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Bioluminescent murine models of bacterial sepsis and scald wound infections for antimicrobial efficacy testing.

ABSTRACT: There are very few articles in the literature describing continuous models of bacterial infections that mimic disease pathogenesis in humans and animals without using separate cohorts of animals at each stage of disease. In this work, we developed bioluminescent mouse models of partial-thickness scald wound infection and sepsis that mimic disease pathogenesis in humans and animals using a recombinant luciferase-expressing Staphylococcus aureus strain (Xen29). Two days post-scald wound infection, mice were treated twice daily with a 2% topical mupirocin ointment for 7 days. For sepsis experiments, mice were treated intraperitoneally with 6 mg/kg daptomycin 2 h and 6 h post-infection and time to moribund monitored for 72 h. Consistent bacterial burden data were obtained from individual mice by regular photon intensity quantification on a Xenogen IVIS Lumina XRMS Series III biophotonic imaging system, with concomitant significant reduction in photon intensities in drug-treated mice. Post-mortem histopathological examination of wounds and bacterial counts in blood correlated closely with disease severity and total flux obtained from Xen29. The bioluminescent murine models provide a refinement to existing techniques of multiple bacterial enumeration during disease pathogenesis and promote animal usage reduction. The models also provide an efficient and information-rich platform for preclinical efficacy evaluation of new drug classes for treating acute and chronic human and animal bacterial infections.

SUBMITTER: Ogunniyi AD

PROVIDER: S-EPMC6047774 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Bioluminescent murine models of bacterial sepsis and scald wound infections for antimicrobial efficacy testing.

Ogunniyi Abiodun D AD Kopecki Zlatko Z Hickey Elizabeth E EE Khazandi Manouchehr M Peel Emma E Belov Katherine K Boileau Alexandra A Garg Sanjay S Venter Henrietta H Chan Wei Yee WY Hill Peter B PB Page Stephen W SW Cowin Allison J AJ Trott Darren J DJ

PloS one 20180716 7

There are very few articles in the literature describing continuous models of bacterial infections that mimic disease pathogenesis in humans and animals without using separate cohorts of animals at each stage of disease. In this work, we developed bioluminescent mouse models of partial-thickness scald wound infection and sepsis that mimic disease pathogenesis in humans and animals using a recombinant luciferase-expressing Staphylococcus aureus strain (Xen29). Two days post-scald wound infection, ...[more]

PMID: 30011298

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Project description:Immune response stimulation to prevent infection progression may be an adjuvant to antimicrobial treatment. Lysophosphatidylcholine (LPC) is an immunomodulator involved in immune cell recruitment and activation. In this study, we aimed to evaluate the efficacy of LPC in combination with colistin, tigecycline, or imipenem in experimental murine models of peritoneal sepsis and pneumonia. We used Acinetobacter baumannii strain Ab9, which is susceptible to colistin, tigecycline, and imipenem, and multidrug-resistant strain Ab186, which is susceptible to colistin and resistant to tigecycline and imipenem. Pharmacokinetic and pharmacodynamic parameters for colistin, tigecycline, and imipenem and the 100% minimal lethal dose (MLD100) were determined for both strains. The therapeutic efficacies of LPC, colistin (60 mg/kg of body weight/day), tigecycline (10 mg/kg/day), and imipenem (180 mg/kg/day), alone or in combination, were assessed against Ab9 and Ab186 at the MLD100 in murine peritoneal sepsis and pneumonia models. The levels of pro- and anti-inflammatory cytokines, i.e., tumor necrosis factor alpha (TNF-?) and interleukin-10 (IL-10), were determined by enzyme-linked immunosorbent assay (ELISA) for the same experimental models after inoculating mice with the MLD of both strains. LPC in combination with colistin, tigecycline, or imipenem markedly enhanced the bacterial clearance of Ab9 and Ab186 from the spleen and lungs and reduced bacteremia and mouse mortality rates (P < 0.05) compared with those for colistin, tigecycline, and imipenem monotherapies. Moreover, at 4 h post-bacterial infection, Ab9 induced higher TNF-? and lower IL-10 levels than those with Ab186 (4 ?g/ml versus 3 ?g/ml [P < 0.05] and 2 ?g/ml versus 3.4 ?g/ml [P < 0.05], respectively). LPC treatment combined with colistin, tigecycline, or imipenem modestly reduced the severity of infection by A. baumannii strains with different resistance phenotypes compared to LPC monotherapy in both experimental models.

Project description:Globally, the application of medicinal plants in the management of acute and chronic wounds can be considered a common occurrence in most traditional medicine practices. In view of this, many plants in the tropical and subtropical regions have been screened for their wound-healing activities. Consequently, plants having antimicrobial activity against multidrug-resistant (MD-R) pathogens can be considered great assets. Therefore, this study evaluated ethanolic and aqueous extracts of five medicinal plants (Psidium guajava, Myrianthus arboreus, Alchornea cordifolia, Momordica charantia, and Justicia flava) for their antimicrobial activities against MD-R bacterial pathogens isolated from post-operative wounds; Methods: This involved the aqueous and ethanolic extraction of the selected medicinal plants. Preliminary phytochemical constituents of the plants were examined. The agar well diffusion method was then used to determine the antibacterial activity of the leaves against reference strains (Escherichia coli ATCC 25922, Salmonella typhi ATCC 19430, Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 25923, and a Methicillin-Resistant Staphylococcus aureus strain) as well as the MDR clinical isolates (E. coli, P. aeruginosa, S. aureus and CoNS) from the wounds; Results: The preliminary phytochemical analysis of the leaves showed the presence of saponins, phenolics, and reducing sugars in almost all the plants tested. All plant extracts were observed to have some antimicrobial activity against at least one reference strain. For the clinical MDR isolates, A. cordifolia from this study showed highest inhibition to growth of all bacteria used. Activity of J. flava against S. aureus was highest as compared to that of E.coli and P. aeruginosa. Similar observation was made for M. arboreus, P. guajava and M. charantia where the highest activity was observed against S. aureus; Conclusion: This study has mainly shown that P. guajava, M. arboreus, A. cordifolia, M. charantia, and J. flava exhibits antimicrobial activities against MD-R bacterial pathogens isolated from post-operative wounds. Also, these plants has bioactive phytochemical compounds with potential medicinal values for the treatment of numerous infections. Therefore, these plants may be helpful in the management of acute and chronic wounds, especially in traditional medicine practices.

Project description:IntroductionAnimal models for the study of sepsis are being increasingly scrutinized, despite their essential role for early translational research. In particular, recent studies have suggested that at the level of the leukocyte transcriptome, murine models of burns, trauma and endotoxemia markedly differ from their human equivalents, and are only weakly similar amongst themselves. We compared the plasma cytokine and leukocyte transcriptome responses between two different low-lethality murine models of polymicrobial intra-abdominal sepsis.MethodsSix to ten week male C57BL/6j mice underwent either the 'gold standard' cecal ligation and puncture (CLP) model of intra-abdominal sepsis or administration of a cecal slurry (CS), where cecal contents are injected intraperitoneally. Surviving mice were euthanized at two hours, one or three days after sepsis.ResultsThe murine leukocyte transcriptomic response to the CLP and CS models of sepsis was surprisingly dissimilar at two hours, one, and three days after sepsis. The Pearson correlation coefficient for the maximum change in expression for the entire leukocyte transcriptome that changed significantly over time (n = 19,071) was R = 0.54 (R2 = 0.297). The CS model resulted in greater magnitude of early inflammatory gene expression changes in response to sepsis with associated increased production of inflammatory chemokines and cytokines. Two hours after sepsis, CLP had more significant expression of genes associated with IL-10 signaling pathways, whereas CS had greater expression of genes related to CD28, apoptosis, IL-1 and T-cell receptor signaling. By three days, the changes in gene expression in both sepsis models were returning to baseline in surviving animals.ConclusionThese analyses reveal that the murine blood leukocyte response to sepsis is highly dependent on which model of intra-abdominal sepsis is employed, despite their similar lethality. It may be difficult to extrapolate findings from one murine model to another, let alone to human sepsis.

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Bioluminescent murine models of bacterial sepsis and scald wound infections for antimicrobial efficacy testing.

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Bioluminescent murine models of bacterial sepsis and scald wound infections for antimicrobial efficacy testing.

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