Chapter 127. Treatment and Prophylaxis of Bacterial Infections (Part 13)

Macrolides and KetolidesErythromycin, clarithromycin, and telithromycin inhibit CYP3A4, the hepatic P450 enzyme that metabolizes many drugs, including cyclosporine, certain statins (lovastatin, simvastatin), theophylline, carbamazepine, warfarin, certain antineoplastic agents (e.g., vincristine, irinotecan), and ergot alkaloids. In ~10% of patients receiving digoxin, concentrations increase significantly whenerythromycin or telithromycin is coadministered, and this increase may lead to digoxin toxicity. Azithromycin has little effect on the metabolism of other drugs. Many drugs (e.g., azole antifungal drugs, diltiazem, verapamil, and nefazodone) can also increase absorption or inhibit erythromycin metabolism. ...
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Chapter 127. Treatment and Prophylaxis of Bacterial Infections (Part 13) Chapter 127. Treatment and Prophylaxis of Bacterial Infections (Part 13) Macrolides and Ketolides Erythromycin, clarithromycin, and telithromycin inhibit CYP3A4, thehepatic P450 enzyme that metabolizes many drugs, including cyclosporine, certainstatins (lovastatin, simvastatin), theophylline, carbamazepine, warfarin, certainantineoplastic agents (e.g., vincristine, irinotecan), and ergot alkaloids. In ~10% ofpatients receiving digoxin, concentrations increase significantly whenerythromycin or telithromycin is coadministered, and this increase may lead todigoxin toxicity. Azithromycin has little effect on the metabolism of other drugs.Many drugs (e.g., azole antifungal drugs, diltiazem, verapamil, and nefazodone)can also increase absorption or inhibit erythromycin metabolism. These effects areassociated with prolongation of the QT interval and a fivefold increase in mortalityrate. This example serves as a reminder that the true significance of drug-druginteractions may be subtle yet profound and that close attention to the evolvingsafety literature is important. Quinupristin/Dalfopristin Quinupristin/dalfopristin is an inhibitor of CYP3A4. Its interactions withother drugs should be similar to those of erythromycin. Linezolid Linezolid is a monoamine oxidase inhibitor. Its concomitant administrationwith sympathomimetics (e.g., phenylpropanolamine) and with foods with highconcentrations of tyramine should be avoided. Many case reports describeserotonin syndrome following coadministration of linezolid with selectiveserotonin reuptake inhibitors. Tetracyclines The most important interaction involving tetracyclines is reducedabsorption when these drugs are coadministered with divalent and trivalentcations, such as antacids, iron compounds, or dairy products. Food also adverselyaffects absorption of most tetracyclines. Inducers of hepatic isoenzymes, such asphenytoin and rifampin, increase the clearance of doxycycline; although theclinical significance of this effect is unknown, use of an alternative antibiotic maybe appropriate. Sulfonamides Sulfonamides, including TMP-SMX, increase the hypoprothrombinemiceffect of warfarin by inhibition of its metabolism or by protein-bindingdisplacement. Fluoroquinolones There are two clinically important drug interactions involvingfluoroquinolones. First, like tetracyclines, all fluoroquinolones are chelated bydivalent and trivalent cations, with a consequential significant reduction inabsorption. Second, ciprofloxacin inhibits the hepatic enzyme that metabolizestheophylline. Scattered case reports suggest that quinolones can also potentiate theeffects of warfarin, but this effect has not been observed in most controlled trials. Rifampin Rifampin is an excellent inducer of many cytochrome P450 enzymes andincreases the hepatic clearance of a large number of drugs, including the following(with the indicated predictable outcomes): HIV-1 protease inhibitors (loss of viralsuppression), oral contraceptives (pregnancy), warfarin (decreased prothrombintimes), cyclosporine and prednisone (organ rejection or exacerbations of anyunderlying inflammatory condition), and verapamil and diltiazem (increaseddosage requirements). Before rifampin is prescribed for any patient, a review ofconcomitant drug therapy is essential. Metronidazole Metronidazole can cause a disulfiram-like syndrome when alcohol isingested. Thus, patients taking metronidazole should be instructed to avoidalcohol. Inhibition of the metabolism of warfarin by metronidazole leads tosignificant rises in prothrombin times. Prophylaxis of Bacterial Infections Antibacterial agents are occasionally indicated for use in patients who haveno evidence of infection but who have been or are expected to be exposed tobacterial pathogens under circumstances that constitute a major risk of infection.The basic tenets of antimicrobial prophylaxis are as follows: (1) The risk orpotential severity of infection should outweigh the risk of side effects from theantibacterial agent. (2) The antibacterial agent should be given for the shortestperiod necessary to prevent target infections. (3) The antibacterial agent should begiven before the expected period of risk (e.g., within 1 h of incision before electivesurgery) or as soon as possible after contact with an infected individual (e.g.,prophylaxis for meningococcal meningitis). Table 127-9 lists the major indications for antibacterial prophylaxis inadults. The table includes only those indications that are widely accept ...