The concentration-dependent nature of in vitro amphotericin B-itraconazole interaction against Aspergillus fumigatus: isobolographic and response surface analysis of complex pharmacodynamic interactions.

Item does not contain fulltextThe interaction between polyenes and azoles is not well understood. We therefore explored the in vitro combination of amphotericin B with itraconazole against 14 clinical Aspergillus fumigatus isolates (9 itraconazole susceptible and 5 itraconazole resistant) with a colorimetric broth microdilution checkerboard technique using two drug interaction models able to explore complicated patterns of interactions: the response surface analysis of Bliss independence and the isobolographic analysis of Loewe additivity zero interaction theories. Synergy was found at combinations with low concentrations of amphotericin B (0.5 mg/L). Synergy was more frequently observed for the itraconazole-resistant isolates than for the itraconazole-susceptible isolates

Safety and Tolerability of Fesoterodine in Older Adult Patients with Overactive Bladder

BackgroundOlder patients (> 65 yr) suffering from overactive bladder (OAB) are more likely to have functional impairment and comorbidity than those without OAB. This article reviews available published studies and discusses how fesoterodine might meet the specific needs of the older OAB patient.MethodsA comprehensive literature search was undertaken in order to evaluate fesoterodine safety in older OAB patients.ResultsFesoterodine offers flexible dosing, allowing the clinician to balance risk and benefits according to the symptoms and preferences of the patient. Its balanced affinity for M2 and M3 muscarinic receptors may lead to its benefit on OAB symptoms. Its active metabolite is a P-gp substrate that is actively transported from the central nervous system (CNS), potentially avoiding adverse CNS effects. Fesoterodine can be used in mild or moderate hepatic or renal insufficiency and no dose adjustment is routinely required. Fesoterodine's benefit has been demonstrated in multiple clinical trials in older and medically vulnerable patients. Fesoterodine was rated as "beneficial" in the LUTS-FORTA classification due to its efficiency and tolerability in older patients.ConclusionHere, the use of fesoterodine in older and vulnerable patients is summarized given the need to approach pharmacotherapy for OAB differently in older adults

Safety and Tolerability of Fesoterodine in Older Adult Patients with Overactive Bladder

BACKGROUND: Older patients (> 65 yr) suffering from overactive bladder (OAB) are more likely to have functional impairment and comorbidity than those without OAB. This article reviews available published studies and discusses how fesoterodine might meet the specific needs of the older OAB patient. METHODS: A comprehensive literature search was undertaken in order to evaluate fesoterodine safety in older OAB patients. RESULTS: Fesoterodine offers flexible dosing, allowing the clinician to balance risk and benefits according to the symptoms and preferences of the patient. Its balanced affinity for M2 and M3 muscarinic receptors may lead to its benefit on OAB symptoms. Its active metabolite is a P-gp substrate that is actively transported from the central nervous system (CNS), potentially avoiding adverse CNS effects. Fesoterodine can be used in mild or moderate hepatic or renal insufficiency and no dose adjustment is routinely required. Fesoterodine’s benefit has been demonstrated in multiple clinical trials in older and medically vulnerable patients. Fesoterodine was rated as “beneficial” in the LUTS-FORTA classification due to its efficiency and tolerability in older patients. CONCLUSION: Here, the use of fesoterodine in older and vulnerable patients is summarized given the need to approach pharmacotherapy for OAB differently in older adults

A colorimetric and spectrophotometric method for in vitro susceptibility testing of Aspergillus species against caspofungin.

The in vitro susceptibility of 45 Aspergillus fumigatus, Aspergillus flavus and Aspergillus terreus isolates against caspofungin (CAS) was assessed by the CLSI reference method with spectrophotometric reading and by a colorimetric method that employed the dye MTT. Perfect agreement was found between the minimal effective concentrations (MECs) and the MIC-2 values (50% growth reduction) obtained by the MTT method. The agreement found between the MICs obtained by the CLSI and the MTT method was dependent on the MIC endpoint used, the antifungal agent tested, and the species investigated

The European multistakeholder PanCareFollowUp project: novel, person-centred survivorship care to improve care quality, effectiveness, cost-effectiveness and accessibility for cancer survivors and caregivers

Background: The majority of childhood cancer survivors are at risk of treatment-related adverse health outcomes. Survivorship care to mitigate these late effects is endorsed, but it is not available for many adult survivors of childhood cancer in Europe. The PanCareFollowUp project was initiated to improve their health and quality of life (QoL) by facilitating person-centred survivorship care. Methods: The PanCareFollowUp consortium was established in 2018, consisting of 14 project partners from ten European countries, including survivor representatives. The consortium will develop two PanCareFollowUp Interventions, including a person-centred guideline–based model of care (Care Intervention) and eHealth lifestyle coaching (Lifestyle Intervention). Their development will be informed by several qualitative studies and systematic reviews on barriers and facilitators for implementation and needs and preferences of healthcare providers (HCPs) and survivors. Implementation of the PanCareFollowUp Care Intervention as usual care will be evaluated prospectively among 800 survivors from Belgium, Czech Republic, Italy and Sweden for survivor empowerment, detection of adverse health conditions, satisfaction among survivors and HCPs, cost-effectiveness and feasibility. The feasibility of the PanCareFollowUp Lifestyle Intervention will be evaluated in the Netherlands among 60 survivors. Results: Replication manuals, allowing for replication of the PanCareFollowUp Care and Lifestyle Intervention, will be published and made freely available after the project. Moreover, results of the corresponding studies are expected within the next five years. Conclusions: The PanCareFollowUp project is a novel European collaboration aiming to improve the health and QoL of all survivors across Europe by developing and prospectively evaluating the person-centred PanCareFollowUp Care and Lifestyle Interventions. © 2021 Elsevier Lt

Real-life patient experiences of TTNS in the treatment of overactive bladder syndrome

INTRODUCTION AND OBJECTIVES: Overactive bladder syndrome (OAB) is defined as urinary urgency, with or without urgent urinary incontinence; it is often associated with urinary frequency and nocturia, in the absence of any pathological or metabolic conditions that may cause or mimic OAB. The aim of this study was to evaluate the long-term real-life adherence of transcutaneous tibial nerve stimulation (TTNS) in the treatment of OAB, patient satisfaction of the treatment, and reasons for quitting therapy. MATERIALS AND METHODS: In this single center study, all patients who had a positive effect on percutaneous tibial nerve stimulation (PTNS) and continued to receive home-based treatment with TTNS since 2012 were included for analysis. Patients were retrospectively asked to fill out a questionnaire regarding satisfaction, reasons for quitting, and additional or next line of therapy. RESULTS: We included 42 patients for this study, 81% of these patients were female (n = 34). The median age was 67 years (range 36–86). Most of the patients (64%, n = 27) were diagnosed with OAB wet. The median TTNS treatment persistence was 16 months (range 1–112 months). Reasons and percentages for stopping therapy were: 55% stopped treatment due to loss of effect, and 24% stopped because of preferring other type of neuromodulation. The mean satisfaction score (scale 1–10) in patients who continued TTNS was 6.2 (n = 9, SD 1.30) versus 5.4 (n = 29, SD 2.24) for patients who quit therapy. We did not find a statistically significant difference between the two groups (p = 0.174). CONCLUSION: TTNS, although effective in the short-term, is not effective in the long-term. In combination with a low satisfaction rate among patients, there is a need for improvement in terms of OAB treatment modalities

Efficacy and Pharmacodynamics of Flucytosine Monotherapy in a Nonneutropenic Murine Model of Invasive Aspergillosis

The therapeutic efficacy of flucytosine (5FC) monotherapy and the pharmacodynamic index predictive of efficacy were evaluated in a nonneutropenic mouse model of acute invasive aspergillosis. Mice were infected intravenously with an Aspergillus fumigatus isolate (the median MICs of 5FC were 128 μg/ml under the standard condition, 0.5 μg/ml at pH 6.0, and 0.031 μg/ml at pH 5.0) 2 h prior to the start of therapy and were treated for 7 days with different 5FC dosing regimens. The total doses ranged from 50 to 800 mg/kg of body weight/day and were administered at 6-, 12-, and 24-h intervals. The efficacy was assessed by means of survival. The survival rates of the treatment groups ranged from 40 to 90%, while the survival rate of the control group was 20%. The efficacy found depended primarily on the total daily dose. However, the power of our sample size may have been too low to exclude an effect of dose fractionation. The pharmacodynamic index that most strongly correlated with the efficacy was the area under the serum concentration-time curve and MIC ratio (R(2) = 0.86). We conclude that 5FC monotherapy is efficacious in a murine Aspergillus fumigatus infection model

Relationship between In Vitro Activities of Amphotericin B and Flucytosine and pH for Clinical Yeast and Mold Isolates

In this study, we investigated the pH dependency of the in vitro activities of amphotericin B (AMB) and flucytosine (5FC) against Candida spp., Cryptococcus neoformans, Aspergillus fumigatus, Rhizopus spp., and Scedosporium prolificans in RPMI 1640 buffered with citrate buffer (pH 4.0, 5.0, 5.4, and 6.0), citrate-phosphate buffer (pH 5.4, 6.0, 6.4, and 7.0), and 3-[N-morpholino]propanesulfonic acid (MOPS) (pH 6.4, 7.0, 7.4, and 7.9). For 5FC, no significant differences were found between MICs obtained with the different buffers, while for AMB, significant differences were found. The MICs obtained with citrate-phosphate buffer were approximately 1 twofold-dilution step higher than the MICs obtained with MOPS. We demonstrated that the in vitro activities of AMB and 5FC against yeast and mold isolates were pH dependent. The in vitro activity of AMB decreased when the pH was lowered, while the in vitro activity of 5FC increased. The effect of the pH on the in vitro activities was dependent not only on the antifungal agent tested but also on the microorganism. For AMB, there was a nonlinear relationship (median r(2), 0.864) for Candida spp., C. neoformans, A. fumigatus, and Rhizopus spp. over the pH range tested. The mean MICs ranged from 0.5 to 2.52 μg/ml at pH 7.0 and from 20.16 to 32 μg/ml at pH 5.0. For S. prolificans, there was no relationship. For 5FC, there was a linear relationship for Candida spp. (median r(2), 0.767) and a nonlinear relationship for C. neoformans and A. fumigatus (median r(2), 0.882) over the pH range tested. The mean MIC values ranged from 0.125 to 1,024 μg/ml at pH 7.0 and from 0.02 to 4 μg/ml at pH 5.0. For Rhizopus spp. and S. prolificans, the relationship could not be determined, since the MIC was >1,024 μg/ml over a pH range of 4.0 to 7.9

Comparison of Fractional Inhibitory Concentration Index with Response Surface Modeling for Characterization of In Vitro Interaction of Antifungals against Itraconazole-Susceptible and -Resistant Aspergillus fumigatus Isolates

Although the fractional inhibitory concentration (FIC) index is most frequently used to define or to describe drug interactions, it has some important disadvantages when used for drugs against filamentous fungi. This includes observer bias in the determination of the MIC and no agreement on the endpoints (MIC-0, MIC-1, or MIC-2 [≥95, ≥75, and ≥50% growth inhibition, respectively]) when studying drug combinations. Furthermore, statistical analysis and comparisons are troublesome. The use of a spectrophotometric method to determine the effect of drug combinations yields quantitative data and permits the use of model fits to the whole response surface. We applied the response surface model described by Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol. Rev. 47:331-385, 1995) to determine the interaction coefficient alpha (ICα) using a program developed for that purpose and compared the results with FIC indices. The susceptibilities of amphotericin B (AM), itraconazole (IT), and terbinafine (TB) were tested either alone or in combination against 10 IT-susceptible (IT-S) and 5 IT-resistant (IT-R) clinical strains of Aspergillus fumigatus using a modified checkerboard microdilution method that employs the dye MTT [3-(4,5-dimethyl-2-thiazyl)2,5-diphenyl-2H-tetrazolium bromide]. Growth in each well was determined by a spectrophotometer. FIC indices were determined and ICα values were estimated for each organism strain combination, and the latter included error estimates. Depending on the MIC endpoint used, the FIC index ranged from 1.016 to 2.077 for AM-IT, from 0.544 to 1.767 for AM-TB, and from 0.656 to 0.740 for IT-TB for the IT-S strains. For the IT-R strains the FIC index ranged from 0.308 to 1.767 for AM-IT, from 0.512 to 1.646 for AM-TB, and from 0.403 to 0.497 for IT-TB. The results indicate that the degree of interaction is not only determined by the agents themselves but also by the choice of the endpoint. Estimates of the ICα values showed more consistent results. Although the absolute FIC indices were difficult to interpret, there was a good correlation with the results obtained using the ICα values. The combination of AM with either IT or TB was antagonistic in vitro, whereas the combination of IT and TB was synergistic in vitro for both IT-S and IT-R strains. The use of response surface modeling to determine the interaction of drugs against filamentous fungi is promising, and more consistent results are obtained by this method than by using FIC indices