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• Evaluate liver function before initiating fluoroquinolone (FQ) therapy, and avoid prescribing these antibiotics for patients at increased risk for hepatotoxicity. C
• Avoid prescribing FQs for patients with a history of prolonged QT syndrome. C
• Closely monitor older patients being treated with FQs, particularly if they have atherosclerosis or epilepsy. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
PATIENT HANDOUT
Taking a fluoroquinolone antibiotic?
CASE Sara Z, a 62-year-old patient with a history of chronic urinary tract infections, presents with a 3-day history of dysuria and urinary frequency. Her last 2 urine cultures found Escherichia coli resistant to trimethoprim-sulfamethoxazole, amoxicillin, and cephalosporins. So her family physician ordered a urine culture and prescribed a 7-day course of ciprofloxacin empirically.
Five days later, Ms. Z returned, suffering from nonbloody diarrhea and bilateral Achilles tendon pain.
If you were treating Ms. Z, what would your next step be?
Widely used to treat urinary tract, skin, and pulmonary infections and to fight infections resistant to other antibiotics, fluoroquinolones (FQ) are generally regarded as safe in both inpatient and outpatient settings. Yet these broad-spectrum antibiotics are associated with both common and rare adverse effects, as well as a number of drug-drug interactions.
The Centers for Disease Control and Prevention estimates that adverse events from FQs leading to emergency department (ED) visits occur at a rate of 9.2 for every 10,000 prescriptions. That’s higher than the ED rates for cephalosporins (6.1 per 10,000) and macrolides (5.1 per 10,000), but far lower than for penicillins (13 per 10,000), clindamycin (18.5 per 10,000), sulfonamides (18.9 per 10,000), and vancomycin (24.1 per 10,000).1
In fact, adverse events associated with FQs range from mild and self-limiting to rare and severe. This review discusses both. Relatively common adverse effects and drug-drug interactions are discussed in the text, while the TABLE2 includes a broader range of potential adverse effects. You’ll also find a handout for patients taking FQs on page 195 that clearly describes signs and symptoms that need to be reported right away.
TABLE
Fluoroquinolones: Adverse effects to guard against*2
Cardiovascular
| Immunologic
|
Dermatologic
| Musculoskeletal
|
Drug-drug interactions
| Neurologic
|
Endocrine/Metabolic
| Ocular
|
Gastrointestinal
| Psychiatric
|
Hematologic
| Respiratory
|
| *This is not a complete list of potential adverse effects associated with fluoroquinolones. †Fluoroquinolones may potentiate warfarin. | |
A black box warning of tendinopathies
FQs exhibit an affinity for connective tissue, with higher concentrations found in bone and cartilage than in serum. While FQs are therefore well suited for treating orthopedic-related infections,3 they also increase the risk of tendinopathies.
In the last 2 decades, numerous case reports linking tendinitis and FQs have been published.4-6 In 2008, the US Food and Drug Administration (FDA) issued a black box warning of tendinitis and tendon rupture. Patients on FQ therapy should be advised to stop taking the antibiotic at the first sign of pain, swelling, or inflammation in a tendon, the FDA advises.7
How common is this adverse effect? A case-control study of 22,194 patients with a diagnosis of nontraumatic tendiopathy determined that FQ use resulted in a 1.3-fold risk of tendon rupture and more than a 4-fold risk of rupture of the Achilles tendon. One Achilles tendon rupture would occur for every 5958 patients treated with FQs, the researchers estimated.8
The precise mechanism by which FQs lead to tendinopathies is not completely understood. Studies suggest that the antibiotics cause a decrease in the synthesis of type I collagen, elastin, fibronectin, and beta (1)-integrin, and time- and concentration-dependent increases of cellular apoptosis.9 In vitro studies have shown inhibition of both cell proliferation and fibroblast metabolism when tissue is exposed to FQs, which may impede tissue healing.10
Which patients are at higher risk? The risk of FQ-associated tendinopathies is greatest in patients older than 60 years; in kidney, heart, and lung transplant recipients; and in patients taking an FQ with concomitant corticosteroid therapy. Decreased renal clearance of the medication may play a role in the increased risk.11
GI problems are common, especially in kids and older patients
Gastrointestinal (GI) disturbances are common in patients taking FQs, and typically occur more frequently in children and older adults, and in those taking higher doses. Reactions attributable to ciprofloxacin, for example, include nausea (affecting 1.4%-4% of adults and 2.7% of children taking the drug), vomiting (1%-2% of adults and 4.8% of children), diarrhea (<1%-2% of adults and 4.8% of children), and abdominal pain or discomfort (<1%-1.7% of adults and 3.3% of children).12
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
Monitor older adults taking FQs. Because the risk of psychiatric adverse events is greatest in older individuals, especially those with known atherosclerotic disease or epilepsy, FQ therapy should be used cautiously—and with close monitoring—in this patient population. Symptoms such as weakness, confusion, tremor, loss of appetite, and depression are often incorrectly attributed simply to age, and thus go unreported as potential adverse effects of FQs.29 The exact mechanism by which FQs may induce seizures is unknown, but it may be related to excitatory effects at GABA receptors in the hippocampus.30
FQs may affect glucose levels
FQs have been reported to have varying effects on glucose metabolism, and have been implicated in both hypo- and hyperglycemia. FQ-related hypoglycemia has been thought to occur as a result of an increase in insulin secretion through a sulfonylurea-like action on pancreatic beta cells,31 via drug-drug interactions in patients with renal impairment,32 or via cytochrome P450 interactions.33 The mechanism of action relating to hyperglycemia is less well understood.
One retrospective cohort study in outpatients at a Veterans Administration facility sought to identify outcomes of hospitalization with a primary diagnosis of either hypo- or hyperglycemia in patients with a new prescription for either an FQ or azithromycin.34 In patients with diabetes, the OR for FQ-associated hypoglycemia (compared with azithromycin) was 2.1 for levofloxacin (95% CI, 1.4-3.3) and 1.1 for ciprofloxacin (95% CI, 0.6-2.0). The ORs for hyperglycemia were 1.8 for levofloxacin (95%, CI 1.2-2.7) and 1.0 for ciprofloxacin (95% CI, 0.6-1.8).
A retrospective chart review of more than 17,000 hospitalized patients who were receiving either an FQ or ceftriaxone revealed that 101 patients had either high (>200 mg/dL) or low (<50 mg/dL) glucose levels within 72 hours of receiving the antibiotic.35 Nearly 89% of those studied had diabetes and 40% had prescriptions for oral hypoglycemic agents. While most of these patients had underlying renal insufficiency, rates of hyperglycemia were greater with levofloxacin than with ceftriaxone. (In this study and the VA study, gatifloxacin had greater effects on glucose levels than the non-FQ antibiotics they were compared with; as noted earlier, however, gatifloxacin was removed from the US market in 2006.)
Diplopia is the most common ophthalmologic effect
A database review found 171 case reports of diplopia associated with FQs; ciprofloxacin was the most commonly implicated FQ, with 75 cases. The median time between medication initiation and the development of diplopia was 9.6 days. Most FQ-associated diplopia is completely reversible upon cessation of drug therapy, as evidenced by 53 published reports in which that was the case.36
Adverse effects of intraocular FQs. Ocular keratitis, corneal infiltrates and precipitates, and delayed corneal epithelial healing have been linked to the administration of intraocular FQs.36-38 In addition, retinal detachment has been found to occur in 3.3% of patients being treated with intraocular FQs, compared with 0.6% of controls (adjusted rate ratio=4.50; number needed to harm= 2500).39
CASE Suspecting CDAD and Achilles tendinitis secondary to ciprofloxacin, you stop the medication. Ms. Z’s urine culture is positive for Klebsiella pneumoniae, which is also sensitive to nitrofurantoin, so a 7-day course is prescribed. And, because a stool test for C difficile is positive, you prescribe a 7-day course of metronidazole, as well. Within 4 weeks of stopping the ciprofloxacin, the Achilles tendinitis had completely resolved.
CORRESPONDENCE
Joel J. Heidelbaugh, MD, Ypsilanti Health Center, 200 Arnet Suite 200, Ypsilanti, MI 48198; [email protected]
1. Shehab N, Patel PR, Srinivasan A, et al. Emergency department visits for antibiotic-associated adverse events. Clin Infect Dis. 2008;47:735-743.
2. Poisindex System. Ann Arbor, Mich: Truven Health Analytics.
3. Melhus A, Apelqvist J, Larsson J, et al. Levofloxacin-associated Achilles tendon rupture and tendinopathy. Scand J Infect Dis. 2003;35:768-770.
4. Damuth E, Heidelbaugh JJ, Malani PN, et al. Case report: an elderly subject with fluoroquinolone-associated Achilles tendinitis. Am J Geriatr Pharmacother. 2008;6:264-268.
5. Gold L, Igra H. Levofloxacin-induced tendon rupture: a case report and review of the literature. J Am Board Fam Pract. 2003;16:458-460.
6. Haddow LJ, Chandra Sekhar M, Hajela V, et al. Spontaneous Achilles tendon rupture in patients treated with levofloxacin. J Antimicrob Chemother. 2003;51:747-748.
7. US Food and Drug Administration. Information for healthcare professionals: fluoroquinolone antimicrobial drugs Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126085.htm. Accessed September 30, 2012.
8. Corrao G, Zambon A, Bertu L, et al. Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study. Drug Saf. 2006;29:889-896.
9. Sendzik J, Shakibaei M, Schafer-Korting M, et al. Fluoroquinolones cause changes in extracellular matrix, signaling proteins, metalloproteinases and caspase-3 in cultured human tendon cells. Toxicology. 2005;212:24-36.
10. Corps AN, Harrall RL, Curry VA, et al. Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin-1beta in human tendon-derived cells: a potential mechanism of fluoroquinolone-induced tendinopathy. Arthritis Rheum. 2002;46:3034-3040.
11. Muzi F, Gravanta G, Tati E, et al. Fluoroquinolones-induced tendinitis and tendon rupture in kidney transplant recipients: 2 cases and a review of the literature. Transplant Proc. 2007;39:1673-1675.
12. Cholongitas E, Georgousaki C, Spyrou S, et al. Ciprofloxacin-induced acute cholestatic hepatitis. Ann Hepatol. 2009;8:400-401.
13. Denève C, Janoir C, Poilane I, et al. New trends in Clostridium difficile virulence and pathogenesis. Int J Antimicrob Agents. 2009;33(suppl 1):S24-S28.
14. Deshpande A, Pant C, Jain A, et al. Do fluoroquinolones predispose patients to Clostridium difficile associated disease? A review of the evidence. Curr Med Res Opin. 2008;24:329-333.
15. Novelle M, Morreale CA. The relationship between inpatient fluoroquinolone use and Clostridium difficile-associated diarrhea. Ann Pharmacother. 2010;44:826-831.
16. Adikwu E, Deo O. Fluoroquinolones reported hepatotoxicity. Pharmacology Pharmacy. 2012;3:328-336.
17. Nicholson SC, Webb CD, Moellering RC. Antimicrobial-associated acute hepatitis. Pharmacotherapy. 2002;22:794-797.
18. Labbe G, Pessayre D, Fromenty B. Drug-induced liver injury through mitochondria dysfunction: mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol. 2008;22:335-353.
19. Mitcheson JS, Chen J, Lim M, et al. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci. 2000;97:12329-12333.
20. US Food and Drug Administration. Determination that Tequin (gatifloxacin) was withdrawn from sale for reasons of safety or effectiveness. Fed Regist. 2008;73:52357-52358.
21. Rubinstein E, Camm J. Cardiotoxicity of fluoroquinolones. J Antimicrob Chemother. 2002;49:593-596.
22. Briasoulis A, Agarwal V, Pierce WJ. QT prolongation and torsade de pointes induced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology. 2011;120:103-110.
23. Prabhakar M, Krahn AD. Ciprofloxacin-induced acquired long QT syndrome. Heart Rhythm. 2004;1:624-626.
24. Demolis JL, Kubitza D, Tenneze L, et al. Effect of a single oral dose of moxifloxacin (400 and 800 mg) on ventricular repolarization in healthy subjects. Clin Pharmacol Ther. 2000;68:658-666.
25. Tome AM, Filipe A. Quinolones: review of psychiatric and neurological adverse reactions. Drug Saf. 2011;34:465-488.
26. Kiangkitiwan B. Levofloxacin-induced delirium with psychotic features. Gen Hosp Psychiatry. 2008;30:381-383.
27. Carbon C. Comparison of side effects of levofloxacin versus other fluoroquinolones. Chemotherapy. 2001;47(suppl 3):S9-S14.
28. LaSalvia EA, Domek GJ, Gitlin DF. Fluoroquinolone-induced suicidal ideation. Gen Hosp Psychiatry. 2010;32:108-110.
29. Stahlmann R, Lode H. Safety considerations of fluoroquinolones in the elderly: an update. Drugs Aging. 2010;27:193-209.
30. Owens RC, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis. 2005;41(suppl):S144-S157.
31. Smith KM, Lomaestro BM. What role do fluoroquinolone antimicrobial agents play in cardiac dysfunction and altered glycemic control? J Pharm Pract. 2003;16:349-360.
32. LeBlanc M, Belanger C, Cossette P. Severe and resistant hypoglycemia associated with concomitant gatifloxacin and glyburide therapy. Pharmacotherapy. 2004;24:926-931.
33. Graumlich JF, Habis S, Avelino RR, et al. Hypoglycemia in inpatients after gatifloxacin or levofloxacin therapy: nested case control study. Pharmacotherapy. 2005;25:1296-1302.
34. Aspinall SL, Good CB, Jiang R, et al. Severe dysglycemia with the fluoroquinolones: a class effect? Clin Infect Dis. 2009;49:402-408.
35. Mohr JF, McKinnon PS, Peymann PJ, et al. A retrospective, comparative evaluation of dysglycemias in hospitalized patients receiving gatifloxacin, levofloxacin, ciprofloxacin, or ceftriaxone. Pharmacotherapy. 2005;25:1303-1309.
36. Fraunfelder FW, Fraunfelder FT. Diplopia and fluoroquinolones. Ophthalmology. 2009;116:1814-1817.
37. Eiferman RA, Snyder JP, Nordquist RE. Ciprofloxacin microprecipitates and macroprecipitates in the human corneal epithelium. J Cataract Refract Surg. 2001;27:1701-1702.
38. Fraunfelder FW. Corneal toxicity from topical ocular and systemic medications. Cornea. 2006;25:1133-1138.
39. Etminan M, Forooghian F, Brophy JM, et al. Oral fluoroquinolones and the risk of retinal detachment. JAMA. 2012;307:1414-1419.
• Evaluate liver function before initiating fluoroquinolone (FQ) therapy, and avoid prescribing these antibiotics for patients at increased risk for hepatotoxicity. C
• Avoid prescribing FQs for patients with a history of prolonged QT syndrome. C
• Closely monitor older patients being treated with FQs, particularly if they have atherosclerosis or epilepsy. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
PATIENT HANDOUT
Taking a fluoroquinolone antibiotic?
CASE Sara Z, a 62-year-old patient with a history of chronic urinary tract infections, presents with a 3-day history of dysuria and urinary frequency. Her last 2 urine cultures found Escherichia coli resistant to trimethoprim-sulfamethoxazole, amoxicillin, and cephalosporins. So her family physician ordered a urine culture and prescribed a 7-day course of ciprofloxacin empirically.
Five days later, Ms. Z returned, suffering from nonbloody diarrhea and bilateral Achilles tendon pain.
If you were treating Ms. Z, what would your next step be?
Widely used to treat urinary tract, skin, and pulmonary infections and to fight infections resistant to other antibiotics, fluoroquinolones (FQ) are generally regarded as safe in both inpatient and outpatient settings. Yet these broad-spectrum antibiotics are associated with both common and rare adverse effects, as well as a number of drug-drug interactions.
The Centers for Disease Control and Prevention estimates that adverse events from FQs leading to emergency department (ED) visits occur at a rate of 9.2 for every 10,000 prescriptions. That’s higher than the ED rates for cephalosporins (6.1 per 10,000) and macrolides (5.1 per 10,000), but far lower than for penicillins (13 per 10,000), clindamycin (18.5 per 10,000), sulfonamides (18.9 per 10,000), and vancomycin (24.1 per 10,000).1
In fact, adverse events associated with FQs range from mild and self-limiting to rare and severe. This review discusses both. Relatively common adverse effects and drug-drug interactions are discussed in the text, while the TABLE2 includes a broader range of potential adverse effects. You’ll also find a handout for patients taking FQs on page 195 that clearly describes signs and symptoms that need to be reported right away.
TABLE
Fluoroquinolones: Adverse effects to guard against*2
Cardiovascular
| Immunologic
|
Dermatologic
| Musculoskeletal
|
Drug-drug interactions
| Neurologic
|
Endocrine/Metabolic
| Ocular
|
Gastrointestinal
| Psychiatric
|
Hematologic
| Respiratory
|
| *This is not a complete list of potential adverse effects associated with fluoroquinolones. †Fluoroquinolones may potentiate warfarin. | |
A black box warning of tendinopathies
FQs exhibit an affinity for connective tissue, with higher concentrations found in bone and cartilage than in serum. While FQs are therefore well suited for treating orthopedic-related infections,3 they also increase the risk of tendinopathies.
In the last 2 decades, numerous case reports linking tendinitis and FQs have been published.4-6 In 2008, the US Food and Drug Administration (FDA) issued a black box warning of tendinitis and tendon rupture. Patients on FQ therapy should be advised to stop taking the antibiotic at the first sign of pain, swelling, or inflammation in a tendon, the FDA advises.7
How common is this adverse effect? A case-control study of 22,194 patients with a diagnosis of nontraumatic tendiopathy determined that FQ use resulted in a 1.3-fold risk of tendon rupture and more than a 4-fold risk of rupture of the Achilles tendon. One Achilles tendon rupture would occur for every 5958 patients treated with FQs, the researchers estimated.8
The precise mechanism by which FQs lead to tendinopathies is not completely understood. Studies suggest that the antibiotics cause a decrease in the synthesis of type I collagen, elastin, fibronectin, and beta (1)-integrin, and time- and concentration-dependent increases of cellular apoptosis.9 In vitro studies have shown inhibition of both cell proliferation and fibroblast metabolism when tissue is exposed to FQs, which may impede tissue healing.10
Which patients are at higher risk? The risk of FQ-associated tendinopathies is greatest in patients older than 60 years; in kidney, heart, and lung transplant recipients; and in patients taking an FQ with concomitant corticosteroid therapy. Decreased renal clearance of the medication may play a role in the increased risk.11
GI problems are common, especially in kids and older patients
Gastrointestinal (GI) disturbances are common in patients taking FQs, and typically occur more frequently in children and older adults, and in those taking higher doses. Reactions attributable to ciprofloxacin, for example, include nausea (affecting 1.4%-4% of adults and 2.7% of children taking the drug), vomiting (1%-2% of adults and 4.8% of children), diarrhea (<1%-2% of adults and 4.8% of children), and abdominal pain or discomfort (<1%-1.7% of adults and 3.3% of children).12
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
Monitor older adults taking FQs. Because the risk of psychiatric adverse events is greatest in older individuals, especially those with known atherosclerotic disease or epilepsy, FQ therapy should be used cautiously—and with close monitoring—in this patient population. Symptoms such as weakness, confusion, tremor, loss of appetite, and depression are often incorrectly attributed simply to age, and thus go unreported as potential adverse effects of FQs.29 The exact mechanism by which FQs may induce seizures is unknown, but it may be related to excitatory effects at GABA receptors in the hippocampus.30
FQs may affect glucose levels
FQs have been reported to have varying effects on glucose metabolism, and have been implicated in both hypo- and hyperglycemia. FQ-related hypoglycemia has been thought to occur as a result of an increase in insulin secretion through a sulfonylurea-like action on pancreatic beta cells,31 via drug-drug interactions in patients with renal impairment,32 or via cytochrome P450 interactions.33 The mechanism of action relating to hyperglycemia is less well understood.
One retrospective cohort study in outpatients at a Veterans Administration facility sought to identify outcomes of hospitalization with a primary diagnosis of either hypo- or hyperglycemia in patients with a new prescription for either an FQ or azithromycin.34 In patients with diabetes, the OR for FQ-associated hypoglycemia (compared with azithromycin) was 2.1 for levofloxacin (95% CI, 1.4-3.3) and 1.1 for ciprofloxacin (95% CI, 0.6-2.0). The ORs for hyperglycemia were 1.8 for levofloxacin (95%, CI 1.2-2.7) and 1.0 for ciprofloxacin (95% CI, 0.6-1.8).
A retrospective chart review of more than 17,000 hospitalized patients who were receiving either an FQ or ceftriaxone revealed that 101 patients had either high (>200 mg/dL) or low (<50 mg/dL) glucose levels within 72 hours of receiving the antibiotic.35 Nearly 89% of those studied had diabetes and 40% had prescriptions for oral hypoglycemic agents. While most of these patients had underlying renal insufficiency, rates of hyperglycemia were greater with levofloxacin than with ceftriaxone. (In this study and the VA study, gatifloxacin had greater effects on glucose levels than the non-FQ antibiotics they were compared with; as noted earlier, however, gatifloxacin was removed from the US market in 2006.)
Diplopia is the most common ophthalmologic effect
A database review found 171 case reports of diplopia associated with FQs; ciprofloxacin was the most commonly implicated FQ, with 75 cases. The median time between medication initiation and the development of diplopia was 9.6 days. Most FQ-associated diplopia is completely reversible upon cessation of drug therapy, as evidenced by 53 published reports in which that was the case.36
Adverse effects of intraocular FQs. Ocular keratitis, corneal infiltrates and precipitates, and delayed corneal epithelial healing have been linked to the administration of intraocular FQs.36-38 In addition, retinal detachment has been found to occur in 3.3% of patients being treated with intraocular FQs, compared with 0.6% of controls (adjusted rate ratio=4.50; number needed to harm= 2500).39
CASE Suspecting CDAD and Achilles tendinitis secondary to ciprofloxacin, you stop the medication. Ms. Z’s urine culture is positive for Klebsiella pneumoniae, which is also sensitive to nitrofurantoin, so a 7-day course is prescribed. And, because a stool test for C difficile is positive, you prescribe a 7-day course of metronidazole, as well. Within 4 weeks of stopping the ciprofloxacin, the Achilles tendinitis had completely resolved.
CORRESPONDENCE
Joel J. Heidelbaugh, MD, Ypsilanti Health Center, 200 Arnet Suite 200, Ypsilanti, MI 48198; [email protected]
• Evaluate liver function before initiating fluoroquinolone (FQ) therapy, and avoid prescribing these antibiotics for patients at increased risk for hepatotoxicity. C
• Avoid prescribing FQs for patients with a history of prolonged QT syndrome. C
• Closely monitor older patients being treated with FQs, particularly if they have atherosclerosis or epilepsy. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
PATIENT HANDOUT
Taking a fluoroquinolone antibiotic?
CASE Sara Z, a 62-year-old patient with a history of chronic urinary tract infections, presents with a 3-day history of dysuria and urinary frequency. Her last 2 urine cultures found Escherichia coli resistant to trimethoprim-sulfamethoxazole, amoxicillin, and cephalosporins. So her family physician ordered a urine culture and prescribed a 7-day course of ciprofloxacin empirically.
Five days later, Ms. Z returned, suffering from nonbloody diarrhea and bilateral Achilles tendon pain.
If you were treating Ms. Z, what would your next step be?
Widely used to treat urinary tract, skin, and pulmonary infections and to fight infections resistant to other antibiotics, fluoroquinolones (FQ) are generally regarded as safe in both inpatient and outpatient settings. Yet these broad-spectrum antibiotics are associated with both common and rare adverse effects, as well as a number of drug-drug interactions.
The Centers for Disease Control and Prevention estimates that adverse events from FQs leading to emergency department (ED) visits occur at a rate of 9.2 for every 10,000 prescriptions. That’s higher than the ED rates for cephalosporins (6.1 per 10,000) and macrolides (5.1 per 10,000), but far lower than for penicillins (13 per 10,000), clindamycin (18.5 per 10,000), sulfonamides (18.9 per 10,000), and vancomycin (24.1 per 10,000).1
In fact, adverse events associated with FQs range from mild and self-limiting to rare and severe. This review discusses both. Relatively common adverse effects and drug-drug interactions are discussed in the text, while the TABLE2 includes a broader range of potential adverse effects. You’ll also find a handout for patients taking FQs on page 195 that clearly describes signs and symptoms that need to be reported right away.
TABLE
Fluoroquinolones: Adverse effects to guard against*2
Cardiovascular
| Immunologic
|
Dermatologic
| Musculoskeletal
|
Drug-drug interactions
| Neurologic
|
Endocrine/Metabolic
| Ocular
|
Gastrointestinal
| Psychiatric
|
Hematologic
| Respiratory
|
| *This is not a complete list of potential adverse effects associated with fluoroquinolones. †Fluoroquinolones may potentiate warfarin. | |
A black box warning of tendinopathies
FQs exhibit an affinity for connective tissue, with higher concentrations found in bone and cartilage than in serum. While FQs are therefore well suited for treating orthopedic-related infections,3 they also increase the risk of tendinopathies.
In the last 2 decades, numerous case reports linking tendinitis and FQs have been published.4-6 In 2008, the US Food and Drug Administration (FDA) issued a black box warning of tendinitis and tendon rupture. Patients on FQ therapy should be advised to stop taking the antibiotic at the first sign of pain, swelling, or inflammation in a tendon, the FDA advises.7
How common is this adverse effect? A case-control study of 22,194 patients with a diagnosis of nontraumatic tendiopathy determined that FQ use resulted in a 1.3-fold risk of tendon rupture and more than a 4-fold risk of rupture of the Achilles tendon. One Achilles tendon rupture would occur for every 5958 patients treated with FQs, the researchers estimated.8
The precise mechanism by which FQs lead to tendinopathies is not completely understood. Studies suggest that the antibiotics cause a decrease in the synthesis of type I collagen, elastin, fibronectin, and beta (1)-integrin, and time- and concentration-dependent increases of cellular apoptosis.9 In vitro studies have shown inhibition of both cell proliferation and fibroblast metabolism when tissue is exposed to FQs, which may impede tissue healing.10
Which patients are at higher risk? The risk of FQ-associated tendinopathies is greatest in patients older than 60 years; in kidney, heart, and lung transplant recipients; and in patients taking an FQ with concomitant corticosteroid therapy. Decreased renal clearance of the medication may play a role in the increased risk.11
GI problems are common, especially in kids and older patients
Gastrointestinal (GI) disturbances are common in patients taking FQs, and typically occur more frequently in children and older adults, and in those taking higher doses. Reactions attributable to ciprofloxacin, for example, include nausea (affecting 1.4%-4% of adults and 2.7% of children taking the drug), vomiting (1%-2% of adults and 4.8% of children), diarrhea (<1%-2% of adults and 4.8% of children), and abdominal pain or discomfort (<1%-1.7% of adults and 3.3% of children).12
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
Monitor older adults taking FQs. Because the risk of psychiatric adverse events is greatest in older individuals, especially those with known atherosclerotic disease or epilepsy, FQ therapy should be used cautiously—and with close monitoring—in this patient population. Symptoms such as weakness, confusion, tremor, loss of appetite, and depression are often incorrectly attributed simply to age, and thus go unreported as potential adverse effects of FQs.29 The exact mechanism by which FQs may induce seizures is unknown, but it may be related to excitatory effects at GABA receptors in the hippocampus.30
FQs may affect glucose levels
FQs have been reported to have varying effects on glucose metabolism, and have been implicated in both hypo- and hyperglycemia. FQ-related hypoglycemia has been thought to occur as a result of an increase in insulin secretion through a sulfonylurea-like action on pancreatic beta cells,31 via drug-drug interactions in patients with renal impairment,32 or via cytochrome P450 interactions.33 The mechanism of action relating to hyperglycemia is less well understood.
One retrospective cohort study in outpatients at a Veterans Administration facility sought to identify outcomes of hospitalization with a primary diagnosis of either hypo- or hyperglycemia in patients with a new prescription for either an FQ or azithromycin.34 In patients with diabetes, the OR for FQ-associated hypoglycemia (compared with azithromycin) was 2.1 for levofloxacin (95% CI, 1.4-3.3) and 1.1 for ciprofloxacin (95% CI, 0.6-2.0). The ORs for hyperglycemia were 1.8 for levofloxacin (95%, CI 1.2-2.7) and 1.0 for ciprofloxacin (95% CI, 0.6-1.8).
A retrospective chart review of more than 17,000 hospitalized patients who were receiving either an FQ or ceftriaxone revealed that 101 patients had either high (>200 mg/dL) or low (<50 mg/dL) glucose levels within 72 hours of receiving the antibiotic.35 Nearly 89% of those studied had diabetes and 40% had prescriptions for oral hypoglycemic agents. While most of these patients had underlying renal insufficiency, rates of hyperglycemia were greater with levofloxacin than with ceftriaxone. (In this study and the VA study, gatifloxacin had greater effects on glucose levels than the non-FQ antibiotics they were compared with; as noted earlier, however, gatifloxacin was removed from the US market in 2006.)
Diplopia is the most common ophthalmologic effect
A database review found 171 case reports of diplopia associated with FQs; ciprofloxacin was the most commonly implicated FQ, with 75 cases. The median time between medication initiation and the development of diplopia was 9.6 days. Most FQ-associated diplopia is completely reversible upon cessation of drug therapy, as evidenced by 53 published reports in which that was the case.36
Adverse effects of intraocular FQs. Ocular keratitis, corneal infiltrates and precipitates, and delayed corneal epithelial healing have been linked to the administration of intraocular FQs.36-38 In addition, retinal detachment has been found to occur in 3.3% of patients being treated with intraocular FQs, compared with 0.6% of controls (adjusted rate ratio=4.50; number needed to harm= 2500).39
CASE Suspecting CDAD and Achilles tendinitis secondary to ciprofloxacin, you stop the medication. Ms. Z’s urine culture is positive for Klebsiella pneumoniae, which is also sensitive to nitrofurantoin, so a 7-day course is prescribed. And, because a stool test for C difficile is positive, you prescribe a 7-day course of metronidazole, as well. Within 4 weeks of stopping the ciprofloxacin, the Achilles tendinitis had completely resolved.
CORRESPONDENCE
Joel J. Heidelbaugh, MD, Ypsilanti Health Center, 200 Arnet Suite 200, Ypsilanti, MI 48198; [email protected]
1. Shehab N, Patel PR, Srinivasan A, et al. Emergency department visits for antibiotic-associated adverse events. Clin Infect Dis. 2008;47:735-743.
2. Poisindex System. Ann Arbor, Mich: Truven Health Analytics.
3. Melhus A, Apelqvist J, Larsson J, et al. Levofloxacin-associated Achilles tendon rupture and tendinopathy. Scand J Infect Dis. 2003;35:768-770.
4. Damuth E, Heidelbaugh JJ, Malani PN, et al. Case report: an elderly subject with fluoroquinolone-associated Achilles tendinitis. Am J Geriatr Pharmacother. 2008;6:264-268.
5. Gold L, Igra H. Levofloxacin-induced tendon rupture: a case report and review of the literature. J Am Board Fam Pract. 2003;16:458-460.
6. Haddow LJ, Chandra Sekhar M, Hajela V, et al. Spontaneous Achilles tendon rupture in patients treated with levofloxacin. J Antimicrob Chemother. 2003;51:747-748.
7. US Food and Drug Administration. Information for healthcare professionals: fluoroquinolone antimicrobial drugs Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126085.htm. Accessed September 30, 2012.
8. Corrao G, Zambon A, Bertu L, et al. Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study. Drug Saf. 2006;29:889-896.
9. Sendzik J, Shakibaei M, Schafer-Korting M, et al. Fluoroquinolones cause changes in extracellular matrix, signaling proteins, metalloproteinases and caspase-3 in cultured human tendon cells. Toxicology. 2005;212:24-36.
10. Corps AN, Harrall RL, Curry VA, et al. Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin-1beta in human tendon-derived cells: a potential mechanism of fluoroquinolone-induced tendinopathy. Arthritis Rheum. 2002;46:3034-3040.
11. Muzi F, Gravanta G, Tati E, et al. Fluoroquinolones-induced tendinitis and tendon rupture in kidney transplant recipients: 2 cases and a review of the literature. Transplant Proc. 2007;39:1673-1675.
12. Cholongitas E, Georgousaki C, Spyrou S, et al. Ciprofloxacin-induced acute cholestatic hepatitis. Ann Hepatol. 2009;8:400-401.
13. Denève C, Janoir C, Poilane I, et al. New trends in Clostridium difficile virulence and pathogenesis. Int J Antimicrob Agents. 2009;33(suppl 1):S24-S28.
14. Deshpande A, Pant C, Jain A, et al. Do fluoroquinolones predispose patients to Clostridium difficile associated disease? A review of the evidence. Curr Med Res Opin. 2008;24:329-333.
15. Novelle M, Morreale CA. The relationship between inpatient fluoroquinolone use and Clostridium difficile-associated diarrhea. Ann Pharmacother. 2010;44:826-831.
16. Adikwu E, Deo O. Fluoroquinolones reported hepatotoxicity. Pharmacology Pharmacy. 2012;3:328-336.
17. Nicholson SC, Webb CD, Moellering RC. Antimicrobial-associated acute hepatitis. Pharmacotherapy. 2002;22:794-797.
18. Labbe G, Pessayre D, Fromenty B. Drug-induced liver injury through mitochondria dysfunction: mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol. 2008;22:335-353.
19. Mitcheson JS, Chen J, Lim M, et al. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci. 2000;97:12329-12333.
20. US Food and Drug Administration. Determination that Tequin (gatifloxacin) was withdrawn from sale for reasons of safety or effectiveness. Fed Regist. 2008;73:52357-52358.
21. Rubinstein E, Camm J. Cardiotoxicity of fluoroquinolones. J Antimicrob Chemother. 2002;49:593-596.
22. Briasoulis A, Agarwal V, Pierce WJ. QT prolongation and torsade de pointes induced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology. 2011;120:103-110.
23. Prabhakar M, Krahn AD. Ciprofloxacin-induced acquired long QT syndrome. Heart Rhythm. 2004;1:624-626.
24. Demolis JL, Kubitza D, Tenneze L, et al. Effect of a single oral dose of moxifloxacin (400 and 800 mg) on ventricular repolarization in healthy subjects. Clin Pharmacol Ther. 2000;68:658-666.
25. Tome AM, Filipe A. Quinolones: review of psychiatric and neurological adverse reactions. Drug Saf. 2011;34:465-488.
26. Kiangkitiwan B. Levofloxacin-induced delirium with psychotic features. Gen Hosp Psychiatry. 2008;30:381-383.
27. Carbon C. Comparison of side effects of levofloxacin versus other fluoroquinolones. Chemotherapy. 2001;47(suppl 3):S9-S14.
28. LaSalvia EA, Domek GJ, Gitlin DF. Fluoroquinolone-induced suicidal ideation. Gen Hosp Psychiatry. 2010;32:108-110.
29. Stahlmann R, Lode H. Safety considerations of fluoroquinolones in the elderly: an update. Drugs Aging. 2010;27:193-209.
30. Owens RC, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis. 2005;41(suppl):S144-S157.
31. Smith KM, Lomaestro BM. What role do fluoroquinolone antimicrobial agents play in cardiac dysfunction and altered glycemic control? J Pharm Pract. 2003;16:349-360.
32. LeBlanc M, Belanger C, Cossette P. Severe and resistant hypoglycemia associated with concomitant gatifloxacin and glyburide therapy. Pharmacotherapy. 2004;24:926-931.
33. Graumlich JF, Habis S, Avelino RR, et al. Hypoglycemia in inpatients after gatifloxacin or levofloxacin therapy: nested case control study. Pharmacotherapy. 2005;25:1296-1302.
34. Aspinall SL, Good CB, Jiang R, et al. Severe dysglycemia with the fluoroquinolones: a class effect? Clin Infect Dis. 2009;49:402-408.
35. Mohr JF, McKinnon PS, Peymann PJ, et al. A retrospective, comparative evaluation of dysglycemias in hospitalized patients receiving gatifloxacin, levofloxacin, ciprofloxacin, or ceftriaxone. Pharmacotherapy. 2005;25:1303-1309.
36. Fraunfelder FW, Fraunfelder FT. Diplopia and fluoroquinolones. Ophthalmology. 2009;116:1814-1817.
37. Eiferman RA, Snyder JP, Nordquist RE. Ciprofloxacin microprecipitates and macroprecipitates in the human corneal epithelium. J Cataract Refract Surg. 2001;27:1701-1702.
38. Fraunfelder FW. Corneal toxicity from topical ocular and systemic medications. Cornea. 2006;25:1133-1138.
39. Etminan M, Forooghian F, Brophy JM, et al. Oral fluoroquinolones and the risk of retinal detachment. JAMA. 2012;307:1414-1419.
1. Shehab N, Patel PR, Srinivasan A, et al. Emergency department visits for antibiotic-associated adverse events. Clin Infect Dis. 2008;47:735-743.
2. Poisindex System. Ann Arbor, Mich: Truven Health Analytics.
3. Melhus A, Apelqvist J, Larsson J, et al. Levofloxacin-associated Achilles tendon rupture and tendinopathy. Scand J Infect Dis. 2003;35:768-770.
4. Damuth E, Heidelbaugh JJ, Malani PN, et al. Case report: an elderly subject with fluoroquinolone-associated Achilles tendinitis. Am J Geriatr Pharmacother. 2008;6:264-268.
5. Gold L, Igra H. Levofloxacin-induced tendon rupture: a case report and review of the literature. J Am Board Fam Pract. 2003;16:458-460.
6. Haddow LJ, Chandra Sekhar M, Hajela V, et al. Spontaneous Achilles tendon rupture in patients treated with levofloxacin. J Antimicrob Chemother. 2003;51:747-748.
7. US Food and Drug Administration. Information for healthcare professionals: fluoroquinolone antimicrobial drugs Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126085.htm. Accessed September 30, 2012.
8. Corrao G, Zambon A, Bertu L, et al. Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study. Drug Saf. 2006;29:889-896.
9. Sendzik J, Shakibaei M, Schafer-Korting M, et al. Fluoroquinolones cause changes in extracellular matrix, signaling proteins, metalloproteinases and caspase-3 in cultured human tendon cells. Toxicology. 2005;212:24-36.
10. Corps AN, Harrall RL, Curry VA, et al. Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin-1beta in human tendon-derived cells: a potential mechanism of fluoroquinolone-induced tendinopathy. Arthritis Rheum. 2002;46:3034-3040.
11. Muzi F, Gravanta G, Tati E, et al. Fluoroquinolones-induced tendinitis and tendon rupture in kidney transplant recipients: 2 cases and a review of the literature. Transplant Proc. 2007;39:1673-1675.
12. Cholongitas E, Georgousaki C, Spyrou S, et al. Ciprofloxacin-induced acute cholestatic hepatitis. Ann Hepatol. 2009;8:400-401.
13. Denève C, Janoir C, Poilane I, et al. New trends in Clostridium difficile virulence and pathogenesis. Int J Antimicrob Agents. 2009;33(suppl 1):S24-S28.
14. Deshpande A, Pant C, Jain A, et al. Do fluoroquinolones predispose patients to Clostridium difficile associated disease? A review of the evidence. Curr Med Res Opin. 2008;24:329-333.
15. Novelle M, Morreale CA. The relationship between inpatient fluoroquinolone use and Clostridium difficile-associated diarrhea. Ann Pharmacother. 2010;44:826-831.
16. Adikwu E, Deo O. Fluoroquinolones reported hepatotoxicity. Pharmacology Pharmacy. 2012;3:328-336.
17. Nicholson SC, Webb CD, Moellering RC. Antimicrobial-associated acute hepatitis. Pharmacotherapy. 2002;22:794-797.
18. Labbe G, Pessayre D, Fromenty B. Drug-induced liver injury through mitochondria dysfunction: mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol. 2008;22:335-353.
19. Mitcheson JS, Chen J, Lim M, et al. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci. 2000;97:12329-12333.
20. US Food and Drug Administration. Determination that Tequin (gatifloxacin) was withdrawn from sale for reasons of safety or effectiveness. Fed Regist. 2008;73:52357-52358.
21. Rubinstein E, Camm J. Cardiotoxicity of fluoroquinolones. J Antimicrob Chemother. 2002;49:593-596.
22. Briasoulis A, Agarwal V, Pierce WJ. QT prolongation and torsade de pointes induced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology. 2011;120:103-110.
23. Prabhakar M, Krahn AD. Ciprofloxacin-induced acquired long QT syndrome. Heart Rhythm. 2004;1:624-626.
24. Demolis JL, Kubitza D, Tenneze L, et al. Effect of a single oral dose of moxifloxacin (400 and 800 mg) on ventricular repolarization in healthy subjects. Clin Pharmacol Ther. 2000;68:658-666.
25. Tome AM, Filipe A. Quinolones: review of psychiatric and neurological adverse reactions. Drug Saf. 2011;34:465-488.
26. Kiangkitiwan B. Levofloxacin-induced delirium with psychotic features. Gen Hosp Psychiatry. 2008;30:381-383.
27. Carbon C. Comparison of side effects of levofloxacin versus other fluoroquinolones. Chemotherapy. 2001;47(suppl 3):S9-S14.
28. LaSalvia EA, Domek GJ, Gitlin DF. Fluoroquinolone-induced suicidal ideation. Gen Hosp Psychiatry. 2010;32:108-110.
29. Stahlmann R, Lode H. Safety considerations of fluoroquinolones in the elderly: an update. Drugs Aging. 2010;27:193-209.
30. Owens RC, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis. 2005;41(suppl):S144-S157.
31. Smith KM, Lomaestro BM. What role do fluoroquinolone antimicrobial agents play in cardiac dysfunction and altered glycemic control? J Pharm Pract. 2003;16:349-360.
32. LeBlanc M, Belanger C, Cossette P. Severe and resistant hypoglycemia associated with concomitant gatifloxacin and glyburide therapy. Pharmacotherapy. 2004;24:926-931.
33. Graumlich JF, Habis S, Avelino RR, et al. Hypoglycemia in inpatients after gatifloxacin or levofloxacin therapy: nested case control study. Pharmacotherapy. 2005;25:1296-1302.
34. Aspinall SL, Good CB, Jiang R, et al. Severe dysglycemia with the fluoroquinolones: a class effect? Clin Infect Dis. 2009;49:402-408.
35. Mohr JF, McKinnon PS, Peymann PJ, et al. A retrospective, comparative evaluation of dysglycemias in hospitalized patients receiving gatifloxacin, levofloxacin, ciprofloxacin, or ceftriaxone. Pharmacotherapy. 2005;25:1303-1309.
36. Fraunfelder FW, Fraunfelder FT. Diplopia and fluoroquinolones. Ophthalmology. 2009;116:1814-1817.
37. Eiferman RA, Snyder JP, Nordquist RE. Ciprofloxacin microprecipitates and macroprecipitates in the human corneal epithelium. J Cataract Refract Surg. 2001;27:1701-1702.
38. Fraunfelder FW. Corneal toxicity from topical ocular and systemic medications. Cornea. 2006;25:1133-1138.
39. Etminan M, Forooghian F, Brophy JM, et al. Oral fluoroquinolones and the risk of retinal detachment. JAMA. 2012;307:1414-1419.