Search

Background: The resistance of Aspergillus flavus to the azole antifungal drugs is an emerging problem. Mutations in the molecular targets of the azole antifungals ‐ CYP 51 A, B and C ‐ are possible mechanisms of resistance, but data to confirm this hypothesis are scarce. In addition, the behaviour of resistant strains in vitro and in vivo is not yet understood. Objectives: This study had 3 objectives. The first was to compare the sequences of CYP51 A, B and C in resistant and susceptible strains of A. flavus. The second was to look for the existence of a fitness cost associated with resistance. The third was to evaluate the activity of voriconazole and posaconazole on resistant strains in the Galleria mellonella model. Methods: The CYP51 A, B and C sequences of seven resistant strains with those of four susceptible strains are compared. Fitness costs were assessed by growing the strains in RPMI medium and testing their virulence in G. mellonella larvae. In addition, G. mellonella larvae infected with strains of A. flavus were treated with voriconazole and posaconazole. Results: In the CYP51A sequences, we found the A91T, C708T and A1296T nucleotide substitutions only in the resistant strains. The resistant strains showed a fitness cost with reduced in vitro growth and reduced virulence in G. mellonella. In vivo resistance to posaconazole is confirmed in a strain with the highest MIC for this antifungal agent. Conclusions: These results allow to conclude that some substitutions in CYP51 genes, in particular CYP51A, contribute to resistance to azole drugs in A. flavus. The study of the relationship between drug dosage and treatment duration with resistance and the reduction of fitness costs in resistant strains is a major perspective of this study. This work could help to establish recommendations for the treatment of infections with resistant strains of A. flavus. [ABSTRACT FROM AUTHOR]

Background: The efficacy and side effects of voriconazole plus 5-flucytosine (Vori + 5-FC) versus amphotericin B deoxycholate plus 5-flucytosine (AmBd + 5-FC) as an induction treatment for cryptococcal meningitis are unknown. Methods: Forty-seven patients treated with Vori + 5-FC and 92 patients treated with AmBd + 5-FC were included in the current study after propensity score matching (PSM) at a ratio of 1:2. Two-week laboratory test results and 90-day mortality were compared between the two groups. Results: After 2 weeks of induction treatment, the CSF Cryptococcus sterile culture rate was 57.1% in the Vori + 5-FC group and 76.5% in the AmBd + 5-FC group (p = .026). No difference was found in the normalization of CSF indicators (glucose, total protein, intracranial pressure and India ink sterile rate) between the two groups. Both the Vori + 5FC regimen and AmBd + 5-FC regimen obviously decreased haemoglobin concentrations, platelet counts and serum potassium levels (all p = .010). Notably, the Vori + 5FC regimen did not influence serum creatinine levels (p = .263), while AmBd + 5FC increased serum creatinine levels (p = .019) after 2-week induction treatment. The Vori + 5-FC group and AmBd + 5-FC group had similar 90-day cumulative survival rates (89.9% vs. 87.8%, p = .926). Conclusion: The Vori + 5-FC regimen was associated with low 2-week CSF sterile culture and was not superior to AmBd + 5-FC as induction therapy in terms of the 90-day cumulative survival rate of CM patients. [ABSTRACT FROM AUTHOR]

Background: The optimal timing for therapeutic drug monitoring (TDM) of voriconazole in Asians, who have higher rates of poor metabolisers than non‐Asians, is unclear. This can cause unexpectedly high concentrations and delays in reaching steady‐state levels. Objectives: To determine the appropriate timing of TDM in Japanese patients receiving voriconazole. Patients/Methods: Trough levels (Cmin) were measured on days 3–5 (recommended timing, RT) and days 6–14 (delayed timing, DT) after starting voriconazole in patients receiving an appropriate dosage. Considering bioavailability, Cmin was only compared in patients receiving oral voriconazole. Results: A total of 289 and 186 patients were included in the safety and pharmacokinetic analyses, respectively. There was a significant difference in Cmin measured no later than and after day 5 (3.59 ± 2.12 [RT] vs. 4.77 ± 3.88 μg/mL [DT], p =.023), whereas no significant difference was observed on cutoff day 6 (3.91 ± 2.60 vs. 4.40 ± 3.94 μg/mL, p =.465), suggesting that Cmin close to the steady‐state was achieved after day 5. DT causes a delay in achieving the therapeutic range. The hepatotoxicity rates were 21.5% and 36.8% in the RT and DT groups, respectively (p =.004); DT was an independent risk factor for hepatotoxicity. Conclusion: Although steady‐state concentrations may not be achieved by day 5, early dose optimisation using RT can prevent hepatotoxicity in Japanese patients. TDM should be performed on days 3–5 to ensure safety. However, subsequent TDM may be necessary due to a possible further increase in Cmin. [ABSTRACT FROM AUTHOR]

Voriconazole (VCZ) is an important first‐line option for management of invasive fungal diseases and approved in paediatric patients ≥24 months at distinct dosing schedules that consider different developmental stages. Information on dosing and exposures in children <24 months of age is scarce. Here we report our experience in children <24 months who received VCZ due to the lack of alternative treatment options. This retrospective analysis includes 50 distinct treatment episodes in 17 immunocompromised children aged between 3 and <24 months, who received VCZ between 2004 and 2022 as prophylaxis (14 patients; 47 episodes) or as empirical treatment (3 patients; 3 episodes) by mouth (46 episodes) or intravenously (4 episodes) based on contraindications, intolerance or lack of alternative options. Trough concentrations were measured as clinically indicated, and tolerability was assessed based on hepatic function parameters and discontinuations due to adverse events (AEs). VCZ was administered for a median duration of 10 days (range: 1–138). Intravenous doses ranged from 4.9 to 7.0 mg/kg (median: 6.5) twice daily, and oral doses from 3.8 to 29 mg/kg (median: 9.5) twice daily, respectively. The median trough concentration was 0.63 mg/L (range: 0.01–16.2; 38 samples). Only 34.2% of samples were in the recommended target range of 1–6 mg/L; 57.9% had lower and 7.9% higher trough concentrations. Hepatic function parameters analysed at baseline, during treatment and at end of treatment did not show significant changes during VCZ treatment. There was no correlation between dose and exposure or hepatic function parameters. In three episodes, VCZ was discontinued due to an AE (6%; three patients). In conclusion, this retrospective analysis reveals no signal for increased toxicity in paediatric patients <24 months of age. Empirical dosing resulted in mostly subtherapeutic exposures which emphasises the need for more systematic study of the pharmacokinetics of VCZ in this age group. [ABSTRACT FROM AUTHOR]

Background: Scedosporiosis/lomentosporiosis is a globally emerging and crucial fungal infection. However, clinical data on Scedosporium/Lomentospora infections in Taiwan are scarce. Objectives: This study aimed to explore the clinical characteristics of Scedosporium/Lomentospora‐infected patients and evaluate the susceptibility of these isolates to antifungal agents. Methods: The clinical features of Scedosporium/Lomentospora‐infected patients at a tertiary teaching hospital in Northern Taiwan between 2014 and 2021 were retrospectively reviewed; isolates from these patients were identified to species level for antifungal susceptibility testing. Results: Among 44 patients, 27 (61.4%) had scedosporiosis/lomentosporiosis, whereas 17 (38.6%) were colonised with Scedosporium/Lomentospora species. Scedosporium apiospermum was the main coloniser; scedosporiosis was primarily caused by S. boydii. Trauma history, steroid and immunosuppressant use were the most common risk factors for developing these infections. Among 27 patients with scedosporiosis/lomentosporiosis, one was lost to follow‐up and seven (7/26, 26.9%) died. Most patients with S. apiospermum infection have a history of trauma, leading to cutaneous, bone and ocular infections. Pulmonary, sinus and disseminated infections and mortality were frequently reported in patients with S. boydii infection. Voriconazole's minimum inhibitory concentration was low for S. boydii, S. apiospermum and S. aurantiacum. Caspofungin, micafungin and anidulafungin were active against S. boydii and S. apiospermum. A potentially novel Scedosporium species was identified in this study, with distinct clinical manifestations and antifungal susceptibility. Conclusions: At our centre, S. boydii is the main causative species of scedosporiosis; voriconazole could be the first‐line treatment in Taiwan. Our study supports the importance of speciation, rather than only categorising these isolates into S. apiospermum species complex. [ABSTRACT FROM AUTHOR]

We evaluated the activity of amphotericin B, itraconazole, posaconazole, voriconazole and caspofungin against 1468 invasive moulds collected worldwide from 2018 to 2021. Most (>92%) of the Aspergillus spp. isolates were wildtype (WT) to amphotericin B, caspofungin and the azoles. Azole–non‐wildtype A. fumigatus rates were higher in Europe (9.5%) and North America (9.1%) than Latin America (0.0%; only 12 isolates) and the Asia‐Pacific region (5.3%). Amphotericin B and caspofungin were active against azole–non‐wildtype A. fumigatus isolates. Posaconazole and amphotericin B were the most active agents against the Mucorales. Among the less common moulds, several expressed a pan‐azole–resistant phenotype; many of these species also showed elevated MIC values (MIC, >2 mg/L) for amphotericin B and caspofungin. Although most isolates of Aspergillus spp. remain WT to the azoles, azole resistance is increasing in both North America and Europe. Amphotericin B and caspofungin exhibit potentially useful activity against azole‐resistant A. fumigatus. [ABSTRACT FROM AUTHOR]

Rhinocladiella mackenziei is a highly neurotropic fungus, mainly reported from the Middle East. However, in recent years, there have been some cases from outside this region. We described an additional fatal case of R. mackenziei cerebral infection for the first time from Turkey and made a literature review of all previously reported cases. During 34 years (1988–2022), there have been 42 R. mackenziei brain abscess cases. Most patients have been reported from Saudi Arabia (n = 14, 33.3%). It is noteworthy that 40.5% of patients, including our case, were immunocompetent at initial diagnosis and mostly presented with a single lesion (n = 10, 23.8%). The most frequent comorbidities were solid organ transplant (n = 9, 21.4%), diabetes mellitus (n = 6, 14.3%), malignancy (n = 6, 14.3%) and prior surgery (n = 3, 7.1%). The most commonly used initial antifungal regimen were amphotericin B together with itraconazole (n = 9, 21.4%), combinations of lipid preparations of amphotericin B, voriconazole and/or posaconazole (n = 9, 21.4%) and amphotericin B alone (n = 8, 19%). Although both surgical procedures and antifungal medication in the majority of patients were performed, mortality rates remained high (90.4%). The area at risk of R. mackenziei cerebral abscess cases extends to other countries. Clinicians should be aware of this emerging disease and take a detailed travel history in patients with atypical and undocumented brain abscesses. Our case confirms the hypothesis that this fungus might spread more widely than previously predicted regions. [ABSTRACT FROM AUTHOR]

Introduction: Sporotrichosis is a subcutaneous and chronic infection caused by traumatic inoculation of pathogenic sporothrix species, usually infecting the skins and subcutaneous tissues of humans and animals. However, the lack of epidemiological data required further molecular identification to describe the distribution of this fungus in our region. In this study, forty‐eight clinical sporothrix isolated from Sun Yat‐Sen Memorial Hospital were classified, and the susceptibility of each strain to seven antifungal agents was determined. Methods: Forty strains of S. globosa and eight strains of S. shenkshii were identified via colony morphology and PCR sequencing of calmodulin gene. Results: Antifungal susceptibility tests of the mycelial phase in vitro showed terbinafine (TRB) and luliconazole (LULI) were the most effective, followed by itraconazole (ITZ) and amphotericin B (AMB). By contrast, voriconazole (VCZ), 5‐flucytosine (5FC) and fluconazole (FCZ) have low efficacy with high MIC. Conclusion: Our results showed a predominantly S. globosa infection trend in southern China. Simultaneously, sporothrix is sensitive to TRB, LULI, ITZ and AMB whereas resistant to FCZ. This study firstly reports antifungal sensitivity test in vitro and epidemiological correlation analysis of sporothrix in southern China, and also the first time to find that sporothrix is sensitive to LULI. [ABSTRACT FROM AUTHOR]

Background: Voriconazole (VRC), a widely used triazole antifungal, exhibits significant inter‐ and intra‐individual pharmacokinetic variability. The main metabolite voriconazole N‐oxide (NOX) can provide information on the patient's drug metabolism capacity. Objectives: Our objectives were to implement routine measurement of NOX concentrations and to describe the metabolic ratio (MR), and the contribution of the MR to VRC therapeutic drug monitoring (TDM) by proposing a suggested dosage‐adjustment algorithm. Patients and Methods: Sixty‐one patients treated with VRC were prospectively included in the study, and VRC and NOX levels were assayed by LC–MS/MS. A mixed logistic model on repeated measures was implemented to analyse risk factors for the patient's concentration to be outside the therapeutic range. Results: Based on 225 measurements, the median and interquartile range were 2.4 μg/ml (1.2; 4.2), 2.1 μg/ml (1.5; 3.0) and 1.0 (0.6; 1.9) for VRC, NOX and the MR, respectively. VRC Cmin <2 μg/ml were associated with a higher MR during the previous visit. MR values >1.15 and <0.48 were determined to be the best predictors for having a VRC Cmin lower than 2 μg/ml and above 5.5 μg/ml, respectively, at the next visit. Conclusions: Measurement of NOX resulted useful for TDM of patients treated with VRC. The MR using NOX informed interpretation and clinical decision‐making and is very interesting for complex patients. VRC phenotyping based on the MR is now performed routinely in our institution. A dosing algorithm has been suggested from these results. [ABSTRACT FROM AUTHOR]

Background: Since February 2021 active screening of COVID‐19‐associated pulmonary aspergillosis (CAPA) has been implemented in our institution. Objectives: To evaluate CAPA incidence in our centre and evaluate performance of our screening protocol. Methods: We screened once per week, collecting endotracheal aspirates for fungal culture and galactomannan (GM) and serum for 1,3‐ß‐D‐glucan (BG). In case of positivity (GM more than 4.5, platelia assay, and/or BG >7 pg/ml, wako and/or positive fungal culture), second‐level investigations were performed to pursue CAPA diagnosis according to ECMM/ISHAM criteria: bronchoalveolar lavage (BAL) fungal culture and GM, chest computed tomography (CT), serum GM. Results: A total of 102 patients were screened (median age 64 years, range 39–79; 28 (27.4%) females). Twenty‐two patients were diagnosed with CAPA (21%). 12 patients were positive for serum BG, 17 patients were positive for endotracheal aspirates GM and 27 patients were positive for endotracheal aspirates fungal culture. Thirty‐two BALs were performed, and 26 patients underwent CT chest. Following the second level investigations 61% of the patients with positive screening tests were diagnosed with CAPA. Serum BG above 20 pg/ml or positive serum GM were always associated with typical CT chest signs of aspergillosis. Compared with 1 single positive test, having 2 positive screening test was significantly more associated with CAPA diagnosis (p =.0004). Conclusions: Active CAPA screening with serum 1,3‐ß‐D‐glucan and endotracheal aspirates galactomannan and fungal cultures and consequent second level investigations led to high number of CAPA diagnosis. Combining more positive fungal biomarkers was more predictive of CAPA diagnosis. [ABSTRACT FROM AUTHOR]

Background: Studies comparing gradient diffusion strips (GDSs) and the EUCAST E.Def 9.4 microdilution method are scarce, thwarted by a low number of isolates, and restricted to selected antifungal agents. Objectives: We evaluated the performance of GDSs to detect azole resistance in A. fumigatus, including cryptic species. Patients/Methods: A. fumigatus sensu stricto (n = 89) and cryptic species (n = 52) were classified as susceptible or resistant to itraconazole, voriconazole, posaconazole and isavuconazole (EUCAST E.Def 9.4; clinical breakpoints v10). A. fumigatus sensu stricto azole‐resistant isolates had the following cyp51A gene mutations: TR34‐L98H (n = 24), G54R (n = 5), TR46‐Y121F‐T289A (n = 1), F46Y‐M172V‐N248T‐D255E‐E427K (n = 1), F165L (n = 1) and cyp51A gene wild type (n = 3). GDSs (ETEST®, bioMèrieux, Marcy‐l'Etoile, France and Liofilchem®, Roseto degli Abruzzi, Italy) MICs were obtained by following the manufacturer's guidelines. Results: For A. fumigatus sensu stricto, itraconazole MICs >1.5 mg/L, voriconazole >0.38 mg/L, posaconazole >0.75 mg/L, and isavuconazole >0.5 mg/L correctly separated resistant from susceptible isolates with two exceptions. Considering the aforementioned cut‐off MICs, sensitivity/specificity values of GDSs to detect azole resistance were: itraconazole (97%/100%), voriconazole (97%/100%), posaconazole (97%/100%) and isavuconazole (93.3%/100%). For cryptic species isolates, voriconazole MICs >1 mg/L and isavuconazole >0.75 mg/L separated resistant isolates from susceptible isolates with 15 and 27 exceptions, respectively. Considering the aforementioned cut‐off MICs, sensitivity/specificity values were as follows: voriconazole (68.1%/100%) and isavuconazole (25%/100%). For itraconazole and posaconazole, it was not possible to establish cut‐off values. Conclusions: We set tentative cut‐off MIC values to correctly spot resistant Aspergillus fumigatus sensu stricto isolates using GDSs. The performance against cryptic species was poor. [ABSTRACT FROM AUTHOR]

Background: The rare occurrence of human cryptococcosis caused by Cryptococcus gattii sensu lato leads to difficulties in establishing the antifungal susceptibility profile between species of this potentially lethal pathogen, which may be crucial for treating cryptococcosis. Objective: To establish an antifungal susceptibility profile of C. gattii s.l. in Taiwan. Methods: A total of 104 environmental C. gattii s.l. strains (including multilocal sequence typing ST7, ST106, ST274, ST328, ST546, ST548 and ST630) and 21 previously collected clinical strains (including ST7, ST44, ST06, ST274, ST328 and ST329) were included in this study. We determined the minimum inhibitory concentrations (MICs) of six antifungal agents (itraconazole, fluconazole, voriconazole, posaconazole, flucytosine and amphotericin B) against environmental C. gattii s.l. strains and compared the antifungal susceptibility profiles of environmental strains with those of clinical strains. Results: The antifungal susceptibility data demonstrated that the MICs of antifungal agents against environmental strains were comparable to those against clinical strains. Compared with strains of Cryptococcus deuterogattii, those of C. gattii sensu stricto were more susceptible to azoles and flucytosine. The differences in antifungal susceptibility between the strains of each sequence type (ST) were significant. Correlation analysis of MICs revealed cross‐resistance between azoles in environmental strains of C. gattii s.l. Geographic differences in the antifungal susceptibility of C. gattii s.l. isolated from different cities in Taiwan were observed in this study. Conclusion: Clinical and environmental strains were indistinguishable in antifungal susceptibility. The antifungal susceptibility of C. gattii s.l. is associated with STs. Therefore, establishing an ST‐oriented domestic antifungal susceptibility database may help treat C. gattii s.l.‐induced cryptococcosis. [ABSTRACT FROM AUTHOR]

Background: There has been an emergence of recalcitrant, recurrent, and difficult‐to‐treat tinea. Monotherapy with oral antifungals leads to partial clearance or high recurrence of lesions. Isotretinoin is a good adjuvant to systemic antifungals in chronic dermatophytosis. Voriconazole could be a future alternative due to its efficacy against dermatophytes and little resistance. Objective: To evaluate the efficacy and safety of oral itraconazole, combined itraconazole/isotretinoin therapy, and voriconazole for recalcitrant tinea. Patients and Methods: This study included 90 patients with chronic, recurrent and/or recalcitrant tinea. They were equally divided into three groups: itraconazole monotherapy, combined itraconazole/isotretinoin therapy, and voriconazole monotherapy. All patients received treatments for 6 weeks. The clinical response was classified as either a complete or incomplete clinical cure. Potassium hydroxide microscopy and culture were performed to identify mycological cure. Patients with complete cure were followed up for another 6 months to detect any recurrence. Results: Complete clinical cure was observed in 53.3% of the itraconazole group, 70% of the itraconazole/isotretinoin group, and 83.3% of the voriconazole group. Mycological cure was detected in 56.7% of the itraconazole group, 83.3% of the itraconazole/isotretinoin group, and 86.7% of the voriconazole group. There was a statistically significant difference between the three groups in favour of voriconazole, then the combined group. No significant adverse effects were observed. The recurrence rate was significantly lower in the voriconazole group compared with the other two groups. Conclusions: Voriconazole could be a future alternative for the treatment of recalcitrant dermatophytosis. [ABSTRACT FROM AUTHOR]

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.

Background: Azole resistance screening in Aspergillus fumigatus isolates can be routinely carried out by using azole‐containing plates (E.Def 10.2 method), that requires filtering conidial suspensions prior inoculum adjustment. Objectives: We evaluated whether skipping the filtration step of conidial suspensions negatively influences the performance of the E.Def 10.2. Patients/Methods: A. fumigatus sensu stricto isolates (n = 92), classified as azole‐susceptible or azole‐resistant according to the EUCAST microdilution E.Def 9.4 method, were studied. Azole‐resistant isolates had either wild type cyp51A gene sequence (n = 3) or the TR34‐L98H (n = 26), G54R (n = 5), TR46‐Y121F‐T289A (n = 1), F46Y‐M172V‐N248T‐D255E‐E427K (n = 1), F165L (n = 1) or G448S (n = 1) cyp51A gene substitutions. In‐house azole‐containing agar plates were prepared according to the EUCAST E.Def 10.2 procedure. Conidial suspensions were obtained by adding distilled water (Tween 20 0.1%). Subsequently, the suspensions were either filtered or left unfiltered prior to inoculum adjustment to 0.5 McFarland. Using microdilution as the gold standard, agreement, sensitivity and specificity of the agar plates inoculated with two inoculums were assessed. Results: Agreements for the agar screening method with either unfiltered or filtered conidial suspensions were high for itraconazole (100%), voriconazole (100%) and posaconazole (97.8%). Sensitivity (100%) and specificity (98.2%) of the procedure to rule in or out resistance when unfiltered suspensions were used were also high. Isolates harbouring the TR34‐L98H, G54R and TR46‐Y121F‐T289A substitutions were detected with the modified method. Conclusions: Unfiltered conidial suspensions does not negatively influence the performance of the E.Def 10.2 method when screening for A. fumigatus sensu stricto. [ABSTRACT FROM AUTHOR]

The treatment of invasive aspergillosis caused by cryptic species remains a challenge due to the lack of randomised clinical trials and investigation of the efficacy and safety of different therapeutic strategies. We aimed to evaluate the in vitro activity of 23 conventional and new antifungal drugs against 54 clinical and environmental Aspergillus oryzae isolates by using the Clinical and Laboratory Standards Institute (CLSI) standard M38‐A3. The lowest geometric mean MIC values were found for luliconazole and lanoconazole (0.001 μg/ml), followed by anidulafungin (0.104 μg/ml), posaconazole (0.15 μg/ml), itraconazole (0.37 μg/ml), efinaconazole (0.5 μg/ml), voriconazole (0.51 μg/ml), tavaborole (0.72 μg/ml), and amphotericin B (0.79 μg/ml). In contrast, ketoconazole, terbinafine, econazole, tioconazole, ravuconazole, miconazole, nystatin, clotrimazole, griseofulvin, sertaconazole, natamycin, tolnaftate, and fluconazole had no or low activity. Further studies are required to determine how well this in vitro activity translates into in vivo efficacy. [ABSTRACT FROM AUTHOR]

Background: Azole resistance complicates treatment of patients with invasive aspergillosis with an increased mortality. Azole resistance in Aspergillus fumigatus is a growing problem and associated with human and environmental azole use. Denmark has a considerable and highly efficient agricultural sector. Following reports on environmental azole resistance in A. fumigatus from Danish patients, the ministry of health requested a prospective national surveillance of azole‐resistant A. fumigatus and particularly that of environmental origin. Objectives: To present the data from the first 2 years of the surveillance programme. Methods: Unique isolates regarded as clinically relevant and any A. fumigatus isolated on a preferred weekday (background samples) were included. EUCAST susceptibility testing was performed and azole‐resistant isolates underwent cyp51A gene sequencing. Results: The azole resistance prevalence was 6.1% (66/1083) at patient level. The TR34/L98H prevalence was 3.6% (39/1083) and included the variants TR34/L98H, TR343/L98H and TR34/L98H/S297T/F495I. Resistance caused by other Cyp51A variants accounted for 1.3% (14/1083) and included G54R, P216S, F219L, G54W, M220I, M220K, M220R, G432S, G448S and Y121F alterations. Non‐Cyp51A‐mediated resistance accounted for 1.2% (13/1083). Proportionally, TR34/L98H, other Cyp51A variants and non‐Cyp51A‐mediated resistance accounted for 59.1% (39/66), 21.2% (14/66) and 19.7% (13/66), respectively, of all resistance. Azole resistance was detected in all five regions in Denmark, and TR34/L98H specifically, in four of five regions during the surveillance period. Conclusion: The azole resistance prevalence does not lead to a change in the initial treatment of aspergillosis at this point, but causes concern and leads to therapeutic challenges in the affected patients. [ABSTRACT FROM AUTHOR]

Antifungal susceptibility testing is an essential tool for guiding antifungal therapy. Reference methods are complex and usually only available in specialised laboratories. We have designed an expanded agar‐based screening method for the detection of azole‐resistant Aspergillus fumigatus isolates. Normally, identification of resistance mechanisms is obtained only after sequencing the cyp51A gene and promoter. However, our screening method provides azole resistance detection and presumptive resistance mechanisms identification. A previous agar‐based method consisting of four wells containing voriconazole, itraconazole, posaconazole and a growth control, detected azole resistance to clinical azoles. Here, we have modified the concentrations of voriconazole and posaconazole to adapt to the updated EUCAST breakpoints against A. fumigatus. We have also expanded the method to include environmental azoles to assess azole resistance and the azole resistance mechanism involved. We used a collection of A. fumigatus including 54 azole‐resistant isolates with Cyp51A modifications (G54, M220, G448S, TR53, TR34/L98H, TR46/Y121F/T289A, TR34/L98H/S297T/F495I), and 50 azole susceptible isolates with wild‐type Cyp51A. The screening method detects azole‐resistant A. fumigatus isolates when there is growth in any of the azole‐containing wells after 48h. The growth pattern in the seven azoles tested helps determine the underlying azole resistance mechanism. This approach is designed for surveillance screening of A. fumigatus azole‐resistant isolates and can be useful for the clinical management of patients prior to antifungal susceptibility testing confirmation. [ABSTRACT FROM AUTHOR]

Background: The T indotineae population shows a high amount of terbinafine resistant isolates based on different point mutations of squalene epoxidase erg1 (ergosterol) gene. A significant proportion of these isolates also show azole resistance. Objectives: Elucidation of the molecular mechanism for azole resistance, especially the identification of mutations in the sterol 14‐α demethylase Erg11 genes, which encode for enzymes interacting with azoles. Methods: Sequencing of putative Erg11 genes and analysis of phenotypic resistance pattern using a microplate‐laser‐nephelometry‐based growth assay. Results: Four different types of Erg11B mutants were detected; two double mutants with Ala230Thr/Asp441Gly, respectively, Ala230/Tyr444His and single mutants with Gly443Glu, Tyr444Cys and Tyr444His. All isolates featured the wild type genotype of Erg11A. All strains demonstrated different combinations of Erg1 and Erg11 genotypes. Conclusion: Resistance against terbinafine and azoles developed several times independently within the T indotineae population. The challenge for fungal treatment is, therefore, that species identification is not enough for prediction of therapeutic efficacy of antifungals. In the future, it will also become important to analyse genes involved in resistance mechanisms. [ABSTRACT FROM AUTHOR]

Background: Isavuconazole is a triazole antifungal drug, approved for the treatment of invasive aspergillosis and mucormycosis. It has been previously reported that an interaction between flucloxacillin and voriconazole may lead to subtherapeutic voriconazole exposure, when used concomitantly. Since isavuconazole is also metabolised via cytochrome P450 enzymes, the same interaction may be expected. Objectives: We aim to document exposure to isavuconazole in patients concomitantly treated with flucloxacillin. Patients: We report two patients treated with both isavuconazole and flucloxacillin, in whom we determined isavuconazole concentrations. Results: Low isavuconazole trough concentrations (<1 mg/L) were observed in two patients under concomitant treatment with flucloxacillin. Conclusions: In combination with flucloxacillin, low isavuconazole concentrations were observed but an adequate isavuconazole exposure may be reached with dose augmentation. Therapeutic drug monitoring of isavuconazole is recommended to ensure an adequate exposure. [ABSTRACT FROM AUTHOR]

Background: Exophiala is the main genus of black fungi comprising numerous opportunistic species. Data on antifungal susceptibility of Exophiala isolates are limited, while infections are potentially fatal. Materials and methods: In vitro activities of eight antifungal drugs (AMB, five azoles, two echinocandins) against 126 clinical (n = 76) and environmental (n = 47) isolates from around the world were investigated. E. oligosperma (n = 58), E. spinifera (n = 33), E. jeanselmei (n = 14) and E. xenobiotica (n = 21) were included in our dataset. Results: The resulting MIC90s of all strains were as follows, in increasing order: posaconazole 0.063 μg/ml, itraconazole 0.125 μg/ml, voriconazole and amphotericin B 1 μg/ml, isavuconazole 2 μg/ml, micafungin and caspofungin 4 μg/ml, and fluconazole 64 μg/ml. Posaconazole, itraconazole and micafungin were the drugs with the best overall activity against Exophiala species. Fluconazole could not be considered as a treatment choice. No significant difference could be found among antifungal drug activities between these four species, neither in clinical nor in environmental isolates. Conclusion: Antifungal susceptibility data for Exophiala spp. are crucial to improve the management of this occasionally fatal infection and the outcome of its treatment. [ABSTRACT FROM AUTHOR]

Background: Oral itraconazole and voriconazole are currently recommended in the initial management of chronic pulmonary aspergillosis (CPA). However, only a few studies have compared outcomes with different anti‐fungal agents (AFAs) in treating CPA. Herein, we perform a network meta‐analysis comparing the efficacy of different AFAs in CPA. Methods: We searched the PubMed and EmBase databases to identify studies (either randomised‐controlled trials [RCTs] or observational) reporting treatment outcomes with AFAs in patients of CPA. The study quality was assessed using the Newcastle‐Ottawa scale (NOS). We performed a network meta‐analysis to compare the relative efficacy of different AFAs in treating CPA. The primary outcome was a favourable response to treatment with AFAs. Results: We found ten studies (718 patients) investigating different AFAs (oral AFAs [n = 5], intravenous AFAs [n = 5]) in the treatment of CPA. There were four RCTs and six observational studies. The studies using oral agents reported long‐term outcomes (>12 weeks), while those with intravenous agents provided only short‐term outcomes (<6 weeks). We found one study of posaconazole and none with isavuconazole for treating CPA. Amongst the oral agents, itraconazole was significantly better than supportive care and was ranked as the best oral AFA on network rank analysis. We found all intravenous AFAs to be equally effective. Intravenous echinocandins and voriconazole were ranked best for achieving a favourable treatment response. Conclusion: Oral itraconazole may be preferred over other azoles as the initial therapy for CPA. Amongst the intravenous agents, echinocandins and voriconazole may be preferred over amphotericin B. Randomised‐controlled trials comparing different AFAs, especially the newer AFAs, are urgently needed. [ABSTRACT FROM AUTHOR]

Background: Voriconazole primary metabolism is catalysed by CYP2C19. A large variability of trough concentrations in patients with invasive fungal infection treated with voriconazole has been observed in clinical practice. It remains controversial whether the CYP2C19 polymorphisms are responsible for voriconazole metabolism in the individual variation. Objectives: The primary aim of this study was to assess the effect of CYP2C19 polymorphisms on voriconazole trough concentrations. Methods: Following a systematic literature review, we performed a meta‐analysis for mean differences (MD) of voriconazole trough concentrations (Cmin), voriconazole dosage adjusted trough concentrations (Cmin/D) and for risk ratio (RR) of the proportion of patients in the target therapeutic range between pairwise comparisons of CYP2C19 phenotypes. Results: Compared with normal metabolisers (NMs), intermediate metabolisers (IMs) (MD: 0.82, 95% CI: 0.57 to 1.07, I2 = 44%, p <.00001) or poor metabolisers (PMs) (MD: 1.59, 95% CI: 1.14 to 2.05, I2 = 46%, p <.00001) had significantly higher voriconazole Cmin (μg·ml−1), while rapid metabolisers (RMs) had significantly lower voriconazole Cmin (MD: −0,87, 95% CI: −1.35 to −0.38, I2 = 0%, p =.0004). In addition, IMs had significantly lower Cmin than PMs (MD: −0.59, 95% CI: −0.97 to −0.20, I2 = 22%, p =.003). Similarly, the Cmin/D (μg·kg·ml−1·mg−1) was significantly higher in IMs (MD: 0.13, 95% CI: 0.05 to 0.22, I2 = 0%, p =.002) and PMs (MD: 0.20, 95% CI: 0.07 to 0.34, I2 = 0%, p =.003) than that in NMs, and also, IMs had significantly lower Cmin/D than PMs (MD: −0.11, 95% CI: −0.14 to −0.08, I2 = 0%, p <.00001). Furthermore, PMs had a significantly higher proportion of the target therapeutic range than NMs (RR: 1.34, 95% CI: 1.09 to 1.64, I2 = 50%, p =.005). Conclusions: Compared to NMs, IMs and PMs had higher voriconazole trough concentrations, especially in Asians, while RMs had lower voriconazole trough concentrations. In addition, PMs had a higher proportion of the target therapeutic range than NMs, especially in Asians. CYP2C19 genotyping is expected to be used to preemptively guide the individualisation of voriconazole in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Candida parapsilosis complex consists of three species, the prevalence and geographical distribution of which might vary. Increasing rates of fluconazole resistance among C. parapsilosis complex were reported from various centres. Objectives: Aim of this study was to identify invasive C. parapsilosis complex strains up to species level, explore rates and molecular mechanisms of azole resistance and analyse temporal changes at a single centre. Methods: Isolates from blood cultures from 1997 to 2017 were included. Species were identified using RFLP of the SADH gene and confirmed with ITS sequencing when needed. In vitro susceptibility to fluconazole, voriconazole and posaconazole was tested and evaluated using EUCAST guidelines. Sequences of ERG11 and MRR1 genes were analysed for fluconazole non‐susceptible isolates. Results: A total of 283 isolates from 181 patients were tested for azole susceptibility. All were C. parapsilosis sensu stricto, except one C. orthopsilosis. All three azoles were effective against 213 of the isolates from 135 patients, including one C. orthopsilosis. Fluconazole resistance was 13.3% (24/181 patients). While the first fluconazole‐resistant isolates were detected in 2004, increase was evident after 2011. In ERG11, Y132F mutation was the most common among fluconazole non‐susceptible isolates (71.7%), followed by G458S (10.9%) and D421N (4.3%). In MRR1, R405K (56.5%) and G927C (8.7%) were detected. However, association of these mutations to azole resistance is yet to be investigated. Conclusions: Rising azole resistance rates in C. parapsilosis sensu stricto isolates particularly after 2011 were of concern. The well‐known Y132F mutation was the predominant mechanism of azole resistance while accompanied with other genetic mutations. [ABSTRACT FROM AUTHOR]

Background: Dermatophytes showing reduced sensitivity to antifungal agents have emerged in several countries. One terbinafine resistant strain of Trichophyton rubrum, TIMM20092, also showed reduced sensitivity to itraconazole (ITC) and voriconazole (VRC). The expression of two genes (TruMDR2 and TruMDR3) encoding multidrug transporters of the ABC family was found to be highly up‐regulated in this strain. Deletion of TruMDR3 in TIMM20092 abolished its resistance to VRC but only slightly reduced its resistance to ITC. Objectives: We examined the potential of T rubrum to develop resistance to ITC by analysing the mechanism of ITC resistance in TIMM20092. Methods: The deletion of TruMDR2 by gene replacement was performed in TIMM20092 and one TruMDR3‐lacking mutant (∆TruMDR3) previously generated from TIMM20092. TruMDR2 single and TruMDR2/TruMDR3 double mutants (∆TruMDR2 and ∆TruMDR2/3) were successfully obtained, respectively. Results: The suppression of TruMDR2 was shown to abolish resistance to ITC in TIMM20092 and the TruMDR3‐lacking mutant, strongly suggesting that TruMDR2 is a major contributor to ITC resistance in TIMM20092. Conclusions: Our study highlights the possible role of the ABC transporter TruMDR2 in ITC resistance of T. rubrum. [ABSTRACT FROM AUTHOR]

Background: Dermatophytes are the most common fungal pathogens causing superficial infections in humans with a high prevalence worldwide. The treatment of these infections is based on the use of topical and systemic antifungal agents. A convenient method with a high predictive value for testing the susceptibilities of dermatophytes is necessary. Objective: To evaluate the ability of the Sensititre YeastOne® in testing the activity of nine antifungal agents against dermatophytes. Methods: We compared Sensititre® with reference procedure for anidulafungin (ANID), micafungin sodium (MCF), caspofungin acetate (CAS), 5‐fluorocytosine (5FC), posaconazole (PCZ), voriconazole (VCZ), itraconazole (ITZ), fluconazole (FLZ) and amphotericin B (AMB) against 79 dermatophyte isolates, the essential agreement (EA) and categorical agreement (CA) between the two methods were obtained. Results: The MICs or MECs obtained by the Sensititre® were usually lower than those obtained by the M38‐A2. The overall EA between the two methods of nine antifungals was best for 5FC (100%), followed by MCF (94.9%), PCZ (84.8%), AMB (67.1%), FLZ (65.8%), VCZ (63.3%), ANID (29.1%), ITZ (20.3%) and CAS (2.5%). The overall CA between the two methods for all drugs was 100% except for ANID (97.4%), MCF (95%) and PCZ (92.5%). Substantial discrepancies were observed with all drugs except for VCZ and 5FC. The results of M38‐A2 in terms of GMIC (or GMEC) and MIC90 (or MEC90) were, in increasing order, as follows: MCF, PCZ, VCZ, ANID, ITZ, CAS, AMB, FLZ and 5FC. Conclusions: The Sensititre YeastOne® shows poor EA with the reference method for dermatophytes; therefore, M38‐A2 should remain the reference procedure for antifungal susceptibility testing against dermatophytes. [ABSTRACT FROM AUTHOR]

Background: Malassezia spp. antifungal susceptibility testing (AFST) capacities are limited by the lack of efficient and standardised AFST procedure, mainly because of the fastidious cultivation of these yeast. Objectives: This study aimed to compare the FastFung broth (FFB) to modified Dixon broth (mDIXB) for the in vitro AFST of Malassezia spp. Fluconazole, ketoconazole, voriconazole and terbinafine MICs against a 19 Malassezia strains, including 6 M furfur, 4 M pachydermatis, 5 M sympodialis and 4 M slooffiae. Methods: The essential agreement (EA) between the two assays, and the intra‐ and inter‐laboratory agreement of each assay were assessed. Results: The MIC data obtained in our study were comparable to those reported in the literature. FFB showed to enhance Malassezia growth and displayed 100% (±2‐fold dilution) EAs demonstrating similar performances to mDIXB. In addition, the MIC data obtained by using the FFB were reproducible between laboratories with EAs ranging from 94.7% to 100%. Conclusions: Therefore, FFB is a suitable alternative to mDXB for Malassezia spp. AFST. [ABSTRACT FROM AUTHOR]

Background: The emergence of azole resistance in non‐fumigatus Aspergillus strains is on the raise. Objectives: To study the susceptibility profiles and the molecular mechanisms of azole resistance of environmental and clinical strains of Aspergillus flavus from Argentina. Methods: Thirty‐five A flavus isolates (18 from soybean seeds and chickpea seeds and 17 from the clinic) were analysed for amphotericin B and azole resistance using the standard microbroth dilution method according to CLSI M38‐A2 guidelines. Sequencing analysis of the cyp51 genes was conducted in those isolates displaying high MICs values to itraconazole, voriconazole and/or posaconazole. Results: Among the environmental isolates, 33.3% of them showed high MIC values for at least one triazole whereas 23.5% of the clinical isolates displayed high MIC values for amphotericin B. Point mutations in the Cyp51C gene were recorded in most environmental isolates with non‐wild‐type MIC values. Conclusions: Susceptibility differences among environmental A flavus isolates might suggest the possibility of native resistance to certain triazole antifungals used in the clinic. To the best of our knowledge, this is the first report of antifungal screening of environmental strains of A flavus in soybean seeds and chickpea seeds from Argentina that showed increased resistance to voriconazole and itraconazole in comparison to clinical strains. [ABSTRACT FROM AUTHOR]

Background: Invasive mould diseases are associated with high morbidity, mortality and economic impact. Its treatment is often started prior to differential pathogen diagnosis. Isavuconazole is approved for treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM) when amphotericin‐B is not indicated. Objectives: To estimate the cost‐effectiveness of isavuconazole vs voriconazole for the treatment of adult patients with possible IA prior to differential pathogen diagnosis, in Spain. Methods: A decision tree analysis was performed using the Spanish Healthcare System perspective. Among all patients with possible IA, it was considered that 7.81% actually had IM. Costs for laboratory analysis, management of adverse events, hospitalisation and drugs per patient, deaths and long‐term effects in life years (LYs) and quality‐adjusted LYs (QALYs) were considered. Efficacy data were obtained from clinical trials and utilities from the literature. Deterministic and probabilistic sensitivity analyses (PSA) were conducted. Results: In patients with possible IA and when compared to voricanozole, isavuconazole showed an incremental cost of 4758.53€, besides an incremental effectiveness of +0.49 LYs and +0.41 QALYs per patient. The Incremental Cost Effectiveness Ratio was 9622.52€ per LY gained and 11,734.79€ per QALY gained. The higher cost of isavuconazole was due to drug acquisition. Main parameters influencing results were mortality, treatment duration and hospitalisation days. The PSA results showed that isavuconazole has a probability of being cost‐effective of 67.34%, being dominant in 24.00% of cases. Conclusions: Isavuconazole is a cost‐effective treatment compared to voriconazole for patients with possible IA for a willingness to pay threshold of 25,000€ per additional QALY. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the antifungal susceptibility of Sporothrix globosa isolated from Shandong, China, and compare the differences of antifungal activity in vitro between yeast and mycelial phases. Methods: The in vitro sensitivity of mycelium phase and yeast phase of Sporothrix globosa to anidulafungin, micafungin, caspofungin, 5‐flucytosine, posaconazole, voriconazole, itraconazole, fluconazole and amphotericin B was tested by Sensititre™ YeastOne™. The minimum inhibitory concentration (MIC) values of mycelium phase and yeast phase were calculated. SPSS 19.0 software was used to conduct non‐parametric rank sum test for MIC values, and P <.05 was considered statistically significant. Results: The mycelium phase and yeast phase were the most sensitive to itraconazole and the least sensitive to fluconazole. The yeast phase of the same strain was more sensitive to itraconazole, voriconazole, posaconazole, micafungin, anidulafungin, caspofungin and 5‐fluorouracil, compared with the mycelium (P <.05). However, fluconazole and amphotericin B had no significant difference in mycelium phase and yeast phase. Conclusions: Itraconazole is the most active antifungal agent in vitro against S globosa. The yeast phase of the same strain is more sensitive than that of the mycelium. [ABSTRACT FROM AUTHOR]

Background: Effects of CYP2C19 polymorphism on voriconazole concentration (C0), dose‐adjusted trough concentrations (C0/dose) and voriconazole‐to‐voriconazole‐N‐oxide concentration ratio (C0/CN) have not been fully investigated. Objectives: To investigate correlations of CYP2C19 polymorphisms with plasma concentrations of voriconazole and the major metabolite voriconazole‐N‐oxide in elderly patients. Methods: A prospective, multi‐centre, non‐intervention, open clinical study was conducted within Southwestern Chinese patients clinically diagnosed with invasive fungal infections, to investigate the associations of CYP2C19∗2 (681G > A), CYP2C19∗3 (636G > A) and CYP2C19∗17 (−806C > T) genetic polymorphisms with voriconazole C0, C0/dose and C0/CN. Results: The study included 131 adult patients, of which 72 were elderly (≥60 years) and 59 were adults (<60 years). The allele frequencies of CYP2C19∗2, ∗3 and ∗17 in the elderly cohort were 61.1%, 29.9% and 7.6%, respectively, which were similar to those in the adult cohort (66.9%, 29.7% and 2.5%, respectively; P >.05). The median voriconazole C0 (C0), C0/dose and C0/CN ratio in patients with the CYP2C19∗1/∗2 and CYP2C19∗2/∗2 genotypes were significantly higher than those in patients with the CYP2C19∗1/∗1 genotype in the adult cohort (P <.05). The C0 and C0/dose in patients with the CYP2C19∗1/∗3 and CYP2C19∗2/∗2 genotypes, and the C0/CN ratio for patients with the CYP2C19∗1/∗2 genotype were numerically higher than those in patients with the CYP2C19∗1/∗1 genotype in the elderly cohort, but this difference was not statistically significant (P > 0.05). The C0, C0/dose and C0/CN in patients with poor metaboliser phenotypes were higher than in those with normal metaboliser phenotypes and C0 in patients with intermediate metaboliser phenotypes were significantly higher than in those with normal metaboliser phenotypes in the adult cohort (P <.05). However, there were no significant differences in the C0, C0/dose and C0/CN among different CYP2C19‐predicted metabolic phenotypes in the elderly cohort. Conclusions: Voriconazole C0, C0/dose and C0/CN ratio are not significantly affected by the CYP2C19∗2/∗3 polymorphisms in the elderly patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Fungal keratitis can be more difficult to treat than bacterial keratitis with worse outcomes. Objective: To evaluate the therapeutic response time of topical voriconazole combined with intrastromal voriconazole, and topical natamycin on Fusarium keratitis. Methods: The stroma of corneas of twelve New Zealand White rabbits was inoculated with Fusarium sp spores. Seven days after inoculation, they were divided into 2 groups randomly. Group A was treated with topical natamycin 5% for 21 days. Group B was treated with intrastromal voriconazole 0.05% single injection at the beginning of treatment, continued with topical voriconazole 1% for 21 days. Clinical evaluations for epithelial defect size and clinical scores in each group were performed on 1st, 3rd, 7th, 10th, 14th and 21st days after treatment. Mycological examinations were performed before and after the treatment. Results: After treatment, there was no statistically significant difference between natamycin and voriconazole in reducing epithelial defect size at first, second or third week after treatment (P =.15; P =.39; and P =.90). The clinical scores on both groups also showed no statistically significant differences at first, second and third weeks after treatment (P =.24; P =.09; and P =.32). Qualitative mycological evaluation before and after the treatment showed no statistically significant difference in KOH examination (P = 1; P = 1) and culture in Sabouraud dextrose agar (P = 1; P = 1). Conclusion: Intrastromal voriconazole injection combined with topical voriconazole seems to give similar response time but not earlier in improving clinical presentation of Fusarium keratitis as topical natamycin. [ABSTRACT FROM AUTHOR]

Summary: Background: Triazole resistance in Aspergillus fumigatus sensu stricto due to mutations in the cyp51A gene has been widely reported. Data from Argentina, and particularly from cystic fibrosis (CF) patients, are limited. Objectives: To investigate the prevalence and molecular mechanisms of azole resistance in A. fumigatus sensu stricto recovered from this population. Methods: Ninety‐three A. fumigatus isolates from 50 CF patients were retrospectively analysed for azole resistance using the standard microbroth dilution method according to CLSI M38‐A2 guidelines. Sequencing analysis of the cyp51A gene and its promoter region was conducted in those isolates displaying high MIC values to itraconazole, voriconazole and/or posaconazole. Results: Overall, 14% of isolates displayed high MIC values to at least one azole. Of them, 30.7% had the mutation TR34‐L98H. No mutations in the cyp51A gene or its promoter were found in the remaining non–wild‐type strains. Therefore, other mechanisms associated with azole resistance can be highly prevalent in these isolates. Conclusions: To the best of our knowledge, this is the first study in Latin America reporting azole‐resistant A. fumigatus strains recovered from respiratory secretions of CF patients. Noteworthy, the prevalence of azole resistance in A. fumigatus sensu stricto in the studied Argentinean CF population is alarmingly high. [ABSTRACT FROM AUTHOR]

Summary: Background: Trichosporonosis is a rare invasive infection in humans mainly due to Trichosporon asahii, and especially recovered from patients having haematological malignancy. Since 2012, IGS1 region sequencing is used as a genotyping method to distinguish isolates, with high frequency of one haplotype worldwide and a geographic specificity for some haplotypes. Objectives: We compared the IGS1 genotyping method and whole genome sequencing (WGS) to study the relationship between clinical isolates involved in two grouped cases in France. Methods: IGS1 sequencing and antifungal susceptibility testing were performed for 54 clinical isolates. Clinical data for 28 isolates included in surveillance programs were analysed. Whole genome was sequenced for 32 clinical isolates and the type strain. Results: All isolates were intrinsically resistant to flucytosine, while voriconazole had the most potent in vitro activity. The majority of the isolates was recovered from patients with haematological malignancies (42.86%), with a high proportion of children (<15 yrs‐old, 32.14%) and a high mortality rate at three months (46.15%). Based on the WGS analysis, isolates exhibiting IGS1 haplotype 1, 3 and 7 belonged to different clades. Five isolates recovered during the first grouped cases had the same IGS1 haplotype and shared 99% of SNPs similarity. For the second grouped cases, four isolates had 98.7% of SNPs similarity while the isolate recovered 4 years earlier was totally unlinked. Conclusions: We confirmed the usefulness of IGS1 sequencing for grouped cases infection of T. asahii. We underlined its limitation for the study of population structure and the utility of WGS analysis for the study of epidemiologically unrelated isolates. [ABSTRACT FROM AUTHOR]

Summary: Background: Hepatotoxicity and visual symptoms are common adverse effects (AEs) of voriconazole therapy. Objective: To retrospectively evaluate the effects of treatment modification based on therapeutic drug monitoring on AEs in patients undergoing voriconazole therapy. Methods: The target voriconazole trough concentration (Cmin) was 1‐5 µg/mL. Receiver operating characteristic curves were used to determine Cmin cut‐offs for AEs. Results: A total of 401 patients were included. Among 108 patients with high initial Cmin, voriconazole was discontinued in 32 and the dose was reduced in 71. Among 44 patients with low initial Cmin, voriconazole was discontinued in 4 and the dose was increased in 19. Hepatotoxicity occurred in 6.0% of patients, after a median of 10 days. Visual symptoms were evident in 9.5% of patients after a median of 4 days. Initial Cmin was significantly associated with visual symptoms but not hepatotoxicity, which suggested the effect of treatment modification on hepatotoxicity. However, both hepatotoxicity and visual symptoms were significantly correlated with Cmin at the onset of AEs, and the Cmin cut‐offs were 3.5 μg/mL for hepatotoxicity and 4.2 μg/mL for visual symptoms. Voriconazole was discontinued after the occurrence of AEs in 62.5% of patients with hepatotoxicity but only 26.3% of patients with visual symptoms. With dose adjustment, treatment was completed in 8/9 patients with hepatotoxicity and 27/28 patients with visual symptoms. Conclusions: A significant preventive effect was demonstrated on hepatotoxicity, but not on visual symptoms because of earlier occurrence. With treatment modification after the occurrence of AEs, most patients completed therapy. [ABSTRACT FROM AUTHOR]

Background: Pulmonary mucormycosis (PM) represents a serious burden in terms of morbidity and mortality in immunocompromised patients. Studies of prognostic factors in patients with PM are limited and have involved small numbers of patients. Methods: Adult patients diagnosed with proven and probable PM according to the modified definitions of the EORTC/MSG 2008 in a tertiary hospital in Seoul, South Korea, between 2008 and 2019 were retrospectively enrolled. Results: A total of 49 patients including 31 (63%) with proven PM and 18 (37%) with probable PM were enrolled. The 90‐day mortality rate was 49% (24/49). Neutropenia, thrombocytopenia, use of voriconazole at clinical suspicion, positivity of non‐sterile culture, use of steroid and treatment without surgery were more common in fatal cases than non‐fatal cases. Voriconazole use at clinical suspicion for invasive mould pneumonia (OR 6.91, P =.01) and prolonged neutropenia (OR 4.86, P =.03) were independent risk factors for mortality. Voriconazole use at clinical suspicion was associated with positive galactomannan (GM) assay (OR 5.93, P =.02) and history of invasive pulmonary aspergillosis (OR, 6.88, P =.05). Conclusion: About half of the patients with PM died within 90 days of diagnosis, and fatal outcomes were common in patients with prolonged neutropenia and empirical voriconazole use. Caution is needed in using voriconazole even in patients with positive GM results and prior histories of invasive pulmonary aspergillosis in whom PM cannot be ruled out by differential diagnosis. [ABSTRACT FROM AUTHOR]

Summary: Objectives: Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus disease 19 (COVID‐19) associated invasive aspergillosis at a single centre in Cologne, Germany. Methods: A retrospective chart review of all patients with COVID‐19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany. Results: COVID‐19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS. Conclusion: Clinicians caring for patients with ARDS due to COVID‐19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co‐infection. [ABSTRACT FROM AUTHOR]

Summary: Background: Causes of voriconazole‐related visual adverse events (VVAE) remained controversial. Objectives: We aimed to explore the relationship between voriconazole serum concentrations and VVAE as well as the potential influence of transient receptor potential melastatin 1 (TRPM1) on VVAE. Patients/methods: This prospective observational cohort study was done in two stages. Patients who received voriconazole for invasive fungal diseases were consecutively enrolled. Correlations between voriconazole trough levels and VVAE were explored in 76 patients. Genotyping was further conducted for 17 tag SNPs of TRPM1 in a larger population of 137 patients. Genotype distributions were compared between patients with and without VVAE. Result: Of the 76 patients, a total of 229 steady‐state voriconazole trough levels were evaluated, 69.9% of which were within the target range (1‐5.5 mg/L). No correlations were found between voriconazole trough levels and VVAE. Of the total 137 patients, VVAE occurred in 37 (27.0%) patients, including visual hallucination (13.9%, 19/137) and visual disturbances (19.0%, 26/137). Significant difference in TRPM1 genotype distribution was only observed in patients with visual hallucination but not with visual disturbances. We found that rs890160 G/T genotype was under‐presented (OR, 0.11; 95% CI, 0.01‐0.84; P =.011) and rs1378847 C/C genotype was more frequently detected (OR, 8.89; 95% CI, 1.14‐69.02; P =.013) in patients with visual hallucination when compared with those without. Conclusion: Transient receptor potential melastatin 1 was genetically associated with voriconazole‐related visual hallucination. The correlation was failed to found between voriconazole trough levels and VVAE. [ABSTRACT FROM AUTHOR]

Summary: Background: Candida auris, a multidrug‐resistant species, has the propensity of nosocomial transmission despite normal decontamination procedures. Here, we describe the isolation of C auris from patients in various hospitals in Kuwait during 2014‐2018. Susceptibility to antifungal drugs and molecular basis of resistance to fluconazole, voriconazole and micafungin were also studied. Methods: Candida auris (n = 314) obtained from 126 patients in eight hospitals were studied. All isolates were identified by PCR amplification and/or PCR‐sequencing of ribosomal DNA (rDNA). Antifungal susceptibility was determined by Etest. Molecular basis of resistance to fluconazole and micafungin was studied by PCR‐sequencing of ERG11 and FKS1 genes, respectively. Findings: Bloodstream (n = 58), urine (n = 124), respiratory (n = 98) and other (n = 34) specimens yielded 314 C auris isolates. The proportion of bloodstream C auris among all yeast isolates was higher (42 of 307, 13.7%) in 2018 as compared to 2014‐2017 (16 of 964, 1.7%) (P =.001). More bloodstream isolates (42 of 139) were cultured in 2018 than during 2014‐2017 (16 of 175) (P =.001). Resistance to amphotericin B, fluconazole, voriconazole and micafungin was detected in 27.1%, 100%, 41.1% and 1.7% isolates, respectively. Fluconazole‐resistant isolates contained either Y132F or K143R mutation in ERG11. Isolates with K143R mutation were additionally resistant to voriconazole. Micafungin‐resistant isolates contained S639F mutation in hot spot 1 of FKS1. Conclusions: Our study highlights spreading of C auris in major hospitals across Kuwait and its increasing role as a bloodstream pathogen in 2018. Cross‐resistance to voriconazole was also seen in isolates with K143R mutation in ERG11, while micafungin‐resistant isolates harboured S639F mutation in hot spot 1 of FKS1. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Background: The efficacy and side effects of voriconazole plus 5-flucytosine (Vori + 5-FC) versus amphotericin B deoxycholate plus 5-flucytosine (AmBd + 5-FC) as an induction treatment for cryptococcal meningitis are unknown., Methods: Forty-seven patients treated with Vori + 5-FC and 92 patients treated with AmBd + 5-FC were included in the current study after propensity score matching (PSM) at a ratio of 1:2. Two-week laboratory test results and 90-day mortality were compared between the two groups., Results: After 2 weeks of induction treatment, the CSF Cryptococcus sterile culture rate was 57.1% in the Vori + 5-FC group and 76.5% in the AmBd + 5-FC group (p = .026). No difference was found in the normalization of CSF indicators (glucose, total protein, intracranial pressure and India ink sterile rate) between the two groups. Both the Vori + 5FC regimen and AmBd + 5-FC regimen obviously decreased haemoglobin concentrations, platelet counts and serum potassium levels (all p ≤ .010). Notably, the Vori + 5FC regimen did not influence serum creatinine levels (p = .263), while AmBd + 5FC increased serum creatinine levels (p = .019) after 2-week induction treatment. The Vori + 5-FC group and AmBd + 5-FC group had similar 90-day cumulative survival rates (89.9% vs. 87.8%, p = .926)., Conclusion: The Vori + 5-FC regimen was associated with low 2-week CSF sterile culture and was not superior to AmBd + 5-FC as induction therapy in terms of the 90-day cumulative survival rate of CM patients., (© 2023 Wiley-VCH GmbH. Published by John Wiley & Sons Ltd.)

Summary: This randomised, double‐blind, placebo‐controlled trial assessed the efficacy, safety and tolerability of voriconazole+anidulafungin (combination) or voriconazole+placebo (monotherapy) for invasive aspergillosis (IA; NCT00531479). We present a post hoc analysis of Korean and non‐Korean patients with IA (including baseline positive serum galactomannan [GM]). Immunocompromised patients ≥ 16 years with IA were randomised 1:1, combination or monotherapy, for ≥ 2 weeks' treatment. The primary endpoint was 6‐ and 12‐week all‐cause mortality (Korean modified intent‐to‐treat [mITT] population). Overall, 454 patients enrolled (Koreans: 56 [combination: 28, monotherapy: 28], non‐Koreans: 398 [combination: 200, monotherapy: 198]). The mITT population comprised 40 Koreans (combination: 23; monotherapy: 17) and 237 non‐Koreans (combination: 112; monotherapy: 125). Week 6 treatment difference in mortality rate between combination and monotherapy was −6.4% in non‐Koreans. This reduction was more marked in Koreans (−22.4%). Week 12 difference in all‐cause mortality between combination and monotherapy was −17.7% (Koreans) and −20.2% at Week 6 (Koreans; positive baseline GM). Week 6 mortality (Koreans [mITT]; baseline GM >0.5‐2.0) was 0/13 (combination) and 2/6 (monotherapy). Serious adverse events were numerically higher for combination than monotherapy (Koreans: 57.1%, 46.4%; non‐Koreans: 49.5%, 46.0%). In Koreans, combination therapy was associated with marginally better outcomes than monotherapy and more so than in non‐Koreans. [ABSTRACT FROM AUTHOR]

Summary: Background: The wide pharmacokinetic variability of voriconazole leads to uncertainty regarding adequate exposure. Objectives: To create a pharmacokinetic model that could help to explain the variability. Methods: Retrospective review of paediatric patients with cancer. Models were built using Pmetrics. Results: We analysed 158 trough measurements in 55 patients; in 41.8%, the serum levels were between 1 and 6 mg/L on initial measurement. After the measurements, dosage adjustments were made in 42 (76.3%) patients, and the percentage of adequate levels rose to 54.5%. Fourteen deaths (25.4%) were attributed to invasive fungal diseases. The mean serum levels were higher in deceased patients (mean ± SD: 3.1 ± 3.2 mg/L vs 2.5 ± 3.6 mg/L in survivors; P = 0.018), but the median doses per kg were higher in survivors. Drug exposure was also higher in deceased patients (mean ± SD of AUC: 19.2 ± 8.1 vs 9.5 ± 19.1 in survivors; P = 0.005). No correlation was found between serum concentrations <1 mg/L and death attributable to fungal disease. Bioavailability was estimated in 50%. The maximum velocity of clearance was reduced in deceased patients. Conclusions: Extremely ill patients can be poor metabolizers of voriconazole. Therapeutic monitoring promotes only a limited improvement in drug management. [ABSTRACT FROM AUTHOR]

Summary: Invasive fungal infections (IFI) of the Central Nervous System (IFI‐CNS) and Paranasal Sinuses (IFI‐PS) are rare, life‐threatening infections in haematologic patients, and their management remains a challenge despite the availability of new diagnostic techniques and novel antifungal agents. In addition, analyses of large cohorts of patients focusing on these rare IFI are still lacking. Between January 2010 and December 2016, 89 consecutive cases of Proven (53) or Probable (36) IFI‐CNS (71/89) and IFI‐PS (18/89) were collected in 34 haematological centres. The median age was 40 years (range 5‐79); acute leukaemia was the most common underlying disease (69%) and 29% of cases received a previous allogeneic stem cell transplant. Aspergillus spp. were the most common pathogens (69%), followed by mucormycetes (22%), Cryptococcus spp. (4%) and Fusarium spp. (2%). The lung was the primary focus of fungal infection (48% of cases). The nervous system biopsy was performed in 10% of IFI‐CNS, and a sinus biopsy was performed in 56% of IFI‐PS (P = 0.03). The Galactomannan test on cerebrospinal fluid has been performed in 42% of IFI‐CNS (30/71), and it was positive in 67%. Eighty‐four pts received a first‐line antifungal therapy with Amphotericine B in 58% of cases, Voriconazole in 31% and both in 11%. Moreover, 58% of patients received 2 or more lines of therapy and 38% were treated with a combination of 2 or more antifungal drugs. The median duration of antifungal therapy was 60 days (range 5‐835). A surgical intervention was performed in 26% of cases but only 10% of IFI‐CNS underwent neurosurgical intervention. The overall response rate to antifungal therapy (complete or partial response) was 57%, and 1‐year overall survival was 32% without significant differences between IFI‐CNS and IFI‐PS. The overall mortality was 69% but the IFI attributable mortality was 33%. Mortality of IFI‐CNS/PS remains high but, compared to previous historical data, it seems to be reduced probably due to the availability of newer antifungal drugs. The results arising from this large contemporary cohort of cases may allow a more effective diagnostic and therapeutic management of these very rare IFI complications in haematologic patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Long‐term oral triazole antifungal therapy is the cornerstone of management for patients with chronic pulmonary aspergillosis (CPA). Itraconazole is the first‐line choice of treatment. Voriconazole, posaconazole or isavuconazole can be used as alternative treatments in case of resistance or intolerance. All of these can cause significant adverse drug reactions. Objectives: To evaluate how CPA patients tolerate voriconazole and isavuconazole after prior triazole therapy. Methods: We performed a retrospective observational study at the UK National Aspergillosis Centre. Medical records for all consecutive CPA patients started on isavuconazole and voriconazole during an observation period of 12 and 6 months respectively were analysed. Results: During this study period, 20 patients were started on isavuconazole and 21 patients on voriconazole. Adverse events were seen in 18 of 21 (86%) the patients in the voriconazole group and 12 of 20 (60%) in the isavuconazole group (P = 0.02). For those who developed adverse events to these agents, the rates of discontinuation of therapy were comparable (ie 10/18 [56%], voriconazole vs 8/12 [67%], isavuconazole; P = 0.54). Five (25%) patients in the isavuconazole group who were intolerant to other triazoles tolerated the standard dose of isavuconazole. Conclusions: Compared with isavuconazole, adverse events were significantly higher in CPA patients commenced on voriconazole. Isavuconazole may be an option for those patients who are intolerant to other triazoles. [ABSTRACT FROM AUTHOR]

Summary: Background: The incidence of cutaneous infections by dematiaceous fungi is rising in our environment due to the high number of solid organ transplant recipients (SOTR). Objective: To review our experience in the management of cutaneous phaeohyphomycoses in a Spanish reference centre for dermatological care of SOTR. Methods: Retrospective clinical, histopathological and microbiological review of all SOTR diagnosed of a phaeohyphomycosis in a 7‐year period. Results: Eleven SOTR were identified (8 lung and 3 kidney). The lesions were solitary in six patients and multiple in five, affecting mostly the lower extremities. Early lesions showed epidermal hyperplasia and a diffuse dermal suppurative granulomatous infiltrate that was progressively substituted by fibrosis when the lesions were treated. Septated fungal structures with refractile walls were identified. DNA sequencing confirmed the presence of Alternaria spp (8 cases), Cladosporium cladosporioides, Microsphaeropsis arundinis and Exophiala oligosperma. Three patients with single lesions were treated with surgery, while the other 8 required long‐term antifungal therapy, including itraconazole, voriconazole and/or terbinafine, combined with surgery and reduction in tacrolimus doses. Conclusion: A clinical, histopathological and microbiological correlation is essential to corroborate this diagnosis. Solitary lesions are easily treated with surgery, but larger or multiple lesions may require long medical treatments combined with surgery and modification of immunosuppressive medication. The list of dematiaceous fungi implicated in cutaneous infections is expanding, in line with the availability of more sophisticated identification methods and the increasing number of immunosuppressed patients. [ABSTRACT FROM AUTHOR]