Ciprofloxacin in polyethylene glycol-coated liposomes: efficacy in rat models of acute or chronic Pseudomonas aeruginosa infection.
In a previous study in experimental Klebsiella pneumoniae pneumonia, the therapeutic potential of ciprofloxacin was significantly improved by encapsulation in polyethylene glycol-coated ("pegylated") long-circulating (STEALTH) liposomes. Pegylated liposomal ciprofloxacin in high doses was nontoxic and resulted in relatively high and sustained ciprofloxacin concentrations in blood and tissues, and hence an increase in the area under the plasma concentration-time curve (AUC). These data correspond to data from animal and clinical studies showing that for fluoroquinolones the AUC/MIC ratio is associated with favorable outcome in serious infections. Clinical failures and the development of resistance are observed for marginally susceptible organisms like Pseudomonas aeruginosa and for which sufficient AUC/MIC ratios cannot be achieved. In the present study the therapeutic efficacy of pegylated liposomal ciprofloxacin was investigated in two rat models of Pseudomonas aeruginosa pneumonia. In the acute model pneumonia developed progressively, resulting in a rapid onset of septicemia and a high mortality rate. Ciprofloxacin twice daily for 7 days was not effective at doses at or below the maximum tolerated dose (MTD). However, pegylated liposomal ciprofloxacin either at high dosage or given at low dosage in combination with free ciprofloxacin on the first day of treatment was fully effective (100% survival). Obviously, prolonged concentrations of ciprofloxacin in blood prevented death of the animals due to early-stage septicemia in this acute infection. However, bacterial eradication from the left lung was not effected. In the chronic model, pneumonia was characterized by bacterial persistence in the lung without bacteremia, and no signs of morbidity or mortality were observed. Ciprofloxacin administered for 7 days at the MTD twice daily resulted in killing of more than 99% of bacteria in the lung; this result can also be achieved with pegylated liposomal ciprofloxacin given once daily. Complete bacterial eradication is never observed.
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands. bakker@kmic.fgg.eur.nl
Irma A J M
IA
Bakker-Woudenberg
Marian T
MT
ten Kate
Luke
L
Guo
Peter
P
Working
Johan W
JW
Mouton
D000208:Acute Disease; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D002908:Chronic Disease; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D018450:Disease Progression; D004337:Drug Carriers; D005260:Female; D008081:Liposomes; D008168:Lung / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D014677:Pharmaceutical Vehicles; D011014:Pneumonia / Q000188:drug therapy / Q000382:microbiology; D011092:Polyethylene Glycols; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D051381:Rats; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D014018:Tissue Distribution
D000890:Anti-Infective Agents; D004337:Drug Carriers; D008081:Liposomes; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols; D002939:Ciprofloxacin