title: Efficacy of ciprofloxacin-gentamicin combination therapy in murine bubonic plague.
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.
authors.affiliation: Laboratoire de Bactériologie-Hygiène, Centre Hospitalier Universitaire, Lille, France. nadine.lemaitre@chru-lille.fr
authors.forename: Nadine
authors.initials: N
authors.lastname: Lemaître
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ricard
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pradel
authors.forename: Benoît
authors.initials: B
authors.lastname: Foligné
authors.forename: René
authors.initials: R
authors.lastname: Courcol
authors.forename: Michel
authors.initials: M
authors.lastname: Simonet
authors.forename: Florent
authors.initials: F
authors.lastname: Sebbane
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000494:pharmacology; D058491:Bacterial Load / Q000187:drug effects; D002939:Ciprofloxacin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005839:Gentamicins / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008826:Microbial Sensitivity Tests; D010930:Plague / Q000188:drug therapy* / Q000382:microbiology*; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D015010:Yersinia pestis / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D005839:Gentamicins; D002939:Ciprofloxacin