Mortality Of Invasive Fungal Infections Research Articles

Discovery of highly potent triazole derivatives with broad-spectrum antifungal activity based on Iodiconazole

The widespread use of broad-spectrum antibiotics, the growing number of immunocompromised individuals, and the emergence of drug-resistant strains have resulted in the increasing incidence and mortality of invasive fungal infections. Azole drugs are the primary treatment for invasive fungal infections, and Iodiconazole is a potent azole drug with strong antifungal activity, but its stability is poor. In order to improve stability, a series of triazole compounds containing ethynyl group were designed and synthesized. Most of the compounds showed strong inhibitory activity against pathogenic fungi, among which compound 20l showed excellent inhibitory activity against pathogenic fungi and drug-resistant fungi. Importantly, and the stability of 20l (T1/2 = 30.2 min) was obviously improved compared with Iodiconazole (T1/2 = 4.39 min). In addition, the preferred compound 20l can prevent fungal phase transition and the formation of fungal biofilm, and show satisfactory fungicidal activity. In addition, the compound 20l was almost non-toxic to mammalian HUVEC cell and 293T cell. In vivo pharmacokinetic studies showed that 20l had acceptable pharmacokinetic properties. These results strongly demonstrate that compound 20l was worth further investigation as a potential antifungal inhibitor.

The Patterns of Antifungal Use and Risk Factors Associated with Mortality in Patients with Invasive Candidiasis and Aspergillosis Infections Among Patients Who were Received Infectious Disease Specialist Consultation Prior to and During the COVID-19 Pandemic in A Resource-Limited Setting: A Retrospective Cohort Study.

Limited data is available concerning the patterns of antifungal use and invasive fungal infection (IFI)-associated mortality risk factors prior to and during the COVID-19 pandemic in a resource-limited setting. A single center retrospective cohort study was conducted to evaluate the patterns of antifungal use and IFI-associated mortality risk factors in a resource-limited setting prior to and during the COVID-19 pandemic. All patients age >18 years diagnosed with IFI were prospectively followed during a 3-year pre-COVID-19 pandemic period (period 1: 1/1/2017-12/31/2019) and a 3-year during COVID-19 pandemic period (period 2: 1/1/2020-12/31/2022). Patient characteristics, patterns of antifungal use, IFI-associated mortality risk factors, and adverse drug events were collected. Multivariate analysis was performed to identify IFI-associated mortality risk factors. There was a total of 133 patients in this study: 60 (45.1%) in period 1 and 73 (54.9%) in period 2. Pre-emptive antifungal therapy was commonly practiced in period 2 (21.7% vs 37%, p=0.05). The presence of a central venous catheter (CVC) (aOR 3.19, p=0.007), hematologic adverse drug events (aOR 17.9, p=0.008) were potentially preventable risks for the overall IFI mortality in both periods. Appropriate antifungal use was protective against the overall IFI mortality in period 2 (aOR 0.09, p=0.009). Several preventable IFI-associated mortality risk factors including the presence of CVC and inappropriate antifungal use were identified and served as key target changes for improvement of infection prevention, national policy to access appropriate antifungal agents, and antifungal stewardship in a resource-limited setting during the COVID-19 pandemic.

Biomarker Driven Antifungal Stewardship (BioDriveAFS) in acute leukaemia—a multi-centre randomised controlled trial to assess clinical and cost effectiveness: a study protocol for a randomised controlled trial

BackgroundAcute leukaemias (AL) are life-threatening blood cancers that can be potentially cured with treatment involving myelosuppressive, multiagent, intensive chemotherapy (IC). However, such treatment is associated with a risk of serious infection, in particular invasive fungal infection (IFI) associated with prolonged neutropenia. Current practice guidelines recommend primary antifungal (AF) prophylaxis to be administered to high-risk patients to reduce IFI incidence. AFs are also used empirically to manage prolonged neutropenic fever. Current strategies lead to substantial overuse of AFs. Galactomannan (GM) and β-D-glucan (BG) biomarkers are also used to diagnose IFI. Combining both biomarkers may enhance the predictability of IFI compared to administering each test alone. Currently, no large-scale randomised controlled trial (RCT) has directly compared a biomarker-based diagnostic screening strategy without AF prophylaxis to AF prophylaxis (without systematic biomarker testing).MethodsBioDriveAFS is a multicentre, parallel, two-arm RCT of 404 participants from UK NHS Haematology departments. Participants will be allocated on a 1:1 basis to receive either a biomarker-based antifungal stewardship (AFS) strategy, or a prophylactic AF strategy, which includes existing standard of care (SoC).The co-primary outcomes will be AF exposure in the 12-month post randomisation and the patient-reported EQ-5D-5L measured at 12-month post randomisation. Secondary outcomes will include total AF exposure, probable/proven IFI, survival (all-cause mortality and IFI mortality), IFI treatment outcome, AF-associated adverse effects/events/complications, resource use, episodes of neutropenic fever requiring hospital admission or outpatient management, AF resistance in fungi (non-invasive and invasive) and a Desirability of Outcome Ranking.The trial will have an internal pilot phase during the first 9 months. A mixed methods process evaluation will be integrated in parallel to the internal pilot phase and full trial, aiming to robustly assess how the intervention is delivered. Cost-effectiveness analysis will also be performed.DiscussionThe BioDriveAFS trial aims to further the knowledge of strategies that will safely optimise AF use through comparison of the clinical and cost-effectiveness of a biomarker-led diagnostic strategy versus prophylactic AF to prevent and manage IFI within acute leukaemia. The evidence generated from the study will help inform global clinical practice and approaches within antifungal stewardship.Trial registrationISRCTN11633399. Registered 24/06/2022.

Change in Global Incidence and Mortality of Invasive Fungal Infection

Change in Global Incidence and Mortality of Invasive Fungal Infection

Effectiveness of high efficiency particulate (HEPA) air condition combined with the antifungal prophylaxis on incidence, morbidity and mortality of invasive fungal infections in patients with acute myeloid leukemia: a retrospective single-center study.

Our monocentric and retrospective study aimed to investigate the clinical effectivity of HEPA filters in combination with the antifungal drug prophylaxis in patients with AML undergoing intensive chemotherapy and allogeneic stem cell transplantation (SCT). We included 177 patients between 2005 and 2015 representing a total of 372 in-hospital stays, 179 in the HEPA cohort (+HEPA) and 193 in the cohort without HEPA filters (-HEPA). No significant additional benefit of HEPA filtration on the risk reduction of IFI was observed. HEPA filtration did not significantly affect the risk of intensive care unit (ICU) admissions or early mortality rates. In patients who received allogeneic SCT in first complete remission with antifungal drug prophylaxis during prior induction treatment, a numerical but not significant improvement in long-term overall survival was noted in the +HEPA cohort compared to the -HEPA cohort (55% to 66%, p = 0.396). For better depicting of the clinical reality, we determined the so-called clinical suspected IFI (csIFI) -defined as cases with antifungal treatment after recommended prophylaxis without fulfilling current EORTC criteria. Especially in patients with a high risk for second IFI, significant risk reduction of csIFI and frequency of ICU admissions was observed when voriconazole was used as secondary antifungal prophylaxis. (csIFI, adjusted effect: OR 0.41, 95% CI (0.21 - 0.82), p = 0.01; csIFI, subgroup-specific effect: OR 0.35, 95% CI (0.15 - 0.78), p = 0.01; ICU, adjusted effect: OR 0.44, 95 CI (0.19 - 1.01), p = 0.05; respectively). In summary, the study suggests the efficacy of secondary antifungal prophylaxis in preventing IFI in AML patients undergoing intensive treatment. The addition of HEPA filtration also demonstrated additional numerous benefits in reducing the frequency of IFI-associated complications.

Intestinal bacteria-a powerful weapon for fungal infections treatment.

The morbidity and mortality of invasive fungal infections are rising gradually. In recent years, fungi have quietly evolved stronger defense capabilities and increased resistance to antibiotics, posing huge challenges to maintaining physical health. Therefore, developing new drugs and strategies to combat these invasive fungi is crucial. There are a large number of microorganisms in the intestinal tract of mammals, collectively referred to as intestinal microbiota. At the same time, these native microorganisms co-evolve with their hosts in symbiotic relationship. Recent researches have shown that some probiotics and intestinal symbiotic bacteria can inhibit the invasion and colonization of fungi. In this paper, we review the mechanism of some intestinal bacteria affecting the growth and invasion of fungi by targeting the virulence factors, quorum sensing system, secreting active metabolites or regulating the host anti-fungal immune response, so as to provide new strategies for resisting invasive fungal infection.

New Perspectives on Primary Prophylaxis of Invasive Fungal Infection in Children Undergoing Hematopoietic Stem Cell Transplantation: A 10-Year Retrospective Cohort Study

Allogenic hematopoietic stem cell transplantation (a-HCT) remains a therapeutic treatment for many pediatric hematological diseases. The occurrence of invasive fungal infections (IFIs) is a complication for which ECIL-8 recommends primary antifungal prophylaxis. In this study, we evaluated the impact of our local strategy of not systematically administering primary antifungal prophylaxis in children undergoing a-HCT on the occurrence and mortality of IFIs. We performed a retrospective monocentric study from 2010 to 2020. We retained all proven and probable IFIs diagnosed during the first year post a-HCT. 308 patients were included. Eighteen patients developed twenty IFIs (thirteen proven, seven probable) (6.5%) among which aspergillosis (n = 10, 50%) and candidosis (n = 7, 35%) were the most frequently diagnosed infections. Only 2% of children died because of an IFI, which represents 14% of all deaths. Multivariate analysis found that age > 10 years (OR: 0.29), the use of a therapeutic antiviral treatment (OR: 2.71) and a low neutrophil count reconstitution (OR: 0.93) were significantly associated with the risk of IFI occurrence. There was also a trend of malignant underlying disease and status ≥ CR2 but it was not retained in multivariate analysis. IFI occurrence was not higher in our cohort than what is reported in the literature with the use of systematic antifungal prophylaxis, with a good survival rate nonetheless. Thus, a prophylaxis could be considered for children with a high risk of IFI such as those aged over 10 years.

Real-life epidemiology and current outcomes of hospitalized adults with invasive fungal infections.

We aimed to describe the current epidemiology of both hosts with invasive fungal infections (IFIs) and causative fungi. And, detail outcomes of these infections at 12 weeks in a real-life cohort of hospitalized patients. The study was retrospective and observational to describe IFI diagnosed in a tertiary hospital (February 2017-December 2021). We included all consecutive patients meeting criteria for proven or probable IFI according to EORTC-MSG and other criteria. A total of 367 IFIs were diagnosed. 11.7% were breakthrough infections, and 56.4% were diagnosed in the intensive care unit. Corticosteroid use (41.4%) and prior viral infection (31.3%) were the most common risk factors for IFI. Lymphoma and pneumocystis pneumonia were the most common baseline and fungal diseases. Only 12% of IFI occurred in patients with neutropenia. Fungal cultures were the most important diagnostic tests (85.8%). The most frequent IFIs were candidemia (42.2%) and invasive aspergillosis (26.7%). Azole-resistant Candida strains and non-fumigatus Aspergillus infections represented 36.1% and 44.5% of the cases, respectively. Pneumocystosis (16.9%), cryptococcosis (4.6%), and mucormycosis (2.7%) were also frequent, as well as mixed infections (3.4%). Rare fungi accounted for 9.5% of infections. Overall, IFI mortality at 12 weeks was 32.2%; higher rates were observed for Mucorales (55.6%), Fusarium (50%), and mixed infections (60%). We documented emerging changes in both hosts and real-life IFI epidemiology. Physicians should be aware of these changes to suspect infections and be aggressive in diagnoses and treatments. Currently, outcomes for such clinical scenarios remain extremely poor.

Evaluation of Posaconazole for Primary Prophylaxis of IFI in Acute Myeloid Leukemia under Intensive Induction Chemotherapy. Comparative Real Life Study with Fluconazole in two Hematological Centers in Algeri

Introduction: Acute myeloid leukemia (AML) is a hematological malignancy with a poor prognosis. The early consequences of induction chemotherapy are represented by pancytopenia with severe immunosuppression, which favors the emergence of so-called “opportunistic” infections and in particular invasive fungal infections (IFI) such as invasive aspergillosis (IA). This justifies the implementation of early, empirical, pre-emptive or prophylactic antifungal treatment. The objective of this study is the evaluation of a comparative study before and after the use of primary prevention with posaconazole versus fluconazole, in terms of incidence and mortality of invasive fungal infections (IFIs) during AML inductions, in real life in Algeria. Patients and methods: This study was performed in two periods in the 2 centers concerning the same AML patients receiving the same induction chemotherapy (daunorubicin 60 mg/m2 for 3 days and cytarabine 100 mg/m2 for 7 days) but with a different type of hospitalization with common rooms for Tlemcen and protected single rooms for Oran. Period 1: The retrospective study was performed from 2014 to 2016 and involved 188 patients. 70 patients were hospitalized in a common room (Tlemcen) and 118 patients in a protected single room (Oran). All patients received as primary IFI prophylaxis fluconazole 400 mg/day. Period 2: The prospective study was conducted from April 2017 to September 2018 and involved 55 patients. Fourteen patients were hospitalized in Tlemcen and 41 patients in an Oran. These patients received posaconazole prophylaxis at a dose of 200 mgx3/day. The evaluation and comparison of descriptive and incidence data was performed using Chi2 statistical tests using SPSS version 19 software. Overall survival (OS) were calculated using the Kaplan-Meier estimate and were compared using the log-rank test with a significance level α of 0.05. Results: Period 1: The incidence rate of IFI: 34% at the Oran hospital versus 49% at the Tlemcen hospital (p=0.049). Among the 74 patients who presented with IFI, 39 (53%) died from IFI as the main cause of death, among these deaths, 16 (40%) were recorded at Oran and 23 (68%) at Tlemcen (p=0.011). Period 2: The IFI rate with fluconazole was 39% and that observed with posaconazole 22% (p=0.001) and the cumulative incidence was 39% at 21 days versus 10% at 15 days (p=0.046) with a highly significant decrease in IFI-related deaths: 53% versus 25% (p=0.004). Conclusion: This work has demonstrated the interest in terms of IFI incidence (17% versus 33%, p=0.04) and IFI-related mortality of posaconazole prophylaxis (25% versus 53%, p=0.004) used during AML in the context of hospitalization in common rooms. Furthermore, this work highlights that the combination of posaconazole prophylaxis and hospitalization in a protected single room allows an optimization of the management of this type of patients.
 
 

Synergistic antifungal effects of curcumin derivatives as fungal biofilm inhibitors with fluconazole.

Lack of novel antifungal agents and severe drug resistance has led to high incidence and associated mortality of invasive fungal infections. To tackle the challenges, novel antifungal agents with anti-resistant potency are highly desirable. Thus, derivatives of curcumin were synthesized to restore the effectiveness of fluconazole (FLC) against FLC-resistant Candida spp. and structure-activity relationships were then discussed. Some novel derivatives showed promising features as novel antifungal lead compounds. Of them, compound 4 showed good alone or synergistic antifungal activity against FLC-resistant Candida spp. Moreover, compound 4 was proven as a potent inhibitor of Candida albicans biofilm formation and yeast-to-hypha morphological transition whether used alone or in combination with FLC, which was further confirmed by the inhibitory effect on cellular surface hydrophobicity of C.albicans. Compound 4 also inhibits intracellular ATP production of C.albicans and disrupts membrane permeability of C.albicans when used in combination with FLC. The results highlighted the potential of curcumin derivatives to overcome fluconazole-related and biofilm-related drug resistance.

Filamentous Fungal Infections in a Tertiary Care Setting: Epidemiology and Clinical Outcome

Information on the distribution of filamentous fungal pathogens, which cause potential life-threatening invasive infections mostly in immunocompromised persons, is of great importance. The aim of this study was to evaluate the epidemiology and clinical outcome in patients with infections due to filamentous fungi at the University Hospital of Vienna, Austria. We conducted a retrospective observational study and consecutively included patients of any age with filamentous fungal infections between 2009 and 2017. The classification for probable and proven invasive filamentous fungal infections was based on the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC) criteria or the expert opinion of an experienced clinical mycologist. We included 129 patients (median age: 52 years; 47.3% female) with episodes of 101 proven and probable invasive and 35 localized filamentous fungal infections (16 sinus, 14 eye, one ear, and four deep cutaneous). Aspergillus fumigatus alone accounted for 50.3% of the fungi, which was followed by the Mucorales group (13.7%) and Fusarium spp. (8.5%). Diagnosis was mainly based on culture findings. The lung was the most frequent site of infection. The 30-day and 90-day overall mortality of invasive fungal infections was 30.2% and 42.7%, respectively. We observed a high all-cause mortality among patients with invasive filamentous fungal infections. Prospective data collection in a nationwide registry would be necessary to provide important information on surveillance to clinicians and other decision-makers.

Evaluation of knowledge and awareness of invasive fungal infections amongst resident doctors in Nigeria.

Introductionit has been estimated that about 11.8% of the Nigerians suffer serious fungal infections annually. A high index of suspicion with early diagnosis and institution of appropriate therapy significantly impacts on the morbidity and mortality of invasive fungal infections (IFIs).Methodswe conducted a cross-sectional multicentre survey across 7 tertiary hospitals in 5 geopolitical zones of Nigeria between June 2013 and March 2015. Knowledge, awareness and practice of Nigerian resident doctors about the diagnosis and management of invasive fungal infections were evaluated using a semi-structured, self-administered questionnaire. Assessment was categorized as poor, fair and good.Results834(79.7%) of the 1046 participants had some knowledge of IFIs, 338(32.3%) from undergraduate medical training and 191(18.3%) during post-graduate (specialty) residency training. Number of years spent in clinical practice was positively related to knowledge of management of IFIs, which was statistically significant (p < 0.001). Only 2 (0.002%) out of the 1046 respondents had a good level of awareness of IFIs. Only 4(0.4%) of respondents had seen > 10 cases of IFIs; while 10(1%) had seen between 5-10 cases, 180(17.2%) less than 5 cases and the rest had never seen or managed any cases of IFIs. There were statistically significant differences in knowledge about IFIs among the various cadres of doctors (p < 0.001) as level of knowledge increased with rank/seniority.Conclusionknowledge gaps exist that could militate against optimal management of IFIs in Nigeria. Targeted continuing medical education (CME) programmes and a revision of the postgraduate medical education curriculum is recommended.

Drug Repurposing of Haloperidol: Discovery of New Benzocyclane Derivatives as Potent Antifungal Agents against Cryptococcosis and Candidiasis.

Despite the high morbidity and mortality of invasive fungal infections (IFIs), effective and safe antifungal agents are rather limited. Starting from antifungal lead compound haloperidol that was identified by drug repurposing, a series of novel benzocyclane derivatives were designed, synthesized, and assayed. Several compounds showed improved antifungal potency and broader antifungal spectra. Particularly, compound B10 showed good inhibitory activities against a variety of fungal pathogens and was proven to be an inhibitor of several virulence factors important for drug resistance. In the in vivo cryptococcosis and candidiasis models, compound B10 could effectively reduce the brain fungal burden of Cryptococcus neoformans and synergize with fluconazole to treat resistant Candida albicans infections. Preliminary antifungal mechanism studies revealed that compound B10 regained cell membrane damage and down-regulated the overexpression of ERG11 and MDR1 genes when used in combination with fluconazole. Taken together, haloperidol derivative B10 represents a promising lead compound for the development of a new generation of antifungal agents.

Stilbene derivatives as new perspective in antifungal medicinal chemistry.

The high incidence and mortality of invasive fungal infections and serious drug resistance have become a global public health issue. There is an urgent need for alternative antimicrobials to control fungal infections and targeting it by antifungal substances from the natural sources represents a promising new strategy for the development of novel antifungal agents. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a phytoalexin produced by plant species in response to environmental stress or pathogenic attacks. It has many known and potential therapeutic applications in human general homeostasis; it mediates a great number of biological responses relevant for human health such as anticancer, cardio and neuroprotective, antioxidant, and antimicrobial activities. Resveratrol is a natural antifungal agent, therefore it can be considered as a scaffold for designing structural relatives potentially capable of mediating more intense responses in a more specific way. Also, stilbenes produced by several plants may be useful lead structure for the chemical synthesis of antifungal. Their antifungal potential represents a useful solution to the drug resistance and side effect complications that occur after pharmacological treatment of infectious diseases. The purpose of this review is to present an overview on resveratrol derivatives, both natural and synthetic, with antifungal activity and summarize the chemical structure and the therapeutic versatility of stilbene-containing compounds.

Synthesis, characterization and anti-fungal potential evaluation of 1, 4 thiazine derivatives by Mannich bases

Plan: The present research work is aimed to synthesize newer, less toxic and more effective Mannich bases of 1, 4 thiazine derivatives and further compare their antifungal activities. Preface: Microbial infections are becoming the most important issue for global health and economy. Among these fungal infections are the major problem these days. The morbidity and mortality of invasive fungal infections are unacceptably high. It is an urgent need for the development of new antifungal agents to treat these life-threatening invasive infections. Methodology: Mannich base was synthesized by using o-amino thiophenol with maleic anhydride. Further, four derivatives of Mannich bases were synthesized from 3-oxo-3, 4-dihydro-2H-1, 4-benzothiazin-2-yl) acetic acid with sulpha drugs, ethanol, and formaldehyde. Then synthesized Mannich bases were docked against Dihydrofolate reductase complexed with NADPH and 6- methyl-5- [3-methyl-3-(3,4,5-trimethoxyphenyl) but-1-yn-1-yl]pyrimidine-2,4-diamine (UCP115A)using Argus Lab software. On this basis, we selected 3QLS as a biological target for docking study of synthesized compound. Outcome: The structures of the synthesized compounds were confirmed by UV, IR and Mass Spectroscopic studies. All the newly synthesized derivatives were screened for antifungal activity against Candida albicans NCIM 3100 and Aspergillus niger NCIM 596 by agar diffusion method (Kirby- Bauer method) using fluconazole (10µg/disc) as the standard and dimethyl sulphoxide as the vehicle. The docking results indicate the Mannich bases of 1, 4-thiazines (ligand binding energy varies from -8.9046kcal/mol to -12,0457kcal/mol) shows considerable antifungal activity against Candida albicans. Out of the four derivatives, E4 (Sulfamethoxazole substituted 1, 4- thiazine) possess the best ligand pose energy (-12.0414 kcal/mol) and two hydrogen bond. Among these synthesized compounds, compound E4([4({[4-(N-(5-methyl-3-isoxazolyl) amino sulfonyl) phenyl] amino} methyl)-3-oxo-3,4-dihydro-2H1,4-benzothiazin-2yl] acetic acid) showed highest antifungal activity due to the presence of 1,4- thiazine with sulfamethoxazole substitution.

Molecular architecture of fungal cell walls revealed by solid-state NMR

The high mortality of invasive fungal infections, and the limited number and inefficacy of antifungals necessitate the development of new agents with novel mechanisms and targets. The fungal cell wall is a promising target as it contains polysaccharides absent in humans, however, its molecular structure remains elusive. Here we report the architecture of the cell walls in the pathogenic fungus Aspergillus fumigatus. Solid-state NMR spectroscopy, assisted by dynamic nuclear polarization and glycosyl linkage analysis, reveals that chitin and α-1,3-glucan build a hydrophobic scaffold that is surrounded by a hydrated matrix of diversely linked β-glucans and capped by a dynamic layer of glycoproteins and α-1,3-glucan. The two-domain distribution of α-1,3-glucans signifies the dual functions of this molecule: contributing to cell wall rigidity and fungal virulence. This study provides a high-resolution model of fungal cell walls and serves as the basis for assessing drug response to promote the development of wall-targeted antifungals.

552 - Comparison of Therapeutic Drug Levels of Adult and Pediatric Patients Undergoing Treatment for Fungal Diseases

Background: The mortality of invasive fungal infections is significant, indicating the critical need for appropriate treatment and dosing of anti-fungal drugs. Variable absorption and pharmacokinetics of triazole antifungal drugs (e.g. posaconazole and voriconazole) create a challenge for physicians to consistently achieve blood levels in the therapeutic range, particularly in patients suffering from comorbidities. The use of therapeutic drug monitoring (TDM) is critical for ensuring efficacy of voriconazole (VOR) and posaconazole (POS) treatment. Dosing in pediatric patients can prove more difficult because there have been fewer studies in these patient populations. Methods: Drug levels of POS and VOR were determined by reverse phase LC MS/MS on plasma or serum samples submitted for testing. Results were de-identified and reviewed to determine whether results fell within the therapeutic range for effective anti-fungal treatment. A large sample set (POS approximately 2500 samples and VOR approximately 5500 samples) was included to reduce the chance of sample size variability. Pediatric samples were defined as those coming from patients 17 years and younger. Results: For POS, in pediatric patients, 7.5% of samples tested had drug levels below the limit of detection of the assay (.1 mcg/mL) compared to 4% in adults; and an additional 19% of samples in pediatric and 13% in adults tested had detectable levels that were below the suggested therapeutic level of .7 mcg/mL. For VOR, the percentage of samples tested with results either above or below the therapeutic window was even higher: 6.7% of adult samples and 10.8% of pediatric samples tested had drug levels below the limit of detection of the assay (.1 mcg/mL), and an additional 21.3% of adult samples and 39.2% of pediatric sample had detectable levels that were below the suggested therapeutic range of 1.0-5.5 mcg/mL. Additionally, 13.4% of adult samples and 7.7% of pediatric samples tested had levels that were above the therapeutic range. Conclusions: From these data it is clear that an alarmingly high number of both adult and pediatric patient samples tested (24% of adult and 46% of pediatric) have antifungal drug levels below the recommended therapeutic levels. These data indicate the criticality of monitoring antifungal drug levels because of the high frequency of sub-therapeutic concentrations due to variations in metabolism, absorption or even patient compliance. Moreover, 7% of VOR results demonstrated levels above the recommended therapeutic levels, putting these patients at risk for toxicity.

Emerging New Targets for the Treatment of Resistant Fungal Infections.

With the increasing morbidity and mortality of invasive fungal infections and the emergence of severe antifungal drug resistance, new drug targets and novel antifungal agents are urgently needed. Recently, better understanding of fungal pathogenesis has contributed to the rapid emergence of potential antifungal drug targets. This perspective aims to provide a comprehensive review of new antifungal targets and of medicinal chemistry efforts toward inhibitor discovery. Particular focus will be placed on the druggability of the targets and their potential to treat resistant fungal infections. Innovative strategies for the next generation of antifungal therapy, such as virulence factors, protein-protein interactions, and immune response-based proteins, will also be highlighted.

Discovery of simplified sampangine derivatives as novel fungal biofilm inhibitors

Lack of novel antifungal agents and severe drug resistance have led to high incidence and associated mortality of invasive fungal infections. To tackle the challenges, novel antifungal agents with new chemotype, fungicidal activity and anti-resistant potency are highly desirable. On the basis of our previously identified simplified analogue of antifungal natural product sampangine, systemic structure-activity relationships were clarified and two novel derivatives showed promising features as novel antifungal lead compounds. Compounds 22b and 22c showed good fungicidal activity against both fluconazole-sensitive and fluconazole-resistant Candida albicans strains. Moreover, they were proven to be potent inhibitors of Candida albicans biofilm formation and yeast-to-hypha morphological transition by down-regulating biofilm-associated genes. In a rat vaginal Candida albicans infection model, compounds 22b and 22c showed excellent therapeutic effects with low toxicity. The results highlighted the potential of sampangine derivatives to overcome fluconazole-related and biofilm-related drug resistance.

Natural Antimicrobial Peptides as Inspiration for Design of a New Generation Antifungal Compounds.

Invasive fungal infections are associated with high mortality rates, despite appropriate antifungal therapy. Limited therapeutic options, resistance development and the high mortality of invasive fungal infections brought about more concern triggering the search for new compounds capable of interfering with fungal viability and virulence. In this context, peptides gained attention as promising candidates for the antimycotics development. Variety of structural and functional characteristics identified for various natural antifungal peptides makes them excellent starting points for design novel drug candidates. Current review provides a brief overview of natural and synthetic antifungal peptides.