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Current issues in Antibiotic Use:the Continued Evolution of Antimicrobial Resistance
Bert K. Lopansri, MDDivision of Infectious Diseases and Clinical
EpidemiologyAssociate Professor, University of Utah
Medical Director, Intermountain Central Laboratory
DISCLOSURES
• Research support from:
– Nanosphere, Inc.
– Ansell, Inc.
– Catheter Connections, Inc.
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Objectives
• Discuss emerging emerging antimicrobial resistant organisms
• Discuss methods to control antimicrobial resistance
• Encourage healthcare workers to think about how antibiotics are used
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Fleming in reference to Penicillin
• The public will demand [the drug and]…then will begin an era… of abuses. The microbes are educated to resist penicillin and a host of penicillin‐fast organisms is bred out which can be passed to other individuals…In such a case the thoughtless person playing with penicillin treatment is morally responsible for the death of the man who finally succumbs to infection with penicillin‐resistant organism. I hope the evil can be averted.
Fleming A. Penicillin’s finder assays its future. New York Times. 1945; 21
Trends in outpatient antibiotic use in U.S. (per 1000 persons)
AGENT 1999 2010 % Change 2010 (UT)
ALL CLASSES 966 801 ‐17 791
Penicillins 352 248 ‐30 293
Macrolides 209 211 NC 176
Cephalosporins 117 114 ‐3 129
Fluoroquinolones 83 94 +13 69
Tetracyclines 71 67 ‐6 73
TMP/Sulfa 74 66 ‐11 51
Other (vanco, linezolid, dapto, polymyxins, carbapenems)
0.33 1.0 +200 0.7
Data from www.cddep.org (Center for Disease Dynamics, Economics & Policy)
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Outpatient antibiotic prescriptions per 1000 Persons, 2010
LA Hicks. NEJM. 368;15. April 11, 2013
Outpatient ABX Use: US vs. Sweden
U.S.(2010)
SWEDEN(2012)
ABX/1000 persons 833 388
Top Antibiotics AzithromycinPenicillins
PCN VKDoxycyclineFloxacillin
PivmecillinamNitrofurantoin
LA Hicks. NEJM. 368;15. April 11, 2013A Ternhag. NEJM. 369;12. Sept 19, 2013
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http://www.cdc.gov/getsmart/campaign‐materials/week/images/antibiotic‐use.jpg
CASE
• 79 y/o woman with HPV, cirrhosis, DM admitted with fever and diarrhea.
• Multiple episodes of daily, non‐bloody diarrhea and abdominal pain x 1 month.
• 1 week PTA, developed regular fevers to 101o F
• +urinary frequency without dysuria or urgency.
• Recently returned from a 3 month stay in India
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CASE• PMHX
– Breast CA s/p lumpectomy 5 months earlier
– DM
– HTN
– Hep B with cirrhosis
– Choledocholithiasis
• PSHX– Lumpectomy
– Cholecystectomy
– R TKA
• EXAM:– Temp 38.4, RR 25, HR 120,
BP 138/71
– Non‐toxic
– ABD distended with diffuse tenderness. Liver and spleen unable to be palpated
• LABS:– WBC 13.0 (PMN 81.4%),
HGB 8.2, PLT 275
– BUN 36, Cr 3.17
– Urine: Cloudy, + Nitrite, Large Leuk Esterase, >30 WBC
Question #1
a) Cefepime
b) Ceftriaxone
c) Imipenem/meropenem
d) Ertapenem
e) Ciprofloxacin
f) Piperacillin/Tazobactam
Patient was diagnosed with urosepsis. What antibiotic regimen would you start?
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Question #2
a) An overhyped, story that is unlikely to be a significant problem where I practice medicine.
b) A global problem
c) A U.S. problem
d) A problem only in certain parts of the world
e) Europe’s fault
f) What in the world is a CRE?
• Carbapenem‐resistant Enterobacteriaceae(CRE) is:
Emerging Antibiotic Resistant Organisms
http://jama.jamanetwork.com/article.aspx?articleid=1391920
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CeftriaxoneResistant
NG
CeftriaxoneResistant
NG
FQR NGFQR NG
FQRCampyFQR
Campy
Penicillin resistant Staph aureus
Penicillin resistant Staph aureus
MRSAMRSA
PCN Res Strep
pneumo
PCN Res Strep
pneumoVREVRE
ESBLESBL CRABCRABFQR E. coliFQR E. coli
MDRO P. aerugMDRO P. aerugCRECRE
FQR= fluoroquinolone resistantMDRO=multidrug resistantMRSA=methicillin resistant Staph aureusNG=Neiserria gonorrheaPCN=penicillin
CRAB=carbapenem resistant Acinetobacter baumaniiCRE=carbapenem resistant EnterobacteriaceaeESBL=extended spectrum β‐lactamaseVRE=vancomycin resistant Enterococcus
Number of β-lactamase enzymes described during age of antibiotics
1973 2013
Number of Unique Enzymes
900
Julian Davies. Micro biol and Molecular Bio Rev. Sept. 2010, p. 417‐433
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• Enzymes that mediate resistance to extended‐spectrum cephalosporins (third generation) and monobactams but do not affect cephamycins(cefoxitin/cefotetan) or carbapenems.
• Activity is reversed by clavulanic acid
Antibiotic Resistance Threats in the U.S., 2013. CDC
Common ESBLs
TEM/SHV CTX‐M
Epidemiology Associated with HAIs Community‐associated infections
Preferential targets
Ceftazidime Cefotaxime
Number of types >100 >50
Distribution Global Global
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Emergence of CTX-M in a Single Health Care System
• 88 proven ESBL isolates
• CTX‐M = 59%
• SHV = 47%
• Most common sources:– Urine (60%)
– Blood (21%)
– Respiratory (10%)
JS Lewis II, and others. AAC. Nov 2007. 51(11):4015
0
5
10
15
20
25
30
35
20002001
20022003
20042005
2006
TOTAL ESBL CTX‐M SHV TEM CTX‐M + SHV
CTX-M E. coli is Resistant to Multiple Classes of Antibiotics (% Resistant)
CTX-M(n=319)
Non-CTX-M(n=58)
P
Ciprofloxacin 95% 60% <0.001
Tobramycin 65% 31% <0.001
Gentamicin 51% 24% <0.001
TMP/SMX 62% 41% 0.06
Tetracycline 63% 41% 0.003
Nitrofurantoin 13% 19% 0.213
Pip/Taz 10% 12% 0.63
Cefepime 93% 36% <0.001
K. Hayakawa. AAC. August 2013. Vol 57(8):4010‐4018
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Risk Factors for ESBL Infections
• Length of hospital stay
• Severity of illness
• Time in ICU
• Mechanical ventilation
• Urinary catheterization
• Previous antibiotic exposure
Bradford PA. Clin Microbiol Rev. 2001;14:933‐951
CASE
E coli susceptibilities
Susceptible CarbapenemsNitrofurantoin
Resistant All cephalosporinsPip/TazobactamCipro/levaquinAmox/ClavAmpicillinTobramycinGentamicinBactrim
• Started on empirically Ciprofloxacin and ceftriaxone
• Blood + urine cultures: for E. coli
• ABX changed to MEROEPNEM
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M. McKenna. Nature. Vol 499. 25 July 2013
MECHANISMS OF CARBAPENEM RESISTANCE
• ESBL or AmpC with porin loss
• Efflux pump
• Carbapenemase
• Common organisms
– Pseudomonas aeruginosa
– Acinetobacter spp.
– Enterobacteriaceae (Klebsiella pneumoniae, E coli)
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CRE = Enterobacteriaceae resistant to one of the carbepenems (Doripenem, imipenem or meropenem) and third generation cephalosporins(ceftriaxone, cefotaxime, ceftazidime)
Guidance for Control of Carbapenem‐resistant Enterobacteriaceae –2012 CRE Toolkit, CDC. Antibiotic Resistance Threats in the U.S., 2013. CDC
Carbapenemases
Ambler Classification
Enzyme Organisms
Class A KPC, SME, IMI,
NMC, GES
Enterobacteriaceae
Class B (metallo‐β‐lactamase)
NDM‐1, IMP, VIM Enterobacteriaceae, Acinetobacter sp, P. aeruginosa
Class D OXA Acinetobacter sp
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Emergence of CRE
M. McKenna. Nature. Vol 499. 25 July 2013
Global Distribution of Klebsiellapneumoniae carbapenemase (KPC)
LS Munoz‐Price. LANCET INFECT DISEASES. Vol 13:785. Sept 2013.
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KPC in U.S.
Regional spread of KPC CRE
S.Y. Won. CID. 2011;53(6):532‐540
1. DELAYED RECOGNITION OF KPC
2. AMPLIFICATION IN LTACHS AND NH
3. DESPITE INVOLVEMENT OF A SINGLE LTACH, KPC QUICKLY BECAME A REGIONAL PROBLEM
4. COORDINATED, REGIONAL EFFORTSAMONG HOSPITALS, LTACHS, ANDPUBLIC HEALTH DEPT
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From www.medicaltourismmag.com
Emergence of CRE
M. McKenna. Nature. Vol 499. 25 July 2013
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Why are CREs clinically important?
KPC NDM‐1
Gene Location Highly transferable plasmids
Treatment options Limited
Outcomes Infections associated with high mortality
Organisms K. pneumoniae, E. coli (other
Enterobacteriaceae)
Outbreaks Mostly clonal Mostly polyclonal
Asymptomatic carriage plays a key
role in transmission
RISK FACTORS FOR CRE AQUISITION
• Exposure to healthcare • Recent organ or stem‐cell transplantation• Mechanical ventilation• Longer length of stay• Poor functional status• Receipt of multiple classes of antibiotics
– Carbapenems– Cephalosporins– Fluoroquinolones– Vancomycin
Neil Gupta. CID. 2011:53. (July 1)
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Antibiotic Susceptibilities for NDM-1UK (n=37) Chennai (n=44) Haryana (n=26)
Imipenem 0% 0% 0%
Meropenem 3% 3% 3%
Piperacillin‐tazobactam 0% 0% 0%
Cefotaxime 0% 0% 0%
Ceftazidime 0% 0% 0%
Cefpirome 0% 0% 0%
Aztreonam 11% 0% 8%
Ciprofloxacin 8% 8% 8%
Gentamicin 3% 3% 3%
Tobramycin 0% 0% 0%
Amikacin 0% 0% 0%
Minocycline 0% 0% 0%
Tigecycline 64% 56% 67%
Colistin 89% 94% 100%
KK Kumarasamy. Lancet ID. Vol 10. September 2010
Outbreak of NDM-1 K. pneumoniae in Denver, CO
• 8 cases between Jan‐Oct 2012 at acute care hospital
– 3 infections
– 5 identified by active surveillance
• K pneumoniae
– Susceptible to tigecycline with colisitin MIC≤2 μg/mL
– Highly related by PFGE
• Multiple transmission events in 3 units
• Not all patients overlapped
• Source not identifiedMMWR. Feb. 15, 2013. 62(06);108
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KPC Treatment Failure: Monotherapyvs. Combination
Mono (%) Combo (%) P
OVERALL 24/49 (49) 14/56 (25) 0.01
Source
Blood 12/24 (50) 9/32 (28) 0.09
Pulmonary 10/15 (67) 5/17 (29) 0.03
Urine 1/8 (13) 0/3 (0) 0.4
Polymyxin failure 8/11 (73) 10/34 (29) 0.03
Carbapenem 12/20 (60) 5/19 (26) 0.03
Tigecycline 2/7 (29) 7/19 (37) 0.4
Aminoglycoside 0/6 (0) 4/24 (17) 0.6
GC Lee and DS Burgess. Annals of Clin Micro and Antimicrobials. 2012, 11:32
Monotherapy with Polymyxin B May Select for Resistance
Monotherapy(n=12)
+ Tigecycline(n=4)
Increased MIC 3/12 (25%) 0
CASE 1 1.5 32 μg/mL
CASE 2 0.75 12 μg/mL
CASE 3 0.75 1024 μg/mL
Jooyun Lee. J Clin Micro. May 2009. Vol 47(5): 1611‐1612
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Seven Ways to Preserve Antibiotics
• US database for antibiotic use and resistance
• Restrict use of antibiotics in agriculture
• Prevent selected nosocomial infections
• Practice antimicrobial stewardship
• Promote use of new diagnostic tests (POC)
• Reduce FDA antibiotic barrier
• Facilitate public‐private partnerships for antibiotic development
Bartlett, JG. CID. 2013:56 (15 May)
Mechanism of Resistance: Horizontal Gene Transfer
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PREVENT SPREAD OF CRE• Awareness
• Hand hygiene
• Contact Isolation– Gloves + Gowns
– Equipment dedicated to room
– Disinfect personal equipment used in room
• Limit HCW exposure
• COMMUNICATE!!!
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Antibiotic Pipeline
PRODUCT STATUS WT P aerug ESBL KPC NDM‐1
Ceftolozane/taxobactama Phase 3 Y Y N N
Ceftazidime‐avibactama Phase 3 Y Y Y N
Ceftaroline‐avibactama Phase 2 N Y Y N
Imipenem/MK‐7655a Phase 2 Y Y Y N
Plazomicinb Phase 2 N Y Y ?
Eravacyclinec Phase 2 N Y Y ?
Brilacidind Phase 3 ? Y ? ?
HW Boucher. CID. 2013;56(12):1685‐94
WT=wild typeESBL=Extended spectrum beta lactamaseKPC=Klebsiella pneumoniae carbapenemaseNDM‐1=New Delhi metallo‐β‐lactamase
a. Β‐lactamase inhibitorb. Aminoglycosidec. Fluorocycline (targets ribosome)d. Peptide defense protein mimetic
FDA approved rapid pathogen identification platforms: blood cultures
METHOD ADVANTAGES DISADVANTAGES
PNA FISHQuick FISH(AdvanDX)
Nucleic acid hybridization
Rapid speciation of Staphylococcus sp,
Enterococcus sp, GNR, Candida sp
No resistancemarkers
Xpert(Cepheid)
PCR Rapid detection of MRSA/MSSA
Limited number of pathogens
Verigene BC‐GP(Nanosphere,Inc.)
Microarray‐basednucleic acid hybridization
Rapid speciation of most common gram positive cocciand resistance markers (mecA,
Van A/Van B)
Gram negative rods pending FDA approval
No Candida sp
Verigene BC‐GN
Drug resistance markers (NDM‐1, KPC, CTX‐M)
Pending FDA approval
Film Array BCID panel (Biofire/bioMerieux)
Multiplex PCR Gram positive, gram negative, yeast, resistance markers (mecA, VanA/Van B)
No gram negative resistance markers
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Impact of rapid identification of MRSA/MSSA (Xpert MRSA kit) combined with
antimicrobial stewardship
Pre-PCR(n=74)
Post-PCR(n=82)
P
Mean (SD) LOS, days 21.5 ± 22.8 15.3 ± 14.1 0.07
Mean (SD) Total hospital cost, USD
$69,737 ±$96,050
$48,350 ±$55,196
0.03
ICU 66% 67% NS
Time to optimal therapy (MSSA)
3.6 2 0.002
Number of vanc to cefazolin/naf changes
8 27
KA Bauer, and others. CID. 2010;51(9):1074‐1080.
SUMMARY
• Antibiotic resistance in gram negative organisms is increasing rapidly
• Preventing spread of organisms in healthcare settings is critical
• We need to be wiser about how we use antibiotics
• New antibiotics are essential however are not the solution for combating antibiotic resistance