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.
BACKGROUND
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.
US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, 21702, USA. henry.heine@amedd.army.mil
Henry S
HS
Heine
Arnold
A
Louie
Fritz
F
Sorgel
Jennifer
J
Bassett
Lynda
L
Miller
Lawrence J
LJ
Sullivan
Martina
M
Kinzig-Schippers
George L
GL
Drusano
D000336:Aerosols; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005839:Gentamicins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D064704:Levofloxacin; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009503:Neutropenia; D015242:Ofloxacin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010930:Plague / Q000188:drug therapy* / Q000382:microbiology; D014176:Protein Biosynthesis / Q000187:drug effects*; D013997:Time Factors; D015010:Yersinia pestis / Q000187:drug effects / Q000502:physiology*
D000336:Aerosols; D000900:Anti-Bacterial Agents; D005839:Gentamicins; D064704:Levofloxacin; D015242:Ofloxacin; D004318:Doxycycline