Preclinical testing of a broad-spectrum antimicrobial endotracheal tube coated with an innate immune synthetic mimic.

BACKGROUND: Endotracheal tubes provide an abiotic surface on which bacteria and fungi form biofilms, and the release of endotoxins and planktonic organisms can cause damaging inflammation and infections. OBJECTIVES: Ceragenins are small molecule mimics of antimicrobial peptides with broad-spectrum antibacterial and antifungal activity, and a ceragenin may be used to provide antimicrobial protection to the abiotic surface of an endotracheal tube. METHODS: A hydrogel film, containing CSA-131, was generated on endotracheal tubes. Elution of CSA-131 was quantified in drip-flow and static systems, antifungal and antibacterial activity was measured with repeated inoculation in growth media, biofilm formation was observed through electron microscopy, safety was determined by intubation of pigs with coated and uncoated endotracheal tubes. RESULTS: Optimized coatings containing CSA-131 provided controlled elution of CSA-131, with concentrations released of less than 1 µg/mL. The eluting ceragenin prevented fungal and bacterial colonization of coated endotracheal tubes for extended periods, while uncoated tubes were colonized by bacteria and fungi. Coated tubes were well tolerated in intubated pigs. CONCLUSIONS: Thin films containing CSA-131 provide protection against microbial colonization of endotracheal tubes. This protection prevents fungal and bacterial biofilm formation on the tubes and reduces endotoxin associated with tubes. This coating is well suited for decreasing the adverse effects of intubation associated with infection and inflammation.

Ceragenins are active against drug-resistant Candida auris clinical isolates in planktonic and biofilm forms.

Background: Candida auris has emerged as a serious threat to human health. Of particular concern are the resistance profiles of many clinical isolates, with some being resistant to multiple classes of antifungals. Objectives: Measure susceptibilities of C. auris isolates, in planktonic and biofilm forms, to ceragenins (CSAs). Determine the effectiveness of selected ceragenins in gel and cream formulations in eradicating fungal infections in tissue explants. Materials and methods: A collection of 100 C. auris isolates available at CDC was screened for susceptibility to a lead ceragenin. A smaller collection was used to characterize antifungal activities of other ceragenins against organisms in planktonic and biofilm forms. Effects of ceragenins on fungal cells and biofilms were observed via microscopy. An ex vivo model of mucosal fungal infection was used to evaluate formulated forms of lead ceragenins. Results: Lead ceragenins displayed activities comparable to those of known antifungal agents against C. auris isolates with MICs of 0.5-8 mg/L and minimum fungicidal concentrations (MFCs) of 2-64 mg/L. No cross-resistance with other antifungals was observed. Fungal cell morphology was altered in response to ceragenin treatment. Ceragenins exhibited activity against sessile organisms in biofilms. Gel and cream formulations including 2% CSA-44 or CSA-131 resulted in reductions of over 4 logs against established fungal infections in ex vivo mucosal tissues. Conclusions: Ceragenins demonstrated activity against C. auris, suggesting that these compounds warrant further study to determine whether they can be used for topical applications to skin and mucosal tissues for treatment of infections with C. auris and other fungi.

Susceptibility of Colistin-Resistant, Gram-Negative Bacteria to Antimicrobial Peptides and Ceragenins.

The susceptibility of colistin-resistant clinical isolates of Klebsiella pneumoniae to ceragenins and antimicrobial peptides (AMPs) suggests that there is little to no cross-resistance between colistin and ceragenins/AMPs and that lipid A modifications are found in bacteria with modest changes in susceptibility to ceragenins and with high levels of resistance to colistin. These results suggest that there are differences in the resistance mechanisms to colistin and ceragenins/AMPs.

Clostridium bacteremia and its implications: A case report.

Background: The Clostridium species is a gram positive, anaerobic, rod-shaped microbe that is known to produce many toxins. Most infections by the Clostridium species involve C. botulinum, C. difficile, and C. perfringens. However, other types of Clostridium species are also clinically relevant, such as C. septicum and C. tertium. Case summary: We discuss a case of a 79-year-old patient with a past medical history of prostate cancer and alcohol abuse who presented to the hospital after being found down. They were admitted to the ICU for septic shock, and initial blood cultures grew C. septicum, C. tertium, and E. coli. A CT of the abdomen and pelvis with IV contrast showed pneumoperitoneum and a loculated pericolic fluid collection concerning for colon perforation. Initially the patient had a benign abdominal exam, but later developed significant distention and tenderness that required an emergent exploratory laparotomy and total abdominal colectomy. The patient was found to have three separate colon perforations, and no malignancy on histopathology. Discussion: C. septicum is a highly virulent pathogen, and there are several cases reporting C. septicum-associated endocarditis, aortitis, and endophthalmitis. It is also associated with colon and hematologic malignancies and neutropenia. Common risk factors for C. tertium include immunocompromised status, neutropenia, hematologic malignancy, exposure to beta-lactam antibiotics, cirrhosis, and intestinal mucosal damage. It seems to have low virulence and low mortality when treated correctly. It is important that any patient found to have Clostridium bacteremia be evaluated for a gastrointestinal source and treated promptly and appropriately.

Closing the Gap Between Mammalian and Invertebrate Peripheral Nerve Injury: Protocol for a Novel Nerve Repair.

BACKGROUND: Outcomes after peripheral nerve injuries are poor despite current nerve repair techniques. Currently, there is no conclusive evidence that mammalian axons are capable of spontaneous fusion after transection. Notably, certain invertebrate species are able to auto-fuse after transection. Although mammalian axonal auto-fusion has not been observed experimentally, no mammalian study to date has demonstrated regenerating axolemmal membranes contacting intact distal segment axolemmal membranes to determine whether mammalian peripheral nerve axons have the intrinsic mechanisms necessary to auto-fuse after transection. OBJECTIVE: This study aims to assess fusion competence between regenerating axons and intact distal segment axons by enhancing axon regeneration, delaying Wallerian degeneration, limiting the immune response, and preventing myelin obstruction. METHODS: This study will use a rat sciatic nerve model to evaluate the effects of a novel peripheral nerve repair protocol on behavioral, electrophysiologic, and morphologic parameters. This protocol consists of a variety of preoperative, intraoperative, and postoperative interventions. Fusion will be assessed with electrophysiological conduction of action potentials across the repaired transection site. Axon-axon contact will be assessed with transmission electron microscopy. Behavioral recovery will be analyzed with the sciatic functional index. A total of 36 rats will be used for this study. The experimental group will use 24 rats and the negative control group will use 12 rats. For both the experimental and negative control groups, there will be both a behavior group and another group that will undergo electrophysiological and morphological analysis. The primary end point will be the presence or absence of action potentials across the lesion site. Secondary end points will include behavioral recovery with the sciatic functional index and morphological analysis of axon-axon contact between regenerating axons and intact distal segment axons. RESULTS: The author is in the process of grant funding and institutional review board approval as of March 2020. The final follow-up will be completed by December 2021. CONCLUSIONS: In this study, the efficacy of the proposed novel peripheral nerve repair protocol will be evaluated using behavioral and electrophysiologic parameters. The author believes this study will provide information regarding whether spontaneous axon fusion is possible in mammals under the proper conditions. This information could potentially be translated to clinical trials if successful to improve outcomes after peripheral nerve injury. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/18706.