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Wriedt, Tanja Roehmer; Skaastrup, Kristoffer Nagy; Andersen, Pernille Lindsoe; Simmelsgaard, Line; Jemec, Gregor B. E.; Saunte, Ditte M. L.
doi: 10.1111/apm.13293pmid: 36645313
Bouazzi, Dorra; Andersen, Pernille Lindsø; Jacobsen, Ester Weihe; Arendrup, Maiken Cavling; Jemec, Gregor B. E.; Saunte, Ditte M. L.
doi: 10.1111/apm.13320pmid: 37186327
Pozzi, Lara; Schläppi, Michel; Livio, Françoise; Blatter, Samuel; Achermann, Yvonne; Wahl, Peter
doi: 10.1111/apm.13290pmid: 36601878
Fungal periprosthetic joint infections (PJI) are difficult to treat, due to important biofilm formation and limited local penetration of systemically administered antifungals. Calcium sulphate (CaSO4) might be a promising carrier to increase local concentration of antifungals. We hypothesized that local amphotericin B release from CaSO4 is high enough to significantly contribute to treatment of fungal PJI. We report joint fluid and serum concentrations of amphotericin B after local application with CaSO4 as an implanted resorbable carrier material as adjunct to standard surgical and systemic antifungal treatment in two cases of PJI with Candida spp. Maximal joint fluid amphotericin B concentration was 14.01 mg/L 5 days after the second local administration of liposomal amphotericin in Case One and 25.77 mg/L 14 days after the second local administration in Case Two. Concentrations higher than minimal inhibitory concentrations (MIC) could be measured for 21 days and 17 days after local administration in Case One and Two, respectively. In Case Two, serum concentration of amphotericin B was <0.01 mg/L 3 days after local administration of 450 mg liposomal amphotericin B. No local or systemic adverse reaction was observed. Fungal PJI was successfully eradicated in both cases with a follow‐up of 12 months in Case One and 20 months in Case Two. Application of amphotericin B‐loaded CaSO4 was associated with joint fluid concentrations higher than minimal inhibitory concentrations for Candida spp. for approximately 3 weeks, with the advantage that the carrier material dissolves spontaneously and does not require secondary removal. Relapse of fungal infections did not occur in these two patients.
Wulff, Signe Marie; Perch, Michael; Helweg‐Larsen, Jannik; Bredahl, Pia; Arendrup, Maiken Cavling; Lundgren, Jens; Helleberg, Marie; Crone, Cornelia Geisler
doi: 10.1111/apm.13317pmid: 37022293
Cytomegalovirus (CMV) and invasive aspergillosis (IA) cause morbidity among lung transplant recipients (LTXr). Early diagnosis and treatment could improve outcomes. We examined rates of CMV after IA and vice versa to assess whether screening for one infection is warranted after detecting the other. All Danish LTXr, 2010–2019, were followed for IA and CMV for 2 years after transplantation. IA was defined using ISHLT criteria. Adjusted incidence rate ratios (aIRR) were estimated by Poisson regression adjusted for time after transplantation. We included 295 LTXr, among whom CMV and IA were diagnosed in 128 (43%) and 48 (16%). The risk of CMV was high the first 3 months after IA, IR 98/100 person‐years of follow‐up (95% CI 47–206). The risk of IA was significantly increased in the first 3 months after CMV, aIRR 2.91 (95% CI 1.32–6.44). Numbers needed to screen to diagnose one case of CMV after IA, and one case of IA after CMV was approximately seven and eight, respectively. Systematic screening for CMV following diagnosis of IA, and vice versa, may improve timeliness of diagnosis and outcomes for LTXr.
Kalimuthu, Shanthini; Pudipeddi, Akhila; Braś, Grażyna; Tanner, Julian A.; Rapala‐Kozik, Maria; Leung, Yiu Yan; Neelakantan, Prasanna
doi: 10.1111/apm.13322pmid: 37150907
Yeasts such as Candida albicans, albeit being ubiquitous members of the skin, oral and vaginal microbiome, can cause superficial to life‐threatening infections. Human cathelicidin LL‐37‐based peptides have antibacterial activity and yet, their antifungal activity remains to be thoroughly characterized. The aim of this study was to comprehensively investigate the activity of LL‐37‐based peptides against C. albicans. LL‐37 and its derivatives were tested for their ability to kill C. albicans planktonic cells in the presence of various biological matrices (serum, plasma, saliva and urine), that have been reported to inactivate peptides. The antibiofilm activity, resistance development and biocompatibility were investigated for the lead peptide. GK‐17, a 17 amino acid peptide, showed remarkable stability to fungal aspartyl proteases and rapidly killed planktonic C. albicans despite the presence of biological matrices. GK‐17 also inhibited adhesion to biotic and abiotic substrates, inhibited biofilm formation and eradicated preformed biofilms in the presence of biological matrices. Compared to nystatin, GK‐17 had a lower propensity to allow for resistance development by C. albicans. The peptide showed concentration‐dependent biocompatibility to red blood cells, with only 30% hemolysis even at 4× the fungicidal concentration. Taken together, GK‐17 is a novel antifungal peptide with promising effects against C. albicans.
Delaney, Christopher; Alapati, Susanth; Alshehri, Muhanna; Kubalova, Dominika; Veena, Chandra Lekha Ramalingham; Abusrewil, Sumaya; Short, Bryn; Bradshaw, David; Brown, Jason L.
doi: 10.1111/apm.13327pmid: 37170476
Candida albicans is frequently identified as a colonizer of the oral cavity in health and has recently been termed a “keystone” commensal due to its role on the bacterial communities. However, the role that C. albicans plays in such interactions is not fully understood. Therefore, this study aimed to identify the relationship between C. albicans and bacteria associated with oral symbiosis and dysbiosis. To do this, we evaluated the ability of C. albicans to support the growth of the aerobic commensal Streptococcus gordonii and the anaerobic pathogens Fusobacterium nucleatum and Porphyromonas gingivalis in the biofilm environment. RNA‐Sequencing with the Illumina platform was then utilized to identify C. albicans gene expression and functional pathways involved during such interactions in dual‐species and a 4‐species biofilm model. Results indicated that C. albicans was capable of supporting growth of all three bacteria, with a significant increase in colony counts of each bacteria in the dual‐species biofilm (p < 0.05). We identified specific functional enrichment of pathways in our 4‐species community as well as transcriptional profiles unique to the F. nucleatum and S. gordonii dual‐species biofilms, indicating a species‐specific effect on C. albicans. Candida‐related hemin acquisition and heat shock protein mediated processes were unique to the organism following co‐culture with anaerobic and aerobic bacteria, respectively, suggestive that such pathways may be feasible options for therapeutic targeting to interfere with these fungal‐bacterial interactions. Targeted antifungal therapy may be considered as an option for biofilm destabilization and treatment of complex communities. Moving forward, we propose that further studies must continue to investigate the role of this fungal organism in the context of the interkingdom nature of oral diseases.
Ajetunmobi, Olabayo H.; Chaturvedi, Ashok K.; Badali, Hamid; Vaccaro, Alessandra; Najvar, Laura; Wormley, Floyd L.; Wiederhold, Nathan P.; Patterson, Thomas F.; Lopez‐Ribot, Jose L.
doi: 10.1111/apm.13342pmid: 37337909
Zhang, Yu; Zhang, Jingxiao; Sun, Jian; Zhang, Min; Liu, Xin; Yang, Longfei; Yin, Yongjie
doi: 10.1111/apm.13353pmid: 37754556
This study was performed to explore the antifungal and antibiofilm effects of polyphyllin I (PPI) on Candida albicans. Microdilution assay was performed to determine the minimal inhibitory concentrations (MIC) of PPI against Candida species. Adhesion assay, hyphal growth assay, biofilm formation, and development were used to test the impacts of PPI on C. albicans virulence factors. Propidium iodide staining was performed to test whether the permeability of cell membrane was influenced by PPI. PPI showed significant antifungal activities against several Candida species, with MIC below or equal to 6.25 μM. PPI also inhibited the adhesion to polystyrene surfaces, hyphal growth, and biofilm formation. PPI significantly increased the permeability of C. albicans cell membrane. In sum, PPI can suppress the planktonic growth and biofilm of C. albicans and its mechanism involves the increased permeability of cell membrane.
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Candida spp. are opportunistic yeasts capable of forming biofilms, which contribute to resistance, increasing the urgency for new effective antifungal therapies. Repurposing existing drugs could significantly accelerate the development of novel therapies against candidiasis. We screened the Pandemic Response Box containing 400 diverse drug‐like molecules active against bacteria, viruses or fungi, for inhibitors of Candida albicans and Candida auris biofilm formation. Initial hits were identified based on the demonstration of >70% inhibitory activity. Dose–response assays were used to confirm the antifungal activity of initial hits and establish their potency. The spectrum of antifungal activity of the leading compounds was determined against a panel of medically important fungi, and the in vivo activity of the leading repositionable agent was evaluated in murine models of C. albicans and C. auris systemic candidiasis. The primary screening identified 20 hit compounds, and their antifungal activity and potency against C. albicans and C. auris were validated using dose–response measurements. From these experiments, the rapalog everolimus, emerged as the leading repositionable candidate. Everolimus displayed potent antifungal activity against different Candida spp., but more moderate levels of activity against filamentous fungi. Treatment with everolimus increased survival of mice infected with C. albicans, but not those with C. auris. The screening of the Pandemic Response Box resulted in the identification of several drugs with novel antifungal activity, with everolimus emerging as the main repositionable candidate. Further in vitro and in vivo studies are needed to confirm its potential therapeutic use.