Francisella tularensis: Dose Response Models
Contents
Francisella tularensis
General overview of Francisella tularensis and tularemia
Francisella tularensis is the causative agent of tularemia or rabbit fever. It is an intracellular pathogenic species of Gram-negative bacteria, replicating mainly in macrophages, and has also been reported in amoebae [1]. Interest in this pathogen grew due to its high infectivity, ease of dissemination and consequently its potential use as biological weapon [2] [3][4] It can be easily disseminated via aerosols that once inhaled may result in tularemia pneumonia, a severe form of disease with high mortality if untreated [5]. Known as one of the most infectious pathogens, only a few F. tularensis organisms may cause infection [6] [7]. The U.S. Centers for Disease Control and Prevention have classified F. tularensis as a Category A bioterrorism agent for public health preparedness.
Summary Data
Day and Berendt[8] exposed 4-5 kg monkeys to aerosol particles of SCHU S-4 strain of F. tularensis. The aerosol particles were administered into different sizes to study the effect of size distribution.
A set of classical dose-response data for F. tularensis infection via oral exposure by Quan et al[9] were used in investigating the effects of inoculation route on the response. Albino mice were infected orally with drinking water contaminated with 104 to 108 organisms of a highly virulent Aa strain.
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*Recommended Model
It is recommended that experiment 274 should be used as the best dose response model for inhalation. Inhalation is much more infective than the oral exposure in this case so that it should receive more attention in terms of emergency preparedness and public intervention.
Optimization Output for experiment 274
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Optimization Output for experiment 275
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Advanced Dose Response Model
Incorporating the time postinoculation into the classical dose-response models for microbial infection generates a class of time-dose-response (TDR) models. The parameter k in the exponential dose-response model (equation 1) and the parameter N50 in the beta-Poisson model (equation 2) were set equal to functions of time that represent in vivo bacterial kinetics. Equations 1-2 with candidate G(t; θ,…) were fit to the time-dependent dose response data from experiment 2. The exponential TDR model (equation 1) incorporating the Weibull distribution (equation 3), where k0 = 0.056, θ1 = 5.66, θ2 = 6.43, provided the best fit to the data. The probability density function of the best-fit model is compared with the observed densities of deaths at different dose levels.
Summary
Noting the very different LD50 for these two exposure route (5.22E6 for oral route and 14.65 for inhalation), substantial variation of virulence with infection site is manifested.
References
- ↑ Titball, R. W. and A. Sjostedt (2003). "Francisella tularensis: an overview." American Society for Microbiology News 69(11): 558-563.
- ↑ World Health Organization (1970). Health Aspects of Chemical and Biological Weapons. Geneva, Switzerland, World Health Organization.
- ↑ Christopher, G. W., T. J. Cieslak, J. A. Pavlin and E. M. Eitzen (1997). "Biological warfare: a historical perspective." JAMA (Journal of the American Medical Association) 278: 412-417.
- ↑ Kaufmann, A. F., M. I. Meltzer and G. P. Schmid (1997). "The economic impact of a bioterrorist attack: are prevention and post-attack intervention programs justifiable?" Emerging Infectious Diseases 2: 83-94.
- ↑ Stuart, B. M. and R. L. Pullen (1945). "Tularemic pneumonia: Review of American literature and report of 15 additional cases." American Journal of the Medical Sciences 210: 223-236.
- ↑ Saslaw, S., H. T. Eigelsbach, J. A. Prior, H. E. Wilson and S. Carhart (1961). "Tularemia vaccine study. II. Respiratory challenge." Arch Intern Med. 107: 702-714.
- ↑ Saslaw, S., H. T. Eigelsbach, H. E. Wilson, J. A. Prior and S. Carhart (1961). "Tularemia vaccine study, I: intracutaneous challenge." Arch Intern Med 107: 121-133.
- ↑ 8.0 8.1 8.2 Day, W. C. and R. F. Berendt (1972). "Experimental Tularemia in Macaca mulatta: Relationship of Aerosol Particle Size to the Infectivity of Airborne Pasteurella tularensis." Infection and Immunity 5(1): 77-82.
- ↑ 9.0 9.1 9.2 Quan, S. F., A. G. McManus and H. von Fintel (1956). "Infectivity of Tularemia Applied to Intact Skin and Ingested in Drinking Water." Science 123: 942-943.
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