EVERY answer sheet MUST include (a) full student name, (b) student number, (c) subject code, (d) subject group, (e) page number & (f) total number of pages. Name: Subject Code Page No.: Chan Tsz Lam SEHH2232 1 Student No.: Subject Group: Total no. of pages: 18147269A 201C 7 Please type your answer below with each question number clearly stated. You do NOT need to start a new page for each question. Question 1a As bleeding occurs, the hemostatic mechanisms are triggered to create inflammatory response in host with the help of granulocytes or polymorphonuclear leukocytes (PMNLs)1. It begins with vascular changes. Vasodilation occurs at the infected site under nervous stimulation, chemical mediators and cytokines released by blood cells, tissues and platelets, like histamines2. Since the blood vessels dilate, more blood flows to the injured tissue, thereby, wound area becomes red and warm to touch2-3. Released prostaglandins increase cyclic AMP level and enhance nociceptor sensitization which irritate the neurons to bradykinin and contribute to pain sensation and fever that Samuel is suffering which gives a protective function4. Fever can be categorized into endogenous and exogenous. Endogenous pyrogens are liberated by granulocytes under process of phagocytosis while exogenous pyrogens are mostly come from the products of Clostridium perfringens which trigger fever as well2. The elevated body temperature helps to stimulate leukocytes to deploy and kill invaders, reducing the available free plasma iron, and inducing interleukin 1 production, which further activates lymphocytes proliferation, maturation and activation in the immune response; reducing the bacteria’s rate of growth and kills them more quickly5. Vasoactive mediators, like serotonin, cause endothelial cells to contract and form gaps, accompanied with the increased permeability of vascular endothelium, allowing influx of fluid dilutes toxic substances2,6. Accumulated leukocytes, such as neutrophils, monocytes and macrophages infiltrate into the extracellular space, containing varying amount of plasma proteins and form exudate2,7. Since the exudate accumulates and increases with pus into the tissue, this creates a local swelling and firmness on the surrounding wound area, causing edema on Samuel’s right shin. Moreover, under PMNLs activity, the complement proteins released by macrophages, monocytes initiated a cascade of reactions including chemotaxis. Some bacterial cells were cleared by phagocytosis to the wound surface and formed slough. Slough is a necrotic non-viable fibrous yellow tissue and appear in greenish color as a result of infection or damaged tissue in the wound 1. Samuel’s exudate not only appears greenish in color, but also gives a foul-smelling on the wound due to tissue breakdown and bacterial colonization8-9. Therefore, odorous greenish discharge was found. Besides, as inadequate local blood supply to the wound, ischemia has occurred and tissue has died, forming eschar which shows little dark-colored necrotic tissue along the edge of Samuel’s wound9-10. Increasing pain over the injured site of prior injury may also indicate the signs of systemic toxicity and gas in the tissue caused by gas gangrene from C. perfringens11. Lastly, the bacterial infection invaded the deeper layers of skin in the unproperly-treated wound, like soft tissues and nerves, causing peripheral neuropathy12-13. The motor nerves may be affected, leading to muscle weakness13as a result of difficulty in walking in Samuel’s case. (Words: 448/450) EVERY answer sheet MUST include (a) full student name, (b) student number, (c) subject code, (d) subject group, (e) page number & (f) total number of pages. Name: Subject Code Page No.: Chan Tsz Lam SEHH2232 2 Student No.: Subject Group: Total no. of pages: 18147269A 201C 7 Question 1b The taxonomic hierarchy of Clostridium perfringens is based on the kingdom of bacteria and phylum is firmicutes, under class of clostridia. The order, family and genus are clostridiales, clostridiaceae and clostridium respectively. C. perfringens ended up as one of the species of clostridium14. C. perfringens are non-motile, rod-shaped, anaerobic, spore-forming Gram-positive pathogenic bacteria that causes gas gangrene associated with wound infections15-16. With the characteristics of Gram-positive bacteria, heat-resistant (20-50C), spore-forming and thick peptidoglycan with chains of teichoic and lipoteichoic acid embedded together facilitate its survival17-18. C. perfringens can be categorized from type A to E, based on its specific toxin production, in which type A strains cause gas gangrene and mostly associated with wound infection as a result of cellulitis19. For infectious cycle, it is introduced to Samuel’s wound as they are mostly found in tap water and soil14,16. After the entry of vegetative cells or spores into body, C. perfringens grow rapidly in host tissue through reducing tissue Redox conditions20. The growing vegetative cells secrete alpha toxins and theta toxin which are crucial virulence factors. Alpha toxin triggers platelet aggregation, thrombosis and histamine release by breaking down host’s cell membranes, compromising blood flow towards infectious area. Theta toxin directly promotes vascular degradation and breakdown of leukocytes, leading to blunted host inflammatory response to the infection21-23. They cause depletion of blood supply and create anaerobic environment that promote growth of C. perfringens. Not only causing local necrosis in muscle, but also allowing progressive spread of infection to systemic circulation20. In terms of prevention of infection, wound cleansing or surgical repair of deep and contaminated wound is the most important. Hydrogels or hydrocolloids dressings would be suitable for infected and necrotic wounds9. Antibiotic therapy like penicillin or clindamycin would be the first-line drug choice for further clostridial wound infection24. (Words: 298/300) Question 2a First, doctor must evaluate Mrs Wong’s overall medical condition. Diabetes mellitus is a common comorbid illness to pneumonia patient25. Normally, a germinated community-acquired pneumonia will prescribe beta-lactamase inhibitor combined with macrolide to patient as initial empiric therapy until the test results are ready, such as ampicillin-sulbactam with clarithromycin26-27. Simultaneously, doctor should assess for any allergic reaction to beta-lactam drugs to prevent more severe complications. A fluroquinolone and clindamycin would be replaced if Mrs. Wong allergic to beta-lactam drugs. However, since Mrs Wong is administering a drug for controlling diabetes every day, this increased risk of drug-drug interactions that causes alteration in pharmacokinetic or pharmacodynamic of drugs, like adverse drug reactions, toxicity and transmutation of drug efficacy28. For example, fluroquinolones would cause fluctuation in blood sugars. Sulfonylureas, the major diabetes pills for older adults, tends to develop hypoglycaemia when it administered with clarithromycin or ciprofloxacin which is a type of broad-spectrum combination antibiotics for EVERY answer sheet MUST include (a) full student name, (b) student number, (c) subject code, (d) subject group, (e) page number & (f) total number of pages. Name: Subject Code Page No.: Chan Tsz Lam SEHH2232 3 Student No.: Subject Group: Total no. of pages: 18147269A 201C 7 treating pneumonia29. Another type of diabetes medication is thiazolidinedione. It neither impedes community-acquired pneumonia, nor decrease the susceptibility to the host30. Therefore, if the doctor has discovered this diabetes medication is continuously administering, it should be impeded for other replacement. Second, the degree of microorganism’s susceptibility to those drugs should be evaluated by using Kirby-Bauer disk-diffusion susceptibility test. It helps to determine which drug is the most effective in treating the infection. For example, the most common communityacquired pneumonia is due to Streptococcus pneumoniae which has high resistance to most antibiotics31. Though old studies found penicillin and macrolides were effective in treating, the modern research have discovered 80% of S. pneumoniae were resistant to both drugs, where 65.2% of S. pneumoniae were resistant to ciprofloxacin. But only 21% of 3rd generation of cephalosporins, ceftriaxone, has the resistance to S. pneumoniae. So, considering ceftriaxone is the most effective treatment in curing community-acquired pneumonia27,32,33. Therefore, the suspected infectious agent must have a certain level of sensitivity to drugs for achieving its optimal antimicrobial therapy. Third, since the identity of microorganism causing the infection has no result yet, doctor can direct to the efficacy at the site of infection and evaluate the age of patient that may affect the drug activity in body34. Geriatric patients have poorer liver and kidney function causing reduction in first-pass metabolism and deteriorated drug clearance respectively. She may have lower blood flow, thereby the bioavailability of drugs may undergo extensive first-pass metabolism. Also, Mrs. Wong’s serum creatinine level may have slightly reduced. For example, aminoglycoside antibiotics will have a narrower therapeutic index in elderly and causing severe adverse effects if the drug accumulates34,35. Therefore, the age that reflects her liver and kidney function should be assessed to determine the drug dosage and route of administration. (Words: 450/450) Question 2b Broad-spectrum antibiotics inhibit both gram-positive and gram-negative bacteria, such as tetracyclines or ampicillin, while narrow-spectrum antibiotics only inhibit either gram-positive or gram-negative bacteria, such as erythromycin or gentamycin36. However, as broad-spectrum target general groups of bacteria, it is easier to create antibiotic-resistant, like azithromycin which has longer half-life and increases resistance to S. pneumoniae37. More side effects and adverse reactions will be found in broad-spectrum antibiotics. For broad-spectrum beta-lactam antibiotics’ mechanism of action, they are bactericidal agents which effectively disrupts the bacterial peptidoglycan formation by binding penicillin-binding proteins (PBPs) into beta-lactam. The rendering of beta-lactam ring of antibiotics bind to different PBPs, causing inability of crosslinking of bacteria for cell wall synthesis, leading to cell death due to osmotic instability or autolysis38. The preferred antibiotics for Mrs Wong is ceftriaxone since it has lower resistance strength39 and up to 95% of sensitivity to the typical pneumonia bacteria40. (Words: 147/150) EVERY answer sheet MUST include (a) full student name, (b) student number, (c) subject code, (d) subject group, (e) page number & (f) total number of pages. Name: Subject Code Page No.: Chan Tsz Lam SEHH2232 4 Student No.: Subject Group: Total no. of pages: 18147269A 201C 7 Question 2c The most common infectious agent is Streptococcus pneumoniae which causes bacterial meningitis, a kind of systemic infection41. The invasion of S. pneumoniae to bloodstream after colonization on nasopharyngeal mucosa will be transmitted to alveoli through inhalation41-42. Fluid surrounding the brain or spine will be infected as S. pneumoniae has entered into system of host. The meningeal vascular endothelial cells are mediated by pneumococcal adhesion to platelet-activating factor which specifically attack meninges. Clinical presentation will be shown nonspecifically42-43, like fever, irritability, anorexia. Neurological abnormality will also be resulted, like delirium, lethargy43. Polysaccharide capsule and hyaluronate lyase are the virulence factors44. When S. pneumoniae has introduced to alveoli, it competes with resident microbes to replicate. The capsule of S. pneumoniae prevents immunoglobulins from interacting with phagocytic cells of host and the degradation of hyaluronic acid that promotes bacterial spread and colonization. With increased pathogenicity and weakened immune system, pneumonia will be resulted42,44. (Words: 150/150) EVERY answer sheet MUST include (a) full student name, (b) student number, (c) subject code, (d) subject group, (e) page number & (f) total number of pages. Name: Subject Code Page No.: Chan Tsz Lam SEHH2232 5 Student No.: Subject Group: Total no. of pages: 18147269A 201C 7 1. Enoch, S., & Price, P. (2004). Cellular, molecular and biochemical differences in the pathophysiology of healing between acute wounds, chronic wounds and wounds in the aged. Wound Healing Research Unite. 2. Talaro, K. P. (2007). Foundations in microbiology basic principles. (6th ed.). McGraw Hill. 3. Institute for Quality and Efficiency in Health Care. (2018). What is an inflammation? Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK279298/ 4. Kidd, B. L., & Urban, L. A. (2001). Mechanisms of inflammatory pain. British Journal of Anaesthesia, 87(1), 3-11. https://doi.org/10.1093/bja/87.1.3 5. Engelkirk, P. G., & Duben-Engelkirk, J. L. (2008). Laboratory diagnosis of infectious diseases: Essentials of diagnostic microbiology. Lippincott Williams & Wilkins. 6. Claesson-Welsh, L. (2015). Vascular permeability—the essentials. Upsala journal of medical sciences, 120(3), 135-143. 7. Anderson, J. M. (2013). Inflammation, wound healing, and the foreign-body response. Biomaterials Science, 3, 503-512. https://doi.org/10.1016/B978-0-08-087780-8.00044-9 8. Fraser, B. (2019). The colour of wounds and its implication for healing. Retrieved from https://healthtimes.com.au/hub/wound-care/59/practice/bf1/the-colour-of-wounds-and-itsimplication-for-healing/45/ 9. Peate, I., & Wild, K. (2018). Nursing practice: Knowledge and care. John Wiley & Sons. 10. Sussman, C., & Bates-Jensen, B. M. (2007). Wound care: A collaborative practice manual. Lippincott Williams & Wilkins. 11. Root, R. K., Waldvogel, F., Corey, L., & Stamm, W. E. (1999). Clinical infectious diseases: A practical approach. Oxford University Press. 12. Biggers, A. (2019). What to know about a foot infection? Retrieved from https://www.medicalnewstoday.com/articles/326186 13. National Health Service. (2019). Peripheral neuropathy. Retrieved from https://www.nhs.uk/conditions/peripheral-neuropathy/complications/ 14. Veillon and Zuber. (1898). Clostridium perfringens. Retrieved from https://www.itis.gov/servlet/SingleRpt/SingleRpt?search_topic=TSN&search_value=5556 46#null 15. Centers for Disease Control and Prevention. (2018). Clostridium perfringens. Retrieved from https://www.cdc.gov/foodsafety/diseases/clostridium-perfringens.html 16. Shimizu, T., Ohtani, K., Hirakawa, H., …Hayashi, H. (2002). Complete genome sequence of Clostridium perfringens, an anaerobic flesh-eater. Proceedings of the National Academy of Sciences of the United States of America, 99(2), 996-1001. https://doi.org/10.1073/pnas.022493799 17. Aryal, S. (2020). Cultural characteristics of Clostridium perfringens. Retrieved from https://microbenotes.com/cultural-characteristics-of-clostridiumperfringens/#Cultural_characteristics_of_Clostridium_perfringens EVERY answer sheet MUST include (a) full student name, (b) student number, (c) subject code, (d) subject group, (e) page number & (f) total number of pages. Name: Subject Code Page No.: Chan Tsz Lam SEHH2232 6 Student No.: Subject Group: Total no. of pages: 18147269A 201C 7 18. Aryal, S. (2019). Morphology of Clostridium perfringens. Retrieved from https://microbenotes.com/morphology-of-clostridium-perfringens/ 19. Hall, H. E., Angelotti, R., Lewis, K. H., & Foter, M. J. (1963). Characteristics of clostridium perfringens strains associated with food and food-borne disease. Journal of bacteriology, 85(5), 1094-1103. 20. Li, J., Paredes-Sabja, D., Sarker, M. R., & McClane, B. A. (2016). Clostridium perfringens sporulation and sporulation-associated toxin production. Microbiology spectrum, 4(3). https://doi.org/10.1128/microbiolspec.TBS-0022-2015 21. Ryan, K. J., & Ray, C. G. (2004). Sherris Medical Microbiology. (4th ed.). McGraw Hill Professional. 22. O’Brien, D. K., & Melville, S. B. (2003). The interactions of clostridium perfringens with phagocytic cells. Dissertation, Faculty of the Virginia Polytechnic Institute and State University. 23. Buboltz, J. B., & Murphy-Lavoie, H. M. (2019). Gas gangrene. StatPearls. 24. Wells, C. L., & Wilkins, T. D. (1996). Medical microbiology. (4th ed.). Galveston: University of Texas Medical Branch. 25. Wesemann, T., Nüllmann, H., Pflug, M. A., Heppner, H. J., Pientka, L., & Thiem, U. (2015). Pneumonia severity, comorbidity and 1-year mortality in predominantly older adults with community-acquired pneumonia: a cohort study. BMC infectious diseases, 15, 2. https://doi.org/10.1186/s12879-014-0730-x 26. Cassel, C. K., Leipzig, R., Cohen, H. J., Larson, E. B., & Meier, D. E. (2006). Geriatric medicine: An evidence-based approach. Springer Science & Business Media. 27. Centre for Health Protection. (2018). Community-acquired pneumoniae. Retrieved from https://www.chp.gov.hk/files/pdf/guidance_notes_community_acquired_pneumonia_full.pd f 28. Noor, S., Ismail, M., & Ali, Z. (2019). Potential drug-drug interactions among pneumonia patients: do these matter in clinical perspectives?. BMC pharmacology & toxicology, 20(1), 45. https://doi.org/10.1186/s40360-019-0325-7 29. Campbell, A. (2018). Antibiotics and diabetes: Do the two mix? Retrieved from https://www.diabetesselfmanagement.com/blog/antibiotics-and-diabetes-do-the-two-mix/ 30. Gorricho, J., Garjón, J., Alonso, A., Celaya, M. C., Saiz, L. C., Erviti, J., & López, A. (2017). Use of oral antidiabetic agents and risk of community-acquired pneumonia: a nested case-control study. British journal of clinical pharmacology, 83(9), 2034–2044. https://doi.org/10.1111/bcp.13288 31. Brown, J. S. (2012). Community-acquired pneumonia. Clinical medicine (London, England), 12(6), 538–543. https://doi.org/10.7861/clinmedicine.12-6-538 32. Pandey, N., & Cascella, M. (2020). Beta Lactam Antibiotics. StatPearls. 33. El-Sokkary, R. H., Ramadan, R. A., El-Shabrawy, M., El-Korashi, L. A., Elhawary, A., Embarak, S., Tash, R., & Elantouny, N. G. (2018). Community acquired pneumonia among EVERY answer sheet MUST include (a) full student name, (b) student number, (c) subject code, (d) subject group, (e) page number & (f) total number of pages. Name: Subject Code Page No.: Chan Tsz Lam SEHH2232 7 Student No.: Subject Group: Total no. of pages: 18147269A 201C 7 adult patients at an Egyptian university hospital: bacterial etiology, susceptibility profile and evaluation of the response to initial empiric antibiotic therapy. Infection and drug resistance, 11, 2141–2150. https://doi.org/10.2147/IDR.S182777 34. Leekha, S., Terrell, C. L., & Edson, R. S. (2011). General principles of antimicrobial therapy. Mayo Clinic proceedings, 86(2), 156–167. https://doi.org/10.4065/mcp.2010.0639 35. Mangoni, A. A., & Jackson, S. H. (2004). Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. British journal of clinical pharmacology, 57(1), 6–14. https://doi.org/10.1046/j.1365-2125.2003.02007.x 36. Levine, R. R., Walsh, C. T., & Schwartz-Bloom, R. D. (2000). Pharmacology: Drug actions and reactions. (7th ed.). CRC Press. 37. Issacs, D. (2008). Evidence-based pediatric infectious diseases. John Wiley & Sons. 38. Bush, K., & Bradford, P. A. (2016). β-Lactams and β-Lactamase Inhibitors: An Overview. Cold Spring Harbor perspectives in medicine, 6(8), a025247. https://doi.org/10.1101/cshperspect.a025247 39. Lutfiyya, M. N., Henley, E., & Chang, L. F. (2006). Diagnosis and treatment of communityacquired pneumonia. American Family Physician, 73(3), 442-450. 40. Corrêa, R. A., Costa, A. N., Lundgren, F., Michelin, L., Figueiredo, M. R., Holanda, M., Gomes, M., Teixeira, P., Martins, R., Silva, R., Athanazio, R. A., Silva, R., & Pereira, M. C. (2018). 2018 recommendations for the management of community acquired pneumonia. Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia, 44(5), 405–423. https://doi.org/10.1590/S180637562018000000130 41. Scheld, W. M., Whitley, R. J., & Marra, C. M. (2004). Infections of the Central Nervous System. Lippincott Williams & Wilkins. 42. Ramirez, J. A. (2020). Overview of community-acquired pneumonia in adults. Retrieved from https://www.uptodate.com/contents/overview-of-community-acquired-pneumonia-inadults#H4217983793 43. Antonieta, C. (2018). Pneumococcal infections (Streptococcus pneumoniae) clinical presentation. Retrieved from https://emedicine.medscape.com/article/225811-clinical#b1 44. Mitchell, A. M., & Mitchell, T. J. (2010). Streptococcus pneumoniae: virulence factors and variation. Clinical Microbiology and Infection, 16(5), 411-418.