decrease in vancomycin use after intervention. Six (7.1%) of 85 patients screened positive for MRSA colonization. During the 12-month follow-up, no colonized patients developed clinical MRSA infections (positive predictive value, 0.0%). Of the 79 noncolonized patients, 2 developed a clinically significant infection (negative predictive value, 97.5%). CONCLUSION: Guideline-focused education can improve vancomycin appropriateness in FN and should be bundled with education and feedback about local MRSA epidemiology and antibiotic use rates for maximal stewardship impact.

Fulminant Sepsis Due to Granulibacter bethesdensis in a 4-Year-Old Boy With X-Linked Chronic Granulomatous Disease.

Granulibacter bethesdensis is a Gram-negative bacillus described as a pathogen exclusively in patients with chronic granulomatous disease, a phagocytic disorder that impairs the ability to clear catalase-producing organisms. Granulibacter usually causes chronic and recurrent lymphadenopathies. We report the fatal case of a 4-year-old boy with chronic granulomatous disease, who presented with sepsis after a few days of abdominal pain and diarrhea.

Association of bactericidal activity of genital tract secretions with Escherichia coli colonization in pregnancy.

OBJECTIVE: Genital tract secretions exhibit bactericidal activity against Escherichia coli. We hypothesized that this defense may be modulated during pregnancy. STUDY DESIGN: Secretions were collected by vaginal swab from 70 pregnant women (35-37 weeks' gestation) and 35 nonpregnant controls. We mixed E coli with swab eluants or control buffer and colonies enumerated to measure bactericidal activity. Cytokines, chemokines, and antimicrobial peptides were quantified by multiplex or enzyme-linked immunosorbent assay. RESULTS: Pregnant women had significantly greater bactericidal activity, higher concentrations of proinflammatory cytokines, and lower levels of beta defensins compared to controls. Seven (10%) pregnant and 8 (23%) nonpregnant women were vaginally colonized with E coli; colonization was inversely associated with bactericidal activity. CONCLUSION: The soluble mucosal immune environment is altered in pregnancy. We speculate that the observed changes may protect against colonization and ascending infection and could provide a biomarker to identify pregnant women at risk for infectious complications including preterm birth.

Annexin A5 binds to lipopolysaccharide and reduces its endotoxin activity.

UNLABELLED: Annexin A5 (AnxA5) has a high affinity for phosphatidylserine. The protein is widely used to detect apoptotic cells because phosphatidylserine, a phospholipid that is normally present in the inner leaflets of cytoplasmic membranes, becomes translocated to the outer leaflets during programmed cell death. Here we report the novel observation that AnxA5 binds to Gram-negative bacteria via the lipid A domain of lipopolysaccharide (LPS). Binding of AnxA5 to bacteria was measured quantitatively, confirmed by fluorescence microscopy, and found to be inhibited by antibodies against lipid A. AnxA5 also bound to purified dot-blotted LPS and lipid A. Through ellipsometry, we found that the binding of AnxA5 to purified LPS was calcium dependent and rapid and showed a high affinity-characteristics similar to those of AnxA5 binding to phosphatidylserine. Initial functional studies indicated that AnxA5 can affect LPS activities. AnxA5 inhibited LPS-mediated gelation in the Limulus amebocyte lysate assay. Incubation of LPS with the protein reduced the quantity of tumor necrosis factor alpha (TNF-α) released by cultured monocytes compared to that released upon incubation with LPS alone. Initial in vivo experiments indicated that injection of mice with LPS preincubated with AnxA5 produced serum TNF-α levels lower than those seen after injection of LPS alone. These data demonstrate that AnxA5 binds to LPS and open paths to investigation of the potential biological and therapeutic implications of this interaction. IMPORTANCE: AnxA5 is highly expressed in cells that have a barrier function-including, among others, vascular endothelium, placental trophoblasts, and epithelial cells lining bile ducts, renal tubules, mammary ducts, and nasal epithelium. The protein has been well characterized for its binding to phospholipid bilayers that contain phosphatidylserine. This report of a previously unrecognized activity of AnxA5 opens the door to investigation of the possibility that this binding may have biological and therapeutic ramifications. In view of the tissue expression of the protein, the present results suggest the possibility that AnxA5 plays a role in modulating the host defense against lipopolysaccharide at these anatomic sites, where cells may interface with microorganisms. These results also raise the intriguing possibility that AnxA5 or analogous proteins or peptides could provide novel approaches to addressing the difficult clinical problem of Gram-negative sepsis.

Improved antimicrobial efficacy with nitric oxide releasing nanoparticle generated S-nitrosoglutathione.

Nitric oxide (NO) plays a vital role in mammalian host defense through a variety of mechanisms. In particular, NO can oxidize to form reactive nitrogen species or interact with protein thiols and metal centers, blocking essential microbial processes. S-nitrosoglutathione (GSNO), a potent NO donor formed by the interaction of NO with intracellular glutathione (GSH), is a major factor in this pathway and is considered one of the strongest naturally occurring nitrosating agent. We previously described the broad-spectrum antimicrobial activity of a nanoparticulate platform capable of controlled and sustained release of NO (NO-np). Interestingly, in vivo efficacy of the NO-np surpassed in vitro data generated. We hypothesized that the enhanced activity was in part achieved via the interaction between the generated NO and available GSH, forming GSNO. In the current study, we investigated the efficiency of NO-np to form GSNO in the presence of GSH was evaluated, and assessed the antimicrobial activity of the formed GSNO against methicillin resistant Staphylococcus aureus (MRSA), Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. When GSH was combined with NO-np, GSNO was rapidly produced and significant concentrations of GSNO were maintained for >24h. The GSNO generated was more effective compared to NO-np alone against all bacterial strains examined, with P. aeruginosa being the most sensitive and K. pneumoniae the most resistant. We conclude that the combination of NO-np with GSH is an effective means of generating GSNO, and presents a novel approach to potent antimicrobial therapy.