Antifungal Choice Research Articles

Initial micafungin treatment does not improve outcomes compared to fluconazole treatment in immunocompromised and critically ill patients with candidaemia.

Candidaemia is associated with poor outcomes including high mortality rates. Controversy remains regarding whether fluconazole or an echinocandin is the optimal choice for initial candidaemia treatment, particularly among high-risk patients such as the immunocompromised or critically ill. To understand optimal initial treatment of candidaemia. We conducted a retrospective study of immunocompromised or ICU adult patients with candidaemia from 2010 to 2014. Patients who received ≥3 consecutive days of initial treatment with fluconazole or micafungin were included. The primary outcome was complete response at day 14, defined as clinical improvement and blood culture sterilization. Secondary outcomes included microbiological and clinical success, survival and recurrent candidaemia. A total of 197 patients were included; 76 received fluconazole and 121 received micafungin. There was no difference in complete response between the fluconazole and micafungin groups (ICU: 38% versus 40%, P = 0.87; immunocompromised: 57% versus 59%, P = 0.80). Secondary outcomes including survival were also similar. In multivariable analysis, among ICU patients, Pitt bacteraemia score < 4 (P = 0.002) and time to antifungal (P = 0.037) were associated with meeting the primary outcome; white blood cell count > 11 cells × 103/µL on day 0 (P < 0.001) and Candida isolated from a non-blood site (P = 0.025) were associated with not meeting the primary outcome. Among immunocompromised patients, white blood cells > 11 × 103/µL (P = 0.003) and Candida isolated from a non-blood site (P = 0.026) were associated with not meeting the primary outcome. These data suggest that among ICU or immunocompromised patients, severity of illness rather than initial antifungal choice drove clinical outcomes.

Comparative assessment of Sensititre YeastOne and Micronaut-AM EUCAST for antifungal susceptibility testing in candidaemia isolates

PurposeAntifungal susceptibility testing (AFST) is essential to ensure appropriate antifungal therapy in candidaemia. This study compared two commercial colorimetric broth microdilution tests: Sensititre YeastOne (SYO; Thermo Scientific) and Micronaut-AM EUCAST AFST (M-AM; Bruker) for the AFST of Candida spp. Material and MethodsA total of 74 yeast strains, including C. albicans (n = 40) and non-albicans Candida species (NACS) (n = 34), were obtained from blood cultures of patients admitted to a tertiary care hospital in Belgium from 2017 to 2022. AFST by SYO and by M-AM were performed according to the manufacturers’ protocols and interpreted using CLSI and EUCAST guidelines, respectively. Essential and categorical agreements (EA and CA), very major, major and minor discrepancies were calculated for amphotericin B, echinocandins and azoles considering SYO as the reference method. ResultsIn total, 441 and 392 isolate-antifungal results were evaluable for EA and CA, respectively. SYO and M-AM, showed a high level of concordance for C. albicans strains, with an EA and CA ≥90 % for all tested antifungals. However, we noted significant discordances for NACS, the lowest EA were observed with micafungin (50 %) and voriconazole (58.8 %). These discrepancies were likely due to differences in the raw MIC values obtained by the two methods and the different interpretation breakpoints used by CLSI and EUCAST. ConclusionOur study showed excellent agreement between SYO and M-AM for AFST of C. albicans, while the equivalency was lower for NACS. AFST method should be carefully selected, considering the results might impact the choice of antifungals for non-albicans candidaemia.

Endogenous Fungal Endophthalmitis: A Single-Center Retrospective Study and Review of the Literature

To evaluate factors that inform systemic antifungal choices in patients with endogenous fungal endophthalmitis (EFE). Single-institution retrospective case series. Charts of EFE patients from 2010 to 2023 were reviewed. Patients treated systemically for EFE with a minimum of 14 days of follow-up were included. Outcome measures included time to improvement in vitritis or chorioretinitis, systemic therapy modification, and need for surgical intervention. A total of 20 eyes of 16 patients were included. Candida species were most common (43.8%), followed by culture-negative EFE (37.5%) and Aspergillus species (18.8%). In all, 90% of eyes had vitritis and/or macula-involving chorioretinitis. The majority of Candida infections (60%) or culture-negative EFE (75%) were treated initially with oral antifungals. Patients with a history of immune compromise, positive fungal culture, or positive Fungitell assay were more likely to be treated with early intravenous (IV) antifungal therapy. Two patients required systemic antifungal therapy modification because of worsening chorioretinitis, in 1 case due to voriconazole-resistant Aspergillosis that demonstrated chorioretinal lesion growth despite intravitreal amphotericin B injections and systemic voriconazole, and in the second case due to worsening chorioretinitis from Candida dubliniensis infection that regressed upon switch from oral to IV fluconazole. Initial systemic treatment decisions in patients with EFE were driven by systemic culture positivity, systemic symptoms, or comorbidities. Intravitreal antifungal therapy may be insufficient to arrest progression of chorioretinal lesions in some cases. Larger studies are needed to determine whether visible end-organ damage in the form of chorioretinitis may be useful for guiding systemic therapy changes.

Assessment of Antimicrobial Utilization among Cancer Patients with Febrile Neutropenia at the Lebanese Hospitals.

Febrile neutropenia is a prevalent oncologic complication. Initiating rapid treatment with empirical antimicrobials in febrile neutropenia patients reduces mortality due to infections. The study aims to evaluate antimicrobial utilization among FN patients in Lebanon in terms of drug choice, dose, and duration of the treatment. This is a retrospective, multicenter, observational study conducted at three different Lebanese university hospitals (in which the Infectious Diseases Society of America (IDSA) guidelines are adopted), between February 2014 and May 2017. Adult cancer patients aged 18 years and older with febrile neutropenia were included in the study. Using the IDSA guidelines as a reference, patients were assessed whether they received the antimicrobial regimen inconsistent with the IDSA reference or not. Statistical analysis was performed using the Statistical Package for the Social Science software (SPSS version 22.0). The adherence to guidelines for the indication and doses of antibiotics and anti-fungal in patients with febrile neutropenia. A total of 124 patients with a mean age of 54.43 ± 17.86 years were enrolled in the study. Leukemia (29.7%) was the most prevalent cancer and the most common infection was sepsis (20.2%). Combination antibiotic lactams are the most prescribed antibiotics (86.8%). Only 94 (86.23%) patients were given the antibiotic therapy appropriate for choice, dose, and duration. Empirical antifungal therapy was initiated in 63.7% of the patients and fluconazole was the most used antifungal (36.3%). In contrast to antibiotics, the majority of antifungal choices were not selected according to the recommendations and they were considered inappropriate for doses and the required treatment duration as proposed by (IDSA). Fifty-eight percent of patients received antivirals, even though it is not recommended as empirical treatment. In conclusion, this study reveals a non-consistent antimicrobial utilization practice at the involved sites concerning FN treatment. Inappropriateness was encountered in drug selection, dose, and duration of treatment with antifungals and antivirals.

Aspergillosis: an Update on Clinical Spectrum, Diagnostic Schemes, and Management.

This review gives an overview of the diseases caused by Aspergillus, including a description of the species involved and the infected clinical systems. We provide insight into the various diagnostic methods available for diagnosing aspergillosis, particularly invasive aspergillosis (IA), including the role of radiology, bronchoscopy, culture, and non-culture-based microbiological methods. We also discuss the available diagnostic algorithms for the different disease conditions. This review also summarizes the main aspects of managing infections due to Aspergillus spp., such as antifungal resistance, choice of antifungals, therapeutic drug monitoring, and new antifungal alternatives. The risk factors for this infection continue to evolve with the development of many biological agents that target the immune system and the increase of viral illnesses such as coronavirus disease. Due to the limitations of present mycological test methods, establishing a fast diagnosis is frequently difficult, and reports of developing antifungal resistance further complicate the management of aspergillosis. Many commercial assays, like AsperGenius®, MycAssay Aspergillus®, and MycoGENIE®, have the advantage of better species-level identification and concomitant resistance-associated mutations. Fosmanogepix, ibrexafungerp, rezafungin, and olorofim are newer antifungal agents in the pipeline exhibiting remarkable activity against Aspergillus spp. The fungus Aspergillus is found ubiquitously around the world and can cause various infections, from harmless saprophytic colonization to severe IA. Understanding the diagnostic criteria to be used in different patient groups and the local epidemiological data and antifungal susceptibility profile is critical for optimal patient management.

Antifungal Choice during Intravenous to Oral Cyclosporine Switch Effects Bioavailability in Patients Who Underwent Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Cyclosporine is a key drug during hematopoietic stem cell transplantation for the prevention of Graft-versus-Host disease with the potential for involvement in drug-drug interactions. We conducted this study to evaluate the effects of antifungals on cyclosporine blood levels and biavailability values. Material and Methods: Patients who had allogeneic hematopoietic stem cell transplantation with normal kidney and liver function and no other drug-drug interactions that could affect cyclosporine blood levels were included in the study. Patients were categorized into moderate (fluconazole) and strong (voriconazole, posaconazole) CYP3A4 inhibitor antifungal users and non-azole (amphotericin B, caspofungin) users. We collected intravenous and oral cyclosporine blood concentrations and doses during cyclosporine administration route changes and evaluated the effects of them according to antifungal groups. Results: We included 94 patients. The moderate and strong CYP3A4 inhibitor user numbers were 54 and 22, respectively. 18 patients with non-azole antifungal prescriptions were included. ANOVA revealed that there was a statistically significant difference in blood corrected concentrations (p<0.0001). The mean oral dose to intravenous dose ratio was 1.44 and 1.53 for the strong and moderate CYP3A4 inhibitor groups, respectively. This ratio was 1.51 for non-azole antifungal users. The median cyclosporine concentrations were higher after switching to oral cyclosporine in three antifungal groups. The highest mean cyclosporine concentration was 378,45 ng/mL and was obtained from patients with strong CYP3A4 inhibitor antifungals. The lowest mean cyclosporine concentration was observed in patients who were prescribed non-azole antifungals, which was subtherapeutic at 165,95 ng/mL. Bioavailability values were 1.17, 0.97, and 0.9 for moderate inhibitor, strong inhibitor, and non-azole users, respectively. In our study, the general oral dose to intravenous dose ratio regardless of the antifungal choice was 1.50. Despite having the lowest dose ratio (1.44), the highest bioavailability (1.17) was achieved by strong CYP3A4 inhibitor users, and nine of them experienced supratherapeutic cyclosporine levels. After applying a 1.53 dose ratio, the highest mean dose ratio among groups, the number of patients with supratherapeutic cylosporine levels increased to twenty-two from six. Eight patients with non-azole antifungal prescriptions still experienced subtherapeutic cyclosporine blood levels after the initiation of a 1.51 mean dose ratio, which suggests non-azole users may need higher oral cyclosporine doses (Figure 1). Conclusion: Cyclosporine is a gold medicine during the allogeneic hematopoeitic stem cell trasnplantation process. Concomitant antifungal therapy affects cyclosporine blood levels during cyclosporine administration.Patients who are prescribed non-azole antifungals such as caspofungin and amphotericin B are at an increased risk of Graft-versus-Host disease due to the lack of therapeutic cyclosporine levels. Patients with azole antifungals may face cyclosporine toxicities during cyclosporine route change due to hepatic enzyme inhibitions. For patients with strong CYP3A4 inhibitor antifungals such as voriconazole and posaconazole, the oral dose to intravenous dose ratio should be adjusted carefully to avoid toxicity. Fluconazole, a moderate CYP3A4 inhibitor, causes a wide range of cyclosporine blood levels, which makes it hard to advise strict dose ratios. Because patient responses to enzyme inhibitors varied in our study, we advise taking precautions on an individual basis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

232 To Report A Rare Case of Fungal Necrotising Otitis Externa (NOE) Centred on The Left Temporomandibular Joint (TMJ)

Abstract Introduction NOE is a rare life-threatening complication of otitis externa, affecting the skull base, mastoid and temporal bones. Pseudomonas aeruginosa account for 95% of cases, making fungal NOE unusual. Complications secondary to NOE include cranial neuropathies, meningitis and dural sinus thrombophlebitis. Case-study A 67-year-old man with stage-5 chronic kidney disease presented with left otalgia and otorrhea. He was treated with antipseudomonal topical antibiotics and microsuction for months as an outpatient. Aspergillus flavus was grown on an initial swab, but subsequent cultures were negative. Computerised Tomography scans revealed inflammatory changes in the left masticator space with mastoid bone involvement suggestive of left NOE. He received three months of intravenous anti-pseudomonal antibiotics, microsuction and topical aminoglycosides. Despite interventions symptoms persisted and magnetic resonance imaging scanning revealed disease progression into the left TMJ, prompting maxillofacial surgical opinion. Following washout of the TMJ, a tissue biopsy was positive for DNA on pan-fungal PCR, and the sequence identified as Aspergillus flavus group. The patient was successfully treated with oral posoconazole and topical amphotericin and discharged home. Conclusions Fungal NOE remains poorly treated as there is limited guidance on antifungal choice and duration of treatment. It should always be considered, particularly in immunocompromised patients with intractable cases of NOE

Impact of CYP2C19, CYP3A4, ABCB1, and FMO3 genotypes on plasma voriconazole in Thai patients with invasive fungal infections.

Voriconazole is the first‐line antifungal choice in the treatment of invasive fungal infections (IFIs). Single nucleotide polymorphisms (SNPs) in drug‐metabolizing and transporter genes may affect voriconazole pharmacokinetics. This study aimed to determine the frequency of the CYP2C19 rs4244285, rs4986893, rs72552267, and rs12248560, CYP3A4 rs4646437, ABCB1 rs1045642, and FMO3 rs2266782 alleles and determine the association between these genetic variants and voriconazole concentrations in Thai patients with invasive fungal infections. The study comprised 177 Thai patients with IFIs in whom seven SNPs in CYP2C19, CYP3A4, ABCB1, and FMO3 were genotyped using TaqMan real‐time polymerase chain reaction (RT‐PCR) 5´ nuclease assays, and voriconazole plasma concentrations were measured by high‐performance liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Of the 177 patients included, 31 were <12 years and 146 were ≥12 years. The CYP2C19 allele frequencies were 0.29 for *2, 0.060 for *3, 0.003 for *6, and 0.008 for *17. The allele frequency of CYP3A4 (rs4646437) was 0.26, ABCB1 (rs1045642) was 0.36, and FMO3 (rs2266782) was 0.16. The median voriconazole dose/weight was significantly lower in patients aged ≥12 years when compared to the patients aged <12 years (P < .001). Patients aged <12 years with CYP2C19*1/*2 exhibited significantly higher median voriconazole plasma concentrations than those with the CYP2C19*1/*1 (P = .038). However, there were no significant differences in median voriconazole plasma concentrations among the CYP2C19 genotypes in the patients aged ≥12 years. There was a lack of association observed among the CYP3A4, ABCB1, and FMO3 genotypes on the plasma voriconazole concentrations in both groups of patients. Our findings indicate that voriconazole plasma concentrations are affected by the CYP2C19*2 allele in patients aged <12 years but not in patients aged ≥12 years.

Frequency of the CYP2C19*17 polymorphism in a Chilean population and its effect on voriconazole plasma concentration in immunocompromised children

Invasive fungal infections (IFIs) are the most frequent cause of morbidity and mortality in immunocompromised children. Voriconazole is the first-line antifungal choice in the treatment of IFIs like aspergillosis. Voriconazole pharmacokinetics vary widely among patients and voriconazole is metabolized mainly in the liver by the CYP2C19 enzyme, which is highly polymorphic. The CYP2C19*17 allele is characterized by the presence of four single nucleotide polymorphisms expressing an ultra-rapid enzyme phenotype with an accelerated voriconazole metabolism, is associated with low (sub-therapeutic) plasma levels in patients treated with the standard dose. Considering that in our center a high percentage of children have sub-therapeutic levels of voriconazole when treated with standard doses, we sought to determine the frequency of the CYP2C19*17 polymorphism (rs12248560) in a Chilean population and determine the association between voriconazole concentrations and the rs12248560 variant in immunocompromised children. First, we evaluated the frequency of the rs12248560 variant in a group of 232 healthy Chilean children, and we found that 180 children (77.6%) were non-carriers of the rs12248560 variant, 49 children (21.1%) were heterozygous carriers for rs12248560 variant and only 3 children (1.3%) were homozygous carriers for rs12248560 variant, obtaining an allelic frequency of 12% for variant in a Chilean population. To determine the association between voriconazole concentrations and the rs12248560 variant, we analyzed voriconazole plasma concentrations in a second group of 33 children treated with voriconazole. In these patients, carriers of the rs12248560 variant presented significantly lower voriconazole plasma concentrations than non-carriers (p = 0,011). In this study, we show the presence of the rs12248560 variant in a Chilean population and its accelerating effect on the pharmacokinetics of voriconazole in pediatric patients. From these data, it would be advisable to consider the variant of the patient prior to calculating the dosage of voriconazole.

377. High Resistance and Mortality Rates in Patients With Ventricular Assist Device (VAD)-Associated Candidemia: A Need for Alternative Antifungal Strategies

BackgroundVADs are increasingly utilized in the management of end-stage heart disease. Infections are frequently encountered in VAD patients, are difficult to manage, and delay heart transplant. Prior studies have illustrated that fungal infections are rarer than bacterial infections but carry a higher mortality rate. Published data regarding the treatment and outcomes of fungal infections in VAD patients are scarceThe objective of this study was to describetreatment patterns, clinical outcomes and antifungal resistance rates in this unique patient population.MethodsThis was a retrospective cohort study that included VAD patients 18 years and older admitted to Baylor St. Luke’s Medical Center in Houston, Texas between 2009 and 2016 with a positive blood culture for Candida spp. Patients with more than one Candida spp. isolated were excluded. Patient data were collected using electronic medical records and microbiology laboratory reports.ResultsOut of 835 VAD patients screened, there were 57 candidemia episodes across 38 patients resulting in an incidence of 6.2%. C. glabrata was the most common species (13/38, 34.2%), followed by C. albicans (10/38, 26.3%), C. parapsilosis (6/38, 15.8), C. tropicalis (5/38, 13.2%), and C. krusei (3/38 (7.9%). Ten patients had an echinocandin nonsusceptible first isolate (26.3%). In patients with recurrent candidemia, echinocandin nonsusceptibility rose as high as 55.6%. Candida species was the only independent risk factor for antifungal nonsusceptibility (OR, 1.9; 95% CI, 1.0–3.4). Micafungin was the most common initial antifungal (34/38, 89.5%) but seven patients required salvage therapy with amphotericin and/or combination therapy (18.4%). Nineteen patients died prior to discharge (50.0%) and 29 patients died within 1 year (76.3%). Independent risk factors for in hospital mortality included APACHE II score (OR, 1.4; 95% CI, 1.1 – 1.8) and persistent candidemia (OR, 12.9; 95% CI, 1.3–129.6). Only three patients survived to heart transplant (7.9%).ConclusionResistance and mortality rates in this patient population are extremely high. Micafungin was the most common antifungal used but antifungal choice did not appear to impact 1 year mortality. While this is the largest cohort of patients with VAD-associated candidemia to date, larger, prospective studies are needed to guide management of these infections.Disclosures N. D. Beyda, Astellas: Grant Investigator and Scientific Advisor, Consulting fee and Research grant.

Iranian HIV/AIDS patients with oropharyngeal candidiasis: identification, prevalence and antifungal susceptibility of Candida species.

The Candida species recovered from oral cavity of 150 Iranian HIV/AIDS patients and their antifungal susceptibility profiles were reported. Candida albicans was the commonest Candida species, followed by C. dubliniensis, C. tropicalis, C. glabrata, C. kefyr and C. africana. All Candida isolates were susceptible to amphotericin B and caspofungin, while resistance to azoles was detected. The growing drug-resistance profile reported in clinical isolates of C. albicans and non-C. albicans strains is a serious problem in hospitals worldwide. Consequently, the suitable antifungal choice to treat the HIV/AIDS population with oral candidiasis needs to be rethought and new therapeutic options must urgently arise.

EQUAL Aspergillosis Score 2018: An ECMM score derived from current guidelines to measure QUALity of the clinical management of invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis is a serious threat to immunocompromised and critical care patients. Recent detailed guidelines and treatment algorithms lead microbiologists and clinicians in diagnosis and treatment of invasive aspergillosis. Currently, there is no tool available that allows to measure guideline adherence. To develop such a tool, we reviewed current guidelines provided by five scientific societies (European Society for Clinical Microbiology and Infectious Diseases, European Confederation of Medical Mycology, European Respiratory Society, Infectious Diseases Society of America (IDSA), and Infectious Diseases Working Party of the German Society for Hematology and Medical Oncology) and selected the strongest recommendations for management as key components for our scoring tool. We integrated diagnostic measures (chest computed tomography, bronchoalveolar lavage with galactomannan, fungal culture, fungal polymerase chain reaction analysis, species identification, susceptibility testing, histology with silver stain, Periodic acid-Schiff staining, and molecular diagnostics), treatment (antifungal choice and therapeutic drug monitoring), and follow-up computed tomography. The EQUAL Aspergillosis Score 2018 aggregates and weighs the components and provides a tool to support antifungal stewardship and to quantify guideline adherence.

Pulmonary Cryptococcosis in the Immunocompetent Patient-Many Questions, Some Answers.

Background. There are no prospective data regarding the management of pulmonary cryptococcosis in the immunocompetent patient. Clinical guidelines recommend oral fluconazole for patients with mild to moderate symptoms and amphotericin B plus flucytosine followed by fluconazole for severe disease. It is unclear whether patients who have histological evidence of Cryptococcus neoformans but negative cultures will even respond to drug treatment. We evaluated and managed a patient whose presentation and course raised important questions regarding the significance of negative cultures, antifungal choices, duration of therapy, and resolution of clinical, serologic, and radiographic findings.Methods. In addition to our experience, to answer these questions we reviewed available case reports and case series regarding immunocompetent patients with pulmonary cryptococcosis for the last 55 years using the following definitions: Definite - Clinical and/or radiographic findings of pulmonary infection and respiratory tract isolation of C. neoformans without other suspected etiologies; Probable - Clinical and radiographic findings of pulmonary infection, histopathologic evidence of C. neoformans, and negative fungal cultures with or without a positive cryptococcal polysaccharide antigen.Results. Pulmonary cryptococcosis resolves in most patients with or without specific antifungal therapy. Clinical, radiographic, and serologic resolution is slow and may take years.Conclusions. Persistently positive antigen titers are most common in untreated patients and may remain strongly positive despite complete or partial resolution of disease. Respiratory fungal cultures are often negative and may indicate nonviable organisms.

Investigation of the changes in Candida epidemiology

The incidence of fungal infections has increased in recent years. Antifungal resistance is a major problem with increasing frequency due to the widespread use of antifungal agents in infections. Identification of the Candida species and susceptibility patterns with the appropriate tests for resistance and selection of the empirical agents used for treatment are important. The aim of the study was to evaluate the changes of the epidemiology of Candida species and minimum inhibitory concentrations (MIC) of the antifungal agents, isolated in Mycology Laboratory of Ondokuz Mayıs University Faculty of Medicine, between 1 January 2009 to 1 July 2012. The study was performed retrospectively based on records in the mycology unit and checked comparatively with the automation system in the hospital. The recurrent reproductions of the same patient were excluded. For the identification of Candida species API®ID 32C (bioMerieux, France) system was used. Information on the isolated material, patient's age, gender and the inpatients' clinics were recorded. The susceptibility of Candida species isolated from blood cultures were studied with Etest (bioMerieux, France) method. A total of 1238 isolates were included in the study. The most common species isolated from clinical samples was C.albicans with a rate of 51.1% (n= 632), followed by C.tropicalis with a rate of 15.8% (n= 195). Among the pediatric intensive care unit (ICU) patients C.parapsilosis 42% (n= 17) was the most common isolate and the second most common isolate was C.albicans 32% (n= 13). However, in the adult ICU the most common isolate was C.albicans 34% (n= 13) and the second was C.parapsilosis 31% (n= 12). When the distribution of Candida species were analyzed from the records of last four years, the frequency rate of C.albicans and non-albicans species was found as 51.1% (n= 632) and %48.9 (n= 606), respectively. Based on these data, a comparison was made between the years and no difference between the two groups in terms of the distribution of fungi within the specified time (x²: 3.2, df: 1, p: 0.073) was determined. Of the Candida species isolated from blood cultures, seven isolates (2.2%) were resistant to fluconazole in the study period. The differences of MIC levels in fluconazole were detected between the years 2010-2012 and 2011-2012. The geometric mean of the MICs in 2012 increased significantly compared to 2010 and 2011 (p< 0.01). There was no resistance to amphotericin B except for intrinsically resistant Candida lusitaniae. There were no significant differences among amphotericin MIC values between years (p> 0.05). According to the sensitivity results, fluconazole is still seen as an option that can be used for the first choice. Although it remains as the first antifungal choice, antifungal susceptibility testing of the identified fungi will help the clinician for the plan and continuation of the treatment.

Clinical features of pulmonary cryptococcosis in non-HIV patients in Japan.

To clarify the clinical features of pulmonary cryptococcosis in Japanese non-HIV population. Retrospective investigation of 151 pulmonary cryptococcosis cases between 1977 and 2012 was executed. The underlying disease (UDs), aggravating factors, radiological characteristics, and treatment were examined. Sixty-seven patients (44.4%) had no UDs. The common UDs were diabetes (32.1%) followed by hematologic disease (22.6%), and collagen disease (22.6%). Peripherally distributed pulmonary nodules/masses were most commonly seen. Lesions in the right middle lobe (p = 0.01) and air bronchogram (P = 0.05) were significantly more frequent, respectively, in patients with UDs than patients without them. Azoles were mainly selected for the patients without meningoencephalitis. Mean treatment duration for patients with and without UDs was 6.64 and 2.87 months, respectively. Patients whose pulmonary nodules improved after treatment continued to experience gradual reduction of cryptococcosis antigen titers, even if antigen titers were positive at the time of treatment cessation. The average time for antigen titers to become negative after treatment cessation was 13.1 and 10.7 months for patients with and without UDs, respectively. When groups were compared according to the presence of meningoencephalitis complications, deaths, and survivals, factors contributing to cryptococcosis prognosis included higher age, hypoproteinemia, hypoalbuminemia, steroid use, high C-reactive protein levels, and meningoencephalitis complications. It is crucial to consider the presence of UDs and meningoencephalitis for the choice of antifungals and treatment duration for cryptococcosis in non-HIV patients. Three- and six months-administration of azoles for pulmonary cryptococcosis with or without UDs, respectively is reasonable.

Fluconazole versus an echinocandin for Candida glabrata fungaemia: a retrospective cohort study

We studied whether fluconazole or echinocandin treatment of Candida glabrata fungaemia results in superior outcomes. A multicentre, retrospective study was performed with 224 adult patients who received ≥ 5 days of therapy with either fluconazole or an echinocandin as their first antifungal treatment after collection of a blood culture that grew C. glabrata. The primary outcome was day 14 complete response. Patients in the echinocandin group were generally more ill, both at baseline and at the time of the index culture. Day 14 complete response was obtained in 58/127 (46%) and 50/97 (52%) of the fluconazole and echinocandin patients, respectively (P=0.383). Logistic regression found intensive care unit admission to be associated with failure [OR 0.456 (0.217-0.957), P=0.038] and echinocandin therapy to be associated with day 14 complete response [OR 2.305 (1.124-4.727), P=0.023]. Twenty-eight day survival was similar between the fluconazole and echinocandin groups and logistic regression did not reveal antifungal therapy choice to be independently predictive of mortality. For patients treated with fluconazole, a dose:MIC ratio >12.5 (when compared with a ratio ≤ 12.5) was associated with a significantly higher day 14 complete response [4/20 (20%) ≤ 12.5 versus 50/102 (49%) >12.5, P=0.025]. Severity of illness and choice of antifungal predict response in patients with C. glabrata fungaemia. Antifungal choice, however, does not influence mortality. In addition, new CLSI C. glabrata fluconazole susceptibility breakpoints are predictive of response when fluconazole is dosed appropriately.

Development of a Peptide Nucleic Acid Probe to Trichosporon Species and Identification of Trichosporonosis by Use of In Situ Hybridization in Formalin-Fixed and Paraffin-Embedded (FFPE) Sections

In order to identify Trichosporon species in formalin-fixed and paraffin-embedded sections from which visual discrimination of non-glabrata Candida species is mostly ineffective but critical for the choice of antifungals, we tested the usefulness of a newly designed peptide nucleic acid probe (PNA) for in situ hybridization (ISH). Results confirmed the usefulness of ISH with our PNA probe in identifying Trichosporon species from Candida albicans.

A study to evaluate the price control of antifungal medicines and its practical applicability

Background:Superficial fungal infections are common and treatment imposes economic burden on the patients. Government of India had introduced price control over griseofulvin and tolnaftate in 1995; however, this measure can only benefit the needy if the policy is harmonized with the health-care service provider, that is, dermatologists. The aim of this study was to evaluate the existing Government mechanisms over price control of antifungal medications and its reach to the people-in-need.Materials and Methods:A questionnaire-based, cross-sectional study was carried out over a period of 6 months. Questionnaire was mailed to members of a state branch of Indian Association of Dermatologists, Venereologists, and Leprologists. Responses reaching investigators within 2 months from the date of mailing were finally analyzed.Results:Among 93 (41.33%) respondents, only 6 (6.5%) were aware of existing price control over griseofulvin but none about tolnaftate. Thirty-nine (41.9%) respondents were in favor of introducing price control on terbinafine and 42 (45.2%) for itraconazole. The topically preferred antifungals were primarily azoles and terbinafine, while among systemic antifungals, dermatologists mostly preferred fluconazole and terbinafine. The choice of antifungals by the dermatologists matched with the evidence-based dermatology data.Conclusion:Currently, price-controlled antifungal drugs are less commonly used by practitioners. Although the dermatologists favor price control, the initiative undertaken by the Government has not reached them. This shows the need to bridge the gap between policy makers and health-care service providers to help the ailing population.

Hospital costs and outcomes among intravenous antifungal therapies for patients with invasive aspergillosis in the United States

This study determined the economic burden of aspergillosis-related hospitalisations in the United States during years when new antifungal treatments were introduced. A retrospective observational cohort study from the hospital perspective was conducted using national administrative data from the Premier Perspective™ Database. Patients (n=1603) coded for infection caused by Aspergillus species during 1835 admissions who received at least 3 days of intravenous antifungal therapy between 2000 and 2006 were included. All costs were inflated to $US 2006. Length of stay, hospital costs and mortality were compared after stratification by initial antifungal therapy. Median hospital costs were $ 52,803 (25,929-100,730) and did not differ by year over the study period. Intravenous antifungals accounted for 7.2% (range: 0.78-15.9%) of the cost of aspergillosis-related hospitalisation. Crude mortality was 36.7% and was the lowest in the last 2 years of the study (2005, 2006). Although antifungal utilisation changed over the course of the study, initial antifungal choice was not independently associated with crude mortality. In contrast, initial therapy with intravenous voriconazole was associated with reduced total hospitalisation costs and length of hospital stay. Treatment with amphotericin B lipid complex or caspofungin was also independently associated with a reduced length of hospital stay. In this large US study, mortality and costs for aspergillosis-related hospitalisations were considerable, but antifungals accounted for a small percentage of total costs associated with treatment and did not independently affect in-hospital crude mortality. Only initial treatment with intravenous voriconazole was associated with reduced total hospitalisation costs.

Antifungal Azoles: Old and New

Management of fungal infections is complex with increasing choice of antifungals. Mortality and morbidity are significant despite treatment. Azoles are commonly used compounds which inhibit fungal lanosterol 14 demethylase, thereby depleting ergosterol in the fungal cell membrane with the accumulation of lanosterol precursors. Imidazoles (miconazole, ketoconazole, clotrimazole) are used in topical preparations. Triazoles are used for prophylaxis, empirical and directed systemic antifungal therapy, and will be the focus of this review. There are important differences in structure, spectrum of activity, pharmacokinetics, drug interactions, and clinical indications.