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PRINCIPLES OF ANTIBIOTIC RESISTANCE

There are four major mechanisms that mediate bacterial resistance to drugs (Table 11–1). (1) Bacteria produce enzymes that inactivate drugs. (2) Bacteria synthesize modified targets against which the drug has a reduced effect. (3) Bacteria reduce permeability to the drug such that an effective intracellular concentration of the drug is not achieved. (4) Bacteria actively export drugs using a “multidrug-resistance pump.” The multidrug-resistant (MDR) pump imports protons and, in an exchange-type reaction, exports a variety of foreign molecules including certain antibiotics, such as tetracyclines.

TABLE 11–1Mechanisms of Drug Resistance

Most drug resistance is due to a genetic change in the organism, either a chromosomal mutation or the acquisition of a plasmid or transposon.

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 results 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. Furthermore, hospital strains are often resistant to multiple antibiotics. This resistance is usually due to the acquisition of plasmids carrying several genes that encode the enzymes that mediate resistance.

Two types of resistant gram-negative rods are especially important in hospital-acquired infection multidrug-resistant (MDR) gram-negative rods and extended spectrum beta-lactamase (ESBL) producing gram-negative rods. MDR gram-negative rods produce beta-lactamases that inactivate penicillins, cephalosporins, and carbapenems. ESBL gram-negative rods produce beta-lactamases that inactivate second, third, and fourth generation cephalosporins. Table 11–2 describes certain medically important bacteria and the main drugs to which they are resistant.

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