SPORANOX
(generic name: intraconazole)

Itraconazole is the generic name of the antifungal medication Sporanox, which belongs to the triazole drug class. It is used in the treatment of various kinds of fungal infections of the nails, blood and lungs. The four major conditions which the drug treats are histoplasmosis, aspergillosis, blastomycosis and onychomycosis. The latter, a fungal nail infection is the most common reason for prescribing Sporanox. The way it kills the infection is by going into the bloodstream and traveling to the site of the infection where it inhibits the production of the molecule of ergosterol, responsible for the fungal infection. Side effects are observed only with long term use of the medication and include hair loss, dizziness, indigestion, abdominal pain.

Diagn Microbiol Infect Dis. 2005 May;52(1):15-20.
Increased frequency of non-fumigatus Aspergillus species in amphotericin B- or triazole-pre-exposed cancer patients with positive cultures for aspergilli.
Lionakis MS, Lewis RE, Torres HA, Albert ND, Raad II, Kontoyiannis DP.
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Invasive aspergillosis (IA) can occur despite prior prophylactic or empiric use of triazoles or amphotericin B (AMB). Although profound immunosuppression may account for breakthrough IA, resistance of Aspergillus to antifungals may also play a role. To examine this question, we measured the minimal inhibitory concentration of 105 Aspergillus isolates recovered from 105 cancer patients (64 with IA, 41 with Aspergillus colonization) to AMB, itraconazole (ITC), and voriconazole (VRC) using the National Committee for Clinical Laboratory Standards (NCCLS) M38-A microdilution and E-test methods. We also determined the minimal fungicidal concentration (MFC) of these agents and the minimal effective concentration (MEC) of caspofungin (CAS) using standardized methods. We then collected information regarding pre-exposure to AMB or triazoles (fluconazole, ITC, VRC) within 3 months before Aspergillus isolation. Pre-exposure of cancer patients to AMB or triazoles was associated with increased frequency of non-fumigatus Aspergillus species. Aspergillus isolates recovered from patients who previously received AMB exhibited higher E-test AMB MICs compared with isolates from patients without prior AMB exposure (P = 0.01). In addition, the AMB MICs by E-test were higher in triazole-pre-exposed patients compared with those not exposed to triazoles (P = 0.001). The ITC and VRC MICs by E-test were not affected by prior AMB or triazole exposure. Finally, neither the AMB, ITC, and VRC MICs and MFCs by NCCLS method nor CAS MECs showed such changes. In conclusion, cancer patients with positive Aspergillus cultures who are pre-exposed to AMB or triazoles have high frequency of non-fumigatus Aspergillus species. These Aspergillus isolates were found to be AMB-resistant by the more sensitive E-test method.

Indian J Ophthalmol. 2001 Sep;49(3):173-6.
Efficacy of topical and systemic itraconazole as a broad-spectrum antifungal agent in mycotic corneal ulcer. A preliminary study.
Agarwal PK, Roy P, Das A, Banerjee A, Maity PK, Banerjee AR.
Regional Institute of Ophthalmology, Medical College, Calcutta, India. pankaj_eye@yahoo.com

PURPOSE: To evaluate the efficacy of topical (1%) and systemic itraconazole against common fungi such as Aspergillus and other filamentous fungi that cause mycotic corneal ulcer. METHODS: A prospective randomised, controlled study was done in 54 clinically suspected cases of fungal keratitis of which 44 were culture proven. Half the cases (n=27) with superficial involvement were treated with only topical itraconazole (1%) and the other half were treated with both topical and systemic itraconazole. RESULTS: Aspergillus, Penicillium and Fusarium were the most common fungi isolated. The ulcer resolved in 42 eyes (77%) and 12 eyes (23%) did not respond well to treatment. Four of 12 non-responding eyes were caused by Fusarium species. CONCLUSION: Itraconazole, given either topically or systemically, is effective in treating mycotic corneal ulcers.

J Clin Pharm Ther. 2005 Jun;30(3):201-6.
Reduced oral itraconazole bioavailability by antacid suspension.
Lohitnavy M, Lohitnavy O, Thangkeattiyanon O, Srichai W.
Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand.

Summary Aims: To investigate the effects of antacid suspension on oral absorption of itraconazole. Methods: A randomized, open-labelled, two-period, crossover study with a 1-week washout period was conducted in 12 healthy Thai male volunteers. The participants were allocated in either treatment A or B in the first period. In treatment A, the volunteers were orally administered with 200 mg of itraconazole alone. In treatment B, the volunteers were administered orally with 200 mg of itraconazole co-administered with antacid suspension. Serial serum samples were collected over the period of 24 h and subsequently analysed by using a validated high-pressure liquid chromatographic method with ultraviolet detection. Pharmacokinetic parameters were determined by non-compartmental analysis. Results: Time to reach maximal concentration (T(max)), maximal concentration (C(max)) and area under the curve (AUC(0--infinity)) were markedly decreased in antacid-treated group. T(max) for treatment A was 3.0 +/- 0.4 and 5.1 +/- 2.7 h for treatment B. C(max) and AUC(0--infinity) of treatments A and B were 146.3 +/- 70.5 vs. 43.6 +/- 16.9 (ng/mL) and 1928.5 +/- 1114.6 vs. 654.8 +/- 452.2 (ng.h/mL) respectively. 90% Confidence interval (90% CI) of C(max) and AUC(0--infinity) were 24.1-42.1 and 16.2-65.9 respectively. Conclusions: Rate and extent of itraconazole oral absorption were markedly decreased by concurrent use of antacid suspension. Hence, co-administration of itraconazole and antacid suspension should be avoided.

Med Mycol. 2005 Feb;43(1):91-5.
Successful therapy of cerebral phaeohyphomycosis due to Ramichloridium mackenziei with the new triazole posaconazole.
Al-Abdely M, Alkhunaizi AM, Al-Tawfiq JA, Hassounah M, Rinaldi MG, Sutton DA.
Section of Infectious Diseases, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. abdely@kfshrc.edu.sa

Cerebral phaeohyphomycosis caused by Ramichloridium mackenziei is universally fatal. All reported cases with long-term follow-up have indicated 100% mortality despite antifungal therapy and surgical intervention. We describe the case of a 62-year-old patient who underwent renal transplantation and had a cerebral abscess caused by R. mackenziei. The infection progressed despite surgical evacuation and therapy with liposomal amphotericin B, itraconazole, and 5-flucytosine. The patient was subsequently treated with the investigational triazole posaconazole oral suspension, 800 mg/day, in divided doses. Treatment with posaconazole resulted in progressive clinical and radiologic improvement. The patient is alive four years after diagnosis and maintained on posaconazole therapy. This case supports the potential role of this extended-spectrum azole in the treatment of this serious fungal infection of the central nervous system.

Int J Clin Pharmacol Ther. 2005 Feb;43(2):109-16.
Simultaneous itraconazole bioequivalence assessment and CYP3A phenotyping in South American subjects.
Estevez-Carrizo FE, Ruiz S, Bellocq B, Leal C, Siri MT, del Campo MJ.
Center for Biomedical Sciences, University of Montevideo, Montevideo, Uruguay. festeve2@adinet.com.uy

OBJECTIVE: The present study evaluates the acute effect of a single-dose itraconazole administration on CYP3A phenotype, as measured by cortisol MR ratio in urine. METHODS: Twenty-four healthy Uruguayan subjects recruited according to strict inclusion criteria participated in an open-label, randomized, two-period, crossover study designed to evaluate the bioequivalence of an itraconazole formulation (Traconal 100 mg, Ache Labs, Sao Paulo, Brazil). The study comprised two treatment periods separated by a wash-out period of 14 days. In each period a series of venous blood samples were drawn over 48 hours. Three urine samples were obtained for CYP3A phenotyping: pre-dose, 24 and 48 hours after dosing. Blood and urine samples were assayed for itraconazole, beta-hydroxycortisol and cortisol using a validated chromatographic method. RESULTS: The ratio of the mean AUC0-inf. T/AUC0-inf. R was included in the bioequivalence range, however, due to high variability, the CI90% was not. It was found that the cortisol metabolic ratio (MR) showed inhibition relative to basal activity in a proportion of subjects 24 hours (68 +/- 6.1%, mean +/- CI95%) and 48 hours (80 +/- 7.3%, mean +/- CI95%) after ingestion of itraconazole. A significant correlation was found between itraconazole AUC0-inf. and normalized basal CYP3A MR for the reference (r = 0.62, t = 3.72, p = 0.001) and the test product (r = 0.74, t = 5.22, p = 0.00003). A good correlation existed between basal cortisol MR and the elimination half-life of itraconazole. CONCLUSIONS: The findings are in line with the hypothesis that the determination of the bioavailability of highly variable CYP3A substrates might be improved by simultaneous non-interfering phenotyping. If this is confirmed, a new methodological paradigm may need to be developed in order to take account of metabolic variability in bioequivalence evaluation of this group of drugs.

Eur J Cancer. 2005 Mar;41(4):647-54. Epub 2005 Jan 18.
The soy isoflavone daidzein improves the capacity of tamoxifen to prevent mammary tumours.
Constantinou AI, White BE, Tonetti D, Yang Y, Liang W, Li W, van Breemen RB.
Department of Surgical Oncology, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612, USA.

The aim of this study was to determine how the efficacy of tamoxifen is affected when combined with soy isoflavones. To address this, female Sprague-Dawley rats were placed on diets supplemented with tamoxifen, genistein, daidzein, or a combination of each isoflavone with tamoxifen; a week later mammary tumours were induced by 7,12 dimethylbenzanthracene. The most effective diet was the tamoxifen/daidzein combination. It reduced tumour multiplicity by 76%, tumour incidence by 35%, tumour burden by over 95%, and increased tumour latency by 62% compared with positive controls. The tamoxifen/daidzein combination diet was in all aspects more effective while the tamoxifen/genistein combination was less effective than the tamoxifen diet. The tamoxifen/daidzein diet significantly decreased 8-oxo-deoxyguanosine levels (an indicator of oxidative DNA damage) in the mammary glands. This study conclusively shows for the first time the combination of daidzein with tamoxifen produces increased protection against mammary carcinogenesis, while the combination of genistein with tamoxifen produces an opposing effect when compared with tamoxifen alone.

Antimicrob Agents Chemother. 2004 Sep;48(9):3279-83.
In vitro activity of caspofungin combined with sulfamethoxazole against clinical isolates of Aspergillus spp.
Yekutiel A, Shalit I, Shadkchan Y, Osherov N.
Department of Human Microbiology, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv 69978, Tel-Aviv, Israel.
Caspofungin (CAS) inhibits fungal cell wall synthesis. Sulfamethoxazole (SMX) inhibits folate biosynthesis and is active in vitro against Aspergillus spp. We studied the activities of the combination of CAS and SMX against 31 Aspergillus isolates and compared them with that of SMX combined with amphotericin B (AMB) or itraconazole (ITC). MICs and minimal effective concentrations (MECs) were determined by the NCCLS broth microdilution method. With MIC endpoints, the combination of SMX and CAS showed synergy or synergy to additivity against 29 of 31 isolates. With MEC endpoints, synergy to additivity was found against 12 of 31 isolates and indifference was displayed against the rest of them. SMX in combination with AMB or ITC was not truly synergistic, while synergy to additivity was found for SMX-AMB and SMX-ITC against 17 of 31 and 3 of 12 isolates, respectively. No antagonism was found with any of the drug combinations. Further analysis of the synergy of CAS and SMX was performed by detailed measurement of hyphal length by microscopy and time-dependent 2,3-bis(2-methoxy-4-nitro-5-[(sulfenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT)-based hyphal damage experiments. With MEC endpoints, the combination of CAS and SMX was characterized by a greater than 50% decrease in hyphal length compared to the hyphal lengths achieved with double the concentration of each drug alone. The XTT-based hyphal damage studies showed a statistically significant (P < 0.05) reduction in viability with CAS and SMX in combination compared to the viabilities achieved with double the concentration of each drug alone. These findings support the synergy results found by using MIC endpoints and suggest that visual MEC measurements may not be sufficient to identify the synergistic interactions seen by more sensitive, quantitative methods. Animal models are required to validate the significance of the synergy of CAS and SMX against Aspergillus spp. observed in vitro.

Antimicrob Agents Chemother. 2004 Sep;48(9):3272-8.
The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp., and Microsporum canis.
Vanden Bossche H, Ausma J, Bohets H, Vermuyten K, Willemsens G, Marichal P, Meerpoel L, Odds F, Borgers M.
Johnson and Johnson Pharmaceutical Research and Development, a Division of Janssen Pharmaceutica, Beerse, Belgium.
R126638 is a novel triazole with in vitro activity similar to that of itraconazole against dermatophytes, Candida spp., and Malassezia spp. In animal models of dermatophyte infections, R126638 showed superior antifungal activity. R126638 inhibits ergosterol synthesis in Candida albicans, Trichophyton mentagrophytes, Trichophyton rubrum, and Microsporum canis at nanomolar concentrations, with 50% inhibitory concentrations (IC(50)s) similar to those of itraconazole. The decreased synthesis of ergosterol and the concomitant accumulation of 14 alpha-methylsterols provide indirect evidence that R126638 inhibits the activity of CYP51 that catalyzes the oxidative removal of the 14 alpha-methyl group of lanosterol or eburicol. The IC(50)s for cholesterol synthesis from acetate in human hepatoma cells were 1.4 microM for itraconazole and 3.1 microM for R126638. Compared to itraconazole (IC(50) = 3.5 microM), R126638 is a poor inhibitor of the 1 alpha-hydroxylation of 25-hydroxyvitamin D(3) (IC(50) > 10 microM). Micromolar concentrations of R126638 and itraconazole inhibited the 24-hydroxylation of 25-hydroxyvitamin D(3) and the conversion of 1,25-dihydroxyvitamin D(3) into polar metabolites. At concentrations up to 10 microM, R126638 had almost no effect on cholesterol side chain cleavage (CYP11A1), 11 beta-hydroxylase (CYP11B1), 17-hydroxylase and 17,20-lyase (CYP17), aromatase (CYP19), or 4-hydroxylation of all-trans retinoic acid (CYP26). At 10 microM, R126638 did not show clear inhibition of CYP1A2, CYP2A6, CYP2D6, CYP2C8, CYP2C9, CYP2C10, CYP2C19, or CYP2E1. Compared to itraconazole, R126638 had a lower interaction potential with testosterone 6 beta hydroxylation and cyclosporine hydroxylation, both of which are catalyzed by CYP3A4, whereas both antifungals inhibited the CYP3A4-catalyzed hydroxylation of midazolam similarly. The results suggest that R126638 has promising properties and merits further in vivo investigations for the treatment of dermatophyte and yeast infections.

Antimicrob Agents Chemother. 2004 Aug;48(8):3151-3.
Pharmacokinetics of intravenous itraconazole in stable hemodialysis patients.
Mohr JF, Finkel KW, Rex JH, Rodriguez JR, Leitz GJ, Ostrosky-Zeichner L.
Division of Infectious Diseases and Center for the Study of Emerging and Re-emerging Pathogens, University of Texas Health Science Center, Houston, Texas 77030, USA. john.mohr@uth.tmc.edu
The pharmacokinetics of intravenous itraconazole (ITC) was studied in dialysis patients. Dialysis had no effect on the half-life and clearance of ITC or OH-ITC. However, dialysis allowed the clearance of hydroxypropyl-beta-cyclodextrin (HP-beta-CD). The area under the concentration-time curve from time zero to infinity (AUC(0- infinity)) for HP-beta-CD administered before dialysis was lower than the AUC(0- infinity) when it was administered after dialysis (P < 0.01). Administration of ITC intravenously just prior to hemodialysis appears to produce adequate systemic exposures of ITC and OH-ITC while allowing dialysis clearance of HP-beta-CD. Studies of multiple administrations are warranted.

Antimicrob Agents Chemother. 2004 Aug;48(8):3147-50.
Effect of pH on the in vitro activities of amphotericin B, itraconazole, and flucytosine against Aspergillus isolates.
Te Dorsthorst DT, Mouton JW, van den Beukel CJ, van der Lee HA, Meis JF, Verweij PE.
Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
The in vitro susceptibilities of 21 Aspergillus isolates were tested against three antifungal agents in RPMI 1640 and yeast nitrogen base at pH 5.0 and 7.0 by a broth microdilution format of the NCCLS method. The MICs of amphotericin B and itraconazole were higher, while those of flucytosine were lower, at pH 5.0 than at pH 7.0. The poor correlation between in vitro results and clinical outcome could be due to a difference in pH between the in vitro susceptibility test and at the site of infection.

Clin Pharmacol Ther. 2004 Aug;76(2):104-12.
Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states.
Yu KS, Cho JY, Jang IJ, Hong KS, Chung JY, Kim JR, Lim HS, Oh DS, Yi SY, Liu KH, Shin JG, Shin SG.
Department of Pharmacology and Clinical Pharmacology Unit, Seoul National University College of Medicine and Hospital, Seoul, South Korea.
OBJECTIVE: Our objective was to investigate the effect of the CYP3A5 genotype on the systemic clearance of midazolam in constitutive, inhibited, and induced metabolic conditions. METHODS: Nineteen healthy volunteers were grouped with regard to the CYP3A5*3 allele, into homozygous wild-type (CYP3A5*1/*1, n = 6), heterozygous (CYP3A5*1/*3, n = 6), and homozygous variant-type (CYP3A5*3/*3, n = 7) subject groups. The pharmacokinetic profile of intravenous midazolam was characterized before and after itraconazole administration (200 mg once daily for 4 days) and also after rifampin (INN, rifampicin) pretreatment (600 mg once daily for 10 days), with a washout period of 2 weeks in between. RESULTS: The pharmacokinetic profiles of midazolam and of its hydroxy metabolites did not show differences between the genotype groups under basal and induced metabolic conditions. However, during the inhibited metabolic state, the CYP3A5*3/*3 group showed a greater decrease in systemic clearance than was seen in the CYP3A5*1/*1 group (8.5 +/- 3.8 L. h(-1). 70 kg(-1) versus 13.5 +/- 2.7 L. h(-1). 70 kg(-1), P =.027). The 1'-hydroxymidazolam-to-midazolam area under the plasma concentration-time curve ratio was also significantly lower in the CYP3A5*3/*3 group (0.58 +/- 0.35 versus 1.09 +/- 0.37 for the homozygous wild-type group, P =.026). CONCLUSIONS: The CYP3A5 genotype did not affect the pharmacokinetics of intravenous midazolam in the basal or induced states. However, during cytochrome P450 (CYP) 3A inhibition by itraconazole, individuals carrying the CYP3A5*1 allele were found to be less susceptible to changes in systemic clearance and showed higher 1'-hydroxymidazolam-to-midazolam area under the plasma concentration-time curve ratios, probably resulting from the relatively CYP3A4-specific inhibition caused by itraconazole.

Infection. 2004 Aug;32(4):239-41.
Chronic necrotizing pulmonary aspergillosis complicated by pneumothorax.
Thurnheer R, Moll C, Rothlin M, Krause M.
Division of Pulmonary Medicine, Dept. of Internal Medicine, Kantonsspital, CH-8596 Munsterlingen, Switzerland. robert.thurnheer@stgag.ch
A 61-year-old man presented with left-sided pneumothorax. On the chest computed tomograghy (CT), severe bilateral emphysema and left-sided pleural thickening were seen. His pneumothorax was drained with a chest tube. Because of a persistent air leakage, video-thoracoscopic wedge-resection of the suspected fistula and muscle-sparing minithoracotomy with extensive wedge resections of the left upper lobe were performed. Biopsy specimens showed micronodular mycetomas with septate hyphae highly suggestive of Aspergillus. The fungus destructed the lung tissue without vessel invasion. The patient had not been taking immunosuppressant drugs and had no prior opportunistic infections. Itraconazole was begun, the lung was expanded and the patient recovered. We propose that extensive resection of affected lung tissue in combination with long-term antifungal therapy with itraconazole is a valuable therapeutic option in patients with a complicated course of chronic necrotizing pulmonary aspergillosis (CNPA).

J Feline Med Surg. 2004 Aug;6(4):271-7.
Concurrent Fusarium chlamydosporum and Microsphaeropsis arundinis infections in a cat.
Kluger EK, Della Torre PK, Martin P, Krockenberger MB, Malik R.
Kirrawee Veterinary Hospital, 540 Princes Highway, Kirrawee, NSW 2232, Australia. ekluger@optusnet.com.au
A 7-year-old cat was presented initially with multiple draining sinuses on the metatarsal region of its right hindlimb. Another lesion had appeared at the same time on the fifth proximal interphalangeal joint of the left forelimb. Histopathological examination of a biopsy from the right hindlimb lesion revealed chronic pyogranulomatous inflammation associated with yeast-like bodies and septate mycelia; a fungus was cultured on conventional media but not identified further. Culture of a swab collected from the left forelimb lesion demonstrated a pigmented fungus, also not characterised further. Although there was initially a favourable response to ketoconazole (Nizoral, Janssen-Cilag Pty. Ltd) and beta-lactam therapy, the infection in the hind limb relapsed subsequently, and Fusarium chlamydosporum was cultured from deep biopsy specimens. Clinical improvement followed debridement and itraconazole (Sporanox, Janssen-Cilag Pty. Ltd; 100 mg orally once daily), however amputation of the limb represented the best chance for a cure. The cat made an uncomplicated recovery following surgery and remained well for five months until the lesion on the left forelimb recurred. Amputation of the distal fourth digit was then performed, and the resected tissue submitted for culture. The dematiaceous fungus Microsphaeropsis arundinis was subsequently cultured. The cat remained well for several months, until a further F. chlamydosporum infection developed on the body wall. This was excised 7 months ago, and no lesions have recurred in this area. Importantly, this is the first reported case of M. arundinis infection in a mammalian host.

Antimicrob Agents Chemother. 2004 Jul;48(7):2742-6.
In vitro susceptibilities of Madurella mycetomatis to itraconazole and amphotericin B assessed by a modified NCCLS method and a viability-based 2,3-Bis(2-methoxy-4-nitro-5- sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) assay.
Ahmed AO, van de Sande WW, van Vianen W, van Belkum A, Fahal AH, Verbrugh HA, Bakker-Woudenberg IA.
Mycetoma Research Group, Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
Susceptibilities of Madurella mycetomatis against amphotericin B and itraconazole in vitro were determined by protocols based on NCCLS guidelines (visual reading) and a 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) assay for fungal viability. The XTT assay was reproducible and sensitive for both antifungals. Itraconazole (MIC at which 50% of the isolates tested are inhibited [MIC(50)]) of 0.06 to 0.13 mg/liter) was superior to amphotericin B (MIC(50) of 0.5 to 1.0 mg/liter).

J Eur Acad Dermatol Venereol. 2004 Jul;18(4):445-9.
Treatment of head and neck dermatitis comparing itraconazole 200 mg and 400 mg daily for 1 week with placebo.
Svejgaard E, Larsen PØ, Deleuran M, Ternowitz T, Roed-Petersen J, Nilsson J.
Department of Dermatology, University Hospital of Copenhagen, Copenhagen, Denmark. else.svejgaard@get2net.dk
BACKGROUND: Head and neck dermatitis (HND) is a variant of atopic dermatitis often seen in young adults. A hypersensitivity to Malassezi antigens is considered to be of pathogenic importance. Previous mostly uncontrolled studies have shown that oral antimycotics might be of use in this condition. OBJECTIVE: To evaluate the efficacy of itraconazole in the treatment of HND in a randomized, double-blind, placebo-controlled trial. PATIENTS: Adult patients with HND were included. Systemic steroids and oral/topical antimycotics were avoided 1 and 2 months prior to the trial. Topical steroids were not allowed in the head and neck area within 2 weeks. Patients in generally good health were included and female patients had to have had a negative urine pregnancy test. The patients signed an informed consent. STUDY DESIGN: The study included a 7-day treatment period and a follow-up period of 105 days. Control visits were carried out on days 3, 7 and 14 and after 15 weeks. METHODS: The SCORAD index (one for the head and neck area and one for the remaining surface area) and global evaluations by patient and investigator were used for clinical evaluation at each visit. Prick tests with Malassezia antigens and Candida albicans antigen were carried out at the start of the trial and included positive and negative controls. The patients were randomized into three groups, which were treated with 400 mg itraconazole daily, 200 mg itraconazole daily or placebo, respectively, for 7 days. RESULTS: The number of patients included was 53: 18 had 200 mg itraconazole daily, 17 had 400 mg itraconazole daily and 18 placebo. At days 7 and 14, significant improvement was seen in the SCORAD of the head and neck area for the groups given 400 mg itraconazole daily (P = 0.0385 and P = 0.0134), and 200 mg daily (P = 0.0104 and P = 0.0006). Patients in the placebo group improved slightly (P = 0.0785). At day 14, comparison of improvement of SCORAD of the head and neck area between all three groups showed a significant difference in favour of the 200 mg itraconazole group compared to the placebo group (P = 0.0318). The prick test was positive for Pityrosporum ovale in 37% and negative for C. albicans in all patients. CONCLUSIONS: One week of treatment with 200 or 400 mg itraconazole as a single treatment has a significant effect on the head and neck area. Compared to placebo there was a significant improvement in SCORAD of the head and neck area in favour of the 200 mg itraconazole group after 14 days. The important observation seems to be that antifungal systemic treatment has a significant SCORAD reduction of atopic dermatitis, irrespective of the presence of allergy.

Nihon Kokyuki Gakkai Zasshi. 2004 Jul;42(7):629-33.
A case of chronic pulmonary paracoccidioidomycosis
Igarashi T, Kurose T, Itabashi K, Nakano I, Okamoto K, Sano A, Kimura K, Kaji H.
Division of Internal Medicine, Iwamizawa Rosai Hospital 4 jo-east 16 5 Iwamizawa, Hokkaido, 068-0004, Japan.
In a 43-year-old Japanese Brazilian who came to Japan in 2001, since subjective symptoms such as cough, sputum, and dyspnea on exertion had become severe, he was referred to our hospital because of suspicion of pulmonary tuberculosis in chest radiography and CT findings. A chest radiograph of initial examination showed interstitial shadows in both lungs with nodular, infiltrative or cavitary changes. No Mycobacterium tuberculosis was found. The mycetocyte with multipolar budding resembling the steerage of a ship, which was characteristic of Paracoccidioides was observed in sputum and transbronchial lung biopsy specimens. We cultured a fungus to show dimorphism of temperature dependency, and a diagnosis of chronic lung paracoccidioidomycosis was arrived at. By administration of ITCZ 200 mg/day, the chest radiography findings and clinical manifestations were improved. This case seems to be worthy of reporting in Japan since the affected site or organ was limited to the two lungs with multiple cavitary lesions and fibrotic changes on radiographic examination, and final diagnosis was made by cytology of sputum and pathology of TBLB specimens.

Antimicrob Agents Chemother. 2004 Jun;48(6):2007-13.
In vitro interactions between amphotericin B, itraconazole, and flucytosine against 21 clinical Aspergillus isolates determined by two drug interaction models.
Te Dorsthorst DT, Verweij PE, Meis JF, Punt NC, Mouton JW.
Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ Nijmegen, The Netherlands.
Combination therapy of flucytosine (5FC) with other antifungal agents could be of use for the treatment of invasive aspergillosis. However, interpretation of the results of in vitro interactions is problematic. The fractional inhibitory concentration (FIC) index is the most commonly used method, but it has several major drawbacks in characterizing antifungal drug interaction. Alternatively, a response surface approach using the concentration-effect relationship over the whole concentration range instead of just the MIC can be used. We determined the in vitro interactions between amphotericin B (AMB), itraconazole, and 5FC against 21 Aspergillus isolates with a broth microdilution checkerboard method that employs the dye MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide]. FIC indices based on three different MIC endpoints (MIC-0, MIC-1, and MIC-2) and the interaction coefficient alpha were determined, the latter by estimation from the response surface approach described by Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol. Rev. 47:331-385, 1995). The value obtained for the FIC index was found to be dependent on the MIC endpoint used and could be either synergistic, indifferent, or antagonistic. The response surface approach gave more consistent results. Of the three combinations tested, the AMB-5FC combination was the most potent in vitro against Aspergillus spp. We conclude that the use of the response surface approach for the interpretation of in vitro interaction studies of antifungals may be helpful in order to predict the nature and intensity of the drug interaction. However, the correlation of these results with clinical outcome remains difficult and needs to be further investigated.

Aust Dent J. 2004 Jun;49(2):94-7.
Histoplasmosis in Australia: a report of a case with a review of the literature.
O'Sullivan MV, Whitby M, Chahoud C, Miller SM.
Princess Alexandra Hospital, Brisbane, Queensland.
Histoplasmosis is a rare but serious fungal infection commonly presenting as mucosal ulceration of the oral cavity. It is increasingly recognized in Australia but the source of infection remains obscure and it is likely to be under-diagnosed. We report a case of chronic mucosal ulceration which failed to fully respond to periodontal therapy. Histology and culture of a gingival biopsy was consistent with histoplasmosis, and the patient responded favourably to treatment with oral itraconazole. Histoplasmosis may present to general dental practitioners as chronic mucosal ulceration and should be considered in the differential diagnosis of such lesions. Diagnosis is best made by culture and histology of biopsy specimens.

Eur J Cancer. 2004 Jun;40(9):1314-9.
An open multicentre comparative study of the efficacy, safety and tolerance of fluconazole and itraconazole in the treatment of cancer patients with oropharyngeal candidiasis.
Oude Lashof AM, De Bock R, Herbrecht R, de Pauw BE, Krcmery V, Aoun M, Akova M, Cohen J, Siffnerova H, Egyed M, Ellis M, Marinus A, Sylvester R, Kullberg BJ; EORTC Invasive Fungal Infections Group.
Nijmegen University Medical Center, St Radboud and Nijmegen University, Center for Infectious Diseases, Nijmegen, The Netherlands.
Oropharyngeal candidiasis is a frequent infection in cancer patients who receive cytotoxic drugs. In this study, the efficacy, safety and tolerance of fluconazole and itraconazole were compared in non-neutropenic cancer patients with oropharyngeal candidiasis. Of 279 patients who were randomised between the two treatment groups, 252 patients were considered to be eligible (126 in each group). The clinical cure rate was 74% for fluconazole and 62% for itraconazole (P=0.04, 95% Confidence Interval (CI): 0.5-23.3%). The mycological cure rate was 80% for fluconazole and 68% for itraconazole (P=0.03, 95% CI: 1.2-22.6%). The safety and tolerance profile of both drugs were comparable. This study has shown that in patients with cancer and oropharyngeal candidiasis, fluconazole has a significantly better clinical and mycological cure rate compared with itraconazole.

Hematology. 2004 Jun;9(3):217-21.
In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin.
Colburn DE, Giles FJ, Oladovich D, Smith JA.
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. dcolburn@mdanderson.org
PURPOSE: Antifungal prophylaxis is an important component of induction therapy for patients with acute myeloid leukemia (AML). Azole antifungal agents are increasingly used in this context. In vitro assays were performed to assess whether cytochrome P450 (CYP450) enzymes were affected by combinations of cytarabine or idarubicin with itraconazole or caspofungin. METHODS: The high throughput microtiter assay was used to determine whether cytarabine, idarubicin and itraconazole or caspofungin were CYP450 isoenzyme substrates, inhibitors of CYP450 isoenzymes, and to determine potential CYP450 metabolism interactions between these agents. RESULTS: Idarubicin is a substrate for CYP450 2D6 and 2C9. Cytarabine is a substrate of CYP450 3A4. Idarubicin inhibits CYP450 2D6, and cytarabine, itraconazole, and caspofungin inhibit CYP450 3A4. Cytarabine metabolism was significantly decreased when combined with caspofungin or itraconazole. CONCLUSIONS: The inhibition of cytarabine metabolism may have important clinical implications. These in vitro findings warrant investigation with in vivo pharmacokinetic studies. Copyright 2004 Taylor and Francis Ltd

J Antimicrob Chemother. 2004 Jun;53(6):1086-9. Epub 2004 Apr 21.
In vitro activity of terbinafine against medically important non-dermatophyte species of filamentous fungi.
Garcia-Effron G, Gomez-Lopez A, Mellado E, Monzon A, Rodriguez-Tudela JL, Cuenca-Estrella M.
Servicio de Micologia, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Ctra Majadahonda-Pozuelo Km 2, 28220 Majadahonda, Madrid, Spain.
OBJECTIVES: The activity in vitro of terbinafine against 442 clinical isolates of several species of filamentous fungi was analysed. METHODS: A broth microdilution test was carried out following the National Committee for Clinical Laboratory Standards reference method, with modifications described previously. RESULTS: The geometric mean (GM) of MICs of terbinafine for non-Aspergillus fumigatus species was 0.24 mg/L whereas the GM for A. fumigatus rose as far as 2.92 mg/L. Terbinafine showed a very strong activity in vitro against Penicillium spp., Paecilomyces spp., Trichoderma spp., Acremonium spp. and Arthrographis spp. with GMs <1 mg/L. However, some species such as Scedosporium spp., Fusarium spp., Scopulariopsis brevicaulis, and most of Mucorales exhibited high MICs of the allylamine with GMs >/= 4 mg/L. CONCLUSIONS: Overall, the GM of MICs of terbinafine was 1.57 mg/L, but significant differences in susceptibilities were seen between genera and species.

J Antimicrob Chemother. 2004 Jun;53(6):1045-53. Epub 2004 Apr 21.
Effects of specific treatment on parasitological and histopathological parameters in mice infected with different Trypanosoma cruzi clonal genotypes.
Toledo MJ, Bahia MT, Veloso VM, Carneiro CM, Machado-Coelho GL, Alves CF, Martins HR, Cruz RE, Tafuri WL, Lana M.
Departamento de Analises Clinicas, Centro de Ciencias da Saude, Bloco I-90, Universidade Estadual de Maringa, Av. Colombo, 5790, 87020-900, Maringa, PR. mjotoledo@uem.br
The goal of this study was to verify the effect of specific treatment on parasitological and histopathological parameters in mice experimentally infected with different Trypanosoma cruzi clonal genotypes. Twenty cloned stocks were selected, representative of the whole phylogenetic diversity of the protozoan and belonging to the clonal genotypes 19 and 20 (T. cruzi I) and 39 and 32 (T. cruzi II). The stocks were inoculated in 40 BALB/c mice divided into four groups: (i) treated with benznidazole, (ii) treated with itraconazole and (iii and iv) untreated control groups (NT) for each drug, respectively. Seven parameters related to parasitaemia curves and histopathological lesions were analysed. Four during the acute phase (AP) and three during both the AP and chronic phase (CP) of infection. Statistical comparison between benznidazole-treated and NT groups for the biological parameters showed significant differences for all genotypes. Benznidazole treatment led to lower patent period, maximum of parasitaemia, day of maximum parasitaemia and area under the parasitaemia curve for all genotypes analysed. Percentage of positive haemoculture during AP and CP was lower for genotypes 19 and 32. Tissue parasitism (TP) and inflammatory process (IP) during AP were lower for genotypes 19 and 32, respectively. In general, itraconazole treatment induced a smaller reduction in these same parameters between treated and NT animals in relation to benznidazole treatment. Our results indicate that phylogenetic divergence among T. cruzi clonal genotypes must be taken in account in chemotherapy and studies dealing with all aspects of the parasite and the disease.

Orv Hetil. 2003 Aug 24;144(34):1677-82.
Therapeutic safety of antimycotics in the treatment of systemic fungal infections
Feher J, Lengyel G.
Semmelweis Egyetem, Altalanos Orvostudomanyi Kar, II. Belklinika, Budapest.
The authors summarize the most important data of antimycotics used in the praxis. The indications of these drugs as well as the absorption, the antimycotic mechanism, the side-effects and drug-interactions of antifungal agents are discussed. The pathomechanism of amphotericin B, flucytosine, fluconasole, ketoconasole, itraconasole and the possibilities of their clinical administrations, further their side-effects and interactions are demonstrated in details. The most beneficial characteristics and more important interactions of these drugs are shown in tables for easier application in the everyday therapy.

Medicine (Baltimore). 2003 Sep;82(5):309-21.
Candidemia in a tertiary care cancer center: in vitro susceptibility and its association with outcome of initial antifungal therapy.
Antoniadou A, Torres HA, Lewis RE, Thornby J, Bodey GP, Tarrand JP, Han XY, Rolston KV, Safdar A, Raad II, Kontoyiannis DP.
Department of Infectious Diseases, Infection Control and Employee Health, Unit 402, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Since the 1990s, changing trends have been documented in species distribution and susceptibility to bloodstream infections caused by Candida species in cancer patients. However, few data are available regarding the association between in vitro antifungal susceptibility and outcome of candidemia in this patient population. We therefore evaluated the association of in vitro antifungal susceptibility and other risk factors with failure of initial antifungal therapy in cancer patients with candidemia. Candidemia cases in cancer patients from 1998 to 2001 (n = 144) were analyzed retrospectively along with their in vitro susceptibility to amphotericin B, fluconazole, and itraconazole (National Committee for Clinical and Laboratory Standards M27-A method). Patients were evaluable for outcome analysis if they received continuous unchanged therapy with either fluconazole or amphotericin B for >/=5 days. We excluded cases of mixed candidemia. In vitro susceptibility testing data of the first Candida bloodstream isolate were analyzed. Appropriate therapy was defined as that using an active in vitro antifungal for >/=5 days. For fluconazole susceptible-dose dependent Candida species, we defined appropriate therapy as a fluconazole dose of >/=600 mg/day. The Candida species distribution was 30% Candida albicans, 24% Candida glabrata, 23% Candida parapsilosis, 10% Candida krusei, 9% Candida tropicalis, and 3% other. Overall, amphotericin B was the most active agent in vitro, with only 3% of the isolates exhibiting resistance to it (>1 mg/L). Dose-dependent susceptibility to fluconazole and itraconazole was seen in 13% and 21% of the isolates, respectively, while resistance to fluconazole and itraconazole was seen in 13% and 26%, respectively.Eighty patients were evaluable for outcome analysis. In multivariate analysis, the following factors emerged as independent predictors of failure of initial antifungal therapy: leukemia (p = 0.01), bone marrow transplantation (p = 0.006), and intensive care unit stay at onset of infection (p = 0.02). Inappropriate antifungal therapy, as defined by daily dose and in vitro susceptibility, was not shown consistently to be a significant factor (it was significant in multivariate analysis, p = 0.04, but not in univariate analysis), indicating the complexity of the variables that influence the response to antifungal treatment in cancer patients with candidemia.

Palliat Med. 2003 Sep;17(6):477-81.
High prevalence of non-albicans yeasts and detection of anti-fungal resistance in the oral flora of patients with advanced cancer.
Bagg J, Sweeney MP, Lewis MA, Jackson MS, Coleman D, Al MA, Baxter W, McEndrick S, McHugh S.
Glasgow Dental Hospital and School, University of Glasgow, Glasgow, UK.
Oral fungal infections frequently develop in individuals with advanced cancer. This study examined the oral mycological flora of 207 patients receiving palliative care for advanced malignant disease. Demographic details and a clinical history were documented from each participant. A tongue swab was collected and cultured on CHROMAgar Candida (CHROMAgar Paris, France). All yeasts were identified by germ tube test, API ID 32C profiles and, for Candida dubliniensis, by species-specific PCR. Susceptibility to fluconazole and itraconazole was determined by a broth microdilution assay according to the National Committee for Clinical Laboratory Standards (NCCLS). At time of sampling, 54 (26%) of the 207 subjects had clinical evidence of a fungal infection and yeasts were isolated from 139 (67%) individuals. In total, 194 yeasts were isolated, of which 95 (49%) were Candida albicans. There was a high prevalence of Candidia glabrata (47 isolates) of which 34 (72%) were resistant to both fluconazole and itraconazole. All nine isolates of C. dubliniensis recovered were susceptible to both azoles. No relationship was established between anti-fungal usage in the preceding three months and the presence of azole resistant yeasts. This study of patients with advanced cancer has demonstrated a high incidence of oral colonization with non-C. albicans yeasts, many of which had reduced susceptibility to fluconazole and itraconazole. The role of improved oral care regimes and novel anti-fungal drugs merits further attention, to reduce the occurrence of fungal infection in these patients.

Transplantation. 2003 Sep 27;76(6):977-83.
Efficacy and safety of itraconazole prophylaxis for fungal infections after orthotopic liver transplantation: a prospective, randomized, double-blind study.
Sharpe MD, Ghent C, Grant D, Horbay GL, McDougal J, David Colby W.
Department of Anesthesia, and Program in Critical Care Medicine, University of Western Ontario, London, Ontario, Canada.
BACKGROUND: There is significant morbidity and mortality related to fungal infections in the solid-organ transplant population. METHODS: A prospective, randomized, double-blind, placebo-controlled, restricted sequential design trial was performed in 71 adults undergoing orthotopic liver transplantation. Patients were randomly assigned to receive either itraconazole (5.0 mg/kg orally, preoperatively, 2.5 mg/kg orally, two times a day, postoperatively) or placebo. Therapy continued for a maximum of 56 days or until patient was discharged from hospital or met a predefined endpoint. Measurements included incidence of fungal colonization, superficial or systemic fungal infections requiring systemic therapy, adverse events, and mortality rate. RESULTS: This trial design supported the superiority of itraconazole in preventing fungal infections; nine patients in the placebo group (24%; 95% confidence interval, 0.118-0.412) and one patient in the itraconazole group (4%; 95% confidence interval, 0.001-0.204) developed fungal endpoints requiring therapy with amphotericin B (P=0.04, Fisher's exact test). At the time of enrollment, fungal colonization occurred in 40% and 37% of itraconazole and placebo patients (P=0.43), respectively. Adverse events were reported by 97% and 100% of the intraconazole and placebo groups, respectively, and one itraconazole and six placebo-group patients died within the study period. There was no relation to trial medication for serious adverse events. CONCLUSION: Prophylaxis with itraconazole reduces fungal infections in patients undergoing orthotopic liver transplantation and is well tolerated.

Emerg Infect Dis. 2003 Sep;9(9):1155-8.
Paecilomyces lilacinus vaginitis in an immuno-competent patient.
Carey J, D'Amico R, Sutton DA, Rinaldi MG.
Division of Infectious Diseases, Beth Israel Medical Center, New York, New York 10003, USA.
Paecilomyces lilacinus, an environmental mold found in soil and vegetation, rarely causes human infection. We report the first case of P. lilacinus isolated from a vaginal culture in a patient with vaginitis.


Ann Hematol. 2003 Sep;82(9):565-9. Epub 2003 Jun 21.
Fungal colonization in neutropenic patients: a randomized study comparing itraconazole solution and amphotericin B solution.
Lass-Florl C, Gunsilius E, Gastl G, Englisch M, Koch G, Ulmer H, Dierich MP, Petzer A.
Department of Hygiene and Social Medicine, University of Innsbruck, Fritz Pregl Strasse 3/III, 6020, Innsbruck, Austria. Cornelia.
We assessed the impact of prophylaxis with the oral itraconazole solution and amphotericin B solution on fungal colonization and infection in a randomized study among patients with hematological malignancies and neutropenia. Infecting and colonizing Candida strains of patients suffering from candidiasis were genotyped by random amplification of polymorphic DNA (RAPD) analysis. A total of 106 patients were evaluated in this study: 52 patients in the itraconazole and 54 in the amphotericin B arm. During neutropenia fungal colonization in the oropharynx occurred in 11 (19.6%) and 24 (40.6%) and in the rectum in 11 (19.6%) and 23 (38.9%) courses in the itraconazole and amphotericin B groups ( P<0.05), respectively. Candida albicans was the most prevalent species in both study groups. Mixed fungal colonization with Candida krusei and Candida glabrata was increased in the amphotericin B group, yet without clinical importance since infections were due to C. albicans. The occurrence of invasive candidiasis was significantly increased in multicolonized compared to monocolonized patients. In the amphotericin B group 20 and in the itraconazole group 2 neutropenic patients showed multicolonization with Candida spp. ( P<0.05). Overall fungal infections were 3.8% in the itraconazole and 14.8% in the amphotericin B group ( P<0.05). RAPD typing showed oropharynx strains involved in superficial infections in four of five patients. In all four patients with deep fungal infections, it appears that the colonizing rectum strains were identical to infecting strains of Candida spp. Itraconazole solution significantly reduced Candida colonization and infection compared to amphotericin B solution. Most patients remained infected with the colonized strains for the entire study period, irrespective of antifungal prophylaxis.