This prospective multicenter study showed that real-time resistance testing may limit the impact of azole resistance on mortality. An isolated positive polymerase chain reaction assay was not... Show moreThis prospective multicenter study showed that real-time resistance testing may limit the impact of azole resistance on mortality. An isolated positive polymerase chain reaction assay was not associated with mortality. Its place in the current EORTC/MSGERC definitions should be reconsidered.Background Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. Methods In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. Results Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). Conclusions Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample). Show less
BackgroundInvasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of... Show moreBackgroundInvasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy.MethodsIn a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA.ResultsOf 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83).ConclusionsReal-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample). Show less
BackgroundInvasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of... Show moreBackgroundInvasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy.MethodsIn a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA.ResultsOf 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83).ConclusionsReal-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample). Show less
Grootveld, R. van; Beek, M.T. van der; Janssen, N.A.F.; Erguen, M.; Dijk, K. van; Bethlehem, C.; ... ; CAPA20 Study Grp 2023
Purpose: COVID-19 associated pulmonary aspergillosis (CAPA) is associated with increased morbidity and mortality in ICU patients. We investigated the incidence of, risk factors for and potential... Show morePurpose: COVID-19 associated pulmonary aspergillosis (CAPA) is associated with increased morbidity and mortality in ICU patients. We investigated the incidence of, risk factors for and potential benefit of a pre-emptive screening strategy for CAPA in ICUs in the Netherlands/Belgium during immunosuppressive COVID-19 treatment.Materials and methods: A retrospective, observational, multicentre study was performed from September 2020-April 2021 including patients admitted to the ICU who had undergone diagnostics for CAPA. Patients were classified based on 2020 ECMM/ISHAM consensus criteria.Results: CAPA was diagnosed in 295/1977 (14.9%) patients. Corticosteroids were administered to 97.1% of patients and interleukin-6 inhibitors (anti-IL-6) to 23.5%. EORTC/MSGERC host factors or treatment with anti-IL-6 with or without corticosteroids were not risk factors for CAPA. Ninety-day mortality was 65.3% (145/222) in patients with CAPA compared to 53.7% (176/328) without CAPA (p = 0.008). Median time from ICU admission to CAPA diagnosis was 12 days. Pre-emptive screening for CAPA was not associated with earlier diagnosis or reduced mortality compared to a reactive diagnostic strategy.Conclusions: CAPA is an indicator of a protracted course of a COVID-19 infection. No benefit of pre-emptive screening was observed, but prospective studies comparing pre-defined strategies would be required to confirm this observation. Show less
Objectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided... Show moreObjectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treat-ment is superior to standard treatment for invasive aspergillosis.Methods: A multicentre ( n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged >= 18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treat-ment initiation of voriconazole and repeated during treatment in both groups. The TDM group had mea-sured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. Results: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups ( P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) ( P < 0.001). Conclusions: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. Clinical trial registration: ClinicalTrials.gov registration no. NCT00893555.(c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ) Show less
Background Fluconazole is commonly used to treat or prevent fungal infections. It is typically used orally but in critical situations, IV administration is needed. Obesity may influence the... Show moreBackground Fluconazole is commonly used to treat or prevent fungal infections. It is typically used orally but in critical situations, IV administration is needed. Obesity may influence the pharmacokinetics and therapeutic efficacy of a drug. In this study, we aim to assess the impact of obesity on fluconazole pharmacokinetics given orally or IV to guide dose adjustments for the obese population. Methods We performed a prospective pharmacokinetic study with intensive sampling in obese subjects undergoing bariatric surgery (n = 17, BMI >= 35 kg/m(2)) and non-obese healthy controls (n = 8, 18.5 <= BMI < 30.0 kg/m(2)). Participants received a semi-simultaneous oral dose of 400 mg fluconazole capsules, followed after 2 h by 400 mg IV. Population pharmacokinetic modelling and simulation were performed using NONMEM 7.3. Results A total of 421 fluconazole concentrations in 25 participants (total bodyweight 61.0-174 kg) until 48 h after dosing were obtained. An estimated bioavailability of 87.5% was found for both obese and non-obese subjects, with a 95% distribution interval of 43.9%-98.4%. With increasing total bodyweight, both higher CL and V-d were found. Sex also significantly impacted V-d, being 27% larger in male compared with female participants. Conclusions In our population of obese but otherwise healthy individuals, obesity clearly alters the pharmacokinetics of fluconazole, which puts severely obese adults, particularly if male, at risk of suboptimal exposure, for which adjusted doses are proposed. Show less
Buil, J.B.; Zanten, A.R.H. van; Bentvelsen, R.G.; Rijpstra, T.A.; Goorhuis, B.; Voort, S. van der; ... ; Verweij, P.E. 2021
We describe four secondary fungal infections caused by Mucorales species in COVID-19 patients. Three COVID-19 associated mucormycosis (CAM) occurred in ICU, one outside ICU. All were men aged >... Show moreWe describe four secondary fungal infections caused by Mucorales species in COVID-19 patients. Three COVID-19 associated mucormycosis (CAM) occurred in ICU, one outside ICU. All were men aged > 50 years, three died. Clinical presentations included pulmonary, rhino-orbital cerebral and disseminated infection. Infections occurred in patients with and without diabetes mellitus. CAM is an emerging disease and our observations underscore the need to be aware of invasive mucormycosis, including in COVID-19 patients without (poorly controlled) diabetes mellitus and outside ICU. Show less
We investigated the prevalence of azole resistance of Aspergillus fumigatus isolates in the Netherlands by screening clinical A. fumigatus isolates for azole resistance during 2013-2018. We... Show moreWe investigated the prevalence of azole resistance of Aspergillus fumigatus isolates in the Netherlands by screening clinical A. fumigatus isolates for azole resistance during 2013-2018. We analyzed azole-resistant isolates phenotypically by in vitro susceptibility testing and for the presence of resistance mutations in the Cyp51A gene. Over the 6-year period, 508 (11%) of 4,496 culture-positive patients harbored an azole-resistant isolate. Resistance frequency increased from 7.6% (95% CI 5.9%-9.8%) in 2013 (58/760 patients) to 14.7% (95% CI 12.3%-17.4%) in 2018 (112/764 patients) (p = 0.0001). TR34/L98H (69%) and TR46/Y121F/T289A (17%) accounted for 86% of Cyp51A mutations. However, the mean voriconazole MIC of TR34/L98H isolates decreased from 8 mg/L (2013) to 2 mg/L (2018), and the voriconazole-resistance frequency was 34% lower in 2018 than in 2013 (p = 0.0001). Our survey showed changing azole phenotypes in TR34/L98H isolates, which hampers the use of current PCR-based resistance tests. Show less
Introduction: Recognizing fungal keratitis based on the clinical presentation is challenging. Topical therapy may be initiated with antibacterial agents and corticosteroids, thus delaying the... Show moreIntroduction: Recognizing fungal keratitis based on the clinical presentation is challenging. Topical therapy may be initiated with antibacterial agents and corticosteroids, thus delaying the fungal diagnosis. As a consequence, the fungal infection may progress ultimately leading to more severe infection and blindness. We noticed an increase of fungal keratitis cases in the Netherlands, especially caused by Fusarium species, which prompted us to conduct a retrospective cohort study, aiming to describe the epidemiology, clinical management, and outcome.Materials and Methods: As fungi are commonly sent to the Dutch mycology reference laboratory for identification and in vitro susceptibility testing, the fungal culture collection was searched for Fusarium isolates from corneal scrapings, corneal swabs, and from contact lens (CL) fluid, between 2005 and 2016. All Fusarium isolates had been identified up to species level through sequencing of the ITS1-5.8S-ITS2 region of the rDNA and TEF1 gene. Antifungal susceptibility testing was performed according to the EUCAST microbroth dilution reference method. Antifungal agents tested included amphotericin B, voriconazole, and natamycin. In addition, susceptibility to the antisepticum chlorhexidine was tested. Ophthalmologists were approached to provide demographic and clinical data of patients identified through a positive culture.Results: Between 2005 and 2016, 89 cases of Fusarium keratitis from 16 different hospitals were identified. The number of cases of Fusarium keratitis showed a significant increase over time (R-2 = 0.9199), with one case in the first 5 years (2005-2009) and multiple cases from 2010 and onwards. The male to female ratio was 1:3 (p = 0.014). Voriconazole was the most frequently used antifungal agent, but treatment strategies differed greatly between cases including five patients that were treated with chlorhexidine 0.02% monotherapy. Keratitis management was not successful in 27 (30%) patients, with 20 (22%) patients requiring corneal transplantation and seven (8%) requiring enucleation or evisceration. The mean visual acuity (VA) was moderately impaired with a logMAR of 0.8 (95% CI 0.6-1, Snellen equivalent 0.16) at the time of Fusarium culture. Final average VA was within the range of normal vision [logMAR 0.2 (95% CI 0.1-0.3), Snellen equivalent 0.63]. CL wear was reported in 92.9% of patients with Fusarium keratitis. The time between start of symptoms and diagnosis of fungal keratitis was significantly longer in patients with poor outcome as opposed to those with (partially) restored vision; 22 vs. 15 days, respectively (mean, p = 0.024). Enucleation/evisceration occurred in patients with delayed fungal diagnosis of more than 14 days after initial presentation of symptoms. The most frequently isolated species was F. oxysporum (24.7%) followed by F. solani sensu stricto (18%) and F. petroliphilum (9%). The lowest MICs were obtained with amphotericin B followed by natamycin, voriconazole, and chlorhexidine.Conclusion: Although Fusarium keratitis remains a rare complication of CL wear, we found a significant increase of cases in the Netherlands. The course of infection may be severe and fungal diagnosis was often delayed. Antifungal treatment strategies varied widely and the treatment failure rate was high, requiring transplantation or even enucleation. Our study underscores the need for systematic surveillance of fungal keratitis and a consensus management protocol. Show less
Background: The prevalence of obesity has shown a dramatic increase over recent decades. Obesity is associated with underdosing of antimicrobial drugs for prophylaxis and treatment. Posaconazole is... Show moreBackground: The prevalence of obesity has shown a dramatic increase over recent decades. Obesity is associated with underdosing of antimicrobial drugs for prophylaxis and treatment. Posaconazole is a broad-spectrum triazole antifungal drug Licensed for prophylaxis and treatment of invasive fungal infections. It is unclear how posaconazole should be dosed in obese patients.Methods: We performed a prospective study investigating the pharmacokinetics of posaconazole in morbidly obese (n = 16) and normal-weight (n = 8) subjects, with a weight ranging between 61.4 and 190 kg, after a 300 or 400 mg IV dose. Population pharmacokinetic modelling was used to assess the effect of body size on posaconazole pharmacokinetics. ClinicalTrials.gov Identifier: NCT03246386.Results: Total body weight best predicted changes in CL and V. Model-based simulations demonstrated that, for treatment of fungal infections, a daily IV dose of 300 mg will result in a PTA of >= 90% in individuals up to 140 kg, after which both twice daily Loading and the daily maintenance dose should be increased to 400 mg. For prophylaxis, a 300 mg IV dose is adequate in patients up to 190 kg.Conclusions: Body size has a significant impact on posaconazole CL and V, resulting in a Lower exposure in obese subjects compared with normal-weight subjects. For therapeutic use of posaconazole, a dose increase is required in patients above 140 kg. For prophylaxis, a 300 mg IV dose is adequate. For oral treatment, these recommendations can act as a starting point followed by therapeutic drug monitoring. Show less
Background: Increasing resistance of Aspergillus fumigatus to triazoles in high-risk populations is a concern. Its impact on mortality is not well understood, but rates from 50% to 100% have been... Show moreBackground: Increasing resistance of Aspergillus fumigatus to triazoles in high-risk populations is a concern. Its impact on mortality is not well understood, but rates from 50% to 100% have been reported.Objectives: To determine the prevalence of voriconazole-resistant A. fumigatus invasive aspergillosis (IA) and its associated mortality in a large multicentre cohort of haematology patients with culture-positive IA.Methods: We performed a multicentre retrospective study, in which outcomes of culture-positive haematology patients with proven/probable IA were analysed. Patients were stratified based on the voriconazole susceptibility of their isolates (EUCAST broth microdilution test). Mycological and clinical data were compared, along with survival at 6 and 12 weeks.Results: We identified 129 A. fumigatus culture-positive proven or probable IA cases; 103 were voriconazole susceptible (79.8%) and 26 were voriconazole resistant (20.2%). All but one resistant case harboured environment-associated resistance mutations in the cyp51A gene: TR34/L98H (13 cases) and TR46/Y121F/T289A (12 cases). Triazole monotherapy was started in 75.0% (97/129) of patients. Mortality at 6 and 12 weeks was higher in voriconazole-resistant cases in all patients (42.3% versus 28.2%, P = 0.20; and 57.7% versus 36.9%, P = 0.064) and in non-ICU patients (36.4% versus 21.6%, P = 0.16; and 54.4% versus 30.7%; P = 0.035), compared with susceptible ones. ICU patient mortality at 6 and 12 weeks was very high regardless of triazole susceptibility (75.0% versus 66.7%, P = 0.99; and 75.0% versus 73.3%, P = 0.99).Conclusions: A very high prevalence of voriconazole resistance among culture-positive IA haematology patients was observed. The overall mortality at 12 weeks was significantly higher in non-ICU patients with voriconazole-resistant IA compared with voriconazole-susceptible IA. Show less