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

Abstract

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.

Demonstrating the Protective Efficacy of the Novel Fluoroquinolone Finafloxacin against an Inhalational Exposure to Burkholderia pseudomallei

“…Due to ciprofloxacin requiring a diluent of a pH >8.0 to achieve solubility, a soluble oral preparation could not be prepared that would match the human AUC, and therefore an alternate formulation of ciprofloxacin was used. The dosing regimen for ciprofloxacin was determined using the dose that matched the human AUC, which equates to 30 mg/kg delivered twice daily via intraperitoneal injection ( 39 ). The co-trimoxazole dosing regimen was determined by matching the time above MIC from previously generated data ( 40 ).…”

The Fluoroquinolone Finafloxacin Protects BALB/c Mice Against an Intranasal Infection With Francisella tularensis Strain SchuS4

“…An intravenous preparation of ciprofloxacin (Ciproxin 2 mg/ml) was purchased from Bayer (Basingstoke, United Kingdom). Dosing regimens were determined using pharmacokinetic data generated from previous studies (Barnes et al, 2017; Hamblin et al, 2017).…”

Inhalational Gentamicin Treatment Is Effective Against Pneumonic Plague in a Mouse Model

“…Using a relatively simple system built in-house, we successfully applied inhalational gentamicin treatment to pneumonic plague-infected mice. In a recently published study (Hamblin et al, 2017 ), a similar approach was applied to administer two liposomal formulations of ciprofloxacin by inhalation to mice infected with pneumonic plague. It is worth noting that mice are a challenging model for inhalation studies due to the stringent restraints regarding the inhaled particle size, which is significantly smaller than the inhalable size for humans (Raabe et al, 1988 ).…”