Bacteria have a rigid outer layer, the cell wall. The cell wall maintains the shape and size of the microorganism, which has a high internal osmotic pressure. Injury to the cell wall (eg, by lysozyme) or inhibition of its formation may lead to lysis of the cell. In a hypertonic environment (eg, 20% sucrose), damaged cell wall formation leads to formation of spherical bacterial “protoplasts” from Gram-positive organ isms or “spheroplasts” from Gram-negative organisms; these forms are limited by the fragile cytoplasmic membrane. If such protoplasts or spheroplasts are placed in an environment of ordinary tonicity, they take up fluid rapidly, swell, and may burst. Specimens from patients being treated with cell wall-active antibiotics often show swollen or misshapen bacteria.

The cell wall contains a chemically distinct complex polymer “mucopeptide” (“peptidoglycan”) consisting of polysaccharides and a highly cross-linked polypeptide. The polysaccharides regularly contain the amino sugars N-acetylglucosamine and N-acetylmuramic acid. The latter is found only in bacteria. To the amino sugars are attached short peptide chains. The final rigidity of the cell wall is imparted by cross-linking of the peptide chains (eg, through pentaglycine bonds) as a result of transpeptidation reactions carried out by several enzymes. The peptidoglycan layer is much thicker in the cell wall of Gram-positive than of Gram negative bacteria.

All β-lactam drugs are selective inhibitors of bacterial cell wall synthesis and therefore active against growing bacteria. This inhibition is only one of several different activities of these drugs, but it is the best understood. The initial step in drug action consists of binding of the drug to cell receptors (penicillin-binding proteins [PBPs]). There are at least six different PBPs (molecular weight [MW], 40–120 kilodaltons [kD]), some of which are transpeptidation enzymes. Different receptors have different affinities for a drug, and each may mediate a different effect. For example, attachment of penicillin to one PBP may result chiefly in abnormal elongation of the cell, but attachment to another PBP may lead to a defect in the periphery of the cell wall with resulting cell lysis. PBPs are under chromosomal control, and mutations may alter their number or their affinity for β-lactam drugs.

After a β-lactam drug has attached to one or more receptors, the transpeptidation reaction is inhibited, and peptidoglycan synthesis is blocked. The next step probably involves removal or inactivation of an inhibitor of autolytic enzymes in the cell wall. This activates the lytic enzyme and results in lysis if the environment is isotonic. In a markedly hypertonic environment, the microbes change to protoplasts or spheroplasts, covered only by the fragile cell membrane. In such cells, synthesis of proteins and nucleic acids may continue for some time.

The inhibition of the transpeptidation enzymes by penicillins and cephalosporins may be attributable to a structural similarity of these drugs to acyl-d-alanyl-d-alanine. The transpeptidation reaction involves loss of a d-alanine from the pentapeptide.

The remarkable lack of toxicity of β-lactam drugs to mammalian cells must be attributed to the absence in animal cells of a bacterial type cell wall with its peptidoglycan. The difference in susceptibility of Gram-positive and Gram negative bacteria to various penicillins or cephalosporins probably depends on structural differences in their cell walls (eg, amount of peptidoglycan, presence of receptors and lipids, nature of cross-linking, and activity of autolytic enzymes) that determine penetration, binding, and activity of the drugs.

Resistance to penicillins may be determined by the organism’s production of penicillin-destroying enzymes (β-lactamases). The α-lactamases open the β-lactam ring of penicillins and cephalosporins and abolish their anti microbial activity. β-Lactamases have been described for many species of Gram-positive and Gram-negative bacteria. Some β-lactamases are plasmid mediated (eg, penicillinase of Staphylococcus aureus), and others are chromosomally mediated (eg, many species of Gram-negative bacteria). All of the plasmid-mediated β-lactamases are produced constitutively and have a high propensity to move from one species of bacteria to another (eg, β-lactamase-producing Neisseria gonorrhoeae, Haemophilus influenzae, and enterococci). Chromosomally mediated β-lactamases may be constitutively produced (eg, Bacteroides and Acinetobacter species), or they may be inducible (eg, Enterobacter, Citrobacter, and Pseudomonas species).

There is one group of β-lactamases that is occasionally found in certain species of Gram-negative bacilli such as, Klebsiella pneumoniae. These enzymes are termed extended spectrum α-lactamases (ESBLs) because they confer upon the bacteria the additional ability to hydrolyze the β-lactam rings of cefotaxime, ceftazidime, or aztreonam.

The classification of β-lactamases is complex, based on the genetics, biochemical properties, and substrate affinity for a β-lactamase inhibitor (clavulanic acid) (Table1 has the two major classification systems). Clavulanic acid, sulbactam, and tazobactam are β-lactamase inhibitors that have a high affinity for and irreversibly bind some β-lactamases (eg, penicillinase of S. aureus) but are not hydrolyzed by the β-lactamase. These inhibitors protect simultaneously present hydrolyzable penicillins (eg, ampicillin, amoxicillin, and piperacillin) from destruction. Certain penicillins (eg, cloxacillin) also have a high affinity for β-lactamases.

Table1. Classification of β-Lactamases

Shortly after their first description almost 3 decades ago, the most common ESBLs were of the class A TEM and SHV plasmid-mediated types (see Table 1). Currently throughout much of the world, the CTX-M enzymes have become more prevalent. These enzymes are more active against cefotaxime and ceftriaxone than ceftazidime and seem to be inhibited more readily by tazobactam than the other β-lactamase inhibitors. Of most concern is the emergence of K. pneumoniae carbapenemases (KPC), which are ESBL type enzymes that confer resistance to third- and fourth generation cephalosporins and carbapenems. This resistance mechanism is plasmid mediated and has spread nosocomially among many hospitals throughout the United States and other countries.

Although they were discovered in the mid-1960s, global spread of genes encoding metallo-β-lactamases has facilitated spread of these broad-range, inhibitor-resistant enzymes among many Gram-negative pathogens. This has ushered in an era of widespread dissemination of carbapenem-resistant Enterobacteriaceae possessing the VIM-type (Verona integron-encoded metallo-β-lactamase) and NDM-type (New Delhi metallo-β-lactamase) of these enzymes. VIM type enzymes first appeared in Pseudomonas aeruginosa and Acinetobacter baumannii, but have spread to Enterobacteriaceae. There are more than 20 types, and they are most prevalent in Europe, the Middle East, and Asia. NDM-1 was described first in a K. pneumoniae strain in Sweden from a patient who had traveled to India. In addition to spread to other Enterobacteriaceae, NDM-1 producing A. baumannii have appeared. Because these organisms often contain genes that encode resistance to other classes of antimicrobials, such as fluoroquinolones and aminoglycosides, options for treatment are very limited to agents such colistin. Therefore, such patients are often placed on maximum infection control precautions to prevent spread to other patients within hospital environments.

A troubling concern has been the emergence and global spread of mobilized colistin resistance determinants (mcr). MCR confers resistance to colistin and polymyxin B by reducing the net negative charge of the Lipid A moiety of LPS. First discovered in Southern China in late 2015, Enterobacteraciae harboring plasmids carrying mcr-1 have spread to over 40 countries covering five of seven continents. It is just a matter of time before there will be infections caused by β-lactamase producing Enterobacteraciae that are essentially untreatable.

There are two other types of resistance mechanisms. One is caused by the absence of some PBPs and occurs as a result of chromosomal mutation; the other results from failure of the β-lactam drug to activate the autolytic enzymes in the cell wall. As a result, the organism is inhibited but not killed. Such tolerance has been observed especially with staphylococci and certain streptococci.

Examples of agents acting by inhibition of cell wall syn thesis are β-lactam drugs such as the penicillins, the cephalosporins, the carbapenems; the monobactam aztreonam; glycopeptide antibiotics such as vancomycin and teicoplanin; and lipoglycopeptides such as oritavancin, telavancin, and dalbavancin. Several other drugs, including fosfomycin, bacitracin, cycloserine, and novobiocin, inhibit early steps in the biosynthesis of the peptidoglycan. Because the early stages of synthesis take place inside the cytoplasmic membrane, these drugs must penetrate the membrane to be effective.

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