isavuconazole and posaconazole

The genus Blastobotrys consists of at least 20 species. Disease in humans has been reported with B adeninivorans, B raffinosifermentans, B proliferans and B serpentis, mostly in immunocompromised patients and those with cystic fibrosis.. We report a lung infection secondary to B raffinosifermentans in a cystic fibrosis patient successfully treated with isavuconazole and review the literature of invasive infections caused this genus. We also evaluated clinical isolates in our laboratory for species identification and antifungal susceptibility.. Phylogenetic analysis was performed on a collection of 22 Blastobotrys isolates in our reference laboratory, and antifungal susceptibility patterns were determined for nine clinically available antifungals against 19 of these isolates.. By phylogenetic analysis, 21 of the 22 isolates in our collection were identified as B raffinosifermentans and only 1 as B adeninivorans. Most were cultured from the respiratory tract, although others were recovered from other sources, including CSF and blood. Isavuconazole, caspofungin and micafungin demonstrated the most potent in vitro activity, followed by amphotericin B. In contrast, fluconazole demonstrated poor activity. The patient in this case responded to isavuconazole treatment for breakthrough infection due to B raffinosifermentans that was cultured from pleural fluid while on posaconazole prophylaxis post-bilateral lung transplantation for cystic fibrosis.. Blastobotrys species are rare causes of infections in humans and primarily occur in immunocompromised hosts. In our collection, the majority of isolates were identified as B raffinosifermentans. To our knowledge, this is the first report of successful treatment of such an infection with isavuconazole.

Topics: Adult; Amphotericin B; Antifungal Agents; Cystic Fibrosis; Female; Fluconazole; Genes, Fungal; Humans; Immunosuppression Therapy; Microbial Sensitivity Tests; Mycoses; Nitriles; Phylogeny; Pneumonia; Pyridines; Saccharomycetales; Triazoles

Chronic pulmonary aspergillosis (CPA) is a chronic lung infection caused by. We discuss the approach to diagnosis and treatment of CCPA. We have searched the PubMed and EmBase databases (from inception till 31 October 2019) to identify studies describing the use of anti-fungal agents in CCPA.. Treatment for CCPA should be initiated with oral itraconazole for at least six months. In case of poor response or intolerance to itraconazole, voriconazole should be considered. Intravenous agents, including amphotericin B and echinocandins, may be used in those with either treatment failure or those who are intolerant to oral antifungal agents. Posaconazole and isavuconazole may be used as salvage therapy due to a better pharmacokinetic/pharmacodynamic profile of the former and reduced drug-drug interactions with the latter.

Topics: Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Disease Management; Echinocandins; Humans; Itraconazole; Nitriles; Practice Guidelines as Topic; Pulmonary Aspergillosis; Pyridines; Triazoles; Voriconazole

Candidiasis is one of the most common opportunistic oral infections that presents different acute and chronic clinical presentations with diverse diagnostic and therapeutic approaches. The present study carries out a bibliographic review on the therapeutic tools available against oral candidiasis and their usefulness in each clinical situation.. Recent studies on treatment of oral candidiasis were retrieved from PubMed and Cochrane Library.. Nystatin and miconazole are the most commonly used topical antifungal drugs. Both antifungal drugs are very effective but need a long time of use to eradicate the infection. The pharmacological presentations of miconazole are more comfortable for patients but this drug may interact with other drugs and this fact should be assessed before use. Other topical alternatives for oral candidiasis, such as amphotericin B or clotrimazole, are not available in many countries. Oral fluconazole is effective in treating oral candidiasis that does not respond to topical treatment. Other systemic treatment alternatives, oral or intravenous, less used are itraconazole, voriconazole or posaconazole. Available novelties include echinocandins (anidulafungin, caspofungin) and isavuconazole. Echinocandins can only be used intravenously. Isavuconazole is available for oral and intravenous use. Other hopeful alternatives are new drugs, such as ibrexafungerp, or the use of antibodies, cytokines and antimicrobial peptides.. Nystatin, miconazole, and fluconazole are very effective for treating oral candidiasis. There are systemic alternatives for treating recalcitrant infections, such as the new triazoles, echinocandins, or lipidic presentations of amphotericin B.

Topics: Administration, Intravenous; Administration, Oral; Administration, Topical; Amphotericin B; Anidulafungin; Antifungal Agents; Azoles; Candidiasis, Oral; Caspofungin; Clotrimazole; Databases, Factual; Drug Interactions; Echinocandins; Fluconazole; Humans; Miconazole; Nitriles; Nystatin; Pyridines; Triazoles

Therapeutic drug monitoring (TDM) may be required to achieve optimal clinical outcomes in the setting of significant pharmacokinetic variability, a situation that applies to a number of anti-mould therapies. The majority of patients receiving itraconazole should routinely be managed with TDM. Voriconazole exhibits highly variable inter-individual pharmacokinetics, and a trough concentration of 1.0-5.5 mg/L is widely accepted although it is derived from relatively low-quality evidence. The case for TDM of posaconazole is currently in a state of flux following the introduction of a newer tablet formulation with improved oral bioavailability, but it may be indicated when used for either prophylaxis or treatment of established disease. The novel broad-spectrum azole drug isavuconazole does not currently appear to require TDM but 'real-world' data are awaited and TDM could be considered in selected clinical cases. For both polyene and echinocandin agents, there are insufficient data regarding the relationship between serum concentrations and therapeutic outcomes to support the routine use of TDM. A number of practical challenges to the implementation of TDM in the treatment of invasive mould infections remain unsolved. The delivery of TDM as a future standard of care will require real-time measurement of drug concentrations at the bedside and algorithms for dosage adjustment. Finally, measures of pharmacodynamic effect are required to deliver therapy that is truly individualized.

Topics: Antifungal Agents; Biological Availability; Drug Monitoring; Fungi; Humans; Invasive Fungal Infections; Itraconazole; Nitriles; Pyridines; Triazoles; Voriconazole

Invasive fungal diseases (IFDs) are a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Improvement in the management of IFDs have been achieved with the availability of new effective and safe antifungal drugs, however, many of these newer treatments have some limitations in their variable toxicity and unique predisposition for pharmacokinetic drug-drug interactions. Areas covered: This article is an update of a previous review published in this journal evaluating the safety profile of the antifungal drugs. Interesting new features include the availability of the new drug isavuconazole and the new tablet and intravenous formulations of posaconazole. Different dosages and new ways of administration of liposomal Amphotericin B (L-AmB) and echinocandins may be considered in the HSCT practice. Expert opinion: Nephrotoxicity continues to be a clinically relevant and frequent side effect of L-AmB which may cause a reduced clearance of other renally eliminated drugs frequently used in HSCT patients. Echinocandins are favorable therapeutic options in view of their low toxicity and uncommon drug-drug interactions. Important limitations of triazoles are represented by hepatic toxicity and certain side effects particularly after prolonged treatments. The new triazole isavuconazole and the new tablet formulation of posaconazole will be probably increasingly used in the HSCT setting not only due to their efficacy but in particular for their interesting toxicity profile and pharmacokinetic characteristics. The knowledge of these pharmacological findings is crucial in the daily care of allogeneic HSCT patients.

Topics: Amphotericin B; Antifungal Agents; Dose-Response Relationship, Drug; Drug Interactions; Hematopoietic Stem Cell Transplantation; Humans; Invasive Fungal Infections; Nitriles; Pyridines; Triazoles

Obesity is a worldwide epidemic associated with multiple comorbidities that increase the risk of hospitalization. Very little pharmacokinetic data are available for antifungal agents in obesity, as this population is often excluded from drug development studies and these agents are less commonly used than other antimicrobials. Systemic antifungal therapy for invasive candidiasis continues to have a high failure rate, and dose optimization in obesity provides an opportunity for improvement. Based on currently available data, some antifungals should be dosed based on total body weight (i.e. fluconazole), while others should not be adjusted for increased body weight (i.e. posaconazole). More studies are needed to determine if and when dosing changes are needed for many of the antifungal agents. Therefore, drug therapy regimens should be individually evaluated for dose optimization due to body weight.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Caspofungin; Echinocandins; Fluconazole; Humans; Lipopeptides; Micafungin; Mycoses; Nitriles; Obesity; Pyridines; Triazoles

Mucormycosis is an opportunistic mold infection whose management is difficult, as there is a paucity of evidence-based data. We summarize the latest advances in diagnosis and management of mucormycosis in transplant recipients.. There is promise for improvement in nonculture-based diagnostics with new biomarkers of Mucorales DNA that can be used for early diagnosis, and monitoring of response. Antifungal treatment consists of high-dose lipid formulations of amphotericin B or isavuconazole as the first-line therapy and posaconazole as salvage therapy. The new, pharmacokinetically more reliable formulations of posaconazole (intravenous, extended-release tablets) are welcomed improvements. Yet, the role of combination therapy is still uncertain. Surgery had a significant role in selected cases, such as in patients with rhinosinusitis form of mucormycosis, which nowadays can be performed with minimal invasive technique.. Mucormycosis remain a life-threatening opportunistic mold infection among transplant patients. Early diagnosis, prompt treatment with effective antifungals in combination with surgery if feasible is essential. Immune adjunct therapy and improvement of early diagnostics are important areas for future research. There are good prospects of progress in diagnostics and management of mucormycosis in transplant patients.

Topics: Amphotericin B; Antifungal Agents; DNA, Fungal; Humans; Mucorales; Mucormycosis; Nitriles; Opportunistic Infections; Pyridines; Salvage Therapy; Transplant Recipients; Triazoles

To review the current literature for the pathogenesis of mucormycosis, discuss diagnostic strategies, and evaluate the efficacy of polyenes, triazoles, and echinocandins as pharmacological treatment options.. An electronic literature search was conducted in PubMed using the MESH terms Rhizopus, zygomycetes, zygomycosis, Mucorales and mucormycosis, with search terms amphotericin B, micafungin, anidulafungin, caspofungin, extended infusion amphotericin B, liposomal amphotericin B, combination therapy, triazole, posaconazole, isavuconazole, diagnosis, and clinical manifestations.. Studies written in the English language from January 1960 to March 2016 were considered for this review article. All search results were reviewed, and the relevance of each article was determined by the authors independently.. Mucormycosis is a rare invasive fungal infection with an exceedingly high mortality and few therapeutic options. It has a distinct predilection for invasion of endothelial cells in the vascular system, which is likely important in dissemination of disease from a primary focus of infection. Six distinct clinical syndromes can occur in susceptible hosts, including rhino-orbital-cerebral, pulmonary, gastrointestinal, cutaneous, widely disseminated, and miscellaneous infection.. Diagnosis of mucormycosis is typically difficult to make based on imaging studies, sputum culture, bronchoalveolar lavage culture, or needle aspirate. Surgical debridement prior to dissemination of infection improves clinical outcomes. Surgery combined with early, high-dose systemic antifungal therapy yields greater than a 1.5-fold increase in survival rates. The Mucorales are inherently resistant to most widely used antifungal agents. Amphotericin B is appropriate for empirical therapy, whereas posaconazole and isavuconazole are best reserved for de-escalation, refractory cases, or patients intolerant to amphotericin B.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Caspofungin; Debridement; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Mucorales; Mucormycosis; Nitriles; Pyridines; Triazoles; Virulence

Mucormycosis is a rare, though increasingly prevalent, life-threatening fungal disease caused by Mucorales. The incidence has increased over the last decade and its mortality remains high at around 50%. Mucormycosis occurs mostly in patients with diabetes mellitus and/or in the context of immunosuppression resulting from chemotherapy for hematological malignancy, hematopoietic stem cell transplantation, or solid-organ transplantation. In this situation, lung and rhino-orbito-cerebral infections are the most frequent localizations of the disease. Prompt initiation of an effective treatment is essential to decrease mortality. However, mucormycosis and aspergillosis share close clinical and radiological features. Invasive procedures such as bronchial endoscopy and/or lung biopsy are necessary to confirm diagnosis, as no indirect tests are yet validated. Therefore, the challenge is to minimize the delay in diagnosis. When present, the reversed halo sign on CT scan is suggestive of mucormycosis. Quantitative polymerase chain reaction is a new promising approach to detect Mucorales DNA in serum and new molecular tools are available to detect Mucorales in tissues as well as to specify species. Recommendations from ECIL and ECMM/ESCMID have recently been published on management of mucormycosis. The recommended treatment is an amphotericin B lipid formulation in combination with surgery and modification of risk factors. High-dose (10 mg/kg) of liposomal amphotericin B is recommended in case of neurological involvement and posaconazole for maintenance therapy. Place of isavuconazole as well as posaconazole new formulations (tablets and intravenous) in first line treatment have to be defined. Improved radiologic descriptions of mucormycosis and new molecular tools may be key elements to help with rapid diagnosis in the future. Clinical trials are warranted to improve therapeutic success and hopefully survival.

Topics: Amphotericin B; Antifungal Agents; Combined Modality Therapy; Debridement; Hematopoietic Stem Cell Transplantation; Humans; Lung Diseases, Fungal; Mucorales; Mucormycosis; Nitriles; Pyridines; Triazoles

Coccidioidomycosis manifests as a variety of clinical manifestations and ranges in severity from asymptomatic exposure with resultant immunity to reinfection, to fulminant, and life-threatening disseminated disease. Primary coccidioidal pneumonia represents the most common clinical form of infection, and the incidence continues to increase. Within the endemic region, primary pulmonary coccidioidomycosis represents up to 29% of all community-acquired pneumonia emphasizing the frequency with which clinicians encounter this endemic mycosis. Chronic infection develops in 3 to 5% of patients, and almost all morbidity and mortality observed in coccidioidomycosis occur in these forms (e.g., chronic pulmonary disease, extrapulmonary manifestations). This review summarizes the ecology, epidemiology, manifestations of disease, and treatment options currently available for coccidioidomycosis.

Topics: Antifungal Agents; Coccidioides; Coccidioidomycosis; Humans; Nitriles; Pneumonia; Pyridines; Risk Factors; Triazoles; Voriconazole

Limited evidence exists on the effect of isavuconazonium sulfate and posaconazole delayed release tablets on tacrolimus dose-to-concentration ratios in lung transplant recipients.. The purpose of this evaluation was to assess the impact of novel triazoles on tacrolimus dose-to-concentration ratios.. This retrospective review included lung transplant recipient ≥18 years of age from January 1, 2017 to October 1, 2020 who received either posaconazole delayed release tablets or isavuconazonium sulfate for. A paired analysis evaluated outcomes pre-triazole and post-triazole initiation.. Forty-one patients met evaluation criteria for inclusion. A total of 34 of 41 patients received posaconazole delayed release tablets. Of these patients, 22 of 34 were transitioned from previous triazole to posaconazole delayed release tablets and experienced a 47% reduction in tacrolimus dose-to-concentration ratio. Twelve patients were newly initiated on posaconazole delayed release tablets and experienced a 50% reduction in tacrolimus dose-to-concentration ratios. Although not statistically significant, a 30% reduction in tacrolimus dose-to-concentration ratio was observed when transitioning to isavuconazonium sulfate from previous triazole therapy.. Limited data exists to provide guidance on tacrolimus dose adjustments with initiation and conversion of novel triazoles, however, this evaluation provides more knowledge on the drug interaction with novel triazoles and tacrolimus.

Topics: Antifungal Agents; Humans; Tablets; Tacrolimus; Triazoles

Invasive fungal infections (IFIs) are a common infectious complication during the treatment of acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS) or post hematopoietic cell transplantation (HCT). For these patients, the National Comprehensive Cancer Network recommends posaconazole or voriconazole for IFI prophylaxis. In clinical practice, however, there has been increased use of isavuconazole due to favorable pharmacokinetic and pharmacodynamic parameters despite limited data for this indication. The comparative prophylactic efficacy of antifungals in this patient population has not been reported, and an analysis is warranted.. This retrospective, matched cohort, single-center study, included AML, MDS, or HCT patients who began treatment or underwent transplant between January 1, 2015 and July 31, 2021. Isavuconazole patients were matched 1:2 with patients receiving posaconazole or voriconazole prophylaxis.. A total of 126 patients were included, 42 received isavuconazole, 81 received posaconazole, and three received voriconazole. The majority of patients were male receiving secondary IFI prophylaxis while receiving steroids for treatment of GVHD. The incidence of possible, probable or proven IFI was 16.7% in the isavuconazole group compared to 10.7% in the posaconazole and voriconazole group (OR 1.28, 95% CI -0.9-1.4; p = .67). Hepatotoxicity occurred in 16 total patients, 14 receiving posaconazole and two receiving isavuconazole.. Patients who received isavuconazole prophylaxis during AML induction therapy or post-HCT experienced a similar incidence of breakthrough fungal infections compared to those who received posaconazole or voriconazole. These results suggest no difference in antifungal prophylactic efficacy; however larger prospective comparative studies are needed.

Topics: Antifungal Agents; Female; Humans; Incidence; Invasive Fungal Infections; Leukemia, Myeloid, Acute; Male; Mycoses; Prospective Studies; Retrospective Studies; Voriconazole

We compared the antifungal susceptibility of 92 Mucorales isolates obtained by visual inspection and spectrophotometric readings following EUCAST (European Committee on Antimicrobial Susceptibility Testing) testing. Amphotericin B minimum inhibitory concentrations (MICs) were up to 1 mg/l against most isolates and variable among species, except for Cunninghamella bertholletiae. Posaconazole MICs against most isolates were up to 1 mg/l and high against Mucor circinelloides, some Rhizopus arrhizus, and Rhizopus microsporus. Isavuconazole MICs ranged between 1 and 8 mg/l but were invariably >8 mg/l against M. circinelloides and C. bertholletiae. The agreement between MICs obtained by visual endpoint or spectrophotometric readings was moderate and higher when using the ≥90% fungal growth inhibition endpoint.. The agreement between minimum inhibitory concentration (MIC) values obtained by visual inspection or spectrophotometric readings was moderate and higher when the ≥90% fungal growth inhibition endpoint was chosen. Isavuconazole presented higher MICs than posaconazole, regardless of the inhibition endpoint used.

Topics: Amphotericin B; Animals; Antifungal Agents; Itraconazole; Microbial Sensitivity Tests; Mucorales

Isavuconazole and posaconazole are commonly used for both prophylaxis and treatment of invasive fungal infections. These agents are formulated for oral administration as a capsule and delayed release (DR) tablet or suspension, respectively. In patients unable to swallow, alternative means of administration, such as crushing posaconazole DR tablets and opening isavuconazole capsules, may be used to avoid IV administration or use of posaconazole suspension, which often produces subtherapeutic concentrations.. To assess the feasibility of achieving target plasma drug concentrations with enteral feeding tube (EFT) administration of crushed posaconazole DR tablets and opened isavuconazole capsules.. We retrospectively reviewed pharmacy records to identify patients receiving EFT administration of posaconazole or isavuconazole with concurrent therapeutic drug monitoring from October 2019 to June 2021. Plasma concentrations of either agent as well as clinical outcomes were documented.. We identified 37 patients receiving 38 courses of EFT isavuconazole or posaconazole. The majority of patients received primary prophylaxis following lung transplantation (64.9%). Plasma concentrations upon first assessment were therapeutic in the majority of patients (posaconazole 71.5%, isavuconazole 83.3%) with a mean level of 1.61 ± 0.77 mg/L for posaconazole and 2.07 ± 1.1 mg/L for isavuconazole. Of those that were subtherapeutic on initial assessment, all but one subsequently achieved target levels upon dose titration. Standard maintenance doses were used in all isavuconazole and most posaconazole patients.. Our case series demonstrates that isavuconazole and posaconazole can be administered via EFT with concurrent therapeutic drug monitoring to achieve target plasma concentrations in the majority of patients.

Topics: Administration, Oral; Antifungal Agents; Capsules; Drug Monitoring; Enteral Nutrition; Humans; Nitriles; Pyridines; Retrospective Studies; Suspensions; Tablets; Triazoles

The surge of COVID-19 associated Mucormycosis (CAM) in India during the second wave of COVID-19 led to lack of availability of amphotericin B(AmB). We retrospectively evaluated the outcome in 28 consecutive patients with CAM who received posaconazole (PCZ) or isavuconazole (ISVCZ) as sole or predominant therapy, based on factors like availability, affordability, site of infection or lack of treatment response. Therapeutic drug monitoring was used for PCZ in all cases & for ISVCZ in some cases. Higher trough levels were aimed to ensure therapeutic effect. Overall, 16 patients were cured, 5 patients improved, 6 patients died, of which 2 deaths were attributable to mucormycosis and 1 patient was lost to follow-up. The outcomes and survival were comparable to those reported in the literature. Although wider applicability of these results cannot be assumed, it leads to a speculation that treatment of mucormycosis with PCZ or ISVCZ, without AmB, is possible.

Topics: Antifungal Agents; COVID-19; COVID-19 Drug Treatment; Humans; Mucormycosis; Nitriles; Pyridines; Retrospective Studies; Triazoles

Calcineurin inhibitors are commonly used in hematopoietic stem cell transplant (HSCT) patients to prevent graft versus host disease, but as CYP3A4 substrates they are frequently involved in drug-drug interactions. The purpose of this study is to characterize the effects of isavuconazole, fluconazole, and posaconazole on tacrolimus and cyclosporine serum concentrations and dose adjustments in allogeneic HSCT patients.. This retrospective study included patients admitted to Oregon Health and Science University between April 2008 and December 2018 who underwent hematopoietic stem cell transplantation and received concomitant tacrolimus or cyclosporine and fluconazole, isavuconazole or posaconazole therapy. Data on patient characteristics, drug dosing, and serum drug concentrations were collected through chart review, and descriptive statistics were used to summarize the results.. A total of 139 patients were included in this study. We found fluconazole initiation leads to a 25% reduction in both tacrolimus and cyclosporine doses in order to maintain goal serum concentrations. Posaconazole and isavuconazole initiation requires tacrolimus dose reductions by 53% and 21%, respectively.. Based on our experience, FLC, POS, and ISA initiation may require CNI dose reductions and close monitoring of CNI levels to ensure levels remain within goal serum concentrations. Larger studies are needed to fully quantify the percentage in CNI dose reductions and characterize differences among these antifungals.

Topics: Antifungal Agents; Cyclosporine; Fluconazole; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Nitriles; Pyridines; Retrospective Studies; Tacrolimus; Triazoles

Resistance of Aspergillus fumigatus to triazoles has been reported increasingly in Europe. As few data are available from Southern France, the objectives of this study were to assess the burden of A. fumigatus isolates with azole resistance from clinical specimens in Lyon, and explore the resistance mechanisms involved. In this retrospective cross-sectional study, 221 consecutive A. fumigatus isolates from respiratory samples were identified from an 8-month period from 195 patients attending the Pulmonary Medicine Departments of Lyon University Hospitals. Morphological identification was confirmed by sequence analysis of the β-tubulin gene. All samples were tested for susceptibilities to itraconazole, voriconazole, posaconazole and isavuconazole using concentration gradient strips, and the results were confirmed using the EUCAST broth microdilution method. Resistance mechanisms were investigated by sequencing the cyp51A gene and its promoter, and by expression analysis of cyp51 and genes encoding several efflux transporters. Four isolates exhibited azole resistance. Three isolates presented with polymorphisms in an intronic region of cyp51A, and one isolate had F46Y, M172V and E427K polymorphisms. No mutations were identified in the cyp51A promoter, but significant induction of cyp51A and cyp51B gene expression was observed for all four and three isolates, respectively. Significant induction of atrF and cdr1B gene expression was observed for two and three isolates, respectively. No significant induction of MDR1/2/3/4, MFS56 and M85 gene expression was observed. To conclude, the observed prevalence of azole resistance was 2.1%. Significant induction of expression of the cyp51 genes and two genes encoding efflux transporters was evidenced, underlying the diversity of resistance mechanisms to be explored.

Topics: Antifungal Agents; Aspergillus fumigatus; Cross-Sectional Studies; Cytochrome P-450 Enzyme System; France; Fungal Proteins; Hospitals, University; Humans; Itraconazole; Microbial Sensitivity Tests; Nitriles; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Pyridines; Respiratory Tract Infections; Retrospective Studies; Triazoles; Tubulin; Voriconazole

Aspergillus species are emerging causative agents of non-dermatophyte mold onychomycosis. In this study, 48 Aspergillus isolates were obtained from patients with onychomycosis in Mashhad, Iran, during 2015-2018. The aim is to identify the Aspergillus isolates to the species level by using partial calmodulin and beta-tubulin gene sequencing and MALDI-TOF MS, and to evaluate their in vitro susceptibility to ten antifungal drugs: terbinafine, itraconazole, voriconazole, posaconazole, ravuconazole, isavuconazole, caspofungin, micafungin, anidulafungin and amphotericin B according to CLSI M38-A3. Our results indicate that A.flavus (n = 38, 79%) is the most common Aspergillus species causing onychomycosis in Mashhad, Iran. Other detected species were A. terreus (n = 3), A. tubingensis (n = 2), A. niger (n = 1), A. welwitschiae (n = 1), A. minisclerotigenes (n = 1), A. citrinoterreus (n = 1) and A. ochraceus (n = 1). Aspergillus flavus, A. terreus and A. niger isolates were correctly identified at the species level by MALDI-TOF MS, while all cryptic species were misidentified. In conclusion, A. flavus is the predominant Aspergillus species causing onychomycosis due to Aspergillus spp. in Mashhad, Iran. MALDI-TOF MS holds promise as a fast and accurate identification tool, particularly for common Aspergillus species. It is important that the current database of reference spectra, representing different Aspergillus species is expanded to increase the precision of the species-level identification. Terbinafine, posaconazole and echinocandins were in vitro most active against the studies Aspergillus isolates and terbinafine could be the first choice for treatment of onychomycosis due to Aspergillus.

Topics: Antifungal Agents; Aspergillus; Calmodulin; Fungal Proteins; Humans; Iran; Microbial Sensitivity Tests; Nitriles; Onychomycosis; Pyridines; Sequence Analysis, DNA; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Triazoles; Tubulin; Voriconazole

In a 3-year cohort study of adult patients with proven or probable IA, fewer patients initially treated with isavuconazole experienced adverse events compared with voriconazole, but more patients required a change in therapy due to lack of clinical efficacy.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Aspergillosis; Cohort Studies; Female; Humans; Invasive Fungal Infections; Male; Middle Aged; Nitriles; Pyridines; Treatment Outcome; Triazoles; Voriconazole

The increasing prevalence of uncommon fungal species and higher antifungal resistance has turned antifungal susceptibility testing into an important monitoring tool. In response, we evaluated the activity of isavuconazole against 522 clinical mold isolates collected worldwide in 2017-2018, including 436 Aspergillus spp. isolates and 86 non-Aspergillus molds. The MIC values using Clinical and Laboratory Standards Institute methods for isavuconazole versus Aspergillus ranged from 0.015 mg/L to >8 mg/L. Isavuconazole showed comparable activity to itraconazole, posaconazole, and voriconazole against A. fumigatus species complex. Most of the Aspergillus spp. isolates tested (>90%) were wild type to all azoles and echinocandins. Eleven isolates were non-wild type to isavuconazole and the other 3 azoles, and 10 of those isolates were from Europe. The azoles and echinocandins showed poor activity against Fusarium and Scedosporium spp. Isavuconazole exhibited excellent activity against most species of Aspergillus and was comparable to itraconazole, posaconazole, and voriconazole against the less common molds.

Topics: Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Drug Resistance, Fungal; Fungi; Humans; Microbial Sensitivity Tests; Nitriles; Public Health Surveillance; Pyridines; Triazoles; Voriconazole

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Topics: 14-alpha Demethylase Inhibitors; Acanthamoeba castellanii; Amebiasis; Amebicides; Animals; Antifungal Agents; Drug Repositioning; Humans; Microbial Sensitivity Tests; Nitriles; Pyridines; Triazoles; Trophozoites

Cases of chromoblastomycosis are frequent in certain parts of the world, especially in some developing countries. Clinical manifestations of chromoblastomycosis are typical. To a certain extent, pathogens causing chromoblastomycosis overlap with those causing phaeohyphomycosis. Although cases of phaeohyphomycosis are not very common, they may end fatally. Therefore early management of these life-threatening infections is rather important. Targeted antifungal therapy and surgery are effective in combating these infections. Recently, several triazole antifungals such as posaconazole and isavuconazole have been available to treat even the most severe cases. Prevention of the infection should be aimed at reducing the risk of subcutaneous trauma, particularly in persons in contact with potential sources of infection such as wood materials important from endemic areas.

Topics: Antifungal Agents; Chromoblastomycosis; Humans; Nitriles; Phaeohyphomycosis; Pyridines; Triazoles

A paucity of data currently exists regarding drug-drug interaction (DDI) with tacrolimus and isavuconazole coadministration. Current literature provides conflicting recommendations on whether an empiric tacrolimus dose reduction is necessary when coadministered with isavuconazole. A 47-year-old African American female with acute lymphoblastic leukemia underwent an allogenic stem cell transplant (alloSCT) and was subsequently placed on routine posttransplant therapy including tacrolimus for immunosuppression and posaconazole for antifungal prophylaxis. Tacrolimus was empirically dose reduced due to the expected DDI with posaconazole based on current recommendations. Due to a persistently prolonged QTc interval and need for mold coverage, antifungal prophylaxis was ultimately changed to isavuconazole at standard recommended dosing. Tacrolimus was empirically dose reduced by 40% based on limited available literature at the time; however, tacrolimus trough concentrations subsequently declined, requiring an increase in tacrolimus dose to maintain therapeutic trough concentrations. Adequate isavuconazole absorption was documented through pharmacokinetic and pharmacodynamic data by measuring an isavuconazole trough concentration and directly observing isavuconazole's shortening effect on the QTc interval, respectively. Our experience in an alloSCT patient suggests that an empiric tacrolimus dose reduction is not required when isavuconazole is initiated, but close tacrolimus therapeutic drug monitoring should rather be performed to guide tacrolimus dosing.

Topics: Allografts; Antifungal Agents; Drug Interactions; Drug Monitoring; Drug Tapering; Female; Humans; Immunosuppressive Agents; Middle Aged; Nitriles; Pyridines; Tacrolimus; Triazoles

Mucorales can cause cutaneous to deep-seated infections, mainly in the immunocompromised host, resulting in high mortality rates due to late and inefficient treatment. In this study, Galleria mellonella larvae were evaluated as a heterologous invertebrate host to study pathogenicity of clinically relevant mucormycetes (Rhizopus spp., Rhizomucor spp., Lichtheimia spp., Mucor spp.). All tested species were able to infect G. mellonella larvae. Virulence potential was species-specific and correlated to clinical relevance. Survival of infected larvae was dependent on (a) the species (growth speed and spore size), (b) the infection dose, (c) the incubation temperature, (d) oxidative stress tolerance, and (e) iron availability in the growth medium. Moreover, we exploited the G. mellonella system to determine antifungal efficacy of liposomal amphotericin B, posaconazole, isavuconazole, and nystatin-intralipid. Outcome of in vivo treatment was strongly dependent upon the drug applied and the species tested. Nystatin-intralipid exhibited best activity against Mucorales, followed by posaconazole, while limited efficacy was seen for liposomal amphotericin B and isavuconazole. Pharmacokinetic properties of the tested antifungals within this alternative host system partly explain the limited treatment efficacy. In conclusion, G. mellonella represents a useful invertebrate infection model for studying virulence of mucormycetes, while evaluation of treatment response was limited.

Topics: Amphotericin B; Animals; Antifungal Agents; Disease Models, Animal; Drug Resistance, Fungal; Larva; Lepidoptera; Microbial Sensitivity Tests; Mucor; Mucorales; Mucormycosis; Nitriles; Pyridines; Rhizopus; Triazoles; Virulence

Posaconazole (PCZ) is widely used for prophylaxis or treatment of invasive fungal infections (IFIs) in leukaemia patients. However, issues with PCZ tolerability can result in treatment interruption. Isavuconazole (ISA) has a similar broad spectrum of activity to PCZ; however, real-world data regarding the tolerability of ISA after PCZ toxicity are lacking.. To describe the tolerability of ISA after PCZ toxicity in leukaemia patients.. We retrospectively assessed tolerability of ISA after PCZ toxicity in adult leukaemia patients (March 2015 to November 2017). We included all patients who received ≥7 days of ISA within 48 hours of PCZ discontinuation. Laboratory markers for liver toxicity were collected at three time points: prior to PCZ, at switch to ISA and after ISA therapy.. We identified 23 such patients. Increased liver function tests (LFTs) were noted in 20 patients on PCZ, while three patients had Grade 3/4 QTc prolongation. No patient discontinued subsequent ISA due to toxicity. Grade 3/4 elevations in LFTs were decreased after changing to ISA (30% after PCZ vs 5% after ISA). No patient had significant QTc prolongation after switching to ISA.. Isavuconazole was well-tolerated in patients discontinuing PCZ due to toxicity, with no patient discontinuing ISA due to toxicity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leukemia; Liver Function Tests; Male; Middle Aged; Mycoses; Nitriles; Pyridines; Retrospective Studies; Triazoles; Young Adult

Invasive fungal infections are a major cause of morbidity and mortality. Newer antifungals may provide similar efficacy with improved safety compared to older more established treatments. This study aimed to compare clinically relevant safety and efficacy outcomes in real world patients treated with isavuconazole, voriconazole, or posaconazole.. This single center retrospective matched cohort study evaluated adults between January 2015 and December 2017. The primary outcome was a composite safety analysis of antifungal related QTc prolongation, elevated liver function tests (> 5 times ULN), or any documented adverse drug event. Key secondary outcomes included: individual safety events, 30-day readmissions, magnitude of drug interactions with immunosuppressive therapy, and overall cost.. A total of 100 patients were included: 34 patients in the voriconazole group and 33 patients within each of the isavuconazole and posaconazole groups. The composite safety outcome occurred in 40% of the total cohort and was different between isavuconazole (24.2%), voriconazole (55.9%), and posaconazole (39.4%; p = 0.028). Change in QTc (p < 0.01) and magnitude of immunosuppression dose reduction (p = 0.029) were different between the three groups. No differences in mortality, length of stay, readmission, or infection recurrence were observed between groups (p > 0.05 for all). The overall medication cost, when including therapeutic drug monitoring, was not different between treatments (p = 0.36).. Patients treated with isavuconazole resulted in fewer composite safety outcomes, driven by decreased incidence of QTc prolongation, compared to patients treated with voriconazole or posaconazole. Overall drug cost was not significantly different between the treatment therapy options.

Topics: Academic Medical Centers; Adult; Aged; Antifungal Agents; Female; Humans; Invasive Fungal Infections; Male; Middle Aged; Nitriles; Pyridines; Retrospective Studies; Triazoles; Voriconazole; Young Adult

There is a growing body of evidence for immunomodulatory side effects of antifungal agents on different immune cells, e.g., T cells. Therefore, the aim of our study was to clarify these interactions with regard to the effector functions of polymorphonuclear neutrophils (PMN). Human PMN were preincubated with fluconazole (FLC), voriconazole (VRC), posaconazole (POS), isavuconazole (ISA), caspofungin (CAS), micafungin (MFG), conventional amphotericin B (AMB), and liposomal amphotericin B (LAMB). PMN then were analyzed by flow cytometry for activation, degranulation, and phagocytosis and by dichlorofluorescein assay to detect reactive oxygen species (ROS). Additionally, interleukin-8 (IL-8) release was measured by enzyme-linked immunosorbent assay. POS led to enhanced activation, degranulation, and generation of ROS, whereas IL-8 release was reduced. In contrast, ISA-pretreated PMN showed decreased activation signaling, impaired degranulation, and lower generation of ROS. MFG caused enhanced expression of activation markers but impaired degranulation, phagocytosis, generation of ROS, and IL-8 release. CAS showed increased phagocytosis, whereas degranulation and generation of ROS were reduced. AMB led to activation of almost all effector functions besides impaired phagocytosis, whereas LAMB did not alter any effector functions. Independent from class, antifungal agents show variable influence on neutrophil effector functions

Topics: Amphotericin B; Antifungal Agents; Interleukin-8; Neutrophils; Nitriles; Phagocytosis; Pyridines; Triazoles; Voriconazole

To evaluate clinical and economic outcomes associated with the use of isavuconazole as antifungal prophylaxis in high-risk immunocompromised patients.. Retrospective, single-centre cohort study of patients who received isavuconazole prophylaxis. Outcomes assessed included breakthrough IFI, early discontinuation of isavuconazole for any reason and antifungal prophylaxis prescribed at discharge. The impact on inpatient drug expenditure was evaluated using current isavuconazole and posaconazole drug costs per observed isavuconazole days of therapy (DOT) during the study period.. One hundred thirty-eight courses of isavuconazole prophylaxis were administered to 98 inpatients (2193 DOT). Relapsed/refractory acute myelogenous leukaemia was the indication for prophylaxis in over half (59.4%) of patients. Breakthrough IFI occurred in 8 (5.8%) courses. Suspected drug-related toxicities led to early discontinuation in 6 (4.3%) courses (five hepatotoxicity, one drug rash). At discharge, 24 (17.4%) courses lacked insurance coverage for isavuconazole. The formulary switch to isavuconazole prophylaxis resulted in an estimated mean drug cost savings of $128.25 per DOT relative to estimated posaconazole costs (P < 0.001).. Isavuconazole may be an option for antifungal prophylaxis in high-risk immunocompromised adults and has the potential to produce significant inpatient drug cost savings. Further studies are needed to confirm the clinical efficacy and cost-effectiveness of isavuconazole in this role.

Topics: Academic Medical Centers; Adult; Antifungal Agents; Chemoprevention; Cost-Benefit Analysis; Female; Humans; Immunocompromised Host; Inpatients; Invasive Fungal Infections; Male; Middle Aged; Nitriles; Oregon; Pyridines; Retrospective Studies; Risk Factors; Triazoles

Recently, the species concept of opportunistic

Topics: Amphotericin B; Antifungal Agents; Humans; Itraconazole; Microbial Sensitivity Tests; Mucor; Mucormycosis; Natamycin; Nitriles; Pyridines; Rhizopus; Species Specificity; Terbinafine; Triazoles

MIC values for amphotericin B and three azoles determined by the EUCAST reference technique and by gradient concentration strips were compared for 30

Topics: Amphotericin B; Antifungal Agents; Azoles; Humans; Itraconazole; Microbial Sensitivity Tests; Mucorales; Nitriles; Pyridines; Triazoles

Isavuconazole is a new triazole approved for the treatment of invasive aspergillosis. We investigated isavuconazole MIC distributions, isavuconazole MIC correlations with those of other azoles and pharmacodynamics of isavuconazole in low-level resistant Aspergillus fumigatus isolates.. Isavuconazole, voriconazole, itraconazole and posaconazole susceptibility of 487 clinical A. fumigatus isolates was determined by EUCAST broth microdilution methodology. Using an in vivo estimation of the pharmacodynamic target and a previously published pharmacokinetic model, the probability of target attainment (PTA) was determined for a range of isavuconazole MICs using three dosing regimens (I, 200 mg once daily; II, 300 mg once daily; and III, 400 mg once daily).. Two hundred and seventy-nine of 487 isolates were phenotypically WT based on epidemiological cut-offs of voriconazole, itraconazole and posaconazole. Twenty-five of 279 phenotypically WT isolates and 196 of 208 non-WT isolates were classified as isavuconazole resistant based on the EUCAST breakpoint of 1 mg/L. Isavuconazole MICs showed very high correlation with voriconazole MICs, but moderate and low correlation with itraconazole and posaconazole MICs. The PTA for isolates with an isavuconazole MIC of 1 mg/L was 92%-99% for 90% effective concentration (EC90) for the three dosing regimens. For isolates with an MIC of 2 mg/L the PTA decreased to 64%-92% for EC90.. Our study indicated that isavuconazole and voriconazole MICs are highly correlated and that high-dose isavuconazole treatment might be an option in patients infected with an A. fumigatus isolate with an isavuconazole MIC of 2 mg/L.

Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Cytochrome P-450 Enzyme System; Drug Resistance, Fungal; Fungal Proteins; Humans; Itraconazole; Microbial Sensitivity Tests; Nitriles; Pyridines; Triazoles; Voriconazole

Recent years have seen important advances in the diagnosis of invasive pulmonary aspergillosis (IPA), complemented by the introduction of new therapies. Despite this, IPA remains a major cause of infection-related mortality in patients with haematological diseases. There are two main reasons for this. First, diagnosis of IPA remains a challenge, since risk factors and the clinical, radiological and mycological presentations vary not only by fungal disease stage, but also by patient group (eg neutropenic vs non-neutropenic patients). Diagnosis is particularly challenging in patients receiving mould-active prophylactic or empirical treatment, which reduces the sensitivity of all diagnostic tests for IPA. Second, treatment of IPA is complex due to unpredictable pharmacokinetic profiles of antifungal agents, small therapeutic window in terms of exposure and adverse events, and multiple drug-drug interactions through the CYP450 system. Here we report a case of a 23-year-old male with severe aplastic anaemia and subpleural nodules. Diagnostic tests for IPA obtained during ongoing mould-active empirical treatment were negative. Intravenous voriconazole was stopped after visual disturbances and hallucinations. The patient then had an anaphylactic reaction to liposomal amphotericin B and was switched to intravenous posaconazole, which had to be discontinued due to a significant increase in transaminase levels. He was treated with oral isavuconazole with reduced dosage, triggered by increasing transaminases under the standard dosage. Even under reduced dosage, blood concentrations of isavuconazole were high and treatment was successful. The case illustrates real-world challenges and unmet needs in the diagnosis and treatment of IPA in patients with haematological diseases.

Topics: Amphotericin B; Anemia, Aplastic; Antifungal Agents; Aspergillus; Hematologic Diseases; Humans; Invasive Pulmonary Aspergillosis; Male; Neutropenia; Nitriles; Pyridines; Transaminases; Treatment Outcome; Triazoles; Voriconazole; Young Adult

Opportunistic infections due to Candida species occur frequently in intensive care settings. We investigated the prevalence of Candida species among 65 clinical specimens obtained from 200 cancer patients by phenotypic and molecular (ITS sequencing and AFLP) methods. Among the 65 yeast isolates, Candida albicans was the most commonly isolated species (n = 34, 52.3%), whereas other Candida species comprised 47.7% (n = 31) and consisted of Candida glabrata (n = 14, 21.5%), Candida tropicalis (n = 5, 7.7%) and uncommon Candida species (n = 12, 18.5%) such as Candida pelliculosa (n = 3, 4.6%), Pichia kudriavzevii (= Candida krusei, n = 2, 3.1%), Candida orthopsilosis (n = 2, 3.1%), Candida parapsilosis (n = 1, 1.5%), Candida infanticola (n = 2, 3.1%), Candida spencermartinsiae (n = 1, 1.5%), and Kluyveromyces marxianus (=Candida kefyr, n = 1, 1.5%). Candida infanticola and Candida spencermartinsiae were recovered from oral lesions of cancer patients. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) easily confirmed these isolates as less common Candida isolates (4.6%). The in vitro antifungal susceptibilities of C. spencermartinsiae and the two strains of C. infanticola were determined according to CLSI guidelines (M27-A3). MIC results among these isolates showed they were susceptible to isavuconazole, posaconazole and voriconazole, however, fluconazole and caspofungin had high MIC values. These Candida species that may occur more commonly in infections remain unnoticed using commonly used phenotypical methods in routine microbiology laboratories. MALDI-TOF MS proved to be a more fast and robust diagnostic technique for identification of the yeasts isolated from different clinical specimens of cancer patients.

Topics: Adolescent; Antifungal Agents; Candida; Candidiasis; Caspofungin; Child, Preschool; Echinocandins; Fluconazole; Humans; Kluyveromyces; Lipopeptides; Male; Microbial Sensitivity Tests; Middle Aged; Neoplasms; Nitriles; Opportunistic Infections; Pichia; Pyridines; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Triazoles; Voriconazole

Gradient diffusion assays Etest and MIC Test Strip for itraconazole, posaconazole and voriconazole as well as isavuconazole (MIC Test Strip) were evaluated for Aspergillus fumigatus against EUCAST broth microdilution. Both assays demonstrated generally good performance; however, posaconazole MIC Test Strip showed low agreement with broth microdilution due to MIC overestimation.

Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Azoles; Disk Diffusion Antimicrobial Tests; Drug Resistance, Fungal; Itraconazole; Microbial Sensitivity Tests; Nitriles; Pyridines; Reproducibility of Results; Triazoles; Voriconazole

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

Topics: Antibodies, Fungal; Antifungal Agents; Aspergillosis; Aspergillus; Biopsy; Bronchoalveolar Lavage; Disease Management; Early Diagnosis; Flucytosine; Galactose; Humans; Immunocompromised Host; Immunologic Tests; Invasive Pulmonary Aspergillosis; Itraconazole; Leukemia, Myeloid, Acute; Magnetic Resonance Imaging; Mannans; Microbial Sensitivity Tests; Myelodysplastic Syndromes; Nitriles; Pyridines; Tomography, X-Ray Computed; Triazoles; Voriconazole

The antifungal activity of some popular analgesic drugs was postulated by several authors.. The aim of this study was to verify the antifungal effectiveness of acetylsalicylic acid, ibuprofen, metamizole, meloxicam and paracetamol against triazole-susceptible and triazole-resistant Candida spp isolates.. The minimal inhibitory concentration as well as fractional inhibitory concentration of selected analgesics and triazole on eighteen Candida spp isolates were determined by the standard microdilution method according to EUCAST.. Among five tested compounds, only ibuprofen showed an antifungal effect against all tested isolates. In combination tests of analgesics with triazole, three types of interaction have been observed: indifference, synergism and antagonism. An azole-resistant strain of C. albicans demonstrated synergism with IBU and each of the 5 tested azole. Posaconazole also demonstrated synergism with IBU in two other cases, namely a C. albicans strain and with C. glabrata, which were both azole-resistant. Combination of FLU and IBU in two cases resulted in antagonism: in experiments with C. glabrata and C. tropicalis. This interaction was also observed when metamizole and fluconazole were used in combination on C. krusei.. The results obtained by us confirmed antifungal activity of ibuprofen, what support purposefulness to continue the study on antimicrobial activity of this group of drugs.

Topics: Acetaminophen; Analgesics; Antifungal Agents; Aspirin; Candida; Candida albicans; Candida glabrata; Candidiasis; Dipyrone; Drug Resistance, Fungal; Fluconazole; Humans; Ibuprofen; Itraconazole; Meloxicam; Microbial Sensitivity Tests; Nitriles; Pyridines; Triazoles; Voriconazole

Clinical use of voriconazole, posaconazole, and itraconazole revealed the need for therapeutic drug monitoring (TDM) of plasma concentrations of these antifungal agents. This need for TDM was not evident from clinical trials. In order to establish whether this requirement also applies to isavuconazole, we examined the plasma concentrations of 283 samples from patients receiving isavuconazole in clinical practice and compared the values with those from clinical trials. The concentration distributions from real-world use and clinical trials were nearly identical (>1 μg/ml in 90% of patients). These findings suggest that routine TDM may not be necessary for isavuconazole in most instances.

Topics: Antifungal Agents; Clinical Trials as Topic; Humans; Itraconazole; Microbial Sensitivity Tests; Nitriles; Pyridines; Triazoles; Voriconazole

Invasive mold diseases (IMDs) are associated with significant morbidity and mortality. Approved treatments include voriconazole (VORI), liposomal amphotericin B (L-AMB), posaconazole (POSA) and isavuconazole (ISAV). A UK-based economic model was developed to explore the cost of treating IMDs with ISAV versus L-AMB followed by POSA.. As indirect comparisons have demonstrated similar efficacy between the comparators, a cost-minimization approach was taken. Drug acquisition, administration & monitoring, and hospitalization costs were evaluated from the healthcare system perspective.. Per-patient costs were UK£14,842 with ISAV versus UK£18,612 with L-AMB followed by POSA. Savings were driven by drug acquisition, and administration & monitoring costs.. ISAV has the potential to reduce IMD treatment costs relative to L-AMB followed by POSA.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Costs and Cost Analysis; Drug Costs; Health Care Costs; Humans; Models, Economic; Mucormycosis; Nitriles; Pyridines; Treatment Outcome; Triazoles; United Kingdom

Voriconazole, isavuconazole, and posaconazole are triazole anti-fungal drugs commonly used to treat invasive fungal infections. Therapeutic drug monitoring is commonly carried out when patients are prescribed these drugs to ensure that the serum concentrations are sufficiently high for efficacy, but do not reach toxic concentrations. Mass spectrometric (MS) assays have been successfully utilized to determine the serum concentrations of these drugs. This protocol describes a sample preparation procedure and a liquid chromatography-tandem mass spectrometry assay for quantifying serum voriconazole, isavuconazole, and posaconazole in a single method. © 2018 by John Wiley & Sons, Inc.

Topics: Antifungal Agents; Chromatography, Liquid; Humans; Nitriles; Pyridines; Tandem Mass Spectrometry; Triazoles; Voriconazole

A fast and easy-to-use liquid chromatography-tandem mass spectrometry method for the determination and quantification of 6 triazoles [fluconazole (FLZ), isavuconazole (ISZ), itraconazole (ITZ), hydroxy-itraconazole (OH-ITZ), posaconazole (PSZ), and voriconazole (VRZ)] in human plasma and serum was developed and validated for therapeutic drug monitoring.. Sample preparation was based on protein precipitation with acetonitrile and subsequent centrifugation. Isotope-labeled analogues for each analyte were used as internal standards. Chromatographic separation was achieved using a 50 × 2.1 mm, 1.9 μm polar Hypersil Gold C18 column and mobile phase consisting of 0.1% formic acid/acetonitrile (45%/55%, vol/vol) at a flow rate of 340 μL/min. The triazoles were simultaneously detected using a triple-stage quadrupole mass spectrometer operated in selected reaction monitoring mode with positive heated electrospray ionization within a single runtime of t = 3.00 minutes.. Linearity of all azole concentration ranges was verified by the Mandel test and demonstrated for all azoles. All calibration curves were linear and fitted using least squares regression with a weighting factor of the reciprocal concentration. Limits of detection (μg/L/L) were FLZ, 9.3; ISZ, 0.3; ITZ, 0.6; OH-ITZ, 8.6; PSZ, 3.4; and VRZ, 2.1. The lower limits of quantitation (μg/L/liter) were FLZ, 28.3; ISZ, 1.0; ITZ, 1.7; OH-ITZ, 26.2; PSZ, 10.3; and VRZ, 6.3. Intraday and interday precisions ranged from 0.6% to 6.6% for all azoles. Intraday and interday accuracies (%bias) of all analytes were within 10.5%. In addition, we report on a 29-year-old white woman (94 kg body weight) with a history of acute myeloid leukemia who underwent stem cell transplantation. Because of diagnosis of aspergillus pneumonia, antifungal pharmacotherapy was initiated with different application modes and dosages of ISZ, and plasma concentrations were monitored over a time period of 6 months.. A precise and highly sensitive liquid chromatography-tandem mass spectrometry method was developed that enables quantification of triazoles in plasma and serum matrix across therapeutically relevant concentration ranges. It was successfully implemented in our therapeutic drug monitoring routine service and is suitable for routine monitoring of antifungal therapy and in severely ill patients.

Topics: Acetonitriles; Adult; Antifungal Agents; Calibration; Chromatography, Liquid; Drug Monitoring; Female; Fluconazole; Humans; Indicators and Reagents; Isotope Labeling; Itraconazole; Nitriles; Plasma; Pyridines; Reproducibility of Results; Tandem Mass Spectrometry; Triazoles; Voriconazole

Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug 'repurposing'-a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially 'druggable' target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM.

Topics: 14-alpha Demethylase Inhibitors; Amebicides; Animals; Antifungal Agents; Cell Proliferation; Central Nervous System Protozoal Infections; Disease Models, Animal; Drug Repositioning; Humans; Microscopy, Electron, Transmission; Naegleria fowleri; Nitriles; Pyridines; Sterol 14-Demethylase; Sterols; Triazoles; Trophozoites

Mucormycosis is a fungal infection associated with high mortality. Until recently, the only licensed treatments were amphotericin B (AMB) formulations. Isavuconazole (ISAV) is a new mucormycosis treatment. A UK-based economic model explored treatment costs with ISAV versus liposomal AMB followed by posaconazole.. As a matched case-control analysis showed similar efficacy for ISAV and AMB, a cost-minimization approach was taken. Direct costs - drug acquisition, monitoring and administration, and hospitalization costs - were estimated from the National Health Service perspective.. Per-patient costs for ISAV and liposomal AMB + posaconazole were UK£26,810 and UK£41,855, respectively, with savings primarily driven by drug acquisition and hospitalization costs.. ISAV may reduce costs compared with standard mucormycosis therapy.

Topics: Amphotericin B; Antifungal Agents; Case-Control Studies; Drug Costs; Hospitalization; Humans; Invasive Fungal Infections; Models, Economic; Mucormycosis; Nitriles; Pyridines; Triazoles; United Kingdom

We assessed prophylactic or continuous therapy of isavuconazole, posaconazole, or voriconazole in treating pulmonary murine mucormycosis. In the prophylaxis studies, only isavuconazole treatment resulted in significantly improved survival and lowered tissue fungal burden of immunosuppressed mice infected with

Topics: Animals; Antibiotic Prophylaxis; Antifungal Agents; Disease Models, Animal; Immunosuppression Therapy; Lung Diseases, Fungal; Mice; Mucormycosis; Nitriles; Pyridines; Rhizopus; Triazoles; Voriconazole

Isavuconazole is a novel, broad-spectrum, antifungal azole. In order to evaluate its interactions with known azole resistance mechanisms, isavuconazole susceptibility among different yeast models and clinical isolates expressing characterized azole resistance mechanisms was tested and compared to those of fluconazole, itraconazole, posaconazole, and voriconazole. Saccharomyces cerevisiae expressing the Candida albicans and C. glabrata ATP binding cassette (ABC) transporters (CDR1, CDR2, and CgCDR1), major facilitator (MDR1), and lanosterol 14-α-sterol-demethylase (ERG11) alleles with mutations were used. In addition, pairs of C. albicans and C. glabrata strains from matched clinical isolates with known azole resistance mechanisms were investigated. The expression of ABC transporters increased all azole MICs, suggesting that all azoles tested were substrates of ABC transporters. The expression of MDR1 did not increase posaconazole, itraconazole, and isavuconazole MICs. Relative increases of azole MICs (from 4- to 32-fold) were observed for fluconazole, voriconazole, and isavuconazole when at least two mutations were present in the same ERG11 allele. Upon MIC testing of azoles with clinical C. albicans and C. glabrata isolates with known resistance mechanisms, the MIC90s of C. albicans for fluconazole, voriconazole, itraconazole, posaconazole, and isavuconazole were 128, 2, 1, 0.5, and 2 μg/ml, respectively, while in C. glabrata they were 128, 2, 4, 4, and 16 μg/ml, respectively. In conclusion, the effects of azole resistance mechanisms on isavuconazole did not differ significantly from those of other azoles. Resistance mechanisms in yeasts involving ABC transporters and ERG11 decreased the activity of isavuconazole, while MDR1 had limited effect.

Topics: Alleles; Antifungal Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Candida albicans; Candida glabrata; Candidiasis; Cytochrome P-450 Enzyme System; Drug Resistance, Fungal; Fluconazole; Fungal Proteins; Gene Expression Regulation, Fungal; Humans; Itraconazole; Membrane Transport Proteins; Microbial Sensitivity Tests; Mutation; Nitriles; Protein Isoforms; Pyridines; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Triazoles; Voriconazole

Despite the common, worldwide, occurrence of dermatophytes, little information is available regarding susceptibility profiles against currently available and novel antifungal agents. A collection of sixty-eight clinical Trichophyton species and Epidermophyton floccosum were previously identified and verified to the species level by sequencing the internal transcribed spacer (ITS) regions of rDNA. MICs of amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole, terbinafine and MECs of caspofungin and anidulafungin were performed based on CLSI M38-A2. The resulting MIC90 s of all strains were, in increasing order, as follows: terbinafine (0.063 mg l(-1) ); posaconazole (1 mg l(-1) ); isavuconazole and anidulafungin (2 mg l(-1) ); itraconazole, voriconazole, amphotericin B, and caspofungin (4 mg l(-1) ) and fluconazole (>64 mg l(-1) ). These results confirm that terbinafine is an excellent agent for treatment of dermatophytosis due to T. rubrum, T. mentagrophytes, T. verrucosum, T. schoenleinii and E. floccosum. In addition, the new azoles POS and ISA are potentially useful antifungals to treat dermatophytosis. However, the clinical effectiveness of these novel antifungals remains to be determined.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Caspofungin; Echinocandins; Epidermophyton; Fluconazole; Humans; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Naphthalenes; Nitriles; Pyridines; Terbinafine; Tinea; Triazoles; Trichophyton; Voriconazole

The in vitro susceptibilities of 24 worldwide Exserohilum isolates belonging to 10 species from human and environmental sources were determined for eight antifungal drugs. The strains were characterized by internal transcribed spacer (ITS) sequencing and amplified fragment length polymorphism fingerprinting. Posaconazole had the lowest geometric mean MIC (0.16 μg/ml), followed by micafungin (0.21 μg/ml), amphotericin B (0.24 μg/ml), itraconazole (0.33 μg/ml), voriconazole (0.8 μg/ml), caspofungin (1.05 μg/ml), isavuconazole (1.38 μg/ml), and fluconazole (15.6 μg/ml).

Topics: Amphotericin B; Amplified Fragment Length Polymorphism Analysis; Antifungal Agents; Ascomycota; Caspofungin; Echinocandins; Fluconazole; Genotype; Itraconazole; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Molecular Sequence Data; Nitriles; Pyridines; Triazoles; Voriconazole

In vitro susceptibilities of a worldwide collection of molecularly identified Phaeoacremonium strains (n = 43) belonging to seven species and originating from human and environmental sources were determined for eight antifungal drugs. Voriconazole had the lowest geometric mean MIC (0.35 μg/ml), followed by posaconazole (0.37 μg/ml), amphotericin B (0.4 μg/ml), and isavuconazole (1.16 μg/ml). Caspofungin, anidulafungin, fluconazole, and itraconazole had no activity.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Ascomycota; Caspofungin; Echinocandins; Fluconazole; Humans; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Mycoses; Nitriles; Pyridines; Triazoles; Voriconazole

We compared EUCAST and CLSI antifungal susceptibility testing (AFST) methods for triazoles and amphotericin B against 124 clinical Mucorales isolates. The EUCAST method yielded MIC values 1- to 3-fold dilutions higher than those of the CLSI method for amphotericin B. The essential agreements between the two methods for triazoles were high, i.e., 99.1% (voriconazole), 98.3% (isavuconazole), and 87% (posaconazole), whereas it was significantly lower for amphotericin B (66.1%). Strategies for harmonization of the two methods for Mucorales AFST are warranted.

Topics: Amphotericin B; Antifungal Agents; Humans; Microbial Sensitivity Tests; Mucorales; Mucormycosis; Nitriles; Pyridines; Species Specificity; Triazoles; Voriconazole

Invasive fungal infections are increasing due to the increase in the number of at risk patients. The antifungal armamentarium has been improved the last few years with new galenic for ampoetericin B, the widening of the azole spectrum with voriconazole, poscaonazole and isavuconazole and the launch of a new antifungal class, the eschinocandins, currently represented by casoefungin and micftungin. The aim of this work is to provide an update in new antifungal drugs available.

Topics: Antifungal Agents; Caspofungin; Drug Therapy; Echinocandins; Humans; Lipopeptides; Micafungin; Mycoses; Nitriles; Pyridines; Treatment Outcome; Triazoles; Voriconazole

Mucormycosis is a highly aggressive disease which is usually fatal in immunocompromised patients. The species of mucormycetes show significant differences in susceptibility to amphotericin B, azoles and terbinafine. The precise species level identification for this fungal group could be achieved by internal transcribed-spacer (ITS) region sequencing. Herein, we present the largest series of antifungal susceptibility data of molecularly characterised isolates of mucormycetes reported so far from India. Eighty isolates originating from 71 patients comprised 50 (62.5%) from pulmonary cases, 15 (19%) from rhino-orbital-cerebral, 13 (16.2%) from cutaneous and 2 (2.5%) from disseminated mucormycosis. ITS and D1/D2 regions sequencing of the isolates identified, Rhizopus arrhizus var. delemar (n = 25), R. arrhizus var. arrhizus (n = 15), R. microsporus (n = 17), R. stolonifer (n = 3), Syncephalastrum racemosum (n = 11), Apophysomyces elegans (n = 2), A. variabilis (n = 2), Lichtheimia ramosa (n = 3) and Mucor circinelloides f. lusitanicus (n = 2). Amplified fragment length polymorphism analysis was done to genotype Rhizopus isolates and revealed 5 clusters of R. arrhizus, which were well separated from R. microsporus. Amphotericin B was the most potent antifungal followed by posaconazole, itraconazole and isavuconazole. Etest and CLSI MICs of amphotericin B showed 87% agreement. Overall, the commonest underlying condition was uncontrolled diabetes mellitus. Records of 54 patients revealed fatalities in 28 cases.

Topics: Amphotericin B; Amplified Fragment Length Polymorphism Analysis; Antifungal Agents; DNA, Fungal; Drug Resistance, Fungal; Humans; India; Itraconazole; Microbial Sensitivity Tests; Mucor; Mucorales; Mucormycosis; Mycological Typing Techniques; Nitriles; Pyridines; Rhizopus; Sequence Analysis, DNA; Specimen Handling; Triazoles

Candida nivariensis is a cryptic species, phenotypically indistinguishable from Candida glabrata and identified by molecular methods. Aside its isolation from broncho-alveolar lavage, we report for the first time the etiologic role of C. nivariensis in 4 patients with vulvovaginal candidiasis. Of 100 phenotypically identified C. glabrata isolates originating from vaginal swabs, 4 were identified as C. nivariensis by polymerase chain reaction and confirmed by sequencing. All of the C. nivariensis isolates exhibited white colonies on CHROMagar. Phylogenetic analysis revealed genotypic diversity in the C. nivariensis isolates originating from within or outside of India. Barring a solitary C. nivariensis isolate with MIC, 16 μg/mL of fluconazole, the rest were susceptible to voriconazole, itraconazole, posaconazole, isavuconazole, amphotericin B, and echinocandins. The patient with high fluconazole MIC did not respond to fluconazole therapy. It is suggested that the prevalence of this species is likely to be much higher than apparent from the sporadic published reports.

Topics: Adult; Amphotericin B; Antifungal Agents; Candida; Candidiasis, Vulvovaginal; DNA, Fungal; Drug Resistance, Fungal; Echinocandins; Female; Fluconazole; Genotype; Humans; India; Itraconazole; Microbial Sensitivity Tests; Nitriles; Phenotype; Phylogeny; Polymerase Chain Reaction; Pyridines; Pyrimidines; Sequence Analysis, DNA; Tertiary Care Centers; Triazoles; Voriconazole; Young Adult

Treatment of disseminated Trichosporon infections still remains difficult. Amphotericin B frequently displays inadequate fungicidal activity and echinocandins have no meaningful antifungal effect against this genus. Triazoles are currently the drugs of choice for the treatment of Trichosporon infections. This study evaluates the inhibitory and fungicidal activities of five triazoles against 90 clinical isolates of Trichosporon asahii. MICs (μg/ml) were determined according to Clinical and Laboratory Standards Institute microdilution method M27-A3 at 24 and 48 h using two endpoints, MIC-2 and MIC-0 (the lowest concentrations that inhibited ∼50 and 100% of growth, respectively). Minimum fungicidal concentrations (MFCs; μg/ml) were determined by seeding 100 μl of all clear MIC wells (using an inoculum of 10(4) CFU/ml) onto Sabouraud dextrose agar. Time-kill curves were assayed against four clinical T. asahii isolates and the T. asahii ATCC 201110 strain. The MIC-2 (∼50% reduction in turbidity compared to the growth control well)/MIC-0 (complete inhibition of growth)/MFC values that inhibited 90% of isolates at 48 h were, respectively, 8/32/64 μg/ml for fluconazole, 1/2/8 μg/ml for itraconazole, 0.12/0.5/2 μg/ml for voriconazole, 0.5/2/4 μg/ml for posaconazole, and 0.25/1/4 μg/ml for isavuconazole. The MIC-0 endpoints yielded more consistent MIC results, which remained mostly unchanged when extending the incubation to 48 h (98 to 100% agreement with 24-h values) and are easier to interpret. Based on the time-kill experiments, none of the drugs reached the fungicidal endpoint (99.9% killing), killing activity being shown but at concentrations not reached in serum. Statistical analysis revealed that killing rates are dose and antifungal dependent. The lowest concentration at which killing activity begins was for voriconazole, and the highest was for fluconazole. These results suggest that azoles display fungistatic activity and lack fungicidal effect against T. asahii. By rank order, the most active triazole is voriconazole, followed by itraconazole ∼ posaconazole ∼ isavuconazole > fluconazole.

Topics: Antifungal Agents; Fluconazole; Itraconazole; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Triazoles; Trichosporon; Voriconazole

Triazoles are first-line agents for treating aspergillosis. The prevalence of azole resistance in Aspergillus fumigatus is increasing, and cross-resistance is a growing concern. In this study, the susceptibilities of 40 A. fumigatus clinical isolates were tested by using the CLSI method with amphotericin B, itraconazole, voriconazole, posaconazole, and the new triazole isavuconazole. Isavuconazole MICs were higher in strains with reduced susceptibilities to other triazoles, mirroring changes in voriconazole susceptibility. Isavuconazole MICs differed depending on the Cyp51A substitution.

Topics: Amino Acid Substitution; Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Cytochrome P-450 Enzyme System; Drug Resistance, Fungal; Fungal Proteins; Humans; Itraconazole; Microbial Sensitivity Tests; Mutation; Nitriles; Pyridines; Pyrimidines; Triazoles; Voriconazole

The in vitro activities of eight antifungal drugs against 106 clinical and environmental isolates of waterborne and cutaneous Exophiala species were tested. The MICs and minimum effective concentrations for 90% of the strains tested (n = 106) were, in increasing order, as follows: posaconazole, 0.063 μg/ml; itraconazole, 0.25 μg/ml; micafungin, 1 μg/ml; voriconazole, 2 μg/ml; isavuconazole, 4 μg/ml; caspofungin, 8 μg/ml; amphotericin B, 16 μg/ml; fluconazole, 64 μg/ml.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Exophiala; Fluconazole; Itraconazole; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Triazoles; Voriconazole

A global collection of Cladophialophora carrionii strains (n = 81) was tested against nine antifungal drugs. MIC90s of all strains were as follows in increasing order: itraconazole and posaconazole, 0.063 μg/ml; terbinafine, 0.125 μg/ml; isavuconazole and voriconazole, 0.25 μg/ml; caspofungin, 2 μg/ml; micafungin, 4 μg/ml; amphotericin B, 8 μg/ml; and fluconazole, 64 μg/ml.

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Caspofungin; Chromoblastomycosis; Echinocandins; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Triazoles; Voriconazole

Cyphellophora guyanensis (n = 15), other Cyphellophora species (n = 11), Phialophora europaea (n = 43), and other Phialophora species (n = 12) were tested in vitro against nine antifungal drugs. The MIC(90)s across all of the strains (n = 81) were, in increasing order, as follows: posaconazole, 0.063 μg/ml; itraconazole, 0.5 μg/ml; voriconazole, 1 μg/ml; micafungin, 1 μg/ml; terbinafine, 2 μg/ml; isavuconazole, 4 μg/ml; caspofungin, 4 μg/ml; fluconazole, 8 μg/ml; amphotericin B, 16 μg/ml.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fluconazole; Itraconazole; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mitosporic Fungi; Naphthalenes; Nitriles; Phialophora; Pyridines; Pyrimidines; Terbinafine; Triazoles; Voriconazole

The in vitro activities of eight antifungal drugs against clinical isolates of Fonsecaea pedrosoi (n = 21), Fonsecaea monophora (n = 25), and Fonsecaea nubica (n = 9) were tested. The resulting MIC(90)s for all strains (n = 55) were as follows, in increasing order: posaconazole, 0.063 microg/ml; itraconazole, 0.125 microg/ml; isavuconazole, 0.25 microg/ml; voriconazole, 0.5 microg/ml; amphotericin B, 2 microg/ml; caspofungin, 2 microg/ml; anidulafungin, 2 microg/ml; and fluconazole, 32 microg/ml.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Ascomycota; Caspofungin; Chromoblastomycosis; Drug Resistance, Fungal; Echinocandins; Fluconazole; Humans; In Vitro Techniques; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Triazoles; Voriconazole

We compared the in vitro activities of isavuconazole, posaconazole, voriconazole, and fluconazole against Dipodascus capitatus (n = 21), Saccharomyces cerevisiae (n = 20), Rhodotorula mucilaginosa (n = 18), and Trichosporon spp. (n = 15). The MIC(50)s, MIC(90)s, and MIC ranges (in microg/ml) obtained using the CLSI M27-A3 procedure were as follows: isavuconazole, 0.125, 0.5, and < or = 0.015 to 2; posaconazole, 0.5, 2, and < or = 0.015 to > 16; voriconazole, 0.125, 2, and < or = 0.015 to 8; and fluconazole, 4, > 128, and < or = 0.125 to > 128. Isavuconazole showed potent activity against the isolates studied.

Topics: Antifungal Agents; Dipodascus; Fluconazole; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Rhodotorula; Saccharomyces cerevisiae; Triazoles; Trichosporon; Voriconazole

The in vitro susceptibilities of a worldwide collection of 350 Cryptococcus gattii isolates to seven antifungal drugs, including the new triazole isavuconazole, were tested. With amplified fragment length polymorphism (AFLP) fingerprinting, human, veterinary, and environmental C. gattii isolates were subdivided into seven AFLP genotypes, including the interspecies hybrids AFLP8 and AFLP9. The majority of clinical isolates (n = 215) comprised genotypes AFLP4 (n = 76) and AFLP6 (n = 103). The clinical AFLP6 isolates had significantly higher geometric mean MICs for flucytosine and fluconazole than the clinical AFLP4 isolates. Of the seven antifungal compounds examined in this study, isavuconazole had the lowest MIC(90) (0.125 μg/ml) for all C. gattii isolates, followed by a 1 log(2) dilution step increase (MIC(90), 0.25 μg/ml) for itraconazole, voriconazole, and posaconazole. Amphotericin B had an acceptable MIC(90) of 0.5 μg/ml, but fluconazole and flucytosine had relatively high MIC(90)s of 8 μg/ml.

Topics: Amphotericin B; Amplified Fragment Length Polymorphism Analysis; Animals; Antifungal Agents; Cryptococcus gattii; Environmental Microbiology; Fluconazole; Flucytosine; Genotype; Humans; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Triazoles; Voriconazole

We measured antifungal activity against 128 cryptococcal isolates (86 of C. neoformans and 42 of C. gattii) to determine if differences in serotype susceptibility exist. Contrary to previous results, we found no serotype susceptibility differences. Isavuconazole, posaconazole, and voriconazole demonstrated excellent potency against each isolate and serotype, including isolates with reduced fluconazole susceptibilities.

Topics: Antifungal Agents; Cryptococcus; Cryptococcus neoformans; Fluconazole; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Serotyping; Triazoles; Voriconazole