Breakthrough Invasive Fungal Infections in Patients With High-Risk Hematological Disorders Receiving Voriconazole and Posaconazole Prophylaxis: A Systematic Review.

BACKGROUND: Primary antifungal prophylaxis with mold-active azoles is used to prevent invasive fungal infections in patients with high-risk hematological disorders; however, breakthrough infections occur, and the reasons for treatment failure are still not fully understood. To help inform clinical decisions, we sought to define microbiological, clinical, and pharmacological characteristics of proven and probable breakthrough invasive fungal infections (bIFIs) in patients with high-risk hematological disorders receiving voriconazole or posaconazole prophylaxis. METHODS: We performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was last conducted on 19 April 2023. RESULTS: We assessed 5293 studies for eligibility, and 300 were selected for data extraction. These studies described 1076 cases of bIFIs occurring under voriconazole (42.5%) or posaconazole (57.5%). The most commonly found pathogens were Aspergillus (40%), Mucorales (20%), Candida (18%), and Fusarium (9%) species. Mucorales were more frequent among voriconazole-emerging cases, whereas Aspergillus and Fusarium were more prevalent among posaconazole-emerging cases. Definitive, putative, or probable antifungal resistance was found in 31% of cases. Therapeutic drug monitoring showed subtherapeutic azole concentration in 32 of 90 (36%) cases. Infection-related mortality was reported in 117 cases and reached 35%. CONCLUSIONS: In our systemic review, the most common bIFIs were aspergillosis, mucormycosis, candidiasis, and fusariosis. Antifungal resistance explains only a minority of cases. Subtherapeutic prophylaxis was frequent but rarely reported. Prospective studies are needed to better understand these infections and to establish optimal management.

European Study of Cerebral Aspergillosis treated with Isavuconazole (ESCAI): A study by the ESCMID Fungal Infection Study Group.

BACKGROUND: Cerebral aspergillosis (CA) is associated with high mortality. According to the European Conference on Infections in Leukemia and the European Society of Clinical Microbiology and Infectious Diseases guidelines, the recommended first-line treatment for all forms of aspergillosis is voriconazole or isavuconazole. However, little is known about the efficacy and safety of isavuconazole in CA. METHODS: We conducted a European multicenter retrospective study of patients treated with isavuconazole for proven or probable CA between 2014 and 2022 and compared the outcomes with those of weighted control groups from the previously published French national cohort of CA, the Cerebral Aspergillosis Lesional Study (CEREALS). RESULTS: Forty patients from 10 countries were included. The main underlying conditions were hematological malignancies (53%) and solid-organ transplantation (20%). Isavuconazole was administered as a first-line treatment to 10 patients, primarily in combination therapy, resulting in control of CA in 70% of these cases. Thirty patients received isavuconazole after a median of 65 days on another therapy, mostly because of side effects (50%) or therapeutic failure (23%) of the previous treatment. Predominantly given as monotherapy, it achieved control of CA in 73% of the patients. Seventeen patients (43%) underwent neurosurgery. When measured, isavuconazole levels were low in cerebrospinal fluid but adequate in serum and brain tissue. Isavuconazole toxicity led to treatment interruption in 7.5% of the patients. Twelve-week mortality was 18%. Comparison with the CEREALS cohort showed comparable survival in patients receiving isavuconazole or voriconazole as a first-line treatment. CONCLUSIONS: Isavuconazole appears to be a well-tolerated treatment. Mortality of CA treated with isavuconazole is similar to that reported with voriconazole.

Ivosidenib significantly reduces triazole levels in patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P-glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P-glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown. METHODS: Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole. RESULTS: Seventy-eight serum triazole levels from 31 patients receiving ivosidenib-containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily. CONCLUSIONS: This study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high-dose posaconazole (>300 mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib.

Interaction of age and CYP2C19 genotypes on voriconazole steady-state trough concentration in Chinese patients.

OBJECTIVES: Both age and CYP2C19 genotypes affect voriconazole plasma concentration; the interaction of age and CYP2C19 genotypes on voriconazole plasma concentration remains unknown. This study aims to investigate the combined effects of age and CYP2C19 genotypes on voriconazole plasma concentration in Chinese patients. METHODS: A total of 480 patients who received voriconazole treatment were recruited. CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893) polymorphisms were genotyped. Patients were divided into the young and the elderly groups by age of 60 years old. Influence of CYP2C19 genotype on steady-state trough concentration (C ss-min ) in overall patients and in age subgroups was analyzed. RESULTS: Voriconazole C ss-min correlated positively with age, and mean voriconazole C ss-min was significantly higher in the elderly group ( P  < 0.001). CYP2C19 poor metabolizers showed significantly increased mean voriconazole C ss-min in the young but not the elderly group. The percentage of patients with subtherapeutic voriconazole C ss-min (<1.0 mg/l) was higher in the young group and that of supratherapeutic voriconazole C ss-min (>5.5 mg/l) was higher in the elderly patients. When the average C ss-min in the CYP2C19 normal metabolizer genotype was regarded as a reference, CYP2C19 genotypes showed greater impact on voriconazole C ss-min in the young group, while the influence of age on voriconazole C ss-min exceeded CYP2C19 genotypes in the elderly. CONCLUSION: CYP2C19 genotypes affects voriconazole exposure is age dependent. Influence of CYP2C19 poor metabolizer genotype on increased voriconazoleexposure is prominent in the young, while age is a more important determinant factor for increased voriconazole exposure in the elderly patients.

Development of a therapeutic drug-monitoring algorithm for outpatients receiving voriconazole: A multicentre retrospective study.

AIMS: Although therapeutic drug monitoring (TDM) of voriconazole is performed in outpatients to prevent treatment failure and toxicity, whether TDM should be performed in all or only selected patients remains controversial. This study evaluated the association between voriconazole trough concentrations and clinical events. METHODS: We investigated the aggravation of clinical symptoms, incidence of hepatotoxicity and visual disturbances, change in co-medications and interaction between voriconazole and co-medications in outpatients receiving voriconazole between 2017 and 2021 in three facilities. Abnormal trough concentrations were defined as <1.0 mg/L (low group) and >4.0 mg/L (high group). RESULTS: A total of 141 outpatients (578 concentration measurements) met the inclusion criteria (treatment, 37 patients, 131 values; prophylaxis, 104 patients, 447 values). The percentages of patients with abnormal concentrations were 29.0% and 31.5% in the treatment and prophylaxis groups, respectively. Abnormal concentrations showed 50% of the concentrations at the first measurement in both therapies. Aggravation of clinical symptoms was most frequently observed in the low treatment group (18.2%). Adverse events were most common in the high group for both therapies (treatment, hepatotoxicity 6.3%, visual disturbance 18.8%; prophylaxis, hepatotoxicity 27.9%). No differences were found in changes to co-medications and drug interactions. In the prophylaxis group, prescription duration in the presence of clinical events tended to be longer than in their absence (47.4 ± 23.4 days vs 39.7 ± 21.9 days, P = .1132). CONCLUSIONS: We developed an algorithm based on clinical events for appropriate implementation of TDM in outpatients. However, future interventions based on this algorithm should be validated.

Individualized treatment with voriconazole in the Chinese population: Inflammation level as a novel marker for dose optimization.

AIMS: The aim of this study was to explore the influence and possible mechanisms of pharmacokinetics-related gene polymorphisms, especially CYP2C19 polymorphisms, and non-genetic factors combined with the inflammatory status on the voriconazole (VRC) metabolism of the Chinese population. METHODS: Clinical studies were performed by collecting more than one VRC trough concentration and C-reactive protein (CRP) level. A total of 265 blood samples were collected from 120 patients. RESULTS: Results of multiple regression analyses demonstrated that CYP2C19 genotypes and albumin (Alb) level remained predictors of Cmin ss/D in patients with no to mild inflammation (R2 = 0.12, P < .001). In addition, in patients with moderate to severe inflammation, it resulted in a significant model containing factors of CRP and total bilirubin (T-Bil) levels (R2 = 0.19, P < .001). In non-clinical studies, 32 rats were divided into control and inflammatory groups, and it was found that the mean residence time (MRT(0-t) ) of VRC in the inflammatory group was significantly longer than that in the control group (P < .001), which may be due to down-regulation of mRNA and protein expression of CYP2C19 (CYP2C6 in rats) through interleukin (IL)-6/signal transducer and activator of transcription (STAT) 3 pathway. CONCLUSIONS: Therefore, the effect of CYP2C19 polymorphisms on VRC metabolism may be masked by inflammatory status, which should be of more concern than CYP2C19 polymorphisms in patients with moderate to severe inflammation. Additionally, the impact of Alb and T-Bil on VRC metabolism should not be disregarded.

Immune outcomes of lung transplant recipients with different cytochrome P450 3A5 phenotypes after discontinuation of voriconazole antifungal prophylaxis.

INTRODUCTION: Tacrolimus forms the backbone of immunosuppression regimens in lung transplant recipients (LTRs). It is extensively metabolized by cytochrome P450 (CYP) 3A5 enzymes, of which polymorphisms can significantly affect tacrolimus dose requirements. It is unknown how coadministration of tacrolimus with voriconazole, a potent CYP3A5 inhibitor, affects rejection rates or empiric dose adjustments needed after voriconazole discontinuation. METHODS: This retrospective cohort study compares LTRs with poor (PR) versus intermediate/extensive (IE) CYP3A5 metabolizer phenotypes. The primary endpoint is cumulative immune outcomes within three months of voriconazole discontinuation; secondary endpoints include change in tacrolimus dose-to-concentration ratios after voriconazole discontinuation. RESULTS: Thirty-four patients underwent full analysis: 13 IE and 21 PR metabolizers. A higher proportion of IE metabolizers were African American (46.2% vs. 9.5%, p = .03). There was no significant difference in composite immune outcomes, though there was a proportionally higher frequency of new donor-specific antibody development in PR metabolizers (14.3% vs 7.7%, p = .56). Both groups required approximately 2.5 to 3-fold tacrolimus dose increases post-voriconazole discontinuation to re-attain therapeutic levels. CONCLUSION: This novel investigation sheds light on how CYP3A5 phenotype could be used to guide tacrolimus dosing, with the goal of preventing both toxicity and organ rejection.

Aspergillus fumigatus-a systematic review to inform the World Health Organization priority list of fungal pathogens.

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of invasive infections caused by Aspergillus fumigatus to inform the first FPPL. The pre-specified criteria of mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence were used to search for relevant articles between 1 January 2016 and 10 June 2021. Overall, 49 studies were eligible for inclusion. Azole antifungal susceptibility varied according to geographical regions. Voriconazole susceptibility rates of 22.2% were reported from the Netherlands, whereas in Brazil, Korea, India, China, and the UK, voriconazole susceptibility rates were 76%, 94.7%, 96.9%, 98.6%, and 99.7%, respectively. Cross-resistance was common with 85%, 92.8%, and 100% of voriconazole-resistant A. fumigatus isolates also resistant to itraconazole, posaconazole, and isavuconazole, respectively. The incidence of invasive aspergillosis (IA) in patients with acute leukemia was estimated at 5.84/100 patients. Six-week mortality rates in IA cases ranged from 31% to 36%. Azole resistance and hematological malignancy were poor prognostic factors. Twelve-week mortality rates were significantly higher in voriconazole-resistant than in voriconazole-susceptible IA cases (12/22 [54.5%] vs. 27/88 [30.7%]; P = .035), and hematology patients with IA had significantly higher mortality rates compared with solid-malignancy cases who had IA (65/217 [30%] vs. 14/78 [18%]; P = .04). Carefully designed surveillance studies linking laboratory and clinical data are required to better inform future FPPL.

Therapeutic Drug Monitoring of Voriconazole in Patients with End-Stage Liver Disease.

BACKGROUND: This study aimed to identify the factors that influence voriconazole (VCZ) plasma concentrations and optimize the doses of VCZ in patients with end-stage liver disease (ESLD). METHODS: Patients with ESLD who received a VCZ maintenance dose of 100 mg twice daily (group A, n = 57) or the VCZ maintenance dose of 50 mg twice daily (group B, n = 37), orally or intravenously, were enrolled in this study. Trough plasma concentrations (Cmin) of VCZ between 1 and 5 mg/L were considered within the therapeutic target range. RESULTS: The VCZ Cmin was determined in 94 patients with ESLD. The VCZ Cmin of patients in group A was remarkably higher than those in group B (4.85 ± 2.53 mg/L vs 2.75 ± 1.40 mg/L; P < 0.001). Compared with group A, fewer patients in group B had VCZ Cmin outside the therapeutic target (23/57 vs. 6/37, P = 0.021). Univariate and multivariate analyses suggested that both body weight and Model for End-Stage Liver Disease scores were closely associated with the VCZ Cmin in group B. CONCLUSIONS: These data indicate that dose optimization based on body weight and Model for End-Stage Liver Disease scores is required to strike an efficacy-safety balance during VCZ treatment in patients with ESLD.

Cerebral phaeohyphomycosis due to Cladophialophora bantiana: case report and systematic review of cases.

PURPOSE: Cladophialophora bantiana is a wonted melanized fungus causing brain abscess. In past many cases were reported from Asia, particularly from India. Of late, there is a rise in cases in places besides Asia and hence a review of the cases is warranted. METHODS: We present a case of fatal cerebral phaeohyphomycosis caused by C. bantiana and conduct a systematic review of culture confirmed brain abscess due to C. bantiana reported between 2015 and 2022. RESULTS: Of the 39 cases found, majority (68%) were immunocompromised. The various clinical presentations were headache (53%), hemiparesis (34%), visual disturbance (25%), altered sensorium (18%), aphasia/dysarthria (12%) and seizures (9%). Isolated lesion was observed in 18 (60%) patients. In the sequence of occurrence, the lesions were in frontal (30%), temporal (27%) and parietal (20%) region. There were five cases with coinfections such as concurrent detection of Nocardia pneumonia in two cases, toxoplasma DNA in brain abscess, coexisting pulmonary Cryptococcus neoformans infection and coexisting Candida in a case of brain abscess in one case each. Surgical intervention was performed in 84% cases. Antifungal therapy included voriconazole (80%), liposomal amphotericin B (76%), 5-fluorocytosine (30%), posaconazole (10%), and amphotericin B deoxycholate (6%). The overall mortality was 50% with lower mortality (42%) in regions outside Asia compared to Asia (63.6%) though not statistically significant. CONCLUSIONS: C. bantiana brain abscess is an emerging infection worldwide. Next generation sequencing is an upcoming promising diagnostic test. Early complete excision of the lesion with effective antifungals may improve the outcome.

Multi-organ involvement caused by Scedosporium apiospermum infection after near drowning: a case report and literature review.

BACKGROUND: Scedosporium apiospermum (S. apiospermum) is a rare fungal pathogen that causes disseminated infections. It rarely affects immunocompetent individuals and has a poor prognosis. CASE PRESENTATION: A 37-year-old woman presented with multiple lesions in the lungs, brain, and eyes, shortly after near drowning in a car accident. The primary symptoms were chest tightness, limb weakness, headache, and poor vision in the left eye. S. apiospermum infection was confirmed by metagenomic next-generation sequencing (mNGS) of intracranial abscess drainage fluid, although intracranial metastases were initially considered. After systemic treatment with voriconazole, her symptoms improved significantly; however, she lost vision in her left eye due to delayed diagnosis. CONCLUSION: While S. apiospermum infection is rare, it should be considered even in immunocompetent patients. Prompt diagnosis and treatment are essential. Voriconazole may be an effective treatment option.

Association of procalcitonin with voriconazole concentrations: a retrospective cohort study.

Inflammation is a potential risk factor of voriconazole (VCZ) overdose, procalcitonin (PCT) is reported to act as a diagnostic marker for bacterial infections. However, the association of PCT with VCZ trough serum concentrations (VCZ-Cmin) is not fully clear. Our study aims to investigate the associations between PCT and VCZ-Cmin. In this retrospective cohort study, we collected the clinical data of 147 patients who received VCZ and monitored the VCZ concentration of them in our hospital from August 2017 to August 2021. All patients underwent routine clinical examinations on the day or the day before VCZ administration. General information and clinical symptoms of these patients were recorded. Multivariate liner analysis showed that PCT was significantly associated with VCZ-Cmin (p < 0.001). Overall, it was shown that VCZ-Cmin was significantly increased by 0.32 µg/mL for each fold increment in PCT in crude model. In the minor adjusted model (Model 1, adjustment for sex, age, albumin, direct bi1irubin, WBC) and fully adjusted model (Model 2, adjustment for sex, age, albumin, direct bilirubin, WBC, AST and ALT), VCZ-Cmin was significantly increased by 0.23 µg/mL and 0.21 µg/mL, respectively, for each fold increment in PCT. In conclusion, this research reveals the correlation between PCT and VCZ-Cmin, indicating that PCT has the potential to serve as a valuable biomarker for drug monitoring in the treatment of VCZ.

A systemic infection involved in lung, brain and spine caused by Scedosporium apiospermum species complex after near-drowning: a case report and literature review.

Scedosporium apiospermum species complex are widely distributed fungi that can be found in a variety of polluted environments, including soil, sewage, and decaying vegetation. Those opportunistic pathogens with strong potential of invasion commonly affect immunosuppressed populations However, few cases of scedosporiosis are reported in immunocompetent individuals, who might be misdiagnosed, leading to a high mortality rate. Here, we reported an immunocompetent case of systemtic infection involved in lung, brain and spine, caused by S. apiospermum species complex (S. apiospermum and S. boydii). The patient was an elderly male with persistent fever and systemtic infection after near-drowning. In the two tertiary hospitals he visited, definite diagnosis was extremely difficult. After being admitted to our hospital, he was misdiagnosed as tuberculosis infection, before diagnosis of S. apiospermum species complex infection by the metagenomic next-generation sequencing. His symptoms were alleviated after voriconazole treatment. In the present case, the details associated with its course were reported and published studies on Scedosporium spp. infection were also reviewed, for a better understanding of this disease and reducing the misdiagnosis rate.

Diagnosis of pulmonary Scedosporium apiospermum infection from bronchoalveolar lavage fluid by metagenomic next-generation sequencing in an immunocompetent female patient with normal lung structure: a case report and literature review.

BACKGROUND: Scedosporium apiospermum (S. apiospermum) belongs to the asexual form of Pseudallescheria boydii and is widely distributed in various environments. S. apiospermum is the most common cause of pulmonary infection; however, invasive diseases are usually limited to patients with immunodeficiency. CASE PRESENTATION: A 54-year-old Chinese non-smoker female patient with normal lung structure and function was diagnosed with pulmonary S. apiospermum infection by metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF). The patient was admitted to the hospital after experiencing intermittent right chest pain for 8 months. Chest computed tomography revealed a thick-walled cavity in the upper lobe of the right lung with mild soft tissue enhancement. S. apiospermum was detected by the mNGS of BALF, and DNA sequencing reads were 426. Following treatment with voriconazole (300 mg q12h d1; 200 mg q12h d2-d20), there was no improvement in chest imaging, and a thoracoscopic right upper lobectomy was performed. Postoperative pathological results observed silver staining and PAS-positive oval spores in the alveolar septum, bronchiolar wall, and alveolar cavity, and fungal infection was considered. The patient's symptoms improved; the patient continued voriconazole for 2 months after surgery. No signs of radiological progression or recurrence were observed at the 10-month postoperative follow-up. CONCLUSION: This case report indicates that S. apiospermum infection can occur in immunocompetent individuals and that the mNGS of BALF can assist in its diagnosis and treatment. Additionally, the combined therapy of antifungal drugs and surgery exhibits a potent effect on the disease.

Compare the efficacy of antifungal agents as primary therapy for invasive aspergillosis: a network meta-analysis.

BACKGROUND: Several antifungal agents are available for primary therapy in patients with invasive aspergillosis (IA). Although a few studies have compared the effectiveness of different antifungal agents in treating IA, there has yet to be a definitive agreement on the best choice. Herein, we perform a network meta-analysis comparing the efficacy of different antifungal agents in IA. METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Clinical Trials databases to find studies (both randomized controlled trials [RCTs] and observational) that reported on treatment outcomes with antifungal agents for patients with IA. The study quality was assessed using the revised tool for risk of bias and the Newcastle Ottawa scale, respectively. We performed a network meta-analysis (NMA) to summarize the evidence on antifungal agents' efficacy (favourable response and mortality). RESULTS: We found 12 studies (2428 patients) investigating 11 antifungal agents in the primary therapy of IA. There were 5 RCTs and 7 observational studies. When treated with monotherapy, isavuconazole was associated with the best probability of favourable response (SUCRA, 77.9%; mean rank, 3.2) and the best reduction mortality against IA (SUCRA, 69.1%; mean rank, 4.1), followed by voriconazole and posaconazole. When treated with combination therapy, Liposomal amphotericin B plus caspofungin was the therapy associated with the best probability of favourable response (SUCRA, 84.1%; mean rank, 2.6) and the best reduction mortality (SUCRA, 88.2%; mean rank, 2.2) against IA. CONCLUSION: These findings suggest that isavuconazole, voriconazole, and posaconazole may be the best antifungal agents as the primary therapy for IA. Liposomal amphotericin B plus caspofungin could be an alternative option.

Superficial abdominal surgical site infection caused by Aspergillus welwitschiae: a case report.

BACKGROUND: Aspergillus spp. are rare causes of surgical site infections (SSIs). Specifically, Aspergillus section Nigri, commonly identified as Aspergillus niger through morphological findings, has infrequently been reported as an abdominal SSI pathogen. CASE PRESENTATION: An 86-year-old woman with a history of hypertension, chronic kidney disease, and atrial fibrillation who was taking 6 mg of prednisolone daily for rheumatoid arthritis was admitted to our hospital because of sudden abdominal pain. She was diagnosed with sigmoid colon perforation and underwent an open Hartmann operation on the day of admission. Subsequently, a superficial abdominal SSI was detected. Through analysis of the calmodulin gene, Aspergillus welwitschiae, which is classified within the Aspergillus section Nigri, was identified as the responsible pathogen. The minimum inhibitory concentration of voriconazole (VRCZ) was 2 mg/L. Surgical removal of the infected tissue and VRCZ administration was effectively used to treat the infection. CONCLUSIONS: Given the reported low susceptibility of Nigri section species to azoles, identification and drug susceptibility testing of these fungi are highly important.

Distribution and antifungal susceptibility profiles of Candida species isolated from candidemia patients admitted to Egyptian tertiary hospitals: a cross-sectional study.

BACKGROUND: Candidemia is a widespread threat that can lead to significant complications in healthcare settings. OBJECTIVES: Our study aimed to identify isolates of Candida isolated from blood culture bottles of patients with candidemia and assess their antifungal susceptibility profiles. METHODS: We conducted a cross-sectional study at Cairo University tertiary care hospitals over 16 months including 90 patients. Candida isolates were collected from blood culture bottles, and identified using MALDI-TOF MS technology of VITEK MS PRIME (bioMérieux) with the corresponding database VITEK IVD Database 3.2. followed by antifungal susceptibility testing using VITEK 2 Compact system. RESULTS: Candida albicans was the most common species isolated from both pediatric and adult patients with percentages of 47.3% and 36.4% respectively, followed by Candida parapsilosis with percentages of 32.6% and 25.0% respectively. Voriconazole showed the highest antifungal activity at 90.9% of isolates in adults and 95.7% in pediatrics, followed by caspofungin and micafungin. The mean hospital stays for adults ranged from 8 to 30 days and from 10 to 42 days in the pediatric group. CONCLUSIONS: C. albicans remains the predominant species isolated from both pediatric and adult candidemia patients, despite a notable increase in other species. C. tropicalis and C. parapsilosis are considered the most common non-albicans Candida (NAC) species. The rise in Candida species other than albicans highlights the urgent need for effective antifungal stewardship programs. Voriconazole exhibited the higher antifungal activity followed by caspofungin and micafungin.

Difference in immunosuppressant dose requirement when transitioning to isavuconazole from other azoles in thoracic transplant recipients.

The triazole antifungal isavuconazole (ISAVU) is used for prevention and treatment of fungal infections in solid organ transplant (SOT). SOT recipients commonly need to transition from one azole to another due to breakthrough infection, toxicity, or other reasons. The purpose of our study was to evaluate the effect of ISAVU on immunosuppressant concentrations in thoracic transplant recipients when ISAVU was started de novo or transitioned from another azole. We conducted a single-center retrospective cohort study including 68 patients (51 lung, 14 heart, and 3 heart/lung transplant). Concentration to dosage ratios (C/D) of immunosuppressants were assessed at baseline, day 3, and weekly for 9 weeks. When starting ISAVU de novo, we observed a temporary doubling of tacrolimus exposure. Cyclosporine and sirolimus required dose decreases. Tacrolimus C/D increased by 110% at day 3 in patients started on ISAVU de novo then returned to baseline C/D ± 17% weeks 2-9 (n = 8). One cyclosporine patient started on ISAVU de novo had variable C/D, and C/D increased by 219% ± 72% in 2 sirolimus patients. When transitioning from other azoles, tacrolimus and cyclosporine required about twice the initial dose. After week 1, tacrolimus C/D decreased by 53% ± 6% in patients transitioned from posaconazole (n = 33), voriconazole (n = 14), or fluconazole (n = 2). Cyclosporine C/D decreased by 45% ± 16% in patients transitioning from other azoles (posaconazole [n = 2], voriconazole [n = 2], fluconazole [n = 1]). Sirolimus C/D decreased by 73% ± 13% in patients transitioned from posaconazole (n = 7). Aside from the initial loading phase, ISAVU had a lesser degree of interaction with immunosuppressants than other azoles in loading phase, ISAVU had a lesser degree of interaction with immunosuppressants than other azoles in adjustments for the 4-week period after initiating antifungal therapy with ISAVU or switching from another agent.

Outcomes in solid organ transplant recipients receiving organs from a donor with Fusarium solani species complex meningitis.

BACKGROUND: Five organs (heart, right lung, liver, right, and left kidneys) from a deceased patient were transplanted into five recipients in four US states; the deceased patient was identified as part of a healthcare-associated fungal meningitis outbreak among patients who underwent epidural anesthesia in Matamoros, Mexico. METHODS: After transplant surgeries occurred, Fusarium solani species complex, a fungal pathogen with a high case-mortality rate, was identified in cerebrospinal fluid from the organ donor by metagenomic next-generation sequencing (mNGS) and fungal-specific polymerase chain reaction and in plasma by mNGS. RESULTS: Four of five transplant recipients received recommended voriconazole prophylaxis; four were monitored weekly by serum (1-3)-ß-d-glucan testing. All five were monitored for signs of infection for at least 3 months following transplantation. The liver recipient had graft failure, which was attributed to an etiology unrelated to fungal infection. No fungal DNA was identified in sections of the explanted liver, suggesting that F. solani species complex did not contribute to graft failure. The remaining recipients experienced no signs or symptoms suggestive of fusariosis. CONCLUSION: Antifungal prophylaxis may be useful in preventing donor-derived infections in recipients of organs from donors that are found to have Fusarium meningitis.

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

BACKGROUND: 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. METHODS: 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. 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). CONCLUSIONS: 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.