The Threat of Multi-drug Resistant Organisms in Hospitalized Patients

David van Duin, MD, PhD

The Threat of Antibiotic Resistance

• WHO 2009: “antibiotic resistance one of the three greatest threats to human health”

• US: annual additional costs of infections caused by resistant organisms $21-34 billion

• Impact on all aspects of modern medicine– Surgery– Oncology– Transplantation

Resistance in Non-lactose Fermenting GNR

0

5

10

15

20

25

30

1999 2000 2001 2002 2003 2004 2005 2006

4.5 6.4 7.7 6.8 9.612.6

18.4 18.2

1.3

55.8 6.5

4.34.2

7.1 9.4

Resistant Intermediate

% imipenem resistance in Acinetobacter species

Hoffmann et al. ICHE 2010;31:196

Resistance is Global

Isturiz. Int J of Antimicrob Agents 2008;32:s201

Trends in Resistance in Enterobacteriaceae

Asensio et al. Eurosurveillance 2011;16:1Vatopoulos. Eurosurveillance 2008;1-3:1

Spain Greece

Carbapenem-Resistant K. pneumoniae (CRKP)

Munoz-Price et al. Lancet ID 2013:13;785

• First report of Klebsiella pneumoniae carbapenemase (KPC) in US

• 1996 patient in North Carolina• Participant in project Intensive Care

Antimicrobial Resistance Epidemiology (iCARE)

K. pneumoniae carbapenemase

• Most common carbapenemase encountered in Enterobacteriaceae

• 13 variants; KPC-2 and KPC-3 most common

• Class A serine-carbapenemase

• Hydrolyzes carbapenems, cephalosporins, penicillins, aztreonam

Ke et al. Biochem 2007;46:5732

• NDM: New Delhi metallo-β-lactamase• Zinc-containing Class B carbapenemase• Hydrolyzes carbapenems, cephalosporins,

penicillins, but not aztreonam• First isolated from a Swede who was

hospitalized in New Delhi, India

What’s in a name?

New Delhi metallo-β-lactamase

‘Members of the Indian Parliament denounced the name choice as “malicious propaganda”’

Global epidemiology of KPC

Lee et al. Front Microbiol 2016

Global epidemiology of NDM

Lee et al. Front Microbiol 2016

Epidemiology: US

Based on CDC data 1/6/17

Antibacterial Resistance is Ancient

D’Costa et al. Nature 2011;477:457

Antibiotic Resistance TimelineAntibiotic first used

Resistance first observed

Clatworthy et al. Nature Chem Biol 2007:3;541

Drivers of Resistance

Hawkey et al. JAC 2009;64:i3

Antibiotic Usage • Outpatient

antibiotics• Defined daily dose

per 1,000 inhabitants per day

• 2004 data

Source: CDC.gov

Goossens et al. CID 2007;44:1091

MDR Bacteria in Waste WaterWaste water from Indian plant receiving water from >90 drug factories

Marathe et al. Plos One 2013;8:e77310

Transfer of Resistance Genes from Soil Bacteria to Pathogens

DNA fragments derived from soil dwelling bacteria

Tetracyclines

Integrase associated with horizontal gene transfer

Forsberg et al. Science 2012;337:1107

aminoglycosides

sulfa

Populations at Risk

• Long term care residents• Kidney disease• ICU patients

– Burn units

• transplant recipients– Solid organ – Hematopoietic stem cell

• Oncology patients

Commonality of Risk Factors

Safdar & Maki. Ann Intern Med 2002;136:834

Endoscope-related outbreaks

Several outbreaks featuring carbapenemase-producing Enterobacteriaceae-NDM and KPC-possibly related to elevator channel in scopes-likely “tip of the iceberg”

The Nursing Home Pyramid

Most commonly treated infections in NH

Respiratory

UTI

Skin

Other

?

Source: cdc.gov

27,000 NH residents have antibiotic-resistant infections

Long Term Acute Care Facilities and ICUs

Chitnis et al. ICHE 2012;33:993

CRACKLE-1: Consortium on Resistance Against Carbapenems in Klebsiella pneumoniae

• Multicenter, prospective, observational cohort study – 2015

• University of Pittsburgh• Ohio State University

– 2014• Akron City Hospital

– 2013 • Detroit Medical Center Hospitals• Summa Health Akron• University of North Carolina Hospitals

– 2012• Cleveland Clinic Health System• University Hospital of Case Western Reserve University• Louis Stokes Cleveland VA Medical Center• Metro Health Medical Center

• Real-time monitoring of all hospitalized patients with carbapenem-resistant K. pneumoniae (CRKP)

Van Duin et al. AAC 2014;58:4035

32 US sites / 79 US hospitals

17 States, DC, and Colombia

3597 projected patient admissions

1000 estimated isolates per year

Additional sites planned › China (n=5) › Pacific (n=10)

Red Stars = Sites

Purple Stars = Central laboratories

Network: Methods

• Study period 12/24/2011 until 6/30/2016• All hospitalized patients with clinical culture

positive for carbapenem-resistant K. pneumoniae (CRKP) were included

• RepPCR for strain typing on all available isolates

• Network analyses at the facility and individual level were performed

Network: Facilities

Network: individuals

• 572/724 (79%) people “connected”

• i.e. at least 5 days at the same facility

• 2007: 22% K. pneumoniae R to carbapenem• National intervention:

– Cohorting/isolation– Dedicated nursing staff– CRE task force– Screening of carriers– Long-term care facilities– Hand hygiene– Standardized methods

• Laboratory detection• Environmental cleaning

Swaber & Carmeli, Clin Infect Dis. 2013;58(5):697

Prevention: Antimicrobial Stewardship

Willmann. AAC 2013,57:1797

Prevention: Prevention of Spread

Beyond Hand Hygiene: Gown and Glove

Harris et al.• RTC with 26,180 patients in 20 US ICUs• Gown/glove vs. standard of care• MRSA acquisition decreased • No difference in VRE acquisition• Gown/glove led to less room entry by health

care workers

Harris et al. JAMA 2013,310:1571

Prevention: Treat and Destroy

• Outbreak with PCN-R N. gonorrhoeae

• 372 contacts identified• 165 contacts had PCN-

R N. gonorrhoeae and were treated

Faruki et al. NEJM 1985,313:607

Mechanisms of ResistanceEfflux pump

B-lactamases

Penicillinbindingproteins

Mulvey & Simor CMAJ 2009;180:408

Don’t Forget Biofilms…

Yang et al. FEMS Immunol Med Micro 2012;65;146

Carbapenem-resistant Enterobacteriaceae

Perez & van Duin, CCJM 2013;80:225

The Impact of MDR-O on Outcomes

• Difficult to study• Reports vary in their definitions of MDR• Many confounders• Patients with MDR-O tend to be:

– More chronically ill– More acutely ill– Treated differently

Impact of MDR on Mortality

Vardakas et al. J Infect 2013;66;401

Predominance of ST258 K. pneumoniae

Data up to 2008

Kitchel et al, AAC 2009;53:3365

ST258 Molecular Dissection

Frank R. DeLeo et al. PNAS 2014;111:4988-4993

ST258 Dissection by repPCR

Pollett et al. J. Clin. Microbiol. 2014;52:4003-9

ST258A vs. ST258B

0

20

40

60

80

100

KPC-2 KPC-3 Urinarysource

Infection admit fromSNF

present onadmission

ST258AST258B

van Duin et al. AAC 2014;58:4035

Antibacterial Susceptibility

0

20

40

60

80

100

colistin tigecycline amikacin gentamicin tmp/smx

ST258AST258B

van Duin et al. AAC 2014;58:4035

ST258A clade is associated with failure in bacteriuria

(per CDC/NHSN)

Multivariable ordinal analysis (success vs. intermediate vs. failure)

Multivariable logistic regression (failure vs. others)

(per CDC/NHSN)

van Duin et al. JAC 2015;70:1203

Outcomes in CRE infections

• BSI/pneumonia: All-cause hospital mortality 39% (“excess mortality” 27%)

• Adjusted HR 30-d mortality– BSI 2.59 (1.52-4.50)– Pneumonia 3.44 (1.80-6.48)

Hauck et al. CMI 2016;22:513

CPE vs. CRE: does it matter?

• Single center, retrospective cohort• carbapenemase vs.

non-carbapenemase producing CRE• n=83

Tamma et al. CID 2017:64;257

Financial cost of CRE• NDM-producing CRE outbreak in UK

– 40 patients in 5 hospitals

• Total costs €1,100,000 ($1,163,415)

Otter et al. CMI 2017;23:188

Treatment of CRE• Limited options…• Toxicity• Efficacy concerns• ?combination

therapy

van Duin et al. DMID 2013;75:115Tumbarello et al. CID. 2012;55:943

Antibiotic Susceptibility

van Duin et al. AAC 2014;58:4035

Resistance: tigecycline

van Duin et al. ICHE 2015; 36(8):942

Resistance: tigecycline

van Duin et al. CMI 2014; 20:O1117

Resistance: colistin

Hindler & Humphries 2013;51:1678Rojas et al. CID 2017;in press

Resistance: colistin

Rojas et al. CID 2017;in press

Liu et al. Lancet ID 2016:16(2):161-8.

MCR-1 decreases polymyxinBinding to lipid Athrough phospho-

ethanolamine transferase activity

Dissemination of mcr-1

untreated

pentamidine

Newer anti-CRE agents

• β-lactam/β-lactamase inhibitors– Ceftazidime-avibactam

• FDA-approved• cUTI and cIAI data

– Meropenem-vaborbactam• Phase III in progress

– Imipenem-relebactam• Phase III in progress

• Plazomicin– Small n data in CRE patients favorable

Wong & van Duin Drugs 2017; in press

Summary

• MDRO are an ongoing and growing threat to hospitalized patients

• Outcomes of patients with MDRO infections likely worse vs. susceptible organisms

• Carbapenem-resistent Enterobacteriaceae especially worrisome– Limited treatment options– Poor outcomes

AcknowledgmentsCase Western Reserve UniversityRobert BonomoFederico PerezSusan D. RudinKris HujierAndrea HujierNick DomitrovicLaura Rojas

CRACKLE investigatorsRobert KalayjianEric CoberSandra RichterRick WatkinsRobert SalataKeith KayeRomney HumphriesJesse JacobGlenn WortmannMichael SatlinJohn FarrelSilvia Munoz-PriceDarren WongDan UslanCesar Arias

CRACKLE investigatorsLillian AbboDev AndersonJulia Garcia-DiazYohei DoiJason GallagherMatthew GrantDavid BanachJennifer HanEbbing LautenbachSamit DesaiBelinda OstrowskyAngela GomezGopi PatelBettina FriesAngela KimMarnie Rosenthal

Funding:NIAIDAntibacterial Resistance Leadership GroupSTERIS Inc.Clinical and Translational Science AwardResearch Program Council of the Cleveland Clinic

Harvard UniversityScott EvansJudith LokMichele EarleyLauren Kamorow

University of North CarolinaAshley BosheJim KennyCheryl HendricksonTania CaravellaMelissa “MJ” JonesMelissa MillerPeter Gilligan

ARLG/DCRIHenry “Chip” ChambersVance FowlerRebecca “Peggy” AriasPeidi GuDavid SoutoCarl SchulerMichelle ProcanynJackie HuvaneCarla AndersonCarol Hill

Duke UniversityJim Moody

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