extended-spectrum beta-lactamase

extended-spectrum beta-lactamase
Name	Extended-spectrum beta-lactamase
EC number	3.5.2.6
CAS number	9073-60-3

extended-spectrum beta-lactamase. Extended-spectrum beta-lactamases are a group of enzymes produced by certain bacteria that confer resistance to a broad range of beta-lactam antibiotics, including penicillins, cephalosporins, and the monobactam aztreonam. These enzymes are a significant evolution of earlier beta-lactamases, such as TEM-1 and SHV-1, through mutations that expand their hydrolytic capabilities. Their emergence represents a major challenge in clinical microbiology and infectious disease management, complicating treatment for common infections.

Overview

The discovery of extended-spectrum beta-lactamases followed the widespread clinical use of third-generation cephalosporins like ceftazidime and cefotaxime in the 1980s. The first variants were identified in strains of Klebsiella pneumoniae isolated from patients in Germany and France. These enzymes are primarily encoded by plasmid-borne genes, which facilitates rapid horizontal gene transfer between different bacterial species within the Enterobacteriaceae family, such as Escherichia coli and Proteus mirabilis. The global dissemination of these resistance determinants is closely monitored by public health agencies like the World Health Organization and the Centers for Disease Control and Prevention.

Classification and types

Extended-spectrum beta-lactamases are primarily classified under the Ambler molecular classification system as Class A beta-lactamases. The most prevalent families are derived from the ancestral TEM-1 and SHV-1 enzymes, with notable variants including CTX-M enzymes, which have become dominant worldwide. Other important types include certain OXA-type enzymes and the less common PER, VEB, and GES families. The Bush-Jacoby-Medeiros functional classification system also groups them based on their substrate profiles and inhibition by clavulanic acid.

Mechanism of action

These enzymes work by hydrolyzing the beta-lactam ring, a core structural component of penicillins, cephalosporins, and aztreonam. The active site contains a critical serine residue that initiates a nucleophilic attack on the carbonyl carbon of the lactam bond. Mutations in genes encoding TEM-1 or SHV-1, often at positions like Gly238Ser or Arg164Ser, alter the enzyme's active site pocket, allowing accommodation and breakdown of the bulkier oximino-cephalosporins. This hydrolysis inactivates the antibiotic before it can bind to its target, the penicillin-binding proteins in the bacterial cell wall.

Epidemiology and clinical significance

The epidemiology of extended-spectrum beta-lactamase-producing organisms is a global concern, with high prevalence reported in hospitals across Asia, Europe, and the Americas. Notable outbreaks have been documented in institutions like the National Institutes of Health Clinical Center. These bacteria are frequent causes of urinary tract infections, bloodstream infections, and pneumonia, leading to increased mortality, hospital length of stay, and healthcare costs. The spread is driven by factors including high antibiotic use in agriculture and human medicine, international travel, and inadequate infection control practices in facilities like long-term care facilities.

Detection and diagnosis

Accurate detection in clinical laboratories is crucial for guiding therapy. Phenotypic methods include the disk diffusion test and broth microdilution, with confirmatory tests like the double-disk synergy test using amoxicillin-clavulanate and third-generation cephalosporins. Automated systems such as VITEK 2 and BD Phoenix also incorporate algorithms for detection. Molecular techniques, including polymerase chain reaction and whole-genome sequencing, are used for identifying specific genes like blaCTX-M and are employed in reference laboratories like those at the Mayo Clinic.

Treatment and prevention

Treatment options are severely limited and often require the use of last-resort agents. Carbapenems, such as meropenem and imipenem, have traditionally been the drugs of choice, but the rise of carbapenem-resistant Enterobacteriaceae complicates this approach. Alternative therapies may include cefepime, piperacillin-tazobactam, ceftolozane-tazobactam, ceftazidime-avibactam, or plazomicin. Prevention relies on robust antimicrobial stewardship programs, strict adherence to contact precautions in healthcare settings, and surveillance initiatives coordinated by bodies like the European Centre for Disease Prevention and Control.

Category:Enzymes Category:Antimicrobial resistance