The efficacy and safety of pulse vs. continuous therapy for dermatophyte toenail onychomycosis.

BACKGROUND: Onychomycosis is a chronic, fungal infection of the nails. Complete cure remains challenging, but oral antifungal medications have been successful in managing the fungus for a significant proportion of patients. Treatment with these drugs can be continuous or intermittent, albeit the evidence on their relative efficacies remains unclear. OBJECTIVE: To determine the relative effectiveness and safety of pulse versus continuous administration, of three common oral therapies for dermatophyte onychomycosis, by conducting multiple-treatment meta-analysis. METHODS: This systematic review and network meta-analysis compared the efficacy (as per mycological cure) and adverse event rates of three oral antifungal medications in the treatment of dermatophyte toenail onychomycosis, namely terbinafine, itraconazole and fluconazole. A total of 30 studies were included in the systematic review, while 22 were included in the network meta-analysis. RESULTS: The likelihood of mycological cure was not significantly different between continuous and pulse regimens for each of terbinafine and itraconazole. Use of continuous terbinafine for 24 weeks - but not 12 weeks - was significantly more likely to result in mycological cure than continuous itraconazole for 12 weeks or weekly fluconazole for 9-12 months. Rank probabilities demonstrated that 24-week continuous treatment of terbinafine was the most effective. There were no significant differences in the likelihood of adverse events between any continuous and pulse regimens of terbinafine, itraconazole and fluconazole. Drug treatments were similar to placebo in terms of their likelihood of producing adverse events. CONCLUSION: More knowledge about the fungal life cycle and drugs' pharmacokinetics in nail and plasma could further explain the relative efficacy and safety of the pulse and continuous treatment regimens. Our results indicate that in the treatment of dermatophyte toenail onychomycosis, the continuous and pulse regimens for terbinafine and itraconazole have similar efficacies and rates of adverse events.

Pharmacokinetic evaluation of oral itraconazole for antifungal prophylaxis in children.

Itraconazole is a first-generation triazole agent with an extended spectrum of activity; it is licensed in adults for superficial and systemic fungal infections; no recommendation has been yet established for use in children patients. Its variable and unpredictable oral bioavailability make it difficult to determine the optimal dosing regimen. Hence, therapeutic drug monitoring, highly available in clinical practice, may improve itraconazole treatment success and safety. The aim of the study was to describe in paediatrics the oral itraconazole pharmacokinetics, used for prophylaxis. Moreover, we evaluated the utility of its therapeutic drug monitoring in this cohort. A fully validated chromatographic method was used to quantify itraconazole concentration in plasma collected from paediatric patients, at the end of dosing interval. Associations between variables were tested using the Pearson test. Mann-Whitney U test has been used to probe the influence of categorical variables on continuous ones. Any predictive power of the considered variables was finally evaluated through univariate and multivariate linear and logistic regression analyses. A high inter-individual variability was shown; ethnicity (beta coefficient, ß -0.161 and interval of confidence at 95%, IC -395.035; -62.383) and gender (ß 0.123 and IC 9.590; 349.395) remained in the final linear regression model with P value of .007 and .038, respectively. This study highlights that therapeutic drug monitoring is required to achieve an adequate target itraconazole serum exposure.

[Two cases of pulmonary aspergilosis, which deteriorated with generic itraconazole].

We experienced two cases of pulmonary aspergillosis, which deteriorated during treatment with generic itraconazole (ITCZ) because of low plasma concentration. One case was chronic pulmonary aspergillosis and the other was allergic bronchopulmonary aspergillosis (ABPA). Treatment of both cases was started with a brand-name-ITCZ, and changed to a generic ITCZ. Deterioration of pulmonary aspergillosis occurred after 8 months and 9 months from change to generic ITCZ respectively. In the first case, the ITCZ-plasma concentration was 46.9 ng/mL and of OH-ITCZ 96.5 ng/mL with generic ITCZ at the dose of 300 mg/day, but increased to 1,559.7 ng/mL and to 2,485.0 ng/mL with the brand-name-ITCZ 300 mg/day, respectively. In the second case, the ITCZ-plasma concentration was 27.2 ng/mL and of OH-ITCZ 20.1 ng/mL with 150 mg/day for generic ITCZ, but reached 857.3 ng/mL and to 1,144.2 ng/ml with the brand-name-ITCZ 300 mg/day, respectively. After treatment failure, the first case was changed to voriconazole, then brand-name-ITCZ 300 mg/day, and the second case to the brand-name-ITCZ 300 mg/day, with successful clinical course. Plasma concentrations of ITCZ can differ significantly depending on the patient or type of ITCZ. The ITCZ-plasma concentration should be controlled after changing from a brand-name-ITCZ to a generic ITCZ.

Treatment of cutaneous sporotrichosis with itraconazole--study of 645 patients.

BACKGROUND: Itraconazole has become the first choice for treatment of cutaneous sporotrichosis. However, this recommendation is based on case reports and small series. The safety and efficacy of itraconazole were evaluated in 645 patients who received a diagnosis on the basis of isolation of Sporothrix schenckii in Rio de Janeiro, Brazil. METHODS: A standard regimen of itraconazole (100 mg/day orally) was used. Clinical and laboratory adverse events were assessed a grades 1-4. A multivariate Cox model was used to analyze the response to treatment. RESULTS: The median age was 43 years. Lymphocutaneous form occurred in 68.1% and fixed form in 23.1%. Six hundred ten patients (94.6%) were cured with itraconazole (50-400 mg/day): 547 with 100 mg/day, 59 with 200-400 mg/day, and 4 children with 50 mg/day. Three patients switched to potassium iodide, 2 to terbinafine, and 4 to thermotherapy. Twenty-six were lost to follow-up. Clinical adverse events occurred in 18.1% of patients using 100 mg/day and 21.9% of those using 200-400 mg/day. The most frequent clinical adverse events were nausea and epigastric pain. Laboratory adverse events occurred in 24.1%; the most common was hypercholesterolemia, followed by hypertriglyceridemia. Four hundred sixty-two patients (71.6%) completed clinical follow-up, and all remained cured. Only 2 variables were significant in explaining the cure: patients with erythema nodosum healed faster, and lymphocutaneous form took longer to cure. CONCLUSIONS: In the current series, the therapeutic response was excellent with the minimum dose of itraconazole, and there was a low incidence of adverse events and treatment failure.

[Level of evidence for therapeutic drug monitoring of itraconazole]. / Niveau de preuve du suivi thérapeutique pharmacologique de l'itraconazole.

Itraconazole is a triazole antifungal agent that is active against Aspergillus, histoplasmosis, and rare fungal infections. Itraconazole exhibit marked variability in drug concentration as a result of inconsistent absorption, metabolism, or interaction with concomitant medications. Preclinical and clinical data have exhibited a relationship between serum concentrations and treatment efficacy or toxicity, thus therapeutic drug monitoring (TDM) of itraconazole is largely used to optimise therapy. The analysis of bibliographic data demonstrate that, even if the utility of itraconazole's TDM has not been proved by randomized controlled trial or pharmaco-economics studies, it could be useful for managing an absence of response or a drug-drug interactions, or interpreting an adverse effect. However, the interest of this monitoring was proved only in some populations of patients (neutropenics or AIDS patients) so its level of proof varies between levels "potentially useful" and "recommended".

Tolerability of oral itraconazole and voriconazole for the treatment of chronic pulmonary aspergillosis: A systematic review and meta-analysis.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) requires prolonged treatment with itraconazole or voriconazole. However, adverse events (AEs) are common with the use of these agents, with the need to discontinue the offending drug in a significant proportion of the patients. The aim of this study was to evaluate the frequency of adverse events of itraconazole and voriconazole for the treatment of CPA. METHODS: We searched Embase and Medline to select clinical studies providing information on AEs to itraconazole or voriconazole for the treatment of CPA from inception to May 2020. Reviews, single case reports, and case series reporting less than 10 patients were excluded. Random effect meta-analysis was performed using STATA 16.0. RESULTS: We included 9 eligible studies with an overall total of 534 CPA patients enrolled. Of these, 69% (n = 366) were treated with voriconazole and 31% (n = 168) with itraconazole. The median daily dose of both itraconazole and voriconazole used was 400mg. In a pooled analysis, AEs were observed in 36% (95% CI: 20-52%, N = 366) of patients on voriconazole and 25% (95% CI: 18 to 31%, N = 168) in those treated with itraconazole. Discontinuation rate due to AEs was the same for both drugs; 35% (47/366) and 35% (15/168) for voriconazole and itraconazole, respectively. There were 70 AEs reported with itraconazole use, the commonest being cardiotoxicity (29%). Skin AEs (28%) were the most frequent among the 204 AEs reported with voriconazole use. None of the studies compared the tolerability of itraconazole head-to-head with voriconazole. CONCLUSIONS: AEs due itraconazole and voriconazole are common and may lead to discontinuation of treatment in a significant proportion of patients. This information can be used to educate patients prior to commencement of these antifungal therapies. PROSPERO REGISTRATION NUMBER: CRD42020191627.

Combined long-pulsed Nd-Yag laser and itraconazole versus itraconazole alone in the treatment of onychomycosis nails.

Background: Oral antifungal therapies are effective for onychomycosis but it was complicated by systemic effects. Effective and safe therapy is needed to improve esthetic appearance of nails.Objective: The present study is an attempt to evaluate and compare the efficacy of of combined treatment of onychomycosis with 1,064-nm long-pulsed Nd-Yag laser and pulse itraconazole therapy versus pulse itraconazole alone.Methods: Thirty onychomycosis patients were divided into two groups: Groups I and II. Patients of Group I are treated by itraconazole pulse therapy. Patients of Group II received six laser sessions with long-pulsed Nd:Yag laser and itraconazole pulse therapy. The investigators rated clearance using "Onychomycosis Severity Index (OSI)", photographs, and mycology at 6 and 9 months after treatment.Results: Group I's clinical improvement response was excellent in two cases, good in six cases, moderate in five cases, and mild in two cases. Mycological improvement response was excellent in two cases, good in two cases, moderate in six cases, and mild in five cases (OSI before treatment was 13.4 ± 3.02 and after was 6.67 ± 3.6). Group II's clinical improvement response was excellent in 10, good in 3, moderate in 1, and mild in 1. Mycological improvement's response was excellent in two cases, good in two cases, moderate in six cases, and mild in five cases (OSI before treatment was 13.33 ± 3.11 and after was 5.07 ± 4.15). There were no adverse effects. The clinical response showed best results with Group II, but the mycological cure was equal in both groups.Conclusions: The use of combined long-pulsed Nd-Yag laser and itraconazole pulse therapy gives the best clinical results and patient's satisfaction.

North American blastomycosis of the eyelid.

A 26-year-old diabetic man presented with a papillomatous eyelid lesion. Histopathology was consistent with Blastomyces dermatitidis. A 1-year course of itraconazole led to resolution in this case. Although skin is the most common extrapulmonary site of blastomycosis, eyelid involvement is rare. Prompt diagnosis and treatment improve morbidity and mortality.

[First autochthonous case report of tinea nigra in Chile]. / Primer reporte de caso autóctono de tinea nigra en Chile.

Tinea nigra is an infrequent superficial mycosis caused by the dematiaceous fungus Hortaea werneckii. It usually occurs in tropical coastal areas, with very few reports in South American countries with temperate climates, generally corresponding to infections imported by travelers. We present the case of a Chilean adult patient, with no previous history of recent trips, with clinical and microbiological background consistent with palmar tinea nigra, treated with oral itraconazole and topical sertaconazole with a favorable response. This article is the first case reported in Chile, of autochthonous origin.

La tinea nigra es una infrecuente micosis superficial causada por el hongo dematiáceo Hortaea werneckii. Se presenta habitualmente en zonas costeras tropicales, siendo muy escasos los reportes en países sudamericanos con climas más templados. Habitualmente corresponde a infecciones importadas por viajeros. Se presenta el caso de una paciente adulta chilena, sin historia previa de viajes recientes, cursando con cuadro clínico y microbiológico compatible con tinea nigra palmar, tratado con itraconazol oral y sertaconazol tópico con respuesta favorable. Esta paciente corresponde al primer caso reportado en Chile de origen autóctono.

Onychomycosis: a new emerging infectious disease in childhood population and adolescents. Report on treatment experience with terbinafine and itraconazole in 36 patients.

BACKGROUND: Onychomycosis is a rare disease in children with an estimated prevalence ranging from 0% to 2.6%. Thus far, only limited experience with itraconazole and terbinafine treatment in children with onychomycosis is available in the literature. AIM OF THE STUDY: Evaluation of treatment experience with itraconazole or terbinafine in childhood onychomycosis. SUBJECTS: Thirty-six children and adolescents (aged 4-17 years, 18 males and 18 females) with clinical and mycologically proven onychomycosis were enrolled in the present study. METHODS AND OUTCOME: In 27 of 36 patients, the causative agent (Trichophyton rubrum in 26 cases and Trichophyton interdigitale in one patient) could be identified by means of cultivation. Nineteen patients were treated with itraconazole 200 mg once daily for 12 weeks, and 17 patients were treated with terbinafine for 12 weeks in a dosage according to their body weight, respectively. Clinical cure was achieved within 1 to 5 months after discontinuation in all patients treated with itraconazole and in all but two patients after cessation of terbinafine treatment. Neither in the itraconazole nor in the terbinafine group were serious adverse events reported. Clinical cure was achieved within 1 to 5 months after discontinuation in all patients treated with itraconazole and in all but two patients after cessation of terbinafine treatment. Neither in the itraconazole nor in the terbinafine group were serious adverse events reported. CONCLUSION: To our experience, a mycological and clinical cure appears in children in a shorter time after treatment discontinuation (average 2-5 months) compared with adults. Itraconazole and terbinafine seem to be safe and effective in childhood onychomycosis; therefore, these antifungals seem to be potential alternatives to griseofulvin.

[Aspergillosis of masticator space including mandibular bone responding to itraconazole treatment in a diabetic adult: case report].

Aspergillosis of the bone is rare and resistant to treatment. We report a case of Aspergillus infection of the masticator space including mandibular bone in a diabetic adult. After extraction of a posterior tooth, the patient began to suffer from facial pain. The pain worsened in spite of antibiotic treatment. The results of serum tests and biopsy showed an invasive aspergillosis of the left masticator space including the mandibular bone six months after the onset. Although invasive aspergillosis can be fatal, the infection in our case responded to itraconazole treatment. Even in diabetes mellitus, invasive aspergillosis may occur after surgical interventions such as tooth extraction.

[Clinical efficacy and safety of itraconazole injection/oral solution sequential therapy for treatment of invasive fungal infection in intensive care unit].

OBJECTIVE: To investigate the therapeutic efficacy and safety of itraconazole injection/oral sequential therapy on invasive fungal infection (IFI) in ICU. METHODS: In this multicenter, post-marketing, open-label study, ICU patients who have met the inclusion IFI criteria will be enrolled in this study. Itraconazole intravenous injection is administered 200 mg twice a day in day 1 - 2, then 200 mg once a day at least for 5 days, and maintenance itraconazole oral solution as sequential therapy, itraconazole oral solution 200 mg twice a day sequential therapy lasts for 2 weeks. Clinical efficacy and adverse reaction were record. RESULTS: A total of 159 patients were enrolled and completed this trial. (1) At the end of first week, total clinical cure rate was 35.2%, and increased to 73.6% after the second week. Clinical cure rate were 72.9% and 72.2% in possible and probable IFI patients, and 78.9% in proven IFI patients at the end of second week. (2) At the end of first week, total fungal clearance was 40.9%, and increased to 75.9% and 92.9% at the end of second and fourth week. Fungal clearance were 90.0% and 64.6% in possible and probable IFI patients, and 84.2% in proven IFI patients at the end of second week respectively. (3) Combined clinical cure rate and fungal clearance, the total clinic efficacy was 44.1% at the end of first week, and increased to 92.9% and 100.0% at the end of second and fourth week. (4) No severe adverse reaction was found. CONCLUSIONS: Itraconazole injection/oral sequential therapy is an effective and safe antibiotic for the treatment of IFI in ICU.

[Case of chronic necrotizing pulmonary aspergillosis successfully treated with a combination of liposomal amphotericin B and itraconazole].

A 58-year-old Japanese man was admitted with high fever, productive cough, marked leukocytosis, and chest X-ray findings of infiltration and fluid levels within lung cysts. He had been treated for pulmonary tuberculosis for 6 months. He was also receiving home oxygen therapy for chronic obstructive pulmonary disease and 10 mg prednisolone daily for rheumatoid arthritis. Aspergillus fumigatus was cultured from bronchial washing fluid and we diagnosed chronic necrotizing pulmonary aspergillosis (CNPA). Micafungin was initially effective but 9 weeks later the symptoms recurred. Micafungin was stopped and after combination therapy of intravenous liposomal amphotericin B and oral itraconazole capsule was started his symptoms and laboratory data markedly improved. Fifteen weeks later his medication was switched to oral voriconazole and he was discharged. CNPA is a chronic infectious disease with poor prognostic and no standard therapy has been confirmed. Each antifungal drug has different mechanisms and sites of action. In the case of treatment failure with several drugs, combination therapy to achieve drug interaction can be a treatment option.

A Randomized Trial of Itraconazole vs Prednisolone in Acute-Stage Allergic Bronchopulmonary Aspergillosis Complicating Asthma.

OBJECTIVE: Whether itraconazole monotherapy is effective in the acute stage of allergic bronchopulmonary aspergillosis (ABPA) remains unknown. The goal of this study was to compare the efficacy and safety of itraconazole and prednisolone monotherapy in ABPA. METHODS: Treatment-naive subjects with ABPA complicating asthma (January 2012 to December 2013) were randomized to receive either oral itraconazole or prednisolone for 4 months. The study was not blinded. The primary outcomes were proportion of subjects exhibiting a composite response after 6 weeks, percent decline in IgE after treatment, and numbers of subjects experiencing exacerbation. The secondary outcomes included the time to first exacerbation, change in lung function, and treatment-related adverse effects. RESULTS: A total of 131 subjects (prednisolone group, n = 63; itraconazole group, n = 68) were included in the study. The number of subjects exhibiting a composite response was significantly higher in the prednisolone group compared with the itraconazole group (100% vs 88%; P = .007). The percent decline in IgE after 6 weeks and 3 months and the number of subjects with exacerbations after 1 and 2 years of treatment were similar in the two groups. The time to first exacerbation (mean: 437 vs 442 days) and the improvement in lung function after 6 weeks was also similar in the two groups. The occurrence of side effects was significantly higher in the glucocorticoid arm (P < .001). CONCLUSIONS: Prednisolone was more effective in inducing response than itraconazole in acute-stage ABPA. However, itraconazole was also effective in a considerable number and, with fewer side effects compared with prednisolone, remains an attractive alternative in the initial treatment of ABPA. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01321827; URL: www.clinicaltrials.gov).