抗生素耐药 resistance to antibiotics课件

Resistance to antibiotics,Intrinsic resistance (examples) penG does not enter gram negative bacteria well why? doesnt penetrate-ampicillin does rifampin doesnt kill fungi why? doesnt get in-weaken barrier with amphotericin and then it does isoniazid does not kill bugs that dont require synthesis of mycolic acids Environmental resistance e.g. sulfonamide resistance if high purines, methionine, thymidine available (such as in an abscess) e.g. aminoglycosides not effective in anaerobic environment Acquired Resistance genetic changes, plasmids with new genes,2006 Antibiogram Harborview/UW,Acquired Drug Resistance,1. enzymatic inactivation (b-lactams, aminoglyc. chloramph),Bacteria keep up with big pharma in the b-lactam antibiotic arms race,bacteria can often express more than one -lactamase,Inactivation of aminoglycosides by acetylation, phosphorylation, and adenylation in drug-resistant organisms,Acquired Drug Resistance,1. enzymatic inactivation (b-lactams, aminoglyc. chloramph),2. rapid efflux of drug out of cell (tetracyclines, ciprofloxacin),Drug export systems in Gram +,Acquired Drug Resistance,1. enzymatic inactivation (b-lactams, aminoglyc. chloramph),2. rapid efflux of drug out of cell (tetracyclines, ciprofloxacin),3. decreased conversion to active form (isoniazid),4. increased concentration of antagonist/competitor (sulfonamide resistance with increased PABA synthesis).,5. altered amount of receptor (trimethoprim-DHFR amplification),6. altered structure of target to reduce binding (methicillin resistance, vancomycin resistance, ciprofloxacin res.),Vancomycin resistance: mechanism,Vancomycin resistance: mechanism,Resistance can be transferred between bacteria,phage transduction transposable elements plasmid transfer during conjugation plasmids can contain multiple resistance genes transfer can occur between non-pathogen and pathogens,Plasmid-mediated drug resistance,Problems with Antibiotic resistance,more than 50% of antibiotics used in domestic animals for sub-therapeutic effect: breeding ground for resistance,There are 7.5 billion chickens, 292 million turkeys, 109 million cattle and 92 million pigs in the United States.,Antibiotics given to pigs as of 2000,“KFC does not purchase poultry treated nontherapeutically with medically important antibiotics.” Letter to “Keep Antibiotics Working,” August 28, 2002 McDonalds Weve listened to the concerns, studied the issue, and the bottom line was we thought it was the right thing to do to discontinue the use of fluoroquinolone antibiotics in poultry, said Walt Riker, spokesman for Oak Brook-based McDonalds. Walt Riker, McDonalds, “Chickens Fed With Antibiotics McGone,” Chicago Sun-Times, February 12, 2002,Prospects for new antibiotics?,new antibiotic development slowed in 80s/90s selective drugs have lower market value 5-15 yr time frame to get new drugs to physicians recent increase in new antibiotic development is encouraging,active against Strep pneumoniae,First reported in a strain of K. pneumoniae QnrA protein 218 aa protein Protects DNA gyrase and topoisomerase IV from the inhibitory activity of quinolones-exact mechanism is not known yet Qnr proteins QnrA2 K. oxytoca (China) QnrB - E. coli, K. pneumoniae, E. cloacae, C. koseri (USA and India) - 40% aa identity with QnrA QnrS S. flexneri (Japan) - 59% aa identity with QnrA The presence of other mechanisms of resistance may increase plasmid-mediated quinolone resistance,Plasmid Mediated Quinolone Resistance (PMQR),PREVALENCE OF PLASMID-MEDIATED RESISTANCE TO QUINOLONES IN Escherichia coli,1% QnrA+ isolates among ciprofloxacin-resistant E.coli from different countries AAC (2003) 47:559 11% QnrA+ isolates among ciprofloxacin-resistant K. pneumoniae and 0% in E.coli from USA AAC (2004) 48: 1295 7.7% QnrA+ isolates among ciprofloxacin-resistant E. coli in Shanghai (China) AAC (2003) 47: 2242 0.4% QnrA+ isolates among nalidixic acid- resistant Escherichia coli (France) AAC (2005) 49: 3091,TB drug development,no new TB drugs in past 40 years multi-drug resistant TB prevalent Johnson & Johnson R207910 targets mycobacterium ATP synthetase,b-Lactam Antibiotic development,spectrum of action resistance to b-lactamase specific b-lactamase inhibitors,Ampicillin,Penicillin G,Amoxicillin,Methicillin,Dicloxacillin,R,b-lactam antibiotics-1,Methicillin resistance,caused by unique peptidyl transferase that does not bind b-lactams had been largely confined to hospital acquired infections more recently-outbreaks in athletic teams, iv drug users, school children, gay community, general population 900 cases in LA county jails (2002),Structure of PBP2a,G,r,ou,p,S,p,e,c,t,r,um,b,-,la,ct,ama,s,e,s,e,n,s,it,ivi,t,y,Na,t,u,r,al,p,e,ni,c,il,l,ins,Pe,n G/,Pe,n,V,n,arro,w s,p,e,ct,r,u,m,gra,m,po,si,t,i,ve,s,e,nsi,t,i,ve,Pe,ni,c,ill,i,n,a,s,e,r,e,sis,ta,n,t,m,e,t,h,i,ci,l,lin,d,i,cl,oxac,il,l,in,n,arro,w s,p,e,ct,r,u,m,r,es,i,st,an,t,b-lactam antibiotics-1,Cephalosporins,Brodys Human Pharmacology,G,r,ou,p,S,p,e,c,t,r,um,b,-,la,ct,ama,s,e,s,e,n,s,it,ivi,t,y,C,e,p,h,a,l,o,s,po,r,i,ns,c,e,fac,l,o,r,c,e,ft,ri,axon,e,b,roa,d s,p,e,ct,r,u,m,var,i,a,bl,e,b-lactam antibiotics-2,Newer b-lactams,aztreonam (monobactam) gram- specific resistant to b-lactamase Carbapenems: imipenem, meropenem broad spectrum (gram+,gram-) resistant to b-lactamase penetrates CSF imipenem a substrate for dehydropeptidase I in kidney, meropenem is not,Brenner,b-lactamase inhibitors,b-lactamase inhibitors,Clavulanic acid (suicide inhibitor for most lactamases) little antibiotic