10 October 2019

• Eimear Brannigan

• Twitter: @eimeartb

• Email: eimear.brannigan@nhs.net

CPE – A UK perspective

Context

• Global context

• UK perspective

• Experience at Imperial

• Improve awareness and understanding of AMR

• Strengthen knowledge through surveillance and research

• Reduce incidence of infection

• Optimise use of antimicrobial agents

• Develop economic case for investment that takes account of needs of all countries, and increase investment in new medicines, diagnostic tools, vaccines and other interventions

CPE

Resistance

Rapid spread

Mortality

Carbapenemase-producing Enterobacteriaceae (CPE): ‘triple threat’

A story

• 70 year old man• Suprapubic pain, vomiting, poor urine output – obstructive AKI, creat >1000, likely bladder /

prostate malignancy

• Critical care admission for monitoring AKI, haemofiltration• Empiric piperacillin – tazobactam started on D3 – ‘low grade temp, chest creps, rising CRP’• Nephrostomies arranged; step down• Later bilateral ureteric stenting and TURBT• 10 days antibiotics, home

• Readmission via ED: confirmed G3pT2 TCC, awaiting cystoprostatectomy• Now presenting with 7 day constipation, suprapubic pain

• WCC 18, Creatinine 196 (170 on discharge previously)• Urine dip - Leuc ++, Blood ++, Protein ++. Nitrite negative. Sent for MC&S

• Antibiotics as per protocol for presumed urosepsis – IV co-amox; stat of aminoglycoside (AK)• 24 hrs later – temp 39.9, resp rate 40; BP and HR ok ; added co-trimoxazole as thought to have HAP

Klebsiella pneumoniae NDM

How it ends..

• Klebsiella bacteraemia and rectal screen positive, obstructed system

• Meropenem 2 g TDS IV (even though resistant) started – evidence of high dosing / infusions overcoming enzymatic activity

• Colistin IV – loading dose, then continuation

• A few days in, awaiting surgery, hypotensive and altered mental state –septic –fosfomycin 8g TDS added, nephrostomy inserted with clinical response

• Surgery - supravesical urinary and bowel diversion

• Reaction to fosfomycin - wheeze during infusion

• Tigecycline + colistin to completion

Summary

• Urinary source

• Colonisation with MDR GNB – enteric carriage

• Use of pip-taz prior to detection of MDR GNB

• Bacteraemia – confirmed pan resistant, limited Rx options

• Use of fosfomycin, colistin, tigecycline

CPE Europe – Feb 2019

- Stable proportions of carbapenem resistance in Klebsiella pneumoniae and E. coli x 4 years; - highly variable across Europe with resistance in invasive isolates ranging from 0 to 65% in 2017; - in 2018 all 37 participating countries reported CPE cases, vs in 2015 3 had still had no cases; - four new countries reporting regional or inter-regional spread; - Greece, Malta, Italy and Turkey all describe their CPE situation as endemic

Gaps in national policy / strategy / planning for containment or guidance for IPC

Data courtesy: M Molloy

CPE trend to end of 2018: Ireland

Adapted from K Burns March 2019

Number of confirmed CPE isolates referred to PHE’s AMRHAI Reference Unit, 2008 – 2017 Source: ESPAUR report 2018

Almost half of local labs have ability to detect main mechanisms of CPEIssued summary of commercially available assays, costs Now only submit isolates from sterile sites with confirmed carbapenemaseAlso isolates suspected of having carbapenemase with meropenem MIC >0.12

Shift in focus by Public Health England reference laboratory

How and when to start with CPE

• Get ready – planning phase – no cases

• Get set – engagement and planning phase –one case

• Go! Ideally – great we have a plan and will implement smoothly

• Go! too late – possible outbreak detected… response phase; engagement later and planning interrupted!

PHE CPE toolkit 2013

• Whom to risk assess

• Whom to screen

• Considerations for planning for cases

• How to prepare the organisation – Board to ward

• Templates for intra-organisation transfers

• IPC practice / cleaning / patient placement/ communication with patients/ primary care/ principles of AMS

Who do I screen?

UK PHE CPE Toolkit screening triggers:

a) an inpatient in a hospital abroad, or

b) an inpatient in a UK hospital which has

problems with spread of CPE (if known), or

c) a‘previously’positive case

Also consider screening admissions to high-

risk units such as ICU, and patients who live

overseas

Iterative development of lab processes

• …

• Rectal swab onto selective agar

• Any growth is identifed →• Enterobacteriacae → OKN

(immunochromatographic) test for our big 3: KPC, NDM and OXA48

• OKN positive → sensitivities, save the isolate and inform IPC

• OKN negative → sensitivities + CIM test– phenotypic test – carbapenem

inhibition method

• If either sens or CIM suggestive of a CPE, then → PCR (big 5)

• If that is negative but we still suspect a CPE (e.g. CIM positive) →send to the ref lab for extended PCR e.g. GES

Dendrogram: relatedness of PFGE profiles for 13 Klebsiella pneumoniae OXA-48 outbreak, 2008–2010

Thomas CP, et al. Int J Antimicrob Agents (2013)

Started with transmission

• Outbreak in renal wards 2008 - 2010 – Thomas et al

• Implemented screening of high risk patients– Adult and paediatric critical care each site

– Bone marrow transplant unit

• Planning, engagement phase for wider – Renal

K. pneumoniae NDM outbreak

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8 cases first identified by clinical culture, 32 by screening culture; of these 32, 14 had a later positive clinical

culture

• 41 cases

• Detected by typing of 3 clinical cases July -March

• Active screening on affected wards

Our strategy• Initially: screening of high risk patient groups

• Outbreak → adapted strategy– Universal admission and weekly screening in affected

wards – renal, vascular

– Later inclusion of all haematology inpatient areas• Both on risk and on recent CPE transmission

• Risk based screening for all admissions ~2017– All patients with an overnight stay who meet criteria

• Culture based methods

Risk factors for CRE carriage on admission

• Risk factors for CRE carriage in multivariable

analysis were previous hospitalisation at our

hospitals in the past 12 months (78% of positive

patients had previous hospitalisation; OR 3.3,

95% CI 2.8-3.8) and admitting speciality

• Renal, vascular, and haematology patients are

higher risk specialities for CRE, and paediatrics

could also be considered a high risk speciality

• Not clear if prevalence is an artefact of increased

screening – which is why we are using

alternative approaches to estimate prevalence

Mookerjee et al ECCMID 2018.

How many screens?

• PHE recommended 3 done at 48hour intervals to determine that a person of unknown status was not colonised

Feasibility of 3 CPE screens in our setting

• Majority of patients stay for ~ 1 day

• Repeated CPE screens did not show an increase in CPE

• Screening for long-stay patients should be part of policy

• Increase in GN and R GNB in 3 back to back screened

patients (n=1509)

• Move from 3 -> 1 admission screen

Mookerjee et al. J Hosp Infect 2018

How many screens?

• PHE recommended 3 done at 48hour intervals to determine that a person of unknown status was not colonised

• Admission screens – 1 only

• Repeated screens probably warranted when suspected transmission / longer admissions

Monitoring: CPE trend Apr-14 to Mar-19

CPE admission screening compliance

MonitoredDiscussed at local forumsImprovement work as needed

Monitor progress

• Impact

– Reduced infection – hard to say

– Reduced transmission – containment maybe

– Other measures – stewardship/ focus on hand hygiene

• Evaluation

Cost hierarchyError bars represent range

0 100000 200000 300000 400000

Ward-based monitors

HPV decontamination

Anti-infective costs

Contact precautions

Bed / bay / ward closures

Screening

Additional length of stay

Staff time

Elective surgical missed revenue

Cost / £

Supporting staff and patients

• Early learning points

– Staff need support to do rectal swab correctly

• Include detail in our guidance

How do I screen?

▪ Rectal swab is best– Insert no more than

2cm into rectum

– Twist gently and withdraw

– Ideally want visible faeces on swab

▪ Patient and staff education as to why this is needed in order to overcome taboos

▪ Alternate specimen is stool sample, but have to wait for the patient to ‘go’

Supporting staff and patients

• Early learning points– Staff need support to do rectal swab correctly

• Include detail in our guidance

– Staff need support to counsel patients about CPE• Being open/ candour

– Having a policy is not the end of the job• Staff in areas where there has been transmission feel under

scrutiny and despite best efforts, feel blamed

– Staff need support with prioritising side room usage• Balance of ‘CPE is important’ vs ‘CPE can be trumped for

isolation by other organisms/ conditions’

– Patients willing when included in discussions

Reviewing strategy

• Is this the right one for us, now?

– Patient demographics/ casemix

– Background epidemiology of CPE (increasing)

– Laboratory techniques/ capacity

– Isolation room capacity

• Unintended consequences

– Antibiotic choices in CPE patients

Review phase

• Optimise our screening– Can we reduce frequency in some areas?

– Do we need to switch from risk based to universal in some areas? And vice versa

• >30 clusters since start 2017, of which 65% occurred on wards that are NOT doing universal admission/ weekly screening– ‘Silent’ transmission

Prevalence survey progress

• Renal satellite units ~ 1400 screened; <0.5% positives– Maintain current position, quarterly and back from abroad

• Surgical floor – four wards near vascular– ~100 screened, 3 new patients detected

• Engagement work in advance each week with screening area (2 wards each site per week)– Lab capacity, site teams, clinical colleagues, patient info

• Rolling programme in all inpatient areas – To date 858 approached; 53 declined (major trauma,

labour ward) and 10 positives, only 4 not previously known; prevalence 0.5%

Role for molecular testing

• Use on all screening tests – admission/ contacts/ risk groups/ discharge • Use in more selective/ targeted approach

• Direct PCR from faecal material • PCR on cultured isolate phenotypically suspicious for carbapenemase production

• Targeted – Admission areas only– High risk only (patient in pre-emptive isolation; or whose pathway will be dictated by result)– Readmission of patient known previously to be CPE affected – can target known mechanism– During an outbreak – screens of contacts

• Influenced by prevalence and understanding of local epidemiology

What is the best CPE screening strategy?

• It depends

– Know your epidemiology

– Gather data, share it, use to inform strategy

– What impact will knowing have on

• Your patients – antibiotic usage/ side room isolation

• Your colleagues

• Your organisation

In practice

• Balance between evidence, feasibility and cost-effectiveness

• Feasibility is our main challenge– Serial screens vs. pragmatic single screen– Maintaining risk assessment– Maintaining weekly screening quality

• Mix of approaches to match risk / feasibility

CPE – a UK perspective

• Thanks:

• Siddarth Mookerjee

• Jon Otter

• Alison Holmes

• Frances Davies

• Tracey Galletly

• Mark Gilchrist