By Jeremy Vandiver
Harrison School of Pharmacy
Auburn (AL) University
With their unique mechanism of action, relatively limited side effect profile, and clinically useful spectrum of activity, fluoroquinolones (FQs) are playing a larger role in treatment of infections. Since their discovery in the 1960s, the original nalidixic acid structure has been continually modified to improve FQ pharmacokinetic profiles and spectrum of coverage. This, coupled with the ability of the FQs to concentrate in some tissues, fluids, and cells of the immune system, has led to a dramatic increase in FQ therapy. This increased utilization involves FQ use in complex situations with multiple drugs being used to treat numerous conditions. It is in these situations that today’s health care practitioner can make an impact by assuring that interactions between the FQs and the patient’s concomitant drug therapy do not compromise patient outcomes. This article highlights interactions with three of the most commonly used FQs: ciprofloxacin, levofloxacin, and gatifloxacin.
The most common FQ interaction known to health care professionals involves their administration with multivalent cations. Through chelation reactions, FQs form complexes with aluminum, calcium, iron, magnesium, and zinc salts. This interaction explains the dramatic decrease in absorption when FQs are administered with antacids, didanosine, iron formulations, multivitamins, sucralfate, and foods high in calcium (e.g., ciprofloxacin can be decreased by >50%-75%). Recommendations for avoiding this interaction when any of these combinations are necessary include administering the agents four to six hours before or one to two hours after the FQ. These are especially pertinent interactions, because they can result in subtherapeutic levels of the FQ and possibly therapeutic failure.
Other interactions with the FQs are related to their hepatic inhibition of the cytochrome P450 isoenzyme 1A2 enzyme system. While ciprofloxacin and levofloxacin have varying degrees of effect on this system, gatifloxacin is the exception, with no known enzyme inhibition interactions. Ciprofloxacin tends to have more pronounced effects than does levofloxacin. Drugs that may be affected include phenytoin, theophylline, caffeine, clozapine, olanzapine, ropinirole, and warfarin. While these interactions are all theoretically possible, there is some doubt regarding the clinical significance of each in the short-term setting. Recommendations for management would include selecting another antibiotic or monitoring more closely for the increased side effects of the object drug if a FQ and one of the mentioned agents are intended to be used concomitantly. There is a significant interpatient variability with these interactions.
Drug interactions that affect the central nervous system have also been proposed with some FQ agents. FQs have been associated with an increased risk of central nervous system stimulation and possibly seizure when administered concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs) or foscarnet. While a theory involving GABA receptors has been proposed for the interaction of NSAIDs with FQs, the mechanism of the foscarnet interaction is theorized to be an additive toxicity effect. Although the incidence is rare, these combinations should be avoided when possible.
Interactions that involve renal considerations include cyclosporine and probenecid. Cyclosporine administration concomitant with FQs has resulted in elevated cyclosporine levels. Administration of probenecid with FQs has led to decreased elimination of FQs and therefore higher concentrations.
Prolongation of the QTc interval is also a concern with use of the FQs. This is represented as a class effect and should be taken into consideration during therapy. While data are lacking at this time to determine the rate of occurrence of this reaction, current recommendations state that the use of FQs with class IA and III antiarrhythmics be avoided, as well as with other drugs suspected of causing QTc prolongation.
FQ interactions causing hyper- or hypoglycemia in patients receiving antidiabetic agents are also receiving renewed interest. The gatifloxacin package insert has been changed to include this interaction in its "Warnings" section. Levofloxacin and ciprofloxacin currently mention this interaction in their "Precautions" sections. These interactions are believed to occur rarely (hypoglycemia incidence with gatifloxacin ~0.55%), but patients receiving one of the above FQs and an antidiabetic agent should have their glucose levels monitored appropriately for their individual situation.
Other drug interactions are known to occur with the FQs. However, this article only illustrates some of the more commonly recognized interactions. A table is provided below that includes other interactions not mentioned in the text; these vary in clinical significance. The text and table should not be considered a complete list of all FQ interactions.
In conclusion, the FQs are an extensively used group of antibiotics that will likely continue to be frequently utilized. However, their use in complex clinical care will continue to create situations involving drug interactions that the health care practitioner will need to evaluate and manage appropriately to provide optimal patient outcomes. (See tables 8 and 9)
References
• Ciprofloxacin (monograph in electronic version). Clinical Pharmacology 2000. Gold Standard Multimedia 2002.
• Ciprofloxacin. In: McEvoy GK, ed. AHFS 2002: Drug Information. Bethesda, MD: American Society of Health System Pharmacists; 2002:775.
• Ciprofloxacin. Drug Information Handbook 2001-2002. 9th ed. Canada. Lexi-Comp; 2001:266.
• Ciprofloxacin. Drug Interactions: Analysis and Management. St. Louis; Facts and Comparisons:3-5.
• Ciprofloxacin (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: Micromedex; 2001.
• Ciprofloxacin. Physicians’ Desk Reference. 55th ed. Montvale, NJ: Medical Economics Co.; 2001:847-52.
• Gatifloxacin (monograph in electronic version). Clinical Pharmacology 2000. Gold Standard Multimedia 2002.
• Gatifloxacin. In: McEvoy GK, ed. AHFS 2002: Drug Information. Bethesda, MD: American Society of Health System Pharmacists; 2002:787.
• Gatifloxacin. Drug Information Handbook 2001-2002. 9th ed. Canada. Lexi-Comp; 2001:559.
• Gatifloxacin (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: Micromedex; 2001.
• Gatifloxacin. Physicians’ Desk Reference. 55th ed. Montvale, NJ: Medical Economics Co.; 2001:1025-30.
• Levofloxacin (monograph in electronic version). Clinical Pharmacology 2000. Gold Standard Multimedia 2002.
• Levofloxacin. Drug Information Handbook 2001-2002. 9th ed. Canada. Lexi-Comp; 2001:711.
• Levofloxacin. Drug Interactions: Analysis and Management. St. Louis; Facts and Comparisons:3-5.
• Levofloxacin. Physicians’ Desk Reference. 55th ed. Montvale, NJ: Medical Economics Co.; 2001:2338-44.
• Levofloxacin (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: Micromedex; 2001.
• Personal communication. Cindy Hall, pharmacy buyer, Huntsville (AL) Hospital System. May 2002.
• Reinke CM, DeRuiter J. "The Quinolone Antibacterial Agents." Class Handout. Auburn (AL) University School of Pharmacy. February 2001.
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