beta-lactamase

MECHANISM: Beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, monobactams) inhibit transpeptidase (penicillin-binding proteins, PBPs), blocking peptidoglycan cross-linking in the bacterial cell wall, which leads to cell lysis. Beta-lactamases cleave the amide bond of the four-membered beta-lactam ring, so the drug can no longer bind PBPs. In gram-positive bacteria, the enzyme is secreted extracellularly in large amounts. In gram-negative bacteria, it is found in the periplasmic space, where it is strategically positioned beneath the outer membrane.

GENETICS: Genes are often carried on plasmids (transferable by conjugation, transformation, or transduction) or transposons. Plasmid carriage allows rapid spread between species. Some are chromosomal and inducible, for example AmpC in Enterobacter, Citrobacter, Serratia, and Pseudomonas.

KEY CLASSES: - Penicillinase (e.g., staphylococcal, TEM-1 in E. coli): hydrolyzes penicillins. Overcome by penicillinase-resistant penicillins (nafcillin, oxacillin, dicloxacillin) or by adding an inhibitor. - Extended-spectrum beta-lactamases (ESBLs; e.g., TEM, SHV, CTX-M): hydrolyze 3rd-generation cephalosporins and aztreonam. Found in E. coli and Klebsiella. Not active against cephamycins or carbapenems. Treat with carbapenems. ESBLs are inhibited by clavulanate. - AmpC beta-lactamases: chromosomal or plasmid-mediated. Hydrolyze cephalosporins and cephamycins. NOT inhibited by clavulanate. Cefepime or carbapenems are often used for treatment. - Carbapenemases (e.g., KPC, NDM-1, OXA-48, VIM): confer resistance to carbapenems, as in CRE (carbapenem-resistant Enterobacterales). KPC is treated with ceftazidime-avibactam or meropenem-vaborbactam. Metallo-beta-lactamases (NDM, VIM) need zinc and are not inhibited by clavulanate or avibactam.

BETA-LACTAMASE INHIBITORS: Clavulanic acid, sulbactam, and tazobactam are "suicide inhibitors" that bind irreversibly to the enzyme. They have little antibacterial activity on their own. Combinations: amoxicillin-clavulanate (Augmentin), ampicillin-sulbactam (Unasyn), piperacillin-tazobactam (Zosyn), ticarcillin-clavulanate. Newer non-beta-lactam inhibitors include avibactam, vaborbactam, and relebactam.

CLINICALLY HIGH-YIELD ORGANISMS: Staphylococcus aureus (most strains produce penicillinase). Haemophilus influenzae, Moraxella catarrhalis, and Neisseria gonorrhoeae (some strains). Bacteroides fragilis. E. coli, Klebsiella (ESBL). Pseudomonas aeruginosa (AmpC).

BETA-LACTAMASE vs. OTHER RESISTANCE: MRSA resistance is NOT due to beta-lactamase. It results from the mecA gene, which encodes an altered PBP2a with low affinity for beta-lactams. Beta-lactamase inhibitors do not overcome MRSA. Treat with vancomycin, linezolid, daptomycin, or ceftaroline. Other beta-lactam resistance mechanisms include altered PBPs (S. pneumoniae), porin loss or efflux pumps (Pseudomonas), and reduced outer membrane permeability.

CLINICAL PEARLS: - Amoxicillin-clavulanate is used for sinusitis, otitis media failing amoxicillin, animal and human bites (Pasteurella, Eikenella), and mixed aerobic or anaerobic infections. - Clavulanate causes diarrhea and cholestatic hepatitis. - Penicillin allergy involves the beta-lactam structure (hapten formation, type I hypersensitivity) and is unrelated to beta-lactamase production. - Lab detection: nitrocefin (chromogenic cephalosporin) disc test turns red when hydrolyzed. Also called the "cefinase" test. It is used for H. influenzae, N. gonorrhoeae, and Staphylococcus. - Piperacillin-tazobactam has excellent anti-pseudomonal and anaerobic coverage. It has been associated with AKI when combined with vancomycin.