Penicillins & Cephalosporins—Cleavage by β-lactamases (penicillinases and cephalosporinases) is by far the most important mechanism of resistance. β-Lactamases have different properties. For example, staphylococcal penicillinase is inducible by penicillin and is secreted outside of the bacterium. In contrast, some β-lactamases produced by several gram-negative rods are constitutively produced within the peri plasmic space and are not secreted outside of the bacterium.
The β-lactamases produced by various gram-negative rods have different specificities: some are more active against cephalosporins, while others are active against penicillins. Clavulanic acid, tazobactam, sulbactam, and avibactam are penicillin analogues that bind strongly to β-lactamases and inactivate them. Combinations of these inhibitors and penicillins (e.g., clavulanic acid plus amoxicillin [Augmentin] and piperacillin plus tazobactam [Zosyn]) can overcome resistance mediated by many but not all β-lactamases.
ESBLs inactivate penicillins and first, second, and third generation cephalosporins. They are produced by several enteric bacteria, notably E. coli, Klebsiella, Enterobacter, and Proteus. Carbapenems, such as imipenem, are the drug of choice to treat infections caused by ESBL-producing bacteria. However, some ESBL-producing bacteria have acquired resistance to carbapenems and can be treated only with colistin, a polypeptide antibiotic.
In 2009, a new strain of highly resistant Klebsiella was isolated in India carrying a plasmid that encoded New Delhi metallo-β-lactamase (NDM-1). This plasmid confers high level resistance to many antibiotics including carbapenems and has spread from Klebsiella to other members of the Enterobacteriaceae. Resistant Enterobacteriaceae carrying NDM-1 have emerged in many countries, including the United States.
Resistance to penicillins is also caused by changes in the penicillin-binding proteins (PBPs) in the bacterial cell mem brane. These changes account for both the low- and high-level resistance exhibited by Streptococcus pneumoniae to penicillin G and for the resistance of S. aureus to nafcillin and other β-lactamase–resistant penicillins. The resistance of methicillin resistant S. aureus (MRSA) to almost all β-lactams is attributed to the presence of PBP2a, which is found particularly in MRSA. Note that PBP2a still performs its transpeptidase function but does not bind penicillins. The relative resistance of Enterococcus faecalis to penicillins may be due to altered PBPs.
Resistance to penicillin is also caused by poor permeability of the drug, as in the case of low-level resistance of Neisseria gonorrhoeae. High-level resistance to penicillin is due to the presence of a plasmid coding for a penicillinase.
Some isolates of S. aureus demonstrate yet another form of resistance, called tolerance, in which growth of the organism is inhibited by penicillin but the organism is not killed. This is attributed to a failure of activation of the autolytic enzymes, murein hydrolases, which degrade the peptidoglycan.
Carbapenems—Resistance to carbapenems, such as imipenem, is caused by carbapenemases that degrade the β-lactam ring. This enzyme endows the organism with resistance to penicillins and cephalosporins as well. Carbapenemases are produced by many gram-negative rods, especially Klebsiella, Escherichia, and Pseudomonas.
Carbapenem-resistant strains of K. pneumoniae are an important cause of hospital-acquired infections and are resistant to almost all known antibiotics. The FDA has approved a combination of meropenem–vaborbactam for the treatment of complicated urinary tract infections caused by E. coli, K. pneumoniae, and others. Vaborbactam is an inhibitor of car bapenemases and other beta-lactamases.
Vancomycin—Resistance to vancomycin is caused by a change in the peptide component of peptidoglycan from D-alanyl-D-alanine to D-alanine-D-lactate, to which vancomycin does not bind. Of the four gene loci mediating vancomycin resistance, VanA is the most important. It encodes enzymes that synthesize D-alanine–D-lactate plus several regulatory proteins and is carried by a transposon on a plasmid, conferring high level resistance to vancomycin.
Aminoglycosides—Resistance to aminoglycosides occurs by three mechanisms: (1) drug modification by plasmid-encoded phosphorylating, adenylylating, and acetylating enzymes (the most important mechanism); (2) chromosomal mutation in the gene that encodes for the target protein in the 30S subunit; and (3) decreased permeability of the bacterium to the drug.
Tetracyclines—Resistance to tetracyclines is primarily due to plasmid-encoded processes that either reduce the uptake of the drug or enhance its transport out of the cell.
Chloramphenicol—A plasmid-encoded acetyltransferase modifies and inactivates the drug.
Erythromycin—A plasmid-encoded methylase modifies the 23S rRNA, thereby blocking binding of the drug. An efflux pump reduces the concentration of erythromycin within the bacterium causing low-level resistance to the drug. Esterase-producing enteric gram-negative rods cleave the macrolide ring and inactivate the drug.
Sulfonamides—Resistance is mediated primarily by two mechanisms: (1) a plasmid-encoded transport system that actively exports the drug out of the cell and (2) a chromosomal mutation in the gene encoding the target enzyme dihydropteroate synthetase, which reduces the binding affinity of the drug.
Trimethoprim—Resistance is due primarily to mutations in the chromosome gene that encodes dihydrofolate reductase, the enzyme that reduces dihydrofolate to tetrahydrofolate.
Quinolones—Resistance is due primarily to chromosomal mutations that modify the bacterial DNA gyrase.
Rifampin—Resistance is due to a chromosomal mutation in the gene encoding the bacterial RNA polymerase, resulting in ineffective binding of the drug. This resistance occurs at high frequency, so rifampin is not solely prescribed for the treatment of infections. It is used alone for the prevention of certain infections because it is administered for only a short time.
Isoniazid—Resistance of Mycobacterium tuberculosis to isoniazid is due to mutations in the organism’s catalase–peroxidase gene, which is required to synthesize the metabolite of isoniazid that inhibits the growth of M. tuberculosis.
Ethambutol—Resistance of M. tuberculosis to ethambutol is due to mutations in the gene that encodes arabinosyl transferase, the enzyme that synthesizes the arabinogalactan in the cell wall.
Pyrazinamide (PZA)—Resistance of M. tuberculosis to PZA is due to mutations in the amidase gene encoding a protein that converts PZA to its active drug, pyrazinoic acid.
