Voriconazole Research Articles

2108. Comparison of Voriconazole vs. Itraconazole in the Treatment of Histoplasmosis – A Retrospective Analysis

BackgroundThe guideline-preferred azole for histoplasmosis (HP) is itraconazole (IC). While voriconazole (VC) has shown success in in-vitro and in retrospective analyses, there has not been enough data to include newer generation azoles as first-line treatment for infections with Histoplasma capsulatum.MethodsWe conducted a single-center retrospective cohort study of adult patients diagnosed with HP from 2002 through 2017. Data included demographics, clinical features and sites of infection, immune status, treatments, and mortality. Patients were categorized into two groups based on initial choice of azole (IC or VC) and mortality was compared between these two groups. The treatment groups were defined based on the first azole received, either IC or VC, as initial or as step-down therapy from amphotericin. Patients initiated on other azoles were excluded.ResultsWe identified 263 cases of HP from 2002 to 2017. After excluding patients initiated on other azoles, 194 patients remained. 175 (90%) patients were started on IC and 19 (10%) were started on VC, either as stepdown or initial choice of antifungal. There were no significant demographic differences between patients receiving IC compared with VC as their initial azole treatment. Patients with hematologic malignancies tended to be prescribed VC more frequently but this was not statistically significant (OR 3.1 [0.77–12.4]). Death occurred in 40 (23%) patients from the IC and 5 (26%) patients from the VC group. The hazard ratio for mortality with the use of VC was 1.21 (CI 0.4–3.6, P = 0.73).ConclusionIC is the mainstay in the treatment for HP. It appears that VC has comparable outcomes to IC and can be considered an alternative treatment option for HP, at least for patients with contraindications to IC treatment. Disclosures All authors: No reported disclosures.

1537. Multicenter Study with Therapeutic Drug Monitoring (TDM) of Voriconazole (VRCZ) in Japanese Patients

BackgroundTDM of VRCZ might be useful, especially in Asian people because of CYP2C19 genetic polymorphisms. However, limited data are available because of the small sample size.MethodsPatients who received VRCZ and had TDM were reviewed retrospectively at five institutions. Adequate VRCZ dosage was defined as a loading dose of 5–6 ± 0.5 mg/kg twice daily followed by a maintenance dose of 3–4 ± 0.5 mg/kg twice daily. For prophylaxis, the loading dose was left to the physician’s discretion. Optimal timing of TDM was defined as 4–7 days after starting therapy. Patients with adequate dosing and optimal timing of TDM were evaluated for analysis of trough levels (Cmin). Target Cmin was set at 1–5 µg/mL.ResultsThe study included 584 patients (treatment: 402; prophylaxis: 182). TDM was conducted on days 4–7 in 66.5% of patients (>7, 30.2%). A low adequate dosage (44.5%) was observed for treatment mainly because of a low performance of the loading dose (46.8%). Achievement of target Cmin was obtained in 62.7% (>5 µg/mL, 32.2%) in the treatment group and in 67.6% (11.0%) in the prophylaxis group. Seventy-one of 81 (81.7%) patients who required a dose reduction reached target Cmin by the second TDM. In 38 patients whose dose was not altered at oral switching, Cmin was significantly reduced from 2.5 ± 1.6 to 1.2 ± 1.3 μg/mL (P = 0.002), which indicated the necessity of TDM after oral switching. Hepatotoxicity occurred in 4.6% and visual symptoms in 7.9% of patients. Visual symptoms resolved without discontinuation of VRCZ in 73.9% of patients. Because of dosage adjustment based on TDM, high Cmin did not cause hepatotoxicity. However, the incidence of visual symptoms was significantly higher in patients with a high Cmin (12.7% vs. 5.4%, P = 0.002).ConclusionOne-third of Japanese patients who underwent VRCZ treatment with a loading dose showed high Cmin. Occurrence of hepatotoxicity was prevented with alteration of dosage in these patients (AMED, JP18fk0108045).Disclosures All authors: No reported disclosures.

2104. Susceptibility Trends in Antifungal Resistance (STAR) Study: Preliminary Data from A New Prospective Antifungal Surveillance Study

BackgroundThe development of new anti-infectives has increased rapidly over the past ten years. The need to support these important, life-saving products has increased as well. The STAR program was developed in 2018 to provide a repository of recent clinical fungal isolates with known susceptibility profiles and to monitor resistance trends over time. STAR reports the susceptibility patterns of the earliest STAR data concerning echinocandins, second-generation triazoles, and fluconazole against clinical Candida albicans and non-albicans strains including C. auris from worldwide sources.MethodsClinical isolates of Candida spp. (n = 203, from 2017–2018) from culture KOL investigator sites in the United States, Asia and the EU, were tested. Of these, 203 were isolated from blood or body tissues, and the remaining 11 from miscellaneous sources. Species distribution included mainly C. albicans, C. glabrata, C. krusei, C. lusitaniae, C. parapsilosis, C. tropicalis, and the emerging pathogen C. auris. Antifungals tested were amphotericin B (AMB), anidulafungin (ANID), fluconazole (FLU), isavuconazole (ISA), posaconazole (POS), and voriconazole (VOR). All testing was performed according to CLSI M27-A4 methodology.ResultsOverall, MIC50, MIC90, MIC range and percent susceptibility for each drug are listed in Table 1. Our data showed that for ANID, ISA and POS ≥ 93% of isolates were susceptible. While 84 and 88% were susceptible to FLU and VOR, respectively. Moreover, only 78% of isolates were susceptible to AMB. Interestingly, our data show that C. auris isolates were resistant to at least 1 antifungal with 15% of the C. auris strains (n = 40) showing multidrug resistance.ConclusionOngoing antifungal resistance surveillance like STAR is of utmost importance in order to monitor the efficacy of traditional empirical therapy and for the development of novel antifungal agents. This repository and ongoing STAR study will provide a resource to better support the biopharmaceutical industry’s goals to develop new and more potent antifungal agents. STAR will continue to monitor yeasts and will also include more unusual fungi including Mucor, Rhizopus amongst others. Disclosures All authors: No reported disclosures.

2118. Antifungal Susceptibility Testing of Clinical Isolates of Aspergillus in Mexico

BackgroundInvasive aspergillosis (IA) is a leading cause of morbidity and mortality in immunocompromised hosts. Triazole resistance in Aspergillus fumigatus is emerging globally. We performed antifungal susceptibility testing (AST) in Aspergillus isolates from Mexico and evaluated risk factors associated with 6 week mortality, including the MICs.MethodsAspergillus isolates from clinical samples were collected in a tertiary care center from 2014 to 2018. Species-level identification and broth microdilution following the CLSI M38 method were performed. MICs were interpreted according to epidemiological cutoff values. PCR and cyp51A gene sequencing were performed in A. fumigatus isolates with voriconazole (VRC) MIC >1 µg/mL. Data from the medical record were obtained to classify patients according to the MSG/EORTC criteria. The relationship between the MICs and 6-week mortality was described. Multivariate analysis of factors associated with six week mortality was performed.ResultsAST was performed on 85 Aspergillus isolates: 60/85 from patients with IA, 15/85 from patients with Aspergillus colonization, 2 patients with Aspergilloma, 1 with chronic otitis media and 1 with endophtalmitis. Information from 6 patients was unavailable. VRC MIC > 1 µg/mL was found in 3/38 (7.8%) A. fumigatus, from two patients with IA. Both had a TR34/L98H mutation in the cyp51A gene. Amphotericin B (AmB) MICs ≥ 2 were found in 16/49 (32%) A. fumigatus, 10/15 (66%) A. flavus and 1/14 (8%) A. niger. Forty-one patients with IA were treated: 29/41 (71%) with VRC or posaconazole, 7/41 (17%) with AmB and 5 with combination therapy. Overall, 6-week mortality was 30/49 (61.2%) among patients with IA; 2/2 (100%) when VRC MIC >1 µg/mL and 12/19 (63%) when AmB > 2 µg/mL, of which only 4 patients received initial treatment with AmB. Age older than 65 years (OR 11.8; 95% CI 1.14–123) and hepatic failure (OR 7.9; 95% CI 1.22–50.9) were independently associated with 6-week mortality in multivariate analysis.ConclusionWe found a VRC MIC >1 µg/mL prevalence of 7.8% among A. fumigatus and a high prevalence of AmB MIC ≥ 2 among clinical isolates of Aspergillus in Mexico. Elevated mortality was seen in IA among older patients with hepatic failure. Larger epidemiological studies are warranted.Disclosures All authors: No reported disclosures.

255. Breakthrough Mucormycosis (BT-MCR) on Antifungals Having Mucorales Activity Portrays Worse Prognosis compared with BT-MCR on Mold-Active Antifungals with no Mucorales Activity

BackgroundBT-MCR is known to develop in the setting of agents having Aspergillus but no Mucorales activity. However, BT-MCR can occur even with the use of antifungals having with Mucorales activity in patients with hematologic malignancies and or stem cell transplant (HM).MethodsWe reviewed the records of HM patients treated for MCR (1994 to 2019) at MD Anderson Cancer Center. We identified patients with BT-MCR on antifungals having Mucorales activity: posaconazole (POSA), isavuconazole (ISA), and amphotericin B (AMB) (group A), and patients with BT-MCR on agents having Aspergillus but no Mucorales activity: voriconazole (VRC), itraconazole (ITZ), echinocandins (group B). BT-MCR was defined as MCR diagnosis (dx) after ≥7days (d) of antifungal use. The primary outcome was 42d mortality after the BT-MCR dx. Chi-square or Fisher’s exact test was used for categorical variables and Wilcoxon rank-sum test used for continuous variables. Cox regression model was used to evaluate the independent variables on outcome.ResultsWe identified 11 patients in group A (3 POSA, 5 ISA, 3 AMB) and 81 patients in group B (61 VRC, 13 echinocandins, 7 ITZ). Both groups were not different in terms of age, sex, underlying HM (AML/MDS in 100% vs. 88% in groups A and B, respectively), status of HM (active disease in 82% vs. 67%), prior stem cell transplant (45% vs. 54%) or GvHD (80% vs. 84%), neutropenia at dx (55% vs. 42%), prior receipt of >600 mg of prednisone (45% vs. 41%) or ICU at MCR dx (36% vs. 26%). Similarly, Mucorales species (Rhizopus spp. in 55% vs. 49%) and type of infection (sino-pulmonary in 73% vs. 68%) were no different between the groups. However, both d42 (82% vs. 46%, P = 0.025) and d84 (100% vs. 60%, P = 0.007) mortality was worse in group A. Similarly, median time to death was faster in patients in group A (26d, range 7-80d), vs. group B (42d, range 4–3146d, P = 0.031). Kaplan–Meier analysis showed a similar difference (Figure 1). In multivariate analysis, neutropenia (P = 0.038) and ICU at dx (P = 0.002) were independent factors on day 42d mortality in all 92 patients with prior Mucorales–active antifungals showing a trend associated with poor outcome (P = 0.17).ConclusionBT-MCR on agents having Mucorales activity is a marker of poor prognosis in HM patients. Early use of investigational immunotherapy and salvage antifungal chemotherapy studies is needed in that subgroup of patients. Disclosures All authors: No reported disclosures.

1696. Epidemiology, Clinical Characteristics and Outcomes of Invasive Aspergillosis in a Tertiary Care Hospital in Mexico

BackgroundInvasive aspergillosis is an important cause of life-threatening infection in immunocompromised patients. The objective was to describe the epidemiology, clinical characteristics, and outcome of patients with invasive aspergillosis (IA) in a tertiary care center in Mexico.MethodsA laboratory-based survey was done to identify patients with positive Aspergillus culture or galactomannan from 2014 to 2018. The medical records were reviewed to include patients with proven and probable IA, according to the EORTC criteria. Descriptive analysis of clinical characteristics and risk factors for 6-week mortality was made through X2, T-test or Mann–Whitney test. A multivariate logistic regression model including variables with a P-value of <0.2 in univariate analysis was made.Results240 cases of IA were identified: 193 (80%) probable, 27 (11%) proven, and 20 (8.3%) not meeting the EORTC criteria but considered infection. 53% were male, median age was 44 years (IQR 28–58), 78 (32.5%) had acute leukemia (AL), 42 (17.5%) hematological neoplasia, 29 (12%) hematopoietic stem-cell transplant (HSCT), 25 (10.4%) solid-organ transplant and 44 (18.3%) autoimmune diseases, 17.5% patients with AL underwent induction remission chemotherapy of which 31% received antifungal prophylaxis. Among patients with IA, 183 (82%) had a positive galactomannan and 109 (45%) had a culture with Aspergillus. Eleven had > 1 species: 55/120 (46%) were A. fumigatus, 18 (15%) A. niger and 18 (15%) A. flavus. Pulmonary disease occurred in 214 (89%). 212 patients (88%) received antifungal treatment with a median duration of 42 days (IQR 20–42). 129 (61%) received voriconazole (VRC), 20 (8.3%) Amphotericin B and 20(8.3%) were randomized to a posaconazole vs. VRC trial. Six-week mortality was 35% (n = 85). Lymphopenia (OR 3.6; 95% CI 1.4–9.0), liver failure (OR 3.3; 95% CI 1.7–6.5) and older age (OR 1.03; 95% CI 1.01–1.05) (marginally) were independently associated with increased 6-week mortality.Conclusion240 patients with IA were identified in a 5-year period in a tertiary care center. Most had hematological neoplasias and low prevalence of antimold prophylaxis due to economical reasons. Six-week mortality was 35%, nonsurvivors had liver failure and lymphopenia more often. Increased awareness to prevent IA is needed. Disclosures All authors: No reported disclosures.

1579. Multidrug-Resistant Candida auris Isolates From New York Hospitals and Healthcare Facilities Are Susceptible to Antifungal Combinations

Background Candida auris outbreak continues unabated in New York with the current case counts exceeding 300 patients. We used a modification of standard CLSI broth microdilution method (BMD) if two-drug combinations are efficacious against C. auris isolates with high-resistance to fluconazole (FZ, MIC50 >256 mg/L), and variable resistance to other broad-spectrum antifungal drugs.MethodsBMD plates were custom-designed and quality controlled by TREK Diagnostic System. The combination tests of 15 drug-resistant C. auris involved microtiter wells with the initial 144 two-drug combinations and their two-fold dilutions (1/2–1/32) to get 864 two-drug combinations finally. We utilized MIC100 endpoints for the drug combination readings as reported earlier for the intra- and inter-laboratory agreements obtained against Candida species and Aspergillus fumigatus (Antimicrob Agents Chemother. 2015. 59:1759–1766). We also tested minimum fungicidal concentrations (MFC).ResultsWe tested all possible 864 two-drug antifungal combinations for nine antifungal drugs in use to yield 12,960 MIC100 readings, and MFC readings for 15 C. auris isolates. Flucytosine (FLC) at 2.0 mg/L potentiated most successful combinations with other drugs. Micafungin (MFG), Anidulafungin (AFG), Caspofungin (CAS) at individual concentrations of 0.25 mg/L combined well with FLC (2.0 mg/L) to yield MIC100 for 14, 13, and 12 of 15 C. auris isolates tested, respectively. MFG/FLC combination was also fungicidal for 4 of 15 isolates. AMB / FLC (0.25/1.0 mg/L) yielded MIC100 for 13 isolates and MFC for three test isolates. Posaconazole (POS), and Isavuconazole (ISA) and Voriconazole (VRC) also combined well with FLC (0.25/2.0 mg/L) to yield MIC100 for 12, 13, and 13 isolates, respectively. POS/FLC combination was fungicidal for three isolates.ConclusionWe identified seven two drug-combinations of antifungals efficacious against drug-resistant C. auris strains. The modified BMD combination susceptibility testing could be used by the clinical laboratories to assist providers with the selection of optimal treatment for C. auris candidemia. Disclosures All authors: No reported disclosures.

738. Potent In Vitro activity of Rezafungin (RZF) Against Aspergillus Clinical Isolates Recovered From Lung Transplant Patients Who Have Received ≥3 Months of Triazole Prophylaxis

BackgroundEmergence of azole resistance globally among Aspergillus species has major one health implications for humans and agriculture. At our center, isavuconazole (ISA), posaconazole (POS) and voriconazole (VOR) have been used as antifungal prophylaxis for at least 3 months or as pre-emptive therapy in solid-organ transplant (SOT) patients. We previously showed that azole breakthrough (BT) fungi were more likely to be non-fumigatus Aspergillus (non-Af) spp. In addition, azole BT isolates exhibited higher azole MICs than non-BT isolates, with 7% pan-azole resistance. RZF is an investigational echinocandin with long serum half-life, suitable for prolonged dosing intervals. We determined caspofungin (CAS) and RZF minimum effective concentrations (MECs) against Aspergillus isolates from our center.Methods Aspergillus recovered from 111 patients between December 2016 and April 2018 were tested. MICs (minimum inhibitory concentrations; azoles) and MECs (echinocandins) were measured. Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258 were used as QC controls.Results71% (79) of isolates were from SOT patients. Aspergillus spp. were A. fumigatus (Af, 73), A. flavus (Afl, 12), A. niger (An, 9), A. terreus (At, 8), A. calidoustus (Ac, 7), and A. lentulus (Al), A. glaucus, A. thermomutatus, and A. thermomutatus (At; 1 each). 7% of Aspergillus isolates exhibited VOR, POS and ISA MICs ≥2, ≥8 and ≥1 µg/mL, respectively. RZF MEC50 and range of MEC by Aspergillus spp.are summarized in the Table. Overall, there was no difference in MECs between CAS and RZF (P = 0.21). 6% (7) and 7% (8) of the non-Af isolates exhibited CAS and RZF MECs >0.5 µg/mL, respectively. 5 isolates exhibited CAS and RZF MEC ≥16 µg/mL.ConclusionDespite concerns over azole resistance among Aspergillus, these agents remain frontline against invasive aspergillosis. The excellent activity of RZF and CAS shown here suggests that the drugs are potential therapeutic options for patients infected with azole BT Aspergillus, including azole-resistant isolates. The long-half-life and high tolerability of RZF make this agent an attractive consideration for antifungal prophylaxis. A clinical trial of RZF prophylaxis in stem cell transplant recipients is planned. Disclosures All authors: No reported disclosures.

2105. Liposomal Amphotericin B Use Before and After Implementation of Voriconazole Prophylaxis in Cancer Patients

BackgroundInvasive fungal infections (IFI) are life-threatening complications of prolonged neutropenia in hematologic cancer or after hematopoietic stem cell transplantation (HSCT). Guidelines recommend mold prophylaxis (ppx) for patients at high risk of IFI. Patients receiving ppx with new signs of infection are often escalated to Liposomal Amphotericin B (L-AmB) for concerns of breakthrough mold infections. We describe the impact of implementing voriconazole (VZL) ppx in cancer patients.MethodsWe performed a quasi-experimental study of all adult patients prescribed L-AmB for ≥1 dose in Cancer Center at the University of Maryland Medical Center. VZL ppx was implemented for patients with hematologic cancer with anticipated prolonged neutropenia (≥ 7 days) in 4/2017. HSCT patients routinely received posaconazole ppx for ≥ 1 year during study period. Comparisons were made pre (November 2015–June 2017) and post (July 2017–December 2018) implementation of VZL ppx allowing for 3-month wash-in period. Cancer center-specific L-AmB days of therapy (DOT) per 1,000 patient-days (PD) were compared using segmented regression and Student t-test. Comparison of patient characteristics, mortality, nephrotoxicity and hospital length of stay (LOS) among patients receiving L-AmB in pre vs. post periods was done using Χ 2 and Student t-test.ResultsThere were 87 (24 pre, 63 post) unique patients included in the analysis, translating to a total of 17.6 L-AmB DOT per 1,000 PD for the study period. Mean L-AmB utilization in cancer center was 9.9 and 24.4 DOT per 1,000 PD (P = 0.0037) for pre and post-implementation, respectively. There was an average 16% increase of L-Amb quarterly (P = 0.93). Among patients receiving L-AmB, most had acute myelogenous leukemia (63% vs. 60%) with lung source (71% vs. 73%, P = 0.8). More patients had proven IFI pre-implementation (42% vs. 29%, P = 0.3). Nephrotoxicity (46% vs. 48%, P = 0.9), median LOS (17 vs. 28, P = 0.4) and inpatient mortality (30 % vs. 38%, p = 0.5) all increased without statistical significance.ConclusionAfter implementation of VZL ppx there was a significant increase in L-AmB use, and associated non-significant increases in LOS, mortality and nephrotoxicity for those receiving L-AmB. Larger, robust longitudinal studies are needed to better understand the implications of VZL ppx on this population. Disclosures All authors: No reported disclosures.

Bacterial flora distribution and antimicrobial resistance of pyogenic liver abscess: a multicenter retrospective study (A report of 897 cases)

Bacterial flora distribution and antimicrobial resistance of pyogenic liver abscess: a multicenter retrospective study (A report of 897 cases)

Frequency, virulence factors and antifungal susceptibility of Candida parapsilosis species complex isolated from patients with candidemia in the central region of Argentina

PurposeOur objectives were to report species distribution and survival of patients with candidemia in Argentina's central region and to establish the prevalence of C.parapsilosis sensu lato species, their virulence factors and their antifungal susceptibility profiles. MethodsYeasts isolated from bloodstream infections in Córdoba (Argentina) (n=35) were molecularly identified. The production of lipase and acid aspartic protease (Sap), the adhesion capacity, and the isolates’ ability to form biofilm were evaluated. The in vitro activity of 7 antifungal drugs was evaluated (CLSIdocument M27-4thed). ResultsC. albicans was the most prevalent species (48.57%) followed by C. parapsilosis sensu lato (28.57%). The 30-day survival rate for C. albicans candidemia was slightly lower than non-albicans blood infections (50.00% vs. 57.90%). C. parapsilosis sensu stricto and C. orthopsilosis account for 60% and 40% of the cryptic species. Sap production and biofilm formation capacity were higher in C. parapsilosis sensu strico than in C.orthopsilosis. All the strains were susceptible to caspofungin (CAS), anidulafungin (AFG), amphotericin B (AMB), posaconazole (POS) and voriconazole (VRC). Azoles were the most potent agent against C. parapsilosis sensu lato followed by echinocandins and AMB. There were no differences between MICs for fluconazole, VRC, POS and AMB. Contrarily, C. parapsilosis sensu stricto strains showed lower MIC than C. orthopsilopsis isolates for itraconazole and higher MIC values for echinocandins (P<0.01). ConclusionsWe report a high frequency of isolation of C.orthopsilosis in candidemia patients of central region. Data on the prevalence, virulence capability and antifungal susceptibility of C. parapsilosis complex provide new epidemiological information about these cryptic species in Argentina.

Voriconazole-Based Salts Are Active against Multidrug-Resistant Human Pathogenic Yeasts.

Voriconazole (VOR) hydrochloride is unequivocally converted into VOR lactates and valinates upon reaction with silver salts of organic acids. This study found that the anticandidal in vitro activity of these compounds was comparable or slightly better than that of VOR. The Candida albicans clinical isolate overexpressing CaCDR1/CaCDR2 genes, highly resistant to VOR, was apparently more susceptible to VOR salts. On the other hand, the susceptibility of another C. albicans clinical isolate (demonstrating multidrug resistance due to the overexpression of CaMDR1) to VOR salts was comparable to that to VOR. Comparative studies on the influence of VOR and its salts on Rhodamine 6G efflux from susceptible and multidrug-resistant C. albicans cells revealed that VOR salts are poorer substrates for the CaCdr1p drug efflux pump than VOR.

Comparison of intravitreal antifungal 100 μg voriconazole and 5 μg amphotericin B in experimental &lt;em&gt;Aspergillus flavus&lt;/em&gt; endophthalmitis model in rabbits

BACKGROUND Fungal endophthalmitis is a sight-threatening disease associated with high morbidity and Aspergillus sp. is the most common causes. Voriconazole (VCZ) and Amphotericin B (AmB) are the most used antifungal drugs, while head-to-head comparison for in vivo intravitreal efficacy is still unknown. This study was aimed to compare the efficacy of both agents against Aspergillus flavus. &#x0D; METHODS A randomized, masked, controlled-experimental study was conducted on 15 albino New Zealand white rabbits. Endophthalmitis was induced by intravitreal inoculation of Aspergillus flavus. Intravitreal injection was given 24 hours post-inoculation, the rabbits were divided into three groups; 100 μg/0.1 ml VCZ intravitreal injection, 5 μg/0.1 ml AmB, and control. Clinical evaluation of corneal opacity, aqueous cells and flare, and vitreous opacity using Yang’s method of quantification were performed at day 1, 3, 5, 7, and 10 after treatment. Mycology quantitative analysis and histopathological examination were performed at the final evaluation. &#x0D; RESULTS Clinical evaluation showed improvement of inflammation in the VCZ and AmB treatment groups (Δ score −2.1 [2.8] and −1.0 [3.2]) compared with the control group (Δ score 0.8 [3.1]). Although the VCZ group demonstrated a better clinical response with less inflammation and relatively intact retina structures in the histopathology result. Number of fungal colony was significantly less in AmB group (CFU/0.1 ml, p &lt; 0.05). &#x0D; CONCLUSIONS Favorable clinical improvement was shown in VCZ group compared to AmB group. Intravitreal VCZ showed a better clinical response tendency for Aspergillus flavus-induced endophthalmitis in rabbits.

Clinical efficacy and safety of the anti-fungus treatment in advanced elderly patients with fungemia admitted into geriatric ICU

Objective To observe the species distribution, clinical features, efficacy and safety of anti-fungus therapy in advanced elderly patients with fungemia. Methods Clinical data of patients aged 70 years and over with fungemia admitted into geriatric intensive care unit (GICU) of our hospital from Nov. 2012 to Nov. 2017 were retrospectively analyzed. The specie distribution, liver toxicity, differences in biochemical liver and renal functions before and after 28 days of treatment between the caspofungin group and the azole group (fluconazole plus voriconazole), and 28-d survival rate and its risk factors for death were analyzed. Results A total of 72 patients were enrolled, with a median age of 85.5 years (83, 90), a median score of Acute Physiology and Chronic Health Enquiry (APACHE-Ⅱ) of 25.5 (20.3, 31.5), a median score of Sequential Organ Failure Assessment (SOFA) 7 (4.0, 9.8). There were 33 patients (45.8%) with diabetes, 2 patients (2.8%) with hematological diseases, 44 patients (61.1%) with solid tumors and 18 patients (25.0%) with renal insufficiency. Thirty patients (41.7%) needed mechanical ventilation. The detection rate of Candida parapsilosis was 73.6% (53 cases), Candida famata 9.7% (7 cases), Candida tropicalis 5.6% (4 cases), Candida albicans 2.8% (2 cases), Candida glabrata 2.8% (2 cases) and others 5.6% (4 cases). The incidence rate of total liver toxicity was 23.6% after anti-fungus treatment. After 28 days of treatment, 29 patients survived in the caspofungin group (n=42) and 16 patients survived in the azole group (n=30). There were no significant differences in liver and renal function between the two groups before and after treatment. Logistic regression analysis showed that solid tumors (OR: 19.904, 95%CI: 1.944-203.808) and the median APACHE Ⅱ score were the independent risk factors for 28-day death in advanced patients with fungemia. Conclusions Fungemia is becoming more and more prominent in the GICU, which requires clinician’s constant attention in order to provide more basis for the treatment of fungemia in elderly patients. Key words: Intensive care; Fungemia

High prevalence of itraconazole resistance among Candida parapsilosis isolated from Iran.

Background and Purpose:Candida parapsilosis isolates usually have a low minimum inhibitory concentration (MIC) against azoles. Although Candida parapsilosis isolates usually have low MICs against azoles, recent studies candida invasive infections due to azole resistant-C. parapsilosis isolates . Regarding this, the main aim of this study was to determine the susceptibility pattern of Iranian clinical C. parapsilosis against available azole antifungal drugs.Materials and Methods:This study was conducted on 105 previously-identified isolates of C. parapsilosis sensu stricto. For the purpose of the study, the isolates were subjected to antifungal susceptibility testing against fluconazole (FLZ), itraconazole (ITZ), voriconazole (VRZ), and two new azole drugs, namely luliconazole (LUZU) and lanoconazole (LZN). The broth microdilution reference method adopted in this study was according to the Clinical & Laboratory Standards Institute M27-A3 and M27-S4 documents.Results:According to the results, 89% (n=94) of C. parapsilosis isolates showed a MIC of ≥ 1 µg/ml, indicating resistance against ITZ. Multi-azole resistance was observed in 3.8% of the isolates. In addition, LUZU and LZN demonstrated the highest efficacy with the MIC50 values of 0.5 and 1 µg/ml, respectively.Conclusion:The majority of the isolates showed high MIC values against ITZ. This may have been associated with the long-term ITZ prophylaxis/therapy in patients infected with candidiasis. Hence, the adoption of an appropriate antifungal agent is a crucial step for starting the treatment.

In vitro synergy of azole antifungals and methotrexate against Candida albicans

ObjectiveThis study aims to evaluate the effective of azoles and MTX for patients with invasive candidiasis. MethodsWe used the disk diffusion assay and the checkerboard assay to evaluate the in vitro interactions between MTX and antifungals. In addition, we used the transmission electron microscopy to observe the ultrastructure of the effect of MTX and fluconazole on Candida albicans. ResultsThe rates of synergy for the combination of MTX with fluconazole (FLC), itraconazole (ITC), and voriconazole (VRZ) were 91.3%, 65.2%, and 87% in checkerboard testing. No antagonism was found between methotrexate and azole antifungals in any of the strains. Furthermore, MTX treated C. albicans showed extensive cell wall vacuolations and the inhibition of blastospores growth, as observed using transmission electron microscopy. There was an apparent destruction of the cell membrane and cell wall resulting in the destruction of cytoplasm, a phenomenon observed when MTX was combined with azoles. ConclusionThis study provides evidence that the combination of azoles and MTX is effective for patients with invasive candidiasis, which on the other hand, will reduce the side effects of the drugs.

Placental and breastmilk transfer of voriconazole to offspring from pregnant and lactating bottlenose dolphins (Tursiops truncatus).

Fungal pneumonia is a common disease in bottlenose dolphins (Tursiops truncatus), including pregnant and lactating ones. Voriconazole (VRCZ) is commonly used to treat respiratory fungal infections in this species; however, it is unknown whether VRCZ is transferred via the placenta and breastmilk and whether its usage is safe in pregnant and lactating dolphins. We measured VRCZ concentrations in breastmilk and dams', umbilical cord, and calves' plasma samples from four dam-calf dolphin pairs in the Port of Nagoya Public Aquarium, Japan, treated with or without VRCZ. Three pregnant and/or lactating dams were administered VRCZ (loading dose 1.5-2.3mg/kg, for 3 days; maintenance dose 1.5-3.1mg/kg, every 5-18 days), twice daily, orally, without side effects in dams or calves. VRCZ was detected in two dams' umbilical cord plasma (0.14 and 2.35μg/ml) and in one calf's plasma (0.18μg/ml), collected immediately after birth. Further, VRCZ was detected in breastmilk samples (maximum 13.45μg/ml) from three VRCZ-administered dams and in plasma from three calves (maximum 7.54μg/ml) given or nursed from VRCZ-administered dams' breastmilk. The calves' plasma VRCZ concentrations varied, depending on the amount of breastmilk and food consumed. VRCZ concentrations were higher in breastmilk samples than in dams' plasma. To our knowledge, this is the first report on placental and breastmilk VRCZ transfer to offspring in bottlenose dolphins. During VRCZ medication in pregnant and lactating bottlenose dolphins, it is crucial to monitor plasma VRCZ concentrations and any side effects in dams as well as in their calves.

Candida türlerinin flukonazol, vorikonazol, amfoterisin B'ye karşı duyarlılıklarının disk difüzyon ve mikrodilüsyon yöntemiyle araştırılması

In this study, we aimed to investigate the antifungal susceptibility profile of Candida isolates obtained in our hospital with two methods. A total of 200 Candida isolates were obtained from samples of patients in various departments of our hospital. Identification of each strain was performed using conventional (germ tube formation, microscopic morphology in corn meal-Tween 80 agar), and commercial kit API 20C (Biomerieux, France). MIC values of fluconazole (FLU), voriconazole (VORI), and amphotericin B (AMB) were evaluated according to Clinical Laboratory Standards Institute broth microdilution and disk diffusion (DD) method. Totally isolated 200 Candida species were identified as 100 C. albicans, 25 C. glabrata, 7 C. krusei, 43 C. parapsilosis, and 25 C. tropicalis. All isolates were susceptible to VORI. High resistance rate (22,5%) was detected for AMB antifungal by reference microdilution method. Between two methods, the best categorical ratio was calculated as VORI (99%), FLU (84.9%), and AMB (72,5%) respectively. Voriconazole exhibited better activity in vitro than fluconazole, even in isolates fluconazole resistant and disk diffusion method can be considered as alternative antifungal sensitivity method for VORI.

In Vitro Efficacy of Chlorhexidine and a riboflavin/UVA Combination on Fungal Agents of Keratitis

ABSTRACT Purpose Mycotic keratitis is a global ophthalmological problem because it is difficult to diagnose and treat. The aim of the current study was to evaluate the efficiency of using antifungal agents amphotericin B (AMB), voriconazole (VRC), 0.02% chlorhexidine (CHX), and a combination of riboflavin and UVA treatment against two fungal genera (Aspergillus and Fusarium) responsible for keratitis. Methods We evaluated antifungal efficiencies of riboflavin/UVA and the antifungal drugs VRC, AMB, and CHX (alone and in combination) against fungal inocula at four concentrations. We recorded colony counts of isolates for Aspergillus terreus, A. flavus, A. fumigatus, Fusarium falciforme, F. proliferatum, and F. solani on Mueller-Hinton agar plates. Results Fungal suspensions exposed to the following treatment combinations did not allow fungal growth: riboflavin/UVA and VRC, riboflavin/UVA and AMB, riboflavin/UVA and CHX, and CHX alone. We observed a statistically significant reduction (P < .05) in the number of colonies on agar plates when fungal suspensions were treated with riboflavin/UVA, VRC, and AMB only. Conclusions Riboflavin/UVA treatment in combination with AMB, VRC, and CHX are capable of killing keratitis-inducing fungi (P < .05). The antiseptic CHX exerted a considerable antifungal effect on all strains we examined. Therefore, we recommend CHX as additional therapy against mycotic keratitis, particularly when keratitis is caused by multi-resistant members of Fusarium.

Metabolomics Investigation of Voriconazole-Induced Hepatotoxicity in Mice.

Voriconazole (VCZ) is a widely used triazole drug for the treatment of serious incidence of invasive fungal infections (IFIs), and its most commonly reported clinical side effect is hepatotoxicity. The mechanism of VCZ-induced hepatotoxicity is unclear, and no specific marker can be used for prediction and diagnosis. This study aims to apply the targeted metabolomics approach to identify specific VCZ-induced metabolites related to hepatotoxicity via liquid chromatography-triple quadrupole mass spectrometry (LC-QqQ-MS) in a C57BL/6 mouse model. Mice treated with three repeated doses of 40 mg/kg VCZ by tail vein injection to induce hepatotoxicity (VCZ-induced hepatotoxicity group, n = 8) were compared with mice without treatment (control group, n = 10). Both liver tissue and plasma were collected and analyzed to propose underlying mechanisms associated with VCZ-induced hepatotoxicity. The results indicated that the metabolites associated with oxidative stress were altered, and alterations in the metabolites involved in glutathione biosynthesis were noticed. The ratio of glutamine to glutamate showed a significant reduction in the VCZ-induced hepatotoxicity group compared to the control group, suggesting that glutamine might be transformed into glutamate for glutathione biosynthesis. Accordingly, we proposed that VCZ-induced hepatotoxicity is associated with oxidative stress to cause cell dysfunction, leading to alterations in energy metabolism, the urea cycle, and nucleoside metabolism. To the best of our knowledge, this is the first study to apply metabolomics for investigating the mechanism of VCZ-induced hepatotoxicity.