Posaconazole-associated severe hyperbilirubinemia in acute myeloid leukemia following chemotherapy: A case report

BACKGROUND Posaconazole is a widely used azole antifungal agent, and posaconazole-associated severe hyperbilirubinemia is usually rare in clinical practice. We herein report a 58-year-old male with acute myeloid leukemia, who developed fungal infection following chemotherapy.CASE SUMMARY After administration of posaconazole oral suspension, the patient developed severe hyperbilirubinemia and jaundice(Common Terminology Criteria for Adverse Events, CTCAE-Grade 3) with a serum total bilirubin(T-BIL) peak level of 170 μmol/L, alkaline phosphatase level of 739 U/L, alanine aminotransferase level of 99 U/L, and gamma-glutamyl transpeptidase level of 638 U/L. After posaconazole withdrawal and symptomatic treatment with liver-protective agents, the level of T-BIL and other laboratory data decreased gradually, and related symptoms disappeared. After medication analysis and literature review, we consider that the patient had a cholestatic type of posaconazoleinduced liver injury, which was related to intracellular mitochondrial DNA damage. The case demonstrates that when patients with hematological malignancy develop severe infection following chemotherapy, combination of anti-infective drugs may contribute to ahigher risk of severe drug-induced liver injury. CONCLUSION This is the first thoroughly documented case report of posaconazole-associated severe hyperbilirubinemia. Therefore, in order to avoid severe adverse events, liver and renal function should be monitored closely before and during the administration of posaconazole.

Treatment of chronic vulvovaginal candidiasis with posaconazole and ciclopiroxolamine

Therapy of chronic recurrent vulvovaginal can- didiasis (VVC) caused by Candida glabrata is still rare in comparison to C. albicans infection, but therapy remains more difficult. Combination therapy with topical antifungals may improve therapy outcome, but still standard agents as fluconazole or itraconazole often fail. Posaconazole is a new systemic triazole with a wide antifungal spectrum including rare Candida species. Up to now, no clinical trials with posa- conazole in chronic recurrent VVC have been undertaken. Here, first results of the application of a new therapy regimen consisting of oral posaconazole in combination with topical ciclopiroxolamine are presented. 15 patients with chronic recurrent VVC caused by C. glabrata have been treated. 14 of these patients experienced successful therapy, clinical and mycological cure 30 days after begin of therapy has been observed. Long-term results are promising, as in 4 patients clinical and mycologic cure persists for more than 1 year up to now.

Analysis of Pharmacokinetic/Pharmacodynamic Parameters and Dosage Regimen of Posaconazole against <i>Candida</i>spp. and <i>Aspergillus</i>spp. Using Monte Carlo Simulation

Invasive fungal infections (IFI) have recently become increasingly more prevalent, resulting in an increased risk of morbidity and mortality. Both Candida spp. and Aspergillus spp. are major causes of IFI. In this study, we aimed to evaluate the cumulative fraction of response of various dosage regimens of posaconazole against nine Candida spp. and six Aspergillus spp. in both children and adults. Monte Carlo simulation (MCS) was performed to optimize selection of posaconazole dosage regimens. For children, a dosage regimen of 120 mg/m2 posaconazole tid was sufficient to treat fungal infections caused by all six Aspergillus spp. and six of the nine Candida spp. (but was not effective against C. glabrata, C. guilliermondii and C. krusei). In contrast, a 400 mg dosage regimen of posaconazole bid achieved the target pharmacokinetic/pharmacodynamics (PK/PD) parameters against all six Aspergillus spp. and eight of the nine Candida spp. (but was not effective against C. glabrata) in the adults. Dosage regimens of 50 mg bid, 100 mg bid, or 200 mg bid were not effective. Posaconazole dosage regimens are likely to achieve their desired PK/PD targets against Candida spp. and Aspergillus spp. in both children and adults.

Effects of Obesity on Posaconazole Kinetics in a Patient with Graft versus Host Disease

Posaconazole, a triazole antifungal agent, displays a highly variable pharmacokinetic profile due in part to the oral solution, the only currently available dosage form. Posaconazole activity appears to be dose-dependent and clinical outcomes correlate with steady-state serum trough concentrations and area under the concentration curve (AUC) over minimum inhibitory concentration (MIC) ratios. Therapeutic drug monitoring (TDM) has been recommended to help overcome the unpredictable nature of the drug. The impact of obesity of posaconazole pharmacokinetics and the use of TDM in this population has not been well described;however, limited data demonstrate increased weight correlates with lower serum concentrations and reduced drug exposure. We describe the use of TDM in an obese man, 12 months status post hematopoietic stem-cell transplant (HSCT), receiving posaconazole therapy for a presumed invasive fungal infection (IFI).

Validated Gradient Stability Indicating UPLC Method for the Determination of Related Substances of Posaconazole in Bulk Drug

A stability-indicating UPLC method has been developed and validated for the determination of related substances of Posaconazole with its four related substances (Hydroxytriazole, Tosylated compound, Deshydroxy posaconazole and Benzylated posaconazole) in the drug substance. Forthwith simple UPLC chromatographic separations were achieved on a Waters Acquity BEH shield C18 (100 mm length, 2.1 mm internal diameter and 1.7 μm particle size) with a mobile phase containing 0.1% Orthophosphoric acid (i.e. 1 mL in 1000 mL water) in gradient combination with acetonitrile (ACN) at a flow rate of 0.5 mL/min and the eluent were monitored at 210 nm. As a result, the resolution of Posaconazole from any of impurities was found to be greater than 2.0. The test solution and spiked solutions were found to be stable in the diluent for 48 h. For the purpose method to be stability indicating, forced degradation studies were conducted and the method resolved the drug from its known impurities, stated above, and from additional impurities generated when POS subjected to forced degradation;the mass balance was found close to 100%. Regression analyses indicate correlation coefficient value greater than 0.999 for Posaconazole and its known impurities. The LOD for Posaconazole and the known impurities was at a level below 0.05%. The method has shown good, consistent recoveries for known impurities (89% - 106%). To summarise, the method was found to be accurate, precise, linear, specific, sensitive, rugged, robust, and stability-indicating.

Pharmacokinetic/Pharmacodynamic Analysis the Probability of Target Attainment of Posaconazole against <i>Mucorales</i>Species in Patients with Mucormycosis

The objective of this study was to investigate the probability of target attainment of various posaconazole dosing regimens against Mucorales species in patients with mucormycosis. According to pharmacokinetic/pharmacodynamic parameters of posaconazole in adults, the dosage regimen of posaconazole for mucormycosis included 50, 100, 200 and 400 mg orally q12h. Monte Carlo Simulation analysed the published parameters of pharmacokinetics and the MIC values of mucormycosis in Mucorales species. The results showed that posaconazole did not affect Rhizopus arrhizus and Mucor sp. The optimal dosage of posaconazole for Rhizopus microsporus and Rhizomucor pusillus was 400 mg orally q12h and the best dosage regimen for Lichtheimia corymbifera was 200 mg orally q12h. The antifungal activity of posaconazole against mucormycosis was different, and the dosage regimen needs to adjust according to fungal species.

Posaconazole对真菌感染有效

在德国柏林召开的医学真菌学治疗趋向会议上公布的一项研究结果显示，对于患有移植物抗宿主病的同种异体干细胞移植患者，与氟康唑相比，posaconazole口服混悬剂型（Ⅰ）可较大程度减少曲菌病和侵入性真菌感染。

Use of bronchoscopy-guided treatment and oral posaconazole to treat pulmonary mucormycosis:a case report and literature review

Background:Pulmonary mucormycosis(PM)is rare condition,which is difficult to diagnose and has a high mortality rate.Currently,there is a lack of effective drugs,with few side effects,to treat PM.There have been a few reports on the use of bronchoscopy and posaconazole for the treatment of adult PM.Methods:A man with diabetes mellitus developed diabetic ketoacidosis and subsequently developed repeated cough,hemoptysis,and fever.He was diagnosed with pneumonia and was treated with antibiotics in a local hospital.However,his condition worsened.After admission to our hospital,chest computed tomography(CT)showed bilateral pneumonia and cavities in the left upper lobe that were significantly worse than those seen previously.Bronchoscopy revealed swelling of the left bronchial mucosa and yellow necrosis adhering to the wall.Histology of transbronchial lung biopsy specimens revealed PM pneumonia,characterized by numerous mucormycelia,spores,and neutrophils between necrotic debris.Results:Following diagnosis,liposomal amphotericin B was administered intravenously,and although the symptoms improved significantly,side effects caused the patient to discontinue taking the drug.An alternative regimen,including oral posaconazole and local injection of amphotericin B was administered via bronchoscopy.Finally,the patient did not experience any discomfort and chest CT showed complete resolution of the consolidation and the lung cavity.Conclusion:Bronchoscopy can play an important role in the diagnosis and treatment of PM.The combination of oral posaconazole and bronchoscopy-guided anti-infective therapy is a novel and effective way to treat PM for patient cannot tolerate liposomal amphotericin B.

Intravenous-oral itraconazole versus oral posaconazole in preventing invasive fungal diseases for acute leukemia patients

Invasive fungal diseases(IFDs)are major and lethal infectious complications for patients with neutropenia after chemotherapy.Prophylaxis with intravenous and oral suspended itraconazole(200 mg Q12h intravenously×2 days followed by 5 mg/kg·d orally in twice)or oral suspension of posaconazole(200 mg Q8h)was administered for preventing IFDs.The only 2 episodes of proven IFDs were not included after propensity-score matching(PSM),while the incidence of possible IFDs was 8.2%(9/110)in itraconazole group and 1.8%(2/110)in posaconazole group,respectively(P=.030).In clinical failure analysis,the failure rate of posaconazole group was lower as compared to the itraconazole group(2.7%vs 10.9%,P=.016).Both intravenous-oral itraconazole and posaconazole suspension are effective in preventing IFDs,while posaconazole suspension seems more tolerable.

Optimized combinations of statins and azoles against Acanthamoeba trophozoites and cysts in vitro

Objective: To evaluate the combination of several statins(atorvastatin, fluvastatin and simvastatin) and azoles(voriconazole, posaconazole and itraconazole) against Acanthamoeba spp. Methods: The efficiency of the different drug combinations against the trophozoite stage of different Acanthamoeba strains were evaluated by Alamar Blue assay. Effect on the cyst stage was observed by inverted microscope. Cytotoxicity of combinations of azoles and statins was evaluated by measuring the release of lactate dehydrogenase from a murine macrophage cell line. Results: Combinations of any of the tested statins and voriconazole or posaconazole were more efficient in inhibiting Acanthamoeba compared to statins or azoles individually. The drug combinations at the combined inhibitory concentrations 50% showed lower toxicity compared to that of the compounds alone.Conclusions: The combinations of statins together with voriconazole and posaconazole are more efficient than these drugs alone, and these combinations have lower cytotoxicity in mammalian cell lines.

FDA批准默沙东公司抗感染药Noxafil的新剂型

3月14日，默沙东公司（Merck ＆ Co）宣布，Noxafil（posaconazole，泊沙康唑）静脉注射剂（intravenous，IV，18mg/ ml）获 FDA 批准，此为一种新配方的 Noxafil。2013年11月，FDA 授予 Noxafil IV 新药申请（NDA）优先审查资格，与此同时，Noxafil（posacon-azole，100 mg）缓释片获 FDA 批准，并且默沙东公司还销售 Noxafil（40mg/ mL）口服混悬液。

Clinical characteristics and prognoses of pulmonary mucormycosis in four children

Importance:Pulmonary mucormycosis is life threatening and carries a poor prognosis.Identification of factors that improve prognosis is urgently necessary.Objective:To analyze the clinical features and outcomes of pulmonary mucormycosis in children.Methods:A retrospective analysis of clinical data of four cases with pulmonary mucormycosis was conducted in Beijing Children's Hospital from January 2017 to December 2018.Results:Underlying diseases were identified in all four cases(diabetes in three individuals and a hematological malignancy in one individual).The predominant clinical manifestations were fever,cough,chest pain and hemoptysis.Imaging features included consolidation or nodules with cavities.All four cases were treated with liposomal amphotericin B,one case underwent lobectomy,and three cases received a full course ofposaconazole.All four cases were cured.Interpretation:Patients with pulmonary mucormycosis often have underlying diseases.Imaging features are relatively characteristic.Treatment with liposomal amphotericin B at an early stage and a sufficient course of posaconazole for maintenance significantly improves prognosis.

Complicated multiple organ infection of Purpureocillium lilacinum and varicella-zoster virus infection in a patient with Evans’ syndrome

Purpureocillium lilacinum(P lilacinum)is a rare pathogenic fungus,which mainly involves immunocompromised individuals.Here,we report a case of complicated multiple-organ infections involving skin,lungs,and spleen in a 63-year-old female with Evans’syndrome after 9 months of glucocorticoid treatment.Microbial examinations of skin biopsy and blood samples revealed Plilacinum infections.Posaconazole was effectivein this patient.During anti-fungitreatment,she developedvaricella-zoster virus infection and was diagnosed through next-generation sequencing examination.In conclusion,Plilacinum may affect different organ systems and is susceptible to posaconazole treatment.The molecular-based methods like microbial cell-free DNA sequencing could provide accurate and timely identification of a wide range of infections.