DIFLUCAN

(generic name: fluconazole)

APMIS. 2005 Apr;113(4):278-83.
In vitro susceptibility of yeasts isolated from patients in intensive care units to fluconazole and amphotericin B during a 3-year period.
Kucukates E, Erturan Z, Susever S, Yegenoglu Y.
Laboratory of Microbiology and Clinical Microbiology, Institute of Cardiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.

Kucukates E, Erturan Z, Susever S, Yegenoglu Y. In vitro susceptibility of yeasts isolated from patients in intensive care units to fluconazole and amphotericin B during a 3-year period. APMIS 113;2005:278-83.Fungal infections have increased dramatically in recent years and candidemia is a major risk factor for morbidity and mortality in intensive care units (ICUs). Candidemia has been considered to be a nosocomial infection that is strongly associated with neutropenia, recent surgery or presence of intravascular lines, and previous colonization is an independent risk factor. We evaluated the in vitro efficacy of fluconazole and amphotericin B against yeasts isolated from various clinical specimens of colonized or infected patients treated in the ICUs of the Institute of Cardiology, Istanbul University. A total of 1397 ICU patients were treated at the Institute of Cardiology between January 2000 and December 2002. A total of 117 yeasts isolated from 97 patients were included in this study. These ICU patients were hospitalized for a mean of 29 days. All yeasts were identified by conventional methods and using the API (20C AUX, ID 32C) system (Bio Merieux, France). Susceptibility to fluconazole and amphotericin B was evaluated using the E-test (AB Biodisk, Solna, Sweden). The most commonly isolated yeast was Candida albicans (72.6%), followed by Candida tropicalis (16.2%), Candida kefyr, Candida krusei, Candida parapsilosis, Trichosporon mucoides and Geotrichum spp. Fluconazole and amphotericin B MIC(90) values were 0.75 mug/ml; 0.19 mug/ml and 1 mug/ml; 0.38 mug/ml for C. albicans and C. tropicalis, respectively. All Geotrichum spp. were found to be susceptible-dose dependent (SDD) (MIC=16-32 mug/ml) to fluconazole. Two C. albicans, two C. tropicalis, one C. krusei and one Geotrichum spp. had a MIC value of >/=0.38 mug/ml for amphotericin B. The rate of colonization was 3.36% (47/1397). Only 10 (0.71%) patients out of a total of 1397 developed candidemia during the period of the investigation. Of these, 7 (70%) were caused by non-albicans Candida spp.

Bone Marrow Transplant. 2005 Mar;35(6):583-6.
Caspofungin as second-line therapy for fever of unknown origin or invasive fungal infection following allogeneic stem cell transplantation.
Trenschel R, Ditschkowski M, Elmaagacli AH, Koldehoff M, Ottinger H, Steckel N, Hlinka M, Peceny R, Rath PM, Dermoumi H, Beelen DW.
1Department of Bone Marrow Transplantation, University Hospital Essen, Essen, Germany.

Summary:Caspofungin (CAS) is the first of a new class of antifungal agents, the echinocandins, that interfere with fungal cell wall synthesis by inhibition of glucan synthesis. Here, we report the results of 31 patients treated with CAS following allogeneic SCT. CAS was administered as a second-line agent to patients with invasive fungal infection (IFI) (n=15) or fever of unknown origin (n=16) who were recalcitrant to or intolerant of prior antifungal therapy. Unsuccessful first-line regimes included amphotericin B (n=17), liposomal amphotericin B (n=5), fluconazole (n=3), itraconazole (n=1), and voriconazole (n=2). All patients received concomitant immunosuppressive therapy for graft-versus-host disease. In 23 patients, cyclosporin A (CSA) and CAS were administered concurrently without any major side effects detected. Observed increases in GPT were not clinically significant. Normalization of serum creatinine and significant reductions in C-reactive protein were observed in response to CAS. Favorable outcome to CAS were documented in eight of 15 patients with IFI and in 15 of 16 patients with fever of unknown origin. CAS is a promising alternative in patients with IFI and fever of unknown origin in the setting of allogeneic SCT.Bone Marrow Transplantation (2005) 35, 583-586. doi:10.1038/sj.bmt.1704859 Published online 31 January 2005.

Mycoses. 2005 Mar;48(2):126-31.
Molecular epidemiology of Candida species isolated from urine at an intensive care unit.
Ergon MC, Gulay Z.
Department of Microbiology and Clinical Microbiology, School of Medicine, Dokuz Eylul University, Izmir, Turkey.

Summary Candida spp. has been the leading microorganism isolated from the urine specimens of patients hospitalized at the Anesthesiology and Reanimation intensive care unit (ICU) of Dokuz Eylul University Hospital, Izmir, since 1998. This study was undertaken to investigate the clonal relationship of Candida urine isolates in order to find the mode of spread among the patients. Epidemiological surveillance of 38 Candida albicans, 15 Candida tropicalis and 12 Candida glabrata recovered from the urine specimens of patients who were hospitalized in the ICU between June 11, 2000 and October 15, 2001 was carried out by antifungal susceptibility testing and randomly amplified polymorphic DNA (RAPD) analysis. Two short primers [Cnd3 (5'-CCAGATGCAC-3') and Cnd4 (5'-ACGGTACACT-3')] were used for RAPD. None of the isolates had high minimal inhibitory concentration (MIC) values (>1 mug ml(-1)) against amphotericin B with MIC(50)values of 0.5 mug ml(-1), 0.5 mug ml(-1) and 0.125 mug ml(-1) for C. albicans, C. tropicalis and C. glabrata isolates, respectively. However, three C. glabrata isolates were resistant and one C. albicans and five C. glabrata isolates were dose-dependent susceptible (D-DS) to fluconazole. Among C. albicans isolates 19 and 20 patterns were detected with primers Cnd3 and Cnd4, respectively. When primers Cnd3 and Cnd4 were evaluated together, three and four genotypes were identified for C. tropicalis and C. glabrata isolates, respectively. Our results suggest that the source of C. albicans isolates was mostly endogenous. It is difficult to interpret the mode of spread of C. tropicalis and C. glabrata urine isolates as we obtained insufficient banding patterns for these species.

Br J Clin Pharmacol. 2005 Feb;59(2):160-6.
The effects of hepatic impairment on the pharmacokinetics of fosfluconazole and fluconazole following a single intravenous bolus injection of fosfluconazole.
Sobue S, Tan K, Haug-Pihale G.
Clinical Pharmacology, Pfizer Global R&D, Tokyo Laboratories, Pfizer Japan Inc., Tokyo, Japan. satoshi.sobue@japan.pfizer.com

AIMS: Fosfluconazole is a phosphate pro-drug of fluconazole (FLCZ). This study was conducted to determine the pharmacokinetics of fosfluconazole and FLCZ following a single intravenous injection of fosfluconazole in subjects with hepatic impairment and to compare them with healthy subjects. METHODS: Twenty-four subjects (12 with normal hepatic function and 12 with chronic stable mild to moderate impaired hepatic function) received a single 1000-mg bolus intravenous injection of fosfluconazole. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 192 h and 48 h postdose, respectively. RESULTS: The total clearance of fosfluconazole was higher and the t(1/2,Z) and mean residence time were shorter in hepatically impaired subjects than in normal subjects. This may reflect more rapid conversion to FLCZ. The degree of protein binding of fosfluconazole (> 90%) and the amount of fosfluconazole excreted in the urine were similar in both groups. Slightly higher mean plasma concentrations of FLCZ were observed in the impaired group than in the normal group; however, hepatic impairment had no statistically significant effect on the FLCZ pharmacokinetic parameters apart from t(max). The t(max) values were 4.8 h and 3.1 h in the normal and impaired subjects, respectively. The shorter t(max) for FLCZ is also consistent with the more rapid conversion in the impaired subjects. The ratios (95% confidence intervals) for C(max) and AUC of FLCZ (impaired/normal) were 106.0% (92.8, 121.2) and 115.6% (86.4, 154.7), respectively. There were no serious adverse events, and no discontinuations due to adverse events or laboratory test abnormalities. The adverse events reported were mostly mild in severity and no trend could be discerned between the groups. CONCLUSIONS: Fosfluconazole was more rapidly converted to FLCZ in the hepatically impaired subjects but the FLCZ pharmacokinetic parameters (except t(max)) were not statistically significantly affected by hepatic impairment. Fosfluconazole was well tolerated by both groups. These results suggest that there is no requirement to adjust the dose of fosfluconazole when administered to subjects with mild to moderate hepatic impairment.

Infect Dis Obstet Gynecol. 2004 Jun;12(2):91-7.
Usage of antifungal drugs for therapy of genital Candida infections, purchased as over-the-counter products or by prescription: I. Analyses of a unique database.
Mardh PA, Wagstrom J, Landgren M, Holmen J.
Department of Obstetrics and Gynaecology, University Hospital, Lund, Sweden. per-anders.mardh@gyn.lu.se

OBJECTIVES: To present sales figures of antifungal drugs for treatment of genital Candida infections in females, which had been purchased in the Swedish county of Skane (with approximately 1.2 million inhabitants) during the 1990s. To study the relative proportions of the drugs sold by prescription and as over-the-counter (OTC) products. METHODS: Sales figures of antifungal drugs for therapy of vulvovaginal candidiasis (VVC) and such recurrent infections (RVVC), for the years 1990--99, were collected from the 'ACS' database of the National Corporation of Swedish Pharmacies. RESULTS: The study showed an increase in sales of the type of drugs studied from 45,000 packages in 1990 until mid-93/94, when approximately 70,000 packages were sold (mainly azoles for topical use and fluconazole for oral intake). Thereafter there was a decrease until the end of November 1999, when 54,000 packages were purchased. Of the total sales, 93% were OTC products. Sales of clotrimazole and econazole (for vaginal installation) in 1993--1994 were equal to 85-90 packages/1000 women in the age group 15-45 years. Extremely high sales volumes of fluconazole and itraconazole, for one single year each, could be explained by marketing-related activities directed to the medical community. CONCLUSIONS: As many women with RVVC are not cured by iatrogenic initiatives and women consider themselves able to diagnose episodes of genital Candida infection, affected women generally turn to self-medication with antifungal OTC products. This stresses the role of pharmacy counseling. Short-term marked alterations in sales volumes may be due to marketing factors rather than changes in the epidemiology of genital Candida infections.