During fluoroquinolone therapy, resistant organisms emerge in about 1 of every 107–109 organisms, especially among staphylococci, P aeruginosa, and Serratia marcescens. Emerging resistance is due to one or more point mutations in the quinolone binding region of the target enzyme or to a change in the permeability of the organism. However, additional mechanisms seem to account for the relative ease with which resistance develops in highly susceptible bacteria. Two types of plasmid-mediated resistance have been described. The first type utilizes Qnr proteins, which protect DNA gyrase from the fluoroquinolones. The second is a variant of an aminoglycoside acetyltransferase capable of modifying ciprofloxacin. Both mechanisms confer low-level resistance that may facilitate the point mutations that confer high-level resistance and also may be associated with resistance to other antibacterial drug classes. Resistance to one fluoroquinolone, particularly if it is of high level, generally confers cross-resistance to all other members of this class.
After oral administration, the fluoroquinolones are well absorbed (bioavailability of 80–95%) and distributed widely in body fluids and tissues (Table 46–1). Serum half-lives range from 3 to 10 hours. The relatively long half-lives of levofloxacin, gemifloxacin, and moxifloxacin permit once-daily dosing. Oral absorption is impaired by divalent and trivalent cations, including those in antacids. Therefore, oral fluoroquinolones should be taken 2 hours before or 4 hours after any products containing these cations. Serum concentrations of intravenously administered drug are similar to those of orally administered drug. Most fluoroquinolones, moxifloxacin being an important exception, are eliminated by renal mechanisms, either tubular secretion or glomerular filtration (Table 46–1). Dosage adjustment is required for patients with creatinine clearances less than 50 mL/min, the exact adjustment depending on the degree of renal impairment and the specific fluoroquinolone being used. Dosage adjustment for renal failure is not necessary for moxifloxacin since it is metabolized in the liver; it should be used with caution in patients with hepatic failure.
Fluoroquinolones (other than moxifloxacin, which achieves relatively low urinary levels) are effective in urinary tract infections caused by many organisms, including P aeruginosa. These
CHAPTER 46 Sulfonamides, Trimethoprim, & Quinolones 839 agents are also effective for bacterial diarrhea caused by Shigella, Salmonella, toxigenic E coli, and Campylobacter. Fluoroquinolones (except norfloxacin, which does not achieve adequate systemic concentrations) are used in infections of soft tissues, bones, and joints and in intra-abdominal and respiratory tract infections, including those caused by multidrug-resistant organisms such as Pseudomonas and Enterobacter. Ciprofloxacin is a drug of choice for prophylaxis and treatment of anthrax; the newer fluoroquinolones are active in vitro, and levofloxacin is also approved by the
U.S. Food and Drug Administration (FDA) for prophylaxis.