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Cephalosporin Resist ant Escherichia coli

Cephalosporin Resist ant Escherichia coli. Dr.T.V.Rao MD. Penicillins Ampicillin Amoxicillin Piperacillin Cephalosporins (generations) 1 st gen: cephalothin 2 nd gen (Cephamycins): cefoxitin, cefotetan 3 rd gen: ceftazidime, cefotaxime, ceftriaxone 4 th gen: cefepime.

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Cephalosporin Resist ant Escherichia coli

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  1. Dr.T.V.Rao MD Cephalosporin ResistantEscherichia coli Dr.T.V.Rao MD

  2. Penicillins Ampicillin Amoxicillin Piperacillin Cephalosporins (generations) 1st gen: cephalothin 2nd gen (Cephamycins): cefoxitin, cefotetan 3rd gen: ceftazidime, cefotaxime, ceftriaxone 4th gen: cefepime Dr.T.V.Rao MD Beta-lactam antibiotics

  3. Definition of beta lactamases • Beta lactamases are enzymes produced by some gram-positive and gram-negative bacteria that hydrolyze beta lactam antibiotics Dr.T.V.Rao MD

  4. Dr.T.V.Rao MD PENICILLIN BETA LACTAM RING BETA LACTAMASES enzymes that inactivate the beta-lactam ring CEPHALOSPORIN BETA LACTAM RING

  5. Dr.T.V.Rao MD The β-lactam family of antibiotics Penicillin's Cephalosporins Cephamycins Carbapenems Monobactams Benzyl-penicillin Cefoxitin Cephalothin 1st Imipenem Aztreonam Cefamandole 2nd Methicillin Cefotetan Ampicillin Cefuroxime 2nd Ertapenem Cefmetazole Carbenicillin Cefotaxime 3rd Mezlocillin Ceftazidime 3rd Ticarcillin Ceftriaxone 3rd Meropenem Cefepime 4th

  6. Monobactam: aztreonam Carbapenems: Imipenem Meropenem Ertapenem Inhibitors Sulbactam (ampicillin/sulbactam: Unasyn) Tazobactam (piperacillin/tazobactam: Zosyn) Clavulanate (amoxicillin/clavulanate: Augmentin) Dr.T.V.Rao MD Other Beta-lactam antibiotics

  7. Dr.T.V.Rao MD What are 3rd Generation Cephalosporins • Third-generation cephalosporins are broad-spectrum drugs with high intrinsic activity against gram-negative species. The rising resistance to these drugs is worrisome because it could be a proxy for the emergence and spread of Enterobacteriaceae strains producing extended-spectrum β-lactamase

  8. Dr.T.V.Rao MD H H S R-CONH C C CH3 C N CH3 O COOH -Lactamase Activity -lactam Enzyme-Ser-OH

  9. Dr.T.V.Rao MD -Lactamase Activity H H S R-CONH C C CH3 O C N CH3 O H COOH HOH Ser Enzyme

  10. Dr.T.V.Rao MD L      L   L         L    L  L     L    L b-lactamase production  L 

  11. Dr.T.V.Rao MD MODE OF ACTION OF BETA LACTAMS IN GRAM NEGATIVES • SUSCEPTIBLERESISTANT • -Lactam Antibiotic •  • Diffusion through  Porin Blocks Entry • Outer Membrane  Efflux Pump •  • Diffusion through  Beta-Lactamase • Peptidoglycan Hydolyzes Beta-Lactam •  • Penicillin Binding Proteins  Changes in PBP results in  Failure to Bind to -Lactam Cell Death

  12. Dr.T.V.Rao MD • Some beta-lactamases only inactivate a small number of antibiotics e.g. penicillin • Others have extended spectrumto all the penicillin's and cephalosporins e.g. cefuroxime, ceftriaxone (ESBLs) • In addition may also carry resistance to other antibiotics e.g. ciprofloxacin.

  13. Extended-spectrum beta-lactamases (ESBLs) are mutant enzymes with a broader range of activity than their parent molecules They: Hydrolyze 3rd and 4th gen cephalosporins and aztreonam Do not affect Cephamycins (2nd gen ceph) or Carbapenems Remain susceptible to beta-lactamase inhibitors Dr.T.V.Rao MD What it means as ESBLs

  14. Primarily found in E. coli and Klebsiella spp. Differ from their parent TEM or SHV enzymes by only 1-4 amino acids >100 TEM- or SHV-derived beta-lactamases have been described – most are ESBLs Dr.T.V.Rao MD Classical ESBLs

  15. Many described, but less common than classical ESBLs CTX-M Found in multiple genera of Enterobacteriaceae Preferentially hydrolyze cefotaxime U.S., Europe, South America, Japan, Canada OXA Mainly in P. aeruginosa Primarily hydrolyze ceftazidime France, Turkey Dr.T.V.Rao MD Non-classical ESBLs

  16. Dr.T.V.Rao MD ESBLsExtended-spectrum β-lactamases • >180 enzymes described (119 TEM, 45 SHV) • All mutations of older TEM and SHV plasmid-mediated β -lactamases • TEM-3, TEM-4, etc. • SHV-2, SHV-3, etc. • CTX-M-1,2, etc. and Toho-type • OXA-type • PER-1 and 2 • Resistance conferred to extended-spectrum penicillins, 3rd and 4th generation cephalosporins and aztreonam (not imipenem or cephamycins) www.lahey.org/studies/webt.htm

  17. Dr.T.V.Rao MD Extended-Spectrum β-Lactamases • β-lactamases capable of conferring bacterial resistance to • the penicillin's • 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

  18. Dr.T.V.Rao MD Plasmid-Mediated AmpCs • B-lactamases derived from chromosomally encoded clavulanate-resistant AmpC cephalosporinases of Citrobacter, Enterobacter & Morganella spp. • Genes are typically encoded on large plasmids and carry additional resistance genes

  19. Dr.T.V.Rao MD Some premises • Growing resistance to 3-gen cephalosporins • Mostly ESBLs in E. coli & Klebsiella; AmpC in Enterobacter, Citrobacter, Serratia… but not always • Identification of mechanism aids • Epidemiological investigation / control • Treatment choice • Recognition of the exceptional e.g. MBLs

  20. Dr.T.V.Rao MD Resistance in E.coli a global concern • IN 2009, E coli resistance levels to third-generation cephalosporins in the United States compared favourably with those of the rest of the developed world with rates about equal to those in Scandinavian countries (Iceland, Estonia, Norway), and a lower reported resistance than the Netherland

  21. Dr.T.V.Rao MD ESBLs characterization • TEM ESBLs - More than 30 described - TEM-6, TEM-10, TEM-12, and TEM-26 • SHV ESBLs - More than 10 • CTX-M ESBLs • AmpC Derived from chromosomal AmpC genes of gram- negative organisms, such as Citrobacter freundii, Enterobacter cloacae, and Aeromonas spp.

  22. Dr.T.V.Rao MD Detecting ESBL producers • steps: • Screen for resistance with an indicator cephalosporin • Do confirmatory test on those found resistant

  23. Dr.T.V.Rao MD Choice of indicator cephalosporin

  24. Dr.T.V.Rao MD Detection of ESBLs: step 2 • Seek ceph/clav synergy in ceph R isolates • Double disc • Combination disc • Etest

  25. Dr.T.V.Rao MD Combination discs Disc with cephalosporin + clavulanic acid Disc with cephalosporin alone

  26. Dr.T.V.Rao MD

  27. Dr.T.V.Rao MD Etest for ESBLs Cefotaxime Cefotaxime + clavulanate

  28. Dr.T.V.Rao MD ESBL – leading cause of Treatment of Failure • ESBLs are bacterial enzymes that confer resistance to many highly effective antibiotic classes that can go undetected if conventional testing methods are used in the lab, ultimately leading to treatment failure.

  29. Dr.T.V.Rao MD Resistance in Gram-negative bacteria: Enterobacteriaceae. • The emergence and spread of resistance in Enterobacteriaceae are complicating the treatment of serious nosocomial infections and threatening to create species resistant to all currently available agents. Approximately 20% of Klebsiella pneumoniae infections and 31% of Enterobacter spp infections in intensive care units in the United States now involve strains not susceptible to third-generation cephalosporins

  30. Chromosomal, but not inducible Normally expressed at low levels Regulated by a growth rate-dependent attenuation mechanism Can become highly expressed with mutations Amp: S Amox/clav: S Piperacillin: S Pip/tazo: S Cefoxitin: S Ceftazidime: S Ceftriaxone: S Cefepime: S Aztreonam: S Imipenem/meropenem: S Dr.T.V.Rao MD The AmpC of E. coli

  31. Dr.T.V.Rao MD ESBLs vs AmpCs

  32. Dr.T.V.Rao MD 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

  33. ESBL genes are often carried on plasmids that also encode resistance to multiple classes of antimicrobials Aminoglycosides, Fluoroquinolones Trimethoprim /Sulphmethoxazole Treatment experience is largely based on classical ESBL producers Carbapenems ß-lactam/inhibitor combinations Dr.T.V.Rao MD Clinical Significance

  34. Dr.T.V.Rao MD ESBL – K pneumonia • Resistance in K pneumoniae to third-generation cephalosporins is typically caused by the acquisition of plasmids containing genes that encode for extended-spectrum beta-lactamases (ESBLs), and these plasmids often carry other resistance genes as well. ESBL-producing K pneumoniae and Escherichia coli are now relatively common in healthcare settings and often exhibit multidrug resistance

  35. Dr.T.V.Rao MD ESBLs: evolution in detection and reportingUntil 2009: • Search for ESBL production by specific phenotypic testing • - All confirmed ESBL-producers to be reported as RESISTANT to all PENICILLINS, CEPHALOSPORINS and AZTREONAM regardless of MICs

  36. Dr.T.V.Rao MD Enterobacteriaceae: Breakpoints revised

  37. Dr.T.V.Rao MD ESBLs: Evolution in detection and reportingMIC (mg/L)

  38. Dr.T.V.Rao MD Escherichia coli ESBL+ (CTX-M-1), CLSI 2012MIC (mg/L) Ampicillin >128 R Amoxi/Clav 32 R Pip/Tazo 8 S Cephalotin 32 R Cefotaxime 32 R Ceftazidime 1 S Cefepime 8 S Ertapenem 0.12 S Meropenem 0.12 S ESBL positive Amikacin 2 S Gentamicin 16 R Ciprofloxacin >32 R Levofloxacin >32 R

  39. Dr.T.V.Rao MD Bacteria not to test for ESBLs • Acinetobacters • Often S to clavulanate alone • S. maltophilia • +ve result by inhibition of L-2 chromosomal b-lactamase, ubiquitous in the species

  40. Dr.T.V.Rao MD Other beta-lactamases capable of hydrolyzing expanded-spectrum cephalosporins: • Some OXA-type variants (e. g. OXA-14/17) • • AmpC beta-lactamases (e. g. CMY, DHA) • • Serine carbapenemases (e. g. KPC) • • Metallo-beta-lactamases (e. g. IMP, VIM, NDM

  41. Dr.T.V.Rao MD Who are At Risk with ESBL+E.coli • Travellers 5.2 times more likely to be colonised by ESBL+ E. coli • Highest rates of ESBL carriage associated with travels to Africa and Indian subcontinent • All ESBL+ E. coli had CTX-M enzymes (71% CTX-M-15, 26% CTX-M-14)

  42. Dr.T.V.Rao MD • Larger Inoculum Effect  • More vulnerable to hydrolysis of β-lactamase • ESBL-KP + 3rd or 4th generation cephalosporin • How about Cephamycins? Little information

  43. Dr.T.V.Rao MD Role of the Microbiology Lab • “ Each laboratory should have a staff member with the time, interest, and expertise to provide leadership in antibiotic testing and resistance. This person would read relevant publications, network with other laboratories, and evaluate potentially useful tests to detect new forms of resistance before new CLSI-recommended tests become available” • - Ken Thomson, Emerging Infect. Dis., 2001

  44. ESBL producers especially prevalent in ICUs and long term care facilities Becoming more widespread in the community also Have been associated with outbreaks Typically arise in ICU Plasmid transfer between GNRs Organism transfer between patients Control of outbreaks Infection control practice – isolation Restriction of 3rd and 4th generation cephalosporins Antimicrobial cycling Dr.T.V.Rao MD ESBL Epidemiology

  45. Dr.T.V.Rao MD ESBL are Emerging Challenges in Patient Care for Clinicians and Microbiologists • ESBLs: complex evolution since the 1980s (multiple enzymes, High-Risk clones) • Now a very major resistance issue in enterics: globally disseminated, ubiquitous (hospital, LTCFs, community), high rates • Challenge of intestinal carriage (intra/inter institutional dissemination, cross-border transmission) and of extra-human reservoirs • Detection and reporting issues • Treatment issues

  46. Dr.T.V.Rao MD • Programme Created by Dr.T.V.Rao MD for Microbiologists and Health Care Workers email • doctortvrao@gmail.com

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