Efficacy of Liposome-Encapsulated Ciprofloxacin in a Murine Model of Q Fever

Abstract

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.

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

“…The concentration-time profile of ciprofloxacin in blood and lung homogenate was determined using liquid chromatography mass spectrometry (LC-MS) as previously described (Hamblin et al, 2014a; Norville et al, 2014). Non-compartmental pharmacokinetic (PK) analysis of the mean concentration–time profiles of ciprofloxacin in the mouse lung and plasma was performed using WinNonlin v.6.1 (Certara, USA).…”

“…In a non-lethal mouse model of Coxiella burnetii infection, intranasally instilled CFI administered at 24 h post-challenge prevented weight loss and the development of clinical signs associated with infection (Norville et al, 2014). However, the efficacy of neither CFI nor DRCFI has been evaluated in BW mouse models once the infection has disseminated.…”

Comment on: Inhaled antimicrobial therapy—Barriers to effective treatment, by J. Weers, Inhaled antimicrobial therapy — Barriers to effective treatment, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2014.08.013

“…We would like to point out that Aradigm has been developing two inhaled liposomal ciprofloxacin products (licensed to Grifols): Lipoquin® -liposomally encapsulated ciprofloxacin, and Pulmaquin® which combines a mixture of free and encapsulated ciprofloxacin [2,3]. Lipoquin has been tested in a Phase 2a study in cystic fibrosis patients [4] and is also being tested (along with Pulmaquin) for non-tuberculous mycobacteria infections [5] and against bioterrorism infections such as plague, tularemia and Q-fever [6,7]. Unfortunately, the results from the cystic fibrosis trial with Lipoquin are missing from Fig.…”

Emerging Opportunities for Inhaled Antibiotic Therapy

“…Other potential inhaled bioterrorism threats include anthrax, tularemia, pneumonic plague and Q-fever. Liposomal ciprofloxacin formulations delivered to the lung have shown promising activity in the prevention and treatment of these infections in animal models and are more fully described below [35][36][37].…”

“…Following aerosol challenge with C. burnetii, mice were treated with seven once-daily doses of intranasal liposomal ciprofloxacin (50 mg/kg) or seven twice-daily doses of oral ciprofloxacin or doxycycline (50 mg/kg) [37]. In contrast to oral ciprofloxacin or doxycycline, for which the mice lost 15-20% of their body weight and showed clinical symptoms (e.g., ruffled fur, arched backs, and dehydration), liposomal ciprofloxacin (Lipoquin) protected the mice against weight loss and symptoms [37].…”