1. Dr David Garner Consultant Microbiologist
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 Red Blood Cells Epithelial 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 Microorganism Absolute Resistance Klebsiella spp.
Ampicillin, Amoxicillin
Proteus spp.
Nitrofurantoin
Gram-negative bacilli
Teicoplanin, Vancomycin
Linezolid
AmpC producing bacteria e.g. Enterobacter cloacae, Citrobacter freundii, Serratia marcescens and Morganella morganii
Cefuroxime, Cefotaxime, Ceftriaxone, Ceftazidime
ESBL producing bacteria
Often multiple antibiotic resistance

13. Implied sensitivity Organism Report Implied results Enterobacteriaceae
Amoxicillin sensitive
Co-amoxiclav sensitive
Cephalosporin sensitive
Mecillinam sensitive
(opposite not true!)
ESBL positive
ALL oral beta-lactams resistant except Mecillinam
Ciprofloxacin resistant
ALL Fluoroquinolones resistant
E. coli
Fosfomycin sensitive (unless reported otherwise)

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
Weight (kg)
eGFR
Calculated GFR
Variance 45 63 33
-30 50 37
-26 55 40
-23 60 44
-19 65 47
-16 70 51
-12 75 -8 80 59 -4

16. How might weight effect Betty’s GFR (ml/min)
Female, Age 87, Creatinine 75
Weight (kg)
eGFR
Calculated GFR
Variance 45 63 33
-30 50 37
-26 55 40
-23 60 44
-19 65 47
-16 70 51
-12 75 -8 80 59 -4

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

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 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 2011

24. The Future is Bleak
Increasing numbers of Meropenem resistant Enterobacteriaceae in the UK from overseas
NDM-1 = New Delhi Metallo-beta-lactamase
KPC = Klebsiella pneumoniae carbapenemase
Now starting to see Amikacin resistance as well
Only antibiotic left is Colistin
60+ years old
Some bacteria are known to be inherently resistant (Proteus sp., Serratia sp.)
May become transferable and then have a real “superbug” for the post-antibiotic era…

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

26. 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:
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

27. 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

28. Should be considered in all patients transferred to UK from abroad
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

29. KPC

30. VIM & IMP

31. NDM

32. OXA-48

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

34. 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)

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

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

37. The Future?

38. The Present?

39. 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…

40. Any Questions?
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