Β-lactamases: Difference between revisions

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Β-lactamases
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==Background==
= Extended-spectrum beta-lactamase (ESBL) =


*Includes a spectrum of molecules that hydrolyze [[β-lactams]], from penicillins to carbapenems
== Definition ==
**See also [[extended-spectrum β-lactamases]] and [[carbapenemases]]


===Ambler Classification===
* Bacteria containing a plasmid that codes for an extended-spectrum beta-lactamase (ESBL)
* Most common with ''Escherichia coli'' and ''Klebsiella''


== Classification ==
*Classification based on amino acid sequences rather than function


{| class="wikitable"
* Class A
!Class
** Constitutively expressed plasmid
!Binding Site
** Most common ESBL in Gram-negative bacteria
!Examples
** Resistance to 2nd and 3rd generation cephalosporins
!Inhibitors
** Common in ''E. coli'', ''Klebsiella'', and ''Proteus'' spp.
|-
* Class C
|A
** Inducible AmpC gene present in the genome
|serine
** Common in ''Citrobacter'', ''Serratia'', and ''Enterobacter''
|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====
== Management ==


*'''Amber classes A, B, and C''' are the serine β-lactamases
* Antibiotic therapy tailored to the resistance pattern
*Contain a serine residue at the active site
* Carbapenems, aminoglycosides, fluoroquinolones, and Septra typically work well
*'''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

===Bush-Jacoby Classification===
{| class="wikitable"
! rowspan="2" |Group
! rowspan="2" |Ambler
! rowspan="2" |Substrates
! colspan="2" |Inhibitors
! rowspan="2" |Definition
! rowspan="2" |Examples
|-
!CA/TZB
!EDTA
|-
! colspan="7" |Group 1: Cephalosporinases
|-
|1
| rowspan="2" |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
|-
! colspan="7" |Group 2: β-Lactamases
|-
|2a
| rowspan="7" |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
| rowspan="3" |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
| rowspan="2" |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
|-
! colspan="7" |Group 3: Carbapenemases
|-
|3a
| rowspan="2" |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 ==
{| class="wikitable"
!β-lactamase[[CiteRef::cantón2008ir]]
!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 β-lactamase|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: [https://doi.org/10.1128/AAC.01009-09 10.1128/AAC.01009-09]
{{DISPLAYTITLE:β-lactamases}}
[[Category:Antibiotics]]

Latest revision as of 17:46, 19 September 2024

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-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

Further Reading

  • Updated Functional Classification of β-Lactamases. Antimicrob Agents Chemother. 2010;54(3):969-976. doi: 10.1128/AAC.01009-09

References

  1. ^  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.

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