Antibiotic prophylaxis and therapy of airborne tularemia

Sawyer, William D.; Dangerfield, H G; Hogge, Arthur L.; Crozier, Dan

doi:10.1128/br.30.3.542-550.1966

Cited by 51 publications

(12 citation statements)

References 10 publications

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“…These are obtained by using the deterministic solution of the birth-death-survival model for extracellular bacteria over time (equation (2.1)) with data from studies in which humans are exposed to aerosolized Schu S4, and inhaled dose and incubation period are explicitly recorded. To this end, the datasets of [32,33] are used, which each contain 16 subjects. The lognormal distribution (m ¼ 26:2,ŝ ¼ 6:05 loghours) is found to provide the best fit to these data (figure 3d) by maximum likelihood.…”

Section: Threshold (M )mentioning

confidence: 99%

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A dose and time response Markov model for the in-host dynamics of infection with intracellular bacteria following inhalation: with application toFrancisella tularensis

Wood

Egan

Hall

2014

J. R. Soc. Interface.

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In a novel approach, the standard birth–death process is extended to incorporate a fundamental mechanism undergone by intracellular bacteria, phagocytosis. The model accounts for stochastic interaction between bacteria and cells of the immune system and heterogeneity in susceptibility to infection of individual hosts within a population. Model output is the dose–response relation and the dose-dependent distribution of time until response, where response is the onset of symptoms. The model is thereafter parametrized with respect to the highly virulent Schu S4 strain of Francisella tularensis, in the first such study to consider a biologically plausible mathematical model for early human infection with this bacterium. Results indicate a median infectious dose of about 23 organisms, which is higher than previously thought, and an average incubation period of between 3 and 7 days depending on dose. The distribution of incubation periods is right-skewed up to about 100 organisms and symmetric for larger doses. Moreover, there are some interesting parallels to the hypotheses of some of the classical dose–response models, such as independent action (single-hit model) and individual effective dose (probit model). The findings of this study support experimental evidence and postulations from other investigations that response is, in fact, influenced by both in-host and between-host variability.

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Section: Threshold (M )mentioning

confidence: 99%

“…a 'point of no return'-see later). In order to assess the validity of the model, results are also plotted from a number of experimental studies involving human infection with aerosolized Schu S4 [32,33,[41][42][43][44] (in [42], the inoculum is aged prior to delivery).…”

Section: Dose-responsementioning

confidence: 99%

A dose and time response Markov model for the in-host dynamics of infection with intracellular bacteria following inhalation: with application toFrancisella tularensis

Wood

Egan

Hall

2014

J. R. Soc. Interface.

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“…One study involved simultaneously exposing men and rhesus monkeys to aerosols that had been aged by 60, 120, or 180 minutes. 85 The infectivity of Schu S4 decreased after 120 minutes of aerosol aging and was reduced 10-fold after 180 minutes, yet the disease course was similar regardless of the age of the aerosol. The effects of aerosol aging were the same across man and rhesus monkey; however, once data were normalized for respective respiratory volumes, data indicated that rhesus monkeys were 3 times more susceptible than man to Schu S4 infection.…”

Section: Existing Data For F Tularensismentioning

confidence: 95%

“…The effects of aerosol aging were the same across man and rhesus monkey; however, once data were normalized for respective respiratory volumes, data indicated that rhesus monkeys were 3 times more susceptible than man to Schu S4 infection. 85 A second study in which rhesus monkeys were exposed to particles ranging from 2.1 to 24 mM in size demonstrated that as particle size decreased, LD 50 , ID 50 , time to disease onset, and time to death also decreased. 19 The signs and symptoms of disease, clinical chemistry, and pathology were all documented during this study.…”

Section: Existing Data For F Tularensismentioning

confidence: 99%

Animal Models forFrancisella tularensisandBurkholderiaSpecies

et al. 2013

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The development and regulatory approval of medical countermeasures (MCMs) for the treatment and prevention of bacterial threat agent infections will require the evaluation of products in animal models. To obtain regulatory approval, these models must accurately recapitulate aspects of human disease, including, but not necessarily limited to, route of exposure, time to disease onset, pathology, immune response, and mortality. This article focuses on the state of animal model development for 3 agents for which models are largely immature: Francisella tularensis, Burkholderia mallei, and Burkholderia pseudomallei. An overview of available models and a description of scientific and regulatory gaps are provided.

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“…The highly virulent SCHU S4 strain has long been utilized as the prototypic type A strain of F. tularensis for use in such models [ 3 ]. Since its original isolation in 1951 [ 4 ], the SCHU S4 strain has been used extensively to study the pathogenesis of pneumonic tularemia in both humans and experimental animals [ 5 , 6 , 7 ], as well as to evaluate the efficacy of potential medical countermeasures [ 5 , 8 , 9 , 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of an Attenuated Substrain of Francisella tularensis SCHU S4 by Phenotypic and Genotypic Analyses

et al. 2021

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Pneumonic tularemia is a highly debilitating and potentially fatal disease caused by inhalation of Francisella tularensis. Most of our current understanding of its pathogenesis is based on the highly virulent F. tularensis subsp. tularensis strain SCHU S4. However, multiple sources of SCHU S4 have been maintained and propagated independently over the years, potentially generating genetic variants with altered virulence. In this study, the virulence of four SCHU S4 stocks (NR-10492, NR-28534, NR-643 from BEI Resources and FTS-635 from Battelle Memorial Institute) along with another virulent subsp. tularensis strain, MA00-2987, were assessed in parallel. In the Fischer 344 rat model of pneumonic tularemia, NR-643 and FTS-635 were found to be highly attenuated compared to NR-10492, NR-28534, and MA00-2987. In the NZW rabbit model of pneumonic tularemia, NR-643 caused morbidity but not mortality even at a dose equivalent to 500x the LD50 for NR-10492. Genetic analyses revealed that NR-10492 and NR-28534 were identical to each other, and nearly identical to the reference SCHU S4 sequence. NR-643 and FTS-635 were identical to each other but were found to have nine regions of difference in the genomic sequence when compared to the published reference SCHU S4 sequence. Given the genetic differences and decreased virulence, NR-643/FTS-635 should be clearly designated as a separate SCHU S4 substrain and no longer utilized in efficacy studies to evaluate potential vaccines and therapeutics against tularemia.

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Antibiotic prophylaxis and therapy of airborne tularemia

Cited by 51 publications

References 10 publications

A dose and time response Markov model for the in-host dynamics of infection with intracellular bacteria following inhalation: with application toFrancisella tularensis

A dose and time response Markov model for the in-host dynamics of infection with intracellular bacteria following inhalation: with application toFrancisella tularensis

Animal Models forFrancisella tularensisandBurkholderiaSpecies

Identification of an Attenuated Substrain of Francisella tularensis SCHU S4 by Phenotypic and Genotypic Analyses

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