Resistant Gram-negative Infections

21st March 2013

Acute Medicine Study Day

Dr Sarah Glover

Consultant in Medical Microbiology and Infectious Diseases

Overview

• Resistance in Enterobacteriaceae (‘coliforms’ e.g. E coli, Klebsiella, Enterobacter)

• ESBLs – what they are• ESBLs – why they matter• Epidemiology• Carbapenemases

Case 1

• 90M• Background of DM, CRF, previous pneumonia• Care home resident, bed bound fully dependent, long

term urinary catheter• Admitted SOB, CRP >250 WCC 35 ?LRTI• Started cefuroxime plus clarithromycin as hx of penicillin

allergy• 24 hrs into admission, blood cultures flagged positive

with Gram negative bacilli• Looking at previous microbiology: MSU from a month

earlier: ESBL-positive E coli• Changed to meropenem

Case 1

• Following day, BC isolate confirmed as ESBL producing E coli, resistant to trimethoprim, co-amoxiclav, cefuroxime, ciprofloxacin. Sensitive to meropenem and gentamicin

• CSU from admission, mixed growth of 3 organisms including ESBL-producing E coli with the same sensitivity pattern

• Good clinical response to carbanepenem treatment

β-lactams & β-lactamases

• β-lactam antibiotics: -penicillins

-cephalosporins-carbapenems

• Inhibit cell wall formation• β lactamases = bacterial enzymes that

hydrolyse β lactam antibiotics rendering them inactive

β-lactams

β-lactamases

• Resistance to penicillins such as ampicillin or amoxicillin very common among coliforms, due to β lactamases (TEM or SHV)– E.g. 60% of invasive E coli isolates in UK are

amp-/amoxicillin-resistant)

β-lactamases

Urine culture Auth

10^5 Escherichia coli /ml

Amoxicillin R Nitrofurantoin S Cefalexin/cefradine S Ciprofloxacin SCo-amoxiclav S Gentamicin STrimethoprim S

Extended-spectrum β-lactamases (ESBLs)

• ESBLs are a group of β lactamases which are capable of hydrolysing (and therefore causing resistance to) not only penicillins, but many other β lactams, including 2nd and 3rd generation cephalosporins

• Initially recognised in clinical isolates of Klebsiella pneumoniae in the 1980s, derived from TEM or SHV β lactamases by point mutation

• Until 2000, most were TEM/SHV

ESBLs

• Since then, CTX-M increasingly prevalent – more than 50 distinct enzymes identified – transferred via plasmids from environmental bacteria (Kluyvera)

• Initially found in South America, now global problem, including in community acquired E coli

• Increasing due to plasmid spread plus clonal expansion eg CTX-M-15 in UK

ESBLs

Urine culture Auth

10^5 Escherichia coli /ml

Amoxycillin R Cefalexin/cefradine R

Cefuroxime R

Cefotaxime R

Ceftazidime R

Clinical relevance – Antibiotic management

• Now present in the most common Gram-negative infector of humans (E.coli)

• Difficult to treat• Resistant to most beta-lactams including 3rd

generation cephalosporins • ESBL + isolates often display co-resistance

to other classes of antibiotics e.g. trimethoprim, fluoroquinolones, aminoglycosides

• Penicillin-inhibitor combinations (e.g. co-amoxiclav, pip-tazo) may appear sensitive in vitro but often result in treatment failure

ESBLs

Urine culture Auth

10^5 Escherichia coli /ml

Amoxycillin R Trimethoprim R Cefuroxime R Ciprofloxacin R

Cefalexin/cefradine R Gentamicin R

Cefotaxime R Augmentin (S) Ceftazidime R Tazocin (S)

Clinical relevance – Antibiotic management

• Outpatient management of uncomplicated UTI – limited oral & once-daily IV options

Clinical relevance – Antibiotic management

• Surviving sepsis – early initiation of appropriate antimicrobials important factor in determining outcome

• Studies have shown that mortality from sepsis due to multi-resistant bacteria is double that of sensitive bacteria

Clinical relevance – Epidemiology

• E. coli and Klebsiella pneumoniae are the major ESBL producers worldwide

• E. coli is primary commensal of the human bowel and the commonest causes in community and hospital settings of:– UTI– Intra-abdominal sepsis– Bacteraemia

Clinical relevance – Epidemiology

• Gram negative infection is increasingly common

• Bacteraemia due to coliforms, particularly E coli, is increasing:

E coli is the commonest cause of bacteraemia in England

Bacteraemia

35% increase in E coli bacteraemias in England, Wales and N Ireland between 2007-2011, compared with a 7% decrease in all bacteraemias

E coli bacteraemia by ageHPA voluntary data

Livermore, D. Tracing, tracking and tackling the big beasts of bacteraemia - Resistance and treatment issues in bloodstream infections ? E. coli.  in Federation of Infection Societies (FIS) Scientific Meeting. 2012. Liverpool, UK, Abstract. SA62

Local data2

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Hospital Acquired Community Acquired

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Resistance

• 10% of E coli bacteraemia isolates from UK were resistant to 3rd generation cephalosporins in 2011

Resistance in E coli bacteraemia HPA voluntary data

Livermore, D. Tracing, tracking and tackling the big beasts of bacteraemia - Resistance and treatment issues in bloodstream infections ? E. coli.  in Federation of Infection Societies (FIS) Scientific Meeting. 2012. Liverpool, UK, Abstract. SA62

Risk factors for resistance

• Elderly• Antibiotic exposure (third generation

cephalosporins, quinolones)• Healthcare contact• Travel from higher prevalence areas• But many pts have no risk factors

2007

2011

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Antibiotic Resistance in E. coli Urine Isolates

Total Isolates % Cefotaxime or Ceftazidime Resistant % Resistant to Gentamicin % Resistant to Ciprofloxacin

% Resistant to Trimethoprim % Resistant to Nitrofurantoin

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ESBL-E.coli in urine (UHS, 2009-2012)

Concomitant resistance to:• Trimethoprim 83%• Ciprofloxacin 69%• Nitrofurantoin 5%• Gentamicin 25%

Local data

Antibiotic options• Carbapenems widely considered antibiotic of

choice for severe ESBL infection: good clinical outcome data when compared with other agents with in-vitro susceptibility

• Aminoglycosides, if susceptible• Quinolones, if susceptible• Nitrofurantoin, if susceptible, for uncomplicated

UTI only• Other orals: fosfomycin, pivmecillinam• Tigecycline

So why not give everyone meropenem?

UHS broad-spectrum antibiotic prescribing

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Drug Type

Kieran Hand, Consultant pharmacist UHS

Case 2

• 28M with congenital biliary dilatation• Presented Sept 2012 with biliary sepsis• Recurrent sepsis with bacteraemia since then• Not amenable to drainage, awaiting liver transplant• Klebsiella pneumoniae recurrently isolated: sensitive

only to ertapenem, meropenem, amikacin and colistin• Repeated courses of carbapenem treatment• Frequent relapses after standard courses therefore

treated with 6 week course of ertapenem

• During 6th week of treatment, fever recurred with breakthrough bacteraemia

• Isolate now ertapenem resistant• Treated with meropenem for 2 weeks• Developed eosinophilia and itch, meropenem

stopped• Recurrent symptoms within 48 hours of

stopping, with recurrent bacteraemia on admission 2 days later

• Isolate showing reduced susceptibility to carbapenems: ref lab report suggests possible metallo-carbapenamase

• Pt is antibiotic dependent• Source control impossible without

transplant• Very limited antibiotic options

Dangers of meropenem overuse

Emergence of carbapenem resistance, esp. K. pneumoniae

• Carbapenemases:– E.g. KPC, NDM-1, VIM, OXA-48

• Other mechanisms:– Accumulation of different β-lactamases – Hyper-production of β-lactamases – Cell membrane porin loss (loss of permeability)– Combinations of the above

Carbapenemase-producing Enterobacteriaceae referred to Health Protection Agency (Colindale) 2003 to 2011

• KPC most prominent – first reported in USA, since 2006 has spread across US, Israel, Greece, Italy with outbreaks in China, Brazil, other European countries. 40% prevalence in Klebsiella pneumoniae bacteraemia in Greece

• NDM occurs in 2-8% of Enterobacteriaceae in teaching hospitals in India, and 27% of inpatients at two military hospitals in Pakistan were carriers

Antibiotic suceptibilities of carbapenemase-producing Enterobacteriaceae from the UK

Health Protection Agency

• Colistin – nephrotoxic and neurotoxic

• Tigecycline – low blood concentrations, unsuitable for UTI as only 22% excreted in urine

• Fosfomycin – borderline susceptibility common in Klebsiella. Not marketed in UK but can import

Control

• Organisms present in gut• Selected for by use of carbapenems, become

predominant flora: judicious use of antibiotics• Control spread: isolation (particularly diarrhoea),

handwashing, identification of carriers, ANTT of drains, environmental cleaning

• Controlling source of infection – pts with undrainable abdominal sepsis present high risk for breeding resistance

Take home points

1. E coli causing a rising number and proportion of bacteraemias

2. Resistance to carbapenems a genuine threat

3. Look at previous microbiology results when choosing empirical treatment regimens for sepsis

4. Carbapenems should be used judiciously

Health Protection Agency

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Antibiotic Resistance in E. coli Urine Isolates

Total Isolates % Cefotaxime or Ceftazidime Resistant % Resistant to Gentamicin % Resistant to Ciprofloxacin

% Resistant to Trimethoprim % Resistant to Nitrofurantoin % Resistant to Co-amoxiclav

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