Resistant Gram-negative Infections 21 st 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 SCiprofloxacin S Co-amoxiclav SGentamicin S Trimethoprim 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 2 nd and 3 rd 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 3 rd 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 RGentamicin 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 , 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 Liverpool, UK, Abstract. SA62

Local data

Resistance 10% of E coli bacteraemia isolates from UK were resistant to 3 rd 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 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

Local data

ESBL-E.coli in urine (UHS, ) 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?

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 6 th 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