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1.
High frequency of azole resistant Candida spp. colonization among presumptive multidrug resistant tuberculosis (MDR-TB) patients.
Darma, S, Ambara, A, Aman, AT, Annisa, L, Nurrokhman, , Nuryastuti, T, Wibawa, T
PloS one. 2020;(11):e0242542
Abstract
BACKGROUND Tuberculosis is one of the major causes of death globally. The problems become even more complicated with the rise in prevalence of multidrug resistant tuberculosis (MDR-TB). Many diseases have been reported to occur with tuberculosis making it more difficult to manage. Candida spp., which are yeast-like fungi and a constituent of normal flora in humans, are notoriously reported to be one of the most common opportunistic nosocomial infections. This study aimed to measure the proportion of presumptive MDR-TB patients colonized with Candida spp. and to characterize its susceptibility against azole group antifungal agents. METHODS Sputum from presumptive MDR-TB patients were collected and examined for the presence of Mycobacterium tuberculosis and its rifampicin resistant status using GeneXpert. It was further cultured on Sabouroud's Dextrose Agar (SDA) to isolate the Candida spp. The Candida species were determined using HiCrome™ Candidal Differential Agar. Antifungal susceptibility was tested using microbroth dilution methods. Checkerboard microdilution assays were performed to measure the interaction between rifampicin and fluconazole to C. albicans. RESULTS There were 355 presumptive MDR-TB patients enrolled. A total of 101 (28.4%) patients were confirmed to have M. tuberculosis. There were 113 (31.8%) sputum positive for Candida spp., which corresponded to 149 Candida spp. isolates. Candida albicans was the most frequent (53.7%) species isolated from all patients. The susceptibility of Candida spp. against fluconazole, itraconazole, and ketoconazole were 38.3%, 1.3%, and 10.7% respectively. There was significant association between rifampicin exposure history and susceptibility of Candida albicans against fluconazole (Odds Ratio: 9.96; 95% CI: 1.83-54.19; p <0.01), but not for ketoconazole and itraconazole. The checkerboard microdilution assays showed that rifampicin decreased the fungicidal activity of fluconazole to C. albicans in a dose-dependent manner. CONCLUSION There was high frequency of azole resistant Candida spp. isolates colonizing the respiratory tract of presumptive MDR-TB patients. This presence might indicate the association of chronic exposure to rifampicin, the main drug for tuberculosis therapy, with the induction of azole resistance.
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Efficacy of a paclitaxel-eluting biliary metal stent with sodium caprate in malignant biliary obstruction: a prospective randomized comparative study.
Jang, SI, Lee, KT, Choi, JS, Jeong, S, Lee, DH, Kim, YT, Lee, SH, Yu, JS, Lee, DK
Endoscopy. 2019;(9):843-851
Abstract
BACKGROUNDS The placement of a self-expandable metal stent (SEMS) is widely used in patients with unresectable malignant biliary obstructions, but SEMSs are susceptible to occlusion by tumor ingrowth or overgrowth. The efficacy and safety of a novel paclitaxel-eluting biliary metal stent incorporating sodium caprate (MSCPM-III) were compared prospectively with those of a covered metal stent (CMS) in patients with malignant biliary obstructions. METHODS Patients with unresectable distal malignant biliary obstructions (n = 106) were prospectively enrolled in this study at multiple treatment centers. Stents were placed endoscopically: MSCPM-III in 54 patients and CMS in 51 patients. The patients received systemic chemotherapy regimens according to their disease characteristics. RESULTS The two groups did not differ significantly in basic characteristics or mean follow-up period. Stent occlusion occurred in 14 patients who received MSCPM-III and in 11 patients who received CMS. Time to recurrent biliary obstruction (RBO) and survival time did not differ significantly between the two groups (P = 0.84 and P = 0.29, respectively). However, tumor size at 2 months after stent insertion was significantly decreased in patients in the MSCPM-III group with bile duct cancers or those who experienced stent migration compared with the CMS group. Complications, including cholangitis and pancreatitis, were found to be acceptable in both groups. CONCLUSIONS Although compared with a CMS the MSCPM-III did not significantly influence time to RBO or survival duration in patients with malignant biliary obstructions, MSCPM-III reduced tumor volume and was used safely in humans.
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3.
[Inhibitory effect of diethylstilbestrol on clinical strains of Candida albicans susceptible and resistant to azoles].
Muthular, M, Passero, P, Bálsamo, F, Jewtuchowicz, V, Miozza, V, Brusca, MI, Pérez, C
Revista iberoamericana de micologia. 2019;(3):115-119
Abstract
BACKGROUND Candida albicans is a microorganism frequently involved in several infections; the patient's oral cavity, caries niches or periodontal disease can sometimes be the reservoir.. The fungal resistance to the available treatments, among other reasons, has led to the search for new antifungal alternatives. AIMS To carry out a comparative study of the in vitro effects of diethylstilboestrol (DES) and fluconazole (FLZ) on the growth of clinical strains of C. albicans. METHODS Seven strains of C. albicans were used: a) one FLZ-sensitive culture collection strain, ATCC 90028 (ATCC); b) four oral isolates from four oncological patients with periodontal disease (period 8, 9, 10, and 11); and c) two oral isolates from an AIDS patient with oropharyngeal candidiasis: one FLZ- sensitive (2-76), and another FLZ- resistant (12-99). The MIC was evaluated by standard spectrophotometric techniques using the CLSI (M27-A3) guidelines. The inhibitory concentration 50% (IC50) was calculated using functional analysis with the Graph Pad software. RESULTS DES inhibited the growth of all C. albicans strains, whether sensitive or resistant to FLZ. Experimental data fitted non-linear functions of inhibitor concentration versus response. Minimum inhibitory concentrations (MIC) for DES and FLZ were as follows: 28.18µg/ml and 4.90µg/ml (ATCC); 17.16µg/ml and 3.14µg/ml (period); 27.64µg/ml and 4.22µg/ml (2-76); 6.16µg/ml and 438.19µg/ml (12-99), respectively. CONCLUSIONS DES showed antifungal activity on all clinical C. albicans strains isolated from patients with dental and medical diseases. It showed the highest potency on the FLZ-resistant isolate.
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Triazole antifungal agents in invasive fungal infections: a comparative review.
Lass-Flörl, C
Drugs. 2011;(18):2405-19
Abstract
Invasive fungal disease continues to be a problem associated with significant morbidity and high mortality in immunocompromised and, to a lesser extent, immunocompetent individuals. Triazole antifungals have emerged as front-line drugs for the treatment and prophylaxis of many systemic mycoses. Fluconazole plays an excellent role in prophylaxis, empirical therapy, and the treatment of both superficial and invasive yeast fungal infections. Voriconazole is strongly recommended for pulmonary invasive aspergillosis. Posaconazole shows a very wide spectrum of activity and its primary clinical indications are as salvage therapy for patients with invasive aspergillosis and prophylaxis for patients with neutropenia and haematopoietic stem-cell transplant recipients. Itraconazole also has a role in the treatment of fungal skin and nail infections as well as dematiaceous fungi and endemic mycoses. Fluconazole and voriconazole are well absorbed and exhibit high oral bioavailability, whereas the oral bioavailability of itraconazole and posaconazole is lower and more variable. Posaconazole absorption depends on administration with a high-fat meal or nutritional supplements. Itraconazole and voriconazole undergo extensive hepatic metabolism involving the cytochrome P450 system. The therapeutic window for triazoles is narrow, and inattention to their pharmacokinetic properties can lead to drug levels too low for efficacy or too high for good tolerability or safety. This makes these agents prime candidates for therapeutic drug monitoring (TDM). Target drug concentrations for voriconazole and itraconazole should be >1 μg/mL and for posaconazole >1.5 μg/mL for treatment. Blood should be drawn once the patient reaches steady state, which occurs after 5 and 7 days of triazole therapy. Routine TDM of fluconazole is not required given its highly favourable pharmacokinetic profile and wide therapeutic index. The aim of this review is to provide a brief update on the pharmacology, activity, clinical efficacy, safety and cost of triazole agents (itraconazole, fluconazole, voriconazole and posaconazole) and highlight the clinical implications of similarities and differences.
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Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers.
Krishna, G, Moton, A, Ma, L, Savant, I, Martinho, M, Seiberling, M, McLeod, J
Clinical therapeutics. 2009;(2):286-98
Abstract
BACKGROUND Like itraconazole and ketoconazole, posaconazole, a broad-spectrum oral triazole antifungal, inhibits the activity of the cytochrome P450 (CYP) isozyme 3A4. Midazolam, a short-acting benzodiazepine, is metabolized by CYP3A4. Potential drug interactions can be expected in patients who are concurrently receiving inhibitors and substrates of CYP3A4 (eg, ketoconazole, posaconazole) and benzodiazepines (eg, midazolam). Because of the potential for drug interactions, it is important to determine the effects of posaconazole on the pharmacokinetic properties of midazolam. OBJECTIVE The aim of this study was to compare the effects of oral administration of posaconazole versus ketoconazole on the pharmacokinetic properties of orally and intravenously administered midazolam. METHODS This Phase I, randomized, open-label, crossover study was conducted at Swiss Pharma Contract Ltd., Allschwil, Switzerland. Healthy volunteers were randomly assigned to 1 of 2 treatment arms. Arm 1 received posaconazole 200 mg BID for 7 days, posaconazole 400 mg BID for 7 days, no drugs during a 28-day washout, and ketoconazole 400 mg once daily for 7 days. Arm 2 received posaconazole and ketoconazole in the reverse order, with a 28-day washout between treatments. An oral/IV midazolam sequence (oral midazolam 2 mg and IV midazolam 0.4 mg) was administered on days -2/-1, 6/7, 13/14 (arm 1), 36/17 (arm 2), 43/44, and 50/51 in both treatment arms. Blood samples were collected up to 24 hours after midazolam administration. Pharmacokinetic parameters, including C(max), C(min) (before azole administration), terminal-phase t(1/2) (t(1/2z)), and AUC to final measurable sampling time (AUC(tf)), were calculated using noncompartmental methods, and drug interactions were evaluated using analysis of variance. Adverse events were collected using physical examination, including vital sign measurements; clinical laboratory analysis; electrocardiography; and direct questioning at predefined time points throughout the study to assess tolerability. RESULTS A total of 12 subjects were enrolled (11 men, 1 woman; all white; mean age, 42.8 years [range, 28-53 years]; mean weight, 80.6 kg; and mean body mass index, 25.6 kg/m(2)). All of the subjects completed the study. Based on point estimates of logarithm-transformed data, posaconazole 200 and 400 mg BID were associated with significant increases in midazolam C(max) (up to 1.3- and 2.4-fold) and AUC(tf) values (up to 4.6- and 6.2-fold), respectively. Ketoconazole 400 mg once daily was associated with significantly increased midazolam C(max) and AUC(tf) (up to 2.8- and 8.2-fold, respectively). When midazolam was concurrently administered with either azole, t(1/2z) was prolonged. Seven of 12 (58%) subjects reported > or =1 adverse event during the study (5 with posaconazole alone and 4 with posaconazole + midazolam). The most common adverse events were diarrhea (3 subjects [25%] with posaconazole alone, 2 [17%] with ketoconazole alone, and 1 [8%] with posaconazole + midazolam) and flatulence (1 [8%] with posaconazole alone and 1 [8%] with midazolam alone). CONCLUSIONS The results from this study in a small, all-white population of healthy volunteers suggest that posaconazole was a potent inhibitor of CYP3A4, but to a lesser extent than was ketoconazole. Monitoring patients for adverse events, the need for dose adjustments, or both during coadministration with posaconazole may be warranted in patients being treated with benzodiazepines that are predominantly metabolized through CYP3A4 (eg, midazolam).
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[In vitro activity of anidulafungin. Comparison with the activity of other echinocandins].
Martín Mazuelos, E, Rodríguez-Tudela, JL
Enfermedades infecciosas y microbiologia clinica. 2008;:7-13
Abstract
Anidulafungin is a new echinocandin that acts by inhibiting (1,3)-beta-D-glucan synthesis in the fungal cell wall. This agent is a semisynthetic lipopeptide synthesized from a fermentation product of Aspergillus nidulans. The spectrum of activity of anidulafungin includes Candida and Aspergillus, the two main etiological agents causing invasive fungal infections. This drug is also active against strains of these genera resistant to azoles or amphotericin B. However, anidulafungin is not active against Cryptococcus spp., Trichosporon spp., Fusarium spp. or Mucorales spp. Data on the activity of this drug against other species are limited and do not allow conclusions to be drawn or recommendations to be made. Echinocandin resistance is uncommon and has little clinical relevance.
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Evaluation and treatment of oral candidiasis in HIV/AIDS patients in Enugu, Nigeria.
Oji, C, Chukwuneke, F
Oral and maxillofacial surgery. 2008;(2):67-71
Abstract
INTRODUCTION Oral candidiasis is one of the common diseases seen in HIV/AIDS patients. It is rare if CD4+ cell counts are above 500 microl. Outbreaks are more common as the count drops to 100 microl. It may be more difficult to treat when CD4+ cell counts fall below 50 microl. MATERIALS AND METHODS A retrospective review of 112 HIV/AIDS patients with lesions in the mouth, head, and neck seen at the oral and maxillofacial surgery units of two public hospitals in eastern Nigeria was carried out between 2000 and 2003. The focus was on oral candidiasis patients. Twenty-nine of these patients, made up of 11 males and 18 females, had oral candidiasis. To compare the action of two drugs, namely, nystatin (a topical antifungal drug) and ketoconazole (a systemic antifungal drug), we treated 15 of the patients with nystatin in the first 2 years and the remaining 14 with ketoconazole in the following 2 years. RESULTS AND DISCUSSION Amongst the 15 patients treated with topical drugs, 7 (46.7%) had complete remission, 2 (13.3%) had partial response, 4 (26.7%) remained stationary, and 2 (13.3%) died. Out of the 14 cases treated with systemic drugs, 11 (78.6%) had complete remission, 2 (14.3%) had partial response, and 1 (7.1%) died.
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Phenotypic heterogeneity can enhance rare-cell survival in 'stress-sensitive' yeast populations.
Bishop, AL, Rab, FA, Sumner, ER, Avery, SV
Molecular microbiology. 2007;(2):507-20
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Abstract
Individual cells within isogenic microbial cultures exhibit phenotypic heterogeneity, an issue that is attracting intense interest. Heterogeneity could confer benefits, in generating variant subpopulations that may be better equipped to persist during perturbation. We tested this hypothesis by comparing the survival of wild-type Saccharomyces cerevisiae with that of mutants which are considered stress-sensitive but which, we demonstrate, also have increased heterogeneity. The mutants (e.g. vma3, ctr1, sod1) exhibited the anticipated sensitivities to intermediate doses of nickel, copper, alkaline pH, menadione or paraquat. However, enhanced heterogeneity meant that the resistances of individual mutant cells spanned a broad range, and at high stress occasional-cell survival in most of these populations overtook that of the wild type. Green fluorescent protein (GFP) reporter studies showed that this heterogeneity-dependent advantage was not related to perturbation of buffered gene expression. Deletion strain screens combined with other approaches revealed that vacuolar alkalinization resulting from loss of Vma-dependent vacuolar H(+)-ATPase activity was not the cause of vma mutants' net stress sensitivities. An alternative Vma-dependent resistance mechanism was found to suppress an influence of variable vacuolar pH on the metal resistances of individual wild-type cells. In addition to revealing new mechanisms of heterogeneity generation, the results demonstrate experimentally a benefit under adverse conditions that arises specifically from heterogeneity, and in populations conventionally considered to be disadvantaged.
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DNA fingerprinting pattern and susceptibility to antifungal drugs in Cryptococcus neoformans variety grubii isolates from Barcelona city and rural environmental samples.
Morera-López, Y, Torres-Rodríguez, JM, Jiménez-Cabello, T, Baró-Tomás, T, Alía-Aponte, C, Lázera, MS
Mycopathologia. 2005;(1):9-14
Abstract
Cryptococcus neoformans var. grubii (serotype A) was isolated from 12 soil samples mixed with pigeon droppings (16.9%) from 71 soil samples in Barcelona and rural areas of Catalonia. C. neoformans was not isolated from indoor dust and Eucalyptus debris. PCR fingerprinting was performed in 22 representative isolates and all of them corresponded to the VNI pattern. Susceptibility testing for the 22 isolates of C. neoformans var. grubii showed that all of them were susceptible to amphotericin B. Three isolates presented MICs (Minimal Inhibitory Concentrations) > or = 1 microg/ml to Itraconazole, five MICs > or = 1 microg/ml to ketoconazole and four were fluconazole resistant, (MICs > or = 64 microg/ml), while three of them were shown to have MICs > or = 1 microg/ml to voriconazole. In spite that all isolates presented the same DNA fingerprinting pattern, the susceptibility to antifungals is very variable. The possibility of acquiring cryptococcosis infection with primarily resistant environment strains is feasible.
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Rationale of frequency of use of ciclopirox 1% shampoo in the treatment of seborrheic dermatitis: results of a double-blind, placebo-controlled study comparing the efficacy of once, twice, and three times weekly usage.
Abeck, D, ,
International journal of dermatology. 2004;:13-6
Abstract
BACKGROUND Seborrheic dermatitis is a common inflammatory skin disorder. Although the precise etiology of seborrheic dermatitis is uncertain, yeasts of the genus Malassezia have been implicated. Ciclopirox is a broad-spectrum, hydroxypyridone-derived, synthetic antifungal agent with anti-inflammatory properties. METHODS A total of 183 patients were enrolled in this randomized, parallel-group, double-blind, vehicle-controlled trial designed to compare three different application frequencies of ciclopirox 1% shampoo: once, twice, and three times weekly. The main efficacy parameters were based on 6-point ordinal scales describing the disease's signs and symptoms (scaling, inflammation and itching), global status of seborrheic dermatitis, and global change of seborrheic dermatitis. RESULTS Each application frequency of ciclopirox 1% shampoo was found to significantly improve the signs and symptoms of seborrheic dermatitis of the scalp after 4 weeks of treatment. Furthermore, the therapeutic index calculated from the global change in seborrheic dermatitis score increased with increasing application frequency; therapeutic index scores increased from vehicle (1.25) to ciclopirox 1% once (3.30), twice (3.50), and three times (3.56) weekly. No serious adverse events were recorded during the course of the study. CONCLUSIONS Ciclopirox 1% shampoo, applied once, twice or three times weekly, is a safe and acceptable preparation that improves seborrheic dermatitis of the scalp, suggesting that this is an alternative treatment for this indication.