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

Karleigh A Hamblin,Carwyn Davies,Stuart J Armstrong,James D Blanchard,Thomas Laws,Sarah V Harding,Helen S Atkins,Kay B Barnes

doi:10.3389/fmicb.2017.00091

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.

Highlights

The Gram-negative bacterium Yersinia pestis is the causative agent of plague, a disease responsible for the death of an estimated 200 million people through devastating pandemics such as the Black Death (Perry and Fetherston, 1997)
Even today there are concerns that plague could be used as a biological weapon (BW) as Y. pestis could be accessed relatively, there is the potential for person to person spread and the mortality rate of plague is high (Inglesby et al, 2000)
The AUC/MIC measurement has been shown to be the PK parameter most strongly associated with the efficacy of ciprofloxacin in animal models (Craig, 1998), this has not been validated for local treatment of lung infections

Summary

Introduction

The Gram-negative bacterium Yersinia pestis is the causative agent of plague, a disease responsible for the death of an estimated 200 million people through devastating pandemics such as the Black Death (Perry and Fetherston, 1997). There are numerous cases throughout history of Y. pestis being used as a biological weapon (BW). During the Second World War the Japanese offensive BW program is alleged to have dropped fleas infected with Y. pestis over parts of China (Harris, 1993). Even today there are concerns that plague could be used as a BW as Y. pestis could be accessed relatively (it can be found on every continent except Australia), there is the potential for person to person spread and the mortality rate of plague is high (Inglesby et al, 2000)

Methods

Results

Conclusion