Alternative Strategies in the Treatment of Clostridioides Difficile Infection

Asian Journal of Medicine and Health

19(4): 38-45, 2021; Article no.AJMAH.68103 ISSN: 2456-8414

Alternative Strategies in the Treatment of Clostridioides difficile Infection

Ryan Goon Hon Au1*

1Nanjing University of Chinese Medicine 138 Xianlin Rd, Nanjing 210023, P.R.C. China.

Author’s contribution

The sole author designed, analyzed, interpreted and prepared the manuscript.

Article Information

DOI: 10.9734/AJMAH/2021/v19i430320 Editor(s): (1) Prof. Darko Nozic, University of Belgrade, Serbia. Reviewers: (1) Nicoleta Negrut, University of Oradea, Romania. (2) Salem Bouomrani, Military Hospital of Gabes, Tunisia. Complete Peer review History: http://www.sdiarticle4.com/review-history/68103

Received 28 February 2021 Review Article Accepted 04 May 2021 Published 11 May 2021

ABSTRACT

Clostridioides difficile (C. diff.) is a leading cause of nosocomial infections worldwide and is a major challenge to public health. Widespread use of antibiotic agents have caused increasing incidence rates of C. diff. infections and the emergence of antibiotic-resistant strains of the potentially-deadly bacteria. The current treatment guidelines include the use of various antibiotics, which further contributes to the problem of antibiotic resistance. There is an urgent need for novel treatment methods in order to halt the emergence of even more antibiotic-resistant bacteria. This review discusses the pathogenesis of C. diff. infections, current treatment strategies, and possible alternative treatment strategies based on breakthrough scientific research.

Keywords: Clostridioides difficile; infection; antibiotic resistance; alternative treatment; nosocomial infection.

1. INTRODUCTION mild diarrhea to severe and potentially fatal pseudomembranous colitis [2]. Because its Clostridioides difficile (C. diff.), formerly known as vegetative form is strictly anaerobic, C. diff. Clostridium difficile before 2016,[1] is a species cannot survive outside of its host’s colonic of Gram-positive anaerobic bacteria that can environment. Under stressful conditions, they produce toxins causing symptoms ranging from produce spores that can resist extreme ______

*Corresponding author: E-mail: [email protected];

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conditions, including resistance to surface the body. Research studies have shown that cleaning and standard ethanol-based sanitizers. antibiotic treatments can induce changes in the This allows the spores to survive in hospital and microbiome and metabolome that increase healthcare settings for long periods of time, susceptibility to C. diff. infection [7]. These making them highly transmissible and infectious changes include an increase in the abundance of [3]. C. diff. infection occurs mainly through the taurocholate, a bile acid used by C. diff. for fecal-oral route, often from exposure to hospital germination, and also an increase in carbon equipment or surfaces contaminated with C. diff sources like stachyose, raffinose, sorbitol, spores [4]. The dormant spores make their way fructose, and mannitol which are all used by C. through the gastrointestinal tract and actively diff. for growth [7]. All of these changes lead to grow to their vegetative form when exposed to an environment favorable to the colonization of different constituents of bile [5]. The vegetative C. diff. and subsequent infection [7]. CDAD form of C. diff. produces and releases toxins into occurs when the vegetative form of C. diff. the colonic environment that causes diarrhea, produces toxins in the large intestine that cause also known as Clostridioides difficile-associated changes to the intestinal epithelial cells leading disease (CDAD). Standard treatment protocols to symptoms like diarrhea, abdominal pain, and mainly call for the use of certain antibiotic agents, fever. but the use of these antibiotic agents are also risk factors for C. diff. infections. Overuse of 2.2 Toxin-Mediated Damage these antibiotic agents also contribute to the growing problem of antibiotic-resistant strains of Toxin A (TcdA), Toxin B (TcdB), and C. difficile many types of bacteria including C. diff. itself, transferase toxin (CDT) are three of the toxins making certain bacterial infections increasingly produced by C. difficile [8-9]. TcdA and TcdB are difficult to treat. It is therefore important to find the two toxins that are highly researched, due to alternative treatment strategies that do not their responsibility for causing the cellular contribute to antibiotic resistance. changes leading to the symptoms of CDAD [8]. On the other hand, it is still unclear what role 2. PATHOGENESIS OF CDAD CDT plays on CDAD progression, although some research studies have shown that the toxin Although C. diff. toxins can cause severe increases bacterial adherence on intestinal diarrhea, the bacteria itself is present in the epithelial cells, implicating a role in C. diff. microbiome of some healthy individuals without colonization. Not all strains of C. diff. produce causing symptoms. Research has shown that C. CDT, but many of the strains isolated from diff. can asymptomatically colonize the gut of 0- patients with severe CDAD are able to produce 17.5% of healthy adults [6]. This implies that this toxin [9]. there are many other factors involved in the development of CDAD, not just the presence of The two main virulence factors in C. diff. are C. diff. in the gut. This section will discuss the TcdA and TcdB, glucosyltransferases that enter various factors involved in the pathogenesis of colonic epithelial cells by receptor-mediated CDAD. endocytosis before deactivating Rho-family GTPases like Rac, and Cdc42 [8]. Inactivation of 2.1 Colonization and Infection these cellular proteins result in cell apoptosis due to structural disruption. Recent research has C. diff. colonizes the gut by the transmission of shown that TcdA and TcdB often work together its spores starting at the mouth through to the to induce cell damage and death, but the large intestine. The spores are resistant to acids absence of either toxin can still result in disease. in the stomach, but start to germinate once they A recent study observed the activities of both come into contact with different bile constituents toxins side by side and found that TcdA causes further down the gastrointestinal tract. apoptosis in target cells dependent on the Fortunately, for healthy adults with an intact gut glucosyltransferase activity of the toxin, while microbiome that has not been treated with TcdB works differently at low and high antibiotic agents, C. diff. has difficulty concentrations [10]. At low concentrations, TcdB establishing itself in the large intestine. Although is dependent on glucosyltransferase activity to C. diff. may still be present in the large intestine, induce cell apoptosis, while at higher it is kept under control by the complex concentrations, it works independently of its interactions between the bacteria in the glucosyltransferase activity to cause cell death microbiome, and between the microbiome and by producing reactive oxygen species [10]. The

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presence of either TcdA or TcdB alone in the gut fidaxomicin, rifaximin, ramoplanin, tigecycline, is enough to produce the full spectrum of and nitazoxanide [17]. Unfortunately, treatment symptoms associated with CDAD [11]. with any type of antibiotic agent, whether it be broad-spectrum or narrow-spectrum, may TcdA and TcdB can act on many different potentially lead to the development of antibiotic mechanisms to cause disease. In addition to resistance. inducing necrosis in intestinal epithelial cells, TcdA and TcdB also degrades and inactivates Other uncommon treatment strategies are YAP and TAZ proteins in the cytoplasm. YAP available to treat more severe presentations of and TAZ are two proteins which act as CDAD, but are not often used due to their lack of transcriptional coactivators downstream of the testing or high price point. Some of these Hippo pathway, which is responsible for tissue treatment strategies include administration of homeostasis and intestinal regeneration [12]. immunoglobulins, monoclonal antibodies, or TcdB has also been shown to damage stem cells vaccines [17]. Immunoglobulins can be in the colon, inhibiting the ability of intestinal administered orally or intravenously, but there epithelial cells to repair itself [13]. By impairing are very few research studies with this treatment the colon’s ability to repair and regenerate on a strategy [18]. Studies have shown promising cellular level, C. diff. toxins create an results from treatment of CDAD with environment suitable for chronic disease. immunoglobulins, but intravenous immunoglobulin therapy is prohibitively 2.3 Disease Presentation expensive. Oral administration of immunoglobulins is promising but needs further The presence of C. diff. in the gut can result in a studies to show clinical efficacy [18]. variety of clinical presentations, ranging from being an asymptomatic carrier to having severe, Administration of monoclonal antibodies is potentially fatal fulminant colitis or toxic another possible treatment, but is not commonly megacolon. Infection by C. diff. can occur after used for CDAD. Bezlotoxumab is a monoclonal starting antibiotic therapy, often presenting as antibody that specifically targets antigens present mild to moderate diarrhea without blood. on the surface of TcdB, resulting in a very Abdominal cramps and anorexia may also effective treatment to prevent recurrent C. diff. accompany the diarrhea [14]. In severe cases, infection. As of 2017, Bezlotoxumab is the only colonoscopy will reveal pseudomembranes in the United States Food and Drug Administration large intestine, presenting as elevated colonic approved monoclonal antibody for C. diff. mucosal nodules or plaques that are white-yellow infection [19]. It is usually administered in color [15]. Severe cases will also present with intravenously as an adjunct treatment to fever, dehydration, electrolyte imbalance, metronidazole. Unfortunately, Bezlotoxumab is leukocytosis, and hypoalbuminemia. In cases extremely expensive at $3800 per vial, in where CDAD has progressed to toxic megacolon addition to the other costs associated with or fulminant colitis, there will be tenderness and administration of the treatment [20]. distention in the abdominal area, often of a severe nature [14]. Case studies have also There are a number of vaccines for the revealed that CDAD may also have extracolonic prevention of CDAD in development, but none manifestations such as small intestinal have been approved for official use yet. Similar involvement, reactive arthritis, cellulitis, to monoclonal antibodies, vaccines for CDAD bacteremia, sepsis, abscesses, and more [16]. target the toxins produced by C. diff., not the bacteria itself. Vaccines for CDAD use 3. STANDARD TREATMENT STRATEGIES recombinant or detoxified forms of TcdA or TcdB to instruct the body to create antibodies to help The treatment strategy upon initial diagnosis of neutralize the toxins. Unfortunately, this C. diff. infection is to always discontinue the approach alone only decreases the symptoms antibiotic agents that may have induced the associated with CDAD, but does not inhibit C. infection. Strangely enough, the standard diff.’s ability to germinate, colonize, and infect the treatment for initial CDAD is to use other gut. Because of this, CDAD vaccines have to be antibiotic agents like metronidazole and used in conjunction with other protocols like vancomycin, with a preference for vancomycin antibiotic treatment [21]. due to its ability to reduce fecal C. diff. counts to undetectable levels. Other possible antimicrobial Currently, the most promising treatment for agents suitable for treating CDAD include CDAD is fecal microbiota transplant (FMT),

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having shown good results in many clinical that can counteract TcdA and TcdB activity, and studies. FMT involves the transplant of fecal others. Below are some of the alternative material from a healthy donor into the colon of remedies that have been shown in laboratory diseased individuals. This process reintroduces settings to have potential therapeutic value in beneficial gut bacteria into the colon of patients treating CDAD. with CDAD, increasing bacterial diversity and essentially renewing their gut microbiome to be 4.1 Shen Ling Bai Zhu San (Ginseng, able to more effectively control the population of Poria, and Atractylodes Macrocephela C. diff. and toxin production [22]. Several routes Powder) of administration are available, including enema, colonoscopy, nasogastric tube, and capsules. A Shen Ling Bai Zhu San (SLBZS) is a very recent study compared the efficacy of all four commonly used TCM herbal formula for the methods of FMT and found that administration by treatment of various gastrointestinal issues, such colonoscopy was superior to nasogastric tube as diarrhea and poor appetite. This formula dates and enema, while administration by capsules back to the Song dynasty, where it was first was comparable to colonoscopy [23]. documented in the “Tai Pin Hui Min He Ji Ju Unfortunately, the C. diff. infection clinical Fang”, which translates to “Formulary of the practice guideline released by the Infectious Pharmacy Service for Benefiting the People in Diseases Society of America and Society for the Taiping Era” [26]. SLBZS has the following Healthcare Epidemiology of America ten herbs: Ren Shen (Radix Ginseng), Bai Zhu recommends antibiotic therapy as the standard (Rhizoma Atractylodis Macrocephalae), Fu Ling protocol for CDAD and only recommends FMT (Poria Cocos), Zhi Gan Cao (Radix Glycyrrhizae after multiple failed rounds of antibiotic therapy, Preparata), Shan Yao (Radix Dioscoreae), Bai indicating recurrent infection [24]. This treatment Bian Dou (Semen Dolichorus), Lian Zi (Semen recommendation inadvertently contributes to the Nelumbinis), Yi Yi Ren (Semen Coicis), Sha Ren growing problem of the development of antibiotic- (Fructus Amomi), and Jie Geng (Radix resistant strains of C. diff. Platycodi). In vitro studies have shown that SLBZS has bacteriostatic activities against 4. POSSIBLE ALTERNATIVE TREATME- different strains of C. diff., inhibiting its growth at NT STRATEGIES various concentrations [27]. Research has shown that the microbiome diversity is decreased in the Alternative medical systems like Traditional gut of patients with CDAD [28]. Expectedly, Chinese Medicine (TCM) have been used to SLBZS has also been shown to alter the gut successfully treat disorders like diarrhea for microbiome, increasing its diversity and restoring millennia. There are many TCM herbal formulas its balance [29]. These actions show a lot of that can treat various presentations of diarrhea. It promise, but SLBZS needs further in-vivo studies comes as no surprise that some of the herbal to confirm its efficacy in the treatment of CDAD. components within these formulas have antimicrobial properties against C. diff. and other 4.2 Qi Pi Yi Fei (Arousing the Spleen and diarrhea-causing microbes. Plant-based Tonifying the Lung) remedies often target bacteria through mechanisms different than conventional Qi Pi Yi Fei (QPYF) is a TCM herbal formula antibiotics and can act as resistance modifying used for treating antibiotic-associated diarrhea. agents, which are compounds that act against QPYF has the following seven herbs: Hong Jing bacterial resistance [25]. Not only would these Tian (Rhodiola Rosea), Fu Ling (Poria Cocos), plant-based remedies help resolve the issue of Dang Shen (Codonopsis Pilosula), Bai Zhu antibiotic resistance, they would also help (Atractylodes Macrocephala), Ge Gen (Radix prevent the development of more difficult-to- Puerariae), Sheng Jiang (Rhizoma Zingiberis), control resistant strains. and Gan Cao (Radix Glycyrrhizae). This formula was studied on a C. diff.-associated diarrhea Similar to strategies of orthodox medicine, there mouse model, where mice were given a mixture are many different approaches to target C. diff. of different antibiotic agents including kanamycin, with natural remedies in the treatment of CDAD. gentamicin, colistin, metronidazole, vancomycin, Some of these approaches include using herbs and clindamycin before being infected with C. that have been shown to have bactericidal or diff. by oral gavage [30]. In this research, an bacteriostatic activity against C. diff., using herbs experimental group of mice were given QPYF that can neutralize C. diff. spores, using herbs

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seven days prior to C. diff. infection as a berberine chloride was able to block the preventative measure. Although this study did outgrowth of spores that started to germinate not directly evaluate the effects of QPYF on C. [32]. Further in-vivo studies and clinical trials may diff., it showed promising results in the confirm if berberine chloride has the ability to prevention of CDAD caused by antibiotic therapy. help control CDAD in humans. Histopathological analysis showed reduced colon tissue damage and immunohistochemical 4.5 Curcuminoids analysis showed reduced expression of the disease pathways tumor necrosis factor-alpha, Curcuminoids are active components found in monocyte chemoattractant protein-1, nuclear turmeric, a yellow rhizome used as a spice and factor kappa-light-chain-enhancer of activated B food coloring in many Asian countries. It is also cells p65, and phosphorylated-nuclear factor- an herb in traditional Indian medicine and kappa-light-chain-enhancer of activated B cells traditional Chinese medicine systems [33]. A p65. Clinical symptoms like diarrhea and weight study researching curcumin, loss were improved and mortality was reduced. demethoxycurcumin, and Toxin secretion was also reduced as shown by bisdemethoxycurcumin, three curcuminoids in toxin analysis. Overall, this study shows that turmeric, found that they all inhibited the growth QPYF given preventatively may help treat CDAD of various C. diff. strains but did not affect spore in mice [30]. Clinical trials with this formula may formation. In addition, these curcuminoids further determine its clinical efficacy in humans. inhibited toxin production and did not have negative effects on major bacteria populating the 4.3 Baicalin human gut like Lactobacillus, Bifidobacterium, and Bacteroides [34]. Further in-vivo studies and Baicalin is an active component found in several clinical trials may confirm if curcuminoids has the TCM herbs, but it is most widely associated with ability to help control CDAD in humans. Huang Qin (Radix Scutellaria baicalensis). Huang Qin itself is an herb that can treat diarrhea 4.6 Manuka Honey or dysentery and is also included in many herbal formulas that treat various gastrointestinal Manuka honey is derived from the flowers of the issues. A recent in-vitro study explored the Manuka tree (Leptospermum scoparium) in New efficacy of baicalin’s ability to reduce C. diff. Zealand. It has recently attracted the attention of sporulation and toxin production and found that the medical field for its strong antimicrobial its subinhibitory concentration significantly properties, due to its methylglyoxal content [35]. reduced C. diff. spore outgrowth, sporulation, Unsurprisingly, Manuka honey has also been and toxin synthesis. The study also found that studied for its antibiotic activity against C. diff. A baicalin significantly downregulated gene study found that Manuka honey has inhibitory expression in C. diff. critical for its pathogenesis and bactericidal activity against various C. diff. [31]. Further in-vivo studies and clinical trials may strains [36]. It can also inhibit spore proliferation confirm if baicalin has the ability to help control but does not completely eradicate them [36]. CDAD in humans. Further in-vivo studies and clinical trials may confirm if Manuka honey has the ability to help 4.4 Berberine control CDAD in humans.

Berberine is an active component found in 5. CONCLUSION several TCM herbs, but it is most widely associated with Huang Lian (Rhizoma Coptidis). Clostridioides difficile is a very problematic Huang Lian itself is an herb that can treat bacterium that can spread virulently and cause diarrhea or dysentery with or without bleeding. severe diarrhea in humans. Their spores are Like Huang Qin, Huang Lian is also included in highly resistant to extreme conditions, allowing many herbal formulas that treat various them to survive and thrive when the right gastrointestinal issues. A commonly conditions become available. C. diff.’s treatment administered form of berberine is berberine with antibiotics like metronidazole and chloride, often found in pills or liquid form. A vancomycin have resulted in the development of study found that berberine chloride had antibiotic resistant strains, further adding to its antibacterial activity against all of the C. diff. virulence and difficulty in treatment. strains investigated but did not affect their Immunoglobulins, monoclonal antibodies, and spores. Although the spores could not be killed,

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