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: 9000 cases Resistance rates differ dramatically between Canada and the U.S.

The Problem Graph of Global Resistance patterns?

Principles of Antibiotic Prescribing Ideal WorldReal 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 humans More 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% % (with up to 5% with high-level resistance) % – 16.9% CMAJ 2002; 167(8)

Figure 1. Percentage of Penicillin Non-Susceptible S. pneumoniae in Canada: Canadian Bacterial Surveillance Network, March 2008

Penicillin Resistant S. pneumoniae Isolates Ontario 1988, Canadian Bacterial Surveillance Network, March 2006

Figure 5. Macrolide-Resistant Pneumococci: Canadian Bacterial Surveillance Network, Canadian Bacterial Surveillance Network, March 2008

Figure 4. Percentage of Non-susceptible Isolates of S. pneumoniae in Geographic Regions of Canada, 2007 Canadian Bacterial Surveillance Network, March 2008

JAMA 1998;279: 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; 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

Figure 6. Fluoroquinolone-Resistant Pneumococci: Canadian Bacterial Surveillance Network, Canadian Bacterial Surveillance Network, March 2008 % Resistant

Figure 7. Fluoroquinolone-Resistant Pneumococci in Respiratory Isolates from Adults >64 years: 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: 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: YearDDD/1000 inhabitants macrolide consumption Resistance of group A strep to erythromycin % % 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 Prescriptions (Canadian Bacterial Surveillance Network. 1988, ) Canadian Bacterial Surveillance Network, Feb. 2006

Erythromycin: Resistance Rates and Prescriptions (Canadian Bacterial Surveillance Network. 1988, ) 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 1 st 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