Beta-Lactam Antibiotics: Classification and Resistance Mechanisms
Classification of Beta-Lactam Antibiotics
Beta-lactam antibiotics are classified into five major structural classes based on their core ring structure and side chains: penicillins, cephalosporins, carbapenems, monobactams, and penems. 1, 2, 3
Major Structural Classes
Penicillins include natural penicillins (benzylpenicillin), aminopenicillins (amoxicillin, ampicillin), penicillinase-resistant penicillins, and extended-spectrum penicillins (piperacillin) 2, 3
Cephalosporins are organized by generations (first through fifth), with each generation offering broader spectrum activity or enhanced stability against beta-lactamases 1, 2
Carbapenems (imipenem, meropenem, ertapenem) represent the broadest spectrum beta-lactams with exceptional stability against most beta-lactamases 4, 2, 3
Monobactams consist primarily of aztreonam, which has a unique monocyclic structure and activity limited to gram-negative bacteria 4, 1, 3
Penems are structurally related to carbapenems but represent a distinct subclass 1
Mechanism of Action
All beta-lactams share a common mechanism: they inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs) at the active-site serine, forming a covalent complex that prevents peptidoglycan cross-linking 4, 5, 1
The affinity for specific PBPs varies among different beta-lactams, and individual PBPs have distinct affinities for different beta-lactam compounds 4
Beta-Lactamase-Mediated Resistance
Resistance to beta-lactams occurs primarily through bacterial production of beta-lactamase enzymes that hydrolyze the beta-lactam ring, thereby inactivating the antibiotic. 5, 6, 3
Classification of Beta-Lactamases (Ambler Classification)
Class A beta-lactamases are serine-based enzymes that include extended-spectrum beta-lactamases (ESBLs) and carbapenemases such as KPC (Klebsiella pneumoniae carbapenemase), which accounts for 47.4% of meropenem-resistant Enterobacterales globally 7, 8
Class B beta-lactamases are metallo-beta-lactamases (MBLs) including NDM, VIM, and IMP enzymes that require zinc ions for activity and represent 20.6% of carbapenem-resistant isolates 7, 8
Class C beta-lactamases are AmpC enzymes that can be chromosomal or plasmid-mediated and confer resistance to oxiimino-beta-lactams (third-generation cephalosporins) while maintaining susceptibility to carbapenems 7
Class D beta-lactamases are oxacillinases including OXA-48-like enzymes, which account for approximately 19% of carbapenemases in Enterobacterales 7, 8
Critical Mechanistic Differences
KPC and other Class A carbapenemases hydrolyze nearly all beta-lactams including carbapenems but are inhibited by novel beta-lactamase inhibitors such as avibactam and vaborbactam 7, 8, 5
Metallo-beta-lactamases hydrolyze all beta-lactam classes except monobactams (aztreonam) and cannot be inhibited by classic serine beta-lactamase inhibitors like clavulanate, sulbactam, tazobactam, avibactam, or vaborbactam 7, 8, 5
AmpC beta-lactamases confer resistance to oxiimino-beta-lactams and beta-methoxy-beta-lactams but are not inhibited by clavulanate, and organisms with chromosomal AmpC can develop high-level expression through mutation 7
Alterations in Penicillin-Binding Proteins
Streptococcus pneumoniae develops resistance through alterations in PBPs rather than beta-lactamase production, with point mutations reducing affinity for beta-lactams 4
The loss of PBP affinity affects all beta-lactams variably—amoxicillin and extended-spectrum cephalosporins typically have MICs two to four times lower than benzylpenicillin against the same organism 4
Carbapenems (imipenem, meropenem, ertapenem) remain the most active beta-lactams against penicillin-resistant S. pneumoniae (PRSP), followed by cefotaxime, ceftriaxone, cefepime, and cefpirome 4
Additional Resistance Mechanisms
Multiple resistance mechanisms often coexist, including beta-lactamase production, PBP modification, upregulation of efflux pumps, and loss of outer membrane porins 5
Porin mutations combined with efflux pump overexpression can render organisms resistant to beta-lactams even without carbapenemase production 5
Pseudomonas aeruginosa exhibits intrinsic resistance through multiple efflux pumps and can acquire plasmid-mediated metallo-beta-lactamases 7
Clinical Implications of Resistance Patterns
Species-Specific Resistance Profiles
Klebsiella pneumoniae is intrinsically resistant to ampicillin and aminopenicillins and frequently acquires ESBLs conferring resistance to cephalosporins and aztreonam 7
Enterobacter, Citrobacter, and Serratia possess inducible chromosomal AmpC beta-lactamases that can be expressed at high levels through mutation, conferring resistance to third-generation cephalosporins 7
Treatment Selection Based on Resistance Mechanism
For KPC-producing organisms, first-line treatment is ceftazidime/avibactam or meropenem/vaborbactam, as these combinations effectively inhibit Class A carbapenemases 8, 5
For MBL-producing organisms, the required regimen is ceftazidime/avibactam PLUS aztreonam (since aztreonam remains stable against MBLs) or cefiderocol as an alternative 8
For OXA-48 producers, ceftazidime/avibactam is the first-line option, similar to KPC producers 8
Critical Pitfall to Avoid
Never assume all carbapenem-resistant bacteria have the same carbapenemase type—using ceftazidime/avibactam monotherapy for an unrecognized MBL producer will result in treatment failure because avibactam cannot inhibit metallo-beta-lactamases 8, 5
Rapid carbapenemase testing to identify the specific enzyme family (KPC vs MBL vs OXA) is essential because treatment efficacy depends entirely on the carbapenemase type present 7, 8