超级细菌的发现、演变、结构、发病机理及预防（英文ppt）课件

Superbug,Dr. Sarma. R.V.S.N.,M.D., M.Sc.(Canada), FIMSA, Senior Consultant Physician & Cardio-Metabolic Specialist,www.drsarma.in,Antimicrobial Resistance,Lancet Infect Dis 2010; 10: 597602,Published Online - August 11, 2010,Worldwide Prevalence of MRSA,Grundmann H et al. Lancet 2006;368:874.,Antibiotic Prescriptions,No Major New Discoveries,A Changing Landscape for Approved Antibacterials,Bars represent number of new antimicrobial agents approved by the FDA during that period,1983-87,1988-92,1993-97,1998-02,2003-05,2008,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,Resistance,Inactive,b Lactam Ring,b - Lactamase,Penicillin Cleavage by Penicillinase,Active,Bacterium Resistant to Penicillin,Penicillinase,Gene for b - Lactamase,Plasmid,This organism can freely grow in the presence of Penicillin,Genomic islands,Prophages,Conjugative Transposons (gram +ve),Super Integrons (Mainly Protobacteria),Integrons,Transposons,Insertion Sequences,The Busy Genome: Elements of Horizontal Exchange,Minimal species Genomic backbone,e.g. Escherichia Coli Common: 4.1 Mb K12 Islands: 0.53 Mb 0157:H7 Islands: 1.34 Mb,Acquisition of Hospital Infections,Inappropriate empiric antibiotic therapy can lead to increases in: mortality morbidity length of hospital stay cost burden resistance selection A number of studies have demonstrated the benefits of early use of appropriate empiric antibiotic therapy for patients with nosocomial infections,Inappropriate Antibiotic Therapy,Inappropriate antibiotic therapy can be defined as one or more of the following: ineffective empiric treatment of bacterial infection at the time of its identification the wrong choice, dose or duration of Rx. use of an antibiotic to which the pathogen is resistant,Inappropriate Antibiotic Therapy,Antibiotic resistance either arises as a result of innate consequences or is acquired from other sources Bacteria acquire resistance by: Mutation: spontaneous single or multiple changes in bacterial DNA Addition of new DNA: usually via plasmids, which can transfer genes from one bacterium to another Transposons: short, specialised sequences of DNA that can insert into plasmids or bacterial chromosomes,Mechanism of Antibiotic Resistance,Structurally modified antibiotic target site, resulting in: Reduced antibiotic binding Formation of a new metabolic pathway preventing metabolism of the antibiotic,Mechanism of Antibiotic Resistance,Structurally Modified Antibiotic Target Site,Interior of organism,Cell wall,Target site,Binding,Antibiotic,Antibiotics normally bind to specific binding proteins on the bacterial cell surface,Structurally Modified Antibiotic Target Site,Interior of organism,Cell wall,Modified target site,Antibiotic,Changed site: blocked binding,Antibiotics are no longer able to bind to modified binding proteins on the bacterial cell surface,Altered uptake of antibiotics, resulting in: Decreased permeability Increased efflux,Altered Uptake Of Antibiotics: Decreased Permeability,Interior of organism,Cell wall,Porin channel into organism,Antibiotic,Antibiotics normally enter bacterial cells via porin channels in the cell wall,Altered Uptake Of Antibiotics: Decreased Permeability,Interior of organism,Cell wall,New porin channel into organism,Antibiotic,New porin channels in the bacterial cell wall do not allow antibiotics to enter the cells,Altered Uptake Of Antibiotics: Decreased Permeability,Altered Uptake of Antibiotics: Increased Efflux,Interior of organism,Cell wall,Porin channel through cell wall,Antibiotic,Entering,Entering,Antibiotics enter bacterial cells via porin channels in the cell wall,Interior of organism,Cell wall,Porin channel through cell wall,Antibiotic,Entering,Exiting,Active pump,Once antibiotics enter bacterial cells, they are immediately excluded from the cells via active pumps,Altered Uptake of Antibiotics: Increased Efflux,Antibiotic inactivation Bacteria acquire genes encoding enzymes that inactivate antibiotics Examples include: -Lactamases Aminoglycoside-modifying enzymes Chloramphenicol acetyl transferase,Antibiotics Inactivation (Cleavage),Interior of organism,Cell wall,Antibiotic,Target site,Binding,Enzyme,Inactivating enzymes target antibiotics,Antibiotics Inactivation (Cleavage),Interior of organism,Cell wall,Antibiotic,Target site,Binding,Enzyme,Enzyme binding,Enzymes bind to antibiotic molecules,Antibiotics Inactivation (Cleavage),Interior of organism,Cell wall,Antibiotic,Target site,Enzyme,Antibiotic destroyed,Antibiotic altered, binding prevented,Enzymes destroy antibiotics or prevent binding to target sites,Antibiotics Inactivation (Cleavage),Multiple Mechanisms Of Antibacterial Resistance,+,Quinolones,+,Trimethoprim,+,Sulphonamide,+,Macrolide,+,Chloramphenicol,+,Tetracycline,+,+,Aminoglycoside,+,Glycopeptide,+,+,+,-lactam,Modified target,Altered uptake,Drug inactivation,-Lactam Antibiotic Resistance Mechanisms,Three mechanisms of -lactam antibiotic resistance are recognised: Reduced permeability Inactivation with -lactamase enzymes Altered penicillin-binding proteins (PBPs),-Lactam Antibiotic Resistance Mechanisms,AmpC and Extended-Spectrum -lactamase (ESBL) production are the most important mechanisms of -lactam resistance in nosocomial infections The antimicrobial and clinical features of these resistance mechanisms are highlighted in the following slides,-Lactam Antibiotic Resistance,-Lactam Resistance: AmpC Production,Worldwide problem: Incidence increased from 17% to 23% between 1991 and 2001 in UK Very common in Gram-negative bacilli AmpC gene is usually sited on chromosomes, but can be present on plasmids Enzyme production is either constitutive (occurring all the time) or inducible (only occurring in the presence of the antibiotic),Pfaller et al. Int J Antimicrob Agents 2002;19:383388; Sader et al. Braz J Infect Dis 1999;3:97110; Livermore et al. Int J Antimicrob Agents 2003;22:1427,An increasing global problem Found in a small, expanding group of Gram-negative bacilli, most commonly the Entero-bacteriaceae spp. Usually associated with large plasmids Enzymes are commonly mutants of TEM- and SHV-type -lactamases,Jones et al. Int J Antimicrob Agents 2002;20:426431; Sader et al. Diagn Microbiol Infect Dis 2002;44:273280,-Lactam Resistance: ESBL Production,Antimicrobial Features of ESBLs,Inhibited by -lactamase inhibitors Usually confer resistance to: 1, 2 and 3rd generation Cephalosporins eg. Ceftazidime Monobactams eg. Aztreonam Carboxypenicillins eg. Carbenicillin Varied susceptibility to Piperacillin / Tazobactam Typically susceptible to Carbapenems and Cephamycins Often non-susceptible to fourth generation Cephalosporins,Features of methicillin-resistant Staphylococcus aureus (MRSA),Introduction of methicillin in 1959 was followed rapidly by reports of MRSA isolates Recognized hospital pathogen since the 1960s Major cause of nosocomial infections worldwide Contributes to 50% of infectious morbidity in ICUs Surveillance studies suggest prevalence has increased worldwide, reaching 2550% in 1997,Jones. Chest 2001;119:397S404S,Emergence of MRSA in the community,MRSA in hospitals leads to an associated rise in incidence in the community Community-acquired MRSA strains may be distinct from those in hospitals In a hospital-based study, 40% of MRSA infections were acquired prior to admission Risk factors for community acquisition included: Recent hospitalization; Previous antibiotic therapy Residence in a long-term care facility; Intravenous drug use,Hiramatsu et al. Curr Opin Infect Dis 2002;15:407413 Layton et al. Infect Control Hosp Epidemiol 1995;16:1217; Naimi et al. 2003;290:29762984,Antimicrobial features of MRSA (1),Mechanism involves altered target site new penicillin-binding protein PBP 2 (PBP 2a) encoded by chromosomally located mecA gene Confers resistance to all -lactams Gene carried on a mobile genetic element staphylococcal cassette chromosome mec (SCCmec) Laboratory detection requires care Not all mecA-positive clones are resistant to methicillin,Hiramatsu et al. Trends Microbiol 2001;9:486493 Berger-Bachi 178:165171,Antimicrobial features of MRSA (2),Cross-resistance common with many other antibiotics Ciprofloxacin resistance is a worldwide problem in MRSA: involves 2 resistance mutations usually involves parC and gyrA genes renders organism highly resistant to ciprofloxacin, with cross-resistance to other quinolones Intermediate resistance to glycopeptides first reported in 1997,Hiramatsu et al. J Antimicrob Chemother 1997;40:135136 Hooper. Lancet Infect Dis 2002;2:530538,Glycopeptide resistance: focus on vancomycin resistance,Vancomycin-resistant enterococci (VRE) Vancomycin-resistant S. aureus (VRSA),Features of quinolone resistance: Gram-negative organisms,Resistance most common in organisms associated with nosocomial infections Pseudomonas aeruginosa Acinetobacter spp. also increasing among ESBL-producing strains Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) surveillance programme (19972000) 13.4% of Gram-negative strains resistant to ciprofloxacin P. aeruginosa and Acinetobacter baumannii are the most prevalent resistant strains increasing prevalence of resistance during surveillance period,Masterton. J Antimicrob Chemother 2002;49:218220 Thomson. J Antimicrob Chemother 1999;43(Suppl. A):3140,Features of quinolone resistance: Gram-positive organisms,MRSA S. aureus occurred in 22.9% of pneumonias in hospitalised patients in USA and Canada (1997 SENTRY data) Enterococcus spp. resistance has developed rapidly, especially among VRE Streptococcus pneumoniae resistance emerging in many countries, including community-acquired resistance Hong Kong (12.1%), Spain (5.3%) and USA (1%) marked cross-resistance with other frequently used antibiotics,Hooper. Lancet Infect Dis 2002;2:530538,Summary,Antibiotic resistance in the hospital setting is increasing at an alarming rate and is likely to have an important impact on infection management Steps must be taken now to control the increase in antibiotic resistance,Cosgrove et al. Arch Intern Med 2002;162:185190,Summary,The Academy for Infection Management supports the concept of using appropriate antibiotics early in nosocomial infections and proposes: selecting the most appropriate antibiotic based on the patient, risk factors, suspected infection and resistance administering antibiotics at the right dose for the appropriate duration changing antibiotic dosage or therapy based on resistance and pathogen information recognising that prior antimicrobial administration is a risk factor for the presence of resistant pathogens knowing the units antimicrobial resistance profile and choosing antibiotics accordingly,Hand washing plays an important role in nosocomial pneumonias Wash hands before and after suctioning, touching ventilator equipment, and/or coming into contact with respiratory secretions. Use a continuous subglottic suction ET tube for intubations expected to be 24 hours Keep the HOB elevated to at least 30 degrees unless medically contraindicated,Outline of the talk,Various Antibiotic Classes Mechanisms of action of Anti Bacterials Mechanisms of Bacterial Resistance Animation on Drug Resistance Lactamases Drug Resistance NDM1 Superbug Concerns Other Superbugs Global Issues How to prevent Drug Resistance Where we are heading in future,Various Antibiotic Classes Mechanisms of action of Anti Bacterials Mechanisms of Bacterial Resistance Animation on Drug Resistance Lactamases Drug Resistance NDM1 Superbug Concerns Other Superbugs Global Issues How to prevent Drug Resistance Where we are heading in future,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. /pa/IDSA_Paper4_final_web.pdf. July, 2004. Accessed March 17, 2007. 2. Talbot GH, et al. Clin Infect Dis. 2006;42:657-68.,Enterobacteriaceae,The rapid and disturbing spread of: extended-spectrum -lactamases AmpC enzymes carbapenem resistance metallo-lactamases KPC and OXA-48 -lactamases quinolone resistance,Extended-Spectrum -Lactamases,-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 -lactamases (TEM-1, TEM-2, and SHV-1) differ from their progenitors by as few as one AA,CTX-M-type ESBLs,Until 2000, most ESBL producers were hospital Klebsiella spp. with TEM and SHV mutant -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 -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,Nordmann P et al. LID 2009,K. pneumoniae carbapenemase-producing bacteria,AmpC -lactamases,Once expressed at high levels, confer resistance to many -lactam antimicrobials (excluding cefepime and carbapenems) In E. coli, constitutive over expression of AmpC -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 -lactamases),Emerging Metallo-Lactamases with Mobile Genetics (SENTRY Program 2001-2005),Novel -lactams,Ceftaroline Ceftobiprole Oral penem Faropenem,Hebeisen P et al. Antimicrob Agents Chemother. 2001. Sader HS et al. Antimicrob Agents Chemother. 2005. Granizo JJ et al. Clin Ther. 2006. Schurek KN et al. Expert Rev Anti Infect Ther. 2007.,Spectrum of Activity,Davies TA et al. ICAAC. 2005. Sahm DF et al. ICAAC. 2006. Van Bambeke F et al. Drugs. 2007. McGee L et al; Morrissey I et al. ICAAC. 2007.,*Multiple mutations in PBP1a, 2b, and 2x. MIC90 of 2 mg/L vs. cefuroxime-resistant strain,Clinical Utility,Boswell FJ et al; Jones RN et al. J Antimicrob Chemother. 2002. Azoulay-Dupuis E et al. Antimicrob Agents Chemother. 2004. Echols R et al; Kowalsky S et al; Lentnek A et al; Drehobl M et al. ICAAC. 2005. Jacqueline C et al; Young C et al; Rubino CM et al. ICAAC. 2006.,Novel Glycopeptides,Dalbavancin Once weekly IV dosing Oritavancin Telavancin Versus vancomycin: Additional mechanisms of action Renal and hepatic excretion No known nephrotoxicity or dose adjustments,Malabarba A et al. J Antimicrob Chemother. 2005,Spectrum of Activity,Streit JM et al. Diag Micro Infect Dis. 2004. Lin G et al. ICAAC. 2005. Thornsberry C et al. ICAAC. 2006. Draghi DC et al; Grover PK et al; Fritsche TR et al. ICAAC. 2007.,*Rapidly bactericidal Also active against macrolide- and FQ-resistant strains,Clinical Utility,Gotfried M et al. ICAAC. 2005. Lehoux D et al. ICAAC. 2007.,Novel Fluoroquinolone,Garenoxacin (PO/IV) Bactericidal MIC90 = 0.06 g/mL for penicillin-, macrolide-, and 6 drug- resistant S. pneumoniae MIC90 = 1 g/mL for CIP- and LEV- resistant S. pneumoniae More potent than MOX,Wu P et al. Antimicrob Agents Chemother. 2001. Jones RN et al. Diag Micro Infect Dis. 2007.,65,Polymyxins,a group of polypeptide antibiotics that consists of 5 chemically different compounds (polymyxins A-E), were discovered in 1947 Only polymyxin B and polym