Is Resistance Futile

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Is Resistance Futile?

• Donald E Low
• University of Toronto
• Ontario Agency for Health Protection and Promotion

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Achievements in Public Health

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

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MMWR 1999 48 (29) 621
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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
7
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 2005401792-8.
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MRSA
DeLeo and Chambers JCI 2009 adapted from Klevens
et al. JAMA I2007
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New emerging threats

• Hospital setting
• Carbapenemases (KPCs)
• Community
• S. pneumoniae
• Community Associated MRSA
• Fluoroquinolone resistant E. coli
• Multi-drug resistant GC

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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
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Carbapenemases

• Ability to hydrolyze penicillins, cephalosporins,
  monobactams, and carbapenems
• Resilient against inhibition by all commercially
  viable ß-lactamase inhibitors

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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

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Streptococcus pneumoniae

• Most important pathogen in mild-to-moderate
  RTIs1
• Greatest morbidity2
• Greatest mortality2

Streptococcus pneumoniae
1File TM Jr. Lancet. 20033621991-2001
2Bartlett JG, et al. Clin Infect Dis.
200031347-382
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Percentage of Penicillin Non-Susceptible
S. pneumoniae in Canada 1988-2008
Canadian Bacterial Surveillance Network, Feb 2009
Oral breakpoints used
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Macrolide-Resistant Pneumococci Canadian
Bacterial Surveillance Network, 1988-2008
Canadian Bacterial Surveillance Network, Feb 2009
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S. pneumoniae colonisation the key to
pneumococcal disease

• NP carriage
• 15 lt6 mos to 40 gt19 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
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Pneumococcal Vaccines

• Although the 23-valent vaccine is immunogenic in
  adults and children older than 5 years, young
  children (lt2 years) have a severely impaired
  antibody response to polysaccharide vaccination

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Introduction of pneumococcal vaccines, Ontario

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

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Invasive pneumococcal disease, elderlyMetropolita
n Toronto, 1995-2000
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Pediatric invasive pneumococcal
diseaseMetropolitan Toronto, 1995-2000
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Pneumococcal vaccines
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Invasive Pneumococcal Disease in Children 5 Years
After Conjugate Vaccine Introduction, 1998--2005

• The overall incidence of IPD among children aged
  lt5 years declined from 99 cases/ 100,000 during
  1998--1999 to 23 cases/100,000 in 2005

MMWR Feb 2008
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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

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Pediatric invasive pneumococcal
diseaseMetropolitan Toronto, 1995-2007
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Invasive pneumococcal disease, elderlyMetropolita
n Toronto, 1995-2001
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Rates of penicillin and amoxicillin resistance
Canada 1988-2008
Canadian Bacterial Surveillance Network, March
2008
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Most Common MDR SPN Serotypes
VS
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Most Common MDR SPN Serotypes
VS
?Plt0.0001
?P0.0009
?Plt0.0001
Plt0.0001
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Worldwide Prevalance of MRSAAmong S. aureus
Isolates
Grundmann H et al. Lancet 2006368874.
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MRSA in Canada, 1995-2005
SourceCNISP
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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

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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 aureusMinnesota 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

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Emergence of CA-MRSA Canada
CMRSA10 (USA300)
CMRSA7 (USA400)
Simore A et al. Canadian Nosocomial Infection
Surveillance Program
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Current Treatment Options for CA-MRSA Infection
Moellering RC CID 2008
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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-resist
  ant in women older than 65 years of age

Mc Isaac WJ et al. Can J Infect Dis Med
Microbiol. 2006
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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
  (plt0.001) tetracycline (plt0.001) and
  erythromycin (plt0.001)
• All isolates were susceptible to cefixime,
  ceftriaxone, azithromycin and spectinomycin

Ota K et al. Can Med Ass J In Press
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Controlling antimicrobial resistance

• Reducing colonization and infection
• Reducing volume of antimicrobial use
• When decision made to treat
• Use right drug
• Right dose
• Right duration

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Controlling antimicrobial resistance

• Reducing infection
• Reducing volume of antimicrobial use
• When decision made to treat
• Use right drug
• Right dose
• Right duration

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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
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Controlling antimicrobial resistance

• Reducing colonization and infection
• Reducing volume of antimicrobial use
• When decision made to treat
• Use right drug
• Right dose
• Right duration

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Respiratory Infections are the 1 Reason for
Office Visits
Number of common office visits (millions)
Source Verispan PDDA 2004
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Nearly Two-thirds of all Oral Solid Antibiotic
Prescriptions are for Sinusitis and Bronchitis
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
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Usage of antibiotics in Europe vs. pneumococcal
penicillin I/R 1997
60
DDD/1000/day
DI/RSP
50
40
38.5
32.5
28.8
30
26.7
24
18
20
13.5
8.9

10
0
France
Portugal
Italy
Germany
Spain
Belgium
UK
Netherlands

• Felmingham et al. J Antimicrob Chemother 2000
  45 191201
• Cars et al. Lancet 2001 35718511853

1996 data
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Controlling antimicrobial resistance

• Reducing colonization and infection
• Reducing volume of antimicrobial use
• When decision made to treat
• Use right drug
• Right dose
• Right duration

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Risks for Penicillin Resistancein Pneumococcus
Multivariate Analysis of Risk Factors

• Other Considerations
• Immunosuppression
• Including steroids
• Multiple medical comorbidities
• Exposure to day care child
• Exposure to any antibiotic

65 y
lt 5 y
Noninvasive disease
Alcoholism
ß-lactam w/in 3 months
0
1
2
3
4
5
6
Odds Ratio
Clavo-Sanchez AJ et al. Clin Infect Dis.
1997241052-1059. Harwell JI, Brown RB. Chest.
2000117530-541. Vanderkooi OG et
al. Clin Infect Dis. 2005401288-1297.

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Prevalence of Erythromycin Resistance Among
Pneumococci by Prior Macrolide Use
P .004
P lt .001
60
P .02
50
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Rate of Macrolide Resistance in Infecting
Isolates ()
30
20
10
0
No Antibiotic
Erythromycin
Clarithromycin
Azithromycin
Vanderkooi OG et al. Clin Infect Dis.
2005401288-1297.
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Relative Risk for Infection With
Fluoroquinolone-Resistant Pneumococci by Prior
Antibiotic Use
20
18
16
14
12
10
Levoofloxacin resistant ()
8
6
4


2
0
No Prior Antibiotic
Prior Antibiotic(not fluoroquinolone)
Prior Fluoroquinolone
Plt.001
Vanderkooi OG et al. Clin Infect Dis.
2005401288-1297.
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Fluoroquinolone PD Profile
140
(72-120)
120
Resistance Prevention AUC/MIC100
100
100
80
(41-69)
Free AUC/MIC
60
(24-40)
35
(13-21)
40
Efficacy AUC/MIC35
20
0
Levofloxacin 500 mg
Levofloxacin 750 mg
Gemifloxacin 320 mg
Moxifloxacin 400 mg
Moran G. J Emerg Med. 200630377-387.
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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
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Fluoroquinolone-Resistant Pneumococci Canadian
Bacterial Surveillance Network, 1997-2008
Resistant
Canadian Bacterial Surveillance Network, Jan 2009
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Resistance Isnt Futile