Transcript Resistant Gram-negative Infections 21st March 2013 Acute Medicine Study Day Dr Sarah Glover Consultant in Medical Microbiology and Infectious Diseases.

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
10^5 Escherichia coli /ml
Amoxicillin R
Cefalexin/cefradine S
Co-amoxiclav S
Trimethoprim S
Auth
Nitrofurantoin S
Ciprofloxacin S
Gentamicin 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
10^5 Escherichia coli /ml
Amoxycillin R
Cefalexin/cefradine R
Cefuroxime R
Cefotaxime R
Ceftazidime R
Auth
Clinical relevance –
Antibiotic management
• Now present in the most common Gramnegative 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. coamoxiclav, pip-tazo) may appear sensitive in
vitro but often result in treatment failure
ESBLs
Urine culture
10^5 Escherichia coli /ml
Amoxycillin R
Cefuroxime R
Cefalexin/cefradine R
Cefotaxime R
Ceftazidime R
Auth
Trimethoprim R
Ciprofloxacin R
Gentamicin R
Augmentin (S)
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 age
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
2012-Qtr4
2012-Qtr3
2012-Qtr2
2012-Qtr1
2011-Qtr4
2011-Qtr3
2011-Qtr2
2011-Qtr1
2010-Qtr4
2010-Qtr3
2010-Qtr2
2010-Qtr1
2009-Qtr4
2009-Qtr3
2009-Qtr2
2009-Qtr1
2008-Qtr4
2008-Qtr3
2008-Qtr2
2008-Qtr1
2007-Qtr4
2007-Qtr3
2007-Qtr2
2007-Qtr1
2006-Qtr4
2006-Qtr3
2006-Qtr2
2006-Qtr1
2005-Qtr4
2005-Qtr3
2005-Qtr2
2005-Qtr1
No. of Patient Isolates/14 day period
Local data
UHSFT E. coli Bacteraemias
100
90
80
70
60
50
40
30
20
10
0
Hospital Acquired
Community Acquired
2012-Qtr4
2012-Qtr3
2012-Qtr2
2012-Qtr1
2011-Qtr4
2011-Qtr3
2011-Qtr2
2011-Qtr1
2010-Qtr4
2010-Qtr3
2010-Qtr2
2010-Qtr1
2009-Qtr4
2009-Qtr3
2009-Qtr2
2009-Qtr1
2008-Qtr4
2008-Qtr3
2008-Qtr2
2008-Qtr1
2007-Qtr4
2007-Qtr3
2007-Qtr2
2007-Qtr1
2006-Qtr4
2006-Qtr3
2006-Qtr2
2006-Qtr1
2005-Qtr4
2005-Qtr3
2005-Qtr2
No. of Patient Isolates/14 day period
Local data
UHSFT E. coli Bacteraemias
100
90
80
70
60
50
40
30
20
10
0
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
2012-Qtr4
2012-Qtr3
2012-Qtr2
2012-Qtr1
2011-Qtr4
2011-Qtr3
2011-Qtr2
2011-Qtr1
2010-Qtr4
2010-Qtr3
2010-Qtr2
2010-Qtr1
2009-Qtr4
2009-Qtr3
2009-Qtr2
2009-Qtr1
2008-Qtr4
2008-Qtr3
2008-Qtr2
2008-Qtr1
2007-Qtr4
2007-Qtr3
2007-Qtr2
2007-Qtr1
2006-Qtr4
2006-Qtr3
2006-Qtr2
2006-Qtr1
No. of Urine Isolates
4,000
3,500
2,500
60%
2,000
50%
1,500
40%
1,000
30%
20%
500
10%
0
0%
Total Isolates
% Cefotaxime or Ceftazidime Resistant
% Resistant to Gentamicin
% Resistant to Ciprofloxacin
% Resistant to Trimethoprim
% Resistant to Nitrofurantoin
Percentage Resistance
Local data
Antibiotic Resistance in E. coli Urine Isolates
100%
90%
3,000
80%
70%
Local data
ESBL-E.coli in urine (UHS, 2009-2012)
Concomitant resistance to:
• Trimethoprim
• Ciprofloxacin
• Nitrofurantoin
• Gentamicin
83%
69%
5%
25%
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
6000
Sum of Total DDD
Standard treatment days per quarter
5000
4000
Drug Type
Meropenem
Piperacillin/Tazobactam
3000
2000
1000
2006
2007
2008
2009
Years Issue Date
Kieran Hand, Consultant
pharmacist UHS
2010
2011
Qtr1
Qtr4
Qtr3
Qtr2
Qtr1
Qtr4
Qtr3
Qtr2
Qtr1
Qtr4
Qtr3
Qtr2
Qtr1
Qtr4
Qtr3
Qtr2
Qtr1
Qtr4
Qtr3
Qtr2
Qtr1
Qtr4
Qtr3
Qtr2
Qtr1
0
2012
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
Local data
Antibiotic Resistance in E. coli Urine Isolates
4,000
100%
90%
3,500
80%
3,000
60%
2,000
50%
40%
1,500
30%
1,000
20%
500
10%
Total Isolates
% Resistant to Ciprofloxacin
% Resistant to Co-amoxiclav
% Cefotaxime or Ceftazidime Resistant
% Resistant to Trimethoprim
2012-Qtr4
2012-Qtr3
2012-Qtr2
2012-Qtr1
2011-Qtr4
2011-Qtr3
2011-Qtr2
2011-Qtr1
2010-Qtr4
2010-Qtr3
2010-Qtr2
2010-Qtr1
2009-Qtr4
2009-Qtr3
2009-Qtr2
2009-Qtr1
2008-Qtr4
2008-Qtr3
2008-Qtr2
2008-Qtr1
2007-Qtr4
2007-Qtr3
2007-Qtr2
2007-Qtr1
2006-Qtr4
2006-Qtr3
0%
2006-Qtr2
0
% Resistant to Gentamicin
% Resistant to Nitrofurantoin
Percentage Resistance
2,500
2006-Qtr1
No. of Urine Isolates
70%