The Resistance Problem• PRSP = Penicillin Resistant Strep. pneumoniae• QRSP = Quinolone Resistant Strep. pneumoniae• MRSA = Methicillin Resistant Staph. aureus• VRE = Vancomycin Resistant Enterococci
– VRE in Canada: 1993: first isolated 1997: >800 cases
– MRSA in Ontario: 1992: <100 cases 2000: >9000 cases
• Resistance rates differ dramatically between Canada and the U.S.
The Problem
• Graph of Global Resistance patterns?
Worldwide Distribution of Penicillin Resistant Pneumococci
Brazil31%
Mexico53%
USA41%
South Africa80%
Saudi Arabia62%
Hong Kong80%
Israel54%
Japan64%
Singapore53%
Kenya49%
Russia7%
Canada14%
Principles of Antibiotic PrescribingIdeal World Real World
1. Known organism(s) with predictable sensitivity
• Organism(s) frequently unknown• Information often unclear in clinical decision-making• Spectrum of sensitivity changing, especially due to bacterial
resistance
2. History, physical exam (+/- simple, available tests) to establish firm working diagnosis
• May or may not be helpful (e.g., URTI vs sinusitis).
3. Natural history of condition is known, and drug intervention is helpful in changing it
• Sometimes true (e.g., AECB), but frequently ignored in decision making (e.g., acute OM; acute bronchitis)
• Evolving knowledge of disease natural history
4. High likelihood that morbidity and complications can be reduced by drug treatment.
• How often do our interventions actually reduce morbidity or complications?
• Primary care practice is failure-based• "It won't do any harm"
5. First and foremost, do no harm‘Primum, non nocere’
• Evidence of real individual and social harm with current patterns of antibiotic use
• Individual harm: Allergy (lifelong), increased intolerance, morbidity, increased susceptibility to other infections
Antimicrobial Resistance
• Understanding Resistance: Darwin’s theory of natural selection Minimum Inhibitory Concentration (MIC) Clinical and Laboratory Standards Institute
(CLSI) reporting system based on MIC: Susceptible (S)
Intermediate (I)
Resistant (R)
Interpretation of Susceptibility Data:
• In vitro susceptibility testing only involves the bug and the drug
• Antimicrobial resistance vs clinical resistance • MIC value needs to be considered in context
of patient factors – Type of infection– Location of infection– Antibiotic distribution– Antibiotic concentration at site of infection
Contributing Factors to Resistance
• Overuse in humansMore than 50% of antibiotics in Canada are prescribed for viral URTI’s
• Animal and agricultural use: Accounts for 50% of all antimicrobials Used for prevention/treatment of infection
and growth promotion Evidence of resistant strains in livestock
Implications Of Resistance
• Treatment failure
• Forced to use more toxic alternatives
• Possibility of no alternate agents (e.g., vancomycin-resistant S. aureus)
• Longer hospital stays
• Forced to use more expensive alternatives and other increased healthcare costs
S. pneumoniae• Spectrum of Disease
– Otitis Media– Sinusitis– Bronchitis– Pneumonia– Meningitis
• Treatment– Penicillin– Cephalosporins– Macrolides– TMP/SMX– Tetracyclines– Quinolones
PRSP - Prevalence
1980s - < 2.0%
1998 - 16.0% (with up to 5% with high-level resistance)
1999 - 12.0%
2000 - 12.3 – 16.9%
CMAJ 2002; 167(8)
Figure 1. Percentage of Penicillin Non-Susceptible Figure 1. Percentage of Penicillin Non-Susceptible S. pneumoniaeS. pneumoniae in Canada: 1988-2007 in Canada: 1988-2007
Canadian Bacterial Surveillance Network, March 2008
0
2
4
6
8
10
12
14
16
18
1988 1993 1995 1997 1999 2001 2003 2005 2007
% intermediate resistance
% high-level resistance
Penicillin ResistantPenicillin Resistant S. pneumoniae Isolates S. pneumoniae Isolates Ontario 1988, 1993-2005 Ontario 1988, 1993-2005
0
2
4
6
8
10
12
14
1988 1993 1995 1997 1999 2001 2003 2005
% Intermediate Resistance
% High-level Resistance
Canadian Bacterial Surveillance Network, March 2006
Figure 5. Macrolide-Resistant Pneumococci: Canadian Figure 5. Macrolide-Resistant Pneumococci: Canadian Bacterial Surveillance Network, 1988-2007Bacterial Surveillance Network, 1988-2007
Canadian Bacterial Surveillance Network, March 2008
0
5
10
15
20
25
Per
cent
age
of Iso
late
s R
esis
tant
to
Ery
thro
myc
in
1988 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Figure 4. Percentage of Non-susceptible Isolates ofFigure 4. Percentage of Non-susceptible Isolates ofS. pneumoniae S. pneumoniae in Geographic Regions of Canada, 2007in Geographic Regions of Canada, 2007
Canadian Bacterial Surveillance Network, March 2008
0
5
10
15
20
25
30
BC PRAIRIES ONT QUE Atlantic
Levo Ceftri (Non-mening) Clind Pen Eryth
JAMA 1998;279:365-370.
• 941 children in observational study• Nasopharyngeal carriage of S.
pneumoniae determined• Low doses and long duration of ß-
lactam treatment was associated with increasing penicillin resistance
PRSP – Cause / Spread
BMJ 2002; 324 - 461 children in Australia
• Examined nasopharyngeal carriage of S. pneumoniae
• Likelihood of carrying PRSP doubled in children who
had used a beta-lactam in the previous 2 months• >7 days of antibiotics resulted in higher PRSP carriage• PRSP present even in children who had not taken
antibiotics for 6 months (likely acquired through transmission from others)
PRSP – Cause / Spread
1) Penicillin exposure selects resistance with S. pneumoniae
Widespread use of antibiotics selects for resistant strains, allowing them to proliferate and spread genes to other bacteria
Message #1
1) Penicillin exposure selects resistance with S. pneumoniae
2) Penicillin resistance is associated with multi-drug resistance
Message #2
Quinolone Resistant S.pneumoniae
Antibiotic Resistance (%)1988
Resistance (%)1997/8
Quinolones 0 1.7
Penicillin 2.4 13.9
Macrolides 1.2 6.7
Cotrimoxazole 1.8 11.6
Tetracycline 2.4 6.9
Quinolone Resistant S.pneumoniae
Figure 6. Fluoroquinolone-Resistant Pneumococci:Figure 6. Fluoroquinolone-Resistant Pneumococci: Canadian Bacterial Surveillance Network, 1997-2007Canadian Bacterial Surveillance Network, 1997-2007
Canadian Bacterial Surveillance Network, March 2008
% R
esis
tant
0
0.5
1
1.5
2
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Moxifloxacin
Levofloxacin
Figure 7. Fluoroquinolone-Resistant Pneumococci in Figure 7. Fluoroquinolone-Resistant Pneumococci in Respiratory Isolates from Adults >64 years: 1988-2007Respiratory Isolates from Adults >64 years: 1988-2007
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1988
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
% R
esis
tant is
ola
tes
Year
Levofloxacin
Moxifloxacin
Canadian Bacterial Surveillance Network, March 2008
• Recommendations:– quinolones be reserved for treatment failure or
known resistance– standard -lactam treatment is effective in
sensitive and intermediate resistant pneumococci
Arch Intern Med. 2000; 160: 1399-1408.
PRSP - Significance
1) Penicillin exposure selects resistance with S. pneumoniae
2) Penicillin resistance is associated with multi-drug resistance
3) Resistance is relative and can be overcome with increasing doses of penicillins, if tolerated.
However, S. pneumoniae resistance to macrolides and TMP-SMX is high level and cannot be overcome by increasing dosages.
Message #3
• Finland:
Year DDD/1000 inhabitants macrolide consumption
Resistance of group A strep to erythromycin
1991 2.40 16.5%
1992 1.38 8.6%
N Engl J Med, August 1997
Resistance – What can be done?
Anti-infective Guidelines
• Independent physician panel
• Arms length from government, industry
• Focus on optimal patient care
• Best available evidence, including Canadian references
• Published 1994, 1997, 2001, 2005
Penicillin: Resistance Rates and PrescriptionsPenicillin: Resistance Rates and Prescriptions(Canadian Bacterial Surveillance Network. 1988, 1993-2005)(Canadian Bacterial Surveillance Network. 1988, 1993-2005)
0
2
4
6
8
10
12
14
16
18
1988 1990 1992 1994 1996 1998 2000 2002 2004
Pe
rce
nt o
f iso
late
sn
ot s
usc
ep
tible
to p
en
icill
in
0
5
10
15
20
25
30
35
40
45
An
nu
al r
ate
of p
resc
riptio
ns
(pe
r 1
00
po
p'n
)
Penicillin non-susceptibility Penicillin use
Canadian Bacterial Surveillance Network, Feb. 2006
Erythromycin: Resistance Rates and PrescriptionsErythromycin: Resistance Rates and Prescriptions(Canadian Bacterial Surveillance Network. 1988, 1993-2005) (Canadian Bacterial Surveillance Network. 1988, 1993-2005)
0
2
4
6
8
10
12
14
16
18
20
1988
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
Per
cent
of
resi
stan
t is
olat
es
0
2
4
6
8
10
12
14
16
18
20
Pre
scrip
tions
per
100
pop
'n
Erythromycin non-susceptibility Macrolide use
Canadian Bacterial Surveillance Network, Feb. 2006
Take Home Messages
Antibiotics are good drugs, when used properly
• Always consider if infection is Bacterial vs Viral
• Try to use NO antibiotic or 1st line antibiotics first
• Narrow vs broad spectrum antibiotics
• Care about the consequences of prescribing antibiotics (resistance, side effect, C.difficile, cost)
• Provide professional/community leadership
• Partner with and educate/support your patients
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