The new β lactamases


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  • Cephamycins : Cephalosporins with a 7α-methoxy side chain that blocks hydrolysis by Classes A n D β, cefotetan n cefmetazoleOxyimino-β-lactams : β-lactams with an oxyimino side chain designed to block the actions of β-lactamases. Eg. IIIrd gen. cephalosporins (cefotaxime, ceftriaxone, ceftazidime) and IVth gen. cephalosporins (cefepime, cefpodoxime)
  • Classes A n D were generally seen in E. coli and other Enterobacteriaceae while classes B n C were confined to a particular bacterial species.
  • Eg. Of β-lactamase inhibitors : Clavulanic acid,tazobactam & sulbactamNitrofurantoin is an alternative for uncomplicated UTIs by ESBL producing organisms
  • TEM were named after the patient Temoneira from whom the Ist clinical isolate was obtained.
  • Diff from class A in hydrolysing cephamycins and not being affected by beta lactamase inhibitors. Spreading plasmid mediated resistance to E. coli, Klebsiella and salmonella
  • Increased gene dosage through gene duplication or carriage on multicopy plasmids. Increased promoter activity through mutations and insertion sequence substitution. In Klebsiella the above mentioned is the mode of development of resistance to cefepime in TEM or SHV type ESBLs or imipenem resistance through Amp-C betalactamases.
  • The new β lactamases

    1. 1. The New β- Lactamases Neha Sharma
    2. 2. Introduction  Major defense of the Gram negative bacteria against the β- lactam antibiotics  These antibiotics have a common four-atom ring known as a beta-lactam. Hydrolysis of the β-lactam ring & decarboxylation of the intermediate  The lactamase enzyme breaks the β-lactam ring open, deactivating the molecule's antibacterial properties  Co-evolved with the β-lactam antibiotics since they came into clinical use.
    3. 3.  Earlier increased in microbes in which they were uncommon (e.g. Staph. aureus) and then spread to pathogens that had previously lacked them ( e.g. H. influenzae and N. gonorrhea)  Introduction of the newer “resistant” β-lactam antibiotics like cephamycins, oxyimino-cephalosporins, carbepenems & monobactams 20 yrs back, resulted in the emergence of a newer set of ESBLs, AmpC enzymes and carbapenemases.
    4. 4. Classification of β-lactamases Ambler Molecular Classification  AA similarity and 10 structure.  Classes A, C & D have serine residues at their active site.  Class B are metallo-β-lactamases that require Zn & Ca ions for their actions.  Classes A (TEM/SHV) & D (OXA) were plasmid mediated.  Class B & C were chromosomal mediated.
    5. 5. Bush-Jacoby-Medieros Functional Classification  Based on functional similarities i.e. substrate and inhibitor profile.  4 main groups (1 to 4) and multiple subgroups.  More of immediate relevance to clinicians and μbiologists because it considers β-lactamase inhibitors and substrates that are clinically relevant.
    6. 6. Classification
    7. 7. Detection of ESBL Production
    8. 8. Class A β-lactamases  Broad and Expanded spectrum β-lactamases  Include TEM, SHV, CTX-M types commonly.  BES, GES/IBC family, PER, SFO, TLA & VEB are members too.  Hydrolyze all classes of penicillins, Ist, IInd, IIIrd, IVth gen. cephalosporins & monobactams.  Co-resistant to quinolones, aminoglycosides & sulphamethoxazole.
    9. 9.  Cephamycins and carbapenems are not affected them, though the latter are the most consistent in their action.  Inhibited by β-lactamase inhibitors  ESBL producing organisms may lose their outer membrane proteins, not related to β- lactamase production & become resistant to cephamycins too.
    10. 10. TEM type β-lactamases  TEM-1, TEM-2 are broad spectrum against which IIIrd, IVth gen. cephalosporins & monobactams were active.  TEM-10, TEM-12 & TEM-26 are ESBLs, in majority now, active against the above, though rarely accompanied by resistance to inhibitors too.  Useful to follow the spread of individual resistance genes.
    11. 11. SHV Type β-lactamases  SHV = sulphydryl variable  SHV-1 is a broad spectrum β-lactamase similar to TEM-1.  Most commonly found in K.pneumoniae.  Are the most common clinically isolated in Europe and USA.
    12. 12.  Within 15 yrs, SHV-2 were found in every inhabited continent, implying that selection pressure from third-generation cephalosporins in the first decade of their use was responsible.  SHV ESBLs have been detected in a wide range of Enterobacteriaceae & outbreaks of SHV- producing P. aeruginosa & Acinetobacter spp. have now been reported.  SHV-5 and SHV-12 are among the most common.
    13. 13. CTX-M ESBLs  Most common group of ESBLs not belonging to the previous two were termed CTX-M to highlight their greater activity against cefotaxime than cefepime or ceftazidime.  Belying their name, they now hydrolyse ceftazidime more than cefotaxime.  Mainly been found in strains of Salmonella enterica serovar Typhimurium and E. coli.
    14. 14.  Widespread findings of CTX-M-type ESBLs in China and India, is speculated that CTX-M-type ESBLs are now actually the most frequent ESBL type worldwide.  Tazobactam exhibits an almost 10-fold greater inhibitory activity than clavulanic acid against CTX-M-type β-lactamases  CTX-M-15 are the most widespread in India, Middle East, Europe and the USA.
    15. 15. Other Class A ESBLs  Uncommon, mostly in P. aeruginosa & at limited areas.  VEB 1 & 2 in South East Asia.  Others are PER-1, GES-1 & 2, IBC-2, PES-1 and may be found in Enterobacteriaceae too.  BES-1, IBC-1, SFO-1 & TLA-1 found only in Enterobacteriaceae.  Include some carbapenemases as well.
    16. 16. Class B β-lactamases  Also called the Metallo β lactamases.  Are Zn dependant enzymes with a different mechanism of action.  Exhibit resistance to penicillins, cephalosporins, carbapenems and β lactamase inhibitors.  Their hyrdolytic profile doesn’t include Aztreonam.  Types include Plasmid-mediated IMP-type carbapenemases, VIM and NDM-1 (New Delhi metallo-β-lactamase)
    17. 17. NDM-1 (New Delhi metallo-β- lactamase)  Originally described from New Delhi in 2009  widespread in Escherichia coli and Klebsiella pneumoniae from India and Pakistan.  As of mid-2010, NDM-1 carrying bacteria have been introduced to other countries (including the United States and UK)  It’s the so called “super bug” spread due to the large number of tourists travelling from these countries.
    18. 18. Class C β-lactamase  Known as the serine cephalosporinases.  Mainly Amp C plasmid induced enzymes.  Substrates include the penicillins, cephalosporins plus cephamycins and β lactam – β lactamase inhibitor combinations.  Cefepime is poorly hydrlolysed by it.  They are mainly inhibited by cloxacillin, oxacillin and aztreonam.  Responsible for the resistance emerging in Enterobacter cloacae.
    19. 19. Class D serine oxacillinases  Initially found to hydrolyse oxacillin at a slow rate.  Confer resistance to penicillins, cephalosporins, extended spectrum cephalosporins, carbapenems and β lactamase inhibitors.  In vitro sodium chloride and chelating agents like EDTA inhibit some carbapenem hydrolysing oxacillinases.
    20. 20. Carbapenemases  Source of concern because they are active against cephalosporins and carbapenems.  Include class A, B and D β lactamases.  Examples are Plasmid mediated IMP type in enteric Gram negative organisms, Pseudomonas and Acinetobacter species. VIM family of carbapenemases KPC enzymes OXA – type β lactamases
    21. 21. Factors influencing β lactamase expression  Expanded spectrum activity may decrease intrinsic hydrolytic activity like in TEM and SHV which can be compensated for by increased gene dosage or a promoter with increased activity.  Active efflux mechanism as in Pseudomonas allows selective enzymes with limited hydrolytic activity to inactivate the drug.  Decreased expression of OMPs required like in K. pneumoniae allow resistance to develop to specific drugs.
    22. 22. Genetics of β lactamases  PLASMIDS: predominate in ESBLs and hospital outbreaks if unifocal in origin like TEM but may be multifocal too like in SHV and spread world wide.  TRANSPOSONS: TEM – 1 and TEM – 2  CHROMOSOMES: Klebsiella strains producing SHV – 1  INTEGRONS: Genes are incorporated into the genome but have their origin elsewhere. So the reservoir is large with ubiquitous spectrum. Eg. CTX – M, Amp – C type
    23. 23. Risk factors Predisposing to infection by β lactamase producing organisms  Diabetes mellitus  Previous antimicrobial exposure (quinolones, third generation cephalosporins, penicillin)  Previous hospital admissions  Older age  Male patients  Prolonged ICU and hospital stay.  Increased severity of illness  Use of a CVC/CAC, urinary catheter, ventilatory assistance
    24. 24. Thank you