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Bacterial resistance to antibiotics
There are four major mechanisms that mediate bacterial resistance to drugs: (1) Bacteria produce enzymes that inactivate the drug (e.g., β-lactamases can inactivate penicillins and cephalosporins by cleaving the β-lactam ring of the drug). (2) Bacteria synthesize modified targets against which the drug has a reduced effect (e.g., a mutant protein in the 30S ribosomal subunit can result in resistance to streptomycin, and a methylated 23S rRNA can result in resistance to erythromycin). (3) Bacteria reduce permeability to the drug such that an effective intracellular concentration of the drug is not achieved (e.g., changes in porins can reduce the amount of penicillin entering the bacterium). (4) Bacteria actively export drugs using a “multidrug-resistance pump” (MDR pump, or “efflux” pump). The term high-level resistance refers to resistance that cannot be overcome by increasing the dose of the antibiotic. A different antibiotic, usually from another class of drugs, is used. Resistance mediated by enzymes such as β-lactamases often result in high-level resistance, as all the drug is destroyed. Low-level resistance refers to resistance that can be overcome by increasing the dose of the antibiotic. Resistance mediated by mutations in the gene encoding a drug target is often low level, as the altered target can still bind some of the drug but with reduced strength. Hospital-acquired infections are significantly more likely to be caused by antibiotic-resistant organisms than are community-acquired infections. This is especially true for hospital infections caused by Staphylococcus aureus and enteric gram-negative rods such as Escherichia coli and Pseudomonas aeruginosa. Antibiotic-resistant organisms are common in the hospital setting because widespread antibiotic use in hospitals selects for these organisms.
Genetic basis of resistance
Chromosomal resistance is due to a mutation in the gene that codes for either the target of the drug or the transport system in the membrane that controls the uptake of the drug. Plasmid-mediated resistance is very important from a clinical point of view for three reasons: (1) It occurs in many different species, especially gram-negative rods. (2) Plasmids frequently mediate resistance to multiple drugs. (3) Plasmids have a high rate of transfer from one cell to another, usually by conjugation. Resistance plasmids (resistance factors, R factors) are extrachromosomal, circular, double-stranded DNA molecules that carry the genes for a variety of enzymes that can degrade antibiotics and modify membrane transport systems. Transposons are genes that are transferred either within or between larger pieces of DNA such as the bacterial chromosome and plasmids. The three genes code for (1) transposase, the enzyme that catalyzes excision and reintegration of the transposon; (2) a repressor that regulates synthesis of the transposase; and (3) the drug resistance gene.
Specific mechanism of resistance
There are several mechanisms of resistance to these drugs. Cleavage by β-lactamases (penicillinases and cephalosporinases) is by far the most important. Resistance to penicillins can also be due to changes in the penicillin-binding proteins (PBPs) in the bacterial cell membrane. Carbapenems—Resistance to carbapenems, such as imipenem, is caused by carbapenemases >span >Vancomycin—Resistance to vancomycin is caused by a change in the peptide component of peptidoglycan from D-alanyl-D-alanine, which is the normal binding site for vancomycin, to D-alanine- D-lactate, to which the drug does not bind. Aminoglycosides—Resistance to aminoglycosides occurs by three mechanisms: (1) modification of the drugs by plasmid-encoded phosphorylating, adenylylating, and acetylating enzymes (the most important mechanism); (2) chromosomal mutation (e.g., a mutation in the gene that codes for the target protein in the 30S subunit of the bacterial ribosome; and (3) decreased permeability of the bacterium to the drug. Tetracyclines—Resistance to tetracyclines is the result of failure of the drug to reach an inhibitory concentration inside the bacteria. This is due to plasmid-encoded processes that either reduce the uptake of the drug or enhance its transport out of the cell. Isoniazid—Resistance of M. tuberculosis to isoniazid is due to mutations in the organism’s catalase–peroxidase gene. Catalase or peroxidase enzyme activity is required to synthesize the metabolite of isoniazid that actually 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 organism’s cell wall. Pyrazinamide—Resistance of M. tuberculosis to pyrazinamide (PZA) is due to mutations in the gene that encodes bacterial amidase, the enzyme that converts PZA to the active form of the drug, pyrazinoic acid.
Non-genetic basis of resistance
There are several nongenetic reasons for the failure of drugs to inhibit the growth of bacteria: (1) Bacteria can be walled off within an abscess cavity that the drug cannot penetrate effectively. Surgical drainage is therefore a necessary adjunct to chemotherapy. (2) Bacteria can be in a resting state (i.e., not growing); they are therefore insensitive to cell wall inhibitors such as penicillins and cephalosporins. (3) Under certain circumstances, organisms that would ordinarily be killed by penicillin can lose their cell walls, survive as protoplasts, and be insensitive to cell wall–active drugs. (4) The presence of foreign bodies makes successful antibiotic treatment more difficult. (5) Several artifacts can make it appear that the organisms are resistant. Three main points of overuse and misuse of antibiotics increase the likelihood of these problems by enhancing the selection of resistant mutants: (1) Some physicians use multiple antibiotics when one would be sufficient, prescribe unnecessarily long courses of antibiotic therapy, use antibiotics in self-limited infections for which they are not needed, and overuse antibiotics for prophylaxis before and after surgery. (2) In many countries, antibiotics are sold over the counter to the general public; this practice encourages inappropriate and indiscriminate use of the drugs. (3) Antibiotics are used in animal feed to prevent infections and promote growth. This selects for resistant organisms in the animals and may contribute to the pool of resistant organisms in humans.
Antibiotic sensitivity testing
For many infections, the results of sensitivity testing are important in the choice of antibiotic. These results are commonly reported as the minimal inhibitory concentration (MIC), which is defined as the lowest concentration of drug that inhibits the growth of the organism. In the treatment of endocarditis, it can be useful to determine whether the drug is effective by assaying the ability of the drug in the patient’s serum to kill the organism. This test, called the serum bactericidal activity. For severe infections caused by certain organisms, such as S. aureus and Haemophilus influenzae, it is important to know as soon as possible whether the organism isolated from the patient is producing β-lactamase. In most cases, the single best antimicrobial agent should be selected for use because this minimizes side effects. However, there are several instances in which two or more drugs are commonly given: (1) To treat serious infections before the identity of the organism is known. (2) To achieve a synergistic inhibitory effect against certain organisms. (3) To prevent the emergence of resistant organisms.