Symposium on Antimicrobial Agents—Part XIIIThe Fluoroquinolones
Section snippets
Mechanism of Action
The quinolones are unique among antimicrobial agents in that they target bacterial topoisomerases.1 Topoisomerases maintain cellular DNA in an appropriate state of supercoiling in both replicating and nonreplicating regions of the bacterial chromosome. Four types of topoisomerases exist. The quinolones target DNA gyrase (also termed “topoisomerase type II”) and topoisomerase IV (types I and III are not targets of the quinolones).
DNA gyrase removes the excess positive supercoiling that builds up
Chemical Structure
Thousands of different quinolone structures have been synthesized. Screening for antimicrobial activity as well as further evaluation and development for clinical safety and usefulness have reduced the number of FDA-approved agents to fewer than 10.
Among the FDA-approved quinolones, several attributes are common, although some of the newer agents have unique features. In the basic quinolone structure, the main feature that distinguishes the fluoroquinolones from their predecessor, nalidixic
Structural-Activity Relationships of Antimicrobial and Pharmacologic Properties
The structural-activity relationships are carefully examined when the quinolones are developed. This allows enhancement of antibacterial activity and reduction of toxicity. These relationships are multifactorial, but a few generalizations can be made.
Although ciprofloxacin (a second-generation quinolone) is not as active against S. aureus or Streptococcus as the third-and fourth-generation quinolones, it remains the most active quinolone against Pseudomonas aeruginosa. Ciprofloxacin has
Pharmacologic Properties
The fluoroquinolones have good bioavailability and tissue penetration as well as favorable pharmacokinetics. Four fluoroquinolones are available in intravenous form: ciprofloxacin, ofloxacin, levofloxacin, and alatrofloxacin (which is converted to trovafloxacin in the serum). The absorption of the oral version of these drugs is excellent, and thus blood levels achieved with the oral version are similar to those with the intravenous route. This property allows early conversion to oral therapy,
Elimination
Among the quinolones, differences in elimination are important. Levofloxacin and ofloxacin depend entirely on renal elimination, and therefore careful dose adjustment is necessary, even with minor changes in renal function.
Because of the lipophilic structure of some of the third-and fourth-generation quinolones (grepafloxacin, sparfloxacin, and trovafloxacin), these agents have preferential hepatic metabolism.9 Grepafloxacin and trovafloxacin are eliminated entirely by the hepatic route, and no
Drug Interactions
The principal drug interaction, impaired absorption of the quinolones by coadministration of multivalent metal cations, was previously mentioned. The quinolones should be administered at least 2 hours (longer for grepafloxacin because of its slower rate of absorption) before these cationic compounds. The absorption of trovafloxacin is also reduced by the use of morphine.19
In contrast to ciprofloxacin, the third-and fourth-generation quinolones do not seem to inhibit theophylline or caffeine
Safety
The quinolones are tolerated as well as or better than any other class of antibacterial agents. The frequency of gastrointestinal upset is about 5%. Allergic reactions, including rash, urticaria, and photosensitivity, occur in 1 to 2% of patients. Agents with an additional fluorine or chloride at position 8 (for example, lomefloxacin and sparfloxacin) have more phototoxicity, which can be reduced if the dose is taken at night.30
Trovafloxacin is associated with a high frequency of dizziness
Resistance to Fluoroquinolones
With widespread use of the fluoroquinolones, selective pressure is exerted on patient populations, particularly those in intensive-care and specialized-care units in hospitals. This selective pressure results in the emergence of quinolone-resistant bacteria.34
For S. aureus and P. aeruginosa, only single mutations in the genes for topoisomerases are needed for resistance, which occurs at a rate of 10−7 to 10−9. Resistance to quinolones in S. aureus also emerges more rapidly among strains that
Summary
No class of antimicrobial agents is exempt from bacterial resistance, particularly when widespread use exerts selective pressure. If quinolone use can be limited to patients in whom first-line therapies are not feasible, then the utility of the quinolones can be perpetuated. With the increasing rate of bacterial resistance among other agents, the quinolones will likely gain more first-line indications in the future.38
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