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Alatrofloxacin and trovafloxacin
See also Fluoroquinolones
General information
Alatrofloxacin is a fluoronaphthyridone that is hydrolysed to the active moiety, trovafloxacin, after intravenous administration. This fourth-generation broad-spectrum fluoroquinolone has activity against Gram-positive, Gram-negative, anerobic, and atypical respiratory pathogens. Because it has significant hepatotoxicity, the list of appropriate indications for trovafloxacin has been restricted.
In a multicenter, double-blind, randomized comparison of trovafloxacin 200 mg and clarithromycin 500 mg bd in 176 subjects with acute exacerbations of chronic bronchitis, the most common adverse effects of trovafloxacin were nausea (5%), dizziness (5%), vomiting (3%), and constipation (3%) [ ]. Because trovafloxacin is hepatotoxic, the list of appropriate indications has been limited to patients who have at least one of several specified infections, such as nosocomial pneumonia or complicated intra-abdominal infections that are serious and life- or limb-threatening in the physician’s judgement.
Trovafloxacin may down-regulate cytokine mRNA transcription in human peripheral blood mononuclear cells stimulated with lipopolysaccharide or lipoteichoic acid [ ]. Likewise, trovafloxacin inhibited Salmonella typhimurium -induced production of TNFα, HIV-1 replication, and reactivation of latent HIV-1 in promonocytic U1 cells at concentrations comparable to the plasma and tissue concentrations achieved by therapeutic dosages [ ].
Organs and systems
Cardiovascular
Phlebitis can occur during parenteral administration of trovafloxacin. High concentrations of trovafloxacin (2 mg/ml) significantly reduced intracellular ATP content in cultured endothelial cells and reduced concentrations of ADP, GTP, and GDP [ ]. These in vitro data suggest that high doses of trovafloxacin 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.
Nervous system
Alatrofloxacin can cause seizures [ ].
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A 37-year-old Asian man received several antibiotics (including intravenous ceftazidime, gentamicin, meropenem, metronidazole, and vancomycin) postoperatively. After 3 weeks he was given alatrofloxacin 75 mg in 25 ml of dextrose 5% (1.875 mg/ml) and developed generalized clonus. On rechallenge, infusing at half the initial rate, the seizure recurred. A CT scan of the brain was normal.
Seizures are rare but have occurred during treatment with other fluoroquinolones. This is the first report of a case of seizures associated with slow infusion of alatrofloxacin. However, as of 21 June 2000, the manufacturers had received 53 reports of seizures through worldwide postmarketing surveillance. In rat hippocampus slices, trovafloxacin had significant convulsive potential; the underlying mechanism is hitherto incompletely understood.
Trovafloxacin has been associated with diffuse weakness due to a demyelinating polyneuropathy in a patient without an underlying neurological disorder [ ].
Sensory systems
Intravitreal trovafloxacin in doses of 50 mg and higher in the pigmented rabbit eye caused retinal and nerve fiber injury; intravitreal doses of 25 mg and lower appear to be safe, with no evidence of ocular toxicity [ ].
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