No abstract

b After a relatively short untreated interval, pneumonic plague has a mortality approaching 100%. We employed a murine model of aerosol challenge with Yersinia pestis to investigate the early course of pneumonic plague in the lung, blood, and spleen. We fit a mathematical model to all data simultaneously. The model fit to the data was acceptable. The number of organisms in the lung at baseline was estimated to be 135 (median) or 1,184 (mean) CFU/g. The doubling time was estimated as 1.5 to 1.7 h. Between 1 and 12 h postexposure, counts declined, but they then increased by 24 h, a finding hypothesized to be due to innate immunity. The model predicted that innate immunity declined with a half-time of 3 to 3.8 h. The threshold for bacteremia was 6.4 ؋ 10 4 to 1.52 ؋ 10 6 CFU/g. By 42 to 48 h, stationary phase was obtained. Lung bacterial burdens exceeded 10 log CFU/g. Obviating early defenses allows for rapid amplification of Y. pestis in bacteremia, making the rapid course with high mortality understandable.

Bacillus anthracis is considered a likely agent to be used as a bioweapon, and the use of a strain resistant to the first-line antimicrobial treatments is a concern. We determined treatment efficacies against a ciprofloxacin-resistant strain of B. anthracis (Cip r Ames) in a murine inhalational anthrax model. Ten groups of 46 BALB/c mice were exposed by inhalation to 7 to 35 times the 50% lethal dose (LD 50 ) of B. anthracis Cip r Ames spores. Commencing at 36 h postexposure, groups were administered intraperitoneal doses of sterile water for injections (SWI) and ciprofloxacin alone (control groups), or ciprofloxacin combined with two antimicrobials, including meropenem-linezolid, meropenem-clindamycin, meropenem-rifampin, meropenemdoxycycline, penicillin-linezolid, penicillin-doxycycline, rifampin-linezolid, and rifampinclindamycin, at appropriate dosing intervals (6 or 12 h) for the respective antibiotics. Ten mice per group were treated for 14 days and observed until day 28. The remaining animals were euthanized every 6 to 12 h, and blood, lungs, and spleens were collected for lethal factor (LF) and/or bacterial load determinations. All combination groups showed significant survival over the SWI and ciprofloxacin controls: meropenem-linezolid (P ϭ 0.004), meropenem-clindamycin (P ϭ 0.005), meropenem-rifampin (P ϭ 0.012), meropenem-doxycycline (P ϭ 0.032), penicillindoxycycline (P ϭ 0.012), penicillin-linezolid (P ϭ 0.026), rifampin-linezolid (P ϭ 0.001), and rifampin-clindamycin (P ϭ 0.032). In controls, blood, lung, and spleen bacterial counts increased to terminal endpoints. In combination treatment groups, blood and spleen bacterial counts showed low/no colonies after 24-h treatments. The LF fell below the detection limits for all combination groups yet remained elevated in control groups. Combinations with linezolid had the greatest inhibitory effect on mean LF levels.

The objective of this study was to evaluate the natural history and pathogenesis of Francisella tularensis in a murine model of inhalational tularemia with the SchuS4 strain. Before the efficacy of antimicrobials could be assessed in this model, further model development was required to determine the optimal time to start therapy. This study helped define the time course of infection after aerosol challenge by quantifying the presence of bacteria in lung, blood, and spleen at multiple harvest points. In this study, mice were infected via a targeted inhaled dose of 100 50% lethal doses (LD 50 s) (LD 50 ‫؍‬ 300 CFU) of F. tularensis by whole-body aerosol. At 1, 24, 36, 48, 60, 72, 75, 78, 81, 84, 87, and 90 h postchallenge, groups of 15 animals were sacrificed and blood, lung, and splenic tissue samples were harvested, homogenized, plated, and incubated to evaluate the bacterial load in those tissues. It was determined that of the 3 sample types harvested, splenic tissue provided the most consistent bacterial counts, which steadily increased with the progressing infection. Further, it was determined that lung samples from all (15/15) animals were positive for infection at 75 h postaerosolization and that 14/15 animals had positive splenic tissue counts. Bacterial levels in blood were not predictive of treatment initiation. For future therapeutic evaluation studies in this model using F. tularensis (SchuS4), it was determined that therapy should be initiated at 75 h postchallenge and validated by spleen involvement.