Comparing the Efficacy of Antibiotics Vs. Fecal Transplant in the Treatment of Clostridium Difficile Infection (CDI)

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Introduction

Electron micrograph of the Ebola Zaire virus. This was the first photo ever taken of the virus, on 10/13/1976. By Dr. F.A. Murphy, now at U.C. Davis, then at the CDC.

By: Yara Awwad

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Clostridium difficile infection (CDI) has become a major source of morbidity and mortality at hospitals in recent years. According to the CDC, around half a million Americans suffer from Clostridium difficile infection each year. Studies show that Clostridium difficile infections became more severe, prevalent, and difficult to treat. The infection is caused by the toxins produced by the bacteria Clostridium Difficile and it spreads through spores.

Clostridium difficile bacteria are found around the environment is soil, food, air, water and feces. Some people have C. diff in their large intestine in an inactive, non-infectious form. The bacteria also produces spores that ensure their survival under extreme conditions. If these spores are formed in the colon, they can survive antibiotics and could turn into a pathogenic active form.

Depending on the severity of the Clostridium difficile infection, it can be treated using antibiotics that stop the bacteria from growing. However, some strains are becoming more resistant to antibiotics which is making CDIs harder to treat. If the infection is severe, surgery is usually performed to remove the diseased portion of the colon. Around 20% of the people with C.diff get the infection again. In recurring cases, antibiotic therapy is conducted, but the effectiveness of this treatment has been declining. Recent research suggests that an alternative strategy for treating recurring CDI is fecal microbiota transplant (FMT) has promising results.

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Bacteria & Pathogenesis

Clostridium difficile is a gram-positive bacillus bacteria that is part of the normal intestinal microbiota of 1-3% of adults and 15-20% of infants. The clostridium genus consists of relatively large, rod shaped, and motile bacteria in the Firmicutes phylum. The genus has more than 100 known species including harmful pathogens such as Clostridium tetani, C. butyricum, and Clostridium sordellii, which produce some of the most potent toxins in human’s history.

Clostridia are anaerobic and spore-forming bacteria that is commonly found in oxygen deficient soil. They produce spores under stress which makes them highly resistant to physical and chemical influences. C . difficile spores germinate in the colon and form vegitative cells that initiate CDI. Due to its anaerobic nature, c. difficile is unable to survive aerobically in the vegitative form. Therefore, during the course of the infection, C. difficile induces the sporulation pathway that produces more dormant spores, which remain stable for long times. The spores are responsible for the persistence and recurrence of the infection in patients. They are also the source of horizontal transmission that occurs between patients.

In the presence of cholic acid derivatives, the germination of spores plays a critical role in the pathogenesis of CDI. Germination of spores is a biophysical process that results in the loss of spore specific properties. This includes the transitioning from the metabolically dormant spore form to the active-growing, toxin forming vegitative form. In C. difficile, this process is initiated by cholate derivatives, bile acids, and amino acid signals from the host cells. Germination is activated when the germinants bind to Ger-type receptors that are found inside or on the surface of the inner spore membrane. The signals trigger cortex hydrolysis by cortex lytic enzymes which are found in the spore coat region. The spore cortex is a thick layer of modified peptidoglycan that surrounds the cell well and helps prevent osmolysis. The coat and the cortex degenerations release Ca-DPA and result in the full core rehydration and the initiation of the outgrowth of a new vegetative cell.

Pathogenic strains of C. difficile grow and produce two major toxins, Toxin A (TcdA) and toxin B (TcdB). Certain C.diff strains are also able to produce a binary toxin called C. diff transferase (CDT), which is not as prevalent or severe as the other two toxins. Only a few strains can produce CDT in the absence of toxins A and B.These toxins are part of the large clostridial glucosylating toxin (LCGT) family. TcdA and TcdB act on the colon epithelium and immune cells, inducing a cascade of complex reactions that result in the secretion of fluids, inflammations, and tissue damage, all of which are important marking features of CDI. Toxins A and B are produced in the Pathogenicity loci (PaLoc) by the genes tcdA and tcdB respectively. The expression of these genes is regulated by several environmental conditions including the availability of nutrients and temperature. PaLoc can be transferred horizontally to non-pathogenic strains converting them into pathogenic strains.

Toxins enter the cells by endocytosis then they are translocated to the host cell cytosol. In the cytosol, TcdA and TcdB glucosylate several members of the Rho subfamily and result in the inactivation of Rho proteins. These proteins have several functions and they interact with the kinases and phospholipases in the host cell that are responsible for signal transduction pathways. Rho proteins regulate actin cytoskeleton, the cell cycle progression, and the phagocytosis and cytokine production. Therefore, the toxins can induce cytopathic effects causing the loss of cell-cell contact and increase the epithelial permeability. All of which lead to cell apoptosis.

Toxin A results in the direct damage of the intestinal mucosa. This causes symptoms of CDI including pseudomembranous colitis, which is the swelling or inflammation of the colon due to the growth of C. difficile. During pseudomembranous colitis, the toxins are able to disrupt the tight junctions of epithelial barriers. This provides a way for neutrophils to accumulate in the intestines. In severe colitis cases, the toxins kill the tissues of the colon’s inner lining and cause the tissues to fall.

Toxin B is an essential virulence factor, but it is not as important as toxin A. This was proven when mutant cells with inactive tcdA still produced the same levels of tcdB, while mutant cells with inactive tcdB produced tcdA 2 to 3 times more.

Risk factors and transmission

Clostridium difficile can live in the human intestines without causing any diseases or illnesses. However, people begin to get sick when the spores are formed. In a healthy intestine with normal microbiota, the germination of C. difficile spores is prevented by other bacteria and the processing of cholate derivatives. Patients receiving several antibiotic treatments usually have most of their intestinal microflora disrupted or killed. This prevents the metabolism of cholates which in turn results in the germination and outgrowth of the c. diff spores. The lower competition in the intestine due to the absence of gut flora helps the spores to thrive and become more pathogenic. The antibiotics that most lead to CDI include penicillin, Fluoroquinolones, Cephalosporins, and Clindamycin.

The majority of CDI cases occur in people who had recent visits to a health facility. In these places, the most common method of infection spread mainly on hands from one person to another. Other risk factors associated with the development of CDI include advanced age, immunocompromised individuals, and renal diseases. One of the studies indicated that becoming infected with CDI is around 10 times greater in people who are 65 years or older. Women and people who previously had the infection are more likely to be infected. The risk continues to rise with each infection.

Spores are metabolically dormant which means that they are intrinsically resistant to antibiotics and attacks from the host's immune system. Therefore, spores from C .difficile are excreted in feces and spread in food and on surfaces when infected individuals do not wash their hands regularly and carefully. Once spores are shed into the environment, they are also resistant to disinfectants that do not have bleach in them. Therefore, the spores can be easily found on surfaces and equipment at hospitals, nursery homes, and households.

The best methods to prevent the transmission of CDI is by washing hands regularly. Soap and warm water are encouraged to maintain hygiene since most hand sanitizers do not effectively destroy the spores. Cleaning products containing bleach should be used to kill spores off of surfaces and objects. It is also very important to avoid the use of unnecessary antibiotics to maintain the healthy functioning of flora in the intestines and prevent the formation of spores.

Symptoms

Clostridium difficile infection ranges from asymptomatic colonization and mild diarrhea to toxic and life threatening megacolon and the inflammation of the lining of the abdominal. The signs and symptoms of the infections take an average of 5 to 10 days to develop. The symptoms of the mild to moderate CDI include diarrhea around three times a day for at least two consecutive days and mild abdominal cramping and tenderness.

Severe CDI, the colon becomes inflamed and sometimes forms patches of raw tissues that bleed or produce pus. The symptoms of the severe infection include blood or pus in the stool, and watery diarrhea 10 to 15 times a day, which leads to severe dehydration due to the lack/disruption of electrolytes in the body. This can cause blood pressure to drop to abnormally low levels which increases the heart rate. If the dehydration occurs quickly and not enough liquid is supplemented, the kidney function rapidly deteriorates which could result in a kidney failure. Fever, nausea, appetite and weight loss, increased white blood cells count, and swollen abdomen are all common symptoms of CDI.

In some rare cases, the colon will be unable to expel gas and stool causing it to become enlarged (megacolon). If the colon is left untreated, it could rupture and cause the bacteria to enter the abdominal cavity. Moreover, in more extreme cases, extensive damage to the lining of the intestine which could lead in the formation of a hole in the large intestine. This also results in bacteria to be spilled from the large intestine into the abdominal cavity. All the aforementioned cases could eventually lead to life threatening consequences.

Treatments:

The first step to treating CDI is by stopping the administration of any other antibiotics that are not prescribed to treat this infection. The most common/standard way of treating this infection is by taking antibiotics that prevent c. difficile from growing. The antibiotics vancomycin and fidaxomicin are usually used for this purpose. Around 10 percent of the patients do not respond to the antibiotic treatment the first time and approximately 20% of treated patients are reinfected with CDI. In cases of non-respondents or recurrence, treatments are usually conducted either by antibiotics or a fecal microbiota transplant. Probiotics are also being extensively tested for the preventative nature of the infection. The role of probiotics in CDI is controversial. However, recent studies are providing emerging evidence for their role in the primary prevention of CDIs.

Antibiotics:

For the first recurrence, tapered and pulsed vancomycin are usually used if vancomycin was used for the first treatment. Tapered/pulsed vancomycin is used to target the spores. After germination, a prolonged course of the tapered/pulsed regimen is given to attack the vegitative form of the cells. An alternative antibiotic is fidaxomicin, which has a narrower range than vancomycin and thus causes minimal disruption in the gut flora. Ridinilazole is another antibiotic used in phase two treatment that targets clostridia while causing minimal damage to the flora.

A study conducted by Vickers and colleagues in which patients who tested positive for CDI were split into two groups, a group that receives oral vancomycin and the other receives oral ridinilazole. They studied the sustained clinical response (SCR) which includes a cure at the end of the treatment and no recurrence after 30 days of infection clearance. The results show that ridinilazole exhibited superiority over vancomycin in a sustained clinical response. Therefore, studies show that ridinilazole and fidaxomicin are generally used in first treatments and they show better results in terms of a sustained clinical response when compared to other antibiotics, but their use is limited due to their high costs. These antibiotics are also used if the first treatment with vancomycin fails. However, the use of ridinilazole or fidaxomicin for recurrent CDI is still being studied.

References

Authored for BIOL 238 Microbiology, taught by Joan Slonczewski, 2018, Kenyon College.