APT Vignette Discussion Session and Master Cards Title: Paula Scott

1. APT VignetteDiscussion Session and Master CardsTitle: Paula Scott

2. Descriptive Information

3. Title: A common infection that can have serious complications • Student Level: Final year (Academic Half Day) • Learning Objectives for this Vignette (focus): • That a relatively common condition in the community can have serious complications. • The signs and symptoms of the disease process in the UK. • The importance of collecting blood, and specimens from other sites, for culture and antibiotic susceptibility testing. • The important organisms involved in the community in the UK, and community antibiotic susceptibility profiles. • The usual antibiotics to use in these circumstances.

4. Which of the 12 Outcomes this Vignette Can Cover (1) This Vignette is primarily designed to help the student achieve outcomes 1- 12. 1. Clinical Skills - Elicit key symptoms and signs of commonest sites of bacterial infection. - Recognise and interpret common symptoms and signs of the inflammatory response. - Interpret symptoms and signs; distinguish between bacterial infection, viral infection and other causes of inflammatory response. - Make a diagnosis of severe pneumonia. - Formulate a management plan. - Record findings. 2. Practical Procedures - Measures of inflammatory response (pulse, temperature, respiratory rate). - Measures of severe pneumonia (blood pressure, respiratory rate, pulse, oximetry). - Relevant near patient testing techniques. - Technique for obtaining microbiology samples from commonest sites of bacterial infection. - Correct methods for storage and transport of microbiology specimens. - Blood culture. Core Resources

5. Which of the 12 outcomes this Vignette can Cover (2) 3. Patient Investigation - General principles of patient investigation. - Appropriate choice and use informed by local protocols. - Laboratory based investigations. - Radiology. 4. Patient Management - Management strategies for common clinical syndromes, including alternatives to antibiotics. - Deciding on duration of treatment, measures of response to treatment and of successful outcome. - Use and abuse of IV antibiotics. - Recognition of complications, persisting or recurrent symptoms and management plan for dealing with them. - Sepsis and its management. • Health Promotion and Disease Prevention - Principles of control of infection in the hospital and in the community. 6 . Communication - Communication of therapeutic objectives, and management plan. - Accessing advice and sharing responsibility with infection control practitioners. Core Resources

6. Which of the 12 outcomes this Vignette can Cover (3) 7. Appropriate Information Handling Skills • Minimum dataset to be recorded in order to support a decision to prescribe antibiotics. • Local antibiotic policy. • Local guidelines. • National guidelines. • Keeping up to date with resistance. • Personal record keeping for professional development: building a portfolio of achievement of learning outcomes. 8. Understanding of Social, Basic and Clinical Sciences and Underlying Principles • Host defences, immunological and non-immunological. • Pathology of inflammation and sepsis. • Mechanisms and spread of antibiotic resistance. • Classes of antibiotics used and shared allergies. • Pharmacokinetics in relation to drug selection for common infections. • Infection control. • Epidemiology of resistance. • Appropriate Attitudes, Ethical Understanding and Legal Responsibilities • Principles of prudent antimicrobial prescribing. • Shared decision making. Core Resources

7. Which of the 12 outcomes the Vignette can Cover (4) 10. Appropriate Decision Making Skills, Clinical Reasoning and Judgement - Coping with uncertainty. - What is an acceptable risk to withholding any antibiotics, when you are uncertain of your diagnosis? - What is an acceptable prevalence of resistance to first line drugs in antibiotic policies? 11. Role of the Doctor within the Health Service - Role of other members of the multi-professional team in prudent antibiotic prescribing. 12. Personal Development - Assessment of own competence as an antibiotic prescriber; evaluating own. capabilities and personal effectiveness. Assessment of need for support in decision making about antibiotics. - Searching for appropriate learning resources for antibiotic prescribing and resistance. - Recognising limits of current understanding and identifying areas that need to be refreshed or extended. - Setting realistic but challenging learning goals as a basis for personal growth. Core Resources

8. B. Case Details

9. History In the early evening, a 23 year-old patient was referred to the Medical Admissions Unit with a 12-hour history of rigors and chills, with associated dysuria, urgency and frequency of micturition. She has been to her General Practitioner several times in the past few months with symptoms of a lower urinary tract infection. On each occasion, cefalexin was prescribed for 3 days, and there had been a rapid recovery. She has recently entered into her first stable relationship, and was taking an oral contraceptive.

10. Clinical Signs On Examination: The patient looked unwell and was flushed and agitated. Her temperature is 38.90C and blood pressure 100/65 mmHg. Marked renal angle tenderness was elicited on the right. No other signs were noted. A specimen of urine was tested at the bedside. On examination, the urine was cloudy. Leucocytes and nitrites (+++), as well as a trace of ketones, were noted by dipstix.

11. Investigations • Investigations: • The House Officer (HO) made the following entry at the end of his notes: • “Plan: 2 hourly observations” • Urine MC & S • FBC • U & E’s • Antibiotics-cefuroxime 750 mg t.d.s. iv • Oral fluids • Blood culture x 1

12. C. Question Categories

13. Consider a Working Diagnosis (1) This case involves a relatively common infection found in sexually active women, with an added complication. 1.1 The symptoms of an uncomplicated lower urinary tract infection are dysuria, frequency and urgency. What is the basis of these? 1.2 The patient has marked renal angle tenderness on the right. What condition do you consider here and how has it arisen? 1.3 The patient is flushed and agitated, and her blood pressure indicates a degree of hypotension. What further complication would you consider here? 1.4 A reasonable working diagnosis is therefore……?

14. This case highlights important aspects in the diagnosis and management of urinary tract infections. Consider a Working Diagnosis (2) 2.1 What are the important periods in life where UTI can be found, in both females and males? 2.2 The patient in this age has a community-acquired UTI. What bacteria are usually involved here?

15. Patient Management (1) On the post-take ward round the next day, the patient feels no better, having had an uncomfortable night. Her most recent temperature is recorded as 38.20C. During this ward round, the SpR in Medical Microbiology phones to say that blood cultures taken the previous evening are growing gram-positive cocci in clusters (aerobic bottle), and gram-negative rods (anaerobic bottle). 3.1 Examine the gram-stain of the blood cultures. What are the two organisms likely to be here?

16. Patient Management (2) Based on the current clinical situation, and the preliminary result on the urine specimen submitted with the blood culture, the Medical Microbiology SpR recommends that the cefuroxime is stopped, and ciprofloxacin 500 mg b.d. by mouth, and a single dose of gentamicin (360 mg), infused over 30 minutes, are given. 4.1 Cite two possible reasons for the failure of the patient to respond when given i.v. cefuroxime (and find the answer here!). 4.2 What is the mode of action and range of activity of the fluorinated quinolone, ciprofloxacin? 4.3 What is the mode of action and the range of activity of the aminoglycoside, gentamicin?

17. Patient Management (3) On day 3, and with the final microbiology reports to review, the HO ‘phones the consultant microbiologist, informing her that the patient is very much better, and she wants to go home. The patient has been apyrexial for 36 hours. She says if the patient is fit for discharge, she should complete a 7 day course of ciprofloxacin. 5.1 Is this a reasonable management decision? 5.2 What additional investigation should be done if the patient returns with a further episode of pyelonephritis some time later? 5.3 Before the patient leaves the ward, she asks you if there are any reasons for her recent UTIs, and if there is any way of preventing these. What do you say?

18. Appropriate Prescribing (1) 6.1 What antibiotics can be used in the community to treat an uncomplicated cystitis, and what is the usual length of treatment? 6.2 What factors influence the choice of antibiotic? 6.3 Which antibiotics are safe to use in pregnancy for an uncomplicated cystitis?

19. Appropriate Prescribing (2) A single dose of gentamicin was given here. In addition to its role in a “synergistic” combination with a -lactam antibiotic in the treatment of infective endocarditis, (to treat both, streptococci and enterococci), gentamicin is particularly useful in the treatment of a gram-negative sepsis, where it may be prescribed for several days. 7.1 What is the usual dosing regime for gentamicin in the “septic” patient? 7.2 What factors should be taken into account in determining the interval between doses? 7.3 What monitoring should be done to ensure safe use of gentamicin?

20. D. Best Practice Statement

21. Summary of Management (1) A case of cystitis complicated with pyelonephritis and early “sepsis” It is important to be aware of the local epidemiology of organisms that cause UTI in the community, and their antibiotic susceptibility profiles. This can be used to determine empirical antibiotic prescribing. UTI in this type of patient, especially when they are recurrent, are clearly distressing. The patient seeks rapid resolution of the problem, and needs to be aware of measures that can reduce the chance of these infections occurring. This case identifies the importance of reviewing all previous and current relevant information of relevance. It is possible that previous courses of cefalexin selected for the extended spectum –lactamase (ESBL) enzyme-producing organism were inappropriate empirical treatment. More importantly, the SpR in Medical Microbiology used information on the urine specimen taken on admission. This specimen was plated-out, with “direct” sensitivities, that evening. After overnight incubation, the susceptibility pattern revealed the ESBL profile.

22. Summary of Management (2) A case of cystitis complicated with pyelonephritis and early “sepsis” In the patient with a fever and/or signs of sepsis, a blood culture set should be collected, in addition to specimen(s) from other relevant sites. Note that one bottle of this blood culture set was contaminated with a coagulase-negative staphylococcus of the skin. Unless care is taken when collecting blood for culture, these contaminants are common, cloud any diagnosis, and are a waste of laboratory resources!!

23. Summary of Management(3) A case of cystitis complicated with pyelonephritis and early “sepsis” When considering sepsis where a gram-negative bacterium is the possible pathogen, a single dose of an aminoglycoside, such as gentamicin, should be given as soon as possible, with blood cultures being taken before. The dosage is 5-7 mg/kg “lean” body mass, infused over 30 minutes. If repeat doses are given, the minimum interval is usually 24 hours. This must be increased in renal failure. A pre-dose gentamicin level should be collected before the second or third dose, and should be less than 1.0 mg/L, if the antibiotic is to be continued. There is usually little need to continue this antibiotic for longer than 4 days in this setting. Plan to stop after 4 days! MCQS

24. E.Correct/Appropriate AnswersF.Potential Responses and FeedbackG.References and Resources Master Cards:

25. 1.1 The symptoms of an uncomplicated lower urinary tract infection are dysuria, frequency and urgency. What is the basis of these? Correct Response and Reason: Bacteria such as uropathogenic strains of Escherichia coli, colonize the introitus, ascend the urethra and attach to the bladder wall by adhesins. Their reproduction stimulates an inflammatory response. Bacterial toxins and enzymes and other metabolites from dead neutrophils irritate the bladder, and the urethra on micturition, causing symptoms of dysuria frequency and urgency

26. 1.2 The patient has marked renal angle tenderness on the right. What condition do you consider here and how has it arisen? Correct Response and Reason: Acute pyelonephritis. The bacteria can ascend the ureter and initiate infection in the renal pelvis and kidney. The inflammatory response and pressure on the pelvic capsule causes pain; renal angle tenderness can be elicited by gently palpating the renal angle with the ball of the hand.

27. 1.3 The patient is flushed and agitated, and her blood pressure indicates a degree of hypotension. What further complication would you consider here? Correct Response and Reason: Bacteria are likely to have entered the blood, and can initiate a gram-negative sepsis. There is a recognised mortality with this process in otherwise healthy young women.

28. 1.4 A reasonable working diagnosis is therefore…… Correct Response and Reason: The patient has cystitis, pyelonephritis, and in addition, gram-negative sepsis is likely.

29. 2.1 What are the important periods in life where UTI can be found, in both females and males? Correct Response and Reason: In females UTI, often asymptomatic, can be found between the ages 3 and 5. Because of physiological/anatomical changes to the cysto-ureteric junction, bacteria can ascend the ureter, and on reaching the kidney can initiate a chronic infection that can cause renal scarring and renal failure. The next important stage is between the ages of 15 and 45. There is a direct relationship here to sexual activity. Post-menopausal women are often disposed to asymptomatic bacteriuria, due to hormonal changes to the urogenital system. With males, UTI’s in the first year of life are usually associated with structural abnormalities. In “old age”, changes to the prostate gland, such as BPH, and as a result of surgical intervention often predispose to often asymptomatic bacteriuria.

30. 2.2 The patient in this age group has a community-acquired UTI. What bacteria are usually involved here? Correct Response and Reason: Coliforms, including Escherichia coli usually account for over 85% of isolates. Other bacteria include group B streptococcus and Staphylococcus saprophyticus.

31. 3.1 Examine the gram-stain of the blood cultures. What are the two organisms likely to be here? (1)

32. 3.1 (2) Correct Response and Reason: The bacteria are likely to be: • Left panel: Coagulase-negative staphylococcus, a skin commensal, present here as a contaminant! • Right panel: A “coliform”, probably Escherichia coli

33. 4.1 Cite two possible reasons for the failure of the patient to respond when given i.v. cefuroxime (and find the answer here!) Correct Response and Reason: • The presence of a perinephric or intrarenal abscess. • An antibiotic resistant isolate of Escherichia coli, see next two slides. This isolate produces an “extended-spectrum -lactamase” (ESBL) enzyme, so that in addition to inactivating amoxicillin, it also inactivates cephalosporins. Such isolates are unfortunately no longer rare in the community setting.

34. Department of Medical MicrobiologySt. Kilda’s NHS Trust

35. Department of Medical MicrobiologySt. Kilda’s NHS Trust

36. 4.2 What is the mode of action and range of activity of the quinolone, ciprofloxacin? Correct Response and Reason: This class of antibiotic binds to the -subunit of the DNA gyrase enzyme, and thus inhibits important steps in DNA manipulation in the cell, such as supercoiling. In general, the fluorinated quinolone ciprofloxacin has very useful activity against a wide range of gram-negative bacteria, including the “coliforms”, Pseudomonas aeruginosa, meningococcus, gonococcus and haemophilus.

37. 4.3 What is the mode of action and the range of activity of the aminoglycoside, gentamicin? Correct Response and Reason: Gentamicin enters the cell of gram-negative bacteria that are in the aerobic “oxidative” mode of metabolism, and include the obligate aerobe, Pseudomonas aeruginosa, and the facultative coliforms. Actively pumped into the bacterial cell, the antibiotic then prevents the initiation of protein synthesis. The aminoglycosides such as gentamicin act on the gram-negative bacteria defined above. They also have useful activity against Staphylococcus aureus (including MRSA). Because aerobic metabolism in required for activity, there is clearly no activity against obligate anaerobic bacteria. (Reminder: Gentamicin can be used in the treatment of endocarditis caused by streptococci and enterococci,but it is used SYNERGISTICALLY with a -lactam antibiotic or glycopeptide. The -lactam damages the cell wall, allowing the aminoglycoside to diffuse in).

38. 5.1 Is this a reasonable management decision? Correct Response and Reason: Yes. Studies in Canada and New Zealand have shown that patients in this setting can be given a single dose of gentamicin (5-7 mg/kg lean body mass) with a second agent such as ciprofloxacin as soon as possible after specimens have been collected. If the patient “settles” within several hours they can be discharged on 7-10 days of oral ciprofloxacin.

39. 5.2 What additional investigation should be done if the patient returns with a further episode of pyelonephritis some time later? Correct Response and Reason: The patient must have imaging of the renal tract done, such as renal ultrasonography.

40. 5.3 Before the patient leaves the ward, she asks you if there are any reasons for her recent UTIs, and if there is any way of preventing these. What do you say? Correct Response and Reason: The patient needs to know that there is a strong correlation with sexual activity and cystitis here. Colonization of the peri-urethral area with uropathogenic strains of Escherichia coli occurs. Manipulation of the introitus enables bacteria to ascend the urethra where they have the potential to initiate cystitis. Patients and their partners may consider this to be a STD. This is not the case, and they need to be reassured. For prevention of recurrence, post-coital micturition can be useful. Post-coital low-dose nitrofurantoin can also be effective.

41. 6.1 What antibiotics can be used in the community to treat an uncomplicated cystitis, and what is the usual length of treatment? Correct Response and Reason: Trimethoprim, cefalexin, and nitrofurantoin can be used. The usual course of treatment for cystitis is 3 days.

42. 6.2 What factors influence the choice of antibiotic? Correct Response and Reason: Cure of treatment and tolerance of the antibiotic are clearly important. The cure rate is to a large extent dependent on the overall resistance profile in a community. For example the laboratory may report values of resistance to trimethoprim of 20% for the usual bacteria isolated. However, this only reflects information from specimens submitted. A General Practitioner can find the trimethoprim cures most of the UTI seen, and will use this successfully for empirical treatment. This is unlikely to be the case with amoxicillin, where the resistance rate determined in the laboratory are usually in excess of 50%. For other antibiotics used in this setting, resistance rates in the order of 5-10% are seen.

43. 6.3 Which antibiotics here are safe to use in pregnancy? Correct Response and Reason: The -lactam antibiotics are the safest class of antibiotics to use in pregnancy, so for cystitis, cefalexin is useful. Trimethoprim should be used with caution in the first trimester, and nitrofurantoin avoided in the last month of the pregnancy. When antibiotic resistant bacteria are encountered in pregnancy, the Medical Microbiologist should be contacted for advice.

44. 7.1 What is the usual dosing regime for gentamicin in the “septic” patient? Correct Response and Reason: Using an estimated “lean” body weight, the dose is 5-7mg/kg, infused over 30 minutes.

45. 7.2 What factors should be taken into account in determining the interval between doses? Correct Response and Reason: In addition to “lean” body mass, age is important. The formula: 160 –age x lean weight in kg Serum creatinine (ug/mL) (Thisgives a reasonable estimate of creatinine clearance, and the interval between doses.) If clearance is > 60 mL/min: 24 hours If clearance is 40-60 mL/min: 36 hours If clearance is 20-39 mL/min: 48 hours

46. 7.3 What monitoring should be done to ensure safe use of gentamicin? Correct Response and Reason: The first pre-dose level should be checked before the second or third dose is given. If the correct interval between doses has been estimated, the blood should be collected and the dose given. The assay result will be available before the next dose is due. The pre-dose level should be < 1.0 mg/L. If it is above this, the interval between doses must be increased. The need for continuing gentamicin beyond 4 days needs to be reviewed with the Medical Microbiologist.

47. Core Resources • JK Struthers and RP Westran (2003) Clinical Bacteriology. Manson Publishing (chapters 1, 3, 4, 11). • Infection and Immunity module course book. • The British National Formulary (BNF.org) Chapter 5: Infections. • Drug and Therapeutic Bulletin (1998) Managing urinary tract infection in women. 36,30-32. • Editorial (2001) Empirical treatment of uncomplicated cystitis. BMJ 323, 1197-1198. • Editorial (1996) Sex and urinary tract infections. NEJM 335, 511. • Latest edition of Mandell’s Principles and Practice of Infectious Diseases.

48. Multiple Choice Questions (1) 1. Regarding cystitis in young women There is no correlation with sexual activity “Coliforms” such as Escherichia coli are the usual pathogen A urine specimen must always be submitted to the laboratory for analysis Urine “dipstix” are of little use in diagnosis The organisms involved are usually transmitted from person to person 2. Regarding the laboratory diagnosis of UTI Urine microscopy is routinely done on all urine specimens The presence of WBC in the urine is the only useful parameter in microscopy Blood agar plates are inoculated Agar plates must always be incubated anaerobically A significant bacteriuria is indicated when there is a pure growth of an organism in excess of 106 colony forming units/ml Answers Summary of Management

49. Multiple Choice Questions (2) 3. Regarding the treatment of uncomplicated cystitis • Amoxicillin is usually effective • The recognised course of treatment is 3 days • A post-treatment urine specimen should be submitted for analysis • Quinolones such as ciprofloxacin should be reserved as second-line agents • Trimethoprim is the most cost-effective agent 4. Regarding the patient in a case such as this, where pyelonephritis is a consideration • The organism is usually Escherichia coli • Bacteria enter the blood as a continuous bacteraemia • A 7-10 course of intravenous antibiotics must be given • Mortality is very unlikely • Renal ultrasonography, at least, is important in recurrent cases Answers

50. Multiple Choice Questions (3) 5. Regarding gentamicin It usually has excellent activity against gram-negative coliforms that are growing under anaerobic conditions It enters the cell by an active, energy dependent process It interferes with protein synthesis In sepsis, a dose of 5-7 mg/kg lean body mass is often used. The interval between doses are the same, irrespective of renal function Answers Summary of Management