β-Lactam antibiotics, named after the active chemical component of the drug, include the 6-membered ring-structured penicillins, monobactams, and carbapenems; and the 7-membered ring-structured cephalosporins and cephamycins. In addition to their chemical structure, the major difference between these 2 subclasses of β-lactams is their susceptibility to β-lactamase destruction, with the cephalosporins, in general, being more resistant.

Antimicrobial Activity

Mode of Action

β-Lactams impair the development of bacterial cell walls by interfering with transpeptidase enzymes responsible for the formation of the cross-links between peptidoglycan strands. These enzymes are associated with a group of proteins in both gram-positive and gram-negative bacteria called the penicillin-binding proteins (PBP). During bacterial cell growth, while the peptidoglycan structure is being formed, autolysins continuously cleave the lattice to provide acceptor sites for new strands. Normal bacterial growth depends on a balance between cell wall deposition and autolysis. Interaction between a β-lactam and a PBP inhibits synthetic enzymes, causing defective cell walls to be formed and subsequent abnormal elongation of cells, formation of spheroplasts, or osmotic lysis. The effect of the β-lactams when present in sufficient concentrations is generally bactericidal. At concentrations lower than minimal inhibitory concentrations (MIC), β-lactam antibiotics do exert residual effects on bacterial structure and function that, in turn, promote phagocytosis.

β-Lactam antibiotics have little influence on formed bacterial cell walls, and even susceptible organisms must be actively multiplying or growing. β-Lactams are most active during the logarithmic phase of bacterial growth. They also tend to be somewhat more active in a slightly acidic environment (pH 5.5–6.5), perhaps because of enhanced membrane penetration.

Efficacy of the β-lactams is related to the time that plasma or tissue drug concentrations exceed the MIC of the infecting organism. Generally, concentrations should remain above the MIC for about ¼ (carbapenems) to ⅔ of the dosing interval.

Bacterial Resistance

Only microorganisms that have cell walls are susceptible to the action of β-lactam antibiotics. Within this range of bacteria, resistance to β-lactams is well recognized and takes a number of forms.

Permeability Barrier

In gram-positive organisms, capsular materials may hinder access to the cytoplasmic membrane, but this rarely limits the diffusion of the cell-wall inhibitors. Gram-negative bacteria have a restricting sieving mechanism (porins) in their outer membranes (external to the cell wall), which reduces the penetration of several types of antibiotics. Different species of gram-negative bacteria exhibit varying permeability barriers to β-lactam antibiotics, and these impair access of the antibiotics to the membrane-associated binding proteins. For example, the permeability barrier of Haemophilus influenzae is readily crossed by β-lactam antibiotics, Escherichia coli presents a greater obstacle to these agents, and the outer membranes of Pseudomonas aeruginosa are penetrated with great difficulty by most β-lactam compounds. Penicillins, aminopenicillins, first- and second-generation cephalosporins, and selected other β-lactams cannot penetrate the outer membrane of Pseudomonas aeruginosa. Further, porins are frequently associated with efflux proteins that effectively remove drug which has successfully penetrated the lipopolysaccharide covering of gram-negative organisms.

The chemical nature of β-lactams (penicillins, cephalosporins, and the β-lactamase inhibitors), as well as their concentration gradients, also greatly influence their penetration of bacteria to their targets at the surface of the cytoplasmic membrane, giving rise to the differences between anti-bacterial spectra of the various classes of penicillin. β-Lactams are often used in combination with other antibiotics that disrupt the integrity of the membranes and thereby facilitate access by β-lactams. The genetic loci controlling permeability generally have been considered to be chromosomally located, but they also may be plasmid-specified genes.

Specific Bacterial Binding Proteins

Resistance to β-lactam antimicrobial agents can be acquired by alterations in the PBP targets of these drugs. A loss or decrease in affinity of crucial PBP can lead to a significant increase in penicillin resistance. Changes in PBP-2 of Staphylococcus sp render the organism resistant to all β-lactams.

L-Forms of Bacteria

A phenotypic form of resistance can occur when spheroplasts (incomplete cell wall) or protoplasts (absence of cell wall) are present. These so-called “L-forms” must be present in a hyperosmotic environment (eg, the renal medulla) to survive; otherwise, they will lyse. The clinical significance of this form of resistance is unclear.

Quiescent Organisms

In any bacterial population, a few organisms will always be quiescent. Because the β-lactams are active only against growing bacteria, the static organisms are unaffected and may persist. These “persisters” may then develop normally after the antibiotic is removed.

Tolerance

Some bacterial isolates, when treated with inhibitors of cell-wall synthesis, undergo inhibition of growth but not lysis at usual concentrations. These “tolerant” organisms are defective in their production or use of autolytic enzymes and can survive exposure to β-lactam antibiotics. Clinically, relapses and failures in serious infections due to tolerant organisms may be prevented by the frequently synergistic effect of the aminoglycosides with β-lactam antibiotics.

β-Lactamase (Penicillinase) Resistance

The most important mechanism of bacterial resistance to penicillins and the other β-lactam antibiotics is enzymatic inactivation. There are at least 6 major types of β-lactamase enzymes that can cleave the β-lactam ring, rendering the drug inactive. β-Lactamases are produced by gram-positive organisms (Staphylococcus aureus, S epidermidis), and 5 of the 6 types of β-lactamases are produced by gram-negative organisms. Some of these enzymes are active exclusively against penicillins, others are principally active against cephalosporins, and several types hydrolyze both equally. The type and concentration of β-lactamases are also bacterial species-specific. Gram-positive β-lactamases generally are excreted into the external environment as exoenzymes, produced in large quantity, plasmid-mediated (single determinant), usually inducible (rarely constitutive), unable to initiate self-transmission (rely principally on transduction), and active primarily against penicillins. Staphylococcal strains are the main gram-positive bacteria in which β-lactamase resistance develops, often very quickly. Gram-negative β-lactamases generally are heterogenous (wide range), retained within the periplasmic space, produced in small quantity, often constitutive (less often inducible), able to initiate self-transmission (conjugation mechanisms), and active against both penicillins and cephalosporins. Gram-negative bacteria capable of resistance as a result of β-lactamase production include Escherichia, Haemophilus, Klebsiella, Pasteurella, Proteus, Pseudomonas, and Salmonella spp; resistance may take longer to develop in some of these strains. The development of newer extended-spectrum cephalosporins resistant to β-lactamase, destruction has been associated with the recent emergence of extended β-lactamases, particularly by E coli, Klebsiella, and Proteus. These enzymes may not be produced during routine culture and susceptibility testing, causing the isolate to appear susceptible.

β-Lactamase-induced resistance is widespread. Of veterinary isolates, ~50–60% of Staphylococcus spp strains and 40–70% of E coli strains are resistant to penicillin G; 15–40% of E coli strains from companion and farm animals may also be resistant to ampicillin.

Last full review/revision March 2012 by Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP