Understanding the acute inflammatory response to Pseudomonas aeruginosa infection: differences between susceptible and multidrug-resistant strains in a mouse peritonitis model

Gómez-Zorrilla, Sílvia; Calatayud, Laura; Juan, Carlos; Cabot, Gabriel; Tubau, Fé; Oliver, Antonio; Domı́nguez, M.A.; Ariza, Javier; Peña, Carmen

doi:10.1016/j.ijantimicag.2016.10.016

Cited by 11 publications

(11 citation statements)

References 32 publications

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“…We and others have reported a survival difference in rodents infected with MDR P. aeruginosa . In this study, we identified an in vivo virulence difference in an additional animal model.…”

mentioning

confidence: 55%

Transcriptional profiles of pulmonary innate immune responses to isogenic antibiotic‐susceptible and multidrug‐resistant Pseudomonas aeruginosa

Tam

Pérez

Ledesma

et al. 2018

Microbiology and Immunology

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The virulence of an isogenic pair of Pseudomonas aeruginosa strains was studied under similar experimental conditions in two animal infection models. The time to death was significantly longer for the multidrug resistant (MDR) than the wild-type strain. The transcriptional profiles of 84 innate immune response genes in the lungs of immune competent Balb/C mice were further compared. Significantly weaker expression of genes involved in production of soluble pattern recognition receptor and complement were observed in animals infected with the MDR strain. Altered patterns of innate immune system activation may explain the attenuated virulence in MDR bacteria.

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“…We and others have reported a survival difference in rodents infected with MDR P. aeruginosa . In this study, we identified an in vivo virulence difference in an additional animal model.…”

mentioning

confidence: 55%

Transcriptional profiles of pulmonary innate immune responses to isogenic antibiotic‐susceptible and multidrug‐resistant Pseudomonas aeruginosa

Tam

Pérez

Ledesma

et al. 2018

Microbiology and Immunology

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“…Another hypothesis to explain the lack of impact of XDR phenotype on mortality could be the influence of the acquisition of resistance mechanisms. It has been hypothesized that it may involve a fitness cost resulting in strains with lower virulence, and with a reduced inflammatory response in the host when compared to susceptible isolates [38][39][40][41]. On the other hand, it has also been reported that not all resistance mutations lead to a biological cost such as the OprD deficiency [42].…”

Section: Discussionmentioning

confidence: 99%

Risk Factors for Mortality among Patients with Pseudomonas aeruginosa Bloodstream Infections: What Is the Influence of XDR Phenotype on Outcomes?

Montero

López-Montesinos

Knobel

et al. 2020

JCM

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This study aimed to assess the impact of extensively drug-resistant (XDR) phenotype on mortality in Pseudomonas aeruginosa bacteremia. A retrospective cohort study was performed in a tertiary hospital from January 2000 to December 2018. All consecutive prospectively recorded P. aeruginosa bacteremia in adult patients were assessed. In this study, 382 patients were included, of which 122 (31.9%) due to XDR P. aeruginosa. Independent factors associated with 14-day mortality were as follows: high-risk source of bacteremia (hazard ratio (HR) 3.07, 95% confidence interval (CI), 1.73–5.46), septic shock (HR 1.75, 95% CI, 1.12–2.75), and higher Pitt scores (one-point increments; HR 1.25, 95% CI, 1.12–1.38). Otherwise, the appropriateness of definitive antibiotic therapy was a protective factor (HR 0.39, 95% CI, 0.24–0.62). The same variables were also associated with 30-day mortality. XDR phenotype was not associated with 14- or 30-day mortality. In a subanalysis considering only high-risk source cases, combined antimicrobial therapy was independently associated with 14-day favorable outcome (HR 0.56, 95% CI, 0.33–0.93). In conclusion, XDR phenotype was not associated with poor prognosis in patients with P. aeruginosa bacteremia in our cohort. However, source of infection, clinical severity, and inappropriate definitive antibiotic therapy were risk factors for mortality. Combined antimicrobial therapy should be considered for high-risk sources.

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“…The quantity of IL-6, IFN-gamma, and TNF-alpha in FT-treated group decreased at 48 hours postinfection but still remained higher than in infected group not treated with FT. IL-6 in lungs of pseudomonas-infected animals was recently shown to contribute to the local protection against some of P. aeruginosa toxins [ 32 ]. At the same time, it was found to be harmful in generalized infection and sepsis [ 33 ]. In our study in contrast to elevated levels of IL-6 levels in lungs, blood IL-6 levels were decreased in FT-treated group compared to nontreated infected mice.…”

Section: Discussionmentioning

confidence: 99%

Small Molecule Inhibitor of Type Three Secretion System Belonging to a Class 2,4-disubstituted-4H-[1,3,4]-thiadiazine-5-ones Improves Survival and Decreases Bacterial Loads in an AirwayPseudomonas aeruginosaInfection in Mice

Sheremet

Zigangirova

Zayakin

et al. 2018

BioMed Research International

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Pseudomonas aeruginosa is a cause of high mortality in burn, immunocompromised, and surgery patients. High incidence of antibiotic resistance in this pathogen makes the existent therapy inefficient. Type three secretion system (T3SS) is a leading virulence system of P. aeruginosa that actively suppresses host resistance and enhances the severity of infection. Innovative therapeutic strategies aiming at inhibition of type three secretion system of P. aeruginosa are highly attractive, as they may reduce the severity of clinical manifestations and improve antibacterial immune responses. They may also represent an attractive therapy for antibiotic-resistant bacteria. Recently our laboratory developed a new small molecule inhibitor belonging to a class 2,4-disubstituted-4H-[1,3, 4]-thiadiazine-5-ones, Fluorothiazinon (FT), that effectively suppressed T3SS in chlamydia and salmonella in vitro and in vivo. In this study, we evaluate the activity of FT towards antibiotic-resistant clinical isolates of P. aeruginosa expressing T3SS effectors ExoU and ExoS in an airway infection model. We found that FT reduced mortality and bacterial loads and decrease lung pathology and systemic inflammation. In addition, we show that FT inhibits the secretion of ExoT and ExoY, reduced bacteria cytotoxicity, and increased bacteria internalization in vitro. Overall, FT shows a strong potential as an antibacterial therapy of antibiotic-resistant P. aeruginosa infection.

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Understanding the acute inflammatory response to Pseudomonas aeruginosa infection: differences between susceptible and multidrug-resistant strains in a mouse peritonitis model

Cited by 11 publications

References 32 publications

Transcriptional profiles of pulmonary innate immune responses to isogenic antibiotic‐susceptible and multidrug‐resistant Pseudomonas aeruginosa

Transcriptional profiles of pulmonary innate immune responses to isogenic antibiotic‐susceptible and multidrug‐resistant Pseudomonas aeruginosa

Risk Factors for Mortality among Patients with Pseudomonas aeruginosa Bloodstream Infections: What Is the Influence of XDR Phenotype on Outcomes?

Small Molecule Inhibitor of Type Three Secretion System Belonging to a Class 2,4-disubstituted-4H-[1,3,4]-thiadiazine-5-ones Improves Survival and Decreases Bacterial Loads in an AirwayPseudomonas aeruginosaInfection in Mice

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