Liposome-encapsulated Ciprofloxacin Research Articles

A new dawn: inhaled antibiotics for patients with bronchiectasis

The absence of licensed medications for non-cystic fibrosis bronchiectasis is concerning in the context of the high and increasing burden of bronchiectasis in adults 1 and children. 2 In The Lancet Respiratory Medicine , Charles Haworth and colleagues 3 report promising data from two double-blind randomised controlled trials (ORBIT-3 and ORBIT-4) examining the efficacy of a once-daily inhaled antibiotic composed of liposome-encapsulated ciprofloxacin and free ciprofloxacin (ARD-3150), which is a welcome advancement in the bronchiectasis field in which few such trials exist. 4 In ORBIT-3 and ORBIT-4, 3 Haworth and colleagues enrolled 278 (ORBIT-3) and 304 (ORBIT-4) patients with non-cystic fibrosis bronchiectasis who were chronically infected with Pseudomonas aeruginosa . Patients were randomly assigned (2:1) to receive either ARD-3150 or placebo, which was self-administered once daily for six 56-day treatment cycles, for 48 weeks. 3 The primary endpoint was time to the first pulmonary exacerbation from the date of randomisation to week 48. Treatment with ARD-3150 resulted in a significant prolongation of median time to first pulmonary exacerbation in ORBIT-4 of 230 days compared with 158 days in the placebo group, a difference of 72 days (hazard ratio 0·72 [95% CI 0·53–0·97], p=0·032), but no significant prolongation was observed in ORBIT-3 or a pooled analysis of both trials. Secondary and post-hoc analyses of pooled data revealed significant risk reductions in exacerbation frequency and severity in those receiving ARD-3150, and significant reductions in sputum P aeroginosa density during active treatment cycles, but no between-group changes in quality of life or lung function. 3

Inhaled Liposomal Ciprofloxacin Protects against a Lethal Infection in a Murine Model of Pneumonic Plague.

Inhalation of Yersinia pestis can lead to pneumonic plague, which without treatment is inevitably fatal. Two novel formulations of liposome-encapsulated ciprofloxacin, ‘ciprofloxacin for inhalation’ (CFI, Lipoquin®) and ‘dual release ciprofloxacin for inhalation’ (DRCFI, Pulmaquin®) containing CFI and ciprofloxacin solution, are in development. These were evaluated as potential therapies for infection with Y. pestis. In a murine model of pneumonic plague, human-like doses of aerosolized CFI, aerosolized DRCFI or intraperitoneal (i.p.) ciprofloxacin were administered at 24 h (representing prophylaxis) or 42 h (representing treatment) post-challenge. All three therapies provided a high level of protection when administered 24 h post-challenge. A single dose of CFI, but not DRCFI, significantly improved survival compared to a single dose of ciprofloxacin. Furthermore, single doses of CFI and DRCFI reduced bacterial burden in lungs and spleens to below the detectable limit at 60 h post-challenge. When therapy was delayed until 42 h post-challenge, a single dose of CFI or DRCFI offered minimal protection. However, single doses of CFI or DRCFI were able to significantly reduce the bacterial burden in the spleen compared to empty liposomes. A three-day treatment regimen of ciprofloxacin, CFI, or DRCFI resulted in high levels of protection (90–100% survival). This study suggests that CFI and DRCFI may be useful therapies for Y. pestis infection, both as prophylaxis and for the treatment of plague.

New anti-infective strategies for treatment of tularemia

New anti-infective strategies for treatment of tularemia

Efficacy of liposome-encapsulated ciprofloxacin in a murine model of Q fever.

Encapsulation of antibiotics may improve treatment of intracellular infections by prolonging antibiotic release and improving antibiotic uptake into cells. In this study, liposome-encapsulated ciprofloxacin for inhalation (CFI) was evaluated as a postexposure therapeutic for the treatment of Coxiella burnetii, the causative agent of Q fever. Intranasal treatment of male A/Jola (A/J) mice with CFI (50 mg/kg of body weight) once daily for 7 days protected mice against weight loss and clinical signs following an aerosol challenge with C. burnetii. In comparison, mice treated twice daily with oral ciprofloxacin or doxycycline (50 mg/kg) or phosphate-buffered saline (PBS) lost 15 to 20% body weight and exhibited ruffled fur, arched backs, and dehydration. Mice were culled at day 14 postchallenge. The weights and bacterial burdens of organs were determined. Mice treated with CFI exhibited reduced splenomegaly and reduced bacterial numbers in the lungs and spleen compared to mice treated with oral ciprofloxacin or doxycycline. When a single dose of CFI was administered, it provided better protection against body weight loss than 7 days of treatment with oral doxycycline, the current antibiotic of choice to treat Q fever. These data suggest that CFI has potential as a superior antibiotic to treat Q fever.

The potential of liposome-encapsulated ciprofloxacin as a tularemia therapy.

Liposome-encapsulation has been suggested as method to improve the efficacy of ciprofloxacin against the intracellular pathogen, Francisella tularensis. Early work with a prototype formulation, evaluated for use against the F. tularensis live vaccine strain, showed that a single dose of liposomal ciprofloxacin given by the intranasal or inhalational route could provide protection in a mouse model of pneumonic tularemia. Liposomal ciprofloxacin offered better protection than ciprofloxacin given by the same routes. Liposomal ciprofloxacin has been further developed by Aradigm Corporation for Pseudomonas aeruginosa infections in patients with cystic fibrosis and non-cystic fibrosis bronchiectasis. This advanced development formulation is safe, effective and well tolerated in human clinical trials. Further evaluation of the advanced liposomal ciprofloxacin formulation against the highly virulent F. tularensis Schu S4 strain has shown that aerosolized CFI (Ciprofloxacin encapsulated in liposomes for inhalation) provides significantly better protection than oral ciprofloxacin. Thus, liposomal ciprofloxacin is a promising treatment for tularemia and further research with the aim of enabling licensure under the animal rule is warranted.

Liposome delivery of ciprofloxacin against intracellular Francisella tularensis infection

The effect of liposome delivery on the controlled release and therapeutic efficacy of ciprofloxacin against intracellular Francisella tularensis infection in vivo was evaluated in this study. Ciprofloxacin was encapsulated in small unilamellar vesicles by a remote loading procedure using an ammonium sulfate gradient. This procedure produced uniform sized liposomes (100 nm) with an entrapment rate of 90±3.5%. Following administration of unencapsulated or liposome-encapsulated ciprofloxacin by intravenous injection or aerosol inhalation, levels of ciprofloxacin in sera, lungs, liver and spleen were determined using 14C-ciprofloxacin as radiotracer for ciprofloxacin. Intravenous injection of liposome-encapsulated ciprofloxacin resulted in higher serum levels of drug in serum, as well as increased drug retention in lungs, liver and spleen, compared to that of free encapsulated drug. Aerosol administration of liposome-encapsulated ciprofloxacin by jet nebulization resulted in significantly higher drug levels and prolonged drug retention in the lower respiratory tract compared to the free drug. Aerosol inhalation of liposome-encapsulated ciprofloxacin, given either prophylactically or therapeutically, provided complete protection to mice against a pulmonary lethal infection model of F. tularensis. In contrast, ciprofloxacin given in its free form, was ineffective. These results suggest that liposome encapsulation of ciprofloxacin enhances drug delivery to the primary site of infection and results in increasing therapeutic efficacy against F. tularensis.

Regional lung deposition of nebulized liposome-encapsulated ciprofloxacin

Liposome-encapsulated ciprofloxacin (22.2 mg ciprofloxacin/ml) was nebulized in 25 nebulizers (five nebulizers from each of five nebulizer types). The aerosol was inhaled by a breath simulator (square wave pattern, 0.75 l tidal volume, 0.3 l/s inhalation flow rate) and inhaled droplet sizes were characterized using in-line phase Doppler anemometry. Filter collection combined with centrifugation, UV spectrophotometry and measurement of original entrapment efficiency using C 14-radiolabelled ciprofloxacin was used to determine % encapsulation in the inhaled aerosol. Cascade impaction combined with chemical assay showed that encapsulated and free ciprofloxacin were homogeneously distributed among the inhaled droplet sizes. Combination of the above measurements with a mathematical lung deposition model allowed prediction of the amounts of encapsulated ciprofloxacin depositing in the tracheo-bronchial, alveolar and extrathoracic regions of the respiratory tract. The nebulizer types (Pari LC STAR, Pari LC+, Medix Sonix 2000, Hudson T-Updraft II, DeVilbiss Permaneb) differed by up to a factor of 30 in the amount of encapsulated ciprofloxacin depositing in the different regions of the lung (e.g. lung deposition of entrapped ciprofloxacin varied from 0.7% to 18.1% of total ciprofloxacin dose placed in the nebulizer). Much of this dramatic difference was due to the differing amounts of liposomal disruption, which varied among the different nebulizer types from no measurable disruption to nearly complete disruption.

Aerosol delivery of liposome-encapsulated ciprofloxacin: aerosol characterization and efficacy against Francisella tularensis infection in mice.

The aerosol delivery of liposome-encapsulated ciprofloxacin by using 12 commercially available jet nebulizers was evaluated in this study. Aerosol particles containing liposome-encapsulated ciprofloxacin generated by the nebulizers were analyzed with a laser aerodynamic particle sizer. Mean mass aerodynamic diameters (MMADs) and geometric standard deviations (GSDs) were determined, and the drug contents of the sampling filters from each run onto which aerosolized liposome-encapsulated ciprofloxacin had been deposited were analyzed spectrophotometrically. The aerosol particles of liposome-encapsulated ciprofloxacin generated by these nebulizers ranged from 1.94 to 3.5 microm, with GSDs ranging from 1.51 to 1.84 microm. The drug contents of the sampling filters exposed for 1 min to aerosolized liposome-encapsulated ciprofloxacin range from 12.7 to 40.5 microg/ml (0.06 to 0.2 mg/filter). By using the nebulizer selected on the basis of most desirable MMADs, particle counts, and drug deposition, aerosolized liposome-encapsulated ciprofloxacin was used for the treatment of mice infected with 10 times the 50% lethal dose of Francisella tularensis. All mice treated with aerosolized liposome-encapsulated ciprofloxacin survived the infection, while all ciprofloxacin-treated or untreated control mice succumbed to the infection (P < 0.001). These results suggest that aerosol delivery of liposome-encapsulated ciprofloxacin to the lower respiratory tract is feasible and that it may provide an effective therapy for the treatment of respiratory tract infections.

Liposome-mediated therapy of human immunodeficiency virus type-1 and mycobacterium infections

AbstractWe review our recent work on the use of liposomes for the delivery of antiviral agents to human immunodeficiency virus type-1 (HIV-1) infected cells, and antimycobactcrial drugs to cells harboring Mycobacterium avium complex or Mycobacterium tuberculosis. Soluble CD4 has been used to target liposomes to HIV-1-infected cells. Antisense oligodeoxynucleotides have been effectively delivered into HIV-1-infected macrophages using pH-sensitive liposomes. pH-sensitive liposomes with serum stability are being developed as in vivo delivery vehicles. Liposomes encapsulating an HIV-1 protease inhibitor were more effective in inhibiting virus production in infected macrophages than the free drug. Anionic liposomes were found to inhibit HIV-1 infectivity, while cationic liposomes had a differential toxicity for HIV-1-infected macrophages. Lipophilic sulfated cyclodextrins have been synthesized as novel antiviral agents. Liposome-encapsulated ciprofloxacin treatment reduced the number of viable M. avium in macr...

Liposome-Encapsulated Ciprofloxacin Is Effective in the Protection and Treatment of BALB/c Mice against Francisella tularensis

Liposome-Encapsulated Ciprofloxacin Is Effective in the Protection and Treatment of BALB/c Mice against Francisella tularensis

Efficacies of liposome-encapsulated streptomycin and ciprofloxacin against Mycobacterium avium-M. intracellulare complex infections in human peripheral blood monocyte/macrophages.

Current treatments of disseminated infection caused by the Mycobacterium avium-M. intracellulare complex (MAC) are generally ineffective. Liposome-mediated delivery of antibiotics to MAC-infected tissues in vivo can enhance the efficacy of the drugs (N. Düzgüneş, V. K. Perumal, L. Kesavalu, J. A. Goldstein, R. J. Debs, and P. R. J. Gangadharam, Antimicrob. Agents Chemother. 32:1404-1411, 1988; N. Düzgüneş, D. A. Ashtekar, D. L. Flasher, N. Ghori, R. J. Debs, D. S. Friend, and P. R. J. Gangadharam, J. Infect. Dis. 164:143-151, 1991). We investigated the therapeutic efficacies of liposome-encapsulated streptomycin and ciprofloxacin against growth of the MAC inside human peripheral blood monocyte/macrophages. Treatment was initiated 24 h after infection of macrophages with the MAC and stopped after 20 h, and the cells were incubated for another 7 days. The antimycobacterial activity of streptomycin was enhanced when the drug was delivered to macrophages in liposome-encapsulated form, reducing the CFU about threefold more than the free drug did throughout the concentration range studied (10 to 50 micrograms/ml). With 50 micrograms of encapsulated streptomycin per ml, the CFU were reduced to 11% of the initial level of infection. Liposome-encapsulated ciprofloxacin was at least 50 times more effective against the intracellular bacteria than was the free drug: at a concentration of 0.1 microgram/ml, liposome-encapsulated ciprofloxacin had greater antimycobacterial activity than the free drug at 5 microgram/ml. With liposome-encapsulated ciprofloxacin at 5 micrograms/ml, the CFU were reduced by more than 1,000-fold at the end of the 7-day incubation period, compared with untreated controls. These results suggest that liposome-encapsulated ciprofloxacin or other fluoroquinolones may be effective against MAC infections in vivo.