Β-lactamases: Difference between revisions

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Β-lactamases
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== Definition ==
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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)
  
  +
**See also [[extended-spectrum β-lactamases]] and [[carbapenemases]]
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* Most common with ''Escherichia coli'' and ''Klebsiella''
  
   
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== Classification ==
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===Ambler Classification===
   
  +
*Classification based on amino acid sequences rather than function
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* Class A
  
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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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* Class C
  
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** Inducible AmpC gene present in the genome
  
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** Common in ''Citrobacter'', ''Serratia'', and ''Enterobacter''
  
   
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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
  
   
  +
*'''Amber classes A, B, and C''' are the serine β-lactamases
  +
*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.
  +
**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
  +
  +
===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<ref>Cantón R, Morosini MI, de la Maza OM, de la Pedrosa EG. IRT and CMT beta-lactamases and inhibitor resistance. Clin Microbiol Infect. 2008 Jan;14 Suppl 1:53-62. doi: [https://doi.org/10.1111/j.1469-0691.2007.01849.x 10.1111/j.1469-0691.2007.01849.x]. PMID: [https://pubmed.ncbi.nlm.nih.gov/18154528/ 18154528].</ref>
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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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|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
  +
|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
  +
|R
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|I/R
  +
|R
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|I/R
  +
|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
  +
|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
  +
|I/R
  +
|S
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|I/R
  +
|-
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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
  +
|R
  +
|-
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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
  +
|R
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|I/R
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|S/I/R
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|}
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  +
==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: [https://doi.org/10.1128/AAC.01009-09 10.1128/AAC.01009-09]
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{{DISPLAYTITLE:β-lactamases}}
 
[[Category:Antibiotics]]
  
[[Category:Antibiotics]]

Latest revision as of 06:04, 29 September 2022

Background

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
  • 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

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-lactamase[1] 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

Further Reading

  • Updated Functional Classification of β-Lactamases. Antimicrob Agents Chemother. 2010;54(3):969-976. doi: 10.1128/AAC.01009-09
  1. ↑ Cantón R, Morosini MI, de la Maza OM, de la Pedrosa EG. IRT and CMT beta-lactamases and inhibitor resistance. Clin Microbiol Infect. 2008 Jan;14 Suppl 1:53-62. doi: 10.1111/j.1469-0691.2007.01849.x. PMID: 18154528.
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