Indomethacin Increases Severity of
            <i>Clostridium Difficile</i>
            Infection in Mouse Model

Muñoz-Miralles, Juan; Trindade, Bruno Caetano; Castro-Córdova, Pablo; Bergin, Ingrid L.; Kirk, Leslie; Gil, Fernando; Aronoff, David M.; Paredes-Sabja, Daniel

doi:10.2217/fmb-2017-0311

Cited by 18 publications

(18 citation statements)

References 49 publications

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“…The effectiveness of lower dose of auranofin could also be explained by their potent anti-inflammatory activity. It was reported that the anti-inflammatory drug, indomethacin, increased the severity of C. difficile infection in mice 36 . Additionally, in previous study investigating the efficacy of auranofin against vancomycin-resistant enterococci peritonitis, lower doses of auranofin provided the best protection (100%) 37 .…”

Section: The Effect Of Simulated Gastric Fluid (Sgf) and Simulated Inmentioning

confidence: 98%

Auranofin, at clinically achievable dose, protects mice and prevents recurrence from Clostridioides difficile infection

Abutaleb

Seleem

2020

Sci Rep

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Clostridioides difficile is the leading cause of nosocomial infections and a worldwide urgent public health threat. Without doubt, there is an urgent need for new effective anticlostridial agents due to the increasing incidence and severity of C. difficile infection (CDI). The aim of the present study is to investigate the in vivo efficacy of auranofin (rheumatoid arthritis FDA-approved drug) in a CDI mouse model and establish an adequate dosage for treatment. The effects of increased C. difficile inoculum, and pre-exposure to simulated gastric intestinal fluid (SGF) and simulated intestinal fluid (SIF), on the antibacterial activity of auranofin were investigated. Auranofin's in vitro antibacterial activity was stable in the presence of high bacterial inoculum size compared to vancomycin and fidaxomicin. Moreover, it maintained its anti-C. difficile activity after being exposed to SGF and SIF. Upon testing in a CDI mouse model, auranofin at low clinically achievable doses (0.125 mg/kg and 0.25 mg/kg) significantly protected mice against CDI with 100% and 80% survival, respectively. Most importantly, auranofin (0.125 mg/kg and 0.25 mg/kg) significantly prevented CDI recurrence when compared with vancomycin. Collectively, these results indicate that auranofin could potentially provide an effective, safe and quick supplement to the current approaches for treating CDI. Clostridioides difficile is the worldwide leading cause of nosocomial infections and antibiotic-associated diarrhea 1. A recent report released by the Centers for Disease Control and Prevention (CDC) stated that about 223,900 patients were hospitalized with C. difficile infections (CDI) in the United States in 2017, which was associated with around 12,800 mortality cases and in excess of $1 billion healthcare cost 2. CDI symptoms range from mild to severe watery diarrhea to more severe life threatening complications such as pseudomembranous colitis, toxic megacolon, colon perforation, sepsis, systemic inflammatory response syndrome and shock 3. Disease manifestations are attributed to the toxin-mediated damage elicited by the two major toxins TcdA and TcdB. These toxins catalyze inactivation of host GTPases (Rac, Rho and CDC42) and perturbation of actin cytoskeleton, ultimately causing intense inflammation, loss of tight junctions of the intestinal mucosal layer, enormous fluid secretion, cell rounding and finally necrosis and apoptosis of the colonic mucosal cells 4,5. The incidence and severity of CDI has increased dramatically due to the overuse of antibiotics and the emergence of hypervirulent epidemic strains such as, but not limited to, pulsed-field gel type North American pulsotype 1 (NAP1) or PCR ribotype 027, which were responsible for several outbreaks globally 6,7. Moreover, the clinical management of CDI is hindered by the ability of C. difficile to produce spores which are highly resistant to environmental conditions, antibiotics and disinfection processes. Spores can persist on unsuitable environments for long periods and spread in the e...

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Section: The Effect Of Simulated Gastric Fluid (Sgf) and Simulated Inmentioning

confidence: 98%

Auranofin, at clinically achievable dose, protects mice and prevents recurrence from Clostridioides difficile infection

Abutaleb

Seleem

2020

Sci Rep

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“…Epidemiological data have established an association between the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and CDI (11). Muñoz-Miralles and colleagues demonstrated that the NSAID indomethacin (Indo) significantly increased the severity of CDI in antibiotic-treated mice when the NSAID was applied following inoculation and throughout the infection (12), and indomethacin exposure is associated with alterations in the structure of the intestinal microbiota (13, 14). NSAIDs are among the most highly prescribed and most widely consumed drugs in the United States (15), particularly among older adults (16), and have been implicated in causing spontaneous colitis in humans (17, 18).…”

Section: Introductionmentioning

confidence: 99%

Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate Clostridium difficile Colitis while Dysregulating the Inflammatory Response

Maseda

Zackular

Trindade

et al. 2019

mBio

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Clostridium difficile infection (CDI) is a spore-forming anaerobic bacterium and leading cause of antibiotic-associated colitis. Epidemiological data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for CDI in humans, a potentially important observation given the widespread use of NSAIDs. Prior studies in rodent models of CDI found that NSAID exposure following infection increases the severity of CDI, but mechanisms to explain this are lacking. Here we present new data from a mouse model of antibiotic-associated CDI suggesting that brief NSAID exposure prior to CDI increases the severity of the infectious colitis. These data shed new light on potential mechanisms linking NSAID use to worsened CDI, including drug-induced disturbances to the gut microbiome and colonic epithelial integrity. Studies were limited to a single NSAID (indomethacin), so future studies are needed to assess the generalizability of our findings and to establish a direct link to the human condition.

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“…Indomethacin increases the severity of Clostridium difficile infection (CDI) by perturbing the gut microbiota and dysregulating intestinal inflammatory response in a mouse model of antibiotic-associated CDI ( Maseda et al., 2019 ). Similarly, both low and high doses of indomethacin increase the severity of Clostridium difficile infection in two different mouse models of antibiotic-associated CDI ( Muñoz-Miralles et al., 2018 ). Such findings support epidemiological data linking NSAID exposure and CDI and warn against the use of NSAIDs in patients at high risk for Clostridium difficile ( Permpalung et al., 2016 ).…”

Section: Impact Of Nsaids On Gut Microbiota Composition and Metabolicmentioning

confidence: 99%

NSAID–Gut Microbiota Interactions

Maseda

Ricciotti

2020

Front. Pharmacol.

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Nonsteroidal anti-inflammatory drugs (NSAID)s relieve pain, inflammation, and fever by inhibiting the activity of cyclooxygenase isozymes (COX-1 and COX-2). Despite their clinical efficacy, NSAIDs can cause gastrointestinal (GI) and cardiovascular (CV) complications. Moreover, NSAID use is characterized by a remarkable individual variability in the extent of COX isozyme inhibition, therapeutic efficacy, and incidence of adverse effects. The interaction between the gut microbiota and host has emerged as a key player in modulating host physiology, gut microbiota-related disorders, and metabolism of xenobiotics. Indeed, host-gut microbiota dynamic interactions influence NSAID disposition, therapeutic efficacy, and toxicity. The gut microbiota can directly cause chemical modifications of the NSAID or can indirectly influence its absorption or metabolism by regulating host metabolic enzymes or processes, which may have consequences for drug pharmacokinetic and pharmacodynamic properties. NSAID itself can directly impact the composition and function of the gut microbiota or indirectly alter the physiological properties or functions of the host which may, in turn, precipitate in dysbiosis. Thus, the complex interconnectedness between host-gut microbiota and drug may contribute to the variability in NSAID response and ultimately influence the outcome of NSAID therapy. Herein, we review the interplay between host-gut microbiota and NSAID and its consequences for both drug efficacy and toxicity, mainly in the GI tract. In addition, we highlight progress towards microbiota-based intervention to reduce NSAIDinduced enteropathy.

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Indomethacin Increases Severity of Clostridium Difficile Infection in Mouse Model

Cited by 18 publications

References 49 publications

Auranofin, at clinically achievable dose, protects mice and prevents recurrence from Clostridioides difficile infection

Auranofin, at clinically achievable dose, protects mice and prevents recurrence from Clostridioides difficile infection

Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate Clostridium difficile Colitis while Dysregulating the Inflammatory Response

NSAID–Gut Microbiota Interactions

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