Deep dermatophytosis caused by Trichophyton rubrum: report of two cases

Two patients presenting with subcutaneous nodules, plaques, papules and ulceration caused by Trichophyton rubrum are described in this report. The first case was a 46-year-old woman referred with erythema and desquamation over her trunk, hands and feet for 30 years, progressing to nodules and ulceration over her trunk, arms and scalp for the last 2 years. The second case was a 34-year-old man who presented with a 2-year-history of itchy, erythema and desquamation over the trunk, progressing to papules, nodules and cyst around his ear, on the neck and scalp for 1 year. The diagnoses were suspected after direct microscopical examinations of the discharge materials, which revealed the presence of hyaline hyphae. The histological examinations showed granulomatous inflammatory infiltrates with fungal elements in the dermis including epithelioid cells, giant cells, lymphocytes and eosinophils, and the periodic acid-Schiff stain showed hypha within the granulomas. Cultures of puncture materials, skin biopsies and nails confirmed the diagnosis identifying T. rubrum. Antifungal therapies with itraconazole were successful in both patients, the lesions were completely clear with atrophic scars after 3 months. Side effects were not noticed during the medication. We discuss the clinical types of granulomatous cutaneous lesions caused by dermatophyte infections and evaluate the therapeutic effect of itraconazole.     

A d-optimal designed population pharmacokinetic study of oral itraconazole in adult cystic fibrosis patients

AIM: The primary objective of the study was to estimate the population pharmacokinetic parameters for itraconazole and hydroxy-itraconazole, in particular, the relative oral bioavailability of the capsule compared with solution in adult cystic fibrosis patients, in order to develop new dosing guidelines. A secondary objective was to evaluate the performance of a population optimal design. METHODS: The blood sampling times for the population study were optimized previously using POPT v.2.0. The design was based on the administration of solution and capsules to 30 patients in a cross-over study. Prior information suggested that itraconazole is generally well described by a two-compartment disposition model with either linear or saturable elimination. The pharmacokinetics of itraconazole and the metabolite were modelled simultaneously using NONMEM. Dosing schedules were simulated to assess their ability to achieve a trough target concentration of 0.5 mg ml(-1). RESULTS: Out of 241 blood samples, 94% were taken within the defined optimal sampling windows. A two-compartment model with first order absorption and elimination best described itraconazole kinetics, with first order metabolism to the hydroxy-metabolite. For itraconazole the absorption rate constants (between-subject variability) for capsule and solution were 0.0315 h(-1) (91.9%) and 0.125 h(-1) (106.3%), respectively, and the relative bioavailability of the capsule was 0.82 (62.3%) (confidence interval 0.36, 1.97), compared with the solution. There was no evidence of nonlinearity. Simulations from the final model showed that a dosing schedule of 500 mg twice daily for both formulations provided the highest chance of target success. CONCLUSION: The optimal design performed well and the pharmacokinetics of itraconazole and hydroxy-itraconazole were described adequately by the model. The relative bioavailability for itraconazole capsules was 82% compared with the solution.     

In vitro susceptibility of the seven Malassezia species to ketoconazole, voriconazole, itraconazole and terbinafine

Fifty-five strains, either authentic or ex-type, of seven Malassezia species were investigated for in vitro susceptibility to various concentrations (0.03-64.0 microg/mL) of three azole drugs, ketoconazole, voriconazole and itraconazole, as well as the allylamine terbinafine, using the agar dilution method. All strains of the seven Malassezia species were susceptible to the three azole drugs at low concentrations. M. furfur, M. sympodialis, M. slooffiae, M. pachydermatis, M. globosa, M. obtusa and M. restricta were most sensitive to ketoconazole and itraconazole, with minimum inhibitory concentrations (MICs) ranging from < or = 0.03 to 0.125 microg/mL. The recently introduced antifungal, voriconazole, was also very effective, with MIC80 values < or = 0.03 microg/mL for 80% of strains. MICs of terbinafine against the seven Malassezia species ranged from itraconazole and terbinafine. Strains of M. furfur, M. globosa and M. obtusa were more tolerant to terbinafine than the remaining Malassezia species; M. sympodialis was highly susceptible. M. furfur strains tested with terbinafine ranged from highly susceptible to relatively resistant. Correct identification of Malassezia species could facilitate selection of appropriate antifungal therapy.     

Onychomycosis caused by Fusarium proliferatum

Fusarium infections in humans are usually opportunistic, but the fungus sometimes infects healthy persons, causing keratomycosis or onychomycosis. Onychomycosis is usually caused by F. solani or F. oxysporum. We report the first two cases of onychomycosis caused by F. proliferatum, and discuss methods of diagnosis and effective treatment. Nail samples from the two patients were examined by direct microscopy, cultured, and identified morphologically and genetically as F. proliferatum. Both patients were treated successfully with oral itraconazole, even though the minimum inhibitory concentration of itraconazole was relatively high in Patient 1. This is the first report of F. proliferatum as an agent of onychomycosis. Itraconazole may be effective in the treatment of onychomycosis caused by F. proliferatum.     

Subcutaneous zygomycosis: report of 10 cases from two institutions in North India

Background Subcutaneous zygomycosis is an uncommon condition observed in tropics. Few series have been published, particularly from the northern regions of India. Objectives The aim of this study was to describe clinical, investigative and therapeutic details in subcutaneous zygomycosis observed in two teaching hospitals in Delhi. Patients and methods Ten patients seen over a period of 10 years (1999–2009) form the material for this report. Results There were four children and six adults. In four children, the presentation was a subcutaneous localized mass or gradually spreading plaque. In the others, it was observed over nasal region of face, spreading inward into mucosal sites and paranasal sinuses, and outward to the contiguous areas. Regional lymphadenopathy was present in two with facial lesions. Majority showed a granulomatous infiltrate with admixture of other cells, mainly eosinophils. Aseptate or poorly septate hyphae were observed in seven. In one patient in whom no hyphae were observed, there was dense perivascular inflammation. Organisms were cultured from four patients, Basidiobolus ranarum in two and Syncephalastrum racemosum in two. The main therapy used was a saturated solution of potassium iodide (KI). Four received only KI of which two attained cure after 3 months and 9 months respectively, and the other two showed signs of regression. In one boy subsidence was associated with reduced circumference of thigh. Ketoconazole or itraconazole was given with KI to hasten regression when response was slow or there were side‐effects to KI. Conclusion Awareness and early recognition will prevent disfigurement produced by advanced disease, misdiagnosis and unnecessary surgical intervention.     

Photosensitivity induced by oral itraconazole

A case of photosensitivity induced by itraconazole is reported. A 70-year-old woman had erythema, oedema and vesicles on sun-exposed areas after 5 days of itraconazole treatment for oral candidiasis. Oral photochallenge using itraconazole and sun irradiation was positive, but photopatch test was negative. Photosensitivity from azoles is an uncommon adverse effect. Only three other cases have been described, two induced by ketoconazole and one by itraconazole.     

伊曲康唑对全反式维甲酸药动学的影响

 目的 研究伊曲康唑对全反式维甲酸(ATRA)药动学的影响,探讨联合用药方法,解决ATRA治疗中耐药问题的可能性。方法 将动物按交叉试验方法给药,先后按单用维甲酸和合用维甲酸与伊曲康唑两种方案给药,以高效液相色谱法测定维甲酸血药浓度,研究两种给药方案的药动学差异。结果 维甲酸在动物体内的药动学过程符合单室开放模型,单用及合用的药动学参数c_max分别为(113.83±62.65),(281.91±75.40) ng·mL^-1(P＜0.01);t_max分别为(3.67±0.50),(2.11±0.60) h(P＜0.01);MRT分别为(4.34±0.83),(2.89±0.34) h(P＜0.01);AUC0～∞分别为(374.9±179.5),(675.5±212.6) ng·h·mL^-10.01＜P＜0.05);t_1/2ke分别为(2.40±0.98),(1.91±1.26) h(P＞0.05)。结论 合用伊曲康唑可以升高ATRA血药峰浓度和维持有效治疗浓度,提示并用伊曲康唑可能是解决维甲酸耐药的一种方法,值得临床作进一步研究。     

Use of a semi-physiological pharmacokinetic model to investigate the influence of itraconazole on tacrolimus absorption,distribution and metabolism in mice

1.?The aim of this study was to investigate the influence of itraconazole (ITCZ) on tacrolimus absorption, distribution and metabolism by developing a semi-physiological pharmacokinetic model of tacrolimus in mice.

2.?Mice were randomly divided into four groups, namely control group (CG, taking 3?mg kg^?1 tacrolimus only), low-dose group (LDG, taking tacrolimus with 12.5?mg kg^?1 ITCZ), medium-dose group (MDG, taking tacrolimus with 25?mg kg^?1 ITCZ) and high-dose group (HDG, taking tacrolimus with 50?mg kg^?1 ITCZ).

3.?Liver clearance (CL_li) decreased significantly (**p?<?0.01) in LDG (35.3%), MDG (45.2%) and HDG (58.7%) mice compared to CG mice. With respect to gut clearance (CL_gu), significant (**p?<?0.01) decrease was also revealed in LDG (35.9%), MDG (50.2%) and HDG (64.6%) mice. A significant (**p?<?0.01) higher tacrolimus brain-to-blood partition coefficient (K_t,br) was found in MDG (25.3%) and HDG (55.9%) mice than in CG mice. Moreover, a significant (*p?<?0.05) increase (16.3%) was found in the absorption rate constant (K_a) in HDG mice compared to CG mice. There was a significant (**p?<?0.01) association between ITCZ dose and the change in CL_gu (ΔCL_gu, r=??0.790), the change in CL_li (ΔCL_li, r=??0.787) and the change in K_t,br (ΔK_t,br, r?=?0.727), while the association between ITCZ dose and the change in K_a (ΔK_a) was not significant (p?>?0.05).

4.?These findings could be useful in predicting the efficacy and toxicity of tacrolimus, and drug–drug interaction of ITCZ and tarcolimus in human.     

One week pulse therapy with itraconazole (200 mg day−1) for onychomycosis. Evaluation of treatment results according to patient background

We investigated background factors of patients that affect the response of onycomycosis to pulse therapy with itraconazole. The regimen used in this study involved administering 200 mg of itraconazole orally on a daily basis for 1 week as one pulse, which is half of the normally recommended dose. The number of pulses was fixed at one per month, and altered in accordance with improvements in the infected nails and/or the patients' request. Patient background (n = 63) including sex, age, occupation, duration of the disease, site of lesion (fingernail, toenail), number of affected nails, clinical types, severity of thickening, presence or absence of pathogens, the presence or absence of underlying diseases such as adult onset diseases, turbidity of the target nails before therapy and the number and duration of pulses was investigated. The efficacy of the therapy was evaluated after 12 months. A complete cure was judged to have taken place if an entirely healthy nail plate re-grew in place of the diseased nail, whereas lack of success was defined as the persistence of lesions beyond the designated time period. The average number and duration of pulses were 4.7 +/- 3.2 times over 5.6 +/- 4.3 months, respectively. The rate of complete cure was 62%. Factors in the patients' background that were judged to have an influence on treatment results were the relative duration of the disease, the number of affected nails, and severity of thickening. With regard to the efficacy of the therapy in terms of the number and duration of pulses, 78% of 23 patients who were given pulse therapy two to six times during a course of 2 to 6 months achieved total cure.