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Bacterial Pathogens in the Hospital and Community: The Need for Newer Antibiotics Donald E Low University of Toronto.

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Presentation on theme: "Bacterial Pathogens in the Hospital and Community: The Need for Newer Antibiotics Donald E Low University of Toronto."— Presentation transcript:

1 Bacterial Pathogens in the Hospital and Community: The Need for Newer Antibiotics Donald E Low University of Toronto

2 Year life expectancy U.S. life expectancy

3 MMWR (29); 621


5 Achievements in 20 th Century  Control of infectious diseases Sanitation and Hygiene Vaccination Antibiotics


7 So What Happened?  Attitudinal

8 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

9 So What Happened?  Attitudinal  Antibiotic overuse/misuse


11 So What Happened?  Attitudinal  Antibiotic overuse/misuse  Fitness of organisms clonal spread

12 Tennessee Cleveland Mexico Colombia Brazil Argentina Uruguay Chile South Africa Singapore Malaysia Thailand Philippines Hong Kong Taiwan South Korea Spain France BM ? Finland Spain 23F – one pneumococcal clone

13 Global Travel and World Population

14 Bad Bugs, No Drugs 1 The Antimicrobial Availability Task Force of the IDSA 1 identified as particularly problematic pathogens – A. baumannii and P. aeruginosa –ESBL-producing Enterobacteriaceae –MRSA –Vancomycin-resistant enterococcus Declining research investments in antimicrobial development 2 1. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews. July, Accessed March 17, Talbot GH, et al. Clin Infect Dis. 2006;42:

15 Between 1962 and 2000, no major classes of antibiotics were introduced Fischbach MA and Walsh CT Science 2009

16 A Changing Landscape for Numbers of Approved Antibacterial Agents Bars represent number of new antimicrobial agents approved by the FDA during the period listed Number of agents approved Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38: ; New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912 Resistance

17 The Problems Gram negatives –Resistant Enterobacteriaceae β-Lactamases –Pseudomonas/Acinetobacter –N. gonorrheae Gram positives –MRSA –Pneumococcus

18 The Gram Negatives

19 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:

20 Enterobacteriaceae The rapid and disturbing spread of: –extended-spectrum ß-lactamases –AmpC enzymes –carbapenem resistance metallo-β-lactamases KPC and OXA-48 β-lactamases –quinolone resistance

21 Copyright restrictions may apply. Livermore, D. M. J. Antimicrob. Chemother :i29-36i; doi: /jac/dkp255 Rise in the proportions of E. coli from bacteraemias in England, Wales and Northern Ireland resistant to fluoroquinolones (white), oxyimino-cephalosporins (grey) and both (black)

22 Increase in numbers of Group 1, 2 and 3 β-lactamases from 1970 to 2009 Group 1/class C cephalosporinases Group 2/class A and class D β-lactamases Group 3/class B metallo- β-lactamases Bush K and Jacoby G AAC 2010

23 Bush K and Jacboy G AAC 2010 Major families of β-lactamases of clinical importance

24 Extended-Spectrum β-Lactamases β-lactamases capable of conferring bacterial resistance to –the penicillins –first-, second-, and third-generation cephalosporins –aztreonam –(but not the cephamycins or carbapenems) These enzymes are derived from group 2b β- lactamases (TEM-1, TEM-2, and SHV-1) –differ from their progenitors by as few as one AA


26 CTX-M-type ESBLs Until 2000, most ESBL producers were hospital Klebsiella spp. with TEM and SHV mutant β-lactamases Now, the dominant ESBLs across most of Europe and Asia are CTX-M enzymes, which originated as genetic escapes from Kluyvera spp Currently recognized as the most widespread and threatening mechanism of antibiotic resistance, both in clinical and community settings –80% of ESBL-positive E. coli from bacteraemias in the UK and Ireland are resistant to fluoroquinolones –40% are resistant to gentamicin Livermore, DM J. Antimicrob. Chemother 2009

27 Carbapenemases Ability to hydrolyze penicillins, cephalosporins, monobactams, and carbapenems Resilient against inhibition by all commercially viable ß-lactamase inhibitors –Subgroup 2df: OXA (23 and 48) carbapenemases –Subgroup 2f : serine carbapenemases from molecular class A: GES and KPC –Subgroup 3b contains a smaller group of MBLs that preferentially hydrolyze carbapenems IMP and VIM enzymes that have appeared globally, most frequently in non-fermentative bacteria but also in Enterobacteriaceae

28 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 and carbapenems

29 Nordmann P et al. LID 2009 K. pneumoniae carbapenemase-producing bacteria

30 Bush K and Jacboy G AAC 2010 Major families of β-lactamases of clinical importance

31 AmpC β-lactamases Once expressed at high levels, confer resistance to many β-lactam antimicrobials (excluding cefepime and carbapenems) In E. coli, constitutive over expression of AmpC β-lactamases can occur because – of mutations in the promoter and/or attenuator region (AmpC hyperproducers) – the acquisition of a transferable ampC gene on a plasmid or other transferable elements (plasmid- mediated AmpC β-lactamases)

32 Emerging Metallo-β-Lactamases with Mobile Genetics (SENTRY Program )


34 Enterobacteriaceae: Breakpoints revised Agent CLSI 2009CLSI 2010 SIRSIR Cefazolin ≤8 16≥32 ≤1 2≥4 Cefotaxime ≤ ≥64 ≤1 2≥4 Ceftriaxone ≤ ≥64 ≤1 2≥4 Ceftazidime ≤8 16≥32 ≤4 8≥16 Aztreonam ≤8 16≥32 ≤4 8≥16 Cefipime ≤8 16≥32 ≤8 16≥32

35 Neisseria gonorrhoeae Wang SA et al. Ann Int Med 2008

36 Prevalence of and risk factors for quinolone- resistant Neisseria gonorrhoeae infection in Ontario Oto KV et al. CMAJ 2009

37 Treatment of N. gonorrhoeae Only current CDC-recommended options for treating N. gonorrhoeae infections are from a single class of antibiotics, the cephalosporins. –Ceftriaxone, available only as an injection, is the recommended treatment for all types of gonorrhea infections (i.e., urogenital, rectal, and pharyngeal). –Cefixime is the only oral agent recommended for treatment of uncomplicated urogenital or rectal gonorrhea Reduced susceptibility to cefixime being described in Japan and other countries

38 The Gram Positives Staphylococcus aureus –MRSA –Reduced-vancomycin susceptibility MRSA MDR Streptococcus pneumoniae

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


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

42 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

43 MRSA Infections Among Patients In The Emergency Department Adult patients with acute, purulent skin and soft- tissue infections presenting to 11 University- affiliated EDs during August 2004 S. aureus was isolated from 320/422 patients 59% overall were MRSA (15% to 74%) 97% of MRSA were USA300 –74% were a single strain (USA ) 98% of MRSA had SCCmec type IV and the PVL toxin gene Moran GJ et al. NEJM 2006; 355:

44 Portland 54% Portland 54% Albuquerque 60% Albuquerque 60% Phoenix 60% Phoenix 60% Los Angeles 51% Los Angeles 51% New Orleans 67% New Orleans 67% Minneapolis 39% Minneapolis 39% Philadelphia 55% Philadelphia 55% New York 15% New York 15% Kansas City 74% Kansas City 74% Atlanta 72% Atlanta 72% Charlotte 68% Charlotte 68% MRSA Infections Among Patients In The Emergency Department Moran GJ et al. NEJM :

45 Chambers H

46 S. aureus resistant or with reduced susceptibility to vancomycin VRSA, VISA and hVISA

47 Streptococcus pneumoniae Most important pathogen in mild-to-moderate RTIs Greatest morbidity Greatest mortality

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

49 Impact of PCV7 Vaccination On NVT-IPD in Children <5 Years, USA ABCs data vs 1998/99.

50 Serotype distribution of S. pneumoniae isolated from invasive disease in children and adults (France: 2007) Dortet L et al. Diag Micro ID 2009

51 Multi-locus sequence typing of MDR serotype 19A isolates (n = 97) Pillai D et al. BMC Genomics 2009

52 Minimum spanning tree of MDR and non-MDDR serotype 19A Pillai D et al. BMC Genomics 2009

53 Emergence of a multidrug-resistant clone (ST320) among invasive serotype 19A pneumococci in Spain Distribution of penicillin-resistant serotype 19A isolates belonging to different clones throughout the study period. The bars indicate the proportion of each serotype 19A clone among penicillin-resistant pneumococci

54 S. pneumoniae Serotype 19A in Children, South Korea From 1991 through 2006, 538 strains of S. pneumoniae were obtained from various clinical specimens Choi EH et al. EID 2008

55 S. pneumoniae Serotype 19A in Children, South Korea Choi EH et al. EID 2008

56 Conclusions Old and continued antimicrobial resistance trends - MRSA (hVISA, VISA, VRSA, tolerance, MDR) - DRSP (MDR, ST320) - VRE (MDR CC-17 E. faecium) - ESBLs in Enterobacteriaceae (CTX-M clones) - MDR P. aeruginosa and Acinetobacter spp. New resistance trends - CA-MRSA (increasing MDR patterns) - Serine carbapenemase in Enterobacteriaceae - Metallo-β-lactamases in all Gram-negative bacilli - MDR N. gonorrhoeae

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