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Antibiotics
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Animal Models of Biodefence Pathogens: Exploring Treatment
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Animal Models of Biodefence Pathogens: Exploring Treatment

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Antibiotics in Animal Health".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 10307

Special Issue Editor

Dr. Michelle Nelson

E-Mail Website
Guest Editor
Defence Science and Technology Laboratory DSTL, Salisbury, UK
Interests: animal models of infectious disease; aerobiology; host response to infection; immunology and histopathology; alternative models of infection and the 3Rs

Special Issue Information

Dear Colleagues,

Infectious diseases account for approximately a quarter of deaths globally and are a significant health and economic burden. A subset of pathogens have the potential to be used intentionally against military or civilian populations. Natural outbreaks of biodefence pathogens occur sporadically in an unpredictable manner, but do not tend to occur by the route of infection that is most relevant to biodefence, i.e., the inhalational route. This makes it difficult to understand the disease and undertake efficacy trials for licensure of products. Therefore, there is much greater reliance on animal data. Ethical use of animal models to study infectious pathogens is critical to understanding disease and, more importantly, identifying and assessing medical interventions to save lives.

The aerosol route of exposure is of particular importance for biodefence and it is not usually the natural route of infection for many of these pathogens. Therefore, infections of the lung offer additional challenges for the usual standard of care drugs. In many cases, better strategies are required to effectively treat inhalational disease, including alternative drugs and/or different delivery systems.

The aim of this Special Issue is to highlight the progress in the development and utilisation of animal models of biodefence pathogens, as well as alternative models. This will help inform prophylaxis and treatment options to combat infection caused by the deliberate release of bacterial agents.

Dr. Michelle Nelson
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • animal models of infectious disease
  • aerobiology
  • host response to infection
  • immunology and histopathology
  • alternative models of infection and the 3Rs

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Published Papers (5 papers)

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17 pages, 1636 KiB  
Article
Ceftobiprole Medocaril Is an Effective Post-Exposure Treatment in the Fischer 344 Rat Model of Pneumonic Tularemia
by Mark M. Hahn, Cheryl A. Triplett, Michael S. Anderson, Jennifer I. Smart, Karine Litherland, Stephen Keech, Franziska von Siebenthal, Mark Jones, Andrew J. Phipps and Lisa N. Henning
Antibiotics 2023, 12(8), 1337; https://doi.org/10.3390/antibiotics12081337 - 19 Aug 2023
Cited by 1 | Viewed by 1454
Abstract
Francisella tularensis subspecies tularensis is a category-A biothreat agent that can cause lethal tularemia. Ceftobiprole medocaril is being explored as a medical countermeasure for the treatment of pneumonic tularemia. The efficacy of ceftobiprole medocaril against inhalational tularemia was evaluated in the Fischer 344 [...] Read more.
Francisella tularensis subspecies tularensis is a category-A biothreat agent that can cause lethal tularemia. Ceftobiprole medocaril is being explored as a medical countermeasure for the treatment of pneumonic tularemia. The efficacy of ceftobiprole medocaril against inhalational tularemia was evaluated in the Fischer 344 rat model of infection. The dose was expected to be effective against F. tularensis isolates with ceftobiprole minimum inhibitory concentrations ≤0.5 µg/mL. Animals treated with ceftobiprole medocaril exhibited a 92% survival rate 31 days post-challenge, identical to the survival of levofloxacin-treated rats. By comparison, rats receiving placebo experienced 100% mortality. Terminally collected blood, liver, lung, and spleen samples confirmed disseminated F. tularensis infections in most animals that died prior to completing treatments (placebo animals and a rat treated with ceftobiprole medocaril), although levels of bacteria detected in the placebo samples were significantly elevated compared to the ceftobiprole-medocaril-treated group geometric mean. Furthermore, no evidence of infection was detected in any rat that completed ceftobiprole medocaril or levofloxacin treatment and survived to the end of the post-treatment observation period. Overall, survival rates, body weights, and bacterial burdens consistently demonstrated that treatment with ceftobiprole medocaril is efficacious against otherwise fatal cases of pneumonic tularemia in the rat model. Full article
(This article belongs to the Special Issue Animal Models of Biodefence Pathogens: Exploring Treatment)
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18 pages, 3453 KiB  
Article
Evaluation of Alternative Doxycycline Antibiotic Regimes in an Inhalational Murine Model of Q Fever
by Kate A. Clay, M. Gill Hartley, Adam O. Whelan, Mark S. Bailey and Isobel H. Norville
Antibiotics 2023, 12(5), 914; https://doi.org/10.3390/antibiotics12050914 - 16 May 2023
Viewed by 1702
Abstract
The timing of the initiation of antibiotic treatment has been shown to impact the clinical outcome of many bacterial infections, including Q fever. Delayed, suboptimal or incorrect antibiotic treatment has been shown to result in poor prognosis, resulting in the progression of acute [...] Read more.
The timing of the initiation of antibiotic treatment has been shown to impact the clinical outcome of many bacterial infections, including Q fever. Delayed, suboptimal or incorrect antibiotic treatment has been shown to result in poor prognosis, resulting in the progression of acute disease to long-term chronic sequalae. Therefore, there is a requirement to identify an optimal, effective therapeutic regimen to treat acute Q fever. In the study, the efficacies of different doxycycline monohydrate regimens (pre-exposure prophylaxis, post-exposure prophylaxis or treatment at symptom onset or resolution) were evaluated in an inhalational murine model of Q fever. Different treatment lengths (7 or 14 days) were also evaluated. Clinical signs and weight loss were monitored during infection and mice were euthanized at different time points to characterize bacterial colonization in the lungs and the dissemination of bacteria to other tissues including the spleen, brain, testes, bone marrow and adipose. Post-exposure prophylaxis or doxycycline treatment starting at symptoms onset reduced clinical signs, and also delayed the systemic clearance of viable bacteria from key tissues. Effective clearance was dependent on the development of an adaptive immune response, but also driven by sufficient bacterial activity to maintain an active immune response. Pre-exposure prophylaxis or post-exposure treatment at the resolution of clinical signs did not improve outcomes. These are the first studies to experimentally evaluate different doxycycline treatment regimens for Q fever and illustrate the need to explore the efficacy of other novel antibiotics. Full article
(This article belongs to the Special Issue Animal Models of Biodefence Pathogens: Exploring Treatment)
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22 pages, 4546 KiB  
Article
An Investigation into the Re-Emergence of Disease Following Cessation of Antibiotic Treatment in Balb/c Mice Infected with Inhalational Burkholderia pseudomallei
by Thomas R. Laws, Kay B. Barnes, Dominic C. Jenner, Alejandro Núñez, Mark I. Richards, Joanne E. Thwaite, Andreas Vente, David Rushton, Michelle Nelson and Sarah V. Harding
Antibiotics 2022, 11(10), 1442; https://doi.org/10.3390/antibiotics11101442 - 20 Oct 2022
Cited by 1 | Viewed by 1925
Abstract
Burkholderia pseudomallei is the causative agent of melioidosis, a multifaceted disease. A proportion of the mortality and morbidity reported as a result of infection with this organism may be due to the premature cessation of antibiotic therapy typically lasting for several months. The [...] Read more.
Burkholderia pseudomallei is the causative agent of melioidosis, a multifaceted disease. A proportion of the mortality and morbidity reported as a result of infection with this organism may be due to the premature cessation of antibiotic therapy typically lasting for several months. The progression of re-emergent disease was characterised in Balb/c mice following cessation of a 14 day treatment course of co-trimoxazole or finafloxacin, delivered at a human equivalent dose. Mice were culled weekly and the infection characterised in terms of bacterial load in tissues, weight loss, clinical signs of infection, cytokine levels and immunological cell counts. Following cessation of treatment, the infection re-established in some animals. Finafloxacin prevented the re-establishment of the infection for longer than co-trimoxazole, and it is apparent based on the protection offered, the development of clinical signs of disease, bodyweight loss and bacterial load, that finafloxacin was more effective at controlling infection when compared to co-trimoxazole. Full article
(This article belongs to the Special Issue Animal Models of Biodefence Pathogens: Exploring Treatment)
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13 pages, 306 KiB  
Perspective
The BALB/c Mouse Model for the Evaluation of Therapies to Treat Infections with Aerosolized Burkholderia pseudomallei
by Michelle Nelson, Kay B. Barnes, Carwyn H. Davies, Christopher K. Cote, J. Matthew Meinig, Sergei S. Biryukov, David N. Dyer, Ondraya Frick, Henry Heine, Denise A. Pfefferle, Amanda Horstman-Smith, Julie Barbaras and Sarah V. Harding
Antibiotics 2023, 12(3), 506; https://doi.org/10.3390/antibiotics12030506 - 3 Mar 2023
Cited by 3 | Viewed by 2699
Abstract
Burkholderia pseudomallei, the causative agent of the disease melioidosis, has been isolated from the environment in 45 countries. The treatment of melioidosis is complex, requiring lengthy antibiotic regimens, which can result in the relapse of the disease following treatment cessation. It is [...] Read more.
Burkholderia pseudomallei, the causative agent of the disease melioidosis, has been isolated from the environment in 45 countries. The treatment of melioidosis is complex, requiring lengthy antibiotic regimens, which can result in the relapse of the disease following treatment cessation. It is important that novel therapies to treat infections with B. pseudomallei be assessed in appropriate animal models, and discussions regarding the different protocols used between laboratories are critical. A ‘deep dive’ was held in October 2020 focusing on the use of the BALB/c mouse model and the inhalational route of infection to evaluate new antibiotic therapies. Full article
(This article belongs to the Special Issue Animal Models of Biodefence Pathogens: Exploring Treatment)
13 pages, 1219 KiB  
Brief Report
Efficacy of Treatment with the Antibiotic Novobiocin against Infection with Bacillus anthracis or Burkholderia pseudomallei
by Christopher P. Klimko, Susan L. Welkos, Jennifer L. Shoe, Sherry Mou, Melissa Hunter, Nathaniel O. Rill, David DeShazer and Christopher K. Cote
Antibiotics 2022, 11(12), 1685; https://doi.org/10.3390/antibiotics11121685 - 23 Nov 2022
Cited by 4 | Viewed by 1891
Abstract
The microbial pathogens Burkholderia pseudomallei and Bacillus anthracis are unrelated bacteria, yet both are the etiologic agents of naturally occurring diseases in animals and humans and are classified as Tier 1 potential biothreat agents. B. pseudomallei is the gram-negative bacterial agent of melioidosis, [...] Read more.
The microbial pathogens Burkholderia pseudomallei and Bacillus anthracis are unrelated bacteria, yet both are the etiologic agents of naturally occurring diseases in animals and humans and are classified as Tier 1 potential biothreat agents. B. pseudomallei is the gram-negative bacterial agent of melioidosis, a major cause of sepsis and mortality globally in endemic tropical and subtropical regions. B. anthracis is the gram-positive spore-forming bacterium that causes anthrax. Infections acquired by inhalation of these pathogens are challenging to detect early while the prognosis is best; and they possess innate multiple antibiotic resistance or are amenable to engineered resistance. Previous studies showed that the early generation, rarely used aminocoumarin novobiocin was very effective in vitro against a range of highly disparate biothreat agents. The objective of the current research was to begin to characterize the therapeutic efficacy of novobiocin in mouse models of anthrax and melioidosis. The antibiotic was highly efficacious against infections by both pathogens, especially B. pseudomallei. Our results supported the concept that specific older generation antimicrobials can be effective countermeasures against infection by bacterial biothreat agents. Finally, novobiocin was shown to be a potential candidate for inclusion in a combined pre-exposure vaccination and post-exposure treatment strategy designed to target bacterial pathogens refractory to a single medical countermeasure. Full article
(This article belongs to the Special Issue Animal Models of Biodefence Pathogens: Exploring Treatment)
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