The Threat of Multi-drug Resistant Organisms in Hospitalized Patients David van Duin, MD, PhD
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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
Questions?
Why is the sky blue?
How come we don’t have wings and fly like birds?
Why does the cat wake up one hour before he has to be fed?
What kind of skulls do ant-eaters have?
Why do people cause pollution?
What is coldness made out of?
What are electrons made of?What is the smallest thing on earth?
Why do people need to sleep?
How does electricity power technology?
Is the new Star Wars movie going to be any good?
What makes waterproof things waterproof?
Why did the dinosaur-killing-comet come to earth?
What are we going to have for dinner?
Why does my brother always bother me?
Why is my sister always so fresh?
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