Comparison of 2 antibiotics that inhibit protein synthesis for the treatment of infection with Yersinia pestis delivered by aerosol in a mouse model of pneumonic plague.

Abstract

INTRODUCTION:

Intentional release of Yersinia pestis will likely be propagated by aerosol exposure. We explored the effects of neutropenia on the outcome of doxycycline and gentamicin therapy.

METHODS:

Female BALB/c mice were exposed to 20 LD(50) of Y. pestis CO92 by aerosol. Treatments were saline (negative control), levofloxacin at 15 mg/kg every 12 h (positive control), doxycycline at 40 mg/kg every 6 h, and gentamicin at 12 mg/kg every 6 h, 24 mg/kg every 12 h, and 48 mg/kg every 24 h in cohorts of normal and neutropenic mice for 5 days.

RESULTS:

Control mice died. Positive control mice (levofloxacin) had 100% survivorship in both neutropenic and nonneutropenic groups. Doxycycline treatment in the presence of granulocytes yielded 90% survivorship; all neutropenic mice died after the termination of treatment (P<<.001). For gentamicin, survivorship of mice receiving drug every 24, 12, and 6 h was, respectively, 80%, 80%, and 90% for normal mice and 80%, 100%, and 70% for neutropenic mice. No significant differences were seen in the neutropenia versus normal mouse comparison or by schedule.

CONCLUSIONS:

Doxycycline behaves in vivo as a bacteriostatic drug, requiring an intact immune system for clearance of the infection after aerosol challenge with Y. pestis. Gentamicin is bactericidal, even when given on a daily schedule. Neutropenia did not significantly affect survivorship.

• Authors: Henry S Heine, Arnold Louie, Fritz Sorgel, Jennifer Bassett, Lynda Miller, Lawrence J Sullivan, Martina Kinzig-Schippers, George L Drusano
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 196 Issue 5 Pg. 782-7 (Sep 01 2007) ISSN: 0022-1899 [Print] United States
• PMID: 17674322 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Aerosols
• Anti-Bacterial Agents
• Gentamicins
• Levofloxacin
• Ofloxacin
• Doxycycline

Topics

• Aerosols
• Animals
• Anti-Bacterial Agents (pharmacokinetics, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Doxycycline (pharmacokinetics, therapeutic use)
• Female
• Gentamicins (pharmacokinetics, therapeutic use)
• Levofloxacin
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Neutropenia
• Ofloxacin (pharmacokinetics, therapeutic use)
• Plague (drug therapy, microbiology)
• Protein Biosynthesis (drug effects)
• Time Factors
• Yersinia pestis (drug effects, physiology)