Fluoroquinolones: Focus on Safety

Fluoroquinolones are bactericidal agents that exhibit concentration-dependent killing against a broad spectrum of pathogens. The high oral bioavailability of some fluoroquinolones allows for convenient 1:1 interchangeable dosing between intravenous and oral formulations. Extensive tissue penetration, particularly against respiratory secretions and in intracellular compartments, is another desirable feature of fluoroquinolones. These agents are prescribed for a variety of infections, primarily respiratory tract infections, sexually transmitted diseases, urinary tract infections, and skin/soft tissue infections.

Uses

Nalidixic acid was the first fluoroquinolone, introduced in 1962. The many limitations?including poor systemic distribution, short half-life, and narrow spectrum of activity?restricted the clinical application of first-generation fluoroquinolones.^1,2 Second-generation fluoroquinolones?norfloxacin (introduced in 1986) and lomefloxacin (1992)?have expanded coverage against the gram-negative Enterobacteriaceae. Other second-generation fluoroquinolones, including ciprofloxacin (1987) and ofloxacin (1990), are active against Enterobac-teriaceae (including Pseudomonas aeruginosa?ciprofloxacin only) as well as atypical intracellular pathogens (Chlamydia, Legionella, and Mycoplasma species).

In addition to coverage of the gram-negative and atypical organisms, third-generation fluoroquinolones?levofloxacin (1996), gatifloxacin (1999), moxifloxacin (1999), and gemifloxacin (2003)?are active against gram-positive aerobic bacteria, particularly Streptococcus pneumoniae. Trovafloxacin, the fourth-generation fluoroquinolone introduced in 1997, has enhanced activity against gram-positive pathogens and additional coverage against anaerobic pathogens.

Side Effects

Fluoroquinolones are well tolerated and relatively safe.³ Common side effects, generally mild and reversible, involve the gastrointestinal (GI) tract, the skin, and the central nervous system (CNS). The incidences of specific adverse effects are listed in the Table.^1,4-6

The most common side effects of all fluoroquinolones are GI-related and include nausea, anorexia, and dyspepsia.⁴ Dermatologic adverse effects also may occur, either with initial (within a few hours) or previous exposure to these drugs.⁷ The degree of severity ranges from mild erythema to extensive bullous lesions.

Phototoxicity

Severe phototoxic reactions, consisting of second-degree burns that have required hospitalization, have occurred with sparfloxacin. Exposure to ultraviolet A rays from direct or indirect sunlight should be avoided during treatment and several days (5 days with sparfloxacin) after the use of the drug.⁸ The degree of phototoxic potential of fluoroquinolones is as follows: lomefloxacin > sparfloxacin > ciprofloxacin or grepafloxacin.⁴ Photosensitive reactions have been reported in 2.3% of patients receiving lomefloxacin, and recovery may take several weeks.⁹ The risk of phototoxicity with other fluoroquinolones, including the recently approved gemifloxacin, is limited.

CNS Effects

CNS adverse effects?primarily headache, dizziness, and drowsiness?have been reported with all fluoroquinolones.^6,10 Trovafloxacin, gatifloxacin, moxifloxacin, ofloxacin, and sparfloxacin have slightly higher rates of CNS effects.^4,6 Severe CNS effects, including seizures, have been reported in patients receiving trovafloxacin. No seizures have been reported with levofloxacin, moxifloxacin, gatifloxacin, and gemifloxacin.¹⁰ Seizures may develop within 3 to 4 days of therapy but resolve with drug discontinuation.⁵ Although seizures are infrequent, fluoroquinolones should be avoided in patients with a history of convulsion, cerebral trauma, or anoxia. Phototoxicity and CNS disturbances have been shown to be associated with chemical modification of the fluoroquinolone structure.^11,12

Musculoskeletal Effects

Concern about the development of musculoskeletal effects, evident in animal studies, has led to the contraindication of fluoroquinolones for routine use in children and in women who are pregnant or lactating. Although arthropathy (1%) and arthralgia (1.5%) have been observed in humans, these effects have been rare and mostly reversible, without leading to long-term sequelae.^13-16 Arthropathy of weight-bearing joints commonly has occurred in patients <30 years of age and has resolved within days to weeks after drug discontinuation.⁶ At least 10 cases of arthropathy associated with fluoroquinolone use, particularly with pefloxacin (marketed in Europe), have been reported in children.¹³

Tendinitis and tendon rupture, mostly involving the Achilles tendon, have occurred in <1% of patients.⁴ Inflammation may persist for >2 months after drug discontinuation.¹⁷ Potential risk factors for tendinopathy include age >50 years, male gender, and concomitant use of corticosteroids.^14,17,18 A recent study found that the use of fluoroquinolones was associated with tendon or join disorders in <1% of children?similar to the incidence with the comparator azithromycin.¹⁹ Data now suggest that the use of these drugs in the pediatric population should be based on risk-to-benefit considerations.^1,6,13,20 Notably, ciprofloxacin recently received approval from the FDA for use in pediatrics. For use during pregnancy, evidence suggests that exposure to these agents (mostly norfloxacin and ciprofloxacin) does not increase the risk for congenital malformations or musculoskeletal effects.^21,22

Hepatoxicity

Elevations in serum transaminases and alkaline phosphatase (above 2-3 times the normal upper limit) are the most common adverse effects on the liver. The overall incidence is 2% to 3% in patients receiving fluoroquinolones.^4,6 Postmarketing surveillance detected 14 cases of acute hepatic failure associated with the use of trovafloxacin for longer than 2 weeks.²³ This severe manifestation of hepatotoxicity resulted in 4 liver transplantations and 5 deaths. After 2 years on the market, trovafloxacin became recommended for restricted use in severe, lifethreatening infections in hospitalized patients.²⁴ Duration of therapy should not exceed 14 days. Severe hepatotoxicity has been observed rarely with other fluoroquinolones.^6,25

Cardiovascular Effects

This class of drugs has been associated with corrected QT (QTc) interval prolongation. Although the incidence is rare, QTc prolongation can be clinically significant and can lead to torsades de pointes, a potentially fatal ventricular tachycardia.²⁶ Specific fluoroquinolones produce these dosedependent cardiac effects with varying incidence and severity.⁶ Evidence suggests that sparfloxacin and grepafloxacin may have the most cardiotoxic potential.^27,28 The incidence of QTc prolongation and of a mean increase in QTc interval are 0.3% to 2.4% and 3%, respectively, in patients receiving sparfloxacin.^29-31 Both sparfloxacin and grepafloxacin have been associated with torsades de pointes and sudden cardiac deaths.^26,29 Consequently, grepafloxacin was voluntarily removed from the market in 1999.³⁰ An international safety board reviewed sparfloxacin and concluded that the risk for QTc prolongation was minimal when this drug was used alone.²⁹ Its concomitant administration with medications that increase the QTc should be avoided, however.

Cases of torsades de pointes have been reported infrequently with other fluoroquinolones (gatifloxacin > levofloxacin > ofloxacin > ciprofloxacin > moxifloxacin).^26,32 Because gemifloxacin was approved only recently, post-marketing surveillance is necessary to determine its impact on QTc prolongation. Although the risk for significant cardiac toxicity with fluoroquinolones (excluding sparfloxacin and grepafloxacin) is extremely minimal, precautionary statements regarding QTc prolongation now appear on the product labels. Fluoroquinolones should be avoided in patients with existing QTc prolongation, significant bradycardia, cardiomyopathy, or hypokalemia.^6,27 They also should be avoided in patients receiving Class IA/III antiarrhythmics (eg, quinidine, amiodarone, sotalol) or other agents that may prolong the QTc (eg, erythromycin, quinine, tricyclic antidepressants).³³ If the use of fluoroquinolones is necessary in these patients, careful monitoring with an electrocardiogram and Holter monitor should be strongly considered.²⁷

Hypoglycemia/Hyperglycemia

Recently, rare cases of hypoglycemia have been reported with gatifloxacin and ciprofloxacin in patients also receiving oral diabetic medications, primarily sulfonylureas.^34-37 Although hypoglycemia has been reported with other fluoroquinolones (levofloxacin and moxifloxacin), the effects have been mild and appear to be unrelated to the fluoroquinolones.^38,39

Hyperglycemia also has been linked with the use of gatifloxacin.^37,40 The exact mechanism of the effects on glucose homeostasis by fluoroquinolones is unclear. Gatifloxacin, however, has been shown to briefly increase serum insulin concentration.⁴¹ Careful monitoring of serum glucose should be considered when initiating fluoroquinolones in diabetic patients who are controlled by medications.

Dr. Le is an assistant professor of pharmacy practice in the College of Pharmacy at Western University of Health Sciences, Pomona, Calif.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to:astahl@mwc.com.