Francisella tularensis: Dose Response Experiments

General Overview

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. Interest in this pathogen grew due to its high infectivity, ease of dissemination and consequently its potential use as biological weapon. 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. Known as one of the most infectious pathogens, only a few F. tularensis organisms may cause infection. The U.S. Centers for Disease Control and Prevention have classified F. tularensis as a Category A bioterrorism agent for public health preparedness.

http://www.cdc.gov/tularemia/

Summary Data

Day and Berendt 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 were used in investigating the effects of inoculation route on the response. Albino mice were infected orally with drinking water contaminated with 10⁴to 10⁸ organisms of a highly virulent Aa strain.

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.

Exponential and betapoisson model.jpg

ID	Exposure Route	# of Doses	Agent Strain	Dose Units	Host type	Μodel	LD50/ID50	Optimized parameters	Response type	Reference
274	inhalation	4.00	SCHU S-4	CFU	monkey	exponential	1.46E+01	k = 4.73E-02	death	Quan, S. F., McManus, A. G., & von Fintel, H. . (1956). Infectivity of Tularemia Applied to Intact Skin and Ingested in Drinking Water. Science, 123, 942-943.
275	oral	5.00	Aa strain	CFU	mice	exponential	5.22E+06	k = 1.33E-07	death	John, D. T., & Hoppe, K. L. (1990). Susceptibility of Wild Mammals to Infection with Naegleria fowleri. The Journal of Parasitology, 76, 6.

Highest quality

Exposure Route:

inhalation

# of Doses:

4.00

Agent Strain:

SCHU S-4

Dose Units:

CFU

Host type:

monkey

Μodel:

exponential

LD50/ID50:

1.46E+01

Optimized parameters: k = 4.73E-02

Response type:

death

Reference:

Infectivity of Tularemia Applied to Intact Skin and Ingested in Drinking Water

Optimization Output for experiment 274

**Monkeys / SCHU S-4 model data**
Dose	Dead	Survived	Total
5	1	5	6
11	3	3	6
32	4	2	6
65	6	0	6

**Goodness of fit and model selection**
Model	Deviance	Δ	Degrees of freedom	χ²_0.95,1 p-value	χ²_0.95,m-k p-value
Exponential	1.26	-0.000367	3	3.84 1	7.81 0.738
Beta Poisson	1.26	-0.000367	2	3.84 1	5.99 0.531
Exponential is preferred to beta-Poisson; cannot reject good fit for exponential.

**Optimized k parameter for the exponential model, from 10000 bootstrap iterations**
Parameter	MLE estimate	Percentiles
Parameter	MLE estimate	0.5%	2.5%	5%	95%	97.5%	99.5%
k	4.73E-02	2.28E-02	2.72E-02	2.98E-02	7.81E-02	9.03E-02	1.11E-01
ID50/LD50/ETC*	1.46E+01	6.27E+00	7.67E+00	8.88E+00	2.33E+01	2.55E+01	3.04E+01
*Not a parameter of the exponential model; however, it facilitates comparison with other models.

Parameter histogram for exponential model (uncertainty of the parameter)

Exponential model plot, with confidence bounds around optimized model

Exposure Route:

oral

# of Doses:

5.00

Agent Strain:

Aa strain