Efficacy of Ciprofloxacin-Gentamicin Combination Therapy in Murine Bubonic Plague

Nadine Lemaître,René Courcol,Isabelle Ricard,Elizabeth Pradel,Benoît Foligné,Florent Sebbane,Michel Simonet,Mikael Skurnik

doi:10.1371/journal.pone.0052503

Abstract

Potential benefits of combination antibiotic therapy for the treatment of plague have never been evaluated. We compared the efficacy of a ciprofloxacin (CIN) and gentamicin (GEN) combination therapy with that of each antibiotic administered alone (i) against Yersinia pestis in vitro and (ii) in a mouse model of bubonic plague in which animals were intravenously injected with antibiotics for five days, starting at two different times after infection (44 h and 56 h). In vitro, the CIN+GEN combination was synergistic at 0.5x the individual drugs’ MICs and indifferent at 1x- or 2x MIC. In vivo, the survival rate for mice treated with CIN+GEN was similar to that observed with CIN alone and slightly higher than that observed for GEN alone 100, 100 and 85%, respectively when treatment was started 44 h post challenge. 100% of survivors were recorded in the CIN+GEN group vs 86 and 83% in the CIN and GEN groups, respectively when treatment was delayed to 56 h post-challenge. However, these differences were not statistically significant. Five days after the end of treatment, Y. pestis were observed in lymph nodes draining the inoculation site (but not in the spleen) in surviving mice in each of the three groups. The median lymph node log10 CFU recovered from persistently infected lymph nodes was significantly higher with GEN than with CIN (5.8 vs. 3.2, p = 0.04) or CIN+GEN (5.8 vs. 2.8, p = 0.01). Taken as the whole, our data show that CIN+GEN combination is as effective as CIN alone but, regimens containing CIN are more effective to eradicate Y. pestis from the draining lymph node than the recommended GEN monotherapy. Moreover, draining lymph nodes may serve as a reservoir for the continued release of Y. pestis into the blood – even after five days of intravenous antibiotic treatment.

Highlights

The Gram-negative bacterium Yersinia pestis is responsible for plague, a zoonotic disease that primarily affects rodents and, to a lesser extent, humans [1]
We sought to determine whether a CIN+GEN combination was more effective than either agent alone when administered to treat experimentally induced bubonic plague in the mouse
The current standard treatment of plague is still based on the use of aminoglycoside monotherapy and a combined antibiotic regimen with streptomycin, ciprofloxacin and ceftriaxone has been recently used to treat cases of human plague in China, its efficacy has not been compared with that of drugs administered singly [3,5,24]

Summary

Introduction

The Gram-negative bacterium Yersinia pestis is responsible for plague, a zoonotic disease that primarily affects rodents and, to a lesser extent, humans [1]. Yersinia pestis is mostly transmitted to susceptible hosts by infected fleas. Y. pestis migrates from the dermis and through the lymphatic vessels to regional lymph nodes, where rapid bacterial multiplication induces a tender, swollen feature (the bubo). The bubo characterizes bubonic plague – the most common form of the disease. The lymph node defenses are overwhelmed and the bacteria disseminate through the circulatory system, which causes life-threatening septicemia and (in some cases) secondary pneumonia. Patients developing secondary pneumonic plague can transmit the pathogen as an expectorated aerosol, with the newly contaminated patient developing primary pneumonic plague [1]

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Conclusion