Download Utilizing PK/PD principles to optimize therapy

Is Resistance Futile?
Donald E Low
University 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 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 ESBLcontaining
Died with pneumonia and respiratory
failure
S Krajden, Roberto Melano, and Dylan R. Pillai
Drug
CLSI breakpoints
MIC (mg/mL)
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 pneumoniae



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-Susceptible
S. pneumoniae in Canada: 1988-2008
18
16
14
% intermediate resistance
% high-level resistance
12
10
8
6
4
2
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
19
88
0
*Oral breakpoints used
Canadian Bacterial Surveillance Network, Feb 2009
Macrolide-Resistant Pneumococci:
Canadian Bacterial Surveillance Network, 1988-2008
20
15
10
5
20
08
20
07
20
06
20
05
20
04
20
03
20
02
20
01
20
00
19
99
19
98
19
97
19
96
19
95
19
94
19
93
0
19
88
Percentage of Isolates Resistant to
Erythromycin
25
Canadian Bacterial Surveillance Network, Feb 2009
S. pneumoniae colonisation: the key
to 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
Kadioglu A., et al. Nat Rev Micro 20
Pneumococcal
Vaccines

Although the 23valent vaccine is
immunogenic in
adults and children
older than 5 years,
young children (<2
years) have a
severely impaired
antibody response to
polysaccharide
vaccination
PPV23
4
6B
9V
2
8
9N
14
18C
19F
23F
10A
11A
12F
15B
1
5
7F
17F
20
22F
3
19A
33F
Introduction of pneumococcal
vaccines, Ontario

Oct 1996 – PPV23 program for adults
– Increased coverage from ?2% to 35% in
adults
Rate per 100,000 per year
Invasive pneumococcal disease,
elderly
Metropolitan Toronto, 1995-2000
100
90
80
70
60
50
40
30
20
10
0
65-74yrs
>75 yrs
1995
1996
1997
1998
1999
2000
Pediatric invasive pneumococcal
disease
Metropolitan Toronto, 1995-2000
Rate per 100,000 per year
70
<2 yrs
2-4 yrs
5-14 yrs
60
50
40
30
20
10
0
1995
1996
1997
1998
1999
2000
Pneumococcal
vaccines
PCV7
PPV23
4
6B
9V
4
6B
9V
2
8
9N
14
18C
19F
23F
14
18C
19F
23F
10A
11A
12F
15B
1
5
7F
17F
22F
33F
3
19A
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
MMWR Feb 2008
Introduction 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
Pediatric invasive pneumococcal
disease
Metropolitan Toronto, 1995-2007
Rate per 100,000 per year
70
60
50
<2 yrs
2-4 yrs
5-14 yrs
40
30
20
10
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Rate per 100,000 per year
Invasive pneumococcal disease,
elderly
Metropolitan Toronto, 1995-2001
100
90
80
70
60
50
40
30
20
10
0
65-74yrs
>75 yrs
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Rates of penicillin and amoxicillin
resistance Canada: 1988-2008
8
7
% Penicillin Resistance
% Amoxicillin Resistance
6
5
4
3
2
1
20
08
20
07
20
06
20
05
20
04
20
03
20
02
20
01
20
00
19
99
19
98
19
97
19
96
19
95
19
94
19
93
19
88
0
Canadian Bacterial Surveillance Network, March 2008
Most Common MDR SPN Serotypes
19F
VS
23F
Serotype
6B
14
9V
19A
6A
15A
Pre-PCV7 (1995-2001)
23A
0
5
10
15
20
% MDR SPN
25
30
35
Most Common MDR SPN Serotypes
19F
VS
P<0.0001
P=0.0009
23F
Serotype
6B
P<0.0001
14
9V
19A
P<0.0001
6A
15A
Pre-PCV7 (1995-2001)
Post-PCV7 (2006-2007)
23A
0
5
10
15
20
% MDR SPN
25
30
35
Worldwide Prevalance of MRSA
Among S. aureus Isolates
Grundmann H et al. Lancet 2006;368:874.
6000
12.0
5000
10.0
4000
8.0
3000
6.0
2000
4.0
1000
2.0
0
0.0
Rate per 1,000 admissions
Number of MRSA cases
MRSA in Canada, 1995-2005
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Source:CNISP
Community -Associated
MRSA
•
•
•
•
•
•
•
•
•
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)
–
•
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)
–
•
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
CMRSA10 (USA300)
CMRSA7 (USA400)
Simore A et al. Canadian Nosocomial Infection Surveillance Program
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 fluoroquinoloneresistant 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 resistance



Reducing colonization and infection
Reducing volume of antimicrobial use
When decision made to treat
– Use right drug
– Right dose
– Right duration
Controlling antimicrobial
resistance
 Reducing infection
 Reducing volume of antimicrobial use
 When decision made to treat
– Use right drug
– Right dose
– Right duration
The Effect of Influenza on Hospitalizations,
Outpatient Visits, and Courses of Antibiotics in
Children
The average excess age-specific numbers of outpatient visits
and courses of antibiotics per 100 children per year
Neuzil KM et al. NEJM 2000
Controlling antimicrobial resistance
 Reducing colonization and infection
 Reducing volume of antimicrobial use
 When decision made to treat
– Use right drug
– Right dose
– Right duration
Number of common office visits (millions)
Respiratory Infections are the # 1
Reason for Office Visits
180
165
160
140
119
120
100
80
65
60
51
40
28
20
0
Respiratory
infections
Source: Verispan PDDA 2004
Hypertension
Disorders of
lipid
metabolism
Diabetes
mellitus
Depressive
disorder
Nearly Two-thirds of all Oral Solid Antibiotic
Prescriptions are for Sinusitis and Bronchitis
Percent oral solid antibiotic use
25
21.5
19.3
20
15
9.6
10
7.6
5.2
5
0
Sinusitis
Bronchitis
Pharyngitis
Pneumonia
Otitis media
Telithromycin (Ketek®) is indicated for acute exacerbations of chronic bronchitis, acute bacterial sinusitis and mild-to-moderate
community-acquired pneumonia
Source: SDI, FANDxRx. Based on all tablets/capsule antibiotics for the 52 weeks ending April 6, 2005
Usage of antibiotics in Europe vs.
pneumococcal penicillin I/R 1997
60
DDD/1000/day
DI/RSP %
50
40
38.5
32.5
30
28.8
26.7
24
18
20
13.5
8.9
10
0
France
Portugal
Spain
* 1996 data
Italy
Belgium
UK
*
Germany
Netherlands
Felmingham et al. J Antimicrob Chemother 2000; 45: 191–201
Cars et al. Lancet 2001; 357:1851–1853
Controlling antimicrobial resistance
 Reducing colonization and infection
 Reducing volume of antimicrobial use
 When decision made to treat
– Use right drug
– Right dose
– Right duration
Risks for Penicillin Resistance
in Pneumococcus
Multivariate Analysis of Risk Factors
≥ 65 y
Other Considerations
<5y
• Immunosuppression
Noninvasive
– Including steroids
• Multiple medical
disease
Alcoholism
comorbidities
β-lactam w/in
• Exposure to day care
3 months
0
1
2
3
4
5
Odds Ratio
6
child
• Exposure to any antibiotic
Clavo-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.
P < .001
P = .004
60
Infecting Isolates (%)
Rate of Macrolide Resistance in
Prevalence of Erythromycin Resistance
Among Pneumococci by Prior Macrolide Use
P = .02
50
40
30
20
10
0
No Antibiotic
Erythromycin Clarithromycin Azithromycin
Vanderkooi OG et al. Clin Infect Dis. 2005;40:1288-1297.
Relative Risk for Infection With FluoroquinoloneResistant Pneumococci by Prior Antibiotic Use
Levoofloxacin resistant (%)
20
18
16
14
12
10
8
6
4
2
*
*
0
No Prior Antibiotic
Prior Antibiotic
Prior
(not fluoroquinolone)
Fluoroquinolone
* P<.001
Vanderkooi OG et al. Clin Infect Dis. 2005;40:1288-1297.
Fluoroquinolone PD Profile
140
(72-120)
120
Free AUC/MIC
Resistance Prevention ~AUC/MIC≥100
100
100
80
(41-69)
60
40
(24-40)
(13-21)
35
Efficacy ~AUC/MIC≥35
20
0
Levofloxacin Levofloxacin Gemifloxacin Moxifloxacin
500 mg
750 mg
320 mg
400 mg
Moran G. J Emerg Med. 2006;30:377-387.
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
% Resistant
Fluoroquinolone-Resistant Pneumococci:
Canadian Bacterial Surveillance Network, 1997-2008
2
Moxifloxacin
1.5
Levofloxacin
1
0.5
0
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Canadian Bacterial Surveillance Network, Jan 2009
Resistance Isn’t Futile