伏立康唑滴眼液的制备及质量控制

目的制备伏立康唑滴眼液并建立其质量控制方法。方法伏立康唑采用被制成羟丙基－β－环糊精包合物的方法来制备滴眼液,并采用高效液相色谱法测定主药含量。结果所得制剂为无色透明液体,鉴别、检查结果均符合中国药典2005年版中的相关规定。伏立康唑检测浓度的线性范围为0．1000～0．9000mg·mL^-1（r=0．99991,平均回收率为99．78％（RSD=0．47％,n=9）。结论该制备工艺简单,质量可控,值得临床推广。     

Successful treatment of Scedosporium apiospermum soft tissue abscess with caspofungin and voriconazole in a severely immunocompromised patient with acute myeloid leukemia

F. Beier, N. Kittan, T. Holzmann, K. Schardt, R. Andreesen, E. Holler, G.C. Hildebrandt. Successful treatment of Scedosporium apiospermum soft tissue abscess with caspofungin and voriconazole in a severely immunocompromised patient with acute myeloid leukaemia.
Transpl Infect Dis 2010: 12: 538–542. All rights reserved. Abstract: We report the case of a 53‐year‐old female patient with refractory acute myeloid leukemia developing a necrotic, soft tissue abscess on the right forearm caused by Scedosporium apiospermum during prolonged severe neutropenia (absolute white blood cell count <500/μL for 49 days). In the context of the severely immunocompromised state of the patient and her need for allogeneic hematopoietic stem cell transplantation (HSCT), surgical treatment options were not favored. Therefore, combined antifungal therapy with voriconazole and caspofungin was started, based on the results of the in vitro testing (minimum inhibitory concentrations of voriconazole, posaconazole, and amphotericin B: 1, 4, and >2 mg/L, respectively). The local site of infection slowly improved clinically and no spread of S. apiospermum infection to other sites was observed. After HSCT, the soft tissue abscess resolved completely and the patient has remained free of S. apiospermum infection since then. We successfully demonstrate that the use of combined antifungal therapy with voriconazole and casopfungin may further improve the clinical course and provides a promising therapeutic option to treat Scedosporium infections in such patients.     

三唑类抗真菌药物治疗药物监测的研究进展

药动学个体差异大以及血药浓度和临床疗效有显著相关性的药物应该进行治疗药物监测。由于在吸收、代谢和排泄等方面的差异和合并用药的影响,许多抗真菌药物血药浓度的个体差异大,并且现有研究结果表明,抗真菌药物血药浓度与疗效有相关性。另外,研究已证实部分抗真菌药的血药浓度和毒副作用也有相关性。本文就三唑类抗真菌药物治疗药物监测的研究进展进行综述。     

Voriconazole and multidrug resistance in Candida albicans

In vitro activity of voriconazole against fluconazole-resistant Candida albicans clinical isolates with identified molecular basis of multidrug resistance (MDR) and recombinant Saccharomyces cerevisiae expressing C. albicans genes coding for major multidrug transporters, CaCdr1p, CaCdr2p or CaMdr1p, was compared with that of fluconazole, ketoconazole and clotrimazole. It was found that overexpression of the MDR genes made the yeast cells less susceptible to voriconazole. The voriconazole resistance indexes, defined as a ratio of minimum inhibitory concentrations (MICs) determined for MDR and sensitive cells, were comparable with those determined for fluconazole. Voriconazole effectively competed with rhodamine 6G for the active efflux mediated by CaCdr1p and CaCdr2p.     

In vitro susceptibilities of Aspergillus spp. causing otomycosis to amphotericin B, voriconazole and itraconazole

Otomycosis is worldwide in distribution and most commonly caused by Aspergillus species. Amphotericin B, itraconazole and voriconazole are used for the treatment of aspergillosis, but recently an increase in resistance to these agents has been reported. We aimed at investigating the in vitro activities of amphotericin B, voriconazole and itraconazole against Aspergillus isolates causing otomycosis. Mycological analysis of samples from the ear canals of patients was performed by culturing onto Sabouraud Dextrose Agar and by evaluating microscopically. Aspergillus species were identified with colony morphology and microscopic appearance, and tested for susceptibilities to amphotericin B, itraconazole and voriconazole by the CLSI reference broth microdilution method (M38-A document). A total of 120 isolates from 120 patients, comprising 57 Aspergillus niger, 42 Aspergillus fumigatus, nine Aspergillus flavus, six Aspergillus nidulans and six Aspergillus terreus strains were tested. No resistance was determined against amphotericin B and voriconazole, while six A. fumigatus and three A. niger isolates were resistant to itraconazole. In vitro data obtained in this study showed the resistance to itraconazole, while all of the isolates were susceptible to voriconazole and amphotericin B. Voriconazole seemed to be an alternative in the treatment of infections related to Aspergillus spp. but further studies are needed to learn more about the antifungal resistance of different species of Aspergillus to different agents.     

Trends in zygomycosis in children

Zygomycosis, or mucormycosis, is associated with significant morbidity and mortality in both children and adults. Studies in adults have shown an increase in the incidence of zygomycosis, particularly among haemtopoietic stem cell transplant (HSCT) recipients and patients with haematologic malignancies. There is a paucity of data on the epidemiology of zygomycosis in children. We performed a retrospective analysis to describe trends in zygomycosis between 1 January 2003 and 31 December 2010. We used the Pediatric Health Information System (PHIS) database to identify paediatric patients who were diagnosed with zygomycosis during the study period. Administrative data on diagnoses, demographics, underlying conditions and clinical experiences were collected. Summary statistics were calculated and tests for trend were conducted. We identified 156 unique patients with zygomycosis. The prevalence of zygomycosis did not significantly increase over time (P=0.284). The most common underlying condition was malignancy (58%) and over half received intensive care. Voriconazole utilisation among all hospitalised children significantly increased during the period (P=0.010). Our study demonstrates that the incidence of zygomycosis is not significantly increasing. During the time period there was a significant increase in the use of voriconazole among children.     

Phaeohyphomycosis due to Alternaria species in transplant recipients

R.D. Boyce, P.J. Deziel, C.C. Otley, M.P. Wilhelm, A.J. Eid, N.L. Wengenack, R.R. Razonable. Phaeohyphomycosis due to Alternaria species in transplant recipients.
Transpl Infect Dis 2010: 12: 242–250. All rights reserved Abstract: Alternaria species are members of a heterogenous group of dematiaceous fungi that rarely cause opportunistic infections in transplant recipients. During a 20‐year period from 1989 to 2008, 8 solid organ transplant recipients (63% males; median age, 48 years) developed Alternaria species infections at the Mayo Clinic. All patients were highly immunocompromised as evidenced by their receipt of multiple transplants, treatment of acute and chronic allograft rejection, and occurrence of other opportunistic infections. All patients presented with non‐tender erythematous or violaceous skin papules, nodules, or pustules in exposed areas of the extremities. No case of visceral dissemination was observed. Itraconazole was the most common drug used for treatment, although voriconazole, posaconazole, and caspofungin could potentially be useful based on our limited clinical data and in vitro antifungal susceptibility testing. One patient was treated with voriconazole, while another patient who was refractory to itraconazole had rapid resolution of lesions after the addition of caspofungin. Attempts at antifungal therapy alone were unsuccessful; all patients eventually required surgical excision of lesions. In conclusion, Alternaria species are rare but increasingly recognized opportunistic infections among highly immunocompromised transplant recipients. Wide excisional surgery combined with prolonged systemic antifungal therapy and reduction in immunosuppressive regimens provided the best chance of cure. Although itraconazole remains the most common drug for treatment, this case series highlights the potential clinical utility of caspofungin, voriconazole, and posaconazole as alternative regimens.     

Safety and efficacy of caspofungin and liposomal amphotericin B, followed by voriconazole in young patients affected by refractory invasive mycosis

OBJECTIVE: Data on the use of combination of liposomal amphotericin B and caspofungin followed by voriconazole, as maintenance or further rescue treatment, in 10 patients with invasive mycosis are reported. MATERIAL AND METHODS: The diagnoses were acute leukemia (7), myelodysplastic syndrome (1) and Hodgkin's lymphoma (1). All patients developed an invasive mycosis (proven, 3; probable, 6; and possible, 1) refractory to first-line antifungal treatment (liposomal amphotericin B in all patients except one who received fluconazole). RESULTS: Rescue therapy with a combination of caspofungin and liposomal amphotericin B was well tolerated, hypokalemia, and thrombophlebitis being the most common side-effects. Combination therapy was administered for a median of 17 d, range 6-40. Among the nine patients with proven or probable mycosis, one was not evaluated because of early death caused by massive hemoptysis whilst in the remaining eight patients, the response was classified as complete, stable and failure in four, three, and one patients, respectively. Complete response was also observed in patient with possible mycosis. Eight of nine patients received voriconazole for a median of 75 d, range 42-194. Voriconazole was well tolerated although some drug interactions were observed during treatment with methotrexate and digoxin. After a median follow-up of 125 d, nine of 10 patients are alive. Overall, a favorable response to antifungal treatment (including the case of possible mycosis) was obtained in eight of 10 patients. CONCLUSION: These data suggest that medical antifungal treatment may be intensified in severely ill patients without significantly compromising patient safety. The combination of synergistic antifungal drugs as well as their sequential use warrants further investigation by a larger randomized controlled study.     

伏立康唑对格列奈类药物降低糖尿病大鼠血糖作用的影响

目的 研究伏立康唑对格列奈药物降低正常和糖尿病大鼠的血糖效应的影响。方法 ①正常大鼠随机分为2组,正常组和伏立康唑组,伏立康唑组大鼠连续灌胃7 d,第8天禁食8 h后于0,1,3,6,9,12,18,24 h眼眶取血,测定血糖。②正常大鼠随机分为4组,瑞格列奈组、瑞格列奈+伏立康唑组、那格列奈组和那格列奈+伏立康唑组。合并用药组伏立康唑连续灌胃7 d,第8天禁食8 h,4组大鼠用对应的格列奈药物灌胃,给药后于0,1,3,6,9,12,18,24?h眼眶取血,测定血糖。③STZ诱导糖尿病大鼠,分组及给药方式同第2部分实验。结果 治疗剂量的伏立康唑增强瑞格列奈和那格列奈在正常和糖尿病大鼠的降糖效应。结论 格列奈降糖药物与伏立康唑合并使用时可能需要调整剂量。