is resistance futile? donald e low university of toronto ontario agency for health protection and...
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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
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.
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
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)
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