Improved efficacy of ciprofloxacin administered in polyethylene glycol-coated liposomes for treatment of Klebsiella pneumoniae pneumonia in rats.
Animal and clinical data show that high ratios of the area under the concentration-time curve and the peak concentration in blood to the MIC of fluoroquinolones for a given pathogen are associated with a favorable outcome. The present study investigated whether improvement of the therapeutic potential of ciprofloxacin could be achieved by encapsulation in polyethylene glycol (PEG)-coated long-circulating sustained-release liposomes. In a rat model of unilateral Klebsiella pneumoniae pneumonia (MIC = 0.1 microg/ml), antibiotic was administered at 12- or 24-h intervals at twofold-increasing doses. A treatment period of 3 days was started 24 h after inoculation of the left lung, when the bacterial count had increased 1,000-fold and some rats had positive blood cultures. The infection was fatal within 5 days in untreated rats. Administration of ciprofloxacin in the liposomal form resulted in delayed ciprofloxacin clearance and increased and prolonged ciprofloxacin concentrations in blood and tissues. The ED(50) (dosage that results in 50% survival) of liposomal ciprofloxacin was 3.3 mg/kg of body weight/day given once daily, and that of free ciprofloxacin was 18.9 mg/kg/day once daily or 5.1 mg/kg/day twice daily. The ED(90) of liposomal ciprofloxacin was 15.0 mg/kg/day once daily compared with 36.0 mg/kg/day twice daily for free ciprofloxacin; 90% survival could not be achieved with free ciprofloxacin given once daily. In summary, the therapeutic efficacy of liposomal ciprofloxacin was superior to that of ciprofloxacin in the free form. PEG-coated liposomal ciprofloxacin was well tolerated in relatively high doses, permitting once daily administration with relatively low ciprofloxacin clearance and without compromising therapeutic efficacy.
Bakker-Woudenberg
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IA
Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center Rotterdam, 3000 DR Rotterdam, The Netherlands. bakker@kmic.fgg.eur.nl
ten Kate
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MT
Guo
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Working
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Mouton
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JW
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D007710:Klebsiella Infections / Q000097:blood / Q000188:drug therapy*; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008081:Liposomes; D018410:Pneumonia, Bacterial / Q000097:blood / Q000188:drug therapy*; D011092:Polyethylene Glycols; D051381:Rats; D016896:Treatment Outcome
D000890:Anti-Infective Agents; D004337:Drug Carriers; D008081:Liposomes; D011092:Polyethylene Glycols; D002939:Ciprofloxacin