Elsevier

Mayo Clinic Proceedings

Volume 74, Issue 10, October 1999, Pages 1030-1037
Mayo Clinic Proceedings

Symposium on Antimicrobial Agents—Part XIII
The Fluoroquinolones

https://doi.org/10.4065/74.10.1030Get rights and content

The quinolones are broad-spectrum antibacterial agents that have a novel mechanism of action. As synthetic compounds, these agents have been developed extensively to optimize antimicrobial activity, pharmacokinetic properties, and drug safety. Although earlier quinolones were effective only in the genitourinary and gastrointestinal tracts and only had activity against aerobic gram-negative bacteria, newer quinolones have wider potential applications and a broader spectrum of activity. Some of the newer quinolones will have a role in the treatment of community-acquired pneumonia and intra-abdominal infections. Ciprofloxacin remains the most potent quinolone against Pseudomonas aeruginosa. Among the quinolones, important differences exist in renal and hepatic elimination and dose-adjustment regimens. Although there are many Food and Drug Administration-approved indications for some of the newer quinolones, the quinolones are the drug of choice for only a few infections. Quinolone-resistant bacteria are being increasingly identified and emerge under selective pressure created by extensive use.

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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