Free serum concentrations of antibiotics determined by ultrafiltration: extensive evaluation of experimental variables.

Aim: To assess the impact of experimental conditions on free serum concentrations as determined by ultrafiltration and HPLC-DAD analysis in a wide range of antibiotics. Materials & methods: Relative centrifugation force (RCF), temperature, pH and buffer were varied and the results compared with the standard protocol (phosphate buffer pH 7.4, 37°C, 1000 × g). Results: Generally, at 10,000 × g the unbound fraction (fu) decreased with increasing molecular weight, and was lower at 22°C. In unbuffered serum, the fu of flucloxacillin or valproic acid was increased, that of basic or amphoteric drugs considerably decreased. Comparable results were obtained using phosphate or HEPES buffer except for drugs which form metal chelate complexes. Conclusion: Maintaining a physiological pH is more important than strictly maintaining body temperature.

[Box: see text].

A Study on the Effect of Quaternization of Polyene Antibiotics' Structures on Their Activity, Toxicity, and Impact on Membrane Models.

Polyene antibiotics have been used in antifungal therapy since the mid-twentieth century. They are highly valued for their broad spectrum of activity and the rarity of pathogen resistance to their action. However, their use in the treatment of systemic mycoses often results in serious side-effects. Recently, there has been a renewed interest in the development of new antifungal drugs based on polyenes, particularly due to the emergence of highly dangerous pathogenic strains of fungi, such as Candida auris, and the increased incidence of mucormycosis. Considerable understanding has been established regarding the structure-biological activity relationships of polyene antifungals. Yet, no previous studies have examined the effect of introducing quaternized fragments into their molecular structure. In this study, we present a series of amides of amphotericin B, nystatin, and natamycin bearing a quaternized group in the side chain, and discuss their biological properties: antifungal activity, cytotoxicity, and effects on lipid bilayers that mimic fungal and mammalian cell membranes. Our research findings suggest that the nature of the introduced quaternized residue plays a more significant role than merely the introduction of a constant positive charge. Among the tested polyenes, derivatives 4b, 5b, and 6b, which contain a fragment of N-methyl-4-(aminomethyl)pyridinium in their structure, are particularly noteworthy due to their biological activity.

Extracellular phospholipase production by Malassezia pachydermatis strains and its inhibition by selected antimycotics and plant essential oil components.

Extracellular phospholipase (EPL) plays an important role in the pathogenesis of the yeast Malassezia pachydermatis. Currently, the attention of researchers is focused on studying the virulence factors involved in this process and searching solutions to reduce their activity. One of the options is the use of natural remedies as anti-virulence agents. This study is aimed at investigating the production of extracellular phospholipase in M. pachydermatis strains (18 samples) and followed by the time-dependent inhibitory effect of selected azole antifungals (itraconazole, posaconazole and voriconazole) and plant essential oil components (terpinen-4-ol, thymol, carvacrol, eugenol and geraniol), evaluated by Egg Yolk Agar plate method. Almost all strains (17 isolates, (94.4%) were found to be intense EPL producers. A significant, time-dependent inhibition of EPL was noted after 1-, 3- and 6-h exposure of Malassezia cells to itraconazole (26.4%, 47.2% and 50.9%, respectively) compared to exposure to posaconazole (26.4%, 28.3% and 28.3%, respectively) and voriconazole (18.8%, 20.8% and 35.8%, respectively). After one-hour exposure to plant essential oil components, the best inhibitory effect was recorded for eugenol (62.3%), followed by terpinen-4-ol and thymol (56.6%), geraniol (41.5%) and carvacrol (26.4%). A 3-h exposure revealed that thymol retained the best inhibitory effect (88.7%) on EPL production, followed by carvacrol (73.6%), eugenol (56.6%), terpinen-4-ol (52.8%) and geraniol (49.1%). After 6-h exposure, no growth of M. pachydermatis strains exposed to carvacrol was observed, and the inhibitory efficiency for the other tested essential oil (EO) components achieved 88.7%. The obtained results indicate the promising efficacy of plant essential oils components in the inhibition of virulence factors such as EPL production.

Synthesis of novel benzylamine antimycotics and evaluation of their antimycotic potency.

A series of 23 novel benzylamines was synthesized by reductive amination from halogen-substituted 3- and 4-benzyloxybenzaldehyde derivatives and 6-methylhept-2-yl amine or n-octylamine. The antimycotic activity of the resulting amines was evaluated in a microdilution assay against the apathogenic yeast Yarrowia lipolytica as test microorganism. Promising compounds were also tested against human pathogenic Candida species. The influence of halogen substituents at the benzyl ether side chain was studied in this screening, as well as the influence of the branched side chain of (±)-6-methylhept-2-yl amine in comparison with the n-octyl side chain.

Antifungal drugs in the aquatic environment: A review on sources, occurrence, toxicity, health effects, removal strategies and future challenges.

Fungal infections pose a significant global health burden, resulting in millions of severe cases and deaths annually. The escalating demand for effective antifungal treatments has led to a rise in the wholesale distribution of antifungal drugs, which consequently has led to their release into the environment, posing a threat to ecosystems and human health. This article aims to provide a comprehensive review of the presence and distribution of antifungal drugs in the environment, evaluate their potential ecological and health risks, and assess current methods for their removal. Reviewed studies from 2010 to 2023 period have revealed the widespread occurrence of 19 various antifungals in natural waters and other matrices at alarmingly high concentrations. Due to the inefficiency of conventional water treatment in removing these compounds, advanced oxidation processes, membrane filtration, and adsorption techniques have been developed as promising decontamination methods.In conclusion, this review emphasizes the urgent need for a comprehensive understanding of the presence, fate, and removal of antifungal drugs in the environment. By addressing the current knowledge gaps and exploring future prospects, this study contributes to the development of strategies for mitigating the environmental impact of antifungal drugs and protecting ecosystems and human health.

Anticandidal Activity of In Situ Methionine γ-Lyase-Based Thiosulfinate Generation System vs. Synthetic Thiosulfinates.

Candida albicans and non-albicans Candida species are a common cause of human mucosal infections, as well as bloodstream infections and deep mycoses. The emergence of resistance of Candida spp. to antifungal drugs used in practice requires the search for new antimycotics. The present study unravels the antifungal potential of the synthetic dialk(en)ylthiosulfinates in comparison with an enzymatic in situ methionine γ-lyase-based thiosulfinate generation system (TGS). The kinetics of the TGS reaction, namely, the methionine γ-lyase-catalyzed ß-elimination of S-alk(en)yl-L-cysteine sulfoxides, was investigated via 1H NMR spectroscopy for the first time, revealing fast conversion rates and the efficient production of anticandidal dialk(en)ylthiosulfinates. The anticandidal potential of this system vs. synthetic thiosulfinates was investigated through an in vitro assay. TGS proved to be more effective (MIC range 0.36-1.1 µg/mL) than individual substances (MIC range 0.69-3.31 µg/mL). The tested preparations had an additive effect with the commercial antimycotics fluconazole, amphotericin B and 5-flucytosine demonstrating a fractional inhibitory coefficient index in the range of 0.5-2 µg/mL. TGS can be regarded as an attractive candidate for the targeted delivery of antimycotic thiosulfinates and for further implementation onto medically implanted devices.

Dosing Optimization of Posaconazole in Lung-Transplant Recipients Based on Population Pharmacokinetic Model.

Although posaconazole tablets show relatively low variability in pharmacokinetics (PK), the proportion of patients achieving the PK/PD target at the approved uniform dose for both prophylaxis and therapy is not satisfactory. The aim of this study was to develop a posaconazole population PK model in lung-transplant recipients and to propose a covariate-based dosing optimization for both prophylaxis and therapy. In this prospective study, 80 posaconazole concentrations obtained from 32 lung-transplant patients during therapeutic drug monitoring were analyzed using nonlinear mixed-effects modelling, and a Monte Carlo simulation was used to describe the theoretical distribution of posaconazole PK profiles at various dosing regimens. A one-compartment model with both linear absorption and elimination best fit the concentration-time data. The population apparent volume of distribution was 386.4 L, while an apparent clearance of 8.8 L/h decreased by 0.009 L/h with each year of the patient's age. Based on the covariate model, a dosing regimen of 200 mg/day for prophylaxis in patients ˃60 years, 300 mg/day for prophylaxis in patients ˂60 years and for therapy in patients ˃60 years, and 400 mg/day for therapy in patients ˂60 years has been proposed. At this dosing regimen, the PK/PD target for prophylaxis and therapy is reached in 95% and 90% of population, respectively, representing significantly improved outcomes in comparison with the uniform dose.

Physicochemical Characteristics of Antimicrobials and Practical Recommendations for Intravenous Administration: A Systematic Review.

Most antimicrobial drugs need an intravenous (IV) administration to achieve maximum efficacy against target pathogens. IV administration is related to complications, such as tissue infiltration and thrombo-phlebitis. This systematic review aims to provide practical recommendations about diluent, pH, osmolarity, dosage, infusion rate, vesicant properties, and phlebitis rate of the most commonly used antimicrobial drugs evaluated in randomized controlled studies (RCT) till 31 March 2023. The authors searched for available IV antimicrobial drugs in RCT in PUBMED EMBASE®, EBSCO® CINAHL®, and the Cochrane Controlled Clinical trials. Drugs' chemical features were searched online, in drug data sheets, and in scientific papers, establishing that the drugs with a pH of <5 or >9, osmolarity >600 mOsm/L, high incidence of phlebitis reported in the literature, and vesicant drugs need the adoption of utmost caution during administration. We evaluated 931 papers; 232 studies were included. A total of 82 antimicrobials were identified. Regarding antibiotics, 37 reach the "caution" criterion, as well as seven antivirals, 10 antifungals, and three antiprotozoals. In this subgroup of antimicrobials, the correct vascular access device (VAD) selection is essential to avoid complications due to the administration through a peripheral vein. Knowing the physicochemical characteristics of antimicrobials is crucial to improve the patient's safety significantly, thus avoiding administration errors and local side effects.

Occurrence, Diversity and Anti-Fungal Resistance of Fungi in Sand of an Urban Beach in Slovenia-Environmental Monitoring with Possible Health Risk Implications.

Beach safety regulation is based on faecal indicators in water, leaving out sand and fungi, whose presence in both matrices has often been reported. To study the abundance, diversity and possible fluctuations of mycobiota, fungi from sand and seawater were isolated from the Portoroz beach (Slovenia) during a 1-year period. Sand analyses yielded 64 species of 43 genera, whereas seawater samples yielded 29 species of 18 genera. Environmental and taxonomical data of fungal communities were analysed using machine learning approaches. Changes in the air and water temperature, sunshine hours, humidity and precipitation, air pressure and wind speed appeared to affect mycobiota. The core genera Aphanoascus, Aspergillus, Fusarium, Bisifusarium, Penicillium, Talaromyces, and Rhizopus were found to compose a stable community within sand, although their presence and abundance fluctuated along with weather changes. Aspergillus spp. were the most abundant and thus tested against nine antimycotics using Sensititre Yeast One kit. Aspergillus niger and A. welwitschiae isolates were found to be resistant to amphotericin B. Additionally, four possible human pollution indicators were isolated during the bathing season, including Meyerozyma, which can be used in beach microbial regulation. Our findings provide the foundations for additional research on sand and seawater mycobiota and show the potential effect of global warming and extreme weather events on fungi in sand and sea.

Antibiotics and antimycotics in waste water treatment plants: Concentrations, removal efficiency, spatial and temporal variations, prediction, and ecological risk assessment.

For investigating the spatial, temporal variations and assessing ecological risk of 10 antibiotics and 6 antimycotics, influent sewage water and treated effluent were collected during three different seasons in 19 waste water treatment plants of Tianjin. High performance liquid chromatography tandem mass spectrometry was used to analyze 16 substances. The concentration range of influent samples was not detected (nd) -547.94 ng/L and the concentration range of effluent samples was nd-52.97 ng/L. By calculating the removal efficiency, it was found that Ciprofloxacin (CIP), Ofloxacin (OFL) and Clotrimazole (CTR) were effectively removed. There were significant spatial and temporal differences, the concentration in the dry season was evidently higher than that in the wet and normal seasons, and the northeast was lower than that in the northwest and southeast. By establishing a data set of influent and effluent, the priority features were extracted by feature engineering, which were temperature and NH3-N. Under the condition of ensuring the best performance of the models, the influent model with 9 features and the effluent model with 4 features were established, and the quantitative relationship between the above features and concentration was obtained through partial dependence analysis. Except for Moxifloxacin (MOX), Norfloxacin (NOR) and OFL in the influent samples, the RQ values for other antibiotics and antimycotics were less than 0.1. Among the effluent samples, only NOR had an RQ value greater than 0.1, and OFL, MOX, and Pefloxacin (PEF) had RQ values between 0.01 and 0.1. Comparing the observations and predictions individual RQ values, the predictions were ideal and matched the observations. This work effectively assessed environmental impact and provided a valuable reference for evaluating antibiotics and antimycotics ecological toxicity.

Enhancement of the antifungal activity of some antimycotics by farnesol and reduction of Candida albicans pathogenicity in a quail model experiment.

Background and Aim: Clinical strains of microorganisms, including pathogenic yeast-like fungi (YLF), are resistant to currently used antifungal agents. Thus, it is relevant to study the combinations of existing antimicrobial drugs and a medicinal extract of plant origin (farnesol). In previous studies, farnesol showed a relatively strong anti-biofilm effect against Candida albicans. This study aimed to determine how much the resistance profile of non-biofilm microorganisms can change. Materials and Methods: Six clinical isolates of C. albicans and one reference strain were used to study the interaction of farnesol with the most used antimycotics. To determine the sensitivity of YLF to antimycotic drugs, such as nystatin (50 µg), amphotericin B (10 µg), ketoconazole (10 µg), clotrimazole (10 µg), voriconazole (10 µg), fluconazole (25 µg), miconazole (10 µg), and intraconazole (10 µg), the classic disk diffusion method was used. In the second stage, one of the six strains was used to simulate candidiasis of the gastrointestinal tract in an in vivo quail model. As an unusual experimental design, this study investigated the effects of pretreated C. albicans in quails, not the in vivo pathogenicity of C. albicans, after treatment with farnesol. Results: The resistance profiles of Candida strains did not improve with farnesol in all strains. All concentrations of farnesol (100, 50, and 25 µM) demonstrated a fungistatic effect (i.e., an increase in drug sensitivity) in 23 of 56 (7×8) cases (41%). The remaining 54% demonstrated no changes in the resistance to antifungal drugs or deterioration of the indicators in rare cases (5%). At 100 µM farnesol, sensitivity improved in 33 of 56 cases (59%). Candidiasis or the severity of clinical disease of the quail digestive tract developed to a lesser extent if fungi were treated with farnesol. Conclusion: Farnesol does not always show a positive result on single cells without biofilm in the laboratory. However, in a biofilm or an in vivo model with biofilms, farnesol can be considered a new antimycotic drug or an additive to existing antimycotics.

Species Diversity in the Fusarium solani (Neocosmospora) Complex and Their Pathogenicity for Plants and Humans.

The Fusarium solani species complex is a large group of soil saprotrophs with a broad adaptive potential, which allows the fungi to exist under various conditions and to parasitize on different hosts. The review analyzes the modern data concerning the genetic peculiarities of species from this complex by the example of F. solani f. sp. pisi and generalizes the data on the most widespread species pathogenic for both plants and humans. The enhanced resistance of the F. solani species complex to the most of modern antifungal agents and the need for novel therapeutic agents against fusariosis has been considered.

Azole fungicides: (Bio)degradation, transformation products and toxicity elucidation.

The increasing consumption of azole antifungal agents leads to their uncontrolled release into the environment. Therefore, it is crucial to remove their residues from natural ecosystems. This study aimed to examine the biological and chemical degradation of four typical azole fungicides: fluconazole (Fc), clotrimazole (Cl), climbazole (Cb), and epoxiconazole (Ep). The biodegradation was investigated using activated sludge and two novel Gram-negative bacterial strains. The chemical degradation experiments aimed to assess the efficiency of fungicides removal through UV treatment, the Fenton reaction, and a combination of these methods. Transformation products of Cb, Ep, and Cl photocatalytic removal were identified by mass spectrometry. In addition, the AlamarBlue® Assay and the MTT Assay allowed careful evaluation of the toxicity of azole derivatives and their transformation products towards newly isolated strains, Stenotrophomonas maltophilia AsPCl2.3 and Pseudomonas monteilii LB2. Among all azole fungicides, Cb was the most susceptible to biological removal while Fc, Ep, and Cl were basically resistant to biodegradation. Cl and Ep showed a significant biosorption on the activated sludge. Under optimized photolysis conditions, the removal efficiency of Cl, Cb, and Ep was significantly higher than that of biodegradation. The Fenton reaction supported by the UV-irradiation offered the best results of fungicides elimination. After 1 min of the experiment, Cl was almost completely removed while Cb and Ep removal rates reached an average of 60%. The proposed main degradation route of azole fungicides during UV-irradiation includes halogen atoms substitution by hydroxyl moieties. The final degradation product was imidazole or triazole. Azole fungicides and their transformation products differently affected the metabolic activity of Gram-negative bacteria. Cl and Cb intermediates showed lower toxicity than parent compounds. The findings help better understand the environmental impact of azole fungicides, their degradation, and toxicity. They also stress the need for reducing their uncontrolled release to the environment.

Malignant Keratitis Caused by a Highly-Resistant Strain of Fusarium Tonkinense from the Fusarium Solani Complex.

Fusarium spp. are moulds ubiquitously distributed in nature and only occasionally pathogenic for humans. Species of the Fusarium solani complex are the predominant keratitis-inducing pathogens, because they are endowed with proper virulence factors. These fungi can adhere to the cornea creating a biofilm and, with the help of enzymes and cytotoxins, penetrate the cornea. Whereas an intact cornea is hardly able to be invaded by Fusarium spp. in spite of appropriate virulence factors, these opportunistic fungi may profit from predisposing conditions, for example mechanical injuries. This can lead to a progressive course of corneal infection and may finally affect the whole eye up to the need for enucleation. Here, we present and discuss the clinical, microbiological and histopathological aspects of a particular case due to Fusarium tonkinense of the Fusarium solani complex with severe consequences in a patient without any obvious predisposing factors. A broad portfolio of antifungal agents was applied, both topically and systemically as well as two penetrating keratoplasties were performed. The exact determination of the etiologic agent of the fungal infection proved likewise to be very challenging.

The role of QT-prolonging medications in a forensic autopsy study from Western Denmark.

Medication-induced prolongation of the QT-interval (miQTP) can lead to cardiac arrhythmia. Our aim was to investigate the prevalence of forensic autopsy cases where fatal cardiac arrhythmia related to treatment with QT-prolonging medications (QT-PMs) could be suspected. We performed a cross-sectional study of 741 forensic autopsies undertaken at our institution in non-drug addicts aged 15 years or above from 2017 to 2019. We defined a high risk of miQTP by one detected QT-PM in a concentration above therapeutic level, or two or more detected QT-PMs in post mortem blood. We reviewed the autopsy reports from cases with a high miQTP-risk to identify cases with no other apparent cause of death. We discarded suicides and cases with lethal levels of QT-PMs. We identified 167 cases (22.5%) with high risk of miQTP, and discarded 36 suicides (4.9%) and 7 (0.9%) with lethal levels of QT-PMs. Apart from a high risk of miQTP, no other apparent explanation of the cause of death was present in seven (0.9%). In 18 cases (2.4%) with high miQTP-risk, the cause of death was primarily attributed to cardiac changes other than acute cardiovascular events. In conclusion, 22.5% had a high risk of miQTP, and fatal cardiac arrhythmia related to treatment with QT-PMs could be suspected in 0.9%. However, a genetic pro-arrhythmic background could not be excluded in our study. Furthermore, it is possible that QT-PMs could have played a role in some of the 2.4% of cases where the cause of death was mainly attributed to cardiac changes and the risk of miQTP was high.

Design, synthesis and biological evaluation of novel diazaspirodecanone derivatives containing piperidine-4-carboxamide as chitin synthase inhibitors and antifungal agents.

A series of novel 2-oxo-(1-oxo-2,8-diazaspiro[4.5]decane-8-yl)ethylpiperidine carboxamide derivatives were designed, synthesized and characterized by 1H NMR, 13C NMR and HRMS spectroscopy. All eighteen newly prepared compounds were evaluated for their inhibition against chitin synthase (CHS) and antifungal activities in vitro. The enzyme assay revealed that compound 5h showed excellent inhibitory activity against CHS with IC50 value of 0.10 mM, and the compounds 5b, 5d and 5q showed good inhibition against chitin synthase with IC50 values of 0.13 mM, 0.18 mM and 0.15 mM, respectively, while IC50 value of ployoxin B was 0.08 mM. Meanwhile, the others of these compounds exhibited moderate inhibition potency against chitin synthase. The antifungal assay showed compound 5h had excellent antifungal activity compared with the control drugs fluconazole and polyoxin B against these tested strains including C. albicans, A. fumigatus, C. neoformans and A. flavus. Its excellent antifungal activity was consistent with its excellent chitin synthase inhibition. Compound 5k and 5l against C. albicans were comparable with fluconazole, and they showed strong antifungal potency against A. flavus with MIC values of 0.07 mmol/L and 0.13 mmol/L respectively. Compound 5m had similar MIC value against A. fumigatus to fluconazole. The phenomenon that compounds 5b, 5d and 5q that showed good enzymatic inhibition didn't exert good antifungal activity, while compounds 5k, 5l and 5m that showed moderate chitin synthase inhibition exhibited excellent antifungal activity was discussed. Furthermore, the trial of drug combination showed that compounds had synergistic effects or additive effects with fluconazole against tested fungi which also verified that these designed compounds targeted different targets from that of fluconazole. Additionally, the antibacterial trial showed that all synthesized compounds had little potency against tested bacteria strains. These results indicated that the designed compounds were potential chitin synthase inhibitors and had selectively antifungal activities.

A review of pharmacokinetic drug interactions between antimicrobial and antiseizure medications in children.

Comorbidity between epilepsy and infectious diseases in children is frequent. Pharmacokinetic drug-drug interactions (DDIs) between antiseizure medications (ASMs) and anti-infectives can occur and influence their efficacy or cause toxicity. All potential DDIs between ASMs and antimicrobial agents used in children were identified through consultation of drug compendia. Clinical studies, case reports and summaries of product characteristics of all identified drugs were also searched. A typical example of a DDI that is often observed in children is that involving valproate (VPA) and carbapenem antibiotics. This DDI has a unique mechanism of action (inhibits the enzyme that catalyses the hydrolysis of VPA-glucuronide) and leads to a fall of around 60% of VPA level, associated with seizure recurrence. An example of bidirectional DDI involves the antimycotic voriconzole and several ASMs. Voriconazole is metabolized and is a strong inhibitor of cytochrome (CYP)3A4, CYP2C9/10 and CYP2C19. There is clinical evidence of induction of voriconazole metabolism with possible loss of its efficacy by phenytoin (PHT), while voriconazole increases the levels of PHT. Other ASMs that are inducers of these enzymes, such as carbamazepine (CBZ), phenobarbital, stiripentol and to a lesser degree, oxcarbazepine, might be predicted to decrease the level of voriconazole. Voriconazole might also be predicted to increase levels of cannabidiol, CBZ, lacosamide, midazolam, and zonisamide. DDIs between ASMs and some antiviral agents are potentially even more frequent and clinically relevant.

Strategies to Better Target Fungal Squalene Monooxygenase.

Fungal pathogens present a challenge in medicine and agriculture. They also harm ecosystems and threaten biodiversity. The allylamine class of antimycotics targets the enzyme squalene monooxygenase. This enzyme occupies a key position in the sterol biosynthesis pathway in eukaryotes, catalyzing the rate-limiting reaction by introducing an oxygen atom to the squalene substrate converting it to 2,3-oxidosqualene. Currently, terbinafine-the most widely used allylamine-is mostly used for treating superficial fungal infections. The ability to better target this enzyme will have significant implications for human health in the treatment of fungal infections. The human orthologue can also be targeted for cholesterol-lowering therapeutics and in cancer therapies. This review will focus on the structural basis for improving the current therapeutics for fungal squalene monooxygenase.

Antimycotic Treatment of Oral Candidiasis in Warfarin Users.

PURPOSE: Azole antimycotics and nystatin oral solution are used to treat oral candidiasis. Azoles inhibit cytochrome (CYP) P450-dependent metabolism of warfarin, which could increase the anticoagulant effect of warfarin. Nystatin is not expected to interfere with warfarin metabolism, but current data are conflicting. With this study, we aimed to explore the potential drug-drug interactions between warfarin and azole antimycotics used in the treatment of oral candidiasis, that is, systemic fluconazole, miconazole oral gel, and nystatin oral solution. METHODS: By linking clinical data on international normalized ratio (INR) measurements with administrative data on filled prescriptions of warfarin and antimycotics during 2000-2015, we explored INR changes in warfarin users relative to initiation of systemic fluconazole (n = 413), miconazole oral gel (n = 330), and nystatin oral solution (n = 399). RESULTS: We found a significant increase in mean INR of 0.83 (95% confidence interval [CI] 0.61-1.04) and 1.27 (95% CI 0.94-1.59) following initiation of systemic fluconazole and miconazole oral gel, respectively. Also, the proportion of patients experiencing an INR-value above 5 was increased after initiation of fluconazole (from 4.3% to 15.3%) and miconazole (from 5.5% to 30.1%). INR was unaffected by initiation of nystatin oral solution (mean change 0.08; 95% CI -0.10 to 0.25). CONCLUSION: Initiation of systemic fluconazole and miconazole oral gel was associated with increased INR in warfarin users. A similar association was not found for nystatin oral solution, which thus appears to be the safest alternative when treating oral candidiasis in warfarin users.

Concise Review; Effects of Antibiotics and Antimycotics on the Biological Properties of Human Pluripotent and Multipotent Stem Cells.

Human Pluripotent Stem Cells (PSCs), including Embryonic Stem Cells (ESCs) and induced Pluripotent Stem Cells (iPSCs), have the remarkable potential to self-renew and develop into various cell lineages. Human Mesenchymal Stem Cells (MSCs) or multipotent stem cells that are present in various organs can self-renew and differentiate into multiple mesenchymal lineages. Both human PSCs and MSCs hold great promise in cell-based therapies, disease modeling, drug discovery, and regenerative medicine. Human stem cells must be cultured under the optimal conditions to use them in transplantology. Therefore, researchers must ensure the sterility of human stem cell lines. Bacterial contamination is a common problem in laboratories and major precautions are required to detect the types of microorganisms, and to eliminate and prevent contamination in cell cultures. Stem cell culture media usually contain antibiotics and antimycotics such as penicillin- streptomycin (pen-strep), gentamicin, and amphotericin B (AmB) to avoid bacterial, fungal, and yeast contaminants. Numerous publications recognized the serious effect of antibiotics and antimycotics on in vitro properties of human stem cells, including proliferation, differentiation, survival, and genetic instability. This review study aimed to understand the impact of routinely used antibiotics and antimycotics such as pen-strep, gentamicin, and AmB on viability, proliferation, and functional properties (differentiation and pluripotency) of human PSCs and MSCs.