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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

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THANK YOU!