Microbiology Nuts & Bolts: A wee bit of resistance and the future of antibiotics

1. Microbiology Nuts & Bolts: A wee bit of resistance and the future of antibiotics Dr David Garner Consultant Microbiologist

2. Aims & Objectives To discuss the management of UTIs in the era of increasing antibiotic resistance To understand how to interpret urine results To consider the benefits and potential pitfalls of prescribing antibiotics To look to the future of microbiology and how this will impact primary care

3. Betty 87 years old nursing home resident Presents with  confusion and new incontinence On examination Temperature 37.5 oC Crackles throughout precordium Cardiovascularly stable How should Betty be managed? What samples would you send to the laboratory? What antibiotics (if any) would you give?

4. Likely urinary tract infection No systemic signs of evolving sepsis Treated for simple UTI with 3 days of Trimethoprim

5. 2 days later not much better Still no systemic signs of evolving sepsis Check of recent bloods eGFR >60ml/min Urine Dipstick Leucocytes ++, Nitrites ++ MSU (How do you take a proper MSU?) sent to lab Microscopy How would you manage Betty now? Started on second line Nitrofurantoin

6. How to interpret a urine result? Urine dipstick Poor PPV, Good NPV Microscopy White blood cells, red blood cells, epithelial cells Culture result Is the organism consistent with the clinical picture?

7. Microscopy of urine White blood cells >100 x106/L definitely significant >10 x106/L significant if properly taken MSU (rare!) Red Blood Cells Poor correlation with UTI, used by urologist and renal physicians Epithelial cells Indicator of contact with, and therefore contamination from, the perineum

8. Culture: how is urine processed? Day 1 Automated Microscopy If values not significant reported as negative If values significant or specific patient group cultured with direct sensitivities Day 2 Reported with identification and sensitivities Patient groups always cultured Cancer and haematology Pregnant Urology Children < 5 years old

9. 2 days later • Much more confused, still incontinent • Very distressed • Vomiting, diarrhoea • Urine result • Microscopy >100 x106/L WBC, no epithelial cells • Culture E. coli • Resistant to Amoxicillin, Co-amoxiclav, Trimethoprim, Cefradine, Ciprofloxacin • Sensitive to Nitrofurantoin • ESBL positive How would you manage Betty?

10. Urine cultures • Is there an inflammatory response? • Is there a risk of contamination? • Is this asymptomatic bacteriuria? • Does the bacterium isolated commonly cause UTIs? • Are there any previous urine results to guide empirical therapy? • What is the simplest antibiotic that can be used?

11. Common causes of UTIs • E. coli • Proteus mirabilis • Klebsiella pneumoniae • Enterobacter cloacae • Staphylococcus saprophyticus • NOT Enterococcus spp., Pseudomonas spp., S. aureus

12. Inherent resistance

13. Implied sensitivity

14. Antibiotic dosing in renal failure • Many antibiotics require dose reduction in renal failure • eGFR is not an accurate predictor of renal function • Use Cockcroft Gault equation • Actual body weight or Ideal Body Weight (IBW) if weight > 20% above IBW • Also use IBW for patients with oedema & ascites

15. How might weight effect Betty’s GFR (ml/min) Female, Age 87, Creatinine 75

16. How might weight effect Betty’s GFR (ml/min) Female, Age 87, Creatinine 75

17. Back to Betty… Started IV Meropenem 500mg BD 55kg, Creatinine 77 Calculated GFR = 39 ml/min

18. Changed to oral Fosfomycin 3g stat Made a full recovery Warning – Betty is now known to be colonised with a Antibiotic-resistant E. coli so her future UTIs are likely to be resistant as well (it is part of her normal flora!)

19. The antibiotic hierarchy • Trimethoprim OR Nitrofurantoin • Amoxicillin • Mecillinam • Cefalexin • Co-amoxiclav • Ciprofloxacin (the route of all evil!) • Fosfomycin (reserved for resistant bacteria)

20. Antibiotic prophylaxis • Cochrane reviews show very weak evidence for efficacy BUT strong association with antibiotic resistance • Recurrent UTI = 2 in 6 months or 3 in 1 year • Is it definitely reinfection and not relapse or asymptomatic bacteriuria? • Does the patient need further investigation e.g. renal USS, urology • Try early treatment or post-coital antibiotics first • Consider narrow spectrum for max. 6-12 months to allow bladder healing then STOP!

21. Caution: Extended Spectrum Beta-lactamase Enzyme excreted into periplasmic space which inactivates antimicrobials by cleaving the b-lactam bond. Cause resistance to almost all b-lactams including 3rd-generation cephalosporins Associated with multiple antibiotic resistances Can be chromosome, plasmid or transposon encoded Can be constitutive or inducible Ideally patients with ESBLs should be managed in side-rooms with contact precautions

22. Transfer of antibiotic resistance

23. Caution: Extended Spectrum Beta-lactamase Source: European Centre for Disease Prevention and Control Antimicrobial resistance surveillance in Europe 2015

24. Caution: Extended Spectrum Beta-lactamase Carbapenems are the treatment of choice Some advocate Beta-lactamase inhibitor combinations (BLI) e.g. Co-amoxiclav, Piptazobactam Insufficient evidence Systematic review & metanalysis JAC 2012; 67: 2793-2803 Carbapenems > non-BLI BLI not< carbapenems BLI not > non BLI How can BLI = carbapenems?! Personally use carbapenems for serious infections caused by ESBL positive bacteria

25. But what about carbapenemases? • Carbapenems are the broadest spectrum antibiotics available • Ertapenem • Meropenem • Imipenem • Doripenem • Carbapenemases are Beta-lactamase enzymes which hydrolyse carbapenems • Confer resistance to ALL Beta-lactam antibiotics • Often transferable on mobile genetic element e.g. plasmid

26. The “Big Five”: • Klebsiella pneumoniae carbapenemase (KPC) • Verona integron-encoded metallo-beta-lactamase (VIM & IMP) • New Delhi metallo-beta-lactamase (NDM) • Oxacillin Carbapenemases (OXA) • Should be considered in all patients transferred to UK from abroad • Recent guidance supports screening and infection control precautions for these patients

27. KPC

28. VIM & IMP

29. NDM

30. OXA-48

31. Investigation • Difficult • No perfect single method for detecting • Treatment • Colistin PLUS carbapenem • Colistin PLUS Tigecycline • Colistin PLUS aminoglycoside (very nephrotoxic) No orals!?

32. Why worry? • Overreliance on single classes of antibiotics is a selective pressure that drives resistance • There are no new antibiotics for Gram-negative bacteria in the pipeline • We are approaching the Post-antibiotic era (only 100 years after the first antimicrobial was discovered – Salvarsan for syphilis 1911)

33. ESBLs in Europe 2002 2012 European Centre for Disease Prevention & Control

34. Carbapenemases? 2012 2022? European Centre for Disease Prevention & Control

35. The Future?

36. The Present?

37. Conclusions • Look at microbiology results in order • Appearance, Microscopy and Culture • There are significant benefits to antibiotics but increasingly there are also dangers • Try to use the simplest treatment possible • Conflict of medicine moving to 1o care but infections moving to 2o care – need for OPAT • The future is looking bleak, we need to try and preserve what we have for as long as we can…

38. Any Questions? Available to buy on