nystatin-a1 and Enterocolitis--Pseudomembranous

Patients with C. difficile infection (CDI) experience intestinal microflora changes that can promote the overgrowth and subsequent translocation of gut resident pathogens into the blood. Consistently, CDI due to PCR-ribotype 027 strain, severe or relapsing CDI, and treatment with high-dosage vancomycin are independent risk factors for candidemia.. We review the role played by the gut microbiota during CDI and its treatment, as well as the clinical profile of CDI patients who are at risk of developing candidemia. Also, we discuss the management of these patients by focusing on pre-emptive strategies aimed at reducing the risk of candidemia, and on innovative anti-C. difficile therapies that may mitigate CDI-related effects such as the altered gut microbiota composition and prolonged intestinal mucosa damage. Expert commentary: A closer clinical and diagnostic monitoring of patients with CDI should help to limit the CDI-associated long-term consequences, including Candida infections, which worsen the outcome of hospitalized patients.

Topics: Anti-Bacterial Agents; Antifungal Agents; beta-Glucans; Candidemia; Clostridioides difficile; Enterocolitis, Pseudomembranous; Humans; Intestinal Mucosa; Microbiota; Nystatin; Risk Factors

Clostridium difficile toxin (CDT) is a binary actin-ADP-ribosylating toxin that causes depolymerization of the actin cytoskeleton and formation of microtubule-based membrane protrusions, which are suggested to be involved in enhanced bacterial adhesion and colonization of hypervirulent C. difficile strains. Here, we studied the involvement of membrane lipid components of human colon adenocarcinoma (Caco-2) cells in formation of membrane protrusions. Depletion of cholesterol by methyl-β-cyclodextrin inhibited protrusion formation in a concentration-dependent manner but had no major effect on the toxin-catalyzed modification of actin in target cells. Repletion of cholesterol reconstituted formation of protrusions and increased velocity and total amount of protrusion formation. Methyl-β-cyclodextrin had no effect on the CDT-induced changes in the dynamics of microtubules. Formation of membrane protrusions was also inhibited by the cholesterol-binding polyene antibiotic nystatin. Degradation or inhibition of synthesis of sphingolipids by sphingomyelinase and myriocin, respectively, blocked CDT-induced protrusion formation. Benzyl alcohol, which increases membrane fluidity, prevented protrusion formation. CDT-induced membrane protrusions were stained by flotillin-2 and by the fluorescent-labeled lipid raft marker cholera toxin subunit B, which selectively interacts with GM1 ganglioside mainly located in lipid microdomains. The data suggest that formation and especially the initiation of CDT-induced microtubule-based membrane protrusions depend on cholesterol- and sphingolipid-rich lipid microdomains.

Topics: Anti-Bacterial Agents; Antifungal Agents; Bacterial Adhesion; Bacterial Toxins; beta-Cyclodextrins; Caco-2 Cells; Cholesterol; Clostridioides difficile; Dose-Response Relationship, Drug; Enterocolitis, Pseudomembranous; Fatty Acids, Monounsaturated; Humans; Membrane Microdomains; Microtubules; Nystatin; Sphingolipids; Sphingomyelin Phosphodiesterase

Topics: Adult; Aged; Anti-Bacterial Agents; Chloramphenicol; Dysentery, Bacillary; Enterocolitis, Pseudomembranous; Erythromycin; Humans; Intestines; Male; Middle Aged; Nalidixic Acid; Nystatin; Penicillins; Pneumonia; Proteus Infections; Rheumatic Heart Disease; Staphylococcal Infections; Streptomycin; Tetracycline