The role of diagnostic tests in antifungal stewardship for treating invasive fungal infections: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article originally published in the journal Open Forum Infectious Diseases. Invasive fungal infections are caused by fungi. They can spread to deeper parts of the body. Some diagnostic tests are slow and may delay treatment. Better tests help to identify infection early in patients. An antifungal stewardship (shortened to AFS) program is a stepwise process to improve how patients are treated. AFS programs using diagnostic tests may help to manage infections. In this study, researchers wanted to know the impact of such AFS programs. To do so, they looked at the information from 17 previously published studies, which is summarized here. WHAT WERE THE RESULTS?: Infections were identified and treated faster in studies with improved diagnostic tests. Treatment cost decreased when infections were identified and treated early. Patients were treated for shorter periods of time. They also spent less time in hospital. Number of deaths were less. WHAT DO THE RESULTS OF THE STUDY MEAN?: AFS programs based on diagnostic tests helped patients.

The Role of Diagnostics-Driven Antifungal Stewardship in the Management of Invasive Fungal Infections: A Systematic Literature Review.

Antifungal stewardship (AFS) programs are key to optimizing antifungal use and improving outcomes in patients with invasive fungal infections. Our systematic literature review evaluated the impact of diagnostics in AFS programs by assessing performance and clinical measures. Most eligible studies were from Europe and the United States (n = 12/17). Diagnostic approaches included serum ß-1-3-D-glucan test (n/N studies, 7/17), galactomannan test (4/17), computed tomography scan (3/17), magnetic resonance (2/17), matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS; 2/17), polymerase chain reaction (1/17), peptide nucleic acid fluorescent in situ hybridization (PNA-FISH) assay (1/17), and other routine methods (9/17). Time to species identification decreased significantly using MALDI-TOF and PNA-FISH (n = 2). Time to targeted therapy and length of empiric therapy also decreased (n = 3). Antifungal consumption decreased by 11.6%-59.0% (7/13). Cost-savings ranged from 13.5% to 50.6% (5/10). Mortality rate (13/16) and length of stay (6/7) also decreased. No negative impact was reported on patient outcomes. Diagnostics-driven interventions can potentially improve AFS measures (antifungal consumption, cost, mortality, and length of stay); therefore, AFS implementation should be encouraged.

Meprin A impairs epithelial barrier function, enhances monocyte migration, and cleaves the tight junction protein occludin.

Meprin metalloproteases are highly expressed at the luminal interface of the intestine and kidney and in certain leukocytes. Meprins cleave a variety of substrates in vitro, including extracellular matrix proteins, adherens junction proteins, and cytokines, and have been implicated in a number of inflammatory diseases. The linkage between results in vitro and pathogenesis, however, has not been elucidated. The present study aimed to determine whether meprins are determinative factors in disrupting the barrier function of the epithelium. Active meprin A or meprin B applied to Madin-Darby canine kidney (MDCK) cell monolayers increased permeability to fluorescein isothiocyanate-dextran and disrupted immunostaining of the tight junction protein occludin but not claudin-4. Meprin A, but not meprin B, cleaved occludin in MDCK monolayers. Experiments with recombinant occludin demonstrated that meprin A cleaves the protein between Gly(100) and Ser(101) on the first extracellular loop. In vivo experiments demonstrated that meprin A infused into the mouse bladder increased the epithelium permeability to sodium fluorescein. Furthermore, monocytes from meprin knockout mice on a C57BL/6 background were less able to migrate through an MDCK monolayer than monocytes from their wild-type counterparts. These results demonstrate the capability of meprin A to disrupt epithelial barriers and implicate occludin as one of the important targets of meprin A that may modulate inflammation.

Meprin A metalloproteases enhance renal damage and bladder inflammation after LPS challenge.

Meprin metalloproteases, composed of alpha and/or beta subunits, consist of membrane-bound and secreted forms that are abundantly expressed in proximal tubules of the kidney as well as secreted into the urinary tract. Previous studies indicated that meprin metalloproteases play a role in pathological conditions such as ischemic acute renal failure and urinary tract infection. The aim of this work was to examine the role of meprins in endotoxemic acute renal failure using meprin alpha knockout (alphaKO), meprin beta knockout (betaKO), and wild-type (WT) mice. Differences among the responses of the genotypes were observed as early as 1 h after challenge with 2.5 mg/kg ip Escherichia coli LPS, establishing roles for meprins in the endotoxemic response. Meprin alphaKO mice displayed lower blood urea nitrogen levels and decreased nitric oxide levels, indicative of a decreased systemic response to LPS compared with WT and meprin betaKO mice. Serum cytokine profiles showed lower levels of IL-1beta and TNF-alpha in the meprin alphaKO mice within 3 h after LPS challenge and confirmed a role for meprins in the early phases of the host response. Meprin alphaKO mice were also hyporesponsive to LPS administered to the bladder, exhibiting significantly less bladder edema, leukocyte infiltration, and bladder permeability than WT mice. These data indicate that meprin A contributes to the renal and urogenital pathogenesis of endotoxicity.