Metastatic renal cell cancer and first-line combinations: for which patients? (focus on tolerance and health-related quality of life).

Until recently, the first-line treatments used in metastatic renal cell carcinoma were based on first-generation anti-VEGFR (vascular endothelial growth factor receptor) tyrosine kinase inhibitors (TKIs) as monotherapy. Trials combining immunotherapy (IO) (anti-CTLA4 + anti-PD-1) or immunotherapy with TKIs showed striking results in the first-line setting with improvement in overall response rates, progression-free survival and overall survival versus sunitinib. This allowed the combinations to gain registration in the US and Europe in the first-line advanced or metastatic clear-cell renal cell carcinoma setting. However, this improved activity comes at the cost of increased toxicity. Immunotherapy-related toxicities usually occur earlier within the first six months. With immunotherapy came a new range of toxicities making it more necessary to work with networks of specialists to better address autoimmune toxicity in particular. The safety profile is also impacted by the type of TKI used. In most cases, health-related quality of life (HRQoL) favours combinations over the comparator sunitinib. This article aims to review and assess the safety and HRQoL data on these new combinations.

Antimicrobial susceptibility patterns of blood culture isolates from foals in Switzerland.

INTRODUCTION: We report blood culture results of 43 foals admitted to an equine hospital for medical or surgical disorders and determine minimal inhibitory concentrations (MIC) of different antibiotics. Eleven foals had a positive blood culture result despite prior administration of antibiotics in 10 of these animals. MIC values above EUCAST and/or CLSI breakpoints were identified in coagulase-negative staphylococci, methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecium. Gram-negative isolates were less frequently identified and did not appear to exhibit increased MIC values. This study shows that bloodstream infections in foals in Switzerland are caused by diverse bacteria including Gram-positive bacteria which exhibit resistance to several classes of antibiotics.

INTRODUCTION: Nous rapportons les résultats d'hémoculture de 43 poulains admis dans un hôpital équin pour des affections médicales ou chirurgicales et déterminons les concentrations minimales inhibitrices (CMI) de différents antibiotiques. Le résultat de l'hémoculture a été positif pour onze poulains malgré l'administration préalable d'antibiotiques à 10 de ces animaux. Des valeurs de CMI supérieures aux seuils EUCAST et/ou CLSI ont été identifiées chez des staphylocoques coagulase négative, chez Staphylococcus aureus résistant à la méthicilline (MRSA) et chez Enterococcus faecium. Les isolats Gram négatifs étaient moins fréquemment identifiés et ne semblaient pas présenter de valeurs de CMI augmentées. Cette étude montre que les infections sanguines des poulains en Suisse sont causées par diverses bactéries, notamment des bactéries Gram positif, qui résistent à plusieurs classes d'antibiotiques.

Antifungal activity of essential oils against azole-resistant and azole-susceptible vaginal Candida glabrata strains.

Candida glabrata is an opportunistic pathogen, associated with endocarditis, meningitis, and disseminated disease, and also with complicated vaginitis. Essential oils derived from aromatic plants are known in traditional medicine as antimicrobial agents and have antifungal properties. The aim of this work was to evaluate whether 12 tested essential oils (tea tree, laurel, anise, basil, bergamot, lavender, mint, oregano, grapefruit, rosemary, winter savory, and ginger) could have a transverse effect on C. glabrata sensitive strains but above all on strains resistant to the three main azole antifungals used (clotrimazole, fluconazole, itraconazole). For this reason, different strains of C. glabrata, vaginal isolated, were characterized (disk diffusion assay, minimal inhibitory concentration) with respect to their response to such antifungals. Electron microscopy analyses were performed to examine cellular damages in depth. Subsequently, we wanted to evaluate the effect of the oils on human cells to estimate their potential cytotoxicity. Oregano and winter savory were the two most effective essential oils, inducing growth inhibition, cell damage of C. glabrata strains (both sensitive and resistant to azole antifungal drugs), and medium-high level of toxicity against human keratinocytes. The results of this work support the research for new alternatives or complementary therapies against vaginal candidiasis.

Syk inhibitor R406 downregulates inflammation in an in vitro model of Pseudomonas aeruginosa infection.

As Pseudomonas aeruginosa infections are characterized by strong inflammation of infected tissues, anti-inflammatory therapies in combination with antibiotics have been considered for the treatment of associated diseases. Syk tyrosine kinase is an important regulator of inflammatory responses, and its specific inhibition was explored as a therapeutic option in several inflammatory conditions; however, this has not been studied in bacterial infections. We used a model of in vitro infection of human monocytic cell line THP-1 and lung epithelial cell line H292 with both wild-type and flagella-deficient mutant of P. aeruginosa strain K, as well as with clinical isolates from cystic fibrosis patients, to study the effect of a small molecule Syk inhibitor R406 on inflammatory responses induced by this pathogen. One-hour pretreatment of THP-1 cells with 10 µmol/L R406 resulted in a significant downregulation of the expression of the adhesion molecule ICAM-1, pro-inflammatory cytokines TNF-α and IL-1ß, and phosphorylated signaling proteins ERK2, JNK, p-38, and IκBα, as well as significantly decreased TNF-α release by infected H292 cells. The results suggest that Syk is involved in the regulation of inflammatory responses to P. aeruginosa, and R406 may potentially be useful in dampening the damage caused by severe inflammation associated with this infection.

Aptamer-Conjugated Calcium Phosphate Nanoparticles for Reducing Diabetes Risk via Retinol Binding Protein 4 Inhibition.

OBJECTIVES: Inhibition of the binding of retinol to its carrier, retinol binding protein 4, is a new strategy for treating type 2 diabetes; for this purpose, we have provided an aptamer-functionalized multishell calcium phosphate nanoparticle. METHODS: First, calcium phosphate nanoparticles were synthesized and conjugated to the aptamer. The cytotoxicity of nanoparticles releases the process of aptamer from nanoparticles and their inhibition function of binding retinol to retinol binding protein 4. RESULTS: After synthesizing and characterizing the multishell calcium phosphate nanoparticles and observing the noncytotoxicity of conjugate, the optimum time (48 hours) and the pH (7.4) for releasing the aptamer from the nanoparticles was determined. The half-maximum inhibitory concentration (IC50) value for inhibition of retinol binding to retinol binding protein 4 was 210 femtomolar (fmol). CONCLUSIONS: The results revealed that the aptamer could prevent connection between retinol and retinol binding protein 4 at a very low IC50 value (210 fmol) compared to other reported inhibitors. It seems that this aptamer could be used as an efficient candidate not only for decreasing the insulin resistance in type 2 diabetes, but also for inhibiting the other retinol binding protein 4-related diseases.

[Efficacy of sodium hydroxide at 2.5 %, chlorhexidine gluconate at 0.5 % and calcium hydroxide against Candida albicans]. / Étude de l'efficacité de l'hypochlorite de sodium à 2,5 %, de la chlorhexidine à 0,5 %, et de l'hydroxyde de calcium sur Candida albicans.

INTRODUCTION: Endodontic flora is dominated in the apical part of the channels by strict anaerobic and some facultative anaerobic bacteria but also by Candida yeasts, especially Candida albicans species that are involved in the maintenance and persistence of endodontic infections. Their elimination of the canal system in practice by chemo-mechanical methods of disinfection is not always guaranteed. Thus, this in vitro study was performed to determine the sensitivity of C. albicans with sodium hypochlorite (NaOCl) dosed at 2.5 %, the chlorhexidine digluconate 0.5 % and calcium hydroxide used in inter-session medication. METHODS: The diffusion method was used initially to test the sensitivity of C. albicans strains with the above products. Then a dilution technique has allowed us to determine the minimum inhibitory concentration of these active products on C. albicans. RESULTS: Strains from infected pulp teeth of patients showed a sensitivity of C. albicans to sodium hypochlorite to a minimum inhibitory concentration less than 70µg/mL and 30µg/mL for chlorhexidine. CONCLUSION: This study demonstrated a sensitivity of C. albicans to sodium hypochlorite and chlorhexidine.

In vitro antimicrobial susceptibility of Mycoplasma bovis clinical isolates recovered from bison (Bison bison).

Mycoplasma bovis is a pathogen globally affecting cattle and bison herds, causing pneumonia, arthritis, mastitis, abortions, and other symptoms, leading to huge economic losses. Many studies have been done regarding the antimicrobial susceptibility of M. bovis isolated from cattle, but no such study is available for isolates recovered from bison. For the first time, in vitro susceptibilities of 40 M. bovis clinical isolates collected from bison herds in Canada are reported here. Minimal inhibitory concentration (MIC) values were determined using Sensititre® plates. The most effective MIC50 and MIC90 were for spectinomycin (1 and >64 µg/mL), tiamulin (1 and >32 µg/mL), and tulathromycin (16 and 64 µg/mL), whereas tetracyclines, fluoroquinolones, and florfenicol failed to inhibit growth of M. bovis bison isolates. Isolates were nonsusceptible to tetracyclines (100%), fluoroquinolones (97.5%), and tilmicosin (100%), whereas the highest susceptibility of bison clinical isolates was seen with spectinomycin (95%) and tulathromycin (67.5%). Two lung isolates (Mb283 and 348) were found resistant to both spectinomycin and tulathromycin. These results show a marked difference in antimicrobial susceptibility of bison isolates as compared with previously reported and laboratory reference cattle isolates, emphasizing the necessity of testing antimicrobial susceptibility of M. bovis bison isolates and to generate better therapeutic regime for improved recovery chances for infected bison herds across North America.

In vitro susceptibility profile of 200 recent clinical isolates of Candida spp. to topical antifungal treatments of vulvovaginal candidiasis, the imidazoles and nystatin agents.

OBJECTIVE: Topical antifungal treatment of vulvovaginal candidiasis is widely recommended. The most commonly recommended topical antifungals (the imidazoles clotrimazole, miconazole and econazole and the polyene nystatin) have been on the market for more than 30 years. There are only a few recent data available on the susceptibility of different Candida species to these antifungals, especially of non-albicans Candida species which appear to be less responsive to treatment with imidazoles. The study aimed to determine the in vitro susceptibility profile of a large number of recent clinical isolates of Candida spp. to the most commonly recommended topical antifungals. MATERIALS AND METHODS: An antifungal susceptibility test was performed according to the CLSI M27-A3 broth microdilution method, and minimal inhibitory concentrations were determined for econazole, miconazole, clotrimazole and nystatin. RESULTS: The clinical isolates comprised of: 113 Candida albicans, 54 Candida glabrata, 11 Candida krusei, 11 Candida tropicalis and 11 Candida parapsilosis. The three azoles agents exhibited MIC90 values of 0.06 mg/L against C. albicans isolates, while nystatin exhibited a MIC90 of 4 mg/L. For non-albicans Candida isolates, MIC90 values ranged from 0.5 to 8 mg/L, from 1 to 4 mg/L and from 0.12 to 4 mg/L, for econazole, miconazole, clotrimazole, respectively. Nystatin MIC90 remained at 4 mg/L for all non-albicans Candida species tested. CONCLUSION: These results confirmed the susceptibility of C. albicans to the most frequently used topical agents and may support the use of alternative agents to imidazoles, such as nystatin, to treat vulvovaginal candidiasis caused by non-albicans Candida species.

[Catheterization and fungal infection risk in the University Hospital of Tlemcen: epidemiology and susceptibility to antifungals]. / Cathétérisme et risque infectieux fongique au centre hospitalo-universitaire de Tlemcen: épidémiologie et sensibilité aux antifongiques.

Fungal infections are a major cause of morbidity and mortality, and are frequently associated with the implantation of vascular catheters, especially in immune-compromised patients. Unfortunately, the therapeutic arsenal available for the treatment of these infections, caused generally by the yeasts of the genus Candida is still limited because of the toxicity and/or of the emergence of resistance against some antifungal agents. That is why we have undertaken this study, which is to determine the incidence and the degree of sensitivity of Candida spp., isolated from peripheral venous catheters at the University Hospital of Tlemcen (Algeria) to caspofungin and amphotericin B. The results show that the rate of colonization of vascular catheters was 19 % by yeasts of Candida spp., of which 60 % are Candida parapsilosis, 20 % Candida albicans, 14.3 % Candida glabrata and 5.7 % Candida famata. The minimum inhibitory concentrations (MIC) for amphotericin B are between 0.5 and 2 µg/mL and for caspofungin, they are between 0.125 and 2 µg/mL.