Is Resistance Futile?

Donald E LowUniversity of Toronto

Ontario Agency for Health Protection and Promotion

Achievements in Public Health

• Control of infectious diseases – Sanitation and Hygiene – Vaccination– Antibiotics

MMWR 1999 48 (29); 621

Antibiotics: the epitome of a wonder drug

• The introduction of antibiotics in the 1940s converted illness into a strictly technical problem:– "virtual elimination of infectious disease as a significant

factor in social life."

Burnet FM. Natural history of infectious disease. 2nd ed. Cambridge: Cambridge University Press, 1953

Prevalence of Isolates of Multidrug-Resistant Gram Negative Rods Recovered Within The First 48 h

After Admission to the Hospital

Pop-Vicas and D'Agata CID 2005;40:1792-8.

MRSA

DeLeo and Chambers JCI 2009 adapted from Klevens et al. JAMA I2007

New emerging threatsNew emerging threats

Hospital setting• Carbapenemases (KPCs)

Community• S. pneumoniae

• Community Associated MRSA

• Fluoroquinolone resistant E. coli

• Multi-drug resistant GC

Clinical Case

A 73 yo M with no travel hx Laparoscopic right radical nephrectomy for

a hypernephroma with post-op pneumonia Empirically treated with various

antimicrobials including the carbapenems Cultures found MDR K.pneumoniae,

initially reported as AmpC- and ESBL-containing

Died with pneumonia and respiratory failure

S Krajden, Roberto Melano, and Dylan R. Pillai

DrugMIC (g/mL)

CLSI breakpoints

Ampicillin >16 R

Cephalothin >16 R

Cefoxitin >16 R

Tobramycin >8 R

Amikacin 32 I

Ceftriaxone >32 R

Ciprofloxacin >2 R

Meropenem 4 S

Carbapenemases

Ability to hydrolyze penicillins,

cephalosporins, monobactams, and carbapenems

Resilient against inhibition by all commercially viable ß-lactamase inhibitors

KPC (K. pneumoniae carbapenemase)

KPCs are the most prevalent of this group of enzymes, found mostly on transferable plasmids in K. pneumoniae

Substrate hydrolysis spectrum includes

cephalosporins, such as cefotaxime. KPCs have transferred to Enterobacter

spp. and in Salmonella spp

Streptococcus pneumoniaeStreptococcus pneumoniae Most important pathogen in

mild-to-moderate RTIs1 Greatest morbidity2

Greatest mortality2

Most important pathogen in mild-to-moderate RTIs1

Greatest morbidity2

Greatest mortality2

Streptococcus pneumoniae

1File TM Jr. Lancet. 2003;362:1991-2001; 2Bartlett JG, et al. Clin Infect Dis. 2000;31:347-382;

Percentage of Penicillin Non-SusceptiblePercentage of Penicillin Non-Susceptible S. pneumoniaeS. pneumoniae in Canada: 1988-2008 in Canada: 1988-2008

Canadian Bacterial Surveillance Network, Feb 2009

0

2

4

6

8

10

12

14

16

18

1988

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

% intermediate resistance

% high-level resistance

*Oral breakpoints used

Macrolide-Resistant Pneumococci: Macrolide-Resistant Pneumococci: Canadian Bacterial Surveillance Network, 1988-2008Canadian Bacterial Surveillance Network, 1988-2008

Canadian Bacterial Surveillance Network, Feb 2009

0

5

10

15

20

25

Per

cent

age

of I

sola

tes

Res

ista

nt t

oE

ryth

rom

ycin

1988

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

S. pneumoniaeS. pneumoniae colonisation: the key colonisation: the key to pneumococcal diseaseto pneumococcal diseaseS. pneumoniaeS. pneumoniae colonisation: the key colonisation: the key to pneumococcal diseaseto pneumococcal disease NP carriage

– 15% <6 mos to 40% >19 mos

– ~10% after age of 10– ~3% in adults

Invasive and mucosal infection involves NP colonization with concurrent viral respiratory infection

NP carriage– 15% <6 mos to 40%

>19 mos– ~10% after age of 10– ~3% in adults

Invasive and mucosal infection involves NP colonization with concurrent viral respiratory infection

Kadioglu A., et al. Nat Rev Micro 2008

Pneumococcal VaccinesPneumococcal Vaccines Although the 23-

valent vaccine is immunogenic in adults and children older than 5 years, young children (<2 years) have a severely impaired antibody response to polysaccharide vaccination

Although the 23-valent vaccine is immunogenic in adults and children older than 5 years, young children (<2 years) have a severely impaired antibody response to polysaccharide vaccination

PPV234 2

6B 8

9V 9N

14 10A

18C 11A

19F 12F

23F 15B

1 17F

5 20

7F 22F

3 33F

19A

Introduction of pneumococcal vaccines, OntarioIntroduction of pneumococcal vaccines, Ontario

Oct 1996 – PPV23 program for adults– Increased coverage from ?2% to 35% in

adults

Oct 1996 – PPV23 program for adults– Increased coverage from ?2% to 35% in

adults

Invasive pneumococcal disease, elderlyMetropolitan Toronto, 1995-2000

Invasive pneumococcal disease, elderlyMetropolitan Toronto, 1995-2000

0102030405060708090

100

1995 1996 1997 1998 1999 2000

Rate

per

100

,000

per

yea

r

65-74yrs

>75 yrs

0102030405060708090

100

1995 1996 1997 1998 1999 2000

Rate

per

100

,000

per

yea

r

65-74yrs

>75 yrs

Pediatric invasive pneumococcal diseaseMetropolitan Toronto, 1995-2000

Pediatric invasive pneumococcal diseaseMetropolitan Toronto, 1995-2000

0

10

20

30

40

50

60

70

1995 1996 1997 1998 1999 2000

Rate

per

100

,000

per

yea

r

<2 yrs2-4 yrs5-14 yrs

0

10

20

30

40

50

60

70

1995 1996 1997 1998 1999 2000

Rate

per

100

,000

per

yea

r

<2 yrs2-4 yrs5-14 yrs

PCV7 PPV234 4 2

6B 6B 8

9V 9V 9N

14 14 10A

18C 18C 11A

19F 19F 12F

23F 23F 15B

1 17F

5 22F

7F 33F

3

19A

Pneumococcal vaccines

MMWR Feb 2008

Invasive Pneumococcal Disease in Children 5 Years After Conjugate Vaccine Introduction, 1998--2005

Invasive Pneumococcal Disease in Children 5 Years After Conjugate Vaccine Introduction, 1998--2005

The overall incidence of IPD among children aged <5 years declined from 99 cases/ 100,000 during 1998--1999 to 23 cases/100,000 in 2005

The overall incidence of IPD among children aged <5 years declined from 99 cases/ 100,000 during 1998--1999 to 23 cases/100,000 in 2005

Introduction of pneumococcal vaccines, OntarioIntroduction of pneumococcal vaccines, Ontario

Oct 1996 – PPV23 program for adults– Increased coverage from ?2% to 35% in adults

Dec 2001 – PCV7 licensed– Gradual increase in use in children (to about 1

dose per child, or 4 doses for 20% of children) Jan 2005 – provincial PCV7 program

– No catch-up; start with birth cohort

Oct 1996 – PPV23 program for adults– Increased coverage from ?2% to 35% in adults

Dec 2001 – PCV7 licensed– Gradual increase in use in children (to about 1

dose per child, or 4 doses for 20% of children) Jan 2005 – provincial PCV7 program

– No catch-up; start with birth cohort

Pediatric invasive pneumococcal diseaseMetropolitan Toronto, 1995-2007

Pediatric invasive pneumococcal diseaseMetropolitan Toronto, 1995-2007

0

10

20

30

40

50

60

70

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Rate

per

100

,000

per

yea

r

<2 yrs2-4 yrs5-14 yrs

0

10

20

30

40

50

60

70

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Rate

per

100

,000

per

yea

r

<2 yrs2-4 yrs5-14 yrs

Invasive pneumococcal disease, elderlyMetropolitan Toronto, 1995-2001

Invasive pneumococcal disease, elderlyMetropolitan Toronto, 1995-2001

0102030405060708090

100

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Rate

per

100

,000

per

yea

r

65-74yrs

>75 yrs

0102030405060708090

100

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Rate

per

100

,000

per

yea

r

65-74yrs

>75 yrs

Rates of penicillin and amoxicillin resistance Canada: 1988-2008

0

1

2

3

4

5

6

7

8

1988

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

% Penicillin Resistance% Amoxicillin Resistance

Canadian Bacterial Surveillance Network, March 2008

Most Common MDR SPN Serotypes

0 5 10 15 20 25 30 35

23A

15A

6A

19A

9V

14

6B

23F

19F

Pre-PCV7 (1995-2001)

% MDR SPN

Ser

oty

pe

VS

0 5 10 15 20 25 30 35

23A

15A

6A

19A

9V

14

6B

23F

19F

Pre-PCV7 (1995-2001)Post-PCV7 (2006-2007)

% MDR SPN

Ser

oty

pe

Most Common MDR SPN Serotypes

P<0.0001

P=0.0009

P<0.0001

P<0.0001

VS

Worldwide Prevalance of MRSAAmong S. aureus Isolates

Grundmann H et al. Lancet 2006;368:874.

MRSA in Canada, 1995-2005

0

1000

2000

3000

4000

5000

6000

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Nu

mb

er

of

MR

SA

case

s

0.0

2.0

4.0

6.0

8.0

10.0

12.0

Rate

per

1,0

00

ad

mis

sion

s

Source:CNISP

Community -AssociatedMRSA

• Sports participants• Inmates in correctional facilities• Military recruits• Children in daycare• Native Americans, Alaskan

Natives, Pacific Islanders• Men who have sex with men• Hurricane evacuees in shelters• Foal watchers• Rural crystal methamphetamine

users

First Outbreaks of CA-MRSA

• Australia (1993)Australia (1993)– Udo EE et al. Genetic analysis of community isolates of

methicillin-resistant Staphylococcus aureus in Western Australia. J. Hosp. Infect. 1993

• US (1999)– CDC. Four pediatric deaths from community-acquired

methicillin-resistant Staphylococcus aureus—Minnesota and North Dakota, MMWR 1999

• Canada (2000) Canada (2000) – Mulvey MR et al. Community-associated Methicillin-resistant

Staphylococcus aureus, Canada EID 2005• Worldwide (2000)

– Vandenesch F et al. Community-Acquired Methicillin-Resistant Staphylococcus aureus Carrying Panton-Valentine Leukocidin Genes: Worldwide Emergence EID 2003

Emergence of CA-MRSA Canada

Simore A et al. Canadian Nosocomial Infection Surveillance Program

CMRSA7 (USA400)

CMRSA10 (USA300)

Current Treatment Options for CA-MRSA Infection

Moellering RC CID 2008

Community-acquired antibiotic resistance in urinary isolates from

adult women in Canada

15% of E. coli isolates from adult women resistant to TMP-SMX

Fluoroquinolone-resistant E coli was 7% • 10% of E coli isolates were fluoroquinolone-

resistant in women older than 65 years of age

Mc Isaac WJ et al. Can J Infect Dis Med Microbiol. 2006

Quinolone-resistant Neisseria gonorrhoeae infections in Ontario Isolates referred to the OPHL between 2002

and 2006 FQ-R increased from 4.0% in 2002 to 27.8%

in 2006 FQ-R strains were more resistant to penicillin

(p<0.001); tetracycline (p<0.001) and erythromycin (p<0.001)

All isolates were susceptible to cefixime, ceftriaxone, azithromycin and spectinomycin

Ota K et al. Can Med Ass J In Press

Controlling antimicrobial resistanceControlling antimicrobial resistanceControlling antimicrobial resistanceControlling antimicrobial resistance Reducing colonization and infection Reducing volume of antimicrobial use When decision made to treat

– Use right drug– Right dose– Right duration

Reducing colonization and infection Reducing volume of antimicrobial use When decision made to treat

– Use right drug– Right dose– Right duration

Controlling antimicrobial Controlling antimicrobial resistanceresistanceControlling antimicrobial Controlling antimicrobial resistanceresistance

Reducing infection Reducing volume of antimicrobial use When decision made to treat

– Use right drug– Right dose– Right duration

Reducing infection Reducing volume of antimicrobial use When decision made to treat

– Use right drug– Right dose– Right duration

The average excess age-specific numbers of outpatient visits and courses of antibiotics per 100 children per year

Neuzil KM et al. NEJM 2000

The Effect of Influenza on Hospitalizations, Outpatient Visits, and Courses of Antibiotics in Children

The Effect of Influenza on Hospitalizations, Outpatient Visits, and Courses of Antibiotics in Children

Controlling antimicrobial resistanceControlling antimicrobial resistanceControlling antimicrobial resistanceControlling antimicrobial resistance

Reducing colonization and infection Reducing volume of antimicrobial use When decision made to treat

– Use right drug– Right dose– Right duration

Reducing colonization and infection Reducing volume of antimicrobial use When decision made to treat

– Use right drug– Right dose– Right duration

Respiratory Infections are the # 1 Respiratory Infections are the # 1 Reason for Office VisitsReason for Office VisitsRespiratory Infections are the # 1 Respiratory Infections are the # 1 Reason for Office VisitsReason for Office Visits

165

119

65

51

28

0

20

40

60

80

100

120

140

160

180

Respiratoryinfections

Hypertension Disorders oflipid

metabolism

Diabetesmellitus

Depressivedisorder

165

119

65

51

28

0

20

40

60

80

100

120

140

160

180

Respiratoryinfections

Hypertension Disorders oflipid

metabolism

Diabetesmellitus

Depressivedisorder

Source: Verispan PDDA 2004

Nu

mb

er

of

co

mm

on

off

ice

vis

its

(m

illi

on

s)

Nearly Two-thirds of all Oral Solid Antibiotic Nearly Two-thirds of all Oral Solid Antibiotic Prescriptions are for Sinusitis and BronchitisPrescriptions are for Sinusitis and BronchitisNearly Two-thirds of all Oral Solid Antibiotic Nearly Two-thirds of all Oral Solid Antibiotic Prescriptions are for Sinusitis and BronchitisPrescriptions are for Sinusitis and Bronchitis

21.5

19.3

9.6

7.6

5.2

0

5

10

15

20

25

Sinusitis Bronchitis Pharyngitis Pneumonia Otitis media

Pe

rce

nt

ora

l so

lid a

nti

bio

tic

us

e

Source: SDI, FANDxRx. Based on all tablets/capsule antibiotics for the 52 weeks ending April 6, 2005

Telithromycin (Ketek®) is indicated for acute exacerbations of chronic bronchitis, acute bacterial sinusitis and mild-to-moderate community-acquired pneumonia

Usage of antibiotics in Europe vs. pneumococcal penicillin I/R 1997

Felmingham et al. J Antimicrob Chemother 2000; 45: 191–201Cars et al. Lancet 2001; 357:1851–1853

38.532.5

28.826.7

24

18

13.58.9

0

10

20

30

40

50

60

France

Spain

Portugal

Belgium

Italy

UK

Germany

Netherlands

DDD/1000/day

DI/RSP %

*

* 1996 data

Controlling antimicrobial resistanceControlling antimicrobial resistanceControlling antimicrobial resistanceControlling antimicrobial resistance

Reducing colonization and infection Reducing volume of antimicrobial use When decision made to treat

– Use right drug– Right dose– Right duration

Reducing colonization and infection Reducing volume of antimicrobial use When decision made to treat

– Use right drug– Right dose– Right duration

Multivariate Analysis of Risk Factors

0 1 2 3 4 5 6

β-lactam w/in

3 months

Alcoholism

Noninvasive

disease

< 5 y

≥ 65 y

Odds Ratio

Other Considerations

• Immunosuppression

– Including steroids

• Multiple medical

comorbidities

• Exposure to day care

child

• Exposure to any

antibioticClavo-Sanchez AJ et al. Clin Infect Dis. 1997;24:1052-1059. Harwell JI, Brown RB. Chest. 2000;117:530-541.

Vanderkooi OG et al. Clin Infect Dis. 2005;40:1288-1297.

Risks for Penicillin Resistancein Pneumococcus

Prevalence of Erythromycin Resistance Among Pneumococci by Prior Macrolide Use

P = .02

P = .004

Vanderkooi OG et al. Clin Infect Dis. 2005;40:1288-1297.

P < .001

0

10

20

30

40

50

60

No Antibiotic Erythromycin Clarithromycin Azithromycin

Rat

e o

f M

acro

lide

Res

ista

nce

in

Infe

ctin

g Is

ola

tes

(%)

Relative Risk for Infection With Fluoroquinolone-Resistant Pneumococci by Prior Antibiotic Use

Vanderkooi OG et al. Clin Infect Dis. 2005;40:1288-1297.

0

2

4

6

8

10

12

14

16

18

20

No Prior Antibiotic Prior Antibiotic

(not fluoroquinolone)

Prior

Fluoroquinolone

Lev

oo

flo

xaci

n r

esis

tan

t (%

)

* *

* P<.001

Fluoroquinolone PD ProfileF

ree

AU

C/M

IC

Levofloxacin

500 mg

Levofloxacin

750 mg

Gemifloxacin

320 mg

Moxifloxacin

400 mg

40 (13-21)

(24-40)

(72-120)

Resistance Prevention ~AUC/MIC≥100

Efficacy ~AUC/MIC≥35

00

20

60

80

100

120

140

(41-69)

Moran G. J Emerg Med. 2006;30:377-387.

100

35

WHO statement 2000

The most effective strategy against antibiotic resistance is:

• “to unequivocally destroy microbes”

• “thereby defeating resistance before it

starts”

WHO Overcoming Antimicrobial Resistance, 2000

Fluoroquinolone-Resistant Pneumococci:Fluoroquinolone-Resistant Pneumococci: Canadian Bacterial Surveillance Network, 1997-2008Canadian Bacterial Surveillance Network, 1997-2008

Canadian Bacterial Surveillance Network, Jan 2009

% R

esis

tant

0

0.5

1

1.5

2

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Moxifloxacin

Levofloxacin

Resistance Isn’t Futile