Levofloxacin

General adverse effects and adverse reactions

The most frequently reported adverse reactions to levofloxacin are nausea and diarrhea; compared with some other quinolones it has a low photosensitizing potential, and clinically significant cardiac and hepatic adverse events are rare [ ].

The adverse reactions rates of levofloxacin are 1.3% for nausea, 0.1% for anxiety, 0.3% for insomnia, and 0.1% for headache. No levofloxacin-related adverse events were reported at a rate higher than 1.3%, and most were less common. High-dose levofloxacin (750 mg) was also well tolerated. Surveillance data reported low adverse event rates: nausea 0.8%, rash 0.5%, abdominal pain 0.4%, and diarrhea, dizziness, and vomiting 0.3%. The adverse drug reactions rate for levofloxacin is still one of the lowest of any fluoroquinolone, at 2% compared with 2–10% for other fluoroquinolones [ ].

Observational studies

In 10 patients who took levofloxacin 500 mg/day and rifampicin 600 mg/day for 2–6 months, there were no adverse reactions in 46% of patients, occasional digestive symptoms in 40%, and mild diarrhea in 13%; these patients also took unspecified anti-inflammatory drugs [ ]. There was sleeplessness in 6% but neither tendinitis nor changes in liver function.

In a prospective, multicenter open trial, 313 patients with clinical signs and symptoms of bacterial infections of the respiratory tract, skin, or urinary tract were treated with levofloxacin [ ]. Of these, 134 patients had a pathogen recovered from the primary infection site and had an MIC of the pathogen to levofloxacin determined. Levofloxacin generated clinical and microbiological response rates of about 95%. These response rates included pathogens such as Streptococcus pneumoniae and Staphylococcus aureus . In a logistic regression analysis, the clinical outcome was predicted by the ratio of peak plasma concentration to MIC and site of infection. Microbiological eradication was predicted by the peak concentration/MIC ratio. Both clinical and microbiological outcomes were most likely to be favorable if the peak concentration/MIC ratio was at least 12.

Of 17 individuals with suspected latent multidrug-resistant tuberculosis treated with pyrazinamide and levofloxacin, 11 developed musculoskeletal adverse reactions related to therapy, five had nervous system reactions, and 15 had raised liver enzymes, uric acid, or creatine kinase [ ].

Comparative studies

In comparative trials involving commonly used regimens, levofloxacin had equivalent if not greater activity in the treatment of community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, acute pyelonephritis, and complicated urinary tract infection [ ].

Cardiovascular

Preclinical and clinical trial data and data from phase IV studies have suggested that levofloxacin causes prolongation of the QT interval [ ], for example in healthy volunteers who took levofloxacin 1000 mg compared with placebo [ ]. There were cardiovascular problems in 1 in 15 million prescriptions compared with 1–3% of patients taking sparfloxacin, who had QT _c prolongation to over 500 ms. Polymorphous ventricular tachycardia with a normal QT interval has been associated with oral levofloxacin in the absence of other causes [ , , , ].

Among 23 patients who took levofloxacin 500 mg/day there was prolongation of the QTc interval by more than 30 ms in four patients and 60 ms in two patients [ ]. There was absolute QT interval prolongation to over 500 ms in four patients, one of whom developed torsade de pointes.

• A 65-year-old woman had torsade de pointes after receiving levofloxacin 250 mg/day intravenously for 3 days [ ].

Phlebitis can occur during parenteral administration of levofloxacin. High concentrations of levofloxacin (5 mg/ml) significantly reduced intracellular ATP content in cultured endothelial cells and reduced ADP, GTP, and GDP concentrations [ ]. These in vitro data suggest that high doses of levofloxacin are not compatible with maintenance of endothelial cell function and may explain the occurrence of phlebitis. Commercial formulations should be diluted and given into large veins.

Respiratory

Eosinophilic pneumonia complicated by bronchial asthma has been attributed to levofloxacin [ ].

• A 76-year-old woman took levofloxacin for a productive cough with non-segmental infiltration in both lung fields. She developed eosinophilia in both the peripheral blood (24%) and the sputum (10%), airflow limitation, hypoxemia, and increased airway responsiveness to methacholine. Bronchoalveolar lavage fluid showed increased total cells and a 55% increase in eosinophils, and the CD4/CD8 ratio was reduced to 0.8. Histological features included increased infiltration of eosinophils in the alveolar and interstitial compartments and goblet cell metaplasia. Levofloxacin was withdrawn, and her symptoms improved without steroid therapy. A leukocyte migration test for levofloxacin was weakly positive.

Pneumonitis has been attributed to levofloxacin and kampo medicine [ ].

• A 55-year-old woman developed dyspnea on exertion. She had hypoxemia and restrictive ventilatory impairment. Chest X-rays showed diffuse patchy infiltration in both lungs. She gradually improved after withdrawal of the drugs. Transbronchial lung biopsy specimens showed lymphocyte dominant infiltration in the alveolar septa and Masson bodies. Lymphocyte stimulation tests were positive for levofloxacin and shin-i-seihai-to, a kampo medicine.

Nervous system

Levofloxacin can cause seizures [ ]. In one study convulsions occurred in two per million prescriptions [ , ].

• A 75-year-old white woman was given oral levofloxacin (500 mg on day 1 followed by 250 mg/day) for ischemic toes [ ]. After three doses she had a seizure. One month later, she was challenged with ciprofloxacin 400 mg intravenously every 12 hours and again had a seizure.

• A 74-year-old white woman was given oral levofloxacin 500 mg/day for bacterial pneumonia and had a seizure after five doses [ ].

• A 75-year-old man with Alzheimer’s disease, chronic renal insufficiency, and seizures was given levofloxacin 500 mg/day for 1 week for a urinary tract infection and developed increased seizure activity over 3 days; the seizure activity ceased after withdrawal of levofloxacin [ ].

In a post-marketing surveillance of spontaneous reports in Japan patients with nephropathies, aged over 75 years, and patients with a history of convulsions were more likely to have convulsions during levofloxacin therapy [ ].

A patient developed benign cranial hypertension after taking levofloxacin for 3 weeks following an orbital fracture after a fall from the horse; there was no trauma to the brain or sinus venous thrombosis; the symptoms resolved 1 week after withdrawal of levofloxacin [ ].

• A 73-year-old man with community-acquired pneumonia took oral levofloxacin after completing treatment with intravenous ceftriaxone and 2 days later became disoriented and confused; the symptoms regressed completely after withdrawal of levofloxacin [ ].

• A myasthenic crisis and respiratory depression occurred in a 45-year-old man 36 hours administration of levofloxacin [ ].

Sensory systems

Taste disturbance occurred in less than three per million prescriptions of levofloxacin [ ].

Psychiatric

Acute psychoses have been attributed to levofloxacin.

• A previously healthy 42-year-old woman took levofloxacin, meclizine, and guaifenesin + phenylpropanolamine for sinusitis and vertigo for 2 days and developed insomnia; by day 4 she had developed agitation, paranoia, and visual and auditory hallucinations. Her symptoms resolved after withdrawal of levofloxacin [ ].

• A 50-year-old man developed a psychosis after taking levofloxacin for 3 days [ ].

Metabolism

Hypoglycemia has uncommonly been reported with levofloxacin [ ]. It appears to occur most often in elderly patients with type 2 diabetes mellitus who are taking oral hypoglycemic drugs.

• A 64-year-old woman with type 2 diabetes treated by diet was given levofloxacin 500 mg/day for a urinary infection and pneumonia [ ]. After 2 days she became lethargic and disoriented. Her blood glucose concentration was 1.8 mmol/l (32 mg/dl) and the simultaneous blood insulin concentration was 6.7 (reference range 5–25) IU/ml. A 30% dextrose infusion was started, and she regained consciousness without any neurological deficit. Although she did not take any insulin during the dextrose infusion, her blood glucose concentrations were 3 and 3.4 mmol/l at 1 hour and 4 hours. On day 3 of levofloxacin treatment, she had another episode of hypoglycemia. Levofloxacin was withdrawn and she was given piperacillin + tazobactam instead. There were no further episodes of hypoglycemia.

• A 65-year-old woman who took levofloxacin 500 mg/day had episodes of hypoglycemia, which stopped spontaneously 6 days after the end of therapy [ ].

• A 78-year-old, non-diabetic man had steroid-induced hyperglycemia, which was treated with glibenclamide; 12 hours after taking levofloxacin 500 mg orally he developed severe hypoglycemia, resulting in anoxic brain injury [ ].

• A critically ill 63-year-old man had several episodes of hypoglycemia while receiving levofloxacin for postoperative peritonitis after resection of a large liposarcoma; he developed a quadriplegia and hypoglycemia-induced central pontine myelinolysis [ ].

• An 86-year-old woman with chronic respiratory insufficiency and insulin-treated type 2 diabetes had episodes of severe hypoglycemia while taking levofloxacin 500 mg/day for a respiratory infection, despite interruption of insulin treatment [ ]. The blood glucose concentrations gradually returned to normal 3 days after withdrawal of levofloxacin.

In two population-based, nested case–control studies in 788 patients who had been treated for hypoglycemia within 30 days after antibiotic therapy, levofloxacin was associated with a slightly increased risk (adjusted OR = 1.5; 95% CI = 1.2–2.0) [ ].

The effect of levofloxacin on serum glucose concentrations has been investigated in rats [ ]. The serum glucose concentration fell after injection of levofloxacin 100 mg/kg, and increased after levofloxacin 300 mg/kg. Adrenaline and histamine concentrations rose after levofloxacin 300 mg/kg. Diphenhydramine prevented the hyperglycemia induced by levofloxacin 300 mg/kg.