1) WITHDRAWAL FROM MARKET: Grepafloxacin was withdrawn from the worldwide market in October 1999 after reports of cardiovascular toxicity; QT prolongation had been associated with its use (S Sweetman , 2000).
2) During a phase I study, QTc prolongation was observed in healthy volunteers (Stahlmann & Lode, 1999).

1) QTc interval prolongation and polymorphic ventricular tachycardia were associated with the use of levofloxacin in an 88-year-old female hospitalized with atrial fibrillation, bronchitis, and mild congestive heart failure (Samaha, 1999). Despite the patient's underlying medical condition, the author noted that the patient continued to have a prolonged QTc interval until levofloxacin was discontinued.

1) Torsade de pointes has been reported as a postmarketing adverse event. The estimated case rate of torsade de pointes was 27 occurrences per 10 million prescriptions of gatifloxacin (8 actual cases reported via the FDA Adverse Events Reporting System) during the first 16 months after initial FDA approval (Frothingham, 2001).
2) Gatifloxacin-associated torsades de pointes (TdP) or ventricular fibrillation was reported in 4 patients considered to be at high risk for drug-acquired QTc interval prolongation (Bertino et al, 2002).

1) QT interval prolongation has been seen in some patients receiving moxifloxacin. The mean effect on QT interval in 787 patients in Phase 3 clinical trials was 6 +/- 26 milliseconds; no morbidity or mortality was attributable to QT prolongation . Predisposing conditions, concomitant therapy with action-potential prolonging drugs, especially Class IA and III, hypokalemia, clinically significant bradycardia, and acute myocardial ischemia may increase the risk for ventricular arrhythmias. QT prolongation may be concentration and/or rate related (Prod Info AVELOX(R) oral tablets, IV injection, 2007).
2) Significant QT interval prolongation occurred in healthy subjects shortly after receiving single doses of moxifloxacin (MFC) 400 milligrams (mg) and 800 milligrams. In a randomized, double-blind, cross-over study, 20 healthy subjects (9 men, 11 women) were assigned to receive single oral doses of MFC 400 mg, MFC 800 mg, or placebo on 3 different study days, each separated by washout phases of 6 to 15 days. Two hours after each dose (at time of approximate maximum MFC plasma concentration), subjects engaged in submaximal exercise testing, up to a target heart rate of 160 beats/minute. Electrocardiographic (ECG) tracings were recorded every 30 seconds during the test. Subjects receiving MFC 400 mg in the active treatment arm showed significant prolongation of ECG Q-T interval at all predetermined R-to-R wave intervals (400 to 1000 milliseconds (ms)), compared with Q-T intervals seen during placebo treatment (mean of 394 ms versus 379 ms, respectively; p less than 0.05). Similar Q-T interval prolongation occurred when patients received MFC 800 mg (mean of 396 ms; p less than 0.05). These interval changes corresponded to mean percentage increases compared with placebo of 4.0% and 4.5%, respectively. Analysis of covariance for individual Q-T interval duration and 2-hour post-dosing MFC plasma concentration is suggestive of a dose dependency with regard to magnitude of Q-T duration extension (Demolis et al, 2000).
3) CASE REPORT: An 87-year-old woman developed torsade de pointes after receiving a dose of intravenous moxifloxacin (400 mg daily) for treatment of pneumonia. The patient had a medical history of atrial fibrillation, chronic stable angina, left ventricular dysfunction (left-ventricular ejection fraction 45%), and pacemaker implantation for sick-sinus syndrome. Her medical history was also significant for non-insulin-dependent diabetes mellitus, hyperlipidemia, and hypothyroidism. Upon admission, the patient was taking digoxin 0.125 mg daily, 500 mg twice daily metformin, glimepiride 4 mg daily, 0.1 mg daily levothyroxine, 20 mg daily omeprazole, 1 mg daily warfarin, and 40 mg daily atorvastatin. The admission ECG showed atrial fibrillation with right bundle branch block and occasional paced ventricular beats. The QTc interval was 458 msec. Intravenous moxifloxacin was initiated to treat pneumonia. Two hours later, a second ECG demonstrated a QTc interval of 550 msec with a paced rhythm of 60 beats per minute. Approximately 8 to 10 hours after moxifloxacin administration, the patient was found unconscious. ECG showed polymorphic ventricular tachycardia consistent with torsades de pointes. She converted to a paced rhythm after two precordial thumps. . After moxifloxacin was discontinued, QTc interval improved to baseline range (465 msec) within 3 days with no further torsade de pointes events noted (Dale et al, 2007).

1) In European trials, QTc prolongation by a mean of 10 msec was reported with sparfloxacin use, but NO clinically significant arrhythmias developed (Lipsky & Baker, 1999).

1) Grand mal epileptic seizures have been reported in 3 cases after receiving CIPROFLOXACIN. However, 2 of the patients had a history of brain disorder prior to ciprofloxacin treatment.
2) It has not been clearly established that the seizures and ciprofloxacin are related (Slavich et al, 1989; Arcieri et al, 1989).

1) A generalized tonic-clonic seizure occurred in a 75-year-old woman 3 days after the initiation of an oral course of levofloxacin 250 mg once daily (after an initial dose of levofloxacin 500 mg) for prophylaxis in the presence of gangrenous toes. The patient had a serum creatinine of 2.8 mg/dL and a concomitant hypomagnesemia (1.3 mg/dL) at the time of the seizure. Levofloxacin was discontinued, the hypomagnesemia was corrected with magnesium sulfate, and the patient remained free from convulsive activity until rechallenged with intravenous ciprofloxacin 400 mg every 12 hours on day 40, after which she experienced a generalized seizure on day 41. The patient was found to have a serum creatinine of 3.3 mg/dL and a concomitant hypomagnesemia (1.3 mg/dL), which was again corrected with supplemental magnesium. Ciprofloxacin was discontinued, and the patient remained free of seizure activity. Dosing of levofloxacin and ciprofloxacin may have been excessive, based on the patients measured serum creatinine and calculated creatinine clearance (Kushner et al, 2001).
2) A generalized seizure occurred in a 74-year-old woman after she received 5 oral doses of levofloxacin 500 mg once daily. All laboratory analysis results were within normal limits. Levofloxacin was discontinued, and the patient remained free of seizure activity thereafter (Kushner et al, 2001)

1) There are at least 7 cases reported of seizures in patients receiving NORFLOXACIN. It has been suggested that 4 of the cases possessed factors that may have predisposed them to seizures and norfloxacin may have lowered their seizure threshold.
2) A clear relationship between norfloxacin and seizures has not been established (Anon, 1990; Anastasio et al, 1988).

1) There are several cases of seizures resulting from the therapeutic administration of OFLOXACIN. Severe renal dysfunction, underlying CNS pathology and a past history of epilepsy were thought to be predisposing factors (Sawada et al, 1991) Walton et al, 1998).

1) Seizure activity was reported in an adult within the first 12 hours of intravenous therapy with trovafloxacin (Menzies et al, 1999).

1) A 90-year-old male developed "whole body tremors and facial spasms" three days after starting ciprofloxacin 500 mg twice daily (Burkhart et al, 2000). Orofacial dyskinesia with truncal and extremity myoclonus was observed during neurological exam. Symptoms resolved completely within 24 hours of drug cessation.

1) Unsteady gait, dizziness and mental confusion were reported in an adult female following 7 days of oral trovafloxacin (200 mg daily) therapy; symptoms resolved gradually over a 2 week period after discontinuation of therapy (Menzies et al, 1999).

1) A 14-year-old female presented in a delirious state with extreme mydriasis and warm and dry skin following ingestion of an unknown amount of ofloxacin, diphenhydramine, and chlormezanone. Both diphenhydramine and chlormezanone plasma concentrations were consistent with therapeutic amounts.

1) TROVAFLOXACIN: Diarrhea was reported in 2% of patients during clinical trials with oral or injectable forms of trovafloxacin (Prod Info Trovan(R), trovafloxacin mesylate (tablets) and alatrovafloxacin mesylate {prodrug of trovafloxacin} (intravenous), 1997).

1) Nausea and vomiting have been reported after one dose of CIPROFLOXACIN in one HIV positive patient (Altes et al, 1989). It was also seen in a 3 gram IV overdose of OFLOXACIN (Kohler et al, 1991).

1) GATIFLOXACIN: Nausea has been reported in therapeutic use in healthy volunteers; incidence 13.3% (4 subjects) (Gajjar et al, 2000).
2) TROVAFLOXACIN: A dose-dependent increase in vomiting was observed in patients during clinical trials with oral and injectable forms of trovafloxacin. Nausea also was reported in both treatment groups with a range of 4% to 8% (Prod Info Trovan(R), trovafloxacin mesylate (tablets) and alatrovafloxacin mesylate {prodrug of trovafloxacin} (intravenous), 1997).

1) CIPROFLOXACIN: Elevated liver enzyme levels were reported after high dose intravenous CIPROFLOXACIN administration in seven hospitalized patients with severe nosocomial infections (Kljucar et al, 1989).
2) OFLOXACIN: Hepatic dysfunction was reported in several cases in the phase IV trials of OFLOXACIN (Sawada et al, 1991), and was reported in an adult 5 days after the start of therapy (Jones & Smith, 1997).
3) LEVOFLOXACIN: Acute, reversible hepatotoxicity developed in a 74-year-old woman within 2 days of beginning an intravenous (IV) regimen of levofloxacin 500 mg daily for the treatment of bronchitis. The patient was also receiving IV methylprednisolone 60 mg daily. Baseline transaminase and bilirubin serum concentrations were within normal limits. After 2 days of levofloxacin therapy, serum alanine and aspartate aminotransferase concentrations increased, to 7071 Units/L and 4962 Units/L, respectively, accompanied by a total serum bilirubin of 2.5 mg/dL and an increase in prothrombin time and international normalized ratio (from 15 to 37 seconds, and from 3 to 9.3, respectively). Ultrasonography of the liver and biliary tract revealed normal findings, and there was no evidence of bleeding, jaundice, rash, or peripheral eosinophilia. Levofloxacin was discontinued, and serum transaminase concentrations markedly decreased within the following week, accompanied by the normalization of prothrombin time (Karim et al, 2001).

1) Acute, fatal hepatitis developed in a 99-year-old man, within 8 days of starting an oral regimen of levofloxacin 500 mg daily for empiric treatment of a urinary tract infection. He had no prior, relevant medical or medication history. The patient presented with jaundice, dehydration, and fluctuating levels of consciousness. Serum concentrations were elevated in alkaline phosphatase (157 International Units/L, gamma glutamyltranspeptidase (117 International Units/L), alanine aminotransferase (4440 International Units/L), and aspartate aminotransferase (5000 International Units/L). The liver was moderately hyperechoic on ultrasonography. Levofloxacin was discontinued; however, the patient died while in hepatic coma 6 days after admission. Postmortem liver biopsy results showed a confluent hepatocellular necrosis with eosinophil cellular infiltration; the appearance of periportal hepatocytes was consistent with cholestasis (Spahr et al, 2001).
2) Acute hepatitis and rhabdomyolysis developed in a 71-year-old man after 4 days of oral levofloxacin 300 mg/day prescribed for the treatment of acute bacterial enteritis. The patient presented on admission with generalized motor weakness of the extremities, general fatigue, and brown urine. Laboratory analysis confirmed the presence of urine myoglobin along with marked elevations in creatine phosphokinase, serum glutamic transaminases, and lactic dehydrogenase. Levofloxacin was discontinued, and the patient was treated with fluid therapy and ursodeoxycholic acid. Diuretics and steroid therapy were also instituted due to acute renal failure secondary to high blood levels of myoglobin. All symptoms had resolved by the eighteenth hospital day (Nakamae et al, 2000).

1) Subfulminant hepatic failure was reported in an 70-year-old male following ofloxacin administration (200 mg twice daily) for 5 days; the patient had no known risk factors for liver disease. Fourteen weeks after the development of symptoms the patient had hepatic encephalopathy and died two weeks later (Carro et al, 2000).

1) Acute cholestatic jaundice was reported in a 70-year-old male following norfloxacin 800 mg/day for 12 days (Lucena et al, 1998). A temporal relationship was suggested; symptoms resolved within one month of exposure.
2) A 58-year-old with alcoholic liver cirrhosis developed acute cholestatic hepatitis after prophylactic use of norfloxacin (Romero-Gomez et al, 1999). Five days after the start of treatment (400 mg twice daily), jaundice and elevated liver enzymes were observed. Norfloxacin was discontinued with baseline hepatic function returning within one month.

1) The use of trovafloxacin has resulted in the development of liver injury which has led to liver transplantation and/or death. Its use should be limited to 2 weeks duration and reserved for patients with serious life- or limb-threatening infections (Prod Info Trovan(R), trovafloxacin mesylate (tablets), 2000).
2) As of June 1999, the USFDA has issued a warning regarding the possible risks of liver toxicity with trovafloxacin use ((Anon, 1999)). Currently, 14 cases of acute liver failure have occurred, of which 6 patients died. Labeling changes have been recommended.
3) Lucena et al (2000) reported three cases of acute hepatitis in adults following the use of trovafloxacin for 7 to 14 days. Other sources of liver injury were ruled out; liver biopsy results suggested an immunoallergic mechanism.

1) CIPROFLOXACIN: A 15-year-old suicidal female ingested 7.5 to 10 g (15 to 20 tablets) of ciprofloxacin and 100 mg of trazodone 24 hours prior to hospital admission. The patient's BUN and creatinine (Cr) rose initially with a persistent rise in Cr. Cr peaked on hospital day 6 to 6.2 mg/dL with anuria. Electron microscopic studies showed distal nephron apoptosis. One week after ingestion, Cr had decreased and laboratory studies were within normal limits within 3 months (Dharnidharka et al, 1998).

1) CIPROFLOXACIN is a mild photosensitizer with a low phototoxic potential (Ferguson & Johnson, 1990).
2) ENOXACIN: Several photosensitivity reactions have been reported after administration of ENOXACIN (Kawabe et al, 1989; Kang et al, 1993).
3) FLEROXACIN: In clinical trials with FLEROXACIN, a trifluorinated quinolone with a very long half-life, almost 10% of the patients had a photosensitivity reaction. All had peeling and some had to be treated with silver sulfadiazine (Bowie et al, 1989).
4) NORFLOXACIN: The photosensitivity seen with nalidixic acid has NOT been seen with norfloxacin (Holmes et al, 1985).
5) OFLOXACIN/ANIMAL DATA: In photosensitization studies in guinea pigs, OFLOXACIN was found to be neither phototoxic, photoallergic, nor a contact allergen (Davis & McKenzie, 1989).

1) OFLOXACIN : A 74-year-old patient developed PHOTOONYCHOLYSIS associated with OFLOXACIN treatment for a skin infection (Baran & Brun, 1986).
2) PEFLOXACIN: An 82-year-old man developed PHOTOONYCHOLYSIS on the 4th day of PEFLOXACIN treatment. No rechallenge was done (Baran & Brun, 1986).

1) CIPROFLOXACIN: The incidence of skin rash and pruritus during therapeutic use of CIPROFLOXACIN is 0.4 to 1.9% (Ball, 1986) (Rahm & Schact, 1989).
2) GATIFLOXACIN: Local intravenous site reaction (including pruritus swelling, and pain) was the most common adverse event reported with use of gatifloxacin in healthy adult volunteers (Gajjar et al, 2000).
3) TROVAFLOXACIN: In large clinical efficacy trials (n=6000), approximately 2% of patients experienced pruritus and rash following intravenous TROVAFLOXACIN (Prod Info Trovan(R), trovafloxacin mesylate (tablets) and alatrovafloxacin mesylate {prodrug of trovafloxacin} (intravenous), 1997).

1) CASE REPORT: An adult developed Henoch-Schonlein purpura (palpable purpura, arthritis, abdominal pain with hematochezia, and glomerulonephritis) following three days of therapy with ciprofloxacin (250 mg orally twice daily) (Gamboa et al, 1995).

1) The authors suggested that trovafloxacin may be capable of causing fulminant TEN (mechanism unknown) either by a single exposure or re-exposure to fluoroquinolones and other antibiotics (patient had received multiple courses of ciprofloxacin and trimethoprim/sulfamethoxazole over the past 2 years).

1) Dogs are apparently more sensitive to the bone and joint changes than are experimentally tested rabbits or rats (Patterson, 1991).
2) No such effects have been observed in children with cystic fibrosis or biliary atresia receiving fluoroquinolone antibiotics for treatment of infections.

1) CIPROFLOXACIN: Tendinitis including Achilles tendon rupture have been associated with the use of ciprofloxacin (Carrasco et al, 1997; Poon & Sundaram, 1997).

1) LEVOFLOXACIN

1) It has been suggested that HIV infected patients may be at a higher risk of developing this type of a reaction (Davis & McKenzie, 1989; Kennedy et al, 1990; Peters & Pinching, 1989; Deamer et al, 1992).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

1) CORNEAL ULCERS
2) BACTERIAL CONJUNCTIVITIS

1) CORNEAL ULCERS-1 YEAR OF AGE AND OLDER
2) BACTERIAL CONJUNCTIVITIS-1 YEAR OF AGE AND OLDER

1) BILATERAL OTITIS MEDIA

1) 1 YEAR OF AGE AND OLDER: On Day 1, instill 1 drop in the affected eye(s) every 2 hours while awake, up to 8 times. On Days 2 through 7, instill 1 drop in the affected eye(s) 2 to 4 times daily while awake (Prod Info gatifloxacin ophthalmic solution, 2016).

1) LESS THAN 50 KG: The usual recommended dose is 8 mg/kg every 12 hours. Maximum dose: 250 mg every 12 hours (Prod Info LEVAQUIN(R) multiple routes, forms, 2012).
2) GREATER THAN 50 KG: The usual recommended dose is 500 mg every 24 hours (Prod Info LEVAQUIN(R) multiple routes, forms, 2012).

1) BACTERIAL CONJUNCTIVITIS: Days 1 and 2, instill 1 to 2 drops in the affected eye(s) every 2 to 4 hours; days 3 through 7, instill 1 to 2 drops in the affected eye(s) 4 times daily (Prod Info Ofloxacin Ophthalmic Solution 0.3%, 2013).
2) BACTERIAL CORNEAL ULCER: Days 1 and 2, instill 1 to 2 drops in the affected eye(s) every 30 minutes while awake, then instill 1 to 2 drops approximately 4 and 6 hours after retiring; days 3 through 7 to 9, instill 1 to 2 drops in the affected eye(s) every hour, while awake; days 7 to 9 through treatment completion, instill 1 to 2 drops in the affected eye(s) 4 times daily (Prod Info Ofloxacin Ophthalmic Solution 0.3%, 2013).

a) DRUG INTERACTIONS - None have been reported (Prod Info, 1990).