Microbiology Nuts Bolts A wee bit of resistance

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

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 www. microbiologynutsandbolts. co. uk

Betty • 87 years old nursing home resident • Presents with confusion and new incontinence • On examination – Temperature 37. 5 o. C – 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? www. microbiologynutsandbolts. co. uk

• Likely urinary tract infection • No systemic signs of evolving sepsis • Treated for simple UTI with 3 days of Trimethoprim www. microbiologynutsandbolts. co. uk

• 2 days later not much better • Still no systemic signs of evolving sepsis • Check of recent bloods – e. GFR >60 ml/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 www. microbiologynutsandbolts. co. uk

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? www. microbiologynutsandbolts. co. uk

Microscopy of urine • White blood cells – >100 x 106/L definitely significant – >10 x 106/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 www. microbiologynutsandbolts. co. uk

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 www. microbiologynutsandbolts. co. uk

2 days later • • Much more confused, still incontinent Very distressed Vomiting, diarrhoea Urine result – Microscopy >100 x 106/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? www. microbiologynutsandbolts. co. uk

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? www. microbiologynutsandbolts. co. uk

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

Inherent resistance Microorganism Klebsiella spp. Proteus spp. Gram-negative bacilli Absolute Resistance Ampicillin, Amoxicillin Nitrofurantoin Teicoplanin, Vancomycin Linezolid Amp. C producing bacteria e. g. Enterobacter cloacae, Citrobacter freundii, Serratia marcescens and Morganella morganii ESBL producing bacteria Ampicillin, Amoxicillin Cefuroxime, Cefotaxime, Ceftriaxone, Ceftazidime Often multiple antibiotic resistance www. microbiologynutsandbolts. co. uk

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

Antibiotic dosing in renal failure • Many antibiotics require dose reduction in renal failure • e. GFR 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 www. microbiologynutsandbolts. co. uk

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

Back to Betty… • Started IV Meropenem 500 mg BD • 55 kg, Creatinine 77 • Calculated GFR = 39 ml/min www. microbiologynutsandbolts. co. uk

• Changed to oral Fosfomycin 3 g 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!) www. microbiologynutsandbolts. co. uk

The antibiotic hierarchy 1. 2. 3. 4. 5. 6. 7. Trimethoprim OR Nitrofurantoin Amoxicillin Mecillinam Cefalexin Co-amoxiclav Ciprofloxacin (the route of all evil!) Fosfomycin (reserved for resistant bacteria) www. microbiologynutsandbolts. co. uk

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! www. microbiologynutsandbolts. co. uk

Caution: Extended Spectrum Beta-lactamase • Enzyme excreted into periplasmic space which inactivates antimicrobials by cleaving the blactam bond. • Cause resistance to almost all b-lactams including 3 rd-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 www. microbiologynutsandbolts. co. uk

Transfer of antibiotic resistance www. microbiologynutsandbolts. co. uk

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

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 www. microbiologynutsandbolts. co. uk

But what about carbapenemases? • Carbapenems are the broadest spectrum antibiotics available – – Ertapenem Meropenem Imipenem Doripenem • Carbapenemases are Betalactamase enzymes which hydrolyse carbapenems • Confer resistance to ALL Betalactam antibiotics • Often transferable on mobile genetic element e. g. plasmid www. microbiologynutsandbolts. co. uk

• The “Big Five”: – Klebsiella pneumoniae carbapenemase (KPC) – Verona integron-encoded metallobeta-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 www. microbiologynutsandbolts. co. uk

KPC www. microbiologynutsandbolts. co. uk

VIM & IMP www. microbiologynutsandbolts. co. uk

NDM www. microbiologynutsandbolts. co. uk

OXA-48 www. microbiologynutsandbolts. co. uk

• Investigation – Difficult – No perfect single method for detecting • Treatment – Colistin PLUS carbapenem – Colistin PLUS Tigecycline – Colistin PLUS aminoglycoside (very nephrotoxic) No orals!? www. microbiologynutsandbolts. co. uk

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) www. microbiologynutsandbolts. co. uk

ESBLs in Europe 2002 2012 European Centre for Disease Prevention & Control www. microbiologynutsandbolts. co. uk

Carbapenemases? 2012 2022? European Centre for Disease Prevention & Control www. microbiologynutsandbolts. co. uk

The Future? www. microbiologynutsandbolts. co. uk

The Present? www. microbiologynutsandbolts. co. uk

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

Any Questions? Available to buy on www. microbiologynutsandbolts. co. uk