Improved Efficacy of Ciprofloxacin Administered in Polyethylene Glycol-Coated Liposomes for Treatment of Klebsiella pneumoniae Pneumonia in Rats

Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center Rotterdam, 3000 DR Rotterdam, The Netherlands.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 06/2001; 45(5):1487-92. DOI: 10.1128/AAC.45.5.1487-1492.2001
Source: PubMed


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.

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    • "A sustained release liposomal ciprofloxacin formulation was developed recently with the aim of reducing the burden of therapy by prolonging the residence time of drug in the lungs to reduce the necessity for frequent administration. Additional potential benefits include improved antimicrobial efficacy by maintaining high antibiotic levels throughout the dosing interval, decreasing systemic toxicity and improving local tolerability by avoiding excessive peak concentrations of antibiotics in the airways [4] [5] [6] [7]. The liposomal formulation is a liquid nanosuspension of ciprofloxacin formulated with lipids and cholesterol and delivered via nebulisation. "
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    ABSTRACT: Liposomal ciprofloxacin formulations have been developed with the aim of enhancing lung residence time, thereby reducing the burden of inhaled antimicrobial therapy which requires multiple daily due to rapid absorptive clearance of antibiotics from the lungs. However, there is a lack of a predictive methodology available to assess controlled release inhalation delivery systems and their effect on drug disposition. In this study three ciprofloxacin formulations were evaluated: a liposomal formulation, a solution formulation and a 1:1 combination of the two (mixture formulation). Different methodologies were utilised to study the release profiles of ciprofloxacin from these formulations: (i) membrane diffusion, (ii) air-interface Calu-3 cells, and (iii) isolated perfused rat lungs. The data from these models were compared to the performance of the formulations in vivo. The solution formulation provided the highest rate of absorptive transport followed by the mixture formulation, with the liposomal formulation providing substantially slower drug release. The rank-order of drug release/transport from the different formulations was consistent across the in vitro and ex-vivo methods, and this was predictive of the profiles in vivo. The use of complimentary in vitro and ex-vivo methodologies provided a robust analysis of formulation behavior, including mechanistic insights, and predicted in vivo pharmacokinetics.
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    ABSTRACT: Prediction of drug delivery performance in the human lung is most often based on observations in commonly used laboratory animals. Even though cell cultures are a useful and inexpensive tool, they are limited to the study of single or a few processes. The complexity and numerous biological interactions of a drug and delivery system can be accurately evaluated only in vivo. The anatomical and physiological differences between species should be carefully considered and are reviewed in this chapter. In addition, the methods of aerosol delivery and dose calculation are presented. Then, techniques and methods to assess drug delivery performance in these in vivo models are reviewed. Lastly, animal models of disease are discussed. These factors are crucial for the correct interpretation of the results of studies and the subsequent extrapolation to humans. KeywordsAnimal models-In vivo testing-Pulmonary disease models-Pharmacokinetics-Methods of aerosol administration-Aerosol dose-Pulmonary drug and vaccine delivery
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