Oral Posaconazole Research Articles

Effectiveness of oral posaconazole and surgical debridement of rhino maxillofacial mucormycosis

Effectiveness of oral posaconazole and surgical debridement of rhino maxillofacial mucormycosis

Approaches for posaconazole therapeutic drug monitoring and their clinical benefits.

This review examines the progress of research on posaconazole therapeutic drug monitoring (TDM) that has focused on differences in the TDM of posaconazole after clinical application in different formulations and in different populations, the factors that affect posaconazole concentrations, the advantages of posaconazole TDM in terms of clinical efficacy and cost savings, and measurement methods. A literature search (2006 to 2024) was performed in PubMed and Embase with the following search terms: noxafil, posaconazole hydrate, posaconazole, drug monitoring, therapeutic drug monitoring, and TDM. Abstracts of review articles, prospective studies, and retrospective studies were reviewed. TDM should be implemented earlier for posaconazole tablets and injections than for oral posaconazole suspensions. Posaconazole TDM is beneficial for improving clinical efficacy, and the incidence of breakthrough invasive fungal infections (IFIs) can be significantly reduced by gradually adjusting the posaconazole dose in response to TDM in patients with inadequate trough concentrations. Early TDM allows more patients to achieve target therapeutic posaconazole concentrations. TDM can also facilitate dose adjustments, which reduce the cost of this expensive drug. Different assay techniques, including chromatography, microbiological detection, chemofluorimetry, paper spray mass spectrometry, and capillary electrophoresis, can be used for posaconazole TDM. Posaconazole TDM has potential clinical utility and cost-saving benefits and could improve the outcomes of IFI treatment.

COVID-19-associated rhino-orbito-cerebral mucormycosis: a single center prospective study of 264 patients

ABSTRACT Purpose Outbreaks of mucormycosis were reported worldwide throughout the COVID-19 pandemic. We report clinical outcomes of a treatment protocol for COVID-19-associated rhino-orbital-cerebral mucormycosis (ROCM). Methods Patients with biopsy-proven mucormycosis and COVID-19 were included. All received intravenous amphotericin B deoxycholate 1 mg/kg and surgical endoscopic sinus debridement (FESS). Those with rhino-orbital or cerebral disease limited to the cavernous sinus were eligible for transcutaneous retrobulbar amphotericin B (TRAMB). Patients were followed with weekly imaging, endoscopic examinations, and serial debridement as necessary. Patients were discharged on oral posaconazole for 6 months. Results In total, 264 patients were followed for a mean of 2.5 months. On presentation, 163 patients (174 eyes) had eye involvement. Of these, 141 eyes (81.0%) had light perception or worse vision. By the last follow-up, 163 patients (176 eyes) were affected, and of these, 96 eyes (54.5%) had no light perception. Twenty-one patients (8%) died and 3 orbits (0.5%) were exenterated. There was no change in mortality (p = 0.38) or exenteration (p = 0.38) in the 55 patients who received TRAMB compared to patients with rhino-orbital or cerebral disease limited to the cavernous sinus who did not. Asymptomatic COVID-19 was associated with higher mortality than symptomatic COVID-19 (p = 0.025). Uncontrolled diabetes was a risk factor for death (p = 0.022). New diabetes was associated with increased mortality versus pre-existing diabetes (p = 0.005). Conclusion A multidisciplinary approach is crucial to manage COVID-19-ROCM. In our cohort, TRAMB therapy did not increase mortality or exenteration rates. While poor vision on presentation was profound, some vision recovery was noted with treatment. COVID-19 immune dysregulation may predispose patients to ROCM, particularly those with asymptomatic disease.

Population Pharmacokinetic Modeling of Posaconazole in Japanese Patients Receiving Fungal Prophylaxis.

Posaconazole is a vital drug to treat and prevent invasive fungal infections. Several factors, such as sex, body weight, total serum proteins, dietary intake, and severe mucositis, affect posaconazole pharmacokinetics (PKs). However, the relevance of other factors that affect the PKs of posaconazole in hematopoietic stem cell transplantation (HSCT) is unknown. This study explored factors influencing the PKs of posaconazole in HSCT recipients and nontransplant patients with hematological diseases. The authors conducted a single-institution, retrospective study. Forty-two Japanese inpatients receiving oral posaconazole tablets as prophylaxis for fungal infections were enrolled in this study. A one-compartment model with first-order absorption was used as the structural pharmacokinetic model. A population PK (PopPK) analysis was performed using a nonlinear mixed-effects modeling program, using a first-order conditional estimation method with interactions. Perl-speaks-NONMEM and R were used to evaluate the goodness of fit and visualize the output. In 29% of the enrolled patients, the serum concentration of posaconazole was <0.5 mcg/mL, considered the effective range. PopPK analysis revealed that the patient had undergone HSCT within 1 year, diarrhea occurred more than 5 times a day, and aspartate aminotransferase were covariates that influenced apparent clearance (CL/F). The CL/F of posaconazole was 1.43-fold higher after HSCT and 1.26-fold higher during diarrhea. PopPK analysis revealed that HSCT, diarrhea, and aspartate aminotransferase were factors associated with the CL/F of posaconazole. The trough concentration of posaconazole may be below the therapeutic range in a few patients with diarrhea and/or after HSCT. As invasive fungal infections in patients with hematologic diseases can be life-threatening, therapeutic drug monitoring of posaconazole is strongly recommended, and patients should be carefully monitored.

Use of nebulized liposomal amphotericin B and posaconazole as antifungal prophylaxis in patients with severe SARS-CoV2 infection in intensive care unit.

COVID-19 associated pulmonary aspergillosis (CAPA) is common and linked with high fatalityrates. To assess the impact on the incidence and outcome of CAPA of an antifungal prophylaxis (AFP) we compared two cohorts of COVID-19 patients admitted to intensive care units (ICU) in Brescia, Italy, from January to August 2021. The study cohort included all mechanically ventilated patients observed between April 2021 and August 2021 with SARS-CoV-2-pneumonia, who received AFP with oral posaconazole (200mg every6h) and nebulized liposomalamphotericin B (50mg every2weeks) from ICU admission to 7days after discharge or, if applicable, until tracheostomy removal. The control cohort included COVID-19 patients admitted to the same ICU between January and March 2021 who did not receive any AFP. Subjects with CAPA at ICU admission were excluded. We included 270 patients, of whom 64 (23.7%) received AFP. In patients in the study group, CAPA-related mortality was significantly reduced (29% vs. 48% p = 0.04), as well as the incidence of CAPA (3.1% vs 12.1%, p = 0.03). Patients who developed CAPA were older (mean of 70-y-old vs 63-y-old, p < 0.001). One subject discontinued posaconazole due to anadverse reaction. Among the 46 patients who received it, only one patient reached an effective plasma concentration of posaconazole. AFP was associated with reduced incidence and mortality from CAPA and was well tolerated in patients with severe COVID-19. Posaconazole concentrations below the efficacy threshold in almost all patients may be attributable to drug interactions and prompt further studies to define its clinical significance.

Surveillance for COVID-19 associated mucormycosis: A coordinated effort in prevention and management of rhino-orbital mucormycosis

Abstract Context: Patients of coronavirus disease 2019 (COVID-19) and factors inducing a diabetogenic state are at increased risk for rhino-orbital mucormycosis (ROM). Efforts to diagnose ROM in its pre-clinical stage would avoid the disease and its consequences. Aim: This study aimed to diagnose ROM in the pre-clinical stage of the disease in high-risk patients and treat patients accordingly. Settings and Design: This is a single-center, prospective study conducted at a tertiary care center in Northern India in collaboration with departments of Otolaryngology, Internal Medicine, and Mycology. Materials and Methods: Fifty-three high-risk patients were enrolled in the study, and all underwent bedside nasal endoscopy with tissue sampling for fungal culture. Patients with suspicious nasal endoscopy findings but negative fungal culture were prescribed oral posaconazole. Those with positive fungal hyphae on nasal endoscopy and culture underwent surgical intervention followed by intravenous amphotericin B, while the remaining patients were kept on follow-up. Statistical Analysis Used: Statistical analysis was performed using the Statistical Package for Social Sciences software. Results: Among the 53 patients, 13 (24.5%) patients had abnormalities on nasal endoscopy, while the remaining 40 (75.5%) patients had normal nasal mucosal cavities. Seven patients (13.2%) underwent surgery and received intravenous liposomal amphotericin B, while another 7 (13.2%) received oral posaconazole. Thirty-five (66.03%) patients were placed under observation, and 4 (7.5%) patients died due to COVID-19-related illness. Conclusions: Nasal endoscopic-guided tissue sampling for fungal culture serves as a valuable surveillance tool for predicting ROM in COVID-19 patients.

Pharmacogenetics and Pharmacokinetics of Posaconazole in Patients with Acute Myeloid Leukemia: Useful Tools for Antifungal Stewardship

DISCUSSION INTRODUCTION Antifungal prophylaxis with posaconazole in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy is usually recommended [1]. Few studies described the clinical impact of suboptimal posaconazole plasma concentrations during prophylaxis, which may be associated with a higher risk of invasive fungal infections (IFI) and a strong impact on clinical outcome [2]. ENDPOINT: The primary endpoint of this study was to evaluate weekly posaconazole Cthrough plasma concentration in AML patients treated with induction chemotherapy. Since polymorphisms of genes encoding enzymes, transporters and transcription factors were also analyzed a possible association amongst plasma exposure, genetic polymorphisms, risk of breakthrough infection and clinical outcam was evaluated . MATERIALS AND METODS: This was a prospective, single center study at “City of Health and Science”, Molinette Hospital in Turin, Italy. Adult Patients with AML undergoing induction chemotherapy admitted to Haematological wards, were enrolled between March 2023 and July 2023. Antifungal prophylaxis with oral posaconazole, 300mg bid the first day and 300 mg qd thereafter was given. Biological samples (plasma for posaconazole quantificatication and whole blood for genetics) were obtained for each patient after loading dose and then posaconazole C trough were evaluated weekly (at 7, 14, 21 and 28 days). The Following genes were evaluated: UGT1A1, UGT1A3, ABCB1, ABCG2, ABCC2, ABCB11, SLCO1B1, SLCO1B3, SLC22A6, PXR, CAR, VDR, CYP27B1, CYP24A1, GC. The mortality was assessed at day 28 from hospital admission. Invasive fungal disease (IFD) was defined as the occurence of a proven or probable IFD according to the European Organization for Research and Treatment of Cancer/National insitute of Allergy and Infection Diseases Micoses Study Group Criteria (EORTC/MSG) revised definitions [3]. Furthermore, according to the clinical suspicion of breakthrough infection, the switch from prophylaxis to antifungal therapy was also recorded as well as antifungal restaging before treatment change. RESULTS: Twenty patients were included: 9 were women (45%) with a median age of 67 years old (±10.5) and a median Charlson Comorbidity Index of 5 (±1.3). Mean posaconazole C through plasma concentrations are reported in Table 1 and were in range for all the different timepoints. According to EORTC criteria, two patients (10%) had a probable IFI on day 14, and antifungal therapy with liposomal amphotericin B was started [3]. One of those patients had low C trough value at time of suspected breaktrough infection (T 14; 0.2 microg/L 9). The 28 day mortality was 10%, due to the haematological underlying disease. Regarding pharmacogenetic analysis, posaconazole C trough at day 7 and 14 was associated with ABCB1 1236 polymorphism with p=0.022 and p=0.038, respectively. Furthermore, VDR ApaI (p=0.010), VDR TaqI (p=0.023), VDR BsmI (p=0.042), ABCB11 (p=0.023) and UGT1A3 023 (p=0.023) genetic variants were reported in patients with probable IFI. There is a potential impact of the use of posaconazole plasma levels monitoring and associated pharmacogenetics to evaluate the risk of underexposure during antifungal prophylaxis, but also at antifungal restaging before treatment switch. These useful tools may help clinicians to identify patients with a higher risk for under-effective plasma concentrations of posaconazole and can be used to improve antifungal stewardship approach in this setting. The utility of such approaches should also be evaluated in azole-to-azole strategies BIBLIOGRAPHY Olivia White et al. Isavuconazonium or posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia. J Oncol Pharm Pract 2023 May 15;10781552231175825. doi: 10.1177/10781552231175825.Tang LA et al. Risk factors for subtherapeutic levels of posaconazole tablet. J Antimicrob Chemother. 2017 Oct 1;72(10):2902-2905. doi: 10.1093/jac/dkx228. PMID: 29091205Peter Donnelly et al. Revision and update of the Consensus definition of Invasive Fungal Disease from the European Organization for Research adn Treatment of Cancer and the Mycoses study Group Education and Research Consortium. Clin Infect Dis 2020 Sep 12;71(6):1367-1376. doi: 10.1093/cid/ciz1008.

A Case Report on Successfully Treated Breakthrough Invasive Fungal Sinusitis with Oral Posaconazole in an Uncontrolled Type 2 Diabetes Mellitus Patient

A Case Report on Successfully Treated Breakthrough Invasive Fungal Sinusitis with Oral Posaconazole in an Uncontrolled Type 2 Diabetes Mellitus Patient

Combination of Liposomal Mitoxantrone, Venetoclax, Homoharringtonine, and Olverembatinib (HQP1351) (MVHO) in Pediatric Patients with Refractory or Relapsed Acute Myeloid Leukemia (AML): Case Series

Introduction: AML accounts for up to 25% of all pediatric acute leukemias. Although overall survival (OS) in pediatric AML has increased to 70% in recent years because of enhanced risk stratified intensive chemotherapy and hematopoietic stem cell transplantation. Unfortunately, more than 30% of patients experience relapse. Further increase intensity of chemotherapy was proven unfeasible for the toxicity and treatment related mortality. Hence, specific targeted therapy has been being explored to treat pediatric AML in recent decade. Because of the heterogeneity of AML and multiple pathways involved in leukemogenesis, single agent targeting one pathway was effective in limited cases. In this study, we designed a regimen to block multiple pathways with combination of Liposomal Mitoxantrone, Venetoclax, Homoharringtonine, and Olverembatinib (MVHO) to investigate its efficacy and safety in treatment of refractory or relapsed AML. Methods: We enrolled patients with relapsed or newly diagnosed AML with poor prognosis with adverse molecular abnormalities, such as NUP98 rearrangements, FUS::ERG, CBFA2T3::GLIS2, and del7/7q, who did not achieve complete remission (CR) after first-line chemotherapy. Patients were administered the MVHO regimen, which included 1 dose of liposome mitoxantrone 8mg/m 2; venetoclax, 300 to 350mg/m 2 once daily, from day1 to day 7, (dose escalation for up to 3days from 50mg/m 2 if high tumor burden occur); homoharringtonine 2mg/m 2 once daily, from day1 to day 7; and Olverembatinib (HQP1351) 20-30mg/m 2 every other day, for 4 doses from day 1 to day 7. Prophylactic oral levofloxacin and posaconazole were administered from day 8 through whole myelosuppression period of every cycles. One cycle (28-35 days, depending on hematopoietic recovery) response, total response, cumulative incidence of relapse (CIR), event-free survival (EFS), hematologic toxicity, and infection during this study were evaluated. Results: A total of 18 patients were enrolled (9 boys and 9 girls), with a median (range) age of 7.3 (4 months-13 years) years, and underwent a total of 27 cycles of MVHO therapy. Half of the patients underwent 1 cycle and the other half, 2 cycles. Per French-American-British (FAB) classification criteria: patients had myelodysplastic syndrome (n = 2); mixed-phenotype acute leukemia (n = 2); and AML subtypes M7 (n = 4), M2 (n = 4), M5 (n = 4), M4 (n = 1), and M0 (n = 1). The median (range) follow-up time was 131 (26-256) days. After cycle one, the objective response rate (ORR, CR plus CR with incomplete hematological recovery [Cri] and partial response [PR]) was 94.4% (17/18), and the remission rate (CR + Cri) was 72.2% (13/18). The total ORR and remission rate before transplantation were 83.3% (15/18) and 66.7% (12/18), respectively. 8 patients among them reached minimum residual disease (MRD) negative remission. For 6 patients with relapsed AML, the ORR and one cycle remission rate was 100% and 66.7%, respectively. A total of 3 patients discontinued because of no response or disease progression, and 12 patients underwent hematopoietic stem cell transplantation (HSCT), after which 1 patient experienced relapse. Remaining 2 patients are being underwent further MVHO cycles. The CIR was 6.7% (1/15). The 8-month mean (± SD) EFS was 60.1% (±19%) and the OS, 100%. Among 26 cycles of MVHO treatment, there were no associated fatal infections or bleeding events. There were 21 episodes of breakthrough infection occurred in 26 cycles of MVHO. There was 1 case of septic shock, and the incidence of ≥grade 3 infection was 80.7%, which included pneumonia, bloodstream infection. Common grade 4 treatment-related adverse events were neutropenia, which was experienced by 100% of patients, and grade 4 thrombocytopenia, which was experienced by 46.1%. Most notably, platelets were stably normal in nearly 20% (5/26) MVHO cycles. Conclusions: MVHO therapy was effective and reasonably well tolerated in pediatric patients with refractory or relapsed AML, suggesting that it may comprise a suitable first-line treatment option for pediatric AML patients.

A Comparative Study of Acute Invasive Fungal Sinusitis During the First and Second Waves of the COVID-19 Pandemic.

We aimed to compare the demography, clinical profile, histopathology, fungal culture, radiology, surgery performed, medical therapy and outcomes of patients with acute invasive fungal sinusitis seen during the first and second waves of the COVID-19 pandemic by retrospectively reviewing their case records. Of 238 patients, 43(18.1%) presented during the first wave and 195(81.9%) during the second wave. Patients seen during the first wave were older (p = 0.04) and more likely to have visual impairment (p = 0.004), frozen eye (p = 0.012), altered sensorium (p = 0.007) and stage 3 disease (p = 0.03). Those seen during the second wave were more often COVID-19 positive and had newly diagnosed diabetes mellitus (p = 0.04)and stage 1 disease (p = 0.03). Most patients had a positive culture for Rhizopus species during both waves. Histopathology showed broad aseptate hyphae in all patients but angioinvasion was seen more often during the first wave (p = 0.04). The majority of patients were treated with endoscopic+/- open debridement followed by intravenous amphotericin B and oral posaconazole. While the overall survival rate was similar (first wave 65.1%; second wave 79%; p = 0.106), mortality after discharge was greater during the first wave (11.6% vs 1.5%; p = 0.001). Mortality was higher in patients with stage 3 disease (p = 0.003). Significant differences in clinical presentation, histopathology, radiological stage of disease and post-discharge survival were noted between the two waves of the COVID-19 pandemic, the causes for which were multi-factorial.

Rhino-orbital Mucormycosis in an Immunocompetent Pediatric Patient, Resembling an Orbital Mass- a Case Report

Rhino-orbital mucormycosis in an immunocompetent pediatric patient can present as an orbital mass. We report a 9-year-old male that presented with periorbital swelling and limitation of left eye movement from one month ago. The patient was treated at another center with a diagnosis of mucormycosis but was referred due to worsening symptoms. Orbital and paranasal sinus CT scan revealed opacities in the left paranasal sinus and soft tissue density in the medial and inferior orbital wall. The patient underwent orbitotomy and mass debulking surgery on suspicion of a possible neoplastic mass. Pathologic evaluations revealed mucormycosis. After receiving intravenous liposomal amphotericin-B that was followed by oral posaconazole syrup for two months and sinus debridement, the symptoms regressed. In immunocompromised pediatric patients, mucormycosis should be considered in the differential diagnosis of an orbital mass.

BI01 Disseminated Nannizziopsis fungal infection in a kidney transplant recipient: iguanas, immunosuppression or international travel?

Abstract Transplant waiting list demographics are changing profoundly in some parts of the UK, partly due to trends in global migration. This has significant implications for the spectrum of post-transplant skin malignancies and skin infections presenting to dermatologists. We present a kidney transplant recipient born in Nigeria who developed disseminated infection with Nannizziopsis spp., an emerging pathogenic fungus in humans and reptiles. A 64-year-old man from Nigeria who received a kidney transplant 10 months earlier was referred to our 2-week-wait skin cancer clinic with a 4-cm tender, ulcerated nodule on his left thigh that had been present for 2 months. He was being investigated for possible pulmonary Aspergillus infection and also had a fluctuant subcutaneous mass over the right tibia with suspected osteomyelitis. On examination, he had a similar plaque on his right hand, fluctuant subcutaneous nodules of his left flank and left upper arm, a 20-cm fluctuant swelling over his right tibia and a 2-cm plaque of his hard palate. Skin biopsy from the left flank and thigh showed suppurative granulomatous inflammation and fungal hyphae in the dermis and macrophages with septation and 45° branching. β-D-Glucan was positive and molecular identification revealed Nannizziopsis spp. Magnetic resonance imaging of the head did not show evidence of central nervous system infection. He was treated with intravenous amphotericin B for 2 months and subsequent oral posaconazole with resolution of skin and lung infection. Nannizziopsis is a genus of fungi that usually infects reptiles such as iguanas, geckos and chameleons, snakes, turtles and crocodiles. It causes cutaneous and musculoskeletal granulomatous infections which can be rapidly fatal. Fewer than 20 human cases have been reported, mostly related to travel to West Africa. Almost all infections are in immunocompromised individuals and species of Nannizziopsis reported to affect humans are generally different from those identified in animals. Our patient denied contact with reptiles, but he had travelled to Nigeria before his transplant where he probably acquired a latent infection that reactivated post-transplant. This case illustrates the importance of biopsy and culture of atypical skin lesions, particularly in immunocompromised patients. With the rising global migration and travel, such infections are likely to be seen more frequently in the UK, and both residential and travel history may be relevant. Finally, zoonotic infections are increasing globally as interspecies barriers break down. Although there is not enough evidence to caution against ownership of exotic pets in immunocompromised individuals, animal sources of rare infections should always be considered in this patient group.

Short intravenous amphotericin B followed by oral posaconazole using a simple, stratified treatment approach for diabetes or COVID-19-associated rhino-orbito-cerebral mucormycosis: a prospective cohort study

ObjectivesTo evaluate the efficacy and safety of short-course intravenous amphotericin B followed by sustained release posaconazole tablets for diabetes or COVID-19-associated rhino-orbito-cerebral mucormycosis. MethodsThis prospective, pragmatic study included adults with diabetes or COVID-19-associated rhino-orbito-cerebral mucormycosis. Patients received short (7–14 days) or long (15–28 days) intravenous antifungal therapy (short intravenous antifungal treatment [SHIFT] or long intravenous antifungal treatment [LIFT], respectively) depending on the presence or absence of brain involvement. All patients received step-down posaconazole tablets, debridement, and glycemic control. The primary outcome was the treatment success at week 14, which was determined by assessing survival and the absence of disease progression through clinical evaluation and nasal endoscopy. Log-binomial regression analysis (risk ratio and 95% CI) was performed to assess factors associated with the primary outcome. ResultsIntravenous therapy was administered to 251 participants: SHIFT, 205 (median duration, 13 days); LIFT, 46 (median duration, 22 days). Treatment success at 3 months was 88% (217/248; 95% CI, 83–91%): SHIFT group, 93% (189/203; 89–96%); LIFT group, 62% (28/45; 47–76%). All-cause mortality was 12% (30/251): SHIFT group, 6% (13/205); LIFT group, 37% (17/46). Age (aRR [95% CI]: 1.02 [1.00–1.05]; p 0.027), diabetic ketoacidosis at presentation (2.32 [1.20–4.46]; p 0·012), glycated haemoglobin A1c (1.19 [1.03–1.39]; p 0.019), stroke (3.93 [1.94–7.95]; p 0·0001), and brain involvement (5.67 [3.05–10.54]; p < 0.0001) were independently associated with unsuccessful outcomes. Discussion: Short intravenous amphotericin B with step-down posaconazole tablets should be further studied as primary treatment option for diabetes or COVID-19-associated mucormycosis in randomized controlled trials.

Optimization of Oral Posaconazole Step Down Therapy in Management of Rhino-Orbital-Cerebral Mucormycosis (ROCM): Outcome of an Institutional Protocol.

All cases of ROCM received antifungal for a prolong period in step down phase. There is no definite guidelines regarding duration. We have formulated and followed an institutional protocol with good results. To determine the outcome of an institutional protocol and required optimum duration of oral posaconazole therapy to cure ROCM in step down phase, 30 ROCM patientswere followed up in step down phase. Oral posaconazole tablet was given for minimum 3, 4 & 1/2 and 6months to stage-II, III & IV cases respectively, with a provision of extension for another 6weeks in suspected active diseases. Nasal endoscopy, MRI, histopathology /culture of suspected tissue and hematologic investigations were done routinely to identify the residual active disease or recurrences at earliest. Outcome of this protocol proved excellent as all cases of ROCM were cured. Oral posaconazole step down therapy for a duration according to the stages of disease cured 18 cases (60%) of ROCM. Fourteen patients required extended duration of therapy as per provision of our treatment protocol. Only one patient needed re-debridement. The cases with deformities needed extended period of posaconazole therapy. No one needed posaconazole therapy for more than 7and1/2months.

Rising Incidence of Post Covid Rhinocerebral Mucormycosis: An Otolaryngologists Prospective.

Mucormycosis or grimmer popular name, "black fungus" has evolved public concern in context of covid-19 pandemic, Covid Associated Mucormycosis (CAM) seen in Covid-19 pandemic and as a post covid sequelae. The present study was conducted to find out the incidence of the Mucormycosis, and to study its association with post-covid status and co-morbidities. A retrospective study conducted at tertiary care centre over a period of four months, involving all patients with mucormycosis of the paranasal sinuses suffering from or having a history of coronavirus disease. 59 patients had CAM, 47 patients had rhino-orbital Mucormycosis, followed by nasal and paranasal Mucormycosis in 8 patients, 3 patients with rhino-orbital-cerebral Mucormycosis, and one patient with pulmonary Mucormycosis. Diabetes mellitus was present in all 59 patients, 60.41% who had HbA1c > 10 (range 7-15), and 39.58% had HbA1c < 10 with range 6-13. Only 8.33% had controlled diabetes status, uncontroled hypertension and diabetes was seen in 34.02%. All patients were started with IV amphotericin B anti-fungal drug, and followed by oral posaconazole. Depending upon the extent of the disease surgical debridement was done in 52 patients. All patients had history of steroid intake. 7 mortality was there. Uncontrolled diabetes, over-zealous use of steroids, uncontrolled underlying primary disease or co-morbidities, prolonged hospitalization in intensive care unit or normal wards, and hyperventilation all these factors together aggravated the CAM. So it's proper management based on, prompt diagnosis, reversal of predisposing condition with proper medical and aggressive surgical debridement remain the corner stone for this deadly CAM.

What Is New in Pulmonary Mucormycosis?

Mucormycosis is a rare but life-threatening fungal infection due to molds of the order Mucorales. The incidence has been increasing over recent decades. Worldwide, pulmonary mucormycosis (PM) presents in the lungs, which are the third main location for the infection after the rhino-orbito-cerebral (ROC) areas and the skin. The main risk factors for PM include hematological malignancies and solid organ transplantation, whereas ROC infections classically are classically favored by diabetes mellitus. The differences between the ROC and pulmonary locations are possibly explained by the activation of different mammalian receptors-GRP78 in nasal epithelial cells and integrin β1 in alveolar epithelial cells-in response to Mucorales. Alveolar macrophages and neutrophils play a key role in the host defense against Mucorales. The diagnosis of PM relies on CT scans, cultures, PCR tests, and histology. The reversed halo sign is an early, but very suggestive, sign of PM in neutropenic patients. Recently, the serum PCR test showed a very encouraging performance for the diagnosis and follow-up of mucormycosis. Liposomal amphotericin B is the drug of choice for first-line therapy, together with correction of underlying disease and surgery when feasible. After a stable or partial response, the step-down treatment includes oral isavuconazole or posaconazole delayed release tablets until a complete response is achieved. Secondary prophylaxis should be discussed when there is any risk of relapse, such as the persistence of neutropenia or the prolonged use of high-dose immunosuppressive therapy. Despite these novelties, the mortality rate from PM remains higher than 50%. Therefore, future research must define the place for combination therapy and adjunctive treatments, while the development of new treatments is necessary.

Bronchoscopic manifestations and interventional treatment of pulmonary mucormycosis

Objective: To analyze the bronchoscopic manifestations and interventional treatment of pulmonary mucormycosis. Methods: Clinical data of patients with pulmonary mucormycosis undergoing bronchoscopy and interventional therapy in 4 tertiary general hospitals in China from May 2006 to May 2022 were retrospectively analyzed and the literature on the subject were reviewed. Results: The data of 10 patients with pathologically diagnosed pulmonary mucormycosis undergoing bronchoscopy and interventional therapy were collected, including 8 males and 2 females. The patients' age ranged from 21 to 72 (44±15) years. The underlying diseases included 6 cases of diabetes ketoacidosis, 3 cases of leukemia, 1 case after operation of lung cancer. Bronchoscopy showed that white viscous necrotic matters grew along the airway and blocked the airway in 9 cases, accompanied by airway bleeding in 3 cases, bloody secretion blocked the airway in 1 case, and bronchopulmonary cavity fistula in 2 cases. The biopsy histopathology of white necrotic matters showed that many mucor filaments were tangled together which were named mucormycelium. Among the 10 patients, 9 were treated with systemic drugs, including intravenous application of amphotericin B deoxycholate in 5 cases, intravenous application of amphotericin B liposome in 4 cases, oral posaconazole in 6 cases and intravenous injection in 1 case. Local drug therapy included aerosol inhalation of amphotericin B deoxycholate in 8 cases and local perfusion under bronchoscope in 5 cases. Bronchoscopic interventional therapy was used to remove mucormycelium in the bronchus, including cryotherapy in 8 cases, biopsy forceps in 7 cases, snare treatment in 2 cases and foreign body forceps in 2 cases. All 10 patients were clinical cured and with no death. Conclusions: Pulmonary mucormycosis is more common in immunocompromised hosts. Bronchoscopy often showed mucormycelium blocking the airway. Systemic and local drug therapy combined with bronchoscopic interventional therapy can achieve good clinical efficacy.

Cladophialophora bantiana brain abscess after pediatric liver transplant: A report of a long-term survivor

We report long-term survival in a child who developed Cladophialophora bantiana brain abscess after liver transplantation with prolonged antifungal medications. A 6-year-old boy developed a left frontal abscess 1 month after orthotopic liver transplantation. Computed tomography-guided stereotactic aspiration was done which grew C. bantiana. The child was started on voriconazole and amphotericin B. Two months later, he underwent left frontal craniotomy with debridement for increase in intracranial lesions. Amphotericin B was administered for 3 weeks. He was discharged on oral posaconazole. On stopping posaconazole after 6 months, the child developed convulsions. Hence, it was restarted. Posaconazole was continued for 6 years and stopped. He is 11 years post liver transplant doing well. C. bantiana brain abscess in a child after liver transplant is very rare and is associated with high mortality. Improved survival mandates surgical evacuation of abscess and prolonged antifungal therapy.

An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy Volunteers.

Posaconazole is widely used for the prophylaxis and treatment of invasive fungal diseases. Because of the limited and variable absorption of the initially available oral suspension, a delayed-release tablet and intravenous formulation were developed. This study aimed to characterize the pharmacokinetics, including the absolute oral bioavailability, of all posaconazole formulations in healthy volunteers. Data from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from eight phase I clinical studies on the three formulations of various single and multiple dosage regimens between 50 and 400 mg. Analysis and simulations were performed using NONMEM 7.5.0. In the covariate analysis, the influence of food (fed vs fasted), nonlinearity, and for the delayed-release tablet, comedication (antacid, ranitidine, esomeprazole, and metoclopramide) were tested. A two-compartment model with respectively, four and eight absorption transit compartments, best described the profiles of the oral suspension and delayed-release tablet. For the suspension, both a food effect and a dose-dependent nonlinear bioavailability were quantified, resulting in lower bioavailability when fasted or at a higher dose. The typical bioavailability of the suspension at 100 mg and 400 mg was derived to be respectively, 17.1% and 10.1% under fasted conditions and 59.1% and 49.2% under fed conditions. The absolute bioavailability of the delayed-release tablet was 58.8% (95% confidence interval 33.2-80.4) under fasted conditions and approached complete absorption under fed conditions for dosages up to 300 mg. Food intake reduced the absorption rate constant of the suspension by 52.2% (confidence interval 45.2-59.2). The impact of comedication on the absorption of the delayed-release tablet was not statistically significant. Model-based simulations indicate that under fed conditions, the licensed dosages of the three formulations yield a steady-state trough concentration ≥0.7 mg/L in over 90% of healthy volunteers. About 35% of healthy volunteers who receive the licensed 300-mg delayed-release tablet under fasted conditions do not achieve this target, while for the suspension this percentage varies between 55 and 85%, depending on the dose. For both oral posaconazole formulations, we quantified bioavailability and absorption rate, including food effects, in healthy volunteers. The pharmacokinetic superiority of the delayed-release tablet was demonstrated under both fed and fasted conditions, compared with the oral suspension. The impact of food on the bioavailability of the delayed-release tablet was larger than anticipated, suggesting that administering the delayed-release tablet with food enhances absorption.

Battling the emerging epidemic of rhino-orbital-cerebral mucormycosis (ROCM) in COVID-19 pandemic: an interventional study.

PurposeThe most recent challenge being faced by the healthcare system during the worldwide COVID-19 pandemic is increase in the incidence rate of coinfection or superinfection; one of the most fatal being mucormycosis. This study aimed to estimate the risk factors, symptoms and signs, treatment outcome and prognosis of COVID-19-associated mucormycosis (CAM) patients.MethodsThis is an interventional study of 35 patients diagnosed and managed as CAM at a tertiary care centre in New Delhi, India.ResultsThe mean age of patients was 40.45 ± 6 years with a male preponderance. CAM did not affect healthy individuals; the major risk factors included diabetes in 65.7% and injudicious steroid use in 51.4% patients. Orbital/facial edema was the most common presenting symptom (25.7%) as well as sign (28.57%). 68.5% patients were stage 3 (involvement of orbit) at presentation; 33.3% showed medial wall involvement. Treatment included intravenous Amphotericin and oral Posaconazole in all patients, paranasal sinus (PNS) debridement in 94.2%, orbital exenteration was done in 8 patients. Adjuvant retrobulbar Amphotericin B injection was administered in 12 patients with radiological resolution seen in 50% after 1 cycle. In patients with Stage 4 disease who underwent exenteration along with PNS debridement, survival rate was 100% at 30 days, and disease reduction occurred in 87.5% patients (P < 0.01). Overall, 68.5% responded to therapy, 8.5% showed progression and mortality rate was 22.85%, at a mean follow up period of 59.5 days.ConclusionA multidisciplinary and aggressive approach is essential in the management of CAM patients.