Design and biological evaluation of a novel type of potential multi-targeting antimicrobial sulfanilamide hybrids in combination of pyrimidine and azoles.

This work explored a novel type of potential multi-targeting antimicrobial three-component sulfanilamide hybrids in combination of pyrimidine and azoles. The hybridized target molecules were characterized by 1H NMR, 13C NMR and HRMS spectra. Some of the developed target compounds exerted promising antimicrobial activity in comparison with the reference drugs norfloxacin and fluconazole. Noticeably, sulfanilamide hybrid 5c with pyrimidine and indole could effectively inhibit the growth of E. faecalis with MIC value of 1 µg/mL. The active molecule 5c showed low cell toxicity and did not obviously trigger the development of resistance towards the tested bacteria strains. Mechanism exploration indicated that compound 5c could not only exert efficient membrane permeability, but also intercalate into DNA of resistant E. faecalis to form 5c-DNA supramolecular complex, which might be responsible for its antimicrobial action. The further investigation showed that this molecule could be effectively transported by human serum albumins through hydrogen bonds and van der Waals force.

Malassezia furfur Emergence and Candidemia Trends in a Neonatal Intensive Care Unit During 10 Years: The Experience of Fluconazole Prophylaxis in a Single Hospital.

BACKGROUND: Because Candida spp is a major cause of mortality and morbidity in preterm infants, fluconazole prophylaxis has been suggested by some experts and hospital policy. In our hospital, fluconazole prophylaxis was used in eligible preterm infants and set as the neonatal intensive care unit (NICU) practice in 2014. PURPOSE: This study focused on fungal bloodstream infections and aimed to evaluate the benefit and harm of fluconazole prophylaxis. METHODS/SEARCH STRATEGY: This retrospective, descriptive study involved medical record reviews in our hospital from April 2005 to October 2016. NICU patients were included if Candida species, yeast-like organisms, or Malassezia species were cultured from their venous catheter tips or blood cultures. FINDINGS/RESULTS: After fluconazole prophylaxis, cases of Candida spp decreased and those of Malassezia furfur emerged. We reviewed 19 cases of catheter-related M furfur colonization and 1 case of M furfur fungemia. The gestational age was 27.3 ± 2.0 weeks and birth weight was 959.2 ± 229.8 g. Hyperalimentation with lipid infusion was used in all cases. All of the neonates survived with antifungal agent use. IMPLICATIONS FOR PRACTICE: This study highlights that prophylactic fluconazole may be an associated factor of Malassezia colonization; M furfur remains a potential concern for fungemia in the care of premature infants and thus requires our attention. IMPLICATIONS FOR RESEARCH: Future studies should further investigate the incidence and impact of noncandidal fungal infections with fluconazole prophylaxis use in premature infants.

Estudo dos fatores de virulência de Cândida spp. isoladas da cavidade bucal de pacientes pediátricos em UTI / Study of the virulence factors of Candida spp. isolated from the oral cavity of pediatric patients in the ICU

O presente estudo teve como objetivo avaliar, in vitro, fatores de virulência e susceptibilidade ao fluconazol, associado ou não a Clorexidina, de Candida spp. isoladas de diferentes sítios da cavidade bucal de crianças hospitalizadas em Unidade de Terapia Intensiva (UTI) comparando com isolados de crianças não hospitalizadas. Para isso, foram utilizados isolados de Candida spp., previamente identificados e estocados, oriundos de 30 pacientes de UTI (G1) e 30 pacientes saudáveis (G2), com idade entre 01 e 13 anos, pareados por sexo e idade. A coleta dos espécimes clínicos foi realizada através de esfregaço de mucosa (swab) e raspagem de biofilme dental supragengival, e a identificação das espécies de Candida se deu por espectrometria de massa (MALDI-TOF). Todos os isolados de Candida (n=60, sendo 46 G1 e 14 G2 (C.albicans n=15, C. tropicalis n=5, C. guilliermondii n=32, C. parapsilosis n=5, C. glabrata n=2, C. kefyr n=1) foram então selecionados para a avaliação de fatores de virulência como, formação de biofilme, produção de fosfolipase e protease, susceptibilidade ao fluconazol (FLZ) e clorexidina (CHX); e, verificação de sinergismo, checkerboard, entre as duas drogas. Os resultados foram analisados através do SPSS versão 20 e comparados por meio dos testes Qui-quadrado, Fisher e Razão de chance (95% IC), com nível de significância de 95% (p≤0,05). Tanto os isolados de G1 (97,8%) quanto os de G2 (100%) produziram biofilme (χ2, p=0,76). Quanto a produção de fosfolipase, somente 3 (6,5%) isolados do G1 (todos de C. albicans) foram produtores, sendo um isolado de mucosa (16,7%) e dois em biofilme (40%); No G2, isso aconteceu de modo similar (1 isolado produtor) (χ2, p=0,66). Já em relação a produção de protease, 42 isolados (91,3%), dos quais 100% dos isolados de C. guilliermondii, seguida de C. albicans (81,8%), produziram esta enzima em G1, sendo esta frequência significativamente maior do que a encontrada no G2 com 9 isolados (64,3%) (χ2, p=0,025). Não houve diferença significativa quando comparamos os fatores de virulência entre os isolados oriundos de diferentes sítios, nos dois grupos. Cinquenta e um (85%) isolados foram resistentes ao FLZ, sendo 38 (82,6%) no G1 e 13 (92,9%) no G2 (χ2, p=0,47), sendo a frequência de isolados resistentes similar entre os sítios (mucosa x biofilme dental) (χ2, p=0,40). Foi observado que os poucos isolados resistentes a Clorexidina (n=2; 1 C. tropicalis do G1 e 1 C. albicans do G2), foram sensíveis a combinação FLZ e CHX, mostrando um sinergismo entre as duas drogas. Conclui-se que os pacientes internados em UTI apresentam maior freqüência de isolados de Candida spp. produtores de protease e que isolados de biofilme dental são tão virulentos quanto os de mucosa nesses pacientes. Ainda, a combinação de fluconazol e clorexidina foi eficiente no controle do crescimento de Candida spp. (AU)

The present study aimed to evaluate, in vitro, virulence and susceptibility factors to fluconazole, associated or not with Chlorhexidine, from Candida spp. isolated from different sites in the oral cavity of children hospitalized in an Intensive Care Unit (ICU) compared with isolates from children not hospitalized. For this, Candida spp. Isolates, previously identified and stored, were used, coming from 30 ICU patients (G1) and 30 healthy patients (G2), aged between 01 and 13 years, matched by sex and age. The collection of clinical specimens was carried out through mucosa smear (swab) and scraping of supragingival dental biofilm, and Candida species were identified by mass spectrometry (MALDI-TOF). All Candida isolates (n = 60, 46 G1 and 14 G2 (C.albicans n = 15, C. tropicalis n = 5, C. guilliermondii n = 32, C. parapsilosis n = 5, C. glabrata n = 2, C. kefyr n = 1) were then selected for the evaluation of virulence factors such as biofilm formation, phospholipase and protease production, susceptibility to fluconazole (FLZ) and chlorhexidine (CHX); and, synergism check, checkerboard, between the two drugs. The results were analyzed using SPSS version 20 and compared using the Chi-square, Fisher and odds ratio tests (95% CI), with a 95% significance level (p≤0.05) Both G1 (97.8%) and G2 isolates (100%) produced biofilm (χ2, p = 0.76). Regarding the production of phospholipase, only 3 (6.5%) isolates from G1 (all of C. albicans) were producers, one isolated from the mucosa (16.7%) and two in biofilm (40%); In G2, this happened in a similar way (1 producer isolate) (χ2, p = 0.66). Regarding protease production, 42 isolates (91.3%), of which 100% of the isolates of C. guilliermondii, followed by C. albicans (81.8%), produced this enzyme in G1, this frequency being significantly greater than that found in G2 with 9 isolates (64.3%) (χ2, p = 0.025). There was no significant difference when comparing the virulence factors between the isolates from different sites, in the two groups. Fifty-one (85%) isolates were resistant to FLZ, 38 (82.6%) in G1 and 13 (92.9%) in G2 (χ2, p = 0.47), the frequency of resistant isolates being similar between sites (mucosa x dental biofilm) (χ2, p = 0.40). It was observed that the few isolates resistant to chlorhexidine (n = 2; 1 C. tropicalis from G1 and 1 C. albicans from G2), were sensitive to the combination of FLZ and CHX, showing a synergism between the two drugs. It is concluded that patients admitted to the ICU have a higher frequency of Candida spp. protease producers and that dental biofilm isolates are as virulent as mucosal ones in these patients. Also, the combination of fluconazole and chlorhexidine was effective in controlling the growth of Candida spp. (AU)

Quality assessment of fluconazole capsules and oral suspensions compounded by pharmacies located in the United States.

OBJECTIVE To evaluate pharmaceutical characteristics (strength or concentration, accuracy, and precision), physical properties, and bacterial contamination of fluconazole compounded products. SAMPLE Fluconazole compounded products (30- and 240-mg capsules; 30- and 100-mg/mL oral suspensions) from 4 US veterinary compounding pharmacies. PROCEDURES Fluconazole compounded products were ordered 3 times from each of 4 pharmacies at 7- or 10-day intervals. Generic fluconazole products (50- and 200-mg tablets; 10- and 40-mg/mL oral suspensions) served as references. Compounded products were evaluated at the time of receipt; suspensions also were evaluated 3 months later and at beyond-use dates. Evaluations included assessments of strength (concentration), accuracy, precision, physical properties, and bacterial contamination. Acceptable accuracy was defined as within ± 10% of the labeled strength (concentration) and acceptable precision as within ± 10%. Fluconazole was quantified by use of high-performance liquid chromatography. RESULTS Physical characteristics of compounded products differed among pharmacies. Aerobic bacterial cultures yielded negative results. Capsules (30 and 240 mg) had acceptable accuracy (median, 96.3%; range, 87.3% to 135.2%) and precision (mean ± SD, 7.4 ± 6.0%). Suspensions (30 and 100 mg/mL) had poor accuracy (median, 73.8%; range, 53.9% to 95.2%) and precision (mean ± SD, 15.0 ± 6.9%). Accuracy and precision were significantly better for capsules than for suspensions. CONCLUSIONS AND CLINICAL RELEVANCE Fluconazole compounded products, particularly suspensions, differed in pharmaceutical and physical qualities. Studies to evaluate the impact of inconsistent quality on bioavailability or clinical efficacy of compounded fluconazole products are indicated, and each study should include data on the quality of the compounded product evaluated.

Correlation between CLSI, EUCAST and Etest methodologies for amphotericin B and fluconazole antifungal susceptibility testing of Candida spp. clinical isolates.

This study analyzed the correlation between the results obtained through two microdilution methods: Clinical and Laboratory Standard Institute (CLSI) (M27-A2) and European Committee on Antibiotic Susceptibility Testing (EUCAST) (document E. Dis. 7.1) and an agar base method Etest for determining minimmun inhibitory concentration (MIC) for amphotericin B and fluconazole against 30 clinical isolates of Candida spp. The agreement between Etest, CLSI and EUCAST MICs within +/- 2 log2 dilutions was higher for amphotericin B than for fluconazole However, Pearson correlation demonstrated a greater agreement for fluconazole. The categorical agreement between MICs provided by the Etest/ CLSI and Etest/EUCAST methodologies was high for both amphotericin B (100%) and fluconazole (> or = 96.66%). This study demonstrated the adequacy of Etest method using Mueller Hinton agar to evaluate amphotericin B and fluconazole susceptibility of clinical isolates of Candida spp.

Synthesis of new thiazolylthiazolidinylbenzothiazoles and thiazolylazetidinylbenzothiazoles as potential insecticidal, antifungal, and antibacterial agents.

A series of 2-{[2'-(3''-chloro-2''-oxo-4''-substitutedaryl-1''-azetidinyl)-1',3'-thiazol-4'-yl] thio}benzothiazoles (4a-4e) and 2-{[(2'-(2''-substitutedaryl-4''-thiazolidinon-3''-yl)-1',3'-thiazol-4'-yl]thio}benzothiazoles (5a-5e) have been synthesized from 2-[(2'-substitutedarylidenylimino-1',3'-thiazol-4'-yl)thio]benzothiazoles (3a-3e). The structure of these compounds has been elucidated by elemental (C, H, N) and spectral (IR, (1)H-NMR, Mass) analysis. Furthermore, compounds 3a-3e, 4a-4e, and 5a-5e were screened for insecticidal activity against Periplaneta americana and antifungal, antibacterial activities in vitro against different strains of fungi and bacteria. Out of the fifteen compounds tested, compound 5b, 2-{[2'-(2''-p-hydroxy-m-methoxyphenyl)-4''-thiazolidinon-3''-yl)-1',3'-thiazol-4'-yl]thio}benzothiazole, was found to possess most prominent insecticidal activity.

Fluconazole preparations on the Belgian market: a comparative study.

Fluconazole preparations formulated as capsules were evaluated with different tests, including in vitro dissolution and assay with previously validated methods according to the guideline of the European network of Official Medicines Control Laboratories (OMCLs). All examined products complied with our requirements and those described in the European and the US Pharmacopoeia and consequently they can be considered as pharmaceutically equivalent.

The comparative bioavailability of a generic and the innovator fluconazole preparations in healthy Thai volunteers.

We studied the pharmacokinetics and compared the oral bioavailability of the "generic" (Biozole, Biolab Company, Thailand) and the "innovator" (Diflucan, Pfizer Incorporation, U.S.A.) fluconazole preparations in 12 healthy Thai volunteers. A 200 mg single oral dose of each preparation was given to the subjects in a randomized double-blind 2-period crossover design with 2 weeks washout period. Blood samples were collected just before and at 0.5, 1, 2, 2.5, 3, 4, 24, 48, 56 and 72 hours after drug administration. Serum fluconazole concentrations were determined by using high performance liquid chromatography. Individual concentration-time profiles and the pharmacokinetic parameters were analyzed by the noncompartmental pharmacokinetic method [TOPFIT, a pharmacokinetic data analysis program]. The pharmacokinetic parameters (Tmax, Cmax, Vd, Cl) of fluconazole in Thai healthy volunteers were comparable to those values observed in Caucasian subjects. The relative bioavailability of the generic Biozole was 102.38 +/- 9.79 per cent of Diflucan. The means and 90 per cent confidence intervals (90% CI) of the [Biozole/Diflucan] ratio of AUC0-72, AUC0-inf and Cmax were 1.02 (0.98-1.06), 0.99 (0.95-1.03) and 1.13 (1.03-1.25), respectively. These values were well within the acceptable bioequivalence ranges of 0.8-1.25 proposed by the US FDA. The means and 90 per cent CI of Tmax differences [Biozole-Diflucan] were -0.46 [(-1.03)-(0.12)]. This value was outside the stipulated bioequivalence range of +/- 0.41 h (+/- 20% of the Tmax of the reference formulation). Nevertheless, the Tmax difference was not expected to be related to the differences in safety and efficacy of the drug. Hence, Biozole and Diflucan were bioequivalent with respect to the extent of absorption (AUC), and the Cmax, and could be used interchangeably.