Candida auris is an emergent fungal pathogen that causes severe infectious outbreaks globally. The public health concern when dealing with this pathogen is mainly due to reduced susceptibility to current antifungal drugs. A valuable alternative to overcome this problem is to investigate the efficacy of combination therapy. The aim of this study was to determine the in vitro interactions of isavuconazole with echinocandins against C. auris. Interactions were determined using a checkerboard method, and absorbance data were analyzed with different approaches: the fractional inhibitory concentration index (FICI), Greco universal response surface approach, and Bliss interaction model. All models were in accordance and showed that combinations of isavuconazole with echinocandins resulted in an overall synergistic interaction. A wide range of concentrations within the therapeutic range were selected to perform time-kill curves. These confirmed that isavuconazole–echinocandin combinations were more effective than monotherapy regimens. Synergism and fungistatic activity were achieved with combinations that included isavuconazole in low concentrations (≥0.125 mg/L) and ≥1 mg/L of echinocandin. Time-kill curves revealed that once synergy was achieved, combinations of higher drug concentrations did not improve the antifungal activity. This work launches promising results regarding the combination of isavuconazole with echinocandins for the treatment of C. auris infections.

Treatment of invasive infections caused by Candida auris is challenging due to the limited therapeutic options. The combination of antifungal drugs may be an interesting and feasible approach to be investigated. The aim of this study was to examine the in vitro activity of amphotericin B in combination with anidulafungin or caspofungin against C. auris. In vitro static time–kill curve experiments were conducted for 48 h with different combinations of amphotericin B with anidulafungin or caspofungin against six blood isolates of C. auris. The antifungal activity of 0.5 mg/L of amphotericin B was limited against the six isolates of C. auris. Similarly, echinocandins alone had a negligible effect, even at the highest tested concentrations. By contrast, 1 mg/L of amphotericin B showed fungistatic activity. Synergy was rapidly achieved (8 h) with 0.5 mg/L of amphotericin B plus 2 mg/L of anidulafungin or caspofungin. These combinations lead to a sustained fungistatic effect, and the fungicidal endpoint was reached against some C. auris isolates. Additionally, ≥0.5 mg/L of either of the two echinocandins with 1 mg/L of amphotericin B resulted in fungicidal effect against all C. auris isolates. In conclusion, combinations of amphotericin B with anidulafungin or caspofungin provided greater killing with a lower dose requirement for amphotericin B compared to monotherapy, with synergistic and/or fungicidal outcomes.

The multidrug-resistant Candida auris is a global health emergency, being responsible for outbreaks of invasive candidiasis worldwide. Limited effective therapeutic options make it difficult to treat this emerging pathogen. In this context, combinations of different antifungal drugs are considered a promising therapeutic alternative. The aim of this work was to analyze the antifungal activity of combinations of amphotericin B and echinocandins against five clinical blood isolates of C. auris . One of these isolates showed an aggregative phenotype already described in C. auris species, forming large aggregates of cells that are very difficult to disintegrate. First, the in vitro activity of these drugs was evaluated both in monotherapy and in combination, and results showed synergistic interactions between amphotericin B and echinocandins in most cases, although higher minimum inhibitory concentration (MIC) values were observed against the aggregative isolate compared to non-aggregative counterparts. The most promising drug combinations were then selected for in vivo activity evaluation using a Caenorhabditis elegans model of candidiasis and by determination of survival rates. The combination of amphotericin B and caspofungin showed the strongest protective effect during C. elegans infection with C. auris blood isolates, achieving up to 99% C . elegans survival. Although the MIC values for micafungin were low in vitro , these drug concentrations had no effect in vivo , and the combination of amphotericin B and micafungin was the least effective. The results of this study showed that the combination amphotericin B and echinocandins might be a promising therapeutic approach for the treatment of invasive candidiasis caused by C. auris . Moreover, the nematode C. elegans is a suitable alternative model for screening of new therapeutic agents capable of overcoming multidrug-resistant C. auris infections. IMPORTANCE: Multidrug resistance is a rising problem among non- Candida albicans species, such as Candida auris . This therapeutic problem has been very important during the COVID-19 pandemic. The World Health Organization has included C. auris in its global priority list of health-threatening fungi, to study this emerging multidrug-resistant species and to develop effective alternative therapies. In the present study, the synergistic effect of the combination of amphotericin B and echinocandins has been demonstrated against blood isolates of C. auris . Different susceptibility responses were also observed between aggregative and non-aggregative phenotypes. The antifungal activity of these drug combinations against C. auris was also demonstrated in the Caenorhabditis elegans host model of candidiasis, confirming the suitability and usefulness of this model in the search for solutions to antimicrobial resistance.

Background: Patients with schizophrenia constitute a particularly vulnerable group for oral diseases. Among the different factors involved, we aimed to examine the evidence of how drugs could contribute to the poorer oral health of this population. Material and Methods: An overview of the potential impact of medication on dental/oral health among people with schizophrenia was proposed focusing on selected literature. Results: Studies show a higher dental caries and degree of periodontal diseases in this population and point to drug-induced xerostomia as an important risk factor for oral health deterioration. The risk of dry mouth depends on not only antipsychotics, but also drugs with anticholinergic activity. We hypothesize that antipsychotic induced glycaemic alterations might contribute to reduced oral health, and that the antimicrobial activity of certain antipsychotics could have an impact on oral microbiota affecting oral condition. Pharmacovigilance data show that involuntary movements are caused by typical and some atypical antipsychotics. Dry mouth is most frequently reported for quetiapine and olanzapine, while clozapine is more frequently associated with sialorrhea. Conclusions: Literature clearly shows higher caries and periodontal disease in schizophrenic patients. However, overall, there is scarce literature about the potential influence of drugs in these disorders. Health professionals should be aware of this issue in order to implement adequate preventive measures in this vulnerable population.

The study of the pharmacological properties of an antifungal agent integrates the drug pharmacokinetics, the fungal growth inhibition, the fungicidal effect and the postantifungal activity, laying the basis to guide optimal dosing regimen selection. The current manuscript reviews concepts regarding the postantifungal effect (PAFE) of the main classes of drugs used to treat Candida infections or candidiasis. The existence of PAFE and its magnitude are highly dependent on both the fungal species and the class of the antifungal agent. Therefore, the aim of this article was to compile the information described in the literature concerning the PAFE of polyenes, azoles and echinocandins against the Candida species of medical interest. In addition, the mechanisms involved in these phenomena, methods of study, and finally, the clinical applicability of these studies relating to the design of dosing regimens were reviewed and discussed. Additionally, different factors that could determine the variability in the PAFE were described. Most PAFE studies were conducted in vitro, and a scarcity of PAFE studies in animal models was observed. It can be stated that the echinocandins cause the most prolonged PAFE, followed by polyenes and azoles. In the case of the triazoles, it is worth noting the inconsistency found between in vitro and in vivo studies.