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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. Worldwide Distribution of Penicillin Resistant Pneumococci The Problem Russia 7% Canada 14% • Graph of Global Resistance patterns? Israel 54% USA 41% Japan 64% Mexico 53% Brazil 31% Kenya 49% Saudi Arabia 62% Singapore 53% South Africa 80% Hong Kong 80% Principles of Antibiotic Prescribing Ideal 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 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% 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 S. pneumoniae in Canada: 1988-2007 18 % intermediate resistance 16 % high-level resistance 14 12 10 8 6 4 2 0 1988 1993 1995 1997 1999 2001 2003 2005 2007 Canadian Bacterial Surveillance Network, March 2008 Penicillin Resistant S. pneumoniae Isolates Ontario 1988, 1993-2005 14 % Intermediate Resistance 12 % High-level Resistance 10 8 6 4 2 0 1988 1993 1995 1997 1999 2001 2003 2005 Canadian Bacterial Surveillance Network, March 2006 Figure 5. Macrolide-Resistant Pneumococci: Canadian Bacterial Surveillance Network, 1988-2007 20 Erythromycin Percentage of Isolates Resistant to 25 15 10 5 0 1988 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Canadian Bacterial Surveillance Network, March 2008 Figure 4. Percentage of Non-susceptible Isolates of S. pneumoniae in Geographic Regions of Canada, 2007 30 25 20 15 10 5 0 BC PRAIRIES Levo ONT Ceftri (Non-mening) QUE Clind Atlantic Pen Eryth Canadian Bacterial Surveillance Network, March 2008 PRSP – Cause / Spread JAMA 1998;279:365-370. • 941 children in observational study • Nasopharyngeal carriage of S. pneumoniae determined • Low doses and long duration of ßlactam 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) Message #1 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 #2 1) Penicillin exposure selects resistance with S. pneumoniae 2) Penicillin resistance is associated with multi-drug resistance Quinolone Resistant S.pneumoniae Quinolone Resistant S.pneumoniae Antibiotic Resistance (%) 1988 Resistance (%) 1997/8 0 1.7 Penicillin 2.4 13.9 Macrolides 1.2 6.7 Cotrimoxazole 1.8 11.6 Tetracycline 2.4 6.9 Quinolones Figure 6. Fluoroquinolone-Resistant Pneumococci: Canadian Bacterial Surveillance Network, 1997-2007 Moxifloxacin % Resistant 2 Levofloxacin 1.5 1 0.5 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Canadian Bacterial Surveillance Network, March 2008 Figure 7. Fluoroquinolone-Resistant Pneumococci in Respiratory Isolates from Adults >64 years: 1988-2007 4.5 3.5 Levofloxacin Moxifloxacin 3 2.5 2 1.5 % Resistant isolates 4 1 0.5 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 1988 0 Year Canadian Bacterial Surveillance Network, March 2008 PRSP - Significance • 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. Message #3 1) Penicillin exposure selects resistance with S. pneumoniae 2) Penicillin resistance is associated with multidrug 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. Resistance – What can be done? • 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 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, 1993-2005) Penicillin use 18 45 16 40 14 35 12 30 10 25 8 20 6 15 4 10 2 5 0 0 1988 1990 1992 1994 1996 1998 2000 2002 Annual rate of prescriptions (per 100 pop'n) Percent of isolates not susceptible to penicillin Penicillin non-susceptibility 2004 Canadian Bacterial Surveillance Network, Feb. 2006 Erythromycin: Resistance Rates and Prescriptions (Canadian Bacterial Surveillance Network. 1988, 1993-2005) 20 6 4 4 2 2 0 0 20 05 6 20 04 8 20 03 8 20 02 10 20 01 10 20 00 12 19 99 12 19 98 14 19 97 14 19 96 16 19 95 16 19 94 18 19 93 18 19 88 Percent of resistant isolates Macrolide use Prescriptions per 100 pop'n Erythromycin non-susceptibility 20 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