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.