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Topic: Evolution of resistance in nosocomial infections cause by the bacteria C. difficile.

Dawson, L.F., E., Valiente, and B.W., Wren. 2009. Clostridium difficile—A continually evolving and problematic pathogen.

This article gives an overview of CDIs and focuses on the virulence factors, including antibiotic resistance. It also emphasizes how the 017, 028 and 078 strains have evolved and explains the virulence factors that make these strains difficult to treat. This article provides extensive details on research techniques used to study the genome of C. difficile strains.

Du, P., B., Cao, and J., Wang, et. al. 2014. Sequence Variation in tcdA and tcdB of Clostridium difficile: ST37 with Truncated tcdA Is a Potential Epidemic Strain in China. Journal of Clinical Microbiology 52:3264-3270.

This article discusses the study of strains of C. difficile found in China that is becoming more resistant to the antibiotics clindamycin and erythromycin. The methods used by the authors included the regions of the genome, tcdA and tcdB, and analyzing SNPs. The results included gaining an understanding of the genetic differences between the strands. The article is limited in its scope of comparing two strains of the bacterium and not how evolution has occurred.

Knight, C.L. and C.M., Surawicz. 2013. Clostridium difficile Infections. Medical Clinics of North America 97:532-536.

This article gives an extensive explanation of CDIs including diagnostic studies and details about various antibiotics. There are pictures and flow-charts that provided additional resources to understanding the effects of this infection. This article will help characterize the different antibiotics and show how the bacteria have evolved to become resistant to many of them.

Terrier, M.C.Z., M.L., Simonet, P. Bichard, and J.L. Frossard. 2014. Recurrent Clostridium difficile infections: The importance of the intestinal microbiota. World Journal of Gastroenterology 20:7416-7423.

This article gives an overview of CDIs including the risk factors of infection and treatment by fecal transplant. There is a focus on the importance of the microbiota in the intestine and how antibiotics cause a change in the variety present, which leads to opportunity for pathogenic infection. This article provides ample general information and may lead to more research in how microbiota in intestine is affected by evolutionary changes.

van Kleef, E., A., Gasparrini, and R., Guy, et. al. 2014. Nosocomial Transmission of C. difficile in English Hospitals from Patients with Symptomatic Infection. PLoS ONE 9: 1-7.

This article discusses the source of transmission of CDI (C. difficile infection) in English hospitals. The methods used included collecting fecal samples, observations of the patients and examining the medical records of patients (admission date, age, etc). The results found were that the most number of cases occurred in teaching hospitals and the role of carriers in one of the statistical projections had a lower correlation than expected. A limitation of the study was that the strains of C. difficile were not tested to see if the infections were part of the same strain. The statistical model used does not accurately reflect the correlation in all hospitals but was very accurate for teaching hospitals.

https://en.wikipedia.org/wiki/Evolutionary_pressure

Antibiotic Resistance Section Improvements
1. This section provides a very generalized overview of how natural selection has led to bacteria that are antibiotic resistant. A more detailed explanation of how the bacteria become resistant over multiple generations would add a greater understanding to the evolutionary process and why this pressure exists.

2. There are not any specific examples of antibiotic resistant bacteria or names of antibiotics that are commonly used to treat illnesses. The addition of specific examples, such as the bacteria C. difficle would enhance the content of the section.

3. In order to demonstrate why evolutionary pressures for antibiotic resistance are significant, it would be beneficial to add more information about the consequences of antibiotic resistance. A suggested area of interest could be how nosocomial infections have developed as a result of antibiotic resistance.

For example, in hospitals, environments are created where pathogens such as C. difficile have developed a resistance to antibiotics.

FINAL DRAFT STARTS HERE
Evolution of resistance in nosocomial infections caused by the bacteria Clostridium difficile

A common occurrence in current healthcare practice is asking your health care provider for an antibiotic prescription when feeling ill. Taking the prescription is the perceived simple solution to eliminate the harmful bacteria in the body, however there exists a great concern in the over and unnecessary consumption of antibiotics. The increase in the number of prescriptions of antibiotics consumed has become a relevant issue in evolutionary biology, especially concerning antibiotic resistant bacteria. This issue is underrepresented as a growing concern among evolutionary biologists, but a look into the implications of Darwinian Medicine show the pertinacity of research in combating antibiotic resistant bacteria. Clostridium difficile, gram-positive bacteria that inhabit the gut of mammals, is a model example of one type of bacteria that a major cause of death by nosocomial infections (Dawson et al. 2009). When the normal gut flora is altered, for instance by taking an antibiotic, an environment suitable for foreign pathogens to proliferate is created and infection rates flourish. The concern stemming in the medical field is the continuation of the established protocol for treatment of a bacterial infection, prescribing an antibiotic. The antibiotic will be effective in killing the pathogenic bacteria but consequences exist if the bacteria do not respond to the antibiotic. It is plausible that the infectivity could be due to the presence of antibiotic-resistant bacteria in the patient. Because C. difficile has evolved to become resistant to many commonly used antibiotics, treating a CDI (Clostridium difficile Infection) has substantiated into an immense challenge for doctors. The field of Darwinian Medicine in evolutionary biology is at the forefront of research in developing new treatments for patients infected with C. difficile. The evolutionary arms race between the rapidly evolving virulence factors of the bacteria and treatment practice of modern medicine, requires evolutionary biologists to understand the mechanisms of resistance in these pathogenic bacteria, especially, considering the growing number of infected hospitalized patients. In order to understand the evolved virulence of C. difficile, it is imperative to examine its treatment origins in medicine. Microbiologists examining fecal matter in 1935 first discovered the bacteria and bestowed the name Bacillus difficilus (Knight and Surawicz 2013). The name was changed to clostridium in the 1970s when more research found that toxins from the spores of the bacteria were the main agents of infection (Knight and Surawicz 2013). The implications of the short evolutionary time period for this bacteria to become resistant to most antibiotics has to be a concern for the pharmaceutical industry in the United States and worldwide. It has been estimated that it costs one-billon dollars per year to treat patients with CDIs in U.S. hospitals (Terrier et al. 2014). This staggering cost could only increase if more people acquire these bacteria that cannot be effectively treated. The rapid evolution of antibiotic resistance places an enormous selective pressure on the advantageous alleles of resistance passed down to future generations. The Red Queen Hypothesis shows that the evolutionary arms race of pathogenic bacteria and humans is a constant battle for evolutionary advantages to outcompete each other. It is obvious there exists a need to develop effective treatments in order to keep humans “in place” evolutionarily. Virulence factors are the characteristics that the evolved bacteria have developed to increase pathogenicity. One of the virulence factors of C. difficile that largely constituents its resistant to antibiotics is its toxins: enterotoxin TcdA and cytotoxin TcdB (Terrier et al. 2014). Toxins produce spores that are difficult to inactivate and remove from the environment. This is especially true in hospitals where an infected patient’s room may contain spores for up to 20 weeks (Kim et al. 1981). The threat of rapid spread of CDIs is therefore dependent on hospital sanitation practices to remove spores from the environment. A study published in the American Journal of Gastroenterology found that to control the spread of CDIs glove use, hand hygiene, disposable thermometers and disinfection of the environment are necessary practices in health facilities (Hsu et al. 2010). The virulence of this pathogen is remarkable and may take a radical change at sanitation approaches used in hospitals to control CDI outbreaks. It is interesting to examine how the evolution of virulence factors has permitted bacteria a survival advantage at the expense of the human host. The bacteria that have evolved to become antibiotic resistant possess an advantage in competing with normal gut flora and these beneficial genes will be passed on to future generations. Because bacteria can multiply rapidly, it does not take long for a strong presence of resistant bacteria to emerge in the population of gut flora. This maladaptation comes at a price for human hosts in the form of Clostridium difficile infections. While the bacteria continue to survive and proliferate in hospital environments, many of the hosts are killed as a result. The evolutionary arms race has existed since the beginning of time for harmful bacteria attempting to colonize the human gut. In this battle for dominance postulated in the Red Queen Hypothesis, the pathogenic bacteria are currently outcompeting the human gut flora. This only adds to the immense pressure on the pharmaceutical industry to engineer new treatment plans to improve human’s ability to fight against these pathogens. The main task faced by evolutionary biologists and doctors is to apply the knowledge of the mechanism of the evolution of virulence factors in order to discover effective treatment plans for nosocomial infections. By decreasing the number of deaths from nosocomial infections, this would help hospitals financially and save more lives of patients. Diagnosis is characterized by severe diarrhea and a stool analysis to detect the presence of C. difficile (Terrier et al 2014). This is logical because the pathogenic bacteria thrive in the gut flora and the body is trying to respond by removing the pathogens in stool. Other methods of testing for the detecting C. difficile includes: enzyme immunoassay (EIA) testing for toxin A, B, and glutamate dehydrogenase (Knight and Surawicz 2013). The article published by Knight and Surawicz characterizes the varying severity of symptoms of CDIs, “Patients with severe CDI frequently have abdominal pain caused by ileus, colonic dilation, and even toxic megacolon.” This confirms the effect that the pathogen has on the digestive system and shows that sever symptoms can be the cause of patient death if not treated. Diagnosis of a CDI has been improved by technological accuracy of diagnostic tests. Darwinian medicine is an active field of research among the scientific community in an effort to combat the increased rates of mortality from nosocomial infections. Research studies in England and China, emphasize the impact these specific infections have on global health which shows this problem is not isolated in the United States. Recent studies in English hospitals have shown that patients can pass CDIs to other patients and this rate may contribute to the growing number of acquired infections in hospitals (van Kleef et al. 2014). In China, researchers are studying a hypervirulent strain of the bacteria, C. difficile RT017, which only produces toxin B, is resistant to the antibiotics erythromycin and clindamycin and is predominately found in Asia The research methods in study in China previously mentioned used analysis of single nucleotide polymorphisms (SNPs) to decipher genetic differences between different strains of C. difficile (Du et al. 2014). This shows how advances in genetic sequencing are fundamental in understanding the intricacies of these infections. The technology that is at the disposal of scientist today, allows for a greater knowledge of where evolution in the genome of bacteria has occurred. The treatment plan for a nosocomial infection is difficult to concoct but physicians currently use several established methods. Although the bacteria have developed resistance to common antibiotics, there are several very strong ones that can be used in initial treatment. Metronidazole is used for a minor infection, while vancomycin is used to treat the onset of a severe infection (Terrier et al. 2014). Vancomycin is well known as an antibiotic that is only used in a scenario in which no other antibiotic treatments have been successful. It can be inferred that, this treatment is applied with caution because of the potential risk of creating vancomycin resistant strains of C. difficile. This generates a strain of bacteria that is resistant to arguably the strongest antibiotic on the pharmaceutical market. One treatment method that has proven to be effective in combating these virulent bacteria is fecal transplants. Fecal matter is taken from a donor and combined with saline before implanted into the gastrointestinal tract of the ill patient (Terrier et al. 2014). The theory behind fecal matter transplant (FMT) is that the infusion of healthy stool will rebalance the microbiota of the patient affected with the pathogen. Any healthy bacteria that could have been eliminated by a broad-spectrum antibiotic will be reinstated to compete with the virulent pathogens. This treatment method has been proven in successful treating CDIs and as evidenced by a review published in 2011, “This review showed that 85%-90% of patients treated with FMT did not develop recurrence during the follow-up period (which varied from 3 d to 5 years), again pointing to FMT as an effective treatment for recurrent CDI” (Gough et al. 2011). Fecal matter transplants (FMT) show great promise as an effective treatment plan for CDIs but more research needs to be completed in order to find an treatment that eradicates the pathogenic bacteria from the body. The evolution of the Clostridium difficile bacteria presents a significant interest in the field of evolutionary biology. The ramifications of not controlling the increase of nosocomial infections caused by antibiotic resistance are dire if no advances are made by the pharmaceutical industry. The creation of “super-viruses” could become a daunting reality if treatments are not found for nosocomial infections. It is extremely contentious to alter a well-established evolutionary arms race between pathogenic bacteria and humans. Currently, the pathogenic bacteria have the advantage but with modern advancements in medical technology, these infections could be eradicated in the future. At the core of the issue of increased antibiotic resistance is the maladaptation acquired by the pathogens. The evolved virulence factors pose a threat to patients in hospitals, who are immunocompromised from illness or antibiotic treatment. The selective pressure results in the resistant alleles passed down to further generation, which keep the alleles in the bacteria population of the gut flora. Hospitals spend billions of dollars worldwide providing care for patients who eventually succumb to death from a CDI. Darwinian medicine is an important sub-discipline of evolutionary biology especially in the context of antibiotic resistance. This is an active area of research and is worth investing capital and resources because the consequences could compromise the medical treatment of patients infected with C. difficile.

Literature Cited

Dawson, L.F., E. Valiente, and B.W. Wren. 2009. Clostridium difficile—A continually evolving and problematic pathogen. Infections,    Genetics and Evolution. 9:1410-1417.

Du, P., B. Cao, J. Wang, W. Li, H. Jia, W. Zhang, J. Lu, Z. Li, H. Yu, C. Chen, and Y. Cheng. 2014. Sequence Variation in tcdA and    tcdB of Clostridium difficile: ST37 with Truncated tcdA Is a Potential Epidemic Strain in China. Journal of Clinical Microbiology    52:3264-3270.

Gough, E., H. Shaikh, and A. R. Manges. 2011. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clinical Infectious Diseases. 53:994–1002

Hsu, J., C. Abad, M. Dinh, and N. Sadfar. 2010. Prevention of endemic healthcare-associated Clostridium    difficile infection: reviewing the evidence. American Journal of Gastroenterology 105:2327–39 quiz 2340.

Kim, K. H., R. Fekety, D. H. Batts, D. Brown, M. Cudmore, J. Silva Jr., and D. Waters. 1981. Isolation    of Clostridium difficile from the Environment and Contacts of Patients with Antibiotic-Associated Colitis. The Journal of Infectious    Diseases 143: 42–50

Knight, C. L., and C. M. Surawicz. 2013. Clostridium difficile Infections. Medical Clinics of    North America 97:532-536.

Terrier, M. C. Z., M. L. Simonet, P. Bichard, and J. L. Frossard. 2014. Recurrent Clostridium    difficile infections: The importance of the intestinal microbiota. World Journal of Gastroenterology 20:7416-7423.

van Kleef, E., A. Gasparrini, R. Guy, B. Cookson, R. Hope, M. Jit, J. V. Robotham, S. R. Deeny, and W. J. Edumunds. 2014. Nosocomial Transmission of C. difficile in English Hospitals from Patients with Symptomatic Infection. PLoS ONE 9: 1-7.

Edit Existing Page Assignment (11/17)
Page edited: https://en.wikipedia.org/wiki/Evolutionary_pressure

Addition:

Nosocomial Infections
Clostridium difficile, gram-positive bacteria that inhabit the gut of mammals, is a model example of one type of bacteria that a major cause of death by nosocomial infections. When the normal gut flora is altered, for instance by taking an antibiotic, an environment suitable for foreign pathogens to proliferate is created and infection rates flourish. The rapid evolution of antibiotic resistance places an enormous selective pressure on the advantageous alleles of resistance passed down to future generations. The Red Queen Hypothesis shows that the evolutionary arms race of pathogenic bacteria and humans is a constant battle for evolutionary advantages to outcompete each other. The evolutionary arms race between the rapidly evolving virulence factors of the bacteria and treatment practice of modern medicine, requires evolutionary biologists to understand the mechanisms of resistance in these pathogenic bacteria, especially, considering the growing number of infected hospitalized patients. The evolved virulence factors pose a threat to patients in hospitals, who are immunocompromised from illness or antibiotic treatment. Virulence factors are the characteristics that the evolved bacteria have developed to increase pathogenicity. One of the virulence factors of C. difficile that largely constituents its resistant to antibiotics is its toxins: enterotoxin TcdA and cytotoxin TcdB. Toxins produce spores that are difficult to inactivate and remove from the environment. This is especially true in hospitals where an infected patient’s room may contain spores for up to 20 weeks. The threat of rapid spread of CDIs is therefore dependent on hospital sanitation practices to remove spores from the environment. A study published in the American Journal of Gastroenterology found that to control the spread of CDIs glove use, hand hygiene, disposable thermometers and disinfection of the environment are necessary practices in health facilities. The virulence of this pathogen is remarkable and may take a radical change at sanitation approaches used in hospitals to control CDI outbreaks.