Voriconazole Group Research Articles

Isavuconazole Versus Voriconazole as the First-line Therapy for Solid Organ Transplant Recipients With Invasive Aspergillosis: Comparative Analysis of 2 Multicenter Cohort Studies.

Isavuconazole (ISA) and voriconazole (VORI) are recommended as the first-line treatment for invasive aspergillosis (IA). Despite theoretical advantages of ISA, both triazole agents have not been compared in solid organ transplant recipients. We performed a post hoc analysis of 2 retrospective multicenter cohorts of solid organ transplant recipients with invasive fungal disease (the SOTIS [Solid Organ Transplantation and ISavuconazole] and DiasperSOT [DIagnosis of ASPERgillosis in Solid Organ Transplantation] studies). We selected adult patients with proven/probable IA that were treated for ≥48 h with ISA (n = 57) or VORI (n = 77) as first-line therapy, either in monotherapy or combination regimen. The primary outcome was the rate of clinical response at 12 wk from the initiation of therapy. Secondary outcomes comprised 12-wk all-cause and IA-attributable mortality and the rates of treatment-emergent adverse events and premature treatment discontinuation. Both groups were comparable in their demographics and major clinical and treatment-related variables. There were no differences in the rate of 12-wk clinical response between the ISA and VORI groups (59.6% versus 59.7%, respectively; odds ratio [OR], 0.99; 95% confidence interval [CI], 0.49-2.00). This result was confirmed after propensity score adjustment (OR, 0.81; 95% CI, 0.32-2.05) and matching (OR, 0.79; 95% CI, 0.31-2.04). All-cause and IA-attributable mortality were also similar. Patients in the ISA group were less likely to experience treatment-emergent adverse events (17.5% versus 37.7%; P = 0.011) and premature treatment discontinuation (8.8% versus 23.4%; P = 0.027). Front-line treatment with ISA for posttransplant IA led to similar clinical outcomes than VORI, with better tolerability and higher treatment completion.

Posaconazole versus voriconazole as antifungal prophylaxis for invasive fungal diseases in patients with hematological malignancies.

The incidence of invasive fungal diseases (IFDs) has risen in hematologic malignancy patients due to neutropenia. While posaconazole is recommended as the first-line antifungal prophylaxis in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients and voriconazole is an alternative, there is currently no direct comparison data available to assess their relative effectiveness. We retrospectively reviewed eligible patient charts from January 2017 to February 2019 to identify breakthrough IFD rates, drug adverse event frequency, and drug acquisition cost in AML/MDS patients. Forty-eight patients received 130 chemo cycles, with 50 (38%) cycles prescribed posaconazole and 80 (62%) prescribed voriconazole as primary IFD prophylaxis. The incidence rates of IFD in the posaconazole group were 8% (4 out of 50), of which two were probable and two were possible infections, while 6.26% (5 out of 80) of patients in the voriconazole group developed IFD, with four possible infections and one probable infection (p = 0.73). A higher percentage of patients in the voriconazole group discontinued prophylaxis due to adverse events, with six patients compared to two patients in the posaconazole group (p = 0.15). The drug acquisition cost of posaconazole is 5.62 times more expensive than voriconazole. The use of voriconazole instead of posaconazole for 130 chemo cycles would save $166,584.6. Posaconazole and voriconazole have comparable efficacy and safety in preventing IFD in AML and MDS patients receiving chemotherapy. However, posaconazole is more costly than voriconazole.

A novel approach to reducing hepatotoxicity related to fungal prophylaxis in pediatric lung transplant recipients.

Pediatric lung transplant patients are at risk for developing invasive fungal infections post-transplant. No consensus exists on optimal antifungal regimens and voriconazole, a common first-line agent, has been shown to cause hepatotoxicity. We describe a single-center experience utilizing a novel antifungal regimen of intravenous micafungin and nebulized amphotericin B immediately post-transplant with conversion to an azole at the time of hospital discharge and compare it to a historical cohort of patients who received voriconazole monotherapy throughout their immediate post-operative course. This is a retrospective review of patients in the age 0-18 who received a lung transplant from June 2016-May 2021. Data points collected included: demographic data, transplant date and discharge date, Aspergillus colonization, type of lung transplant, hospitalization and level of care information, induction and antifungal medication regimen; AST, ALT, GGT, bilirubin, and direct bilirubin at various timepoints; and respiratory and blood culture results. The two patient groups were compared by assessment of changes in LFTs and culture results. Forty-two patients were included in the analysis, with 24 patients receiving micafungin and nebulized amphotericin and 18 patients receiving voriconazole. All patients in both groups experienced a post-operative elevation in at least one transaminase or bilirubin. More patients in the micafungin/amphotericin group had resolution of all abnormal LFTs by 1 month post-transplant (p = .036). Additionally, patients in the micafungin/amphotericin group experienced faster normalization of their LFTs compared with the voriconazole group (p < .001). Ten patients in the micafungin/amphotericin group and five patients in the voriconazole group were found to have fungal growth on culture post-transplant, but this difference was not found to be statistically significant (p = .507). An antifungal regimen of micafungin and nebulized amphotericin B liposomal may be useful at decreasing the duration of elevated liver enzymes in pediatric patients in the immediate post-lung transplant period when compared with voriconazole monotherapy. Larger prospective studies looking at antifungal regimens in pediatric patients post-lung transplant are warranted.

A comparison of antimicrobial regimen outcomes and antibiogram development in microbial keratitis: a prospective cohort study in Alexandria, Egypt

IntroductionAntimicrobial resistance in microbial keratitis has not been previously explored in Alexandria. We aim to recommend effective therapies through identification of etiological agents, determination of antimicrobial susceptibilities, and comparing outcomes of empiric topical antimicrobials.MethodsIn this 2022 prospective cohort conducted in Alexandria Main University Hospital cornea clinic, antimicrobial susceptibilities of isolated microorganisms from corneal scrapings were detected and antibiograms were developed. Bacterial (BK), fungal (FK), or mixed fungal/bacterial keratitis (MFBK) patients on empiric regimens were compared for ulcer healing, time-to-epithelialization, best-corrected visual acuity, interventions, and complications.ResultsThe prevalent microorganisms in 93 positive-cultures were coagulase-negative staphylococci (CoNS, 30.1%), Pseudomonas aeruginosa (14%), and Aspergillus spp. (12.9%). CoNS were susceptible to vancomycin (VAN, 100%) and moxifloxacin (MOX, 90.9%). Gram-negative bacteria showed more susceptibility to gatifloxacin (90.9%) than MOX (57.1%), and to gentamicin (GEN, 44.4%) than ceftazidime (CAZ, 11.8%). Methicillin-resistance reached 23.9% among Gram-positive bacteria. Fungi exhibited 10% resistance to voriconazole (VRC). Percentages of healed ulcers in 49 BK patients using GEN + VAN, CAZ + VAN and MOX were 85.7%, 44.4%, and 64.5%, respectively (p = 0.259). Their median time-to-epithelialization reached 21, 30, and 30 days, respectively (log-rank p = 0.020). In 51 FK patients, more ulcers (88.9%) healed with natamycin (NT) + VRC combination compared to VRC (39.1%) or NT (52.6%) (p = 0.036). Their median time-to-epithelialization was 65, 60, and 22 days, respectively (log-rank p < 0.001). The VRC group required more interventions (60.9%) than NT + VRC-treated group (11.1%) (p = 0.018). In 23 MFBK patients, none healed using NT + CAZ + VAN, while 50% healed using VRC + CAZ + VAN (p = 0.052). Regimens had comparable visual outcomes and complications.ConclusionBased on the higher detected susceptibility, we recommend empiric MOX in suspected Gram-positive BK, gatifloxacin in Gram-negative BK, and GEN + VAN in severe BK. Due to better outcomes, we recommend NT + VRC in severe FK.Trial registrationClinicalTrials.gov identifier, NCT05655689. Registered December 19, 2022– Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05655689?cond=NCT05655689.&draw=2&rank=1

Toxicity of simultaneous intrastromal and intracameral injection of voriconazole on corneal endothelium in a rabbit model

Purpose To investigate the toxicity of repeated simultaneous intrastromal and intracameral injections of voriconazole in corneal endothelial cells in a rabbit model. Methods Thirty-six eyes of 18 New Zealand white rabbits (six eyes per group) were divided into 6 groups according to the concentration of voriconazole (Group A, 0%; Group B, 0.05%; Group C, 0.1%; Group D, 0.25%; Group E, 0.5%; Group F, 1%). A combination of intrastromal and intracameral voriconazole injections were administrated to the eyes of each group three times on days 0, 3, and 7. Corneal clouding grades and central corneal thickness (CCT) were examined on days 0, 3, 7, 10, and 14. The endothelial cell counts (ECC) were measured on days 0 and 14. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were performed on day 14. Results Group F (1%) showed more severe corneal clouding than the other groups (Groups A–E) from day 7 (p < 0.05, respectively). There were no significant differences in CCT and ECC among the six groups at any time point (p > 0.05, respectively). SEM revealed blurring of the cell border and loss of microvilli at concentrations ≥0.25% (Groups D–F). TEM revealed microstructural changes in endothelial cells at concentrations ≥0.1% (Groups C–F), and multiple vacuoles were observed at a concentration of 1% voriconazole (Group F). Conclusions Repeated simultaneous intrastromal and intracameral voriconazole injections at a concentration of 0.1% or higher induced microstructural endothelial damage in rabbit corneal endothelial cells.

Incidence of breakthrough fungal infections on isavuconazole prophylaxis compared to posaconazole and voriconazole.

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

Amniotic membrane transplantation with intra-stromal Voriconazole versus amniotic membrane transplantation with argon laser photocoagulation for treatment of resistant fungal keratitis

Background Fungal keratitis is a serious problem that may affect vision. Many procedures like argon laser, voriconazole injection, and amniotic membrane transplantation (AMT) may be used to control infection. Aim To compare between intrastromal voriconazole injection with AMT and argon laser photocoagulation with AMT as treatment for fungal keratitis. Patients and methods Mycotic keratitis cases were divided in two groups, with 15 cases each. In one group, intrastromal voriconazole injection and AMT in the same setting was done, and in the other group, argon laser photocoagulation and AMT in the same setting was done. The studied cases included 21 cases with mixed infection and nine cases were pure fungal keratitis according to culture results. In the voriconazole group, intrastromal injection followed by AMT was done, whereas in the argon group, the corneal ulcer was irradiated with argon after fluorescein staining followed by AMT in the same settings. Results Healing was achieved in both groups in 2–6 weeks in all cases. Less than 50% of cases of the voriconazole group healed by the third week, whereas 80% of cases of the argon laser group healed by the third week. Vision was increased in four (26.7%) patients in the voriconazole group, whereas in six (40%) cases in the argon laser group. Conclusions Argon laser with AMT gives better results than intrastromal voriconazole injection with AMT for the treatment of resistant mycotic keratitis.

635. Is Azole Prophylaxis in Liver Transplant Recipients Effective in Preventing Invasive Candidiasis in the Era of Emerging Resistance?

Abstract Background Antifungal prophylaxis (px) in liver transplant (LT) recipients reduces invasive candidiasis (IC) and its associated mortality. Studies from our institution (UPMC) and others have shown that targeted px was as effective as universal px. Antifungal resistance has emerged among Candida spp., with ∼7% of the bloodstream isolates tested at CDC resistant to fluconazole. We sought to determine if our targeted antifungal px in LT recipients remained effective in the era of rising azole resistance. Methods We performed a retrospective study of patients undergoing LT at UPMC between 11/2010 and 06/2021. IC episodes were included if they occurred within 6 months of transplant. IC was defined using EORTC/MSGERC criteria, 2020. CLSI’s M60 2nd edition was used for antifungal susceptibility interpretation. Px was with fluconazole or voriconazole, based on risk factors for yeast or mold infection, respectively (Fig. 1). Results 1065 patients (pts) underwent LT over the study period. The most common indications for LT were HCC and NASH cirrhosis. Thirty-four pts (3%) developed IC within six months. 74% and 65% of these pts had risk factors for yeast or mold infection at some point, respectively (Table 1). Twenty-five of 34 (73.5%) pts received antifungal px, with voriconazole most commonly. Sixteen pts with IC (47%) had living donor transplant, and 11 (32%) had Roux-en-Y anastomosis. Types of IC were intra-abdominal candidiasis in 19 (56%), fungemia in 11 (32%), and intra-abdominal IC with secondary fungemia in 4 (12%). Seventeen (50%) episodes were breakthrough (BT) IC (most BT occurred in the voriconazole group), eight (24%) developed after stopping px, and nine (26%) occurred in those without px (Table 2). C. albicans and C. glabrata were the most common species (Fig. 2). Sixteen isolates underwent susceptibility testing: 12% and 44% were resistant and S-DD to fluconazole (Fig. 2); none were resistant to voriconazole. Attributable mortality of IC was 8%. Conclusion Targeted antifungal px in LT recipients with fluconazole or voriconazole effectively prevented IC, even in the era of rising azole resistance among Candida spp. We recommend antifungal susceptibility testing for Candida spp. obtained from infected sites to guide antifungal therapy. Disclosures Fernanda P. Silveira, MD, Ansun: Grant/Research Support|Janssen: Honoraria|Merck: Grant/Research Support|Novartis: Grant/Research Support|Regeneron: Grant/Research Support|Takeda: Advisor/Consultant|Takeda: Grant/Research Support.

Efficacy and safety of isavuconazole against deep-seated mycoses: A phase 3, randomized, open-label study in Japan

ObjectivesIsavuconazole is a convenient triazole antifungal agent with a broad antifungal spectrum. A randomized, open-label study (ClinicalTrials.gov, NCT03471988) was conducted to evaluate the efficacy and safety of isavuconazole in Japanese patients with deep-seated mycoses. Patients and methodsIn Cohort A, patients with aspergillosis (chronic pulmonary aspergillosis and invasive aspergillosis) were randomized in a 2:1 ratio to isavuconazole or voriconazole, and in Cohort B, patients with cryptococcosis and mucormycosis were assigned to isavuconazole for up to 84 days of treatment. The overall outcome was evaluated according to the clinical, radiological, and mycological responses at Days 42 and 84 and at the end of treatment (EOT). ResultsA total of 103 participants were enrolled and received the study drug. The overall response rate of patients with chronic pulmonary aspergillosis in the isavuconazole (52 patients) and voriconazole (27 patients) groups was 82.7% and 77.8% at EOT, respectively. The response rate in patients with cryptococcosis (10 patients, isavuconazole group only) was 90.0%. One of three participants with invasive aspergillosis and one of three participants with mucormycosis responded in the isavuconazole group. In the safety evaluation, the incidence of adverse events in participants with chronic pulmonary aspergillosis was similar in both groups. Adverse drug reactions were reported in 32 (61.5%) patients receiving isavuconazole and 23 (85.2%) patients receiving voriconazole. ConclusionsIsavuconazole showed efficacy and safety in Japanese patients with chronic pulmonary aspergillosis and cryptococcosis, for which the drug is not currently indicated.

Efficacy and Safety of Combination Antifungals as Empirical, Preemptive, and Targeted Therapies for Invasive Fungal Infections in Intensive-Care Units.

PurposeTo determine whether combinations of antifungal drugs are effective and safe for patients in intensive-care units.MethodsThis study compared the efficacy and safety of caspofungin (CAS), voriconazole (VOR), amphotericin B liposome (L-AmB), CAS+VOR, and CAS+L-AmB as empirical, preemptive, and targeted therapies for invasive fungal infection (IFI).ResultsComparing the CAS, VOR, and CAS+VOR groups revealed that there were no differences in response rates between all therapy types, IFI-associated death within 90 days was less common in the CAS+VOR group (1.8%) than the VOR group (14.3%), and there were more adverse events in the VOR group than in the CAS group (P < 0.05). For empirical or preemptive therapy, the CAS group had a better response rate (80.0%) than the CAS+VOR group (47.1%), and there were more adverse events in the VOR group than in the CAS group (P < 0.05). For targeted therapy, no differences were found for efficacy and safety. There were no differences among the CAS, L-AmB, and CAS+L-AmB groups in efficacy and safety.ConclusionPatients who received CAS monotherapy as an empirical or preemptive therapy could achieve good outcomes. Patients who received CAS+VOR or CAS+L-AmB achieved almost the same outcomes when compared with those who received CAS, VOR, and L-AmB monotherapy as targeted therapies, but those who received CAS+VOR had a lower IFI mortality rate than did those who received VOR monotherapy.

Antifungal prophylactic effectiveness and intrapulmonary concentrations of voriconazole versus posaconazole in lung transplant recipients.

Invasive fungal diseases (IFDs) are one of the leading causes of death in lung transplant recipients. This study aimed to compare the antifungal prophylactic effectiveness, intrapulmonary and plasma levels of voriconazole with posaconazole in lung transplant recipients. This retrospective cohort study analyzed adult recipients who underwent lung transplantation between June 2017 and December 2020. Voriconazole oral tablets or posaconazole oral suspension was used for prophylaxis against posttransplant IFD. Drug concentrations in bronchoalveolar lavage fluid (BALF) and plasma were measured by using liquid chromatography-mass spectrometry. The 182 recipients included 142 in the voriconazole group and 40 in the posaconazole group. The trough plasma levels were comparable between voriconazole and posaconazole (1.65 ± 0.09 vs. 1.69 ± 0.03 μg/ml, P = 0.55). However, the BALF levels were significantly higher for posaconazole than voriconazole (17.47 ± 11.51 vs. 0.56 ± 0.49 μg/ml, P < 0.001). There was no significant difference in the total incidence of breakthrough IFDs between the voriconazole and posaconazole groups (10.6% vs. 7.5%, P = 0.77). The intrapulmonary concentrations of posaconazole were significantly higher than voriconazole. The two agents had comparable antifungal prophylactic effectiveness.

Voriconazole is superior to combined itraconazole/isotretinoin therapy and itraconazole monotherapy in recalcitrant dermatophytosis.

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. To evaluate the efficacy and safety of oral itraconazole, combined itraconazole/isotretinoin therapy, and voriconazole for recalcitrant tinea. 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. 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. Voriconazole could be a future alternative for the treatment of recalcitrant dermatophytosis.

Efficacy of Intrabronchial Voriconazole Instillation for Inoperable Pulmonary Aspergilloma: A Pilot Randomized Controlled Trial

Background: Endobronchial administration of voriconazole is a potential therapeutic option for inoperable aspergilloma. Objective: This study aimed to assess the efficacy of endobronchial instillation of voriconazole for inoperable pulmonary aspergilloma. Method: Patients with mild to moderate hemoptysis, due to inoperable aspergilloma, were randomized to receive either medical therapy (MT) alone or bronchoscopic instillation of voriconazole with MT and followed up till 3 months. The primary objective of this study was to compare the percentage of patients achieving reduction in the severity of hemoptysis assessed on visual analogue scale (VAS) in intervention and control arm at 3 months. Results: This study included 60 patients (female = 47) with mean (SD) age of 40.6 (13.2) years who were randomized to receive either bronchoscopic instillation of voriconazole (n = 30) or MT alone (n = 30). At 3-month follow-up, the primary objective was achieved in 26/30 (86.7%) patients in intervention group as compared to 11/30 (36.7%) in the control group (p value <0.0001). The VAS score at 3 months was significantly lower in voriconazole group 13.9 (9.3) mm as compared to MT alone group 22.3 (11.5) mm, p value of 0.003. Bronchoscopic instillation of voriconazole was also associated with reduction in cough severity and size of the aspergilloma; however, there was no benefit of this therapy in terms of requirement of hospitalization and BAE. Conclusions: Our study shows that for nonoperable aspergilloma, bronchoscopic instillation of voriconazole is associated with reduction in the severity of hemoptysis. This therapy should be evaluated in large multi-center trials.

Comparison of Corneal Collagen Cross-Linking and Voriconazole Treatments in Experimental Fungal Keratitis for Aspergillus fumigatus.

AimsTo compare the antifungal efficacy of corneal cross-linking (CXL) and voriconazole in experimental Aspergillus keratitis models.MethodsThirty-nine New Zealand rabbits were divided into three groups: a control group, a voriconazole group (M group), and a voriconazole combined with CXL group (CXL-M group). The ulcer area was measured via slit lamp imaging, the corneal and corneal epithelial thickness, and ulcer depth was measured via anterior segment optical coherence tomography (AS-OCT). The existence time of the hyphae was observed via in vivo confocal microscopy (IVCM), and the cornea was taken for pathological examination after modeling and at the end of the study to determine the hyphae and corneal repair. The observation times were as follows: at successful modeling and at 1, 4, 7, 14, 21, and 28 days after intervention.ResultsIn the CXL-M group, ulcer area and depth decreased continuously from Day 4 to Day 28 after CXL (all P < 0.05). In the CXL-M group, ulcer area and depth were smaller than those in the other two groups from Day 4 to Day 21 after CXL (all P < 0.05, except ulcer area in the CXL-M vs. M group on Day 21). The duration of hyphae in the CXL-M group was significantly shorter than in the other two groups (P = 0.025). On Day 28, in CXL-M group, corneal thickness was thicker than baseline (P < 0.05). Meanwhile, in CXL-M group, corneal and corneal epithelial thickness were significantly thinner than in the other two groups (P < 0.001). The CXL-M group had no complications, such as corneal perforation, at the end of the study.ConclusionsVoriconazole combined with CXL is effective in treating Aspergillus-infected keratitis. Combined therapy could effectively inhibit Aspergillus, accelerate corneal repair, and shorten the course of the disease.

Multicenter Registry of Patients Receiving Systemic Mold-Active Triazoles for the Management of Invasive Fungal Infections.

Introduction‘Real-world’ data for mold-active triazoles (MATs) in the treatment of invasive fungal infections (IFIs) are lacking. This study evaluated usage of MATs in a disease registry for the management of IFIs.MethodsData were collected for this multicenter, observational, prospective study from 55 US centers, between March 2017 and April 2020. Eligible patients received isavuconazole, posaconazole, or voriconazole as MAT monotherapy (one MAT) or multiple/sequenced MAT therapy (more than one MAT) for prophylaxis or treatment. Patients were enrolled within 60 days of MAT initiation. The primary objective was to characterize patients receiving a MAT and their patterns of therapy. The full analysis set (FAS) included eligible patients for the relevant enrollment protocol, and the safety analysis set (SAF) included patients who received ≥ 1 MAT dose.ResultsOverall, 2009 patients were enrolled in the SAF. The FAS comprised 1993 patients (510 isavuconazole; 540 posaconazole; 491 voriconazole; 452 multiple/sequenced MAT therapies); 816 and 1177 received treatment and prophylaxis at study index/enrollment, respectively. Around half (57.8%) of patients were male, and median age was 59 years. Among patients with IFIs during the study, the most common pathogens were Aspergillus fumigatus in the isavuconazole (18.2% [10/55]) and voriconazole (25.5% [12/47]) groups and Candida glabrata in the posaconazole group (20.9% [9/43]); the lungs were the most common infection site (58.2% [166/285]). Most patients were maintained on MAT monotherapy (77.3% [1541/1993]), and 79.4% (1520/1915) completed their MAT therapies. A complete/partial clinical response was reported in 59.1% (591/1001) of patients with a clinical response assessment. Breakthrough IFIs were reported in 7.1% (73/1030) of prophylaxis patients. Adverse drug reactions (ADRs) were reported in 14.7% (296/2009) of patients (3.9% [20/514] isavuconazole; 11.3% [62/547] posaconazole; 14.2% [70/494] voriconazole).ConclusionsIn this ‘real-world’ study, most patients remained on their initial therapy and completed their MAT therapy. Over half of patients receiving MATs for IFIs had a successful response, and most receiving prophylaxis did not develop breakthrough IFIs. ADRs were uncommon.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00661-5.

Efficacy and Safety of Voriconazole Versus AmphotericinB Deoxycholate Induction Treatment for HIV-Associated Talaromycosis: A Prospective Multicenter Cohort Study in China.

IntroductionCurrent guidelines recommend amphotericin B as the preferred drug for induction therapy; however, amphotericin B is not available in certain settings. Induction therapy with amphotericin B deoxycholate or voriconazole has been shown to be an effective treatment for talaromycosis. However, prospective clinical trials comparing these two antifungal drugs are absent from the literature.MethodsIn this open-labeled, multicenter, prospective controlled trial, we enrolled patients at 15 hospitals in China from 2019 to 2020. Participants received induction treatment with either amphotericin B deoxycholate intravenously at a dose of 0.5 to 0.7 mg per kilogram per day or voriconazole at a dose of 6 mg/kg intravenously twice daily for the first day, followed by 4 mg/kg intravenously twice daily for 3 days, and then voriconazole was given either intravenously (4 mg/kg intravenously twice daily) or orally (200 mg twice daily) for the remaining 10 days. The primary outcome was all-cause mortality during 48 weeks after baseline. Secondary outcomes were mortality at week 2 or week 24, clinical resolution of talaromycosis, and fungal clearance at week 2. A propensity score (PS) matching analysis was performed to control confounding factors.ResultsWe observed no difference in the risk of death at week 2, at week 24, or at week 48 in either the unmatched cohort or the matched cohort. Both in the unmatched and the matched cohorts, logistic regression analysis revealed a significantly lower odds ratio of clinical resolution (OR 0.450, 95% CI 0.291–0.696, p < 0.001; OR 0.443, 95% CI 0.261–0.752, p = 0.003) and fungal clearance (OR 0.514, 95% CI 0.333–0.793, p = 0.003; OR 0.542, 95% CI 0.318–0.923, p = 0.024) in voriconazole users compared to amphotericin B deoxycholate users over the course of 2 weeks. In the induction therapy without ART subgroup patients in the amphotericin B deoxycholate group showed a significantly higher rate of clinical resolution and fungal clearance than those in the voriconazole group (56.1% vs. 30.4%, 95% CI 13.4–36.5, p = 0.000; 63.8% vs. 40.4%, 95% CI 11.1–34.7, p = 0.000), whereas there was no significant difference in clinical resolution and fungal clearance in the induction therapy combined with ART subgroup.ConclusionsInduction therapy using voriconazole had a similar efficacy, in terms of all-cause mortality rate, to induction therapy using amphotericin B deoxycholate in HIV-infected patients with talaromycosis over a 48-week observation period. Amphotericin B deoxycholate contributed to earlier fungal clearance and earlier clinical resolution of symptoms in the induction therapy without ART subgroup, whereas amphotericin B deoxycholate use did not contribute to a significant difference in clinical resolution and fungal clearance in the induction therapy combination with ART subgroup.Trial RegistrationChiCTR1900021195. Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362.

The importance of CYP2C19 genotype in tacrolimus dose optimization when concomitant with voriconazole in heart transplant recipients.

Voriconazole remains the mainstay for the treatment of invasive fungal infections in heart transplant patients and can significantly increase tacrolimus exposure because of drug-drug interaction (DDI). However, the magnitude of this DDI is highly variable and difficult to predict. The purpose of this study was to present the characteristics of the DDI between tacrolimus and voriconazole, and further identify the various predictors of tacrolimus dose modification. We retrospectively enrolled 69 heart transplant recipients who did not use voriconazole as the control and 68 patients received voriconazole treatment in voriconazole group. CYP3A4*1G, CYP3A5*3 and CYP2C19*2 or *3 were thereafter genotyped by Sanger sequencing. The dose of tacrolimus required to achieve the therapeutic concentrations and tacrolimus dose-corrected trough concentration (C0 /D) before and after VRC administration was evaluated. The DDI between tacrolimus and voriconazole displayed a large interindividual variability with more than 10-fold changes in tacrolimus dose (range 1.28-13.00) and C0 /D (range 1.43-13.75). In addition, the fold changes for the tacrolimus dose were associated with CYP2C19 genotype, which was found to be significantly lower in CYP2C19 extensive metabolizers than in CYP2C19 intermediate metabolizers or poor metabolizers (4.06 ± 1.85 vs 5.49 ± 2.47, P = .0031). However, no significant difference was found in both CYP3A4 and CYP3A5 genotypes. Moreover, CYP2C19 genotype and hematocrit acted as independent predicting factors for tacrolimus dose modification after voriconazole co-therapy. The findings of this study have identified the various important factors to adjust tacrolimus dosage when co-administrated with voriconazole in individual patients. CYP2C19 genotype and haematocrit should be considered when tailoring tacrolimus dose.

Differences in kinetics of tacrolimus concentration after letermovir discontinuation by type of concomitant azole antifungal.

Letermovir is commonly used for CMV prophylaxis after allogeneic hematopoietic cell transplantation (HCT). Pharmacokinetic studies have shown an increase in tacrolimus exposure among healthy volunteers who took letermovir. However, studies in HCT recipients are needed because these patients are typically using concomitant antifungals with different degrees of CYP3A4 inhibition that may further interact with tacrolimus pharmacokinetics. In this study, we retrospectively evaluated the kinetics of tacrolimus concentration after letermovir discontinuation by type of concomitant azole antifungal in 57 HCT recipients. The median fold change in tacrolimus concentration-to-dose (C/D) ratio after discontinuing letermovir was 0.64 (range 0.43-0.99) with fluconazole and 1.10 (range 0.59-1.73) with voriconazole (p < 0.001). The tacrolimus C/D ratio decreased ≥ 30% after discontinuing letermovir (p < 0.001) in 66% of patients on fluconazole and 9% on voriconazole. Among patients whose tacrolimus C/D ratio decreased ≥ 30%, three (9%) patients in the fluconazole group and one (4%) in the voriconazole group experienced worsening of GVHD. Careful monitoring of tacrolimus concentration is important after letermovir discontinuation to avoid worsening of GVHD due to decreased tacrolimus concentration.

Amphotericin B versus Voriconazole in the treatment of fungal keratitis

Purpose Evaluate the efficiency and safety of Voriconazole compared with Amphotericin B in the treatment of fungal keratitis. Background Fungal keratitis in Egypt is considered the second prevalent corneal infection after bacterial keratitis. It is one of the main causes of corneal blindness in Egypt. Many recalcitrant cases are frequently met with. Delay in the diagnosis and management usually leads to complications. Patients and methods During the period from July 2016 to October 2019, 106 patients who were clinically diagnosed in one eye as fungal keratitis, followed by culture and histopathological proof were recruited. They were divided into groups A and B. One hundred and six eyes of 106 patients whose age ranged from 10 to 74 years of both sexes were recruited, 53 eyes in each group. Group A received Amphotericin B while group B received Voriconazole. Adjuvant measures were used in deteriorating progressive cases in the form of cyanoacrylate glue with a high oxygen permeability contact lens in impending perforation, intrastromal Voriconazole injection, and lastly therapeutic penetrating keratoplasty. Follow-up was done on days 1, 3, 7, then weekly until cure. Size, depth, deep vascularization, presence of satellites, intraocular pressure monitoring, hypopyon, and any complication were recorded. Visual acuity and healing outcome and duration to achieve were also recorded. Results In all, 80 cases (39 of group A and 41 of group B) were healed, 21 cases (11 of group A and 10 of group B) progressed and needed adjuvant treatment to heal, five cases (three of group A and two of group B) needed urgent therapeutic penetrating keratoplasty. Voriconazole group showed a shorter time for healing and less complications. Discussion Voriconazole was slightly better than Amphotericin B as regards the duration for healing, progression of keratitis, extent of deep vascularization, density of the healed scar, and visual acuity. Conclusion Both Amphotericin B and Voriconazole were successful in treating fungal keratitis. Voriconazole showed statistically significant better results.

Impact of Oral Voriconazole As Prophylaxis during Intensive Chemotherapy for Adult Patients with Acute Myeloid Leukemia: A Retrospective Cohort Study Using Japanese Administrative Database

BackgroundPrevention of invasive fungal infections (IFIs) during chemotherapy is an important issue for patients with hematologic malignancies. Although preventive effects of antifungal drugs on hematological stem cell transplantation (HSCT) has been reported, the appropriate approach for prophylaxis of IFIs during intensive chemotherapy for patients with acute myeloid leukemia (AML) has been still unclear. To solve this issue, we analyzed the Diagnosis Procedure Combination/Per-Diem Payment System (DPC/PDPS) database instituted by the Ministry of Health, Labour and Welfare of Japan as a payment system for medical services, which contains a large nationwide inpatient administrative data. The objective of this study is to investigate the effectiveness of oral voriconazole (VRCZ) as prophylaxis of IFIs in adult AML patients undergoing intensive chemotherapy.MethodsThis is a retrospective cohort study analyzing data of which were extracted from the DPC database collected from July 2010 to June 2015. The prophylactic usage of oral antifungal drugs is defined as administration of these drugs for more than 3 consecutive days prescribed within 3 days after the onset of chemotherapy. The selection criteria were as follows: patients diagnosed as AML, aged 18 years or older, conducted intensive chemotherapy under aseptic management, and administrated either of oral fluconazole (FLCZ), itraconazole (ITCZ) or VRCZ for the prophylactic usage defined as above. The data for HSCT were excluded. The main analyses were conducted in these 2 groups: the group of patients administrated oral VRCZ, and the other oral azoles (FLCZ or ITCZ). Primary outcome was the intravenous antifungal drug usage within 30 days after the onset of chemotherapy. Subgroup analyses were performed in the following categories: 1) VRCZ group vs FLCZ group/VRCZ group vs ITCZ group; 2) Age < 65/ Age ≥ 65. Secondary outcomes were 1) length of hospital stay, and 2) in-hospital mortality. The log-transformed values were used for analyses of length of hospital stay because its distribution was right-skewed. Panel instrumental variable (IV) method was carried out to address unobserved time-invariant characteristics of individuals, time-variant factors, and the endogeneity due to the unmeasured bias.ResultsA total of 63,197 inpatient data of 923 hospitals for AML patients aged 18 years or older were screened. Finally, 10,083 data of 413 hospitals, including 655 in VRCZ group, 4,445 in FLCZ group, and 4,983 in ITCZ group, were met to the selection criteria. The result of panel IV approach showed that prophylactic administration of oral VRCZ was significantly associated with the reduction of intravenous antifungal drug usage within 30 days after the onset of chemotherapy compared to the other azoles (RD −0.13, 95%CI −0.22 to −0.03, p = 0.012). It was also associated with the shortening the log-transformed value of length of hospital stay compared to the other oral azoles (RD −0.11, 95%CI −0.23 to −0.00, p = 0.043), but not with in-hospital mortality (RD 0.02, 95%CI −0.04 to 0.08, p = 0.513). In the subgroup analyses, prophylactic administration of oral VRCZ was significantly associated with the reduction of intravenous antifungal drug usage compared with FLCZ (RD −0.18, 95%CI −0.28 to −0.08, p < 0.001), but not with ITCZ (RD −0.07, 95%CI −0.16 to 0.34, p = 0.150). When the data was analyzed by age groups, it was significantly associated with the reduction of intravenous antifungal drug usage in patients under the age of 65 (RD −0.18, 95%CI −0.35 to −0.02, p = 0.033), but not in patients aged 65 years or older (RD −0.09, 95%CI −0.22 to 0.04, p = 0.196) compared to the other azoles.ConclusionsBy analyzing the large nationwide database, the present results revealed that the prophylactic administration of oral VRCZ would be effective for reducing the intravenous antifungal drug usage and shortening of hospital stay, which might contribute to reduction of IFIs and improvement of quality of life especially for young AML patients receiving the intensive chemotherapy. DisclosuresYoshida:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Nippon Kayaku Co.,Ltd.: Honoraria.