The quinolones are synthetic analogs of nalidixic acid. The mode of action of all quinolones involves inhibition of bacterial DNA synthesis by blocking of DNA gyrase and topoisomerase IV.

The earlier quinolones (nalidixic acid, oxolinic acid, and cinoxacin) did not achieve systemic antibacterial levels after oral intake and thus were useful only as urinary antiseptics. The fluorinated derivatives (eg, ciprofloxacin, norfloxacin, and others; see Figure 1) have greater antibacterial activity and low toxicity and achieve clinically useful levels in blood and tissues.

Fig1. Structures of some fluoroquinolones.

Antimicrobial Activity

 The fluoroquinolones inhibit many types of bacteria, but the spectrum of activity varies from one drug to another. The drugs are highly active against Enterobacteriaceae, including those resistant to third-generation cephalosporins, Haemophilus species, neisseriae, chlamydiae, and others. P. aeruginosa and legionellae are inhibited by somewhat larger amounts of these drugs. The quinolones vary in their activity against Gram-positive pathogens. Some are active against multidrug-resistant S. pneumoniae. They may be active against methicillin-susceptible staphylococci and E. faecalis. VRE are usually resistant to the quinolones. Newer fluoroquinolones have increased activity against anaerobic bacteria, allowing them to be used as monotherapy in the treatment of mixed aerobic and anaerobic infections.

The fluoroquinolones may also have activity against M. tuberculosis, M. fortuitum, Mycobacterium kansasii, and sometimes M. chelonei.

During fluoroquinolone therapy, the emergence of resistance of pseudomonads, staphylococci, and other pathogens has been observed. At least two major mechanisms of quinolone resistance have been described. Chromosomal resistance develops by mutation and involves either an alteration in the A or B subunit of the target enzyme, DNA gyrase, or mutations in ParC or ParE of topoisomerase IV. A change in outer membrane permeability results in decreased drug accumulation in the bacterium. Finally, plasmid-encoded efflux pumps such as QepA and OqxAB have also been described.

Absorption and Excretion

 After oral administration, representative fluoroquinolones are well absorbed and widely distributed in body fluids and tissues to varying degrees, but they do not reach the CNS to a significant extent. The serum half-life is variable (3–8 hours) and can be prolonged in renal failure depending on the specific drug used.

The fluoroquinolones are mainly excreted into the urine via the kidneys, but some of the dose may be metabolized in the liver.

Clinical Uses

 Fluoroquinolones are generally effective in urinary tract infections, and several of them benefit patients with prostatitis. Some fluoroquinolones are valuable in the treatment of sexually transmitted diseases caused by N. gonorrhoeae and C. trachomatis but have no effect on Treponema pallidum. Developing resistance, however, precludes their use as first line treatment for gonorrhea. These drugs can control lower respiratory infections caused by infection with H. influenzae (but may not be drugs of choice) and enteritis caused by salmonellae, shigellae, or campylobacters. Fluoroquinolones may be suitable for the treatment of major gynecologic and soft tissue bacterial infections and for osteomyelitis of Gram-negative origin. Although they can benefit some exacerbations of cystic fibrosis caused by pseudomonads, about one-third of such mucoid organisms are drug resistant. Fluoroquinolones have increased in use for the treatment of mycobacterial infections, including multi-drug-resistant M. tuberculosis.

Side Effects

 The most prominent adverse effects are nausea, insomnia, head ache, and dizziness. Occasionally, other gastrointestinal disturbances, impaired liver function, skin rashes, and superinfections occur, particularly with enterococci and staphylococci. In pup pies, prolonged administration of fluoroquinolones produces joint damage, and for that reason, the fluoroquinolones have been seldom prescribed for children but are used as needed in cystic fibrosis patients. The FDA issued a drug safety warning regarding the occurrence of tendinitis in adults resulting in ten don rupture, most frequently of the Achilles tendon. Other more serious adverse events include prolongation of the QTc interval. Disturbances of blood glucose leading to significant hypoglycemia have been reported with newer agents, such as gatifloxacin, causing its discontinued use in the United States. Extensive fluoroquinolone use is believed to be responsible for the global increase in C. difficile colitis.

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