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,Click to edit Master title style,Click to edit Master title style,*,Superbug,Dr.Sarma.R.V.S.N.,M.D.,M.Sc.(Canada),FIMSA,Senior Consultant Physician&,Cardio-Metabolic Specialist,Antimicrobial Resistance,Lancet Infect Dis 2010;10:597602,Published Online-August 11,2010,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,0,0,2,4,6,8,10,12,14,16,18,Number of agents approved,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,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,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,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,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,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,Enzymebinding,Enzymes,bind,to,antibiotic,molecules,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),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 ofGram-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 3,rd,generation Cephalosporins eg.Ceftazidime,M,onobactams eg.,A,ztreonam,C,arboxypenicillins eg.,C,arbenicillin,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,C,ontributes,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,mec,A gene,Confers,resistance to all,-lactams,Gene carried on a mobile genetic element staphylococcal cassette chromosome,mec,(SCC,mec,),Laboratory detection requires care,Not all,mec,A-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,par,C and,gyr,A 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(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 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,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-,-Lactamaseswith 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,Organism,MIC,90,(,g/mL),CTL,CBP,FAR,Pen-S,0.016,0.015,0.25,Pen-I,0.06,0.12,0.008,Pen-R,0.25,1,1,CTX-R*,0.5,1,ND,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.,MIC,90,of 2 mg/L vs.cefuroxime-resistant strain,Clinical Utility,ABx,Route,In vivo,Efficacy,Cross-Resistance,Limitations,CTL,IV,Good lung penetration in rabbit model,None-all active against MDR strains,Presumed or reported cross-hypersensitivity to,-lactams,CBP,IV,Equal to CTX in murine model,FAR,PO,Eradication of,S.pneumoniae,;NI to AMX,CLV,CPX,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,Organism,MIC,90,(,g/mL),VAN,DAL,*,ORI*,TEL*,Pen-S,0.5,0.03,0.004,0.03,Pen-NS,0.25-2,0.03,0.008,0.015,MDR,ND,ND,0.008,0.03,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,ABx,Route,In vivo,Efficacy,Cross-Resistance,AEs,DAL,IV,Animal model of PCN-resistant NBPP,Partial with vancomycin;clinical significance unclear,Redman syndrome with TEL;,Rare,in platelets,ORI,IV,High AUC:MIC ratios in ELF and plasma in murine NBPP,TEL,IV,Good penetration into ELF and AMs in human volunteers;Phase III trial pending,Gotfried M,et al,.ICAAC.2005.Lehoux D,et al,.ICAAC.2007.,Novel Fluoroq,uinolone,Garenoxacin,(PO/IV),Bactericidal,MIC,90,=0.06,g/mL for penicillin-,macrolide-,and 6 drug-resistant,S.pneumoniae,MIC,90,=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,polymyxin E(colistin),have been used in clinical practice,the primary route of excretion is renal,66,Colistin,The target of antimicrobial activity of colistin is the bacterial cell membrane,Colistin has also potent anti-e
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