Chapter 127. Treatment and Prophylaxis of Bacterial Infections (Part 13) Macrolides and Ketolides Erythromycin, 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 when erythromycin 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. These effects are associated with prolongation of the QT interval and a fivefold increase in mortality rate. This example serves as a reminder that the true significance of drug-drug interactions may be subtle yet profound and that close attention to the evolving safety literature is important. Quinupristin/Dalfopristin Quinupristin/dalfopristin is an inhibitor of CYP3A4. Its interactions with other drugs should be similar to those of erythromycin. Linezolid Linezolid is a monoamine oxidase inhibitor. Its concomitant administration with sympathomimetics (e.g., phenylpropanolamine) and with foods with high concentrations of tyramine should be avoided. Many case reports describe serotonin syndrome following coadministration of linezolid with selective serotonin reuptake inhibitors. Tetracyclines The most important interaction involving tetracyclines is reduced absorption when these drugs are coadministered with divalent and trivalent cations, such as antacids, iron compounds, or dairy products. Food also adversely affects absorption of most tetracyclines. Inducers of hepatic isoenzymes, such as phenytoin and rifampin, increase the clearance of doxycycline; although the clinical significance of this effect is unknown, use of an alternative antibiotic may be appropriate. Sulfonamides Sulfonamides, including TMP-SMX, increase the hypoprothrombinemic effect of warfarin by inhibition of its metabolism or by protein-binding displacement. Fluoroquinolones There are two clinically important drug interactions involving fluoroquinolones. First, like tetracyclines, all fluoroquinolones are chelated by divalent and trivalent cations, with a consequential significant reduction in absorption. Second, ciprofloxacin inhibits the hepatic enzyme that metabolizes theophylline. Scattered case reports suggest that quinolones can also potentiate the effects of warfarin, but this effect has not been observed in most controlled trials. Rifampin Rifampin is an excellent inducer of many cytochrome P450 enzymes and increases the hepatic clearance of a large number of drugs, including the following (with the indicated predictable outcomes): HIV-1 protease inhibitors (loss of viral suppression), oral contraceptives (pregnancy), warfarin (decreased prothrombin times), cyclosporine and prednisone (organ rejection or exacerbations of any underlying inflammatory condition), and verapamil and diltiazem (increased dosage requirements). Before rifampin is prescribed for any patient, a review of concomitant drug therapy is essential. Metronidazole Metronidazole can cause a disulfiram-like syndrome when alcohol is ingested. Thus, patients taking metronidazole should be instructed to avoid alcohol. Inhibition of the metabolism of warfarin by metronidazole leads to significant rises in prothrombin times. Prophylaxis of Bacterial Infections Antibacterial agents are occasionally indicated for use in patients who have no evidence of infection but who have been or are expected to be exposed to bacterial pathogens under circumstances that constitute a major risk of infection. The basic tenets of antimicrobial prophylaxis are as follows: (1) The risk or potential severity of infection should outweigh the risk of side effects from the antibacterial agent. (2) The antibacterial agent should be given for the shortest period necessary to prevent target infections. (3) The antibacterial agent should be given before the expected period of risk (e.g., within 1 h of incision before elective surgery) 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 in adults. The table includes only those indications that are widely accepted, supported by well-designed studies, or recommended by expert panels. Prophylaxis is also used but is less widely accepted for recurrent cellulitis in conjunction with lymphedema, recurrent pneumococcal meningitis in conjunction with deficiencies in humoral immunity or CSF leaks, traveler's diarrhea, gram- negative sepsis in conjunction with neutropenia, and spontaneous bacterial peritonitis in conjunction with ascites. The use of antibacterial agents in children to prevent rheumatic fever and otitis media under certain circumstances is also common practice. Table 127-9 Prophylaxis of Bacterial Infections in Adults Condition Antibacterial Agent Timing or Durationof Prophylaxis Nonsurgical Cardiac lesions susceptible to bacterial Amoxicillin a Before and after procedures endocarditis causing bacteremia Recurrent S. aureus infections Mupirocin 5 days (intranasal) Contact with patient with meningococcal meningitis Rifampin Fluoroquinolone 2 days Single dose Bite wounds b Penicillin V or amoxicillin/clavulanic acid 3–5 days Recurrent cystitis Trimethoprim- sulfamethoxazole or a fluoroquinolone or nitrofurantoin 3 times per week for up to 1 year or after sexual intercourse Surgical Clean (cardiac, Cefazolin (vancomycin) c Bef ore and vascular, neurologic, or orthopedic surgery) during procedure Ocular Topical combinations and subconjunctival cefazolin During and at end of procedure Clean-contaminated (head and neck, high- risk gastroduodenal or biliary tract surgery; high- risk cesarean section; hysterectomy) Cefazoli n (or clindamycin for head and neck) Before and during procedure Clean-contaminated (vaginal or abdominal hysterectomy) Cefazolin or cefoxitin or cefotetan Before and during procedure Clean-contaminated (high- risk genitourinary surgery) Fluoroquinolone Before and during procedure Clean-contaminated (colorectal surgery or appendectomy) Cefoxitin or cefotetan (add oral neomycin + erythromycin for colorectal) Before and during procedure Dirty b (ruptured viscus) Cefoxitin or cefotetan ± gentamicin , clindamycin + gentamicin, or another appropriate regimen directed at anaerobes and gram- negative aerobes Before and for 3– 5 days after procedure Dirty b (traumatic wound) Cefazolin Before and for 3– 5 days after trauma a Gentamicin should be added to the amoxicillin regimen for high- risk gastrointestinal and genitourinary procedures; vancomycin should be used in penicillin-allergic patients. b In these cases, use of antibacterial agents actually constitutes treatment of infection rather than prophylaxis. c Vancomycin is recommended only in institutions that have a high incidence of infection with methicillin-resistant staphylococci. The major use of antibacterial prophylaxis is to prevent infections following surgical procedures. Antibacterial agents are administered just before the surgical procedure—and, for long operations, during the procedure as well—to ensure high drug concentrations in serum and tissues during surgery. The objective is to eradicate bacteria originating from the air of the operating suite, the skin of the surgical team, or the patient's own flora that may contaminate the wound. In all but colorectal surgical procedures, prophylaxis is predominantly directed against staphylococci and cefazolin is the drug most commonly recommended. Prophylaxis is intended to prevent wound infection or infection of implanted devices, not all infections that may occur during the postoperative period (e.g., UTIs or pneumonia). Prolonged prophylaxis (beyond 24 h) merely alters the normal flora and favors infections with organisms resistant to the antibacterial agents used. A focus on appropriate surgical prophylaxis by the Centers for Medicare and Medicaid Services, coupled with national efforts by surgical societies, appears to be having a favorable impact on the appropriate use of antimicrobial drugs in the surgical setting, although additional improvements are needed. . Chapter 127. Treatment and Prophylaxis of Bacterial Infections (Part 13) Macrolides and Ketolides Erythromycin, clarithromycin, and telithromycin inhibit CYP3A4,. practice. Table 127- 9 Prophylaxis of Bacterial Infections in Adults Condition Antibacterial Agent Timing or Durationof Prophylaxis Nonsurgical Cardiac lesions susceptible to bacterial Amoxicillin a . avoid alcohol. Inhibition of the metabolism of warfarin by metronidazole leads to significant rises in prothrombin times. Prophylaxis of Bacterial Infections Antibacterial agents are occasionally