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

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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

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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

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cent

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of Iso

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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

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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

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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

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1988 1990 1992 1994 1996 1998 2000 2002 2004

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An

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)

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)

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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