The DNA gyrase of E. coli is composed of two 105,000 Da A subunits and two 95,000 Da B subunits encoded by the gyrA and gyrB genes, respectively. The A subunits, which carry out the strand-cutting function of the gyrase, are the site of action of the quinolones (Figure 52–3). The drugs inhibit gyrase-mediated DNA supercoiling at concentrations that correlate well with those required to inhibit bacterial growth (0.1-10 μg/mL). Mutations of the gene that encodes the A subunit polypeptide can confer resistance to these drugs (Hooper, 2005a).
Topoisomerase IV is also composed of four subunits encoded by the parC and parE genes in E. coli (Hooper, 2005a). Topoisomerase IV separates interlinked (catenated) daughter DNA molecules that are the product of DNA replication. Eukaryotic cells do not contain DNA gyrase, but they do contain a conceptually and mechanistically similar type II DNA topoisomerase that removes positive supercoils from DNA to prevent its tangling during replication. This enzyme is the target for some antineoplastic agents (Chapters 60 and 61). Quinolones inhibit eukaryotic type II topoisomerase only concentrations (100-1000 μg/mL) much higher than those that inhibit bacterial DNA gyrase (Mitscher and Ma, 2003).
Antibacterial Spectrum. The fluoroquinolones are potent bactericidal agents against E. coli and various species of Salmonella, Shigella, Enterobacter, Campylobacter, and Neisseria (Hooper, 2005a). MICs of the fluoroquinolones for 90% of these strains (MIC90) usually are <0.2 μg/mL. Ciprofloxacin is more active than norfloxacin (noroxin) against P. aeruginosa; values of MIC90 range from 0.5-6 μg/mL. Fluoroquinolones also have good activity against staphylococci, but not against methicillin-resistant strains (MIC90 = 0.1-2 μg/mL).
Activity against streptococci is limited to a subset of the quinolones, including levofloxacin (levaquin), gatifloxacin, and moxifloxacin (avelox) (Hooper, 2005a). Several intracellular bacteria are inhibited by fluoroquinolones at concentrations that can be achieved in plasma; these include species of Chlamydia, Mycoplasma, Legionella, Brucella, and Mycobacterium (including Mycobacterium tuberculosis) (American Thoracic Society, 2003). Ciprofloxacin (cipro, others), ofloxacin (floxin), and pefloxacin have MIC90 values from 0.5-3 μg/mL for M. fortuitum, M. kansasii, and M. tuberculosis; ofloxacin and pefloxacin (not available in U.S.) are active in animal models of leprosy (Hooper, 2005a). However, clinical experience with these pathogens remains limited.
Several fluoroquinolones, including garenoxacin (not available in U.S.) and gemifloxacin, have activity against anaerobic bacteria (Medical Letter, 2000, 2004).
Resistance to quinolones may develop during therapy via mutations in the bacterial chromosomal genes encoding DNA gyrase or topoisomerase IV or by active transport of the drug out of the bacteria (Oethinger et al., 2000). No quinolone-modifying or -inactivating activities have been identified in bacteria (Gold and Moellering, 1996). Resistance has increased after the introduction of fluoroquinolones, especially in Pseudomonas and staphylococci. Increasing fluoroquinolone resistance also is being observed in C. jejuni, Salmonella, N. gonorrhoeae, and S. pneumoniae.
As mentioned in Chapter 48, the pharmacokinetic and pharmacodynamic parameters of antimicrobial agents are important in preventing the selection and spread of resistant strains and have led to description of the mutation-prevention concentration, which is the lowest concentration of antimicrobial that prevents selection of resistant bacteria from high bacterial inocula. β-Lactams are time-dependent agents without significant post-antibiotic effects, resulting in bacterial eradication when unbound serum concentrations exceed MICs of these agents against infecting pathogens for >40-50% of the dosing interval. By contrast, fluoroquinolones are concentration- and time-dependent agents, resulting in bacterial eradication when unbound serum area under the curve-to-MIC ratios exceed 25-30. An extended release formulation of ciprofloxacin (proquin xr) exemplifies this principle.
Absorption, Fate, and Excretion. The quinolones are well absorbed after oral administration and are distributed widely in body tissues. Peak serum levels of the fluoroquinolones are obtained within 1-3 hours of an oral dose of 400 mg, with peak levels ranging from 1.1 μg/mL for sparfloxacin to 6.4 μg/mL for levofloxacin. Relatively low serum levels are reached with norfloxacin and limit its usefulness to the treatment of urinary tract infections. Food does not impair oral absorption but may delay the time to peak serum concentrations. Oral doses in adults are 200-400 mg every 12 hours for ofloxacin, 400 mg every 12 hours for norfloxacin and pefloxacin, and 250 to 750 mg every 12 hours for ciprofloxacin. Bioavailability of the fluoroquinolones is >50% for all agents and >95% for several. The serum t1/2 is 3-5 hours for norfloxacin and ciprofloxacin. The volume of distribution of quinolones is high, with concentrations of quinolones in urine, kidney, lung and prostate tissue, stool, bile, and macrophages and neutrophils higher than serum levels. Quinolone concentrations in cerebrospinal fluid, bone, and prostatic fluid are lower than in serum. Pefloxacin and ofloxacin levels in ascites fluid are close to serum levels, and ciprofloxacin, ofloxacin, and pefloxacin have been detected in human breast milk.
Most quinolones are cleared predominantly by the kidney, and dosages must be adjusted for renal failure. Exceptions are pefloxacin and moxifloxacin, which are metabolized predominantly by the liver and should not be used in patients with hepatic failure. None of the agents is removed efficiently by peritoneal dialysis or hemodialysis.
Urinary Tract Infections. Nalidixic acid is useful only for UTI caused by susceptible microorganisms. The fluoroquinolones are significantly more potent and have a much broader spectrum of antimicrobial activity. Norfloxacin is approved for use in the U.S. only for urinary tract infections. Comparative clinical trials indicate that the fluoroquinolones are more efficacious than trimethoprim-sulfamethoxazole for the treatment of UTI (Hooper, 2005b). Ciprofloxacin XR is FDA-approved only for UTI.
Prostatitis. Norfloxacin, ciprofloxacin, and ofloxacin all have been effective in uncontrolled trials for the treatment of prostatitis caused by sensitive bacteria. Fluoroquinolones administered for 4-6 weeks appear to be effective in patients not responding to trimethoprim-sulfamethoxazole.
Sexually Transmitted Diseases. The quinolones are contraindicated in pregnancy. Fluoroquinolones lack activity for Treponema pallidum but have activity in vitro against C. trachomatis and H. ducreyi. For chlamydial urethritis/cervicitis, a 7-day course of ofloxacin is an alternative to a 7-day treatment with doxycycline or a single dose of azithromycin; other available quinolones have not been reliably effective. A single oral dose of a fluoroquinolone such as ofloxacin or ciprofloxacin had been effective treatment for sensitive strains of N. gonorrhoeae, but increasing resistance to fluoroquinolones has led to ceftriaxone being the first-line agent for this infection (Newman et al., 2004). Chancroid (infection by H. ducreyi) can be treated with 3 days of ciprofloxacin.
GI and Abdominal Infections. For traveler's diarrhea (frequently caused by enterotoxigenic E. coli), the quinolones are equal to trimethoprim-sulfamethoxazole in effectiveness, reducing the duration of loose stools by 1-3 days (Hill et al., 2006). Norfloxacin, ciprofloxacin, and ofloxacin given for 5 days all have been effective in the treatment of patients with shigellosis, with even shorter courses effective in many cases. Ciprofloxacin and ofloxacin treatment cures most patients with enteric fever caused by S. typhi, as well as bacteremic nontyphoidal infections in AIDS patients, and it clears chronic fecal carriage. Shigellosis is treated effectively with either ciprofloxacin or azithromycin. The in vitro ability of the quinolones to induce the Shiga toxin stx2 gene (the cause of the hemolytic-uremic syndrome) in E. coli suggests that the quinolones should not be used for Shiga toxin–producing E. coli (Miedouge et al., 2000). Ciprofloxacin and ofloxacin have been less effective in treating episodes of peritonitis occurring in patients on chronic ambulatory peritoneal dialysis likely owing to the higher MICs for these drugs for the coagulase-negative staphylococci that are a common cause of peritonitis in this setting.
Respiratory Tract Infections. The major limitation to the use of quinolones for the treatment of community-acquired pneumonia and bronchitis had been the poor in vitro activity of ciprofloxacin, ofloxacin, and norfloxacin against S. pneumoniae and anaerobic bacteria. However, newer fluoroquinolones, including gatifloxacin (available only for ophthalmic use in U.S.) and moxifloxacin, have excellent activity against S. pneumoniae. The fluoroquinolones have in vitro activity against the rest of the commonly recognized respiratory pathogens, including H. influenzae, Moraxella catarrhalis, S. aureus, M. pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. Either a fluoroquinolone (ciprofloxacin or levofloxacin) or azithromycin is the antibiotic of choice for L. pneumophila (Edelstein & Cianciotto, 2005). Fluoroquinolones have been very effective at eradicating both H. influenzae and M. catarrhalis from sputum. Mild to moderate respiratory exacerbations owing to P. aeruginosa in patients with cystic fibrosis have responded to oral fluoroquinolone therapy. Emerging clinical data are demonstrating a clear role for the newer fluoroquinolones as single agents for treatment of community-acquired pneumonia (Hooper, 2005b). However, on the horizon is a decreasing susceptibility of S. pneumoniae to fluoroquinolones (Chen et al., 1999; Wortmann and Bennett, 1999).
Bone, Joint, and Soft Tissue Infections. The treatment of chronic osteomyelitis requires prolonged (weeks to months) antimicrobial therapy with agents active against S. aureus and gram-negative rods. The fluoroquinolones, by virtue of their oral administration and appropriate antibacterial spectrum for these infections, may be used appropriately in some cases; recommended doses are 500 mg every 12 hours or, if severe, 750 mg twice daily. Bone and joint infections may require treatment for 4-6 weeks or more. Dosage should be reduced for patients with severely impaired renal function. Clinical cures have been as high as 75% in chronic osteomyelitis in which gram-negative rods predominated (Hooper, 2005b). Failures have been associated with the development of resistance in S. aureus, P. aeruginosa, and Serratia marcescens. In diabetic foot infections, which are commonly caused by a mixture of bacteria including gram-negative rods, anaerobes, streptococci, and staphylococci, the fluoroquinolones in combination with an agent with antianaerobic activity are a reasonable choice.