The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile

Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell’s cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI.

Molecular Mechanisms of Resistance to Antifungals in Candida albicans

Invasive Candidiasis (IC) presents a global mortality rate greater than 40%, occupying the fourth place worldwide as the most frequent opportunistic nosocomial disease. Although the genus Candida consists of around 200 species, only 20 are reported as etiological agents of IC, being Candida albicans the most frequent causal agent. Even when there is a broad range of antifungals drugs for Candida infections, azoles, polyenes, and echinocandins are considered among the most effective treatment. However, there is some incidence for antifungal resistance among some Candida strains, limiting treatment options. Several molecular mechanisms with antifungal agents have been reported for C. albicans where insertions, deletions, and point mutations in genes codifying target proteins are frequently related to the antifungal drug resistance. Furthermore, gene overexpression is also frequently associated to antifungal resistance as well as an increase in the activity of proteins that reduce oxidative damage. This chapter summarizes the main molecular mechanisms to C. albicans antifungal drug resistance, besides offering an overview of new antifungal agents and new antifungal targets to combat fungal infections.

Characterization of Clostridioides difficile Strains, the Disease Severity, and the Microbial Changes They Induce

Background: Clostridioides difficile infection (CDI) is a major nosocomial disease. The characteristics of different strains, the disease severity they cause, their susceptibility to antibiotics, and the changes they inflict on gut microbiome, have not been comprehensively studied in Israel. Methods: A severity score was calculated for 70 patients. Stool samples were tested for toxins presence using a special kit. Bacteria were isolated, identified by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) and antibiotic susceptibility tests were performed for several antibiotics. Strains were classified by Multi-locus sequence typing (MLST), and changes in gut microbiome were tested. Results: ST04 (22.5%) and ST37 (12.7%) were the most frequent strains. Clade (phylogenetic lineage) 1 was the most (81.4%) prevalent. We found significant associations between ST and age (p = 0.024) and between ST and moxifloxacin susceptibility (p = 0.001). At the clade level, we found significant associations with binary toxin gene occurrence (p = 0.002), and with susceptibility to both metronidazole and vancomycin (p = 0.024, 0.035, respectively). Differences in intestine microbiome were affected by age, clades’ distribution and STs. Conclusions: By defining the characteristics of the different strains and clades, clinicians can choose medical interventions based on the predicted response or disease severity associated with each strain, enabling new advances in the field of personalized medicine.

Hazardous and Toxic Waste Management in Bhayangkara Hospital Tk. I Raden Said Sukanto

The hospital is one of the objects that has a major role in contributing medical waste, where the waste is classified as hazardous and toxic waste. Medical waste that not treated properly will bring nosocomial disease to humans and pollute the environment. For this reason, waste management is very needed. Medical waste produced by Bhayangkara Hospital Tk. I Raden Said Sukanto came from patient care rooms and medical support rooms. The amount of medical hazardous and toxic waste generated in January 2020 was 16.866 kg which included infectious, pharmaceutical, chemical and sharps waste. Medical hazardous and toxic solid waste management in Bhayangkara Tk. I Raden Said Sukanto Hospital includes reduction, packaging, symbol and labeling, storage, transportation, and processing. Bhayangkara Tk. I Raden Said Sukanto Hospital is guided by government regulations that forced in Indonesia. However, there was still some discrepancies between the existing conditions and regulations caused by the lack of adequate Human Resources.

The Processing of Hazardous and Toxic Hospital Solid Waste in Dr. Soetomo Hospital Surabaya

The increasing number of hospital, increases medical waste in Indonesia. Medical waste is categorized as hazardous and toxic waste as mentioned in Appendix I of Government Regulation number 101 in 2014. The hazardous and toxic waste management in hospital is necessary because if it is not managed properly can cause injury, environmental pollution, and nosocomial disease. Hazardous and toxic hospital waste management can minimize the effect of it. The purpose of this study was to identify the flow of hazardous and toxic waste management in RSUD Dr. Soetomo according to the regulations. The research type was descriptive observational using secondary data from the installation of environmental sanitation. Data was compared to the Minister of Environment and Forestry Regulation No. P.56 in 2015 about Technical Procedures and Technical Requirements for the Hazardous and Toxic Waste’ s Management from Health Service Facilities. The results showed that the management of hazardous and toxic waste in RSUD Dr. Soetomo was fulfill the requirements in the regulation of the Minister of Environment and Forestry No. P.56 of 2015 from the reduction and segregation, storage, transportation and treatment of hazardous and toxic waste.

Structure and assembly of aClostridioides difficilespore polar appendage

Clostridioides difficile, a strict anaerobic spore-former, is the main cause of nosocomial disease associated to antibiotic therapy in adults and a growing concern in the community. Spores are the main infectious, persistence and transmission vehicle. Spore germination occurs in the intestine and the resulting vegetative cells will produce the toxins responsible for the disease symptoms, and spores. During sporulation, a wild type population bifurcates into two main spore morphotypes, with or without a thick exosporium. We show that this bifurcation extends to the formation of spores with a robust polar appendage or spores with a short appendage or that lack this structure. The cysteine-rich CdeM protein localizes to the appendage and around the entire surface of the spore, and is a major structural component of the exosporium, which we show is continuous with the appendage. In aCdeMmutant, when present, the polar appendage is short and disorganized. We show that wild type andcdeMspores with a short or no appendage germinate poorly in response to taurocholate, compared to those with an appendage.cdeMspores of the two types, however, germinate faster than their wild type counterparts. Thus, while the absence of CdeM may increase the permeability of spores to taurocholate, proper assembly of the appendage is also important for germination. Consistent with an overall enhancement of germination, acdeMmutant shows increased virulence in a hamster model of disease. For a wild type population, spores with a short or no appendage germinate slower than the appendage-bearing spores. Differences in transmission, persistence and disease severity may result, in part, from their proportion in a spore population.

Morganella morganii: associated sinusitis with orbital abscess in a diabetic patient

<p class="abstract"><em>Morganella morganii</em> is a gram negative pathogen and may cause lethal disease in patients with immunosuppressive disease. It is commonly found in long term urinary catheter used and immune system deficiency patients as nosocomial disease. <em>Morganella morganii</em> was also involving skin, skeletal system and central nervous system. In this case we present sporadic <em>Morganella morganii</em> infection on sinonasal region with the presence of sinusitis, orbital absess, preseptal cellulitis and lamina propasia defect on 58 year old female diabetic patient. Microbiological assessment from nasal tissue and sinus puss discharge were reported as <em>Morganella morganii</em>. This is the first case of sinonasal <em>Morganella morganii</em> infection with sinonasal, preseptal cellulitis and orbital absess with lamina papyracea bone destruction.</p>