In vitro antifungal combination effects of micafungin with fluconazole, voriconazole, amphotericin B, and flucytosine against clinical isolates of Candida species

Micafungin (MCFG) is an echinocandin antifungal agent that exhibits potent activity against most species of Candida and Aspergillus. We investigated the in vitro antifungal combination effects of MCFG with four other antifungal agents — fluconazole (FLCZ), voriconazole (VRCZ), amphotericin B, and flucytosine — against clinical isolates of 54 Candida spp. by checkerboard analysis. The synergistic antifungal effects of MCFG-FLCZ and MCFG-VRCZ were 11% and 15%, respectively, and the latter displayed a synergistic activity of 63% against Candida glabrata. Antagonism was not observed in any of the combinations tested.     

Rapid improvement of disseminated aspergillosis with caspofungin/voriconazole combination in an adult leukemic patient

A 57-year-old man with acute myeloid leukemia (AML) French-American-British (FAB) 4 developed disseminated invasive cerebral and pulmonary aspergillosis during postinduction aplasia. According to international consensus, infection was categorized as probable (two host factors: deep neutropenia for >10 days and refractory fever for >96 h; major clinical criteria of lower respiratory tract and CNS invasive fungal infection; positive results for galactomannan antigen in three blood samples). After the failure of standard amphotericin-based therapy, the spectacular regression of multifocal brain and lung lesions was rapidly achieved under a caspofungin acetate/voriconazole combination. Further permanent caspofungin maintenance with voriconazole added during aplasia periods permitted two consolidation courses and autograft-based intensification without any delay.     

Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders

We investigated the role of therapeutic dose monitoring (TDM) in the treatment of fungal infections with voriconazole through 49 analyses of 34 patients who received treatment for hematologic diseases. Voriconazole concentration was highly variable among patients regardless of renal, liver functions, or age, and the effect of dose enhancement was not constant. This indicates the difficulty of predicting voriconazole concentration without TDM. We evaluated the outcome with the composite assessment system where patients were assumed non-responders when they failed to show improvement in at least 2 of the following 3 criteria: clinical, radiologic, and mycologic. We showed that concentration–response relationship depended on the status of underlying hematologic diseases; this relationship was observed only in cases without refractory hematologic diseases, but not in those with refractory diseases. In the former group, cases with >2 mg/L of concentration were associated with good response to voriconazole. On the other hand, elevation of hepatic enzyme was frequently observed when voriconazole concentration was >6 mg/L. From these results, we concluded that TDM should be executed and targeted to 2–6 mg/L to improve efficacy and to avoid side effects.     

Successful treatment of multiple Pseudallescheria boydii brain abscesses and ventriculitis/ependymitis in a 2-year-old child after a near-drowning episode

Rationale We report on a cerebral infection by Pseudallescheria boydii in a 21-month-old boy after a near-drowning episode. MRI revealed multiple (>60) intracerebral abscesses.Methods The surgical therapy included CSF drainage and microsurgical resection of one abscess for microbiological diagnosis. Antimycotic therapy included terbinafine and intraventricular caspofungin in addition to voriconazole.Results Systemic side effects of chemotherapy were not observed. After placement of a ventriculoperitoneal shunt, the boy was transferred to a rehabilitation clinic and improved neurologically. After 20 months, MRI documented a continuing remission of the disease.Conclusion Our case proves that an aggressive treatment should be undertaken and can be successful in CNS pseudallescheriasis.     

Development and validation of a fast HPLC/photodiode array detection method for the measurement of voriconazole in human serum samples. A reference laboratory experience

The aim of this study was the development and validation of a fast and simple high performance liquid chromatography method for measuring voriconazole in human serum using ravuconazole as an external standard. The experience of the reference laboratory in therapeutic drug monitoring of voriconazole is also reported. This method is based on the precipitation of proteins in human serum and detection by HPLC/UV. Chromatographic separation is achieved using an isocratic solvent delivery with detection at 255 nm and a run time of 7 min. The assay was validated according to international guidelines and was also applied to the analysis of 141 trough serum samples from patients treated with voriconazole. All validation parameters met the criteria set out in FDA guidelines for bioanalytical methods. A high interpatient and intrapatient variability was observed in clinical samples. This method is accurate enough to perform therapeutic drug monitoring in patients receiving voriconazole treatment.     

Usefulness of a colorimetric method for testing antifungal drug susceptibilities of Aspergillus species to voriconazole

 The usefulness of a colorimetric method using Alamar Blue (Alamar Blue method) for susceptibility testing of Aspergillus species to voriconazole and three existing antifungal agents, itraconazole (ITCZ), flucytosine (5-FC), and amphotericin B (AMPH-B), was studied using four ATCC strains of three species, including two strains of A. fumigatus and one each of A. flavus and A. niger. For comparison, the broth microdilution method for antifungal susceptibility testing of filamentous fungi proposed by the National Committee for Clinical Laboratory Standards (NCCLS method M38-P) was also used. Minimun inhibitory concentration (MIC) endpoints were read spectrophotometrically for the Alamar Blue method and visually for the NCCLS method after 46–50 h. Like the NCCLS method, Alamar Blue produced highly reproducible results for all the drugs and strains tested; most MIC values obtained by nine tests were within the range of 2 twofold dilutions for each strain. Voriconazole and ITCZ susceptibility testing with the Alamar Blue method and the NCCLS method yielded comparable results in 94% of the tests, meaning that the endpoints obtained were identical or differed by no more than 2 twofold dilutions. On the other hand, susceptibility testing for 5-FC and AMPH-B yielded scores of 25% and 64%, respectively. Our study suggests the potential value of the Alamar Blue method as a convenient alternative to the NCCLS M38-P method for routine testing of Aspergillus species susceptibility to at least voriconazole and ITCZ. Received: April 22, 2002 / Accepted: July 23, 2002     

Are epidemiologic cut-off values predictors of the in vivo efficacy of azoles in experimental aspergillosis?

We tried to correlate the in vitro activity and the in vivo efficacy of voriconazole (VRC) and posaconazole (POS) against Aspergillus flavus and Aspergillus niger. The in vitro susceptibility of a large set of isolates was determined by broth microdilution and disk diffusion methods, while the in vivo efficacy was assessed in a murine model of disseminated infection. For A. flavus, VRC showed efficacy even for strains with MICs above the epidemiologic cutoff value (ECV) (1 μg/mL). For A. niger, VRC was ineffective against those strains for which the MIC was 1 dilution below the corresponding ECV (2 μg/mL). POS showed efficacy against all the strains of both species included in the study, although isolates with MICs > ECV were not tested.     

米卡芬净在儿童恶性血液病患者合并肺部真菌感染中的临床应用

目的 探讨米卡芬净治疗儿童恶性血液病并侵袭性肺部真菌感染的疗效及安全性.方法 选取柘城县人民医院血液/肿瘤病区治疗恶性血液病合并肺部真菌感染患儿51例,随机分为两组,分别给予米卡芬净与伏立康唑治疗,比较两组的治疗有效率、痊愈率和不良反应发生率.结果 两组患儿在有效率和痊愈率方面比较差异无统计学意义（P〉0.05）,但在不良反应发生率方面,米卡芬净组患儿低于伏立康唑组患儿,差异有统计学意义（P〈0.05）.结论 米卡芬净与伏立康唑对儿童恶性血液病侵袭性肺部真菌感染均具有良好的疗效,但米卡芬净具有更好的安全性.     

Voriconazole and the liver

Voriconazole is an azole useful for the prophylaxis and the treatment of aspergillosis and other fungal infections in immunosuppressed subjects, as those found in aplasia after aggressive polychemotherapy treatments, after hematopoietic stem cell, liver or lung transplantation. Its administration in therapeutic doses lead to extremely varied serum levels from patient to patient and even to the same patient. The explanations are varied: nonlinearpharmacokinetics, certain patient-related factors, including genetic polymorphisms in the cytochrome P450 2C19 gene, the kidney and liver function, simultaneous administration with other drugs metabolised by the same cytochrome. It is recommended to maintain the serum concentrations of voriconazole between 1.5 and 4 μg/m L. At lower values its efficacy decreases and at higher values the risk of neurological toxicity increases. Even at these concentrations it is not excluded the possible appearance of a variety of toxic effects, including on the liver, manifested by cholestasis, hepatocytolisis, or their combination. It is recommended to monitor the clinical and laboratory evolution of all patients treated with voriconazole, and of the serum levels of the drug of those who belong to risk groups, even if there is still no consensus on this issue, given the lack of correlation between the serum level and the occurrence of adverse effects in many patients.