Diflucan
In vitro activities of voriconazole, fluconazole, and itraconazole against 566 clinical isolates of Cryptococcus neoformans from the United States and Africa.

Pfaller MA, Zhang J, Messer SA, Brandt ME, Hajjeh RA, Jessup CJ, Tumberland M, Mbidde EK, Ghannoum MA.

Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA. mpfaller blue.weeg.uiowa.edu

We investigated the in vitro activity of voriconazole compared to those of fluconazole and itraconazole against 566 clinical isolates of Cryptococcus neoformans from Africa (164) and the United States (402). Isolates were obtained from cerebrospinal fluid (362), blood (139), and miscellaneous sites (65). Voriconazole (MIC at which 90% of the isolates are inhibited [MIC90], 0.12 to 0.25 microg/ml) was more active than either itraconazole (MIC90, 0.5 microg/ml) or fluconazole (MIC90, 8.0 to 16 microg/ml) against both African and U. S. isolates. Isolates inhibited by >/=16 microg of fluconazole per ml were almost all (99%) inhibited by </=1 microg of voriconazole per ml. These results suggest that voriconazole may be useful in the treatment of cryptococcosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9869586&dopt=Abstract fluconazole Diflucan



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Pharmacokinetics of intraperitoneal fluconazole during continuous cycling peritoneal dialysis.

Dahl NV, Foote EF, Searson KM, Fein JL, Kapoian T, Steward CA, Sherman RA.

College of Pharmacy, Rutgers, State University of New Jersey, Piscataway 09954, USA.

OBJECTIVE: To investigate the pharmacokinetic characteristics of intraperitoneal fluconazole in patients undergoing continuous cycling peritoneal dialysis (CCPD). DESIGN: Prospective, nonrandomized, single-dose, open-label study. PARTICIPANTS: Five noninfected volunteer CCPD patients. INTERVENTIONS: Patients received a single dose of intraperitoneal fluconazole 200 mg during their long daytime dwell. Blood samples were collected before and 1, 3, 6, 12 (end of first dwell), 24 (after overnight cycling), 48, 72, 96, and 120 hours after dosing. Used dialysate was collected throughout the study. Unless the patient was anuric, urine was collected for the first 48 hours. MAIN OUTCOME MEASURE: Fluconazole concentrations were assayed by gas-liquid chromatography. Pharmacokinetic parameters were calculated using standard noncompartmental techniques. RESULTS: The bioavailability of intraperitoneal fluconazole was 96% +/- 2% over a 12-hour dwell, absorption half-life was 2.5 +/- 1.2 hours, serum elimination half-life was 71.65 +/- 12.76 hours, and volume of distribution was 0.66 +/- 0.13 L/kg. Peritoneal clearance was 5.96 +/- 0.93 mL/min and proportional to total dialysate volume. Renal clearance was proportional to renal creatinine clearance. CONCLUSIONS: Current treatment guidelines for fungal peritonitis suggest fluconazole 200 mg intraperitoneally every 24 hours. Our data suggest that this dose, administered every 48 hours, is more than sufficient to maintain serum and peritoneal concentrations above the minimum inhibitory concentration for most Candida spp. Other factors, such as residual renal function and dialysis prescription, may also need to be considered.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9876807&dopt=Abstract fluconazole Diflucan



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Molecular epidemiology and antifungal susceptibility of Cryptococcus neoformans isolates from Ugandan AIDS patients.

Pfaller M, Zhang J, Messer S, Tumberland M, Mbidde E, Jessup C, Ghannoum M.

Department of Pathology, University of Iowa College of Medicine, Iowa City 52242, USA.

Little is known of the antifungal susceptibility patterns and molecular epidemiology of Cryptococcus neoformans from tropical regions. We studied 164 clinical isolates of C. neofomans from 120 Ugandan AIDS patients with cryptococcal meningitis by analyzing their electrophoretic karyotypes and antifungal susceptibility profiles. Computer-assisted analysis of karyotype patterns was performed to generate dendrograms. MICs of fluconazole and flucytosine were determined by reference methods. A total of 43 distinguishable DNA types were identified among the 164 isolates. Only 30 patients (25%) were infected with their own unique strain of c. neoformans, whereas 75% of the patients shared their infecting strain with at least one other patient. Among 17 patients with more than one CSF isolate of C. neoformans, sequential isolates were identical or highly related in 12 (71%) and were different in five patients (29%). The isolates were susceptible to both fluconazole and flucytosine and there were no instances in which a stepwise increase in either fluconazole or flucytosine MICs was observed among serial isolates. These findings suggest that the epidemiology of cryptococcal disease in AIDS patients from tropical regions may be somewhat different from that observed in more temperate climates.

PIP: Even though Cryptococcus neoformans var. neoformans is a leading cause of life-threatening mycotic infection among AIDS patients worldwide, little is known about its antifungal susceptibility patterns and molecular epidemiology in tropical regions. The authors studied 164 clinical isolates of C. neoformans from 120 Ugandan AIDS patients with cryptococcal meningitis by analyzing their electrophoretic karyotypes and antifungal susceptibility profiles. Computer-assisted analysis of karyotype patterns was performed to generate dendrograms, while the MICs of fluconazole and flucytosine were determined using reference methods. 43 distinguishable C. neoformans DNA types were identified among the 164 isolates. 30 patients (25%) were infected with their own unique strain of C. neoformans, while 75% of the patients shared their infecting strain with at least 1 other patient. Among 17 patients with more than 1 cerebrospinal fluid isolate of C. neoformans, sequential isolates were identical or highly related in 12 (71%) and were different in 5 patients (29%). The isolates were susceptible to both fluconazole and flucytosine, and there was no instance in which a stepwise increase in either fluconazole or flucytosine MICs was observed among serial isolates. These findings suggest that the epidemiology of cryptococcal disease in AIDS patients from tropical regions may be somewhat different from that observed in more temperate climates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9884835&dopt=Abstract fluconazole Diflucan



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In vitro interaction of fluconazole and amphotericin B administered sequentially against Candida albicans: effect of concentration and exposure time.

Ernst EJ, Klepser ME, Pfaller MA.

College of Pharmacy, University of Iowa, Iowa City 52242, USA.

This study investigated the potential antagonism of fluconazole on amphotericin B activity against Candida albicans when administered sequentially in vitro. Yeast cells were exposed to fluconazole for time periods ranging from 0 to 24 h before the addition of amphotericin B. The combination showed fungicidal (> or = 3 log 10 reduction in CFU/mL) activity. After 4 h of exposure to fluconazole, amphotericin B activity was partially inhibited at the lower concentration tested (0.25 x MIC). Amphotericin B activity was dramatically decreased by previous exposure to fluconazole for greater than or equal to 8 h at both the high and low concentrations tested. The activity of amphotericin B against yeast exposed to fluconazole for at least 8 h was indistinguishable from fluconazole alone and was fungistatic (< or = 2 log 10 reduction in CFU/mL). This inhibition of amphotericin B activity persisted for a very short period (< 6 h) after removal of fluconazole from the culture medium, indicating the need for continued exposure to fluconazole for lasting inhibition of amphotericin B activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9884837&dopt=Abstract fluconazole Diflucan



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Inhibition of cytochrome P-450 3A (CYP3A) in human intestinal and liver microsomes: comparison of Ki values and impact of CYP3A5 expression.

Gibbs MA, Thummel KE, Shen DD, Kunze KL.

Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195-7610, USA.

The purpose of this study was to compare the kinetics of intestinal and hepatic cytochrome P-450 3A (CYP3A) inhibition by using microsomal midazolam 1'-hydroxylation as a marker of enzyme activity. The effect of two antifungal agents commonly implicated in CYP3A drug-drug interactions was examined. Inhibition type and affinities were determined for human liver and intestinal microsomes screened for the presence or absence of CYP3A4 and CYP3A5, as well as for cDNA-expressed CYP3A4 and CYP3A5 microsomes. Ketoconazole and fluconazole were found to be noncompetitive inhibitors of both enzymes. Ketoconazole exhibited a Ki for cDNA-expressed CYP3A4 of 26. 7 +/- 1.71 nM, whereas the Ki for cDNA expressed CYP3A5 was 109 +/- 19.7 nM. Corresponding Ki values for fluconazole were 9.21 +/- 0.51 microM and 84.6 +/- 12.9 microM. For liver and intestinal microsomes that contained only CYP3A4, the average ketoconazole Ki was found to be 14.9 +/- 6.7 nM and 17.0 +/- 7.9 nM, respectively, whereas fluconazole yielded mean respective Ki values of 10.7 +/- 4.2 microM and 10.4 +/- 2.9 microM. Liver and intestinal microsomes that contained an equal or greater amount of CYP3A5, in addition to CYP3A4, were less susceptible to inhibition by both ketoconazole and fluconazole. These findings suggest that there can be significant differences in the affinity of these two enzymes for inhibitors. This may further broaden interindividual variability with respect to the magnitude of in vivo drug-drug interactions. We also conclude that there is no significant difference in inhibition type and affinity of ketoconazole and fluconazole for hepatic versus intestinal CYP3A4.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9929500&dopt=Abstract fluconazole Diflucan



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[Pediatric onychomycosis treated with oral antifungal drugs]

[Article in Japanese]

Maeng DJ, Hiruma M, Takimoto R, Kawai M, Ogawa H.

Department of Dermatology, Juntendo University School of Medicine 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421.

Pediatric onychomycosis is a rare disease and it is difficult to decide in such cases whether or not an oral antifungal is indicated. We have observed 6 pediatric cases with onychomycosis who were treated with fluconazole or itraconazole: four male and two female patients, ranging in age from three to 14 years. One patient suffered infection in the fingernails and toenails. The etiologic organism was identified as Trichophyton rubrum. The treatment regimen consisted of systemically administering fluconazole to four of the patients and itraconazole to the other two. Treatment resulted in three of the 4 patients treated with fluconazole, and one of the 2 treated with itraconazole being healed completely. The other two patients treated with fluconazole and itraconazole showed an alleviation of symptoms. Further results of our study were that while younger patients respond quickly and positively to treatment, long-term follow-up is necessary even after treatment ceases due to the easy recurrence of this condition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9929579&dopt=Abstract fluconazole Diflucan



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Timing and necessity of endoscopy in AIDS patients with dysphagia or odynophagia.

Lai YP, Wu MS, Chen MY, Chuang CY, Shun CT, Lin JT.

Department of Internal Medicine, National Taiwan University, Taipei.

BACKGROUND/AIMS: Dysphagia and odynophagia are common problems with significant morbidity in acquired immunodeficiency syndrome (AIDS) patients. Endoscopy in AIDS patients with esophageal symptoms is valuable for diagnosis, but the timing and necessity of routine endoscopy remains controversial. METHODOLOGY: We retrospectively studied 40 AIDS patients undergoing upper gastrointestinal endoscopy. Among them, 25 patients were enroled with dysphagia and/or odynophagia and were put on empirical fluconazole treatment before endoscopic evaluation. RESULTS: Fourteen (56%) of 25 patients improved after fluconazole treatment, while 11 patients had persistent symptoms. Among the 14 patients with symptomatic improvement, 7 were found to have esophageal candidiasis which improved after continuation of fluconazole for 1-2 more weeks. The other 7 patients had a normal endoscopic appearance. In contrast, among 11 patients with persistent symptoms, there were 3 patients with azole-resistant candidiasis, 3 with cytomegalovirus esophagitis, 1 with herpes simplex virus esophagitis with candidiasis, 1 with Kaposi's sarcoma, and 3 with idiopathic esophageal ulcer. They were successfully treated with Amphotericin B, Ganciclovir, Acyclovior, and oral steroids, except for the patient with Kaposi's sarcoma. CONCLUSIONS: Routine endoscopy may not necessarily be indicated in every AIDS patient with dysphagia or odynophagia. Empirical fluconazole treatment can improve symptoms in 50% of patients. It is only indicated when patients have persistent symptoms after empirical treatment. With endoscopic examination, etiologic agents other than common candidiasis can be determined and the patients can thus be put on specific treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9951891&dopt=Abstract fluconazole Diflucan



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In vitro susceptibilities of Candida dubliniensis isolates tested against the new triazole and echinocandin antifungal agents.

Pfaller MA, Messer SA, Gee S, Joly S, Pujol C, Sullivan DJ, Coleman DC, Soll DR.

Departments of Pathology, University of Iowa, Iowa City, Iowa, USA. michael-pfaller uiowa.edu

Candida dubliniensis is a newly recognized fungal pathogen causing mucosal disease in AIDS patients. Although preliminary studies indicate that most strains of C. dubliniensis are susceptible to established antifungal agents, fluconazole-resistant strains have been detected. Furthermore, fluconazole-resistant strains are easily derived in vitro, and these strains exhibit increased expression of multidrug resistance transporters, especially MDR1. Because of the potential for the development of resistant strains of C. dubliniensis, it is prudent to explore the in vitro activities of several of the newer triazole and echinocandin antifungals against isolates of C. dubliniensis. In this study we tested 71 isolates of C. dubliniensis against the triazoles BMS-207147, Sch 56592, and voriconazole and a representative of the echinocandin class of antifungal agents, MK-0991. We compared the activities of these agents with those of the established antifungal agents fluconazole, itraconazole, amphotericin B, and 5-fluorocytosine (5FC) by using National Committee for Clinical Laboratory Standards microdilution reference methods. Our findings indicate that the vast majority of clinical isolates of C. dubliniensis are highly susceptible to both new and established antifungal agents. Strains with decreased susceptibilities to fluconazole remained susceptible to the investigational agents as well as to amphotericin B and 5FC. The increased potencies of the new triazole and echinocandin antifungal agents may provide effective therapeutic options for the treatment of infections due to C. dubliniensis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9986880&dopt=Abstract fluconazole Diflucan