Is Resistance Futile? Donald E Low University of Toronto Ontario Agency for Health Protection and Promotion

Achievements in Public Health Control of infectious diseases –Sanitation and Hygiene –Vaccination –Antibiotics

MMWR (29); 621

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

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 2005;40:

MRSA DeLeo and Chambers JCI 2009 adapted from Klevens et al. JAMA I2007

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

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

Drug MIC (  g/mL) CLSI breakpoints Ampicillin>16R Cephalothin>16R Cefoxitin>16R Tobramycin>8R Amikacin32I Ceftriaxone>32R Ciprofloxacin>2R Meropenem4S

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

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

Streptococcus pneumoniae l Most important pathogen in mild-to-moderate RTIs 1 l Greatest morbidity 2 l Greatest mortality 2 Streptococcus pneumoniae 1 File TM Jr. Lancet. 2003;362: ; 2 Bartlett JG, et al. Clin Infect Dis. 2000;31: ;

Percentage of Penicillin Non-Susceptible S. pneumoniae in Canada: Percentage of Penicillin Non-Susceptible S. pneumoniae in Canada: Canadian Bacterial Surveillance Network, Feb 2009 *Oral breakpoints used

Macrolide-Resistant Pneumococci: Canadian Bacterial Surveillance Network, Canadian Bacterial Surveillance Network, Feb 2009

S. pneumoniae colonisation: the key to pneumococcal disease l NP carriage –15% 19 mos –~10% after age of 10 –~3% in adults l Invasive and mucosal infection involves NP colonization with concurrent viral respiratory infection Kadioglu A., et al. Nat Rev Micro 2008

Pneumococcal Vaccines l Although the 23- valent vaccine is immunogenic in adults and children older than 5 years, young children (<2 years) have a severely impaired antibody response to polysaccharide vaccination PPV B8 9V9N 1410A 18C11A 19F12F 23F15B 117F 520 7F22F 333F 19A

Introduction of pneumococcal vaccines, Ontario l Oct 1996 – PPV23 program for adults –Increased coverage from ?2% to 35% in adults l Oct 1996 – PPV23 program for adults –Increased coverage from ?2% to 35% in adults

Invasive pneumococcal disease, elderly Metropolitan Toronto,

Pediatric invasive pneumococcal disease Metropolitan Toronto,

PCV7PPV B 8 9V 9N 14 10A 18C 11A 19F 12F 23F 15B 117F 522F 7F33F 3 19A Pneumococcal vaccines

MMWR Feb 2008 Invasive Pneumococcal Disease in Children 5 Years After Conjugate Vaccine Introduction, l The overall incidence of IPD among children aged <5 years declined from 99 cases/ 100,000 during to 23 cases/100,000 in 2005

Introduction of pneumococcal vaccines, Ontario l Oct 1996 – PPV23 program for adults –Increased coverage from ?2% to 35% in adults l Dec 2001 – PCV7 licensed –Gradual increase in use in children (to about 1 dose per child, or 4 doses for 20% of children) l Jan 2005 – provincial PCV7 program –No catch-up; start with birth cohort l Oct 1996 – PPV23 program for adults –Increased coverage from ?2% to 35% in adults l Dec 2001 – PCV7 licensed –Gradual increase in use in children (to about 1 dose per child, or 4 doses for 20% of children) l Jan 2005 – provincial PCV7 program –No catch-up; start with birth cohort

Pediatric invasive pneumococcal disease Metropolitan Toronto,

Invasive pneumococcal disease, elderly Metropolitan Toronto,

Rates of penicillin and amoxicillin resistance Canada: Canadian Bacterial Surveillance Network, March 2008

Most Common MDR SPN Serotypes VS

Most Common MDR SPN Serotypes  P<  P=  P< P< VS

Worldwide Prevalance of MRSA Among S. aureus Isolates Grundmann H et al. Lancet 2006;368:874.

MRSA in Canada, Source:CNISP

Community -Associated MRSA 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

First Outbreaks of CA-MRSA Australia (1993)Australia (1993) –Udo EE et al. Genetic analysis of community isolates of methicillin-resistant Staphylococcus aureus in Western Australia. J. Hosp. Infect US (1999) –CDC. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus—Minnesota and North Dakota, MMWR 1999 Canada (2000)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

Emergence of CA-MRSA Canada Simore A et al. Canadian Nosocomial Infection Surveillance Program CMRSA7 (USA400) CMRSA10 (USA300)

Current Treatment Options for CA-MRSA Infection Moellering RC CID 2008

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- resistant in women older than 65 years of age Mc Isaac WJ et al. Can J Infect Dis Med Microbiol. 2006

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 (p<0.001); tetracycline (p<0.001) and erythromycin (p<0.001)  All isolates were susceptible to cefixime, ceftriaxone, azithromycin and spectinomycin Ota K et al. Can Med Ass J In Press

Controlling antimicrobial resistance l Reducing colonization and infection l Reducing volume of antimicrobial use l When decision made to treat –Use right drug –Right dose –Right duration

Controlling antimicrobial resistance  Reducing infection  Reducing volume of antimicrobial use  When decision made to treat –Use right drug –Right dose –Right duration

The average excess age-specific numbers of outpatient visits and courses of antibiotics per 100 children per year Neuzil KM et al. NEJM 2000 The Effect of Influenza on Hospitalizations, Outpatient Visits, and Courses of Antibiotics in Children

Controlling antimicrobial resistance  Reducing colonization and infection  Reducing volume of antimicrobial use  When decision made to treat –Use right drug –Right dose –Right duration

Respiratory Infections are the # 1 Reason for Office Visits Source: Verispan PDDA 2004 Number of common office visits (millions)

Nearly Two-thirds of all Oral Solid Antibiotic Prescriptions are for Sinusitis and Bronchitis Source: SDI, FANDxRx. Based on all tablets/capsule antibiotics for the 52 weeks ending April 6, 2005 Telithromycin (Ketek ® ) is indicated for acute exacerbations of chronic bronchitis, acute bacterial sinusitis and mild-to-moderate community-acquired pneumonia

Usage of antibiotics in Europe vs. pneumococcal penicillin I/R 1997 Felmingham et al. J Antimicrob Chemother 2000; 45 : 191–201 Cars et al. Lancet 2001; 357 :1851– France Spain Portugal Belgium Italy UK Germany Netherlands DDD/1000/day DI/RSP % * * 1996 data

Controlling antimicrobial resistance  Reducing colonization and infection  Reducing volume of antimicrobial use  When decision made to treat –Use right drug –Right dose –Right duration

Multivariate Analysis of Risk Factors β -lactam w/in 3 months Alcoholism Noninvasive disease < 5 y ≥ 65 y Odds Ratio Other Considerations Immunosuppression –Including steroids Multiple medical comorbidities Exposure to day care child Exposure to any antibiotic Clavo-Sanchez AJ et al. Clin Infect Dis. 1997;24: Harwell JI, Brown RB. Chest. 2000;117: Vanderkooi OG et al. Clin Infect Dis. 2005;40: Risks for Penicillin Resistance in Pneumococcus

Prevalence of Erythromycin Resistance Among Pneumococci by Prior Macrolide Use P =.02 P =.004 Vanderkooi OG et al. Clin Infect Dis. 2005;40: P < No AntibioticErythromycinClarithromycinAzithromycin Rate of Macrolide Resistance in Infecting Isolates (%)

Relative Risk for Infection With Fluoroquinolone- Resistant Pneumococci by Prior Antibiotic Use Vanderkooi OG et al. Clin Infect Dis. 2005;40: No Prior AntibioticPrior Antibiotic (not fluoroquinolone) Prior Fluoroquinolone Levoofloxacin resistant (%) * * * P<.001

Fluoroquinolone PD Profile Free AUC/MIC Levofloxacin 500 mg Levofloxacin 750 mg Gemifloxacin 320 mg Moxifloxacin 400 mg 40 (13-21) (24-40) (72-120) Resistance Prevention ~AUC/MIC≥100 Efficacy ~AUC/MIC≥ (41-69) Moran G. J Emerg Med. 2006;30:

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

Fluoroquinolone-Resistant Pneumococci: Canadian Bacterial Surveillance Network, Canadian Bacterial Surveillance Network, Jan 2009 % Resistant

Resistance Isn’t Futile