N

Stabilize positive node (+)

Reseal break on front side (

Break back segment

FIGURE 43-3 Model of the formation of negative DNA supercoils by DNA gyrase. The enzyme binds to two segments of DNA (1), creating a node of positive (+) superhelix. The enzyme then introduces a double-strand break in the DNA and passes the front segment through the break (2). The break is then resealed (3), creating a negative (-) super-coil. Quinolones inhibit the nicking and closing activity of the gyrase and also block the decatenating activity of topoi-somerase IV.

not against methicillin-resistant strains. Activity against streptococci is limited to a subset of the quinolones, including levofloxacin (levaquin), gatifloxacin (tequin), and moxifloxacin (avelox). Several intracellular bacteria are inhibited by fluoroquinolones; these include species of Chlamydia, Mycoplasma, Legionella, Brucella, and Mycobacterium (including Mycobacterium tuberculosis). Ciprofloxacin, ofloxacin (floxin), and pefloxacin inhibit M. fortuitum, M. kansasii, and M. tuberculosis.

Resistance to quinolones may develop via mutations in the bacterial chromosomal genes encoding DNA gyrase or topoisomerase IV or by active transport of the drug out of the bacteria. No quinolone-inactivating mechanisms have been identified. Resistance has increased, especially in Pseudomonas and staphylococci. Fluoroquinolone resistance also is increasing in C. jejuni, Salmonella, Neisseria gonorrhoeae, and S. pneumoniae.

ABSORPTION, FATE, AND EXCRETION The quinolones are well absorbed after oral administration and are widely distributed. Peak serum levels of the fluoroquinolones occur within 1-3 hours of an oral dose of 400 mg. 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 250-750 mg every 12 hours for ciprofloxacin. Bioavailability of the fluoroquinolones exceeds 50% for all agents and 95% for several. The serum half-lives range from 3 to 5 hours for norfloxacin and ciprofloxacin to 20 hours for sparfloxacin. The volume of distribution of quinolones is high, with concentrations in urine, kidney, lung and prostate tissue, stool, bile, and macrophages and neutrophils higher than serum levels. Quinolone concentrations in CSF, bone, and prostatic fluid are lower than in serum. Pefloxacin and ofloxacin levels in ascites fluid approach serum levels, and ciprofloxacin, ofloxacin, and pefloxacin have been detected in human breast milk.

Most quinolones are cleared predominantly by the kidney, and dose must be adjusted for renal failure. Pefloxacin and moxifloxacin are metabolized predominantly by the liver and should not be used in patients with hepatic failure. None is removed efficiently by peritoneal or hemodialysis.

THERAPEUTIC USES Urinary Tract Infections

Norfloxacin is approved for use in the U.S. only for urinary tract infections. The fluoroquinolones are more efficacious than trimethoprim—sulfamethoxazole for the treatment of urinary tract infections.

Prostatitis

Norfloxacin, ciprofloxacin, and ofloxacin are effective 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 N. gonorrhoeae, Chlamydia trachomatis, and Haemophilus ducreyi. For chlamydial urethritis/cervicitis, a 7-day course of ofloxacin or sparfloxacin is an alternative to a 7-day course with doxycycline or a single dose of azithromycin. A single oral dose of a fluoroquinolone such as ofloxacin or ciprofloxacin is effective treatment for sensitive strains of N. gonorrhoeae, but increasing resistance to fluoroquinolones has made ceftriaxone the first-line agent. Pelvic inflammatory disease has been treated effectively with a 14-day course of ofloxacin combined with an antibiotic with activity against anaerobes (clindamycin or metronidazole). Chancroid (infection by H. ducreyi) can be treated with 3 days of ciprofloxacin.

Gastrointestinal and Abdominal Infections

For traveler's diarrhea (frequently caused by enterotoxigenic E. coli), the quinolones are equal to trimethoprim—sulfamethoxazole in effectiveness. Norfloxacin, ciprofloxacin, and ofloxacin given for 5 days all are effective in the treatment of patients with shigellosis, with even shorter courses effective in many cases. Norfloxacin is superior to tetracyclines in decreasing the duration of diarrhea in cholera. Ciprofloxacin and ofloxacin cure most patients with enteric fever caused by S. typhi, as well as bacteremic nontyphoidal infections in AIDS patients. Shigellosis is treated effectively with either ciprofloxacin or azithromycin. The in vitro ability of the quinolones to induce the Shiga toxin (the cause of the hemolytic-uremic syndrome) in E. coli suggests that the quinolones should not be used for Shiga toxin—producing E. coli. Ciprofloxacin and ofloxacin are less effective in treating episodes of peritonitis occurring in patients on chronic ambulatory peritoneal dialysis, likely owing to their higher MICs for coagulase-negative staphylococci commonly seen in this setting.

Respiratory Tract Infections

The major limitation to the use of quinolones for the treatment of community-acquired pneumonia and bronchitis was the poor activity against S. pneumoniae and anaerobic bacteria. Many of the newer fluoroquinolones, including gatifloxacin and moxifloxacin, have excellent activity against S. pneumoniae and have shown efficacy comparable to b-lactam antibiotics. The fluoroquinolones have activity against the rest of the common respiratory pathogens, including H. influenzae, Moraxella catarrhalis, S. aureus, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. Either a fluoroquinolone (ciprofloxacin or levofloxacin) or azithromycin is the antibiotic of choice for L. pneumophila. Fluoroquinolones can effectively eradicate 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 fluoroquinolones.

Bone, Joint, and Soft Tissue Infections

The treatment of chronic osteomyelitis requires prolonged antimicrobial therapy with agents active against S. aureus and gram-negative rods. The fluoroquinolones, by virtue of their oral administration and antibacterial spectrum, may appropriately be used 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. Ciprofloxacin should not be given to children or pregnant women. Clinical cures have been as high as 75% in chronic osteomyelitis in which gram-negative rods predominated. Failures have been associated with the development of resistance in S. aureus, P. aeruginosa, and Serratia marcescens. In diabetic foot infections, which commonly are polymi-crobial, the fluoroquinolones in combination with an agent with antianaerobic activity are a reasonable choice. Ciprofloxacin as sole therapy is effective in ~50% of diabetic foot infections.

Other Infections

Ciprofloxacin received wide usage for the prophylaxis of anthrax and is effective for the treatment of tularemia. The quinolones may be used as part of multiple-drug regimens for the treatment of multidrug-resistant tuberculosis and for the treatment of atypical mycobacterial infections and Mycobacterium avium complex infections in AIDS (see Chapter 47). In neutropenic cancer patients with fever, the combination of a quinolone with an aminoglycoside is comparable to b-lactam-aminoglycoside combinations; quinolones are less effective when used alone. Quinolones, when used prophylactically in neutropenic patients, have decreased the incidence of gram-negative rod bacteremias. Ciprofloxacin plus amoxicillin-clavulanate is effective as an oral empirical therapy for fever in low-risk patients with granulocytopenia secondary to cancer chemotherapy.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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