C difficile and FQ resistance. The extent to which Clostridium difficile-associated diarrhea (CDAD) is attributable to FQs has been subject to controversy in recent years. A previously uncommon strain of C difficile (B1/NAP1) with variations that have become more resistant to FQs has been linked to an increased incidence of CDAD across both the United States and Europe.13 A systematic review suggested that FQs predispose patients to CDAD,14 while a retrospective case-control study of 174 adult inpatients with CDAD determined that FQ administration did not significantly increase the rate of complications from C difficile (odds ratio [OR]=1.37; 95% confidence interval [CI], 0.72-2.61).15
Factors that affect risk of hepatotoxicity
Hepatitis/transaminitis, pancreatitis, jaundice, liver injury, and hepatic failure have all been reported in patients taking FQs, with the extent of hepatotoxicity varying based on the particular FQ taken, the dosage, and the patient’s baseline hepatic function.16,17 Comorbidities, including renal failure, may increase the potential for FQ-associated hepatotoxicity, as well. Thus, some experts recommend that clinicians evaluate a patient’s liver function before initiating FQ therapy and avoid prescribing FQs for those at added risk.
The exact mechanism by which FQ-induced hepatotoxicity occurs is unknown. One theory posits that the drugs generate oxidative radicals involved in mitochondrial damage, RNA processing, transcription, and inflammation;18 another suggests that FQs generate oxidative radicals in the liver as a result of cytochrome P450 metabolism.16 Case reports have shown that hepatitis resolves when the drug is discontinued, but often recurs in patients who are switched to a different FQ.16,17
Torsades de pointes is the key cardiovascular risk
FQs prolong the QT interval by blocking voltage-gated potassium channels, causing a reduction of the rapid component of the delayed rectifier potassium current in a dose-dependent fashion.19 But the average QT interval prolongation caused by FQs over a 3- to 6-month period does not appear to have clinical significance, nor is it associated with any discernible cardiac symptoms or impairment.19
For most, risk is minimal. There appears to be considerable variation in QT interval prolongation among FQs. A retrospective database analysis of published case reports of patients who received FQs over a 15-year period found 25 cases of torsades de pointes; moxifloxacin (highest), levofloxacin, and gatifloxacin (which was taken off the market by the FDA in 2006)20 were associated with a higher incidence than ciprofloxacin.21 Ciprofloxacin appears to be the safest FQ for cardiovascular events, with the lowest reported risk of torsades de pointes.22 However, several small randomized controlled trials have found that levofloxacin, like ciprofloxacin, did not significantly affect the QT interval.23,24
These patients face a higher risk. Notably, individuals with abnormal baseline QT prolongation (>440 ms in men; >460 ms in women) are at increased risk of developing torsades de pointes from the use of FQs, regardless of the dose.19 In fact, anyone with a history of prolonged QT syndrome should avoid these antibiotics, particularly if he or she is taking class Ia (eg, procainamide, quinidine) or class III (eg, amiodarone, sotalol) antiarrhythmics.19 Patients taking warfarin may be candidates for FQ therapy, but because the antibiotics may potentiate the anticoagulant, close monitoring is required. (Other potential drug-drug interactions are detailed in the TABLE.)
Evaluation of risk vs benefit is imperative prior to prescribing FQs for patients with increased risk for adverse cardiovascular events. An electrocardiogram is advisable, as well.
Mild neurologic and psychiatric effects not uncommon
Studies examining central nervous system (CNS) effects have estimated that neurotoxicity occurs in approximately 1% to 4.4% of patients taking FQs, with serious adverse effects occurring less than 0.5% of the time.25 Common—and milder—CNS effects include headache, dizziness, and insomnia. More severe CNS effects include tremors, restlessness, anxiety, light-headedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, and suicidal thoughts or attempts.25,26 Case reports have documented FQ-induced psychosis, catatonia, seizures, and delirium, with a higher incidence associated with higher doses of the antibiotic.26
A literature review aimed at identifying case reports yielded reports of 232 adverse psychiatric and neurologic drug reactions attributable to FQs in 145 patients.27 Nearly half were related to ciprofloxacin, with psychiatric reactions such as mania and acute psychosis being the most common. Most adverse CNS events (eg, convulsion, confusional state, agitation) developed rather quickly—in some cases within a few minutes of FQ administration and in others, within the first one to 8 days. In most reported cases, the patients had no known underlying psychiatric diseases or concomitant medication likely to have precipitated the development of delirium, psychosis, or seizures.28