Efficacy of ciprofloxacin-gentamicin combination therapy in murine bubonic plague
Nadine Lemaître1, Isabelle Ricard, Elizabeth Pradel
1Laboratoire de Bactériologie-Hygiène, Centre Hospitalier Universitaire, Lille, France. nadine.lemaitre@chru-lille.fr
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 log(10) 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.
Insights
Combination antibiotic therapy for plague using ciprofloxacin (CIN) and gentamicin (GEN) showed similar efficacy to CIN alone. Regimens with CIN were more effective at eradicating Yersinia pestis from lymph nodes than gentamicin monotherapy.
Area of Science:
- Infectious Diseases
- Microbiology
- Pharmacology
Background:
- Plague, caused by Yersinia pestis, remains a significant public health concern.
- The efficacy of combination antibiotic therapy for plague has not been previously evaluated.
- Understanding optimal treatment strategies is crucial for combating Yersinia pestis infections.
Purpose of the Study:
- To evaluate the efficacy of a ciprofloxacin (CIN) and gentamicin (GEN) combination therapy against Yersinia pestis.
- To compare combination therapy with monotherapy using CIN or GEN in a mouse model of bubonic plague.
- To assess the eradication of Yersinia pestis from lymph nodes post-treatment.
Main Methods:
- In vitro susceptibility testing of Yersinia pestis to CIN, GEN, and their combination.
- In vivo study using a mouse model of bubonic plague with intravenous antibiotic administration.
- Treatment initiation at two time points post-infection (44 h and 56 h) for five days.
- Assessment of survival rates and bacterial load in draining lymph nodes and spleen.
Main Results:
- In vitro, the CIN+GEN combination demonstrated synergy at 0.5x MIC and indifference at higher concentrations.
- In vivo, survival rates were comparable between CIN+GEN and CIN alone, and slightly higher than GEN alone, regardless of treatment timing.
- Yersinia pestis persisted in draining lymph nodes in all treatment groups, with significantly lower bacterial loads in CIN and CIN+GEN groups compared to GEN alone.
Conclusions:
- Combination therapy with ciprofloxacin and gentamicin is as effective as ciprofloxacin monotherapy for treating plague in a mouse model.
- Regimens containing ciprofloxacin are superior to gentamicin monotherapy in eradicating Yersinia pestis from draining lymph nodes.
- Draining lymph nodes may act as a reservoir for Yersinia pestis, potentially leading to persistent bacteremia even after treatment.
Related Concept Videos
01:15Determination of Multiple Dosing Parameters: Steady-State, Minimum and Maximum Concentrations
01:27Combined Effects of Drugs: Synergism
Such synergistic combinations...