Extended-spectrum beta-lactamases (ESBLs)

Extended-spectrum beta-lactamases (ESBLs) are enzymes produced by certain bacteria that confer resistance to beta-lactam antibiotics, including penicillins, cephalosporins, and monobactams. ESBL-producing bacteria pose a significant threat to public health as they can cause infections that are difficult to treat due to limited antibiotic options. Here's a detailed overview of ESBLs, including their history, mechanism of resistance, types, and clinical significance:

History:

• ESBLs were first identified in the 1980s and were initially reported in Klebsiella pneumoniae and Escherichia coli.
• The widespread use of broad-spectrum antibiotics, such as third-generation cephalosporins, contributed to the emergence and dissemination of ESBL-producing bacteria.

Mechanism of Resistance:

• ESBLs are enzymes that hydrolyze beta-lactam antibiotics, rendering them ineffective against the bacteria.
• These enzymes are able to cleave the beta-lactam ring of antibiotics, including penicillins, cephalosporins, and monobactams, thus inactivating their antibacterial properties.
• ESBLs are encoded by genes located on plasmids, which are mobile genetic elements that can be transferred between bacteria, facilitating the spread of resistance.

Types of ESBLs:

• Extended-spectrum beta-lactamases (ESBLs) belong to several molecular classes, with the most common ones being TEM (Temoniera), SHV (Sulfhydryl variable), and CTX-M (Cefotaxime-Munich). Each class encompasses various subtypes that differ in their amino acid sequences and substrate specificities. Here's an overview of each type of ESBL:

  1. TEM (Temoniera):

  • History: The TEM enzymes were initially identified in the 1960s in a strain of Escherichia coli (TEM-1).
  • Subtypes: Over 200 TEM variants have been identified, with TEM-1 and TEM-2 being the most prevalent.
  • Substrate Specificity: TEM enzymes are capable of hydrolyzing penicillins and first- and second-generation cephalosporins but have limited activity against third-generation cephalosporins.

  2. SHV (Sulfhydryl variable):

  • History: The SHV enzymes were first described in the 1970s in a strain of Klebsiella pneumoniae (SHV-1).
  • Subtypes: More than 60 SHV variants have been identified, with SHV-1 being the prototype.
  • Substrate Specificity: Similar to TEM enzymes, SHV enzymes exhibit activity against penicillins and first- and second-generation cephalosporins but are less active against third-generation cephalosporins.

  3. CTX-M (Cefotaxime-Munich):

  • History: The CTX-M enzymes were first identified in the late 1980s in a strain of Klebsiella pneumoniae (CTX-M-1).
  • Subtypes: CTX-M enzymes are currently the most prevalent ESBLs worldwide, with over 150 variants identified. Common variants include CTX-M-1, CTX-M-2, CTX-M-9, and CTX-M-15.
  • Substrate Specificity: CTX-M enzymes have a higher affinity for third-generation cephalosporins, particularly cefotaxime, compared to penicillins and first- and second-generation cephalosporins.

  Other ESBLs:

  In addition to TEM, SHV, and CTX-M, there are other less common ESBLs, including:

  • PER (Pseudomonas extended-resistance): Identified primarily in Pseudomonas aeruginosa.
  • VEB (Vietnamese extended-spectrum beta-lactamase): Identified in Enterobacteriaceae and often associated with resistance to ceftazidime.
  • GES (Guiana extended-spectrum): Identified in Enterobacteriaceae and Acinetobacter spp., associated with resistance to extended-spectrum cephalosporins.
  • OXA (Oxacillinase): While predominantly class D beta-lactamases, certain OXA enzymes possess extended-spectrum activity.

Clinical Significance:

• ESBL-producing bacteria are associated with healthcare-associated infections (e.g., urinary tract infections, bloodstream infections, pneumonia) as well as community-acquired infections.
• Treatment of infections caused by ESBL-producing bacteria can be challenging due to limited antibiotic options.
• Carbapenems, such as imipenem, meropenem, and ertapenem, are often considered the antibiotics of choice for treating infections caused by ESBL-producing bacteria.
• The emergence of ESBLs has led to the need for antibiotic stewardship programs and infection control measures to prevent the spread of resistant bacteria in healthcare settings.

Detection and Diagnosis:

• ESBL detection is typically performed using phenotypic methods, such as the double-disc synergy test or the combination disc test, which assesses the susceptibility of bacteria to cephalosporins with and without the addition of beta-lactamase inhibitors.
• Molecular methods, such as polymerase chain reaction (PCR), can also be used to detect specific ESBL genes in bacterial isolates.

In summary, ESBLs represent a major public health concern due to their ability to confer resistance to a broad range of beta-lactam antibiotics. The spread of ESBL-producing bacteria underscores the importance of antibiotic stewardship and infection control measures in healthcare settings to prevent the dissemination of antibiotic resistance.