Use Of Fluconazole Research Articles

Clinical Outcome of Fungal Keratitis after Topical use of Injectable Fluconazole

Objectives: To evaluate the clinical outcome of fungal keratitis after topical use of injectable Fluconazole. Materials and Methods: This cross sectional study was conducted in the Department of ophthalmology in Nishtar Medical University, Multan and the duration of this study were from January 2022 to June 2022. Totally 100 patients who were suffering from fungal keratitis were enrolled. The enrolled patients were given topical 2% Fluconazole using Injectable fluconazole 2mg/ml and making it to 2% topical solution. They were also added topical 1% Atropine, lubricant and Cyclosporin A 0.05% was used for corneal melting. Patients were followed after 1 week and 1 month. A predesign questionnaire was used to collect data. Results: Out of total 100 patients, 79 were male and 21 were female with mean age of 38.70 ±9.41 years. The most common age group was 20-35 years and 36-50 years, followed by >50 years of age group. Out of total patients, 69 (69.0%) patients had full recovery of appreciable vision, quality of life and pain related complaints. 30 (30%) patients had no improvement in vision. 1 (1%) patient had worsening of keratitis. Practical implication: This study suggest that topical use of injectable fluconazole is a safe and effective antifungal drug for the treatment of fungal keratitis. So this study will help the ophthalmologist to select better treatment option in order to recover the patients at time. Conclusion: It is concluded that Fluconazole in the form of injection can be a very useful treatment for severe fungal keratitis. Keywords: Fluconazole, Fungal Keratitis, Topical, Injectable, Ophthalmology, Sight-Threatening,

Study on the mechanisms of action of berberine combined with fluconazole against fluconazole-resistant strains of Talaromyces marneffei

Talaromyces (Penicillium) marneffei (T. marneffei) is a thermally dimorphic fungus that can cause opportunistic systemic mycoses. Our previous study demonstrated that concomitant use of berberine (BBR) and fluconazole (FLC) showed a synergistic action against FLC-resistant T. marneffei (B4) in vitro. In this paper, we tried to figure out the antifungal mechanisms of BBR and FLC in T. marneffei FLC-resistant. In the microdilution test, the minimum inhibitory concentration (MIC) of FLC was 256 μg/ml before FLC and BBR combination, and was 8 μg/ml after combination, the partial inhibitory concentration index (FICI) of B4 was 0.28. After the treatments of BBR and FLC, the studies revealed that (i) increase reactive oxygen species (ROS), (ii) reduce ergosterol content, (iii) destroy the integrity of cell wall and membrane, (iv) decrease the expression of genes AtrF, MDR1, PMFCZ, and Cyp51B however ABC1 and MFS change are not obvious. These results confirmed that BBR has antifungal effect on T. marneffei, and the combination with FLC can restore the susceptibility of FLC-resistant strains to FLC, and the reduction of ergosterol content and the down-regulation of gene expression of AtrF, Mdr1, PMFCZ, and Cyp51B are the mechanisms of the antifungal effect after the combination, which provides a theoretical basis for the application of BBR in the treatment of Talaromycosis and opens up new ideas for treatment of Talaromycosis.

Impact of concomitant fluconazole on direct oral anticoagulant bleeding risk.

The aim of this study was to evaluate the effect on bleeding risk when fluconazole is administered concomitantly with direct oral anticoagulants (DOACs). This was a retrospective cohort study including hospitalized adult patients prescribed a DOAC with or without fluconazole. The Ohio State University Wexner Medical Center, a tertiary care academic medical center with more than 1800 beds. Hospitalized patients ages 18-89 years who received apixaban or rivaroxaban with or without fluconazole from October 1, 2016, to September 30, 2021, were included. The minimum duration of DOAC or DOAC with fluconazole therapy was 48h. Patients were excluded if they received fluconazole <400 mg daily or a DOAC at doses outside those recommended for atrial fibrillation or venous thromboembolism treatment or prophylaxis. Patients were matched based on DOAC received. Patients who received a DOAC with fluconazole were compared with those receiving a DOAC alone. The primary outcome was a composite of major, clinically relevant nonmajor, and minor bleeding events at 30 days. There were 216 patients included, 108 in the DOAC with fluconazole group and 108 in the DOAC alone group. More patients in the DOAC with fluconazole group experienced bleeding at 30 days compared with the DOAC alone group [35/108 (32%) vs. 21/108 (19%), respectively; p=0.03]; however, after adjusting for proven confounding variables (hemoglobin and concomitant carvedilol) this was found not to be statistically significant [adjusted odds ratio 1.71, 95% confidence interval 0.85-3.40]. Patients receiving a DOAC with fluconazole were not at significantly increased risk for bleeding at 30 days compared with those receiving a DOAC alone after controlling for confounding variables. As an increasing number of patients are prescribed DOACs, the results of this study may inform clinical decision-making on the safety of concomitant DOAC and fluconazole use.

Population pharmacokinetics of everolimus in adult liver transplant patients: Comparison to tacrolimus disposition and extrapolation to pediatrics.

Everolimus has recently been used to prevent graft rejection in liver transplantation and reduces the incidence of kidney dysfunction caused by calcineurin inhibitors. In this study, a population pharmacokinetic analysis was conducted to improve the individualization of everolimus therapy. Japanese post-liver transplant patients whose blood everolimus concentrations were measured between March 2018 and December 2020 were included in this study. A nonlinear mixed-effect modeling program was used to explore covariates that affect everolimus pharmacokinetics. Individual everolimus pharmacokinetic parameters estimated by the post-hoc Bayesian analysis using the final model were compared with the tacrolimus dose per trough concentration (D/C) ratio in each patient. The final model was extrapolated to pediatric liver transplant patients for external evaluation. A total of 937 concentrations from 87 adult patients were used in the model-building process. Everolimus clearance was significantly affected by the estimated glomerular filtration rate, concomitant use of fluconazole, sex, as well as total daily dose of everolimus (TDM effect). The estimated individual apparent clearance of everolimus by the post-hoc Bayesian analysis was moderately correlated with the D/C ratio of tacrolimus in each patient (R2 =0.330, p < 0.0001). The estimation accuracy in pediatric patients was considerably high, except for one infant out of 13 patients. In conclusion, population pharmacokinetic analysis clarified several significant covariates for everolimus pharmacokinetics in liver transplant patients. Everolimus pharmacokinetics moderately correlated with tacrolimus pharmacokinetics and could be extrapolated from adult to pediatric patients by body size correction, except for infants.

Iatrogenic Cushing's syndrome with secondary adrenal insufficiency due to concomitant use of chronic intranasal steroids and fluconazole - a dangerous combination

Iatrogenic Cushing's syndrome with secondary adrenal insufficiency due to concomitant use of chronic intranasal steroids and fluconazole - a dangerous combination

Fluconazole in hypercalciuric patients with increased 1,25(OH)2D levels: the prospective, randomized, placebo-controlled, double-blind FLUCOLITH trial

BackgroundHypercalciuria is one of the most frequent metabolic disorders associated with nephrolithiasis and/or nephrocalcinosis possibly leading to chronic kidney disease (CKD) and bone complications in adults. Orphan diseases with different underlying primary pathophysiology share inappropriately increased 1,25(OH)2D levels and hypercalciuria, e.g., hypersensitivity to vitamin D and renal phosphate wasting. Their management is challenging, typically based on hyperhydration and dietary advice.The antifungal azoles are known to inhibit the 1α-hydroxylase and therefore decrease 1,25(OH)2D levels; they are commonly used, with well described pharmacokinetic and tolerability data. Fluconazole has been successfully reported to reduce calciuria in patients with CYP24A1 or SLC34A3 mutations, with no safety warnings. Thus, based on these case reports, we hypothesize that fluconazole is effective to decrease and normalize calciuria in patients with hypercalciuria and increased 1,25(OH)2D levels.MethodsThe FLUCOLITH trial is a prospective, interventional, randomized in parallel groups (1:1), placebo-controlled, double-blind trial. A total of 60 patients (10–60 years) with nephrolithiasis and/or nephrocalcinosis history, hypercalciuria (> 0.1 mmol/kg/day), increased 1,25(OH)2D levels (> 150 pmol/L), and 25-OH-D levels >20 nmol/L will be included. Inclusions will be performed only from mid-September to the beginning of February to avoid bias due to sunlight-induced vitamin D synthesis. The primary endpoint will be the proportion of patients with normalization of 24-h calciuria between baseline and 16 weeks, or with a relative decrease of at least 30% of 24-h calciuria in patients who still display at W16 a 24-h hypercalciuria.DiscussionThe current challenge is to propose an efficient treatment to patients with hypercalciuria and increased 1,25(OH)2D levels in order to prevent later complications and notably CKD that can ultimately lead to end-stage renal disease. Based on improvement of knowledge in phosphate/calcium metabolism, pathophysiology and genetics, the “off-label” use of fluconazole was recently reported to be useful in hypercalciuric patients with increased 1,25(OH)2D levels. Thus, the FLUCOLITH study is a unique opportunity to develop a new indication of a well-known and not expensive drug in orphan renal diseases, the ultimate objective being the secondary prevention of CKD worsening in these patients.Trial registrationClinicalTrials.gov NCT04495608. Registered on July 23, 2020.

The use of fluconazole in the treatment of superficial fungal infections- A meta-analysis

The study evaluated the efficacy of the once-weekly dose of oral fluconazole 150 mg therapy in dermatophytosis in comparison to placebo or comparator in the adult patient. A systematic literature search was conducted to identify relevant studies published from 2011 until March 2021. Two reviewers independently abstracted data and assessed study quality. Oral fluconazole 150 mg tablet per week is effective in reducing dermatophytosis after 4 weeks (OR 0.14 95% Cl -1.81-1.82). The heterogenicity test shows no substantial changes between the two studies included in the meta-analysis (Chi=2.36, df=1, I=56.68%; P=0.124). Weekly treatment of fluconazole 150 mg by oral route for 4 weeks is effective against dermatophytosis.

Trends in Systemic Antifungal Use in Australia, 2005–2016: a Time-Series Analysis

Data on antifungal utilization trends are important for encouraging antifungal stewardship. This study explored the use of antifungal agents for systemic application and the impact of reimbursement policy changes in Australia. We analyzed national data from the Australian Pharmaceutical Benefits Scheme (PBS) (2005-2016) and determined patterns of use over time and the impact of reimbursement decisions using an interrupted time-series model. From 2005-2016, there was an increase in the use of most antifungals, especially fluconazole, itraconazole, and posaconazole. Ketoconazole was the most commonly dispensed systemic antifungal agent (46.0%) prior to being removed from the PBS list and being replaced by fluconazole (69.8%). The PBS event "Fluconazole and itraconazole restrictions eased" led to the immediate increased use of fluconazole (0.025/1,000 per day), with both the highest rates and numerical increases attributed to obstetricians and gynecologists (1,969%; 1,851 dispensed prescriptions), as well as dermatologists (1,723%; 1,689 dispensed prescriptions) in 2010 and 2016. This is the first Australian national longitudinal estimate of systemic antifungal use. Our findings show an overall increase in the prescription of most antifungals during the investigated period, with reimbursement decisions impacting utilization. These data provide a baseline to inform the development of national antifungal guidelines and policies to encourage more targeted antifungal stewardship.

Ibrexafungerp in the Treatment of Vulvovaginal Candidiasis.

To review the pharmacology, efficacy, and safety of ibrexafungerp in the management of vulvovaginal candidiasis (VVC). Literature was sought using PubMed (1966-February 2022) and EMBASE (1973-February 2022), and clinicaltrials.gov. Search terms included ibrexafungerp, SCY-078, and VVC. All studies including humans and published in English with data assessing the efficacy and safety of ibrexafungerp for the treatment of VVC were evaluated. A phase 2 dose-finding study found ibrexafungerp had similar efficacy to fluconazole in the clinical cure of VVC (51.9% vs 58.3%, respectively). Two phase 3 clinical trials demonstrated ibrexafungerp had statistical superiority over placebo for clinical cure in moderate to severe VVC (P < 0.001 and P = 0.023, respectively). The most frequently reported adverse reactions in the clinical trials were gastrointestinal-related symptoms. To date, data comparing efficacy of ibrexafungerp and topical imidazoles in the treatment of VVC are nonexistent. Topical imidazoles and oral fluconazole are effective for the treatment of uncomplicated VVC. Due to increased resistance, limited fluconazole coverage for non-Candida albicans species, and potential for significant drug interactions associated with fluconazole use, alternative treatments for VVC are needed. Ibrexafungerp is a new oral triterpenoid antifungal agent indicated for the treatment of VVC. Additional clinical trials are needed to evaluate long-term safety data as well as efficacy and safety in specialty populations. Ibrexafungerp, a recently approved triterpenoid antifungal agent, is an effective and well-tolerated option for the treatment of VVC.

Invasive candidiasis in Africa, what is the current picture?

Invasive candidiasis is a serious, progressive, and potentially deadly infection that can affect the brain, heart, bones, eyes, and other parts of the body. It is associated with risk factors such as the use of indwelling medical devices, prolonged hospital stay, and broad-spectrum antibiotics use. It is especially seen in immunocompromised individuals such as patients with prolonged hospital stay, gastrointestinal surgery, haematological malignancies, and respiratory diseases. We have conducted a systematic search of literature using a select group of databases and appropriate search words and found that in Africa, there are 18293 documented/reported cases of invasive candidiasis in the last few decades (1976-2021) and 16636(91%) were cases of candidaemia. South Africa had the highest number of reported cases-15002(82%), which may be due to underreporting of cases in other countries. HIV positive persons with invasive candidiasis in Africa accounted for 1 052(5.8%). Candida albicans was the most frequently isolated species 6 328(32.6%), followed by Candida parapsilosis 5 910(30.4%), and Candida auris 1 505(7.8%). Due to the affordability and availability of blood culture, it was used for diagnosis in most of the studies examined, while a few studies combined other techniques and just three studies from two countries used serological tests. Echinocandins are recommended as first-line therapy but are only available in 12 countries and are highly priced. The use of fluconazole, because of its availability and relatively inexpensive nature, has led to increased resistance of Candida species to the drug.

External Evaluation of a Single Center Precision Tacrolimus Dosing Model for Pediatric Heart Transplant

<h3>Purpose</h3> Extensive variability in tacrolimus pharmacokinetics (PK) influences attainment of therapeutic immunosuppression following pediatric heart transplant. Population PK (popPK) model-based personalized dosing of tacrolimus can reduce the need for tacrolimus titration and improve long-term pediatric heart transplant outcomes. The objective of this study was to externally evaluate a previously described single-center popPK model for personalized tacrolimus therapy. <h3>Methods</h3> A multicenter, retrospective analysis utilized demographics, tacrolimus dosing and concentration data, and laboratory values collected from pediatric inpatients during the first 6 weeks post-transplant, or until discharge, from three sites. PopPK analysis used the modeling software NONMEM v7.2. Observed concentration data were compared to data simulated with our single-center popPK model, using median prediction error (MPE, a measure of bias, <15% acceptable) and median absolute prediction error (MAPE, a measure of accuracy, <30% acceptable). <h3>Results</h3> A total of 285 children: 115 female, 196 white, 32 black, were included. Median age and creatinine clearance were 9.1 years and 101 mL/min/1.73m², respectively. Fluconazole use was rare, occurring in only 6 subjects. When utilizing all data the MPE and MAPE (interquartile range) were acceptable, at -3% (-25%, 10%) and 18% (5%, 49%), respectively, and not different by institution. However, when allowed only 3 concentrations (i.e. the minimum number to adequately predict future concentrations in our prior single-center study) the model poorly predicted future concentrations at all sites (MPE=31%; MAPE=47%). MPE and MAPE varied by site, ranging from 7 to 61% and 30 to 63%, respectively. Including site as a covariate in the popPK model improved predictions (MPE=21%; MAPE=37%) and decreased variability in predictive ability between sites (MPE: 11 to 34%; MAPE: 32 to 45%). <h3>Conclusion</h3> Our single-center popPK model did not adequately predict tacrolimus concentrations from external institutions. Study site appears to drive some of the poor model performance. Future directions include identifying study site differences that influence model performance, as well as identifying additional patient-specific factors affecting tacrolimus dosing requirements.

Comparative Efficacy and Safety of Antifungal Agents in the Prophylaxis of Oropharyngeal Candidiasis among HIV-Infected Adults: A Systematic Review and Network Meta-Analysis

The objective of the study was to compare the efficacy and safety of antifungal agents used in the prevention of oropharyngeal candidiasis among HIV-infected adults. A systematic search was conducted in four databases (MEDLINE, Scopus, CENTRAL, and Embase) for eligible randomized control trials (RCTs). The network meta-analyses (NMA) were performed using a random-effects model. Interventions were ranked based on the efficacy and safety using the surface under the cumulative ranking curve (SUCRA). The quality of evidence was assessed using the GRADE approach. From a total of 1574 studies screened, 7 RCTs comprising 959 participants were included in NMA. The use of fluconazole as a prophylactic agent was associated with a significant reduction in incidence of OPC compared to placebo (RR, 0.45 (95% CI: 0.27–0.77)) in HIV-infected adults. The overall quality of evidence was graded as moderate. Fluconazole was ranked the best antifungal for efficacy (SUCRA—95.6%) as well as safety (SUCRA—39.3%) in HIV-infected adults. Overall, the quality of evidence was graded as moderate. Fluconazole can be considered as an effective agent with a better safety profile for the prophylaxis of OPC in HIV-infected adults. However, similar to any other antimicrobial agent, the risk of possibility of resistance must be weighed against the benefits.

Bleeding Risk Following Systemic Fluconazole or Topical Azoles in Patients with Atrial Fibrillation on Apixaban, Rivaroxaban, or Dabigatran

BackgroundBleeding safety in relation to use of systemic fluconazole and topical azoles among patients with atrial fibrillation treated with apixaban, rivaroxaban, or dabigatran is insufficiently explored, despite clinical relevance and several reports suggesting associations. MethodsUsing nationwide Danish registers, we identified patients with atrial fibrillation initiated on apixaban, rivaroxaban, or dabigatran from 2012-2018. We investigated associations between bleeding incidents and systemic fluconazole or topical azole treatment using a case-crossover design with 30-day exposure windows and reported odds ratios (OR) with 95% confidence intervals (CI). ResultsWe included 32,340 (36%), 32,409 (36%), and 24,940 (28%) patients initiated on apixaban, rivaroxaban, and dabigatran, respectively. Patients on apixaban were older (median age: 77 years; interquartile range [IQR] 70-84) compared with rivaroxaban users (median age: 75 years; IQR 68-82) and patients on dabigatran (median age: 73 years; IQR 66-80). Apixaban users had a significantly increased risk of bleeding following exposure to systemic fluconazole: odds ratio (OR) 3.5; 95% confidence interval (CI), 1.4-10.6. No increased risk was found among rivaroxaban and dabigatran users: ORs of 0.9 (95% CI, 0.2-3.0) and 1.7 (95% CI, 0.5-5.6), respectively. As to bleeding risk pertaining to topical azole exposure among apixaban, rivaroxaban, and dabigatran users, no association was found, with corresponding ORs of 0.8 (95% CI, 0.5-1.3); 1.3 (95% CI, 0.9-2.1); and 1.2 (95% CI 0.8-1.8), respectively. ConclusionIn patients with atrial fibrillation on either apixaban, rivaroxaban, or dabigatran, an association between an elevated bleeding risk and use of systemic fluconazole was found among patients on apixaban. We found no increased risk of bleeding following co-exposure to topical azoles.

Comparative analysis of infectious complications with outpatient vs. inpatient care for adults with high-risk myeloid neoplasm receiving intensive induction chemotherapy

We recently reported an early hospital discharge (EHD) care strategy following intensive acute myeloid leukemia (AML)-like chemotherapy is safe. To evaluate its impact on infectious outcomes, we compared all adults treated from 8/1/2014 to 7/31/2018 discharging within 72 h of completing chemotherapy (EHD) with hospitalized patients (controls) across 354 induction and 259 post-remission cycles. While overall outcomes were similar, gram-positive bacteremias were more common in EHD patients than control (p<.001), although they received fewer days of IV antimicrobials (p< .001). Notably, cumulative infection risks in EHD patients were similar after induction and post-remission therapy. In multivariable analysis, only EHD status was independently associated with risk for gram-positive bacteremia (p= .01), whereas the only independent risk factor for fungal infection was fluconazole (vs. posaconazole) use (p< .001). The observation of increased rates of gram-positive bacteremias with EHD identifies improvements in catheter management as one area to further increase the safety of this care approach.

Prophylactic Use of Fluconazole in Very Premature Infants.

Objective: To evaluate the efficacy, safety, and fungal sensitivity of prophylactic fluconazole use in very premature infants.Methods: We performed a retrospective historical comparative analysis of 196 very premature infants (113 in the prophylaxis group and 83 in the rescue group). The incidence of nosocomial fungal infection (NCFI) and pathogenic fungi, their drug sensitivity, and the minimum inhibitory concentration (MIC) of fluconazole were compared between the two groups. We also analyzed differences in short-term adverse outcomes, such as drug-induced liver or renal function disruption, fungal-attributable death, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), periventricular leukomalacia (PVL), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC), between the groups. The effects of the prophylactic fluconazole strategy on NCFI and short-term adverse outcomes were assessed by multivariate logistic regression.Results: Candida albicans (46.7%) and Candida glabrata (43.3%) were the main culprit pathogens causing NCFI. The incidence of NCFI was significantly lower in the prophylaxis group than in the rescue group (15.9 vs. 45.8%, P < 0.001). However, fewer fungi were completely sensitive to fluconazole (40 vs. 85%, P < 0.05) and the MIC of fluconazole was higher [16.0 (3.5 ~ 16.0) vs. 3.0 (1.0 ~ 8.0) μg/ml, P < 0.001] in the prophylaxis group than in the rescue group. Compared with the rescue group, the prophylaxis group had a lower risk of NCFI (adjusted OR 0.25; 95% CI 0.11, 0.55). Additionally, the prophylaxis group had significantly lower risks of combined outcomes (one or more complications, such as BPD, ROP needing interventions, PVL/IVH (grade > 2), NEC stage ≥2, and fungal-attributable death) (adjusted OR 0.44; 95% CI 0.21, 0.92). There was no significant difference in serum alanine transferase (ALT), aspartate transaminase (AST), creatinine (Cr), or direct bilirubin (DBIL) levels between the two groups.Conclusions: Fluconazole prophylaxis reduced NCFI and improved combined clinical outcomes in very premature infants, with no increased risks of serious short-term adverse side effects; however, the MIC of fluconazole showed significant increases. Therefore, further optimization of preventive strategies is necessary to maintain the sensitivity of fluconazole against fungal isolates.

Impact of antifungal stewardship interventions on the susceptibility of colonized Candida species in pediatric patients with malignancy

There is a worldwide concern regarding the antimicrobial resistance and the inappropriate use of antifungal agents, which had led to an ever-increasing antifungal resistance. This study aimed to identify the antifungal susceptibility of colonized Candida species isolated from pediatric patients with cancer and evaluate the clinical impact of antifungal stewardship (AFS) interventions on the antifungal susceptibility of colonized Candida species. Candida species colonization was evaluated among hospitalized children with cancer in a tertiary teaching hospital, Shiraz 2017–2018. Samples were collected from the mouth, nose, urine, and stool of the patients admitted to our center and cultured on sabouraud dextrose agar. The isolated yeasts identified by polymerase chain reaction–restriction fragment length polymorphisms (PCR–RFLP). DNA Extracted and PCR amplification was performed using the ITS1 and ITS4 primer pairs and Msp I enzyme. The broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) for amphotericin B, caspofungin, and azoles. The prevalence of Candida albicans in the present study was significantly higher than other Candida species. Candida albicans species were completely susceptible to the azoles. The susceptibility rate of C. albicans to amphotericin B and caspofungin was 93.1% and 97.1%, respectively. The fluconazole MIC values of Candida albicans decreased significantly during the post-AFS period (P < 0.001; mean difference: 72.3; 95% CI of the difference: 47.36–98.62). We found that ‏52.5% (53/117) of the isolated C. albicans were azole-resistant before AFS implementation, while only 1.5% (2/102) of the isolates were resistant after implementation of the AFS program (P < 0.001). C. albicans fluconazole and caspofungin resistant rate also decreased significantly (P < 0.001) after implementation of the AFS program [26 (32.9%) versus 0 (0.0%) and 11 (10.9%) versus 1 (0.9%), respectively]. Besides, fluconazole use (p < 0.05) and fluconazole expenditure reduced significantly (about one thousand US$ per year) after the AFS program. Our results confirm the positive effect of optimized antifungal usage and bedside intervention on the susceptibility of Candida species after the implementation of the AFS program. C. albicans and C. glabrata exhibited a significant increase in susceptibility after the execution of the AFS program.

Deciphering the epidemiology of invasive candidiasis in the intensive care unit: is it possible?

Invasive candidiasis (IC) has emerged in the last decades as an important cause of morbidity, mortality, and economic load in the intensive care unit (ICU). The epidemiology of IC is still a difficult and unsolved enigma for the literature. Accurate estimation of the true burden of IC is difficult due to variation in definitions and limitations inherent to available case-finding methodologies. Candidemia and intra-abdominal candidiasis (IAC) are the two predominant types of IC in ICU. During the last two decades, an increase in the incidence of candidemia has been constantly reported particularly in the expanding populations of elderly or immunosuppressed patents, with a parallel change in Candida species (spp.) distribution worldwide. Epidemiological shift in non-albicans spp. has reached worrisome trends. Recently, a novel, multidrug-resistant Candida spp., Candida auris, has globally emerged as a nosocomial pathogen causing a broad range of healthcare-associated invasive infections. Epidemiological profile of IAC remains imprecise. Though antifungal drugs are available for Candida infections, mortality rates continue to be high, estimated to be up to 50%. Increased use of fluconazole and echinocandins has been associated with the emergence of resistance to these drugs, which affects particularly C. albicans and C. glabrata. Crucial priorities for clinicians are to recognize the epidemiological trends of IC as well as the emergence of resistance to antifungal agents to improve diagnostic techniques and strategies, develop international surveillance networks and antifungal stewardship programmes for a better epidemiological control of IC.

Ketorolac-fluconazole: A New Combination Reverting Resistance in Candida albicans from Acute Myeloid Leukemia Patients on Induction Chemotherapy: In vitro Study.

Background and ObjectivesCandida albicans is a significant source of morbidity and mortality for patients with acute myeloid leukemia (AML). Prolonged use of fluconazole as empirical antifungal prophylaxis in AML patients leads to overexpression of efflux pump genes that resulted in the emergence of azole-resistant species. Consequently, the introduction of a new strategy to improve the management of C. albicans infections is an urgent need. Nonsteroidal anti-inflammatory drug (NSAID) ketorolac is associated with a reduction in cancer relapses. The present study was performed to investigate the use of ketorolac-fluconazole combination to reverse fluconazole resistance in C. albicans isolated from AML patients on induction chemotherapy.Patients and MethodsOne hundred and seventy AML patients were evaluated. Fifty C. albicans were isolated and subjected to disc diffusion assay and broth microdilution for fluconazole alone and combined with different concentrations of ketorolac. Efflux pump gene (CDR1, CDR2, and MDR1) expressions were quantified by real-time PCR.ResultsThe tested ketorolac acted synergistically with fluconazole against resistant C. albicans with the minimum inhibitory concentration (MIC) of fluconazole decreased from >160 μg/mL to 0.3–1.25 μg/mL in (93.8%) of resistant isolates with fractional inhibitory concentration index (FICI) value of 0.25. The majority of the resistant isolates overexpressed CDR1 (71.1%) and MDR1 (60%).ConclusionKetorolac-fluconazole in vitro combination would be a promising strategy for further clinical in vivo trials to overcome fluconazole resistance in AML patients on induction chemotherapy.

Coexistent CYP24A1 and PHEX Gene Mutations With Hypervitaminosis D Plus Hypercalcemia Treated With Fluconazole

Background: CYP24A1 and PHEX gene mutations are rare and can cause hypercalcemia, hypervitaminosis D and elevated FGF23 levels. Fluconazole, an antifungal medication, has shown therapeutic benefit in achieving normocalcemia plus normalisation of vitamin D levels in this case report. Clinical Case: A 42 year old man was referred to the endocrine clinic with a history of severe nephrocalcinosis and recurrent nephrolithiasis requiring surgical intervention and gradual decline in kidney function over 20 years. Biochemical investigations revealed hypercalcaemia with adjusted calcium levels of 2.83 mmol/L (R 2.2–2.6 nmol/L) and suppressed PTH 1.1 pmol/L(R 1.6–6.9 pmol/L). Twenty-four hour urine calcium/creatinine clearance ratio was above 0.0578 mmol/mmol indicating hypercalciuria. Vitamin D metabolites 25 OH Vitamin D was elevated at 201 nmol/L, (R 50–120 nmol/L) along with intermittently elevated 1,25 OH Vitamin D 147 pmol/L(R 55–139 pml/L). 24,25 Vitamin D was low at 2.0 nmol/L producing a 25:24,25 dihydroxyvitamin D ratio of 80 (n<25). This biochemical data was highly suggestive of a loss of function mutation in the CYP24A1 gene that codes for the enzyme 24-hydroxylase, which is responsible for conversion of 1,25 vitamin D to 24,25 vitamin D. A pathogenic variant (heterozygous c.756G>A) was confirmed on genetic testing.Plasma FGF23 (immutopics) was raised (with a peak of 596 RU/mL, n<100 RU/mL) but a full body octreotide scan did not reveal malignancy or other paraneoplastic syndromes such as oncogenic osteomalacia. A pathogenic variant in his PHEX gene (homozygous c.1874A>T) was also identified that has been associated with increased levels of FGF23 plus hypophosphataemia. Fluconazole at 50 mg once daily was initiated. Azoles inhibit cytochrome P450 enzymes and have been used in sarcoidosis to block vitamin D-synthesizing enzymes such as 25-hydroxylases and 1-α-hydroxylase that are P450 dependent. Few cases of CYP24A1 gene defects have been treated with fluconazole, which has a favourable side effect profile and yields good results. Adjusted calcium reduced to 2.62 nmol/L, 25 OH Vitamin D normalised to 111 nmol/L and 24:24,25 dihydroxyvitamin D ratio is now 17. Patient’s liver functions and full blood count has been monitored regularly during the course of treatment and the drug was well tolerated. Conclusion: Genetic causes of hypercalcemia can be left undiagnosed for long periods and there is a lack of proven or definitive therapeutic agents for correction of elevated calcium. Here fluconazole has been shown to reduce the hypercalcaemic burden and effectively lowered the Vitamin D levels in this case of a CYP24A1 mutation. This study augments fluconazole use in these cases but further studies are needed to elucidate the long term safe usage.

Cost-effectiveness analysis of flucytosine as induction therapy in the treatment of cryptococcal meningitis in HIV-infected adults in South Africa

BackgroundCryptococcal meningitis in HIV-infected patients in sub-Saharan Africa accounts for three-quarters of the global cases and 135,000 deaths per annum. Current treatment includes the use of fluconazole and amphotericin B. Recent evidence has shown that the synergistic use of flucytosine improves efficacy and reduces toxicity, however affordability and availability has hampered access to flucytosine in many countries. This study investigated the evidence and cost implications of introducing flucytosine as induction therapy for cryptococcal meningitis in HIV-infected adults in South Africa.MethodsA decision analytic cost-effectiveness and cost impact model was developed based on survival estimates from the ACTA trial and local costs for flucytosine as induction therapy in HIV-infected adults with cryptococcal meningitis in a public sector setting in South Africa. The model considered five treatment arms: (a) standard of care; 2-week course amphotericin B/fluconazole (2wk AmBd/Flu), (b) 2-week course amphotericin B/flucytosine (2wk AmBd/5FC), (c) short course; 1-week course amphotericin B/flucytosine (1wk AmBd/5FC) (d) oral course; 2-week oral fluconazole/flucytosine (oral) and e) 1-week course amphotericin B/fluconazole (1wk AmBd/Flu). A sensitivity analysis was conducted on key variables.ResultsThe highest total treatment costs are in the 2-week AmBd/5FC arm followed by the 2-week oral regimen, the 1-week AmBd/5FC, then standard of care with the lowest cost in the 1-week AmBd/Flu arm. Compared to the lowest cost option the 1-week flucytosine course is most cost-effective at USD119/QALY. The cost impact analysis shows that the 1-week flucytosine course has an incremental cost of just over USD293 per patient per year compared to what is currently spent on standard of care. Sensitivity analyses suggest that the model is most sensitive to life expectancy and hospital costs, particularly infusion costs and length of stay.ConclusionsThe addition of flucytosine as induction therapy for the treatment of cryptococcal meningitis in patients infected with HIV is cost-effective when it is used as a 1-week AmBd/5FC regimen. Savings could be achieved with early discharge of patients as well as a reduction in the price of flucytosine.