Ibuprofen Potentiates the
            <i>In Vivo</i>
            Antifungal Activity of Fluconazole against Candida albicans Murine Infection

Costa-de-Oliveira, Sofia; Miranda, Isabel M.; Silva-Dias, Ana; Silva, Ana Paula; Rodrigues, Acácio G.; Pina-Vaz, Cidália

doi:10.1128/aac.05056-14

Cited by 33 publications

(17 citation statements)

References 25 publications

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“…Another potential caveat was that concomitant administration of ibuprofen was mandatory during murine experimentation. Ibuprofen has been shown to potentiate the in vivo activity of fluconazole against resistant C. albicans in a murine infection (35). When retesting the trailing isolates in the neutropenic 24-h model without ibuprofen, fluconazole efficacy remained unchanged (data not shown).…”

Section: Figmentioning

confidence: 97%

Implications of the EUCAST Trailing Phenomenon in Candida tropicalis for the In Vivo Susceptibility in Invertebrate and Murine Models

Astvad

Sanglard

Delarze

et al. 2018

Antimicrob Agents Chemother

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isolates often display reduced but persistent growth (trailing) over a broad fluconazole concentration range during EUCAST susceptibility testing. Whereas weak trailing (<25% of the positive growth control) is common and found not to impair fluconazole efficacy, we investigated if more pronounced trailing impacted treatment efficacy. Fluconazole efficacy against two weakly (≤25% growth), two moderately (26% to 50% growth), and one heavily (>70% growth) trailing resistant isolate and one resistant (100% growth) isolate were investigated and (in a survival model and two nonlethal murine models). expression levels and sequences were characterized. The survival in fluconazole-treated was inversely correlated with the degree of trailing (71% to 9% survival in treatment groups). In mice, resistant and heavily trailing isolates responded poorly to fluconazole treatment. expression was significantly higher in trailing and resistant isolates than in wild-type isolates (1.4-fold to 10-fold higher). All isolates exhibited wild-type alleles. Heavily trailing isolates were less responsive to fluconazole in all models, indicating an impact on fluconazole efficacy. upregulation may have contributed to the observed differences. Moderately trailing isolates responded less well to fluconazole in larvae only. This confirms clinical data suggesting fluconazole is effective against infections with such isolates in less severely ill patients and supports the current 50% growth endpoint for susceptibility testing. However, it is still unclear if the gradual loss of efficacy observed for moderately trailing isolates in the larva model may be a reason for concern in selected vulnerable patient populations.

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Section: Figmentioning

confidence: 97%

Implications of the EUCAST Trailing Phenomenon in Candida tropicalis for the In Vivo Susceptibility in Invertebrate and Murine Models

Astvad

Sanglard

Delarze

et al. 2018

Antimicrob Agents Chemother

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“…In C. albicans expressing CDR efflux pumps, ibuprofen induced azole intracellular accumulation, changing the resistant phenotype to susceptible [59,160]. In a murine model of systemic infection, ibuprofen acts synergically with fluconazole against a fluconazole-resistant strain, drastically reducing the fungal burden and morbidity [162]. This potent anti-inflammatory, non-steroidal drug might play important role in future therapeutic strategies.…”

Section: Strategies To Overcome Antifungal Resistance and Tolerancementioning

confidence: 99%

Candida albicans Antifungal Resistance and Tolerance in Bloodstream Infections: The Triad Yeast-Host-Antifungal

2020

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Candida albicans represents the most frequent isolated yeast from bloodstream infections. Despite the remarkable progress in diagnostic and therapeutic approaches, these infections continue to be a critical challenge in intensive care units worldwide. The economic cost of bloodstream fungal infections and its associated mortality, especially in debilitated patients, remains unacceptably high. Candida albicans is a highly adaptable microorganism, being able to develop resistance following prolonged exposure to antifungals. Formation of biofilms, which diminish the accessibility of the antifungal, selection of spontaneous mutations that increase expression or decreased susceptibility of the target, altered chromosome abnormalities, overexpression of multidrug efflux pumps and the ability to escape host immune defenses are some of the factors that can contribute to antifungal tolerance and resistance. The knowledge of the antifungal resistance mechanisms can allow the design of alternative therapeutically options in order to modulate or revert the resistance. We have focused this review on the main factors that are involved in antifungal resistance and tolerance in patients with C. albicans bloodstream infections.

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“…Ibuprofen, a NSAID, is crucial for the reversion of azole resistance in C. albicans . In a murine model of systemic infection, the combination of ibuprofen, and fluconazole can potentiate the antifungal activity of fluconazole by decreasing the MIC of fluconazole from 64 to 2 μg/ml and reduce the fungal burden and morbidity in fluconazole resistant strains (Pina-Vaz et al, 2000; Arai et al, 2005; Costa-de-Oliveira et al, 2015). As a potential Cdrp blocker, ibuprofen can directly damage C. albicans cell membranes, but the molecular mechanisms of ibuprofen against C. albicans are still being uncovered (Ricardo et al, 2009; de Quadros et al, 2011).…”

Section: Cyclooxygenasementioning

confidence: 99%

Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review

Liu

Wang

et al. 2016

Front. Microbiol.

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Candida is an important opportunistic fungal pathogen, especially in biofilm associated infections. The formation of a Candida biofilm can decrease Candida sensitivity to antifungal drugs and cause drug resistance. Although many effective antifungal drugs are available, their applications are limited due to their high toxicity and cost. Seeking new antifungal agents that are effective against biofilm-associated infection is an urgent need. Many research efforts are underway, and some progress has been made in this field. It has been shown that the arachidonic acid cascade plays an important role in fungal morphogenesis and pathogenicity. Notably, prostaglandin E2 (PGE2) can promote the formation of a Candida biofilm. Recently, the inhibition of PGE2 has received much attention. Studies have shown that cyclooxygenase (COX) inhibitors, such as aspirin, ibuprofen, and indomethacin, combined with fluconazole can significantly reduce Candida adhesion and biofilm development and increase fluconazole susceptibility; the MIC of fluconazole can be decrease from 64 to 2 μg/ml when used in combination with ibuprofen. In addition, in vivo studies have also confirmed the antifungal activities of these inhibitors. In this article, we mainly review the relationship between PGE2 and Candida biofilm, summarize the antifungal activities of COX inhibitors and analyze the possible antifungal activity of microsomal prostaglandin E synthase-1 (MPGES-1) inhibitors; additionally, other factors that influence PGE2 production are also discussed. Hopefully this review can disclose potential antifungal targets based on the arachidonic acid cascade and provide a prevailing strategy to alleviate Candida albicans biofilm formation.

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Ibuprofen Potentiates the In Vivo Antifungal Activity of Fluconazole against Candida albicans Murine Infection

Cited by 33 publications

References 25 publications

Implications of the EUCAST Trailing Phenomenon in Candida tropicalis for the In Vivo Susceptibility in Invertebrate and Murine Models

Implications of the EUCAST Trailing Phenomenon in Candida tropicalis for the In Vivo Susceptibility in Invertebrate and Murine Models

Candida albicans Antifungal Resistance and Tolerance in Bloodstream Infections: The Triad Yeast-Host-Antifungal

Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review

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