Prepared by:Abdul Qadeer MBBS, MPH, CPHI(C), CIC Public Health PractitionerSeptember 22 , 2014

Lets Be AWARE!• Antibiotic resistance is a threat at focal, local

and global level.• The data collected so far is a snapshot of the

complex problem of antibiotic resistance .• An immediate action is required to address the

threat.• The consequences of inaction may be

catastrophic.

Microbial Threats to Mankind

CampB

Gonorrhea

Acinetobacter

Anthrax

MRSA

Salmonella

MTB

VRE VISA/VRSA

Influenza

Malaria

Candida

CPE

Information to Share with You Today!

• What are CPE and how they are different from other ARO?

• The mechanism of antimicrobial resistance.

• Global distribution of CPE.

• Current status of CPE in Ontario.

• Why are CPE of concerns?

• Why surveillance of CPE is necessary?

• The guidelines for controlling the transmission of CPE.

Resources used

CPE Has Arrived Here

September 22, 2014

Myths about Superbugs

1. Antibiotic resistant organisms are more virulent.2. Irrational use of drugs (antimicrobials) cause

antibiotic resistance.

Truth about Superbugs

1. Antibiotic resistant strain appear to be more virulent because we cannot kill them by conventional antibiotic or stop their growth.

Antibiotics dispensed by retail pharmacies in Canada, 2000 to 2009

Source: The Chief Public Health Officer’s Report on the State of Public Health in Canada, (2013): Infectious Disease—The Never-ending Threat.

Figure: Total number of prescriptions per 1,000 population

Truth about Superbugs

•2. Antibiotic select out the resistant strain.

• Faulty use or widespread use of antibiotics

• increases the probability of such selection.

Epidemiology of Antimicrobial Resistance

The Chief Public Health Officer’s Report on the State of Public Health in Canada, 2013. Infectious Disease—The Never-ending Threat. http://www.phac-aspc.gc.ca/cphorsphc-respcacsp/2013/resistance-eng.php

Simply Overloaded

Intrinsic Microbial Resistance

Bacteria may be naturally resistant or insensitive to antimicrobial agents.

resistance occurs by different mechanisms.

the MAJORITY of the strains of bacterial species can show intrinsic resistance.

ORGANISMS NATURAL RESISTANCE AGAINST: MECHANISM

Anaerobic bacteria Aminoglycosides Lack of oxidative metabolism to drive uptake of aminoglycosides

Aerobic bacteria Metronidazole Inability to anaerobically reduce drug to its active form

Gram-positive bacteria Aztreonam (a beta-lactam) Lack of penicillin binding proteins (PBPs) that bind and are inhibited by this beta lactam antibiotic

Gram-negative bacteria Vancomycin Lack of uptake resulting from inability of vancomycin to penetrate outer membrane

Klebsiella spp. Ampicillin (a beta-lactam) Production of enzymes (beta-lactamases) that destroy ampicillin before the drug can reach the PBP targets

Stenotrophomonas. maltophila Imipenem (a beta-lactam) Production of enzymes (beta lactamases) that destroy imipenem before the drug can reach the PBP targets.

Lactobacilli andLeuconostoc Vancomycin Lack of appropriate cell wall precursor target to allow vancomycin to bind and inhibit cell wall synthesis

Pseudomonas aeruginosa Sulfonamides, trimethoprim, tetracycline, or chloramphenicol

Lack of uptake resulting from inability of antibiotics to achieve effective intracellular concentrations

Enterococci Aminoglycosides Lack of sufficient oxidative metabolism to drive uptake of aminoglycosides

All cephalosporins Lack of PBPs that effectively bind and are inhibited by these beta lactam antibioticshttp://amrls.cvm.msu.edu/microbiology/molecular-basis-for-antimicrobial-resistance/intrinsic-resistance

Acquired Microbial Resistance

Acquired resistant develop after exposure to antimicrobial agents. It can occur through:

• Alteration in cell wall that restrict drug entry into the microbial cell (e.g. porin loss).

• Presence of ‘pumps’ which remove antimicrobial.• Development of substitute ‘proteins’ that are not

targeted by drugs.• Development of ‘enzyme’ that destroy or inactivate

antimicrobials. Acquired resistance is LESS COMMON, existing only in

some bacterial strains.

Mechanism of Action of ARO

Carbapenemase Producing Enterobacteriacea (CPE)

are bacteria:

• in the family of Enterobacteriaceae

• acquired resistant to carbapenem is due to Cabapenemase enzyme.

Enterobateriacea Family

Enterobacteriaceae

Lactose Fermenter

Eschericha

Klebsiella

Enterobacter

Citrobacter

Non-Lactose Fermenter

Salmonella

Shigella

Proteus

Yersinia

Generalities of Enterobacteriaceae

All Gram negative rods, resident of GI & Urinary tract.

• Transmission:

Fecal-oral

Ascending migration to urethra

Colonization of lumen of Foley and Central lines

• Toxin: Produce enterotoxin

• Pathology:

Diarrhoea

Pneumonia

E. coli

Normal flora of colon; Motile and become virulent.

Virulence factors:

Mucosal adherence with pilli, intestinal epithelial invasion

Toxin production (exo & endo)

Clinical: 6 serotypes Diarrhea (ETEC-TD); (EHEC- HUS, BD); (EIEC- BD with WBC)

UTI

Neonatal meningitis

Sepsis in hospitalized pts

Treatment: Cephalosporin, Aminoglycoside, Fluoroquinolones

Klebsiella pneumoniae

• Non-motile enteric

• 2nd most common cause of HAI

Pathology:

HA-UTI and Sepsis

HA- pneumonia with bloody sputum, commonly in alcoholics or those with underlying lung Ds.

Treatment: 3rd gen. Cephalosporin and Cipro

Initially resistant G nve organism called - CRO

Resistant Enterobateriaceae called – CRE• Resistance developed due to combinations of a β-lactamase

enzyme and porin loss.

• These strains rarely spread.

Resistant Enterobacteriacea due to Carbapenemase

enzyme that inactivate Carbapenems - CPE

• CPE are the more serious risk and are beginning to spread

worldwide.

Confusing Terms used for Carbapenem Resistance

CPE are More Virulent than CRE

BIG Concern about CPE

o CPE have highly mobile genetic elements which allows them to transfer resistance genes very rapidly between different bacteria.

o EVIDENCE suggested that plasmid spread has occurred among and between K.pneumoniae

and E.colli via conjugation.

CPE Recognition in Lab

• Several different classes exist and each class has a three-letter acronym.KPC = klebsiella pneumoneae cabapenemase

NDM = New Delhi metallo-𝜷-lacatamaseVIM= Verona integeron-encoded metallo-𝛽-lacatamase

OXA 48 = Oxacillinase type 48 carbapenemase

IMP = Imepenem types carbapenemase

E.Coli and K. pneumoniae are CRE & CPE

o E.Coli & K. pneumoniae that have developed resistance due to β-lactamase enzyme and porin loss are called -

o E.Coli & K. pneumoniae that have acquired multi-drug resistance due to production of Cabapenemase enzyme – . These species are more serious risk.

Carbapenemase producing Enterobacteriaceae (CPE)

23 1

CPE Surveillance in Ontario!

o Reported (imported) in Ontario since 2008.

o PHO and MOHLTC initiated a voluntary surveillance program to assess the

epidemiology of CPE in 2011.

o Epidemiological data is critical for informing IPAC policies and procedures that will help prevent the likelihood of CPE becoming endemic in Ontario.

picture

CPE: Klebsiella pneumoniae carbapenemase (KPC)

GlobalUSA

EuropeChina

Geographic distribution of VIM and IMPproducers

Europe

Global

Global distribution of (OXA-48) type producers

Current Status of CPE in Ontario -Snapshot

•2008- 2011: • 74 CPE positive isolates identified.

• Central Ontario & GTA.

•In 2012: • 82/458 (18%) positive isolates identified.

•In 2013: • 84/504 (17%) positive isolates identified.

In 2014 (January-March)

• 26/150 (17%) positive isolates identified.

Status of CPE in Ontario 2008 – 2011 (PHO Lab data)

Number of carbapenemase-producing Enterobacteriaceae referred to the Public Health Ontario Laboratories from 2008 to 2011 (N=73)

2008 - 2011:

• 73 CPE positive isolates.

• Central Ontario & GTA.

• 4 types of Carbapenemases

were identified.

Roberto G. Melano, David J Farrell, Donald E Low, and Samir N Patel(2012), Carbapenemase-producing Enterobacteriaceae in Ontario, 2008-2011, Public Health Ontario, Public Health Laboratory – Toronto, Toronto, ON Canada.

49% NDM

15.6%OXA

4.4% VIM

31% KPC

CPE classified by geographic place of isolation 2008-2011

GTA: Greater Toronto Area, GHS: Greater Horseshoe valley, SW: Southwestern Ontario, TO: Toronto, Ott: Ottawa area

Roberto G. Melano, David J Farrell, Donald E Low, and Samir N Patel(2012), Carbapenemase-producing Enterobacteriaceae in Ontario, 2008-2011, Public Health Ontario, Public Health Laboratory – Toronto, Toronto, ON Canada.

CPE Classified by Site of Isolation 2008 -2011

Roberto G. Melano, David J Farrell, Donald E Low, and Samir N Patel(2012), Carbapenemase-producing Enterobacteriaceae in Ontario, 2008-2011, Public Health Ontario, Public Health Laboratory – Toronto, Toronto, ON Canada.

CPE Epidemiological Data Summary 2012

January -December 2012

Source of submission No. of CPEpositive isolates

Percentage ofall positive isolates

(%)

Total submitted

isolates

Large community hospital48

59 231

Acute teaching hospital 19 23 95

Community laboratory 14 17 129

Complex Continuing Care& Rehabilitation

1 1 1

Small community hospital 0 0 2

Total 82 100 458

Number & percentage of CPE positive isolates by source of submission in Ontario

Source: Public Health Ontario Laboratories, Carbapenemase Producing Enterobacteriaceae database, extracted by Public Health Ontario [2013/07/02]

Attack rate

82÷458 ×100 =18%

CPE Epidemiological Data Summary 2012

SiteJanuary - December 2012

No. of CPE positive

isolates

Percentage of all positive

isolates (%)

Total submitted isolates

Urine 40 49 244

Rectal swab 26 32 99

Blood 3 4 24

Sputum 3 4 22

Wound 0 0 11

Other 10 12 56

Unknown 0 0 2

Total 82 100 458

Number & percentage of CPE positive isolates by site in Ontario

Source: Public Health Ontario Laboratories, Carbapenemase Producing Enterobacteriaceae database, extracted by Public Health Ontario [2013/07/01]

CPE positive isolates by LHIN- Jan-Dec 2013

Source: Public Health Ontario Laboratories, Carbapenem Producing Enterobacteriaceae database,

extracted by Public Health Ontario [2014/1/20]

CPE Epidemiological Data Summary - 2013

SiteJanuary - December 2013

No. of CPE positive isolates Percentage of allpositive isolates (%)

Total submittedisolates

Urine 36 43 291

Rectal swab 34 40 91

Wound 5 6 21

Blood 2 2 22

Sputum 0 0 17

Other 6 7 50

Unknown 1 1 12

Total 84 100 504Source: Public Health Ontario Laboratories, Carbapenemase Producing Enterobacteriaceae database, extracted by Public Health Ontario [2014/01/20]

CPE positive isolates between Jan-March 2014

• 150 isolates were submitted for confirmatory testing at the Public Health Ontario Laboratories (PHOL).

• Twenty-six positive CPE isolates were identified

Hospitalization and Travel history of CPE-positive patients in Ontario, January – March 2014

Patient Classification by Hospitalization History

Patients hospitalized outside of Canada 13 /23India 8

Angola 1

China 1

Italy 1

Pakistan 1

Vietnam 1

Patients hospitalized within Canada 4 /23Patients that have not travelled outside North America 3

Patient that have travelled outside North America 1

Patient with no hospitalization history 3 /23Patients that have not travelled outside North America 1

Patients that have travelled outside North America 1

Patient that have unknown travel history 1

Patients with unknown hospitalization history information 3 /23

Number and proportion of CPE positive isolates by site in Ontario,January – March 2014

Site

January – March 2014

No. of CPEpositiveisolates

Percentage of allpositive isolates

(%)

TotalSubmitted

isolates

Urine 5 19 77

Rectal swab 15 58 42

Blood 0 0 3

Sputum 1 4 6

Wound 1 4 4

Other 4 15 16

Unknown 0 0 2

Total 26 100 150

The STATS of CPE in Ontario could be misleading

• These numbers are only a snapshot.

• May not be a complete data.

• All important enzymes have been implicated in several Ontario hospitals.

• Data from private lab is also missing.

• Data from March-September 2014 is not tabulated yet.

Why CPE are of Concern?•“Enterobacteriaceae are the commonest cause of nosocomial infections”

Relative frequencies of nosocomial infections in Long-Term Care Facility 4

21

38 Lower respiratory tract infections

Symptomatic urinary tract infections

Skin and soft tissue infections

Acute gastroenteritis

Bacteremias

18

19

Why CPE are of Concern?

• Enterobacteriaceae have become resistant to many antibiotics such as, Cephalosporines , Penicillines, Fluroquinolones and Aminoglycosides.

• Now resistant to Carbapenems.

• Panresistant is possible due to mobile plasmids.

• There are no new antibiotics in development that have actively against the resistant gene.

Antibiotic Resistance

Trends in retail sales of Carbapenem antibiotics (2005-2010) for Gram-negative bacteria

www.thelancet.com/infection Published online November 17, 2013 http://dx.doi.org/10.1016/S1473-3099(13)70318-9

The Lancet Infectious Diseases Commission (2013): Antibiotic resistance—the need for global solutions

More alarming concerns about CPE

• Once colonized CPE may not be eradicated as these organisms are part of the normal gut flora- Resistant Gut Flora.

• The therapeutic options for CPE infections are very limited now.

• Colistin is only option right now. Serious side effects.

• Lab test for Carbapenemases may fail.

• CFR could be 50%

This Superbug may visit your facility too!!

o The Village of Walkerville is receiving its first CPE case (Mr. Brown) from the hospital after rehabilitation.

o The staff at the facility has challenges to handle this situation.

o Which of the following strategies facility can adopt in implementing a surveillance programfor this MDRO?

1) Screen all patients for CPE on admission.

2) Implement routine practices all the time.

3) Placed all colonized or infected patients on contact precautions.

4) Placed all colonized or infected patients on contact precautions.

5) Minimize invasive devices.

6) Communicate results to Healthcare providers.

Circle your Strategies for Surveillance of CPE

What Should You Do About It?

o Understand the Epi Triad:

Host risk factors

Environmental risk factors

o Implement Surveillance:

o Use IPAC interventions:

Before a case is identified

After a case is identified

Epi-Triad: Risk Factors for CPE acquisition

• Host risk factors: have compromised immune systems

have invasive devices e.g., ventilators, intravenous catheters, urinary catheters

irrational use of antibiotics

• Environmental risk factors: Exposure tocritical care units, burn units

hospitalized in endemic areas outside Canada.

Epi-Triad: Transmission of CPE

•Transmission is via:

direct contact: person to person

via wound, stool, sputum

indirect contact:

environment surfaces, sinks

Epi-Triad - Interventions

1. Preventing transmission the colonized or infected patient is identified.

2. Preventing transmission the colonized or infected patient is identified.

Interventions a case is identified

• Routine Practices

• Antimicrobial stewardship Program (ASP)

Developing an ASP program in your facilityhttp://www.oahpp.ca/services/antimicrobial-stewardship-program.html

• Appropriate specimen testing, such as:

rectal swab, urine, blood, wound swab

Interventions a case is identified.

(Targeted)Public health notification Routine practices continued + Contact precautionsSignage for visitorsHealthcare worker education CPE screening based on risk factorsMinimize use of invasive devices Environmental sanitation CohortingInter-facility communication

Look deeper than Tip of the Iceberg - Active Surveillance

Best Practices for Surveillance of Health Care-associated Infections in Patient and Resident Populations | July 2014

Active Surveillance for CPE

•Point prevalence screening: Whole unit screening, if a new case is

identified.

•In a CPE outbreak: Absolute cohorting and dedication of

equipment and PH notification.

•Flagging of known CPE carrier and rescreened on readmission.

Decolonization

CPE decolonization is NOT recommended unless to reduce the bio-burden in an uncontrolled

outbreak.

Occupational Health & Safety Requirements

• OH&S in hospitals and LTCH do not requireroutine screening of staff unless there is an epi-link to the transmission of CPE.

• If CPE is acquired due to an occupational exposure, it is reportable to WSIB.

Inter-Facility Communication (info sharing)

• Ensure if patient transferred within the facility that Routine practices are continued.

• Ensure if patient transferred to another facility patient information(CPE) is shared with accepting facility.

Antimicrobial Resistance is a Shared Responsibility

ACT AS A TEAM

CONCLUSION- ARO

• ARO is inevitable, but can be delayed.

• ARO are not restricted to healthcare facilities.

• Inappropriate use of antimicrobial agents and limited research into and development of new agents have helped accelerate antimicrobial resistance.

• Treatment of diseases caused by antimicrobial-resistant organisms takes more time, uses more resources and is more costly.

The Chief Public Health Officer’s Report on the State of Public Health in Canada, 2013; Infectious Disease—The Never-ending Threat, Antimicrobial Resistance—A Shared Responsibility. PHA Canada.

CONCLUSION- ARO

• The WHO has recognized antimicrobial resistance as one of the most serious public health threats to the treatment of

infectious diseases worldwide.

• Managing antimicrobial use is everyone’s responsibility.

• Lets PLAY responsibly!

References • By Roberto G. Melano, David J Farrell, Donald E Low, and Samir N Patel

(2012), Carbapenemase-producing Enterobacteriaceae in Ontario, 2008-2011, Public Health Ontario, Public Health Laboratory – Toronto, Toronto, ON Canada.

• Patrice Nordmann, Thierry Naas, and Laurent Poirel (2011): Global Spread of Carbapenemase- producing Enterobacteriaceae, Emerging Infectious Diseases , www.cdc.gov/eid , Vol. 17, No. 10.

• Guidance for control of Carbapenem-resistant Enterobacteriaceae(CRE):CDC 2012 CRE Toolkit.

• Monnet DL. Update on EARS-NET AMR & HAI activities and workplan[for] 2012. [Presentation] Warsaw 2011 November 23-25 [cited 2012 July 11]. www.EARSnet.europa.eu/en/activities/diseaseprogrammes/ARHAI/Presentations2011Warsaw/ARHAI-networks-meeting_parallel-session-five-1-Dominique-Monnet-AMR-HAI-activities.pdf.130

References

• PIDAC Annex A- screening, testing and surveillance of antibiotic resistant organisms (AROs) in ALL health Care Settings-Feb 2013.

• Routine practices and Additional precautions in ALL HC Settings 3rd edition Nov. 2012, PHO, PIDAC.

• APIC Text of Infection Prevention and Control 3rd edition, 2009

• Carbapenemase-producing Enterobacteriaceae (CPE) Surveillance Report, VOLUME 3, ISSUE 1 (2013 ANNUAL SUMMARY) PUBLISHED IN JUNE 2014.

• The Chief Public Health Officer’s Report on the State of Public Health in Canada, 2013; Infectious Disease—The Never-ending Threat, Antimicrobial Resistance—A Shared Responsibility. PHA Canada.

• Best Practices for Surveillance of Health Care-associated Infections in Patient and Resident Populations | July 2014

References

• Carbapenemase Producing, Enterobacteriaceae (CPE) Surveillance Report,VOLUME 2, ISSUE 1 (OCTOBER 2013)

• Quarterly Carbapenemase Producing Enterobacteriaceae (CPE) Surveillance Report, VOLUME 1, ISSUE 3, December 2012.

• Carbapenemase Producing Enterobacteriaceae (CPE) Surveillance Report, VOLUME 1, ISSUE 4 (2012 ANNUAL SUMMARY)

• Public Health Ontario Laboratories, Carbapenemase Producing Enterobacteriaceae database, extracted by Public Health Ontario [2013/07/02]

• Ramanan Laxminarayan, Adriano Duse, Chand Wattal, et,al; (2013): Antibiotic resistance—the need for global solutions,The Lancet Infectious Diseases Commission. www.thelancet.com/infection Published online November 17, 2013 http://dx.doi.org/10.1016/S1473-3099(13)70318-9