Β-lactamases: Difference between revisions
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Β-lactamases
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==Background== |
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*Includes a spectrum of molecules that hydrolyze [[β-lactams]], from penicillins to carbapenems |
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* Bacteria containing a plasmid that codes for an extended-spectrum beta-lactamase (ESBL) |
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**See also [[extended-spectrum β-lactamases]] and [[carbapenemases]] |
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* Most common with ''[[Escherichia coli]]'' and ''[[Klebsiella]]'' |
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== Classification |
===Ambler Classification=== |
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*Classification based on amino acid sequences rather than function |
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* Classes A, B, and C: serine β-lactamases |
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** '''Class A''': inhibited by clavulanic acid or tazobactam |
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*** Constitutively expressed plasmid |
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*** Most common ESBL in Gram-negative bacteria |
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*** Resistance to 2nd and 3rd generation cephalosporins |
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*** Common in ''[[E. coli]]'', ''[[Klebsiella]]'', and ''[[Proteus]]'' spp. |
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*** Examples include: |
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**** Penicillinases: TEM-1 (common in GNBs), SHV-1 |
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**** ESBLs: CTX-M, TEM-3 |
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**** Carbapenemases: ''K. pneumoniae'' carbapenemase (KPC) |
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** '''Class C''': not inhibited by clavulanic acid or EDTA, resistant to cefoxitin, inhibited by clox in vitro |
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*** AmpC = chromosomal |
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*** Often an inducible AmpC gene present in the genome |
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*** Common in ''[[Citrobacter]]'', ''[[Serratia]]'', and ''[[Enterobacter]]'' |
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** '''Class D''': not inhibited by EDTA, variably inhibited by clavulanic acid; hard to identify |
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*** Common in ''[[Pseudomonas]]'' |
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*** Difficult to detect with routine screening |
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*** Examples include: |
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**** ESBLs: OXA-11 |
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**** Carbapenemases: OXA-23, OXA-48 |
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* '''Class B''': metallo-β-lactamase, inhibited by EDTA, not inhibited by clavulanic acid |
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** Examples include: |
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*** Carbapenemases: |
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**** New Delhi metallo-beta-lactamase (NDM-1) |
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**** IMP |
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*** NDM |
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{| class="wikitable" |
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== Management == |
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!Class |
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!Binding Site |
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!Examples |
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!Inhibitors |
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|- |
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|A |
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|serine |
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|TEM, SHV, KPC, CTX-M, GES |
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|clavulanic acid, tazobactam, avibactam, vaborbactam, relebactam |
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|- |
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|B |
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|metallo |
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|VIM, NDM, IMP |
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| |
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|- |
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|C |
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|serine |
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|AmpC, P99 |
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|avibactam, vaborbactam, relebactam |
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|- |
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|D |
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|serine |
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|OXA (oxacillinase) enzymes |
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|avibactam (OXA-48), ±clavulanic aciid |
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|} |
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====Serine β-lactamases==== |
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* Antibiotic therapy tailored to the resistance pattern |
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* Carbapenems, aminoglycosides, fluoroquinolones, and Septra typically work well |
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*'''Amber classes A, B, and C''' are the serine β-lactamases |
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*Contain a serine residue at the active site |
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*'''Class A''': inhibited by [[clavulanic acid]] or [[tazobactam]] |
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**Constitutively expressed plasmid |
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**Most common ESBL in [[Gram-negative bacteria]] |
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**Resistance to 2nd and 3rd generation [[cephalosporins]] |
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**Common in ''[[E. coli]]'', ''[[Klebsiella]]'', and ''[[Proteus]]'' spp. |
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**Examples include: |
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***Penicillinases: TEM-1 (common in GNBs), SHV-1 |
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***ESBLs: CTX-M, TEM-3 |
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***Carbapenemases: ''K. pneumoniae'' carbapenemase (KPC) |
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*'''Class C''': not inhibited by [[clavulanic acid]] or EDTA, resistant to [[cefoxitin]], inhibited by [[cloxicillin]] in vitro |
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**AmpC = chromosomal |
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**Often an inducible AmpC gene present in the genome |
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**Common in ''[[Citrobacter]]'', ''[[Serratia]]'', and ''[[Enterobacter]]'' |
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*'''Class D''': not inhibited by EDTA, variably inhibited by [[clavulanic acid]]; hard to identify |
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**Common in ''[[Pseudomonas]]'' |
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**Difficult to detect with routine screening |
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**Examples include: |
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***ESBLs: OXA-11 |
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***Carbapenemases: OXA-23, OXA-48 |
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====Metallo-β-lactamases==== |
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*'''Ambler Class B''' are the metallo-β-lactamases |
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*Contain a zinc ion at the active site |
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*Inhibited by EDTA, not inhibited by [[clavulanic acid]] |
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*Examples include: |
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**Carbapenemases: |
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***New Delhi metallo-beta-lactamase (NDM-1) |
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***Imipenemases (IMP) |
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***Verona integron-encoded metallo-β-lactamases (VIM) |
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***L1 β-lactamase, present in the [[Stenotrophomonas maltophilia]] chromosome |
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===Bush-Jacoby Classification=== |
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{| class="wikitable" |
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! rowspan="2" |Group |
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! rowspan="2" |Ambler |
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! rowspan="2" |Substrates |
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! colspan="2" |Inhibitors |
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! rowspan="2" |Definition |
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! rowspan="2" |Examples |
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|- |
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!CA/TZB |
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!EDTA |
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|- |
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! colspan="7" |Group 1: Cephalosporinases |
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|- |
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|1 |
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| rowspan="2" |C |
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|[[cephalosporins]] |
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|— |
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|— |
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|hydrolyzes cephalosporins better than benzylpenicillin, and hydrolyzes cephamycins |
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|''E. coli'' AmpC, P99, ACT-1, CMY-2, FOX-1, MIR-1 |
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|- |
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| |
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|[[cephalosporins]] |
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|— |
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|— |
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|increased hydrolysis of ceftazidime and other oxyimino-β-lactams |
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|GC1, CMY-37 |
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|- |
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! colspan="7" |Group 2: β-Lactamases |
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|- |
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|2a |
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| rowspan="7" |A |
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|[[penicillins]] |
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|yes |
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|— |
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|hydrolyzes benzylpenicillin better than cephalosporins |
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|PC1 |
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|- |
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|2b |
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|[[penicillins]] and early [[cephalosporins]] |
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|yes |
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|— |
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|hydrolyzes benzylpenicillin similar to cephalosporins |
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|TEM-1, TEM-2, SHV-1 |
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|- |
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|2be |
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|extended-spectrum [[cephalosporins]], [[monobactams]] |
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|yes |
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|— |
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|increased hydrolysis of oxyimino-β-lactams (third-generation plus monobactams) |
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|TEM-3, SHV-2, CTX-M-15, PER-1, VEB-1 |
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|- |
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|2br |
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|[[penicillins]] |
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|— |
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|— |
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|resistance to clavulanic acid, sulbactam, and tazobactam |
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|TEM-30, SHV-10 |
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|- |
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|2ber |
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|extended-spectrum [[cephalosporins]], [[monobactams]] |
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|— |
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|— |
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|increased hydrolysis of oxyimino-β-lactams plus resistance to clavulanic acid, sulbactam, and tazobactam |
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|TEM-50 |
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|- |
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|2c |
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|[[carbenicillin]] |
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|yes |
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|— |
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|increased hydrolysis of carbenicillin |
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|PSE-1, CARB-3 |
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|- |
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|2ce |
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|[[carbenicillin]], [[cefepime]] |
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|yes |
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|— |
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|increased hydrolysis of carbenicillin, cefepime, and cefpirome |
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|RTG-4 |
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|- |
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|2d |
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| rowspan="3" |D |
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|[[cloxacillin]] |
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|variable |
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|— |
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|increased hydrolysis of cloxacillin or oxacillin |
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|OXA-1, OXA-10 |
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|- |
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|2de |
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|extended-spectrum [[cephalosporins]] |
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|variable |
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|— |
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|hydrolyzes cloxacillin or oxacillin and oxyimino-β-lactams |
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|OXA-11, OXA-15 |
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|- |
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|2df |
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|[[carbapenems]] |
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|variable |
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|— |
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|hydrolyzes cloxacillin or oxacillin and carbapenems |
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|OXA-23, OXA-48 |
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|- |
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|2e |
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| rowspan="2" |A |
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|extended-spectrum [[cephalosporins]] |
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|yes |
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|— |
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|hydrolyzes cephalosporins, and inhibited by clavulanic acid but not aztreonem |
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|CepA |
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|- |
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|2f |
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|[[carbapenems]] |
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|variable |
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|— |
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|increased hydrolysis of carbapenems, oxyimino-β-lactams, cephamycins |
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|KPC-2, IMI-1, SME-1 |
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|- |
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! colspan="7" |Group 3: Carbapenemases |
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|- |
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|3a |
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| rowspan="2" |B |
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|[[carbapenems]] |
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|— |
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|yes |
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|broad-spectrum hydrolysis including carbapenems but not monobactams |
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|IMP-1, VIM-1, CcrA, IND-1, L1, CAU-1, GOB-1, FEZ-1 |
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|- |
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|3b |
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|[[carbapenems]] |
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|— |
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|yes |
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|preferential hydrolysis of carbapenems |
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|CphA, Sfh-1 |
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|} |
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===Epidemiology=== |
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*The most common β-lactamase is TEM-1 |
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*The most common carbapenemases in the US are KPCs, followed by NDM and OXA-48-like carbapenemases |
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== Common β-Lactamases == |
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{| class="wikitable" |
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!β-lactamase[[CiteRef::cantón2008ir]] |
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!AMX |
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!AMC |
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!TIC |
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!TIM |
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!PIP |
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!TZP |
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!CFZ |
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!FOX |
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!CRO |
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|- |
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|TEM-1 |
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|R |
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|S |
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|R |
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|S |
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|I/R |
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|S |
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|S/I/R |
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|S |
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|S |
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|- |
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|TEM-1 hyperproduction |
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|R |
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|I/R |
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|R |
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|I/R |
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|R |
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|S/I/R |
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|I/R |
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|S |
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|S |
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|- |
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|OXA-1 |
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|R |
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|I/R |
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|R |
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|I/R |
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|R |
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|I/R |
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|R |
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|S |
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|S |
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|- |
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|IRT type |
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|R |
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|I/R |
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|I/R |
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|I/R |
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|S/I/R |
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|S/I/R |
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|S |
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|S |
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|S |
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|- |
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|CMT type |
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|R |
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|R |
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|R |
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|I/R |
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|R |
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|I/R |
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|I/R |
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|S |
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|I/R |
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|- |
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|ESBL type |
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|R |
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|S/I |
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|R |
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|S |
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|I/R |
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|S/I |
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|R |
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|S |
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|R |
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|- |
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|[[AmpC β-lactamase|AmpC hyperproduction]] |
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|R |
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|R |
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|I/R |
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|I/R |
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|I/R |
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|I/R |
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|R |
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|I/R |
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|S/I/R |
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|} |
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==Management== |
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*Antibiotic therapy tailored to the resistance pattern |
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*[[Carbapenems]], [[aminoglycosides]], [[fluoroquinolones]], and [[TMP-SMX]] typically work well |
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*See also [[Carbapenem-resistant organisms]] |
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==Further Reading== |
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*Updated Functional Classification of β-Lactamases. ''Antimicrob Agents Chemother''. 2010;54(3):969-976. doi: [https://doi.org/10.1128/AAC.01009-09 10.1128/AAC.01009-09] |
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{{DISPLAYTITLE:β-lactamases}} |
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[[Category:Antibiotics]] |
[[Category:Antibiotics]] |
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Latest revision as of 17:46, 19 September 2024
Background
- Includes a spectrum of molecules that hydrolyze β-lactams, from penicillins to carbapenems
- See also extended-spectrum β-lactamases and carbapenemases
Ambler Classification
- Classification based on amino acid sequences rather than function
| Class | Binding Site | Examples | Inhibitors |
|---|---|---|---|
| A | serine | TEM, SHV, KPC, CTX-M, GES | clavulanic acid, tazobactam, avibactam, vaborbactam, relebactam |
| B | metallo | VIM, NDM, IMP | |
| C | serine | AmpC, P99 | avibactam, vaborbactam, relebactam |
| D | serine | OXA (oxacillinase) enzymes | avibactam (OXA-48), ±clavulanic aciid |
Serine β-lactamases
- Amber classes A, B, and C are the serine β-lactamases
- Contain a serine residue at the active site
- Class A: inhibited by clavulanic acid or tazobactam
- Constitutively expressed plasmid
- Most common ESBL in Gram-negative bacteria
- Resistance to 2nd and 3rd generation cephalosporins
- Common in E. coli, Klebsiella, and Proteus spp.
- Examples include:
- Penicillinases: TEM-1 (common in GNBs), SHV-1
- ESBLs: CTX-M, TEM-3
- Carbapenemases: K. pneumoniae carbapenemase (KPC)
- Class C: not inhibited by clavulanic acid or EDTA, resistant to cefoxitin, inhibited by cloxicillin in vitro
- AmpC = chromosomal
- Often an inducible AmpC gene present in the genome
- Common in Citrobacter, Serratia, and Enterobacter
- Class D: not inhibited by EDTA, variably inhibited by clavulanic acid; hard to identify
- Common in Pseudomonas
- Difficult to detect with routine screening
- Examples include:
- ESBLs: OXA-11
- Carbapenemases: OXA-23, OXA-48
Metallo-β-lactamases
- Ambler Class B are the metallo-β-lactamases
- Contain a zinc ion at the active site
- Inhibited by EDTA, not inhibited by clavulanic acid
- Examples include:
- Carbapenemases:
- New Delhi metallo-beta-lactamase (NDM-1)
- Imipenemases (IMP)
- Verona integron-encoded metallo-β-lactamases (VIM)
- L1 β-lactamase, present in the Stenotrophomonas maltophilia chromosome
- Carbapenemases:
Bush-Jacoby Classification
| Group | Ambler | Substrates | Inhibitors | Definition | Examples | |
|---|---|---|---|---|---|---|
| CA/TZB | EDTA | |||||
| Group 1: Cephalosporinases | ||||||
| 1 | C | cephalosporins | — | — | hydrolyzes cephalosporins better than benzylpenicillin, and hydrolyzes cephamycins | E. coli AmpC, P99, ACT-1, CMY-2, FOX-1, MIR-1 |
| cephalosporins | — | — | increased hydrolysis of ceftazidime and other oxyimino-β-lactams | GC1, CMY-37 | ||
| Group 2: β-Lactamases | ||||||
| 2a | A | penicillins | yes | — | hydrolyzes benzylpenicillin better than cephalosporins | PC1 |
| 2b | penicillins and early cephalosporins | yes | — | hydrolyzes benzylpenicillin similar to cephalosporins | TEM-1, TEM-2, SHV-1 | |
| 2be | extended-spectrum cephalosporins, monobactams | yes | — | increased hydrolysis of oxyimino-β-lactams (third-generation plus monobactams) | TEM-3, SHV-2, CTX-M-15, PER-1, VEB-1 | |
| 2br | penicillins | — | — | resistance to clavulanic acid, sulbactam, and tazobactam | TEM-30, SHV-10 | |
| 2ber | extended-spectrum cephalosporins, monobactams | — | — | increased hydrolysis of oxyimino-β-lactams plus resistance to clavulanic acid, sulbactam, and tazobactam | TEM-50 | |
| 2c | carbenicillin | yes | — | increased hydrolysis of carbenicillin | PSE-1, CARB-3 | |
| 2ce | carbenicillin, cefepime | yes | — | increased hydrolysis of carbenicillin, cefepime, and cefpirome | RTG-4 | |
| 2d | D | cloxacillin | variable | — | increased hydrolysis of cloxacillin or oxacillin | OXA-1, OXA-10 |
| 2de | extended-spectrum cephalosporins | variable | — | hydrolyzes cloxacillin or oxacillin and oxyimino-β-lactams | OXA-11, OXA-15 | |
| 2df | carbapenems | variable | — | hydrolyzes cloxacillin or oxacillin and carbapenems | OXA-23, OXA-48 | |
| 2e | A | extended-spectrum cephalosporins | yes | — | hydrolyzes cephalosporins, and inhibited by clavulanic acid but not aztreonem | CepA |
| 2f | carbapenems | variable | — | increased hydrolysis of carbapenems, oxyimino-β-lactams, cephamycins | KPC-2, IMI-1, SME-1 | |
| Group 3: Carbapenemases | ||||||
| 3a | B | carbapenems | — | yes | broad-spectrum hydrolysis including carbapenems but not monobactams | IMP-1, VIM-1, CcrA, IND-1, L1, CAU-1, GOB-1, FEZ-1 |
| 3b | carbapenems | — | yes | preferential hydrolysis of carbapenems | CphA, Sfh-1 | |
Epidemiology
- The most common β-lactamase is TEM-1
- The most common carbapenemases in the US are KPCs, followed by NDM and OXA-48-like carbapenemases
Common β-Lactamases
| β-lactamase1 | AMX | AMC | TIC | TIM | PIP | TZP | CFZ | FOX | CRO |
|---|---|---|---|---|---|---|---|---|---|
| TEM-1 | R | S | R | S | I/R | S | S/I/R | S | S |
| TEM-1 hyperproduction | R | I/R | R | I/R | R | S/I/R | I/R | S | S |
| OXA-1 | R | I/R | R | I/R | R | I/R | R | S | S |
| IRT type | R | I/R | I/R | I/R | S/I/R | S/I/R | S | S | S |
| CMT type | R | R | R | I/R | R | I/R | I/R | S | I/R |
| ESBL type | R | S/I | R | S | I/R | S/I | R | S | R |
| AmpC hyperproduction | R | R | I/R | I/R | I/R | I/R | R | I/R | S/I/R |
Management
- Antibiotic therapy tailored to the resistance pattern
- Carbapenems, aminoglycosides, fluoroquinolones, and TMP-SMX typically work well
- See also Carbapenem-resistant organisms
Further Reading
- Updated Functional Classification of β-Lactamases. Antimicrob Agents Chemother. 2010;54(3):969-976. doi: 10.1128/AAC.01009-09
References
- ^ R. Cantón, M.I. Morosini, O. Martin, S. de la Maza, E. Gomez G. de la Pedrosa. IRT and CMT β-lactamases and inhibitor resistance. Clinical Microbiology and Infection. 2008;14:53-62. doi:10.1111/j.1469-0691.2007.01849.x.
