Novel therapeutic strategies for Clostridium difficile infections

Introduction: In recent years, Clostridium difficile has become the primary cause of antibiotic-associated diarrhea and pseudomembranous colitis, resulting in long and complicated hospital stays that represent a serious burden for patients as well as health care systems. Currently, conservative treatment of C. difficile infection (CDI) relies on the antibiotics vancomycin, metronidazole or fidaxomicin, or in case of multiple recurrences, fecal microbiota transplantation (FMT).

Areas covered: The fast-spreading, epidemic nature of this pathogen urgently necessitates the search for alternative treatment strategies as well as antibiotic targets. Accordingly, in this review, we highlight the recent findings regarding virulence associated traits of C. difficile, evaluate their potential as alternative drug targets, and present current efforts in designing inhibitory compounds, with the aim of pointing out possibilities for future treatment strategies.

Expert opinion: Increased attention on systematic analysis of the virulence mechanisms of C. difficile has already led to the identification of several alternative drug targets. In the future, applying state of the art ‘omics’ and the development of novel infection models that mimic the human gut, a highly complex ecological niche, will unveil the genomic and metabolic plasticity of this pathogen and will certainly help dealing with future challenges.     

Emerging therapies for Clostridium difficile infections

Introduction: Clostridium difficile infection (CDI) is the leading identifiable gastrointestinal disease in healthcare institutions, but the response rates to the two standard therapies for CDI are declining and so innovative therapies are being developed for CDI. The purpose of this paper is to review the data on the efficacy and safety of emerging therapies for CDI and assess their potential for effectiveness based on the clinical phase of development and marketing challenges.

Areas covered: Emerging therapies for CDI are reviewed including new antibiotics, peptides, immune regulators, probiotics and toxin binders. PubMed, Medline and Google Scholar and online clinical trial registers are searched from 1976 to 2010 for articles unrestricted by language. Secondary searches by author, manufacturing companies and FDA websites are also performed.

Expert opinion: Of the emerging therapies for CDI, several may ultimately reduce the incidence of CDI and the economic burden of this disease on the healthcare system. Several emerging treatments (fidaxomicin, rifaximin and mAbs) show the most promise, although only one is currently being actively developed. Use of other clostridial strains, probiotic strains and immune enhancers have great potential as therapies, but require further development.     

Novel avenues for Clostridium difficile infection drug discovery

Introduction: Clostridium difficile is the etiologic agent of nosocomial and community-acquired diarrhea associated with exposure to antibiotics that disrupt the normal colonic flora. As antibacterials currently used for primary C. difficile infections favor recurrences, new agents able to neutralize the bacterium without affecting the gut microbiota are badly needed.

Areas covered: This article investigates the most promising strategies aimed at developing therapies with minimal or no effect on intestinal flora. These therapies include new narrow-spectrum antibiotics and antimicrobial peptides, bacteriophages and phage lysins, virulence-targeting factors such as riboswitch ligands and quorum sensing-interfering factors. It also reviews bacteriotherapy based on probiotics, fecal transplants, and toxin-targeting molecules.

Expert opinion: Beyond the development of new antibiotics, virulence-targeting factors or phage cocktails seem promising strategies, which could replace antibiotics avoiding the emergence of resistant strains and the onset of C. difficile infection (CDI). Until broad-spectrum antimicrobials will be in use, C. difficile-specific lytic phages could help to prevent CDI by eliminating C. difficile in patients and in the hospital staff, and for the prevention and treatment of recurrences. Phage therapy is not currently available in Western countries, but, in our opinion, it should have a new chance. Fecal therapy is emerging as a very effective and readily available treatment for recurrences. The shift is from a standardized, drug-based antibacterial therapy toward the forthcoming less expensive and nonpatentable procedures of a more personalized medicine. This will imply profound changes affecting both patient–physician interactions and the current profit-oriented approach to the pharmacologic therapy of infections.     

Clinical review of Clostridium difficile infection: an update on treatment and prevention

ABSTRACT

Introduction: Clostridium difficile infection (CDI) has become a significant healthcare-associated infection and is strongly associated with antibiotic use. Practice guidelines have recently been revised incorporating updated recommendations for diagnosis, treatment, and prevention.

Areas covered: This review discusses updated aspects of CDI management. New and emerging pharmacologic options for treatment and prevention are reviewed.

Expert opinion: Metronidazole is associated with lower rates of treatment success compared to vancomycin and should no longer be used as primary therapy for the first episode of CDI or recurrent disease. Vancomycin or fidaxomicin are now recommended for first-line therapy for most cases of CDI. Fecal microbiota transplant is effective and safe for the treatment of recurrent CDI. Evidence supports the use of fidaxomicin and bezlotoxumab for prevention of recurrent CDI; however, the costs associated with these therapies may limit their use. Validated risk prediction tools are needed to identify patients most likely to benefit from these treatments. Future advancements in microbiota targeting treatments will emerge as promising alternatives to standard CDI treatments. Antibiotic stewardship and infection control measures will remain essential components for CDI management.     

Bezlotoxumab: A Novel Agent for the Prevention of Recurrent Clostridium difficile Infection

During the past decade, the incidence and severity of Clostridium difficile infection (CDI) have significantly increased, leading to a rise in CDI‐associated hospitalizations, health care costs, and mortality. Although treatment options exist for CDI, recurrence is frequent following treatment. Furthermore, patients with at least one CDI recurrence are at an increased risk of developing additional recurrences. A novel approach to the prevention of recurrent CDI is the use of monoclonal antibodies directed against the toxins responsible for CDI as an adjunct to antibiotic treatment. Bezlotoxumab, a human monoclonal antibody that binds and neutralizes C. difficile toxin B, is the first therapeutic agent to receive United States Food and Drug Administration approval for the prevention of CDI recurrence. Clinical studies have demonstrated superior efficacy of bezlotoxumab in adults receiving antibiotic therapy for CDI compared with antibiotic therapy alone for the prevention of CDI recurrence. Bezlotoxumab was well tolerated in clinical trials, with the most common adverse effects being nausea, vomiting, fatigue, pyrexia, headache, and diarrhea. The demonstrated efficacy, safety, and characteristics of bezlotoxumab present an advance in prevention of CDI recurrence.     

Ridinilazole for the treatment of Clostridioides difficile infection

Introduction: Ridinilazole is a novel antibiotic being developed for the treatment of Clostridioides difficile infection (CDI). Ridinilazole has completed two phase II trials and phase III trials which are denoted Ri-CoDIFy 1 and 2, are planned (ClinicalTrials.gov identifiers: NCT03595553 and NCT03595566).

Areas covered: This article covers the chemistry, mechanism of action, in vitro microbiology versus C. difficile and host microbiota, pre-clinical and clinical efficacy, pharmacokinetics, pharmacodynamics and safety and tolerability of ridinilazole.

Expert opinion: Ridinilazole is a novel antibiotic with ideal properties for the treatment of CDI. Given the promising results from the phase II clinical trial, ridinilazole may have the capability to lower the risk for CDI recurrence thus improving sustained clinical response rates – a current unmet medical need. Assuming a positive phase III trial, ridinilazole will enter a market with heightened awareness on the importance of prevention of CDI. This along with further research into the economic consequences and decreased patient quality of life associated with recurrent CDI, should provide clinicians with further evidence for the need for therapy that limits CDI recurrence and improves sustained clinical cure.     

Therapy of Clostridium difficile infection: perspectives on a changing paradigm

Introduction: Clostridium difficile disease (CDI) have increased in frequency and severity over the past decade and are a leading cause of hospital acquired infections, contributing to increased hospital length of stay and costs, as well as associated increased mortality, especially amongst the elderly. Standard therapy has been associated with 20 – 30% relapse rates. Consequently, new CDI therapeutic approaches have emerged.

Areas covered: The role of metronidazole, vancomycin, fidaxomicin, rifaximin, nitizoxanide, tigecycline, fusidic acid, LFF-571, cardazolid, SMT 19969, CamSA and surotomycin were reviewed.

Expert opinion: New IDSA/SHEA guidelines are expected within the next year and may impact selection of primary therapy for CDI. Until then, metronidazole will likely remain as first line therapy because of low cost and despite its inferiority compared to vancomycin. Vancomycin will likely see increasing use, especially as generics become available. Fidaxomicin will emerge as an important therapy for relapse patients and perhaps as initial therapy for patients at greatest risk for relapse, with concomitant antibiotics, multiple comorbidities and renal insufficiency, advanced age and hypoalbuminemia. Biotherapeutics such as fecal microbiota transplantation and non-toxogenic C. difficile prevention will emerge as the preferred therapy in multiple relapse patients and the development of an oral formulation will occur within five years.     

Cadazolid for the treatment of Clostridium difficile

Introduction: Antibiotic development goals for CDI include potent antimicrobial effect against C. difficile, limited killing of host microbiota, potential effect on spores, and ability to interfere with toxin production. Cadazolid, a novel, non-absorbable hybrid antibiotic has many of these criteria. In phase I and II clinical trials, cadazolid was shown to be safe, well tolerated, and efficacious positioning itself as a potential future viable therapeutic option for CDI.

Areas covered: This review provides an in-depth evaluation of the chemistry, microbiology, pharmacodynamics, pharmacokinetics, and clinical trial results for cadazolid. Clinical therapeutic outcomes are compared between cadazolid, fidaxomicin, and surotomycin.

Expert opinion: Preclinical and early clinical studies demonstrated that cadazolid has unique properties that will likely be valuable to treat CDI and reduce recurrent infection. With compelling phase II clinical results, results from the ongoing phase III trial will better define the role of cadazolid for treating CDI in the future.     

Non-antibiotic strategies for the prevention/treatment of Clostridium difficile infection

Background: Clostridium difficile infection has become a serious concern in both hospital and secondary healthcare environments. In the presence of repeated or prolonged antibiotic treatment, the C. difficile spores can germinate in the colon and produce toxins that cause colonic inflammation and diarrhea. The standard treatment for C. difficile-associated disease (CDAD) usually involves the withdrawal of the antibiotic treatment that led to the CDAD followed by a course of oral metronidazole or vancomycin, but there has been an increasing number of treatment failures and recurrences of disease. Over the past 10 – 15 years, researchers have begun exploring the possibility of using alternative means to combat C. difficile infection. Objective/methods: Over the course of the past 5 years, there has been a considerable amount of patent literature focused on non-antibiotic alternatives, including passive and active immunizations, monoclonal antibodies, antitoxins, inert binders and probiotic therapies. Results/conclusion: Current antibiotic therapies for the treatment of CDAD are not as effective as they once were. There is some promising work on non-antibiotic alternatives for CDAD prevention and treatment.     

Therapies in early development for the treatment of urinary tract inflammation

Introduction: Urinary tract inflammation is a very common clinical condition. It is caused by several pathogens and antibiotic treatment is the mainstay of therapy. Increasing antimicrobial resistance and high recurrence rates represent a challenge. Consequently, there is an unmet need for new therapeutic options.

Areas covered: The authors discuss the rationale of emerging management strategies and current experimentation. Furthermore, they focus on both acute and recurrent urinary tract infections (UTIs) and examine a range of therapeutics, including new antibiotics, vaccines, mannosides, hyaluronic acid, probiotics, immunomodulant agents and novel compounds derived from nanotechnology.

Expert opinion: Basic science studies have elucidated the pathogenesis of UTIs and built up the ground for the development of new therapies. Evidence is mainly derived from animal studies on murine models of bacterial cystitis. However, clinical trials are scanty and cannot provide us with robust evidence. Hetereogeneity and virulence of uropathogens pose a threat that scientists and clinicians are struggling to overcome.     

Fidaxomicin (OPT-80) for the treatment of Clostridium difficile infection

Importance of the field: Clostridium difficile infection (CDI) has become an increasingly important healthcare-associated complication in many countries. CDI outbreaks, a new ‘hypervirulent’ form and increased worldwide rates have underscored four urgent unmet needs for this disease: i) effective prevention of CDI; ii) therapies to produce faster resolution of CDI symptoms; iii) therapies to treat severe CDI more effectively and reduce its mortality; and iv) therapies to reduce the CDI recurrence rate following treatment.

Areas covered in this review: Fidaxomicin, a new macrocyclic antibiotic, has demonstrated potent in vitro activity against C. difficile with limited or no activity against normal fecal flora. It is minimally absorbed from the intestinal tract, even in the presence of intestinal inflammation. When tested against oral vancomycin in clinical studies of CDI therapy, it has equivalent efficacy for curing CDI at end of treatment and a comparable safety profile to that agent. However, fidaxomicin therapy of CDI is associated with significantly fewer CDI recurrences in the 28 days following treatment. Symptom resolution is also slightly quicker in some CDI patients. Additional fecal flora analysis in the CDI trials showed that fewer individuals developed intestinal colonization with vancomycin-resistant enterococci (VRE) among the fidaxomicin-treated group. This new molecule, which has just completed two large Phase III multicenter studies, successfully addresses two of the four urgent and unmet needs for dealing with CDI.

What the reader will gain: Fidaxomicin is as effective and as safe as vancomycin therapy for treating CDI but is associated with far fewer recurrences post-treatment and a decreased risk of VRE acquisition.

Take home message: Fidaxomicin is a potential new therapy for CDI which has the capacity to substantially decrease post-treatment recurrences and is as safe and well-tolerated as standard vancomycin treatment.     

Targeted therapies for the myeloid leukaemias

Although the standard approach to myeloid leukaemias remains chemotherapy, the agents currently available rarely result in cure. Recent advances in understanding the biology of these disorders have lead to the development of targeted treatment strategies. In acute promyelocytic leukaemia (APL), all-trans retinoic acid (ATRA), sodium phenylbutyrate and arsenic trioxide are agents which either induce differentiation or apoptosis and have been used to successfully achieve remission. The tyrosine kinase inhibitor, STI-571, antisense oligonucleotides, and bcr-abl vaccines are strategies which focus on the oncogenic events in chronic myelogenous leukaemia (CML). Two anti-CD33 monoclonal antibody conjugates, Y90-HuM195 and CMA-676, have been used in acute myelogenous leukaemia (AML) and have shown some efficacy. Although the preliminary results with these targeted therapies are promising, further studies are needed to establish them as effective, less toxic alternatives to the current standard of care.     

Clostridium Perfringens Enterotoxin (CPE) and CPE-Binding Domain (c-CPE) for the Detection and Treatment of Gynecologic Cancers

Clostridium perfringens enterotoxin (CPE) is a three-domain polypeptide, which binds to Claudin-3 and Claudin-4 with high affinity. Because these receptors are highly differentially expressed in many human tumors, claudin-3 and claudin-4 may provide an efficient molecular tool to specifically identify and target biologically aggressive human cancer cells for CPE-specific binding and cytolysis. In this review we will discuss these surface proteins as targets for the detection and treatment of chemotherapy-resistant gynecologic malignancies overexpressing claudin-3 and -4 using CPE-based theranostic agents. We will also discuss the use of fluorescent c-CPE peptide in the operative setting for real time detection of micro-metastatic tumors during surgery and review the potential role of CPE in other medical applications.     

治疗难辨梭菌感染的新18元大环内酯抗生素非达霉素

难辨梭茵感染（Clostridium difficile infection,CDI）发病率正在升高,在有些国家已成为医院获得性感染主要致病茵之一。经典药物治疗是采用万古霉素和／或甲硝唑治疗,但近年随着甲硝唑耐药新突变株出现,临床对其处理日益困惑。2011年1月非达霉素获美国食品和药物管理局批准上市,为本病治疗开辟了新的治疗途径。本文就非达霉素药效学、药动学、安全性、药物相互作用以及临床应用进行了综合介绍,并对比了非达霉素与万古霉素在治疗CDI时药理作用等区别,供临床应用时参考。     

Risk factors for the development of Clostridium difficile toxin‐associated diarrhoea: a pilot study

This study was a pilot investigation of risk factors for the development of Clostridium difficile toxin‐associated diarrhoea and in particular the differential influence of antimicrobial agents. The study was a retrospective case—control design conducted at Freeman Hospital, Newcastle upon Tyne. Cases were inpatients with stool positive C. difficile toxin diarrhoea and two controls were drawn for each case matched for age (+/?5 years) and type of admission (emergency or elective). Using conditional logistic regression analysis, cephalosporins and erythromycin were found to be statistically significantly associated with Clostridium difficile toxin associated‐diarrhoea. The results form the basis for designing a larger, prospective study. Copyright © 2001 John Wiley & Sons, Ltd.     

Novel prevention strategies for bacterial infections in cirrhosis

Introduction: Bacterial infections are a serious complication of cirrhosis, as they can lead to decompensation, multiple organ failure, and/or death. Preventing infections is therefore very relevant. Because gut bacterial translocation is their main pathogenic mechanism, prevention of infections is mostly based on the use of orally administered poorly absorbed antibiotics such as norfloxacin (selective intestinal decontamination). However, antibiotic prophylaxis leads to antibiotic resistance, limiting therapy and increasing morbidity and mortality. Prevention of bacterial infections in cirrhosis should therefore move away from antibiotics.

Areas Covered: This review focuses on various potentially novel methods to prevent infections in cirrhosis focusing on non-antibiotic strategies. The use of probiotics, nonselective intestinal decontamination with rifaximin, prokinetics and beta-blockers or fecal microbiota transplant as means of targeting altered gut microbiota, bile acids and FXR agonists are all potential alternatives to selective intestinal decontamination. Prokinetics and beta-blockers can improve intestinal motility, while bile acids and FXR agonists help by improving the intestinal barrier. Finally, granulocyte colony stimulating factor (G-CSF) and statins are emerging therapeutic strategies that may improve immune dysfunction in cirrhosis.

Expert Opinion: Evidence for these strategies has been restricted to animal studies and proof-of concept studies but we expect this to change in coming years.     

Impact of adding prophylactic probiotics to a bundle of standard preventative measures for Clostridium difficile infections: enhanced and sustained decrease in the incidence and severity of infection at a community hospital

Abstract

Background:

In 2003, hospitals in Quebec, Canada experienced an increase of NAP1/027 Clostridium difficile infections following antibiotic administration (CDIAA). At Pierre-Le Gardeur Hospital (PLGH), the incidence increased from 10 to over 25 cases per 1000 patient admissions.     

Differences in the rate of carbapenem-resistant Enterobacteriaceae colonisation or Clostridium difficile infection following frontline treatment with tigecycline vs. meropenem for intra-abdominal infections

Objectives

We hypothesised that treatment with a tigecycline-based antimicrobial regimen for intra–abdominal infection (IAI) could be associated with lower rates of subsequent carbapenem-resistant Enterobacteriaceae (CRE) colonisation or Clostridium difficile infection (CDI) compared with a meropenem-based regimen.

Modulators of the ghrelin system as potential treatments for obesity and diabetes

Background: Ghrelin is a stomach-derived octanoylated hormone that has been implicated in body weight regulation and glucose homeostasis. It mediates its pharmacological activities primarily through the ghrelin receptor (GhR). The discovery of small molecule GhR antagonists and other biological agents that can modulate ghrelin activity has attracted considerable interest over the past few years. Objectives: This review summarizes the role of ghrelin and its receptor in regulating body weight and glucose homeostasis and describes ghrelin system modulators that have appeared in the patent literature from 2002 to 2008. Results/conclusions: A variety of different agents that alter ghrelin activity have been disclosed, including peptidyl and non-peptidyl receptor antagonists as well as biological agents such as monoclonal antibodies, catalytic activating antibodies, vaccines and Spiegelmers. Many of these agents have been shown to decrease food intake and reduce body weight, although the effect of these modulators on glucose homeostasis has yet to be examined.     

Development of a Highly Sensitive and Specific Monoclonal Antibody Based on Indirect Competitive Enzyme-Linked Immunosorbent Assay for the Determination of Zearalenone in Food and Feed Samples

Zearalenone (ZEN) contamination in food and feed is prevalent and has severe effects on humans and animals post-consumption. Therefore, a sensitive, specific, rapid, and reliable method for detecting a single residue of ZEN is necessary. This study aimed to establish a highly sensitive and specific ZEN monoclonal antibody (mAb) and an indirect competitive enzyme-linked immunosorbent assay (icELISA) for the detection of ZEN residues in food and feed. The immunogen ZEN-BSA was synthesized via the amino glutaraldehyde (AGA) and amino diazotization (AD) methods and identified using 1H nuclear magnetic resonance (1H NMR), a high-resolution mass spectrometer (HRMS), and an ultraviolet spectrometer (UV). The coating antigens ZEN-OVA were synthesized via the oxime active ester (OAE), formaldehyde (FA), 1,4-butanediol diglycidyl ether (BDE), AGA, and AD methods. These methods were used to screen the best antibody/antigen combination of a heterologous icELISA. Balb/c mice were immunized with a low ZEN-BSA dose at long intervals and multiple sites. Suitable cell fusion mice and positive hybridoma cell lines were screened using a homologous indirect non-competitive ELISA (inELISA) and an icELISA. The ZEN mAbs were prepared by inducing ascites in vivo. The immunological characteristics of ZEN mAbs were then assessed. The standard curves of the icELISA for ZEN were constructed under optimal experimental conditions, and the performance of the icELISA was validated. The two ZEN-BSA immunogens (conjugation ratios, 11.6:1 (AGA) and 9.2:1 (AD)) were successfully synthesized. Four hybridoma cell lines (2B6, 4D9, 1A10, and 4G8) were filtered, of which 2B6 had the best sensitivity and specificity. The mAb 2B6-based icELISA was then developed. The limit of detection (LOD), the 50% inhibitive concentration (IC50), and the linear working range (IC20 to IC80) values of the icELISA were 0.76 μg/L, 8.69 μg/L, and 0.92–82.24 μg/L, respectively. The cross-reactivity (CR) of the icELISA with the other five analogs of ZEN was below 5%. Three samples were spiked with different concentrations of ZEN and detected using the icELISA. The average intra-assay recoveries, inter-assay recoveries, intra-assay coefficients of variations (CVs), and inter-assay CVs were 93.48–99.48%, 94.18–96.13%, 12.55–12.98%, and 12.53–13.58%, respectively. The icELISA was used to detect ZEN in various samples. The results were confirmed using high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) (correlation coefficient, 0.984). The proposed icELISA was highly sensitive, specific, rapid, and reliable for the detection of ZEN in food and feed samples.