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Bacterial Pathogens in the Hospital and Community: The Need for Newer Antibiotics Donald E Low University of Toronto U.S. life expectancy 1900-1960 life expectancy 70 62 54 1900 46 38 1900 1910 1920 1930 Year 1940 1950 1960 MMWR 1999 48 (29); 621 MMWR 1999 48 (29); 621 Achievements in 20th Century Control of infectious diseases • Sanitation and Hygiene • Vaccination • Antibiotics So What Happened? Attitudinal 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 So What Happened? Attitudinal Antibiotic overuse/misuse So What Happened? Attitudinal Antibiotic overuse/misuse Fitness of organisms • clonal spread Spain 23F – one pneumococcal clone Finland France BM4200 1978 ? Spain Cleveland South Korea Tennessee Taiwan Hong Kong Thailand Philippines Mexico Colombia Malaysia Singapore Brazil Chile Uruguay Argentina South Africa 400 6.7 350 5.7 300 4.7 250 3.7 200 2.7 150 1.7 100 50 0.7 0 -0.3 1850 1875 1900 1925 1950 1975 2000 Population in Billions Days to Circumnavigate Global Travel and World Population Bad Bugs, No Drugs1 • The Antimicrobial Availability Task Force of the IDSA1 identified as particularly problematic pathogens – A. baumannii and P. aeruginosa – ESBL-producing Enterobacteriaceae – MRSA – Vancomycin-resistant enterococcus • Declining research investments in antimicrobial development2 1. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews. http://www.idsociety.org/pa/IDSA_Paper4_final_web.pdf. July, 2004. Accessed March 17, 2007. 2. Talbot GH, et al. Clin Infect Dis. 2006;42:657-68. Between 1962 and 2000, no major classes of antibiotics were introduced Fischbach MA and Walsh CT Science 2009 A Changing Landscape for Numbers of Approved Antibacterial Agents 16 14 12 Resistance Number of agents approved 18 10 8 6 4 2 0 0 1983-87 1988-92 1993-97 1998-02 2003-05 2008 Bars represent number of new antimicrobial agents approved by the FDA during the period listed. Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286; New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912 The Problems • Gram negatives – Resistant Enterobacteriaceae • β-Lactamases – Pseudomonas/Acinetobacter – N. gonorrheae • Gram positives – MRSA – Pneumococcus The Gram Negatives 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;40:1792-8. 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 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) Livermore, D. M. J. Antimicrob. Chemother. 2009 64:i29-36i; doi:10.1093/jac/dkp255 Copyright restrictions may apply. Increase in numbers of Group 1, 2 and 3 β-lactamases from 1970 to 2009 Group 2/class A and class D β-lactamases Group 1/class C cephalosporinases Group 3/class B metalloβ-lactamases Bush K and Jacoby G AAC 2010 Major families of β-lactamases of clinical importance Bush K and Jacboy G AAC 2010 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 βlactamases (TEM-1, TEM-2, and SHV-1) – differ from their progenitors by as few as one AA E. coli and Klebsiella ESBL Phenotype Rates by Country (SENTRY Program) 65 60 55 Frequency (%) 50 45 40 35 30 25 20 15 10 5 0 Switzer Sweden Spain Ireland Germany UK France Country Klebsiella E. coli Italy Israel Turkey Greece Poland 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 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 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 K. pneumoniae carbapenemase-producing bacteria Nordmann P et al. LID 2009 Major families of β-lactamases of clinical importance Bush K and Jacboy G AAC 2010 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 (plasmidmediated AmpC β-lactamases) Emerging Metallo-β-Lactamases with Mobile Genetics (SENTRY Program 2001-2005) Genetic group Geographic origin Characterized enzymes imp Japan vim spm gim vim sim Italy Brazil Germany USA Korea IMP-1 through IMI-13a IMP-14, and IMP-16a VIM-1 through VIM-7a SPM-1a GIM-1a VIM-7a,b SIM-1 Enterobacteriaceae: Breakpoints revised CLSI 2009 Agent CLSI 2010 S I R S I R Cefazolin ≤8 16 ≥32 ≤1 2 ≥4 Cefotaxime ≤8 16-32 ≥64 ≤1 2 ≥4 Ceftriaxone ≤8 16-32 ≥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 Neisseria gonorrhoeae Wang SA et al. Ann Int Med 2008 Prevalence of and risk factors for quinoloneresistant Neisseria gonorrhoeae infection in Ontario Oto KV et al. CMAJ 2009 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 The Gram Positives • Staphylococcus aureus – MRSA – Reduced-vancomycin susceptibility MRSA • MDR Streptococcus pneumoniae MRSA DeLeo and Chambers JCI 2009 adapted from Klevens et al. JAMA I2007 Worldwide Prevalance of MRSA Among S. aureus Isolates Grundmann H et al. Lancet 2006;368:874. 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 MRSA Infections Among Patients In The Emergency Department • Adult patients with acute, purulent skin and softtissue infections presenting to 11 Universityaffiliated 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 (USA300-0114) • 98% of MRSA had SCCmec type IV and the PVL toxin gene Moran GJ et al. NEJM 2006; 355:666-74. MRSA Infections Among Patients In The Emergency Department Portland 54% Los Angeles 51% Moran GJ et al. NEJM 2006 355:666-74. Minneapolis 39% New York 15% Philadelphia 55% Charlotte Kansas City Phoenix 68% 74% 60% Atlanta 72% Albuquerque New Orleans 67% 60% Chambers H www.mrsai.org S. aureus resistant or with reduced susceptibility to vancomycin VRSA, VISA and hVISA Streptococcus pneumoniae • Most important pathogen in mild-to-moderate RTIs • Greatest morbidity • Greatest mortality Invasive Pneumococcal Disease in Children 5 Years After Conjugate Vaccine Introduction 1998 - 2005 • The overall incidence of IPD among children aged <5 years declined from 99 cases/100,000 during 1998 - 1999 to 23 cases/100,000 in 2005 MMWR Feb 2008. Impact of PCV7 Vaccination On NVT-IPD in Children <5 Years, USA 1998-2003 ABCs data. 2003 vs 1998/99. Serotype distribution of S. pneumoniae isolated from invasive disease in children and adults (France: 2007) Dortet L et al. Diag Micro ID 2009 Multi-locus sequence typing of MDR serotype 19A isolates (n = 97) Pillai D et al. BMC Genomics 2009 Minimum spanning tree of MDR and non-MDDR serotype 19A Pillai D et al. BMC Genomics 2009 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 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 S. pneumoniae Serotype 19A in Children, South Korea Choi EH et al. EID 2008 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