Longitudinal evaluation of the cutaneous and rectal microbiota of German shepherd dogs with perianal fistulas undergoing therapy with ciclosporin and ketoconazole.

BACKGROUND: Perianal fistulas are painful ulcers or sinus tracts that disproportionately affect German shepherd dogs and are proposed as a spontaneous animal model of fistulising Crohn's disease. OBJECTIVES: To characterise the rectal and cutaneous microbiota in German shepherd dogs with perianal fistulas and to investigate longitudinal shifts with lesion resolution during immunomodulatory therapy. ANIMALS: Eleven German shepherd dogs with perianal fistulas and 15 healthy German shepherd dogs. MATERIALS AND METHODS: Affected dogs were evaluated and swabbed at three visits, 30 days apart, while undergoing treatment with ciclosporin and ketoconazole. Healthy German shepherd dogs were contemporaneously sampled. Sites included the rectum, perianal skin and axilla. The microbiome was evaluated following sequencing of the V4 hypervariable region of the 16S ribosomal RNA (rRNA) gene. RESULTS: Alpha diversity was not significantly different between healthy and affected dogs at each of the three body sites (p > 0.5), yet rectal and perianal beta diversities from affected dogs differed significantly from those of healthy dogs at Day 0 (p = 0.004). Rectal and perianal relative abundance of Prevotella spp. increased and perianal Staphylococcus spp. relative abundance decreased in affected dogs over time, coincident with lesion resolution. CONCLUSIONS AND CLINICAL RELEVANCE: Changes in lesional cutaneous and rectal microbiota occur in German shepherd dogs with perianal fistulas and shift over time with lesion resolution during immunomodulatory therapy. Further investigations of the role of cutaneous and enteric microbiota in the pathogenesis of perianal fistulas, and whether manipulation of microbial populations may ameliorate disease, are needed.

Treatment with the Topical Antimicrobial Peptide Omiganan in Mild-to-Moderate Facial Seborrheic Dermatitis versus Ketoconazole and Placebo: Results of a Randomized Controlled Proof-of-Concept Trial.

Facial seborrheic dermatitis (SD) is an inflammatory skin disease characterized by erythematous and scaly lesions on the skin with high sebaceous gland activity. The yeast Malassezia is regarded as a key pathogenic driver in this disease, but increased Staphylococcus abundances and barrier dysfunction are implicated as well. Here, we evaluated the antimicrobial peptide omiganan as a treatment for SD since it has shown both antifungal and antibacterial activity. A randomized, patient- and evaluator-blinded trial was performed comparing the four-week, twice daily topical administration of omiganan 1.75%, the comparator ketoconazole 2.00%, and placebo in patients with mild-to-moderate facial SD. Safety was monitored, and efficacy was determined by clinical scoring complemented with imaging. Microbial profiling was performed, and barrier integrity was assessed by trans-epidermal water loss and ceramide lipidomics. Omiganan was safe and well tolerated but did not result in a significant clinical improvement of SD, nor did it affect other biomarkers, compared to the placebo. Ketoconazole significantly reduced the disease severity compared to the placebo, with reduced Malassezia abundances, increased microbial diversity, restored skin barrier function, and decreased short-chain ceramide Cer[NSc34]. No significant decreases in Staphylococcus abundances were observed compared to the placebo. Omiganan is well tolerated but not efficacious in the treatment of facial SD. Previously established antimicrobial and antifungal properties of omiganan could not be demonstrated. Our multimodal characterization of the response to ketoconazole has reaffirmed previous insights into its mechanism of action.

Cushing's disease: adrenal steroidogenesis inhibitors.

Cushing's disease (CD), caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, is the most common form of Cushing's syndrome (CS), accounting for approximately 70% of cases. CD requires a prompt diagnosis, an adequate treatment selection, and long-term management to limit hypercortisolism duration and long-term complications and improve patient outcomes. Pituitary surgery is the first-line option, which is non-curative in one third of patients, therefore requiring additional treatments. Medical therapy has recently acquired an emerging role, with the availability of several drugs with different therapeutic targets, efficacy and safety profiles. The current review focuses on efficacy and safety of steroidogenesis inhibitors, and particularly the historical drugs, ketoconazole and metyrapone, and the novel drugs levoketoconazole and osilodrostat, which seem to offer a rapid, sustained, and effective disease control. Ketoconazole should be preferred in females and in patients without severe liver disease; levoketoconazole may offer an alternative to classical ketoconazole, appearing characterized by a higher potency and potential lower hepatotoxicity compared to ketoconazole. Metyrapone should be preferred in males and in patients without severe or uncontrolled hypokalemia. Both ketoconazole and metyrapone may be preferred for short-term more than for long-term treatment. Osilodrostat may represent the best choice for long-term treatment, in patients with poor compliance to the multiple daily administration schedule, and in patients without severe or uncontrolled hypokalemia. Steroidogenesis inhibitors may be used alone or in combination, and associated with pituitary directed drugs, to improve the efficacy of the single drugs, allowing a potential use of lower doses for each drug, and hypothetically reducing the rate of adverse events associated with the single drugs. Clinicians may tailor medical therapy on the specific clinical scenario, considering disease history together with patients' characteristics and hypercortisolism's degree, addressing the needs of each patient in order to improve the therapeutic outcome and to reduce the burden of illness, particularly in patients with persistent or recurrent CD.

Ketoconazole 2% cream alters the skin fungal microbiome in seborrhoeic dermatitis: a cohort study.

BACKGROUND: Seborrhoeic dermatitis (SD) is a common chronic inflammatory dermatosis. Current theories on the pathogenesis of SD highlight the role of microbes on the skin surface. Ketoconazole is commonly used for the treatment of SD; however, there are limited data focusing on the effects of ketoconazole in shaping the skin microbiome in patients with SD. AIM: In this prospective cohort study, we used a high-throughput DNA sequencing method to characterize the cutaneous microbial communities of patients with SD before and after topical ketoconazole treatment. METHODS: In total, 30 patients with facial SD and 15 age- and sex-matched healthy controls (HCs) were enrolled in this study. Skin swabs were collected from SD lesional sites of the cheek at baseline, after ketoconazole treatment and 2 weeks post-treatment. DNA was extracted from skin samples. The bacterial 16S V3V4 rRNA and fungal internal transcribed spacer 1-5F regions were sequenced, and the microbial community compositions were analysed. RESULTS: Significantly lower bacterial and fungal diversities were detected at the lesional sites of facial SD compared with HCs. A decreased relative abundance of Cutibacterium and increased abundances of Malassezia and Staphylococcus were found in facial SD. Disease diversity was positively correlated with the relative abundances of Malassezia, Staphylococcus and Corynebacterium, while transepidermal water loss was negatively associated with the relative abundance of Cutibacterium. After ketoconazole treatment, fungal Shannon diversity and the relative abundances of Candida and Aspergillus were significantly increased at the lesional sites, and the relative abundance of Malassezia showed a decreasing trend. These changing trends were maintained until 2 weeks post-treatment. CONCLUSION: Facial SD showed lower fungal diversity accompanied by increased relative abundances of Malassezia and Staphylococcus and decreased relative abundance of Cutibacterium. Ketoconazole treatment reduced Malassezia and increased fungal diversity to restore skin microbial communities.

The effectiveness of topical forms of dexamethasone in the treatment of oral lichen planus- A systematic review.

The goal of this systematic review was to assess the efficacy of dexamethasone compared to other treatments in oral lichen planus (OLP). The literature search used the following inclusion criteria: randomized controlled trials (RCT) comparing dexamethasone and other treatment strategies in patients with OLP. The outcome measures included relief of symptoms, decrement of erosive area size, and changes in quality of life. A computer and manual search was performed in Pubmed, Web of Science, and Cochrane Library up to January 31, 2021. The risk of bias was measured with the Revised Cochrane risk-of-bias tool for randomized trials. Eight trials with 131 study participants and 132 controls were identified. The following interventions were compared dexamethasone mouthwash, and 5% methylene blue-mediated photodynamic therapy, low-level laser therapy, amlexanox, clobetasol mouthwash, ketoconazole with amitriptyline, and thalidomide 1% paste. The therapeutic outcomes were more advantageous for dexamethasone in comparison with photodynamic therapy (PDT) (2 RCT) and low-level laser therapy (LLLT). Comparable effects were observed for dexamethasone, amlexanox, thalidomide, and PDT (1 RCT). Clobetasol showed more effective action than dexamethasone. Given the small sample sizes, heterogeneity and the few studies included, there is limited evidence to support the selection of treatment for OLP.

Ketoconazole Reverses Imatinib Resistance in Human Chronic Myelogenous Leukemia K562 Cells.

Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the oncogene BCR-ABL1, which encodes an oncoprotein with tyrosine kinase activity. Imatinib, a BCR-ABL1 tyrosine kinase inhibitor, performs exceptionally well with minimal toxicity in CML chemotherapy. According to clinical trials, however, 20-30% of CML patients develop resistance to imatinib. Although the best studied resistance mechanisms are BCR-ABL1-dependent, P-glycoprotein (P-gp, a drug efflux transporter) may also contribute significantly. This study aimed to establish an imatinib-resistant human CML cell line, evaluate the role of P-gp in drug resistance, and assess the capacity of ketoconazole to reverse resistance by inhibiting P-gp. The following parameters were determined in both cell lines: cell viability (as the IC50) after exposure to imatinib and imatinib + ketoconazole, P-gp expression (by Western blot and immunofluorescence), the intracellular accumulation of a P-gp substrate (doxorubicin) by flow cytometry, and the percentage of apoptosis (by the Annexin method). In the highly resistant CML cell line obtained, P-gp was overexpressed, and the level of intracellular doxorubicin was low, representing high P-gp activity. Imatinib plus a non-toxic concentration of ketoconazole (10 µM) overcame drug resistance, inhibited P-gp overexpression and its efflux function, increased the intracellular accumulation of doxorubicin, and favored greater apoptosis of CML cells. P-gp contributes substantially to imatinib resistance in CML cells. Ketoconazole reversed CML cell resistance to imatinib by targeting P-gp-related pathways. The repurposing of ketoconazole for CML treatment will likely help patients resistant to imatinib.

Medical treatment of recurrent ischaemic priapism: a review of current molecular therapeutics and a new clinical management paradigm.

OBJECTIVES: To examine the current molecular therapeutics in the medical treatment of recurrent ischemic priapism (RIP). To propose a stepwise clinical management paradigm for the treatment of RIP. METHODS: We performed a literature search using the PubMed database for the terms 'recurrent ischemic priapism' and 'stuttering priapism' up until December 2020. We assessed pre-clinical and clinical studies regarding medical management of RIP and molecular pathophysiology. Case series and randomized trials were evaluated by study quality and patient outcomes to determine a potential clinical management scheme. RESULTS: Recent research has fostered an improved understanding of the underlying molecular pathophysiology of RIP that has paved the way forward for developing new therapeutic agents. Medications targeting neurovascular, hormonal and haematological mechanisms associated with RIP show great promise towards remedying this condition. A host of therapeutic agents operating across different mechanistic directions may be implemented according to a clinical management scheme to potentially optimize RIP outcomes. CONCLUSION: RIP remains a medically neglected condition with current management focused on treating the acute condition rather than modulating the course of disease. Continued research into the molecular mechanisms of RIP and standardized clinical pathways can improve the quality of care for patients suffering from this condition.

Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushing's syndrome.

PURPOSE: The efficacy of levoketoconazole in treating hypercortisolism was demonstrated in an open-label phase 3 study (SONICS) of adults with endogenous Cushing's syndrome (CS) and baseline mean urinary free cortisol (mUFC) ≥ 1.5× ULN. Clinical signs and symptoms and patient-reported outcomes from the SONICS trial were evaluated in the current manuscript. METHODS: Patients titrated to an individualized therapeutic dose entered a 6-month maintenance phase. Secondary endpoints included investigator-graded clinical signs and symptoms of CS during the maintenance phase, and patient-reported quality of life (CushingQoL questionnaire) and depression symptoms (Beck Depression Inventory II [BDI-II]). RESULTS: Of 94 enrolled patients, 77 entered the maintenance phase following individualized dose titration. Significant mean improvements from baseline were noted at end of maintenance (Month 6) for acne, hirsutism (females only), and peripheral edema. These improvements were observed as early as Day 1 of maintenance for hirsutism (mean baseline score, 7.8; ∆ - 1.9; P < 0.0001), end of Month 1 for acne (mean baseline score, 2.8; ∆ - 1.2; P = 0.0481), and Month 4 for peripheral edema (mean baseline score, 1.0; ∆ - 0.5; P = 0.0052). Significant mean improvements from baseline were observed by Month 3 of maintenance for CushingQoL (mean baseline score, 44.3; ∆ + 6.9; P = 0.0018) and at Month 6 for BDI-II (mean baseline score, 17.1; ∆ - 4.3; P = 0.0043) scores. No significant mean improvement was identified in a composite score of 7 other clinical signs and symptoms. CONCLUSIONS: Treatment with levoketoconazole was associated with sustained, meaningful improvements in QoL, depression, and certain clinical signs and symptoms characteristic of CS. ClinialTrials.gov identifier: NCT01838551.

Thiol-ene Reaction: An Efficient Tool to Design Lipophilic Polyphosphoesters for Drug Delivery Systems.

Poly(ethylene glycol)-b-polyphosphoester (PEG-b-PPE) block copolymer nanoparticles are promising carriers for poorly water soluble drugs. To enhance the drug loading capacity and efficiency of such micelles, a strategy was investigated for increasing the lipophilicity of the PPE block of these PEG-b-PPE amphiphilic copolymers. A PEG-b-PPE copolymer bearing pendant vinyl groups along the PPE block was synthesized and then modified by thiol-ene click reaction with thiols bearing either a long linear alkyl chain (dodecyl) or a tocopherol moiety. Ketoconazole was used as model for hydrophobic drugs. Comparison of the drug loading with PEG-b-PPE bearing shorter pendant groups is reported evidencing the key role of the structure of the pendant group on the PPE backbone. Finally, a first evidence of the biocompatibility of these novel PEG-b-PPE copolymers was achieved by performing cytotoxicity tests. The PEG-b-PPE derived by tocopherol was evidenced as particularly promising as delivery system of poorly water-soluble drugs.

In vitro study on the potential fungicidal effects of atorvastatin in combination with some azole drugs against multidrug resistant Candida albicans.

The resistance of Candida albicans to azole drugs represents a great global challenge. This study investigates the potential fungicidal effects of atorvastatin (ATO) combinations with fluconazole (FLU), itraconazole (ITR), ketoconazole (KET) and voriconazole (VOR) against thirty-four multidrug-resistant (MDR) C. albicans using checkerboard and time-kill methods. Results showed that 94.12% of these isolates were MDR to ≥ two azole drugs, whereas 5.88% of them were susceptible to azole drugs. The tested isolates exhibited high resistance rates to FLU (58.82%), ITR (52.94%), VOR (47.06%) and KET (35.29%), whereas only three representative (8.82%) isolates were resistant to all tested azoles. Remarkably, the inhibition zones of these isolates were increased at least twofold with the presence of ATO, which interacted in a synergistic (FIC index ≤ 0.5) manner with tested azoles. In silico docking study of ATO and the four azole drugs were performed against the Lanosterol 14-alpha demethylase enzyme (ERG11) of C. albicans. Results showed that the mechanism of action of ATO against C. albicans is similar to that of azole compounds, with a docking score (-4.901) lower than azole drugs (≥5.0) due to the formation a single H-bond with Asp 225 and a pi-pi interaction with Thr 229. Importantly, ATO combinations with ITR, VOR and KET achieved fungicidal effects (≥ 3 Log10 cfu/ml reduction) against the representative isolates, whereas a fungistatic effect (≤ 3 Log10 cfu/ml reduction) was observed with FLU combination. Thus, the combination of ATO with azole drugs could be promising options for treating C. albicans infection.

Guinea pig seborrheic dermatitis model of Malassezia restricta and the utility of luliconazole.

Seborrheic dermatitis (SD) is a multifactorial disease in which Malassezia restricta has been proposed as the predominant pathogenic factor. However, experimental evidence supporting this hypothesis is limited. A guinea pig SD model using a clinical isolate of M. restricta was used to elucidate the pathogenicity of M. restricta. Also, the efficacy of 1% luliconazole (LLCZ) cream, a topical imidazole derivative, against M. restricta was compared with that of a 2% ketoconazole (KCZ) cream in the same guinea pig model. Dorsal skin hairs of guinea pig were clipped and treated with M. restricta by single or repeated inoculations without occlusion. Skin manifestations were examined macroscopically and histologically. A quantitative polymerase chain reaction (PCR) assay was also performed for mycological evaluation. An inflammatory response mimicking SD occurred after repeated as well as single inoculation but not in abraded skin. The inflammation score attained its maximum on day 11 and persisted until day 52. The yeast form of the fungal elements was distributed on the surface of stratum corneum and around the follicular orifices, and an epidermal and dermal histological reaction was observed. Application of 1% LLCZ or 2% KCZ cream significantly improved the skin manifestations and decreased the quantity of M. restricta rDNA in the skin lesions. The efficacy of topical antifungal drugs suggested that M. restricta is a pathogenic factor contributing to SD.

Unusual dermatomycoses caused by Nannizzia nana: the geophilic origin of human infections.

BACKGROUND: Fungal infections of the skin, hair, and nails are the largest and most widespread group of all mycoses. Nannizzia nana is a relatively rare etiological factor of dermatomycosis in humans, as it usually affects animals, e.g. pigs and boars. In addition to the zoophilic nature, there are also reports of the geophilic reservoir of this dermatophyte species. OBJECTIVE: In this study, we present symptomatic infections with N. nana aetiology in humans reported recently in Poland. Interestingly, these cases had a non-specific clinical picture and occurred as skin lesions on the neck and foot as well as onychomycosis of the toenails. From the medical history, the patients had no contact with pigs. METHODS: Diagnostics of these infections was performed with a combination of classical phenotypic and molecular genomic methods. The genomic diversity of the isolates was determined using the MP-PCR method. In vitro antifungal susceptibility tests against itraconazole, ketoconazole, terbinafine and naftifine hydrochloride were also performed. RESULTS: Nannizzia nana has been identified as an etiological factor of dermatomycosis. Moreover, heterogeneity of the genomes was revealed for the obtained strains. In vitro activities of antifungal agents showed that isolates were susceptible to all tested drugs. The patients were treated with oral terbinafine and topical ketoconazole cream, which led to a complete recovery. CONCLUSIONS: In conclusion, the cases studied by us may indicate that the infrequency of N. nana infections may not necessarily be related to the low infectivity of this fungal agent, but they are rather associated with misdiagnosis. Furthermore, N. nana reservoirs should also be sought in soil.

The Influence of Different Triazole Antifungal Agents on the Pharmacokinetics of Cyclophosphamide.

Background: Cyclophosphamide is one of the most important chemotherapeutic drugs. Known as a widely accepted treatment strategy, chemotherapy may damage the immune function of cancer patients; as a result, invasive fungal infections (IFIs) occur. Triazole antifungal agents are the most acceptable drugs for IFI treatment, especially those infections caused by chemotherapy. Objective: We aimed to investigate the effects of different triazole antifungal drugs, including fluconazole, itraconazole, and ketoconazole, on the pharmacokinetics (PK) of cyclophosphamide. In addition, we also characterize the potential drug-drug interactions (DDIs) between cyclophosphamide and various triazole antifungal drugs. Methods: The necessary pharmacokinetic parameters and physicochemical data were obtained from published studies. Physiologically based pharmacokinetic (PBPK) models were developed and validated in virtual subjects using Simcyp software. The validated PBPK models were used to evaluate potential DDIs between cyclophosphamide and different triazole antifungal agents in cancer patients. Triazole antifungal agents were simulated by oral administration, whereas cyclophosphamide was simulated by intravenous administration. Results: Simulated plasma concentration-time curves of fluconazole, itraconazole, ketoconazole, and cyclophosphamide were in good consistency with the observed profiles. Our results suggested that the pharmacokinetic parameters of cyclophosphamide were increased by various extents when coadministered with different triazole antifungals. The area under the plasma concentration-time curve of cyclophosphamide was increased when combined with fluconazole, itraconazole, or ketoconazole. Conclusions and Relevance: Ketoconazole had the greatest effect on the PK of cyclophosphamide among the 3 triazole antifungals. Our study provides clues that the toxicity and adverse drug reactions that are associated with cyclophosphamide should be closely monitored when coadministered with ketoconazole.

Cutaneous candidiasis - an evidence-based review of topical and systemic treatments to inform clinical practice.

Cutaneous candidiasis is a common skin disease, and several treatments have been investigated within the last fifty years. Yet, systematic reviews are lacking, and evidence-based topical and systemic treatment strategies remain unclear. Thus, the aim of this review was to summarize efficacy and adverse effects of topical and oral therapies for cutaneous candidiasis in all age groups. Two individual researchers searched PubMed and EMBASE for 'cutaneous candidiasis' and 'cutaneous candidiasis treatment', 'intertrigo', 'diaper dermatitis' and 'cheilitis'. Searches were limited to 'English language', 'clinical trials' and 'human subjects', and prospective clinical trials published in abstracts or articles were included. In total, 149 studies were identified, of which 44 were eligible, comprising 41 studies of 19 topical therapies and four studies of three systemic therapies for cutaneous candidiasis. Topical therapies were investigated in infants, children, adolescents, adults and elderly, while studies of systemic therapies were limited to adolescents and adults. Clotrimazole, nystatin and miconazole were the most studied topical drugs and demonstrated similar efficacy with complete cure rates of 73%-100%. Single-drug therapy was as effective as combinations of antifungal, antibacterial and topical corticosteroid. Four studies investigated systemic therapy, and oral fluconazole demonstrated similar efficacy to oral ketoconazole and topical clotrimazole. Limitations to this review were mainly that heterogeneity of studies hindered meta-analyses. In conclusions, clotrimazole, nystatin and miconazole were the most studied topical drugs and demonstrated equal good efficacy and mild adverse effects similar to combinations of antifungal, antibacterial and topical corticosteroids. Oral fluconazole was as effective as topical clotrimazole and is the only commercially available evidence-based option for systemic treatment of cutaneous candidiasis.

Effects of ketoconazole, voriconazole, and itraconazole on the pharmacokinetics of apatinib in rats.

We investigated the effect of azole antifungal drugs (ketoconazole, voriconazole, and itraconazole) on the pharmacokinetics of apatinib in rats. The rats in ketoconazole, voriconazole, and itraconazole groups received single-dose apatinib 30 mg/kg after the oral administration of ketoconazole, voriconazole, and itraconazole, respectively. Co-administration of ketoconazole or voriconazole significantly increased the apatinib Cmax and AUC(0-t) and decreased the clearance. Co-administration of itraconazole did not significantly affect the pharmacokinetics parameters of apatinib. It could be concluded that both ketoconazole and voriconazole significantly increase the exposure of apatinib, and affect the pharmacokinetics of apatinib in rat. Apatinib can be co-administered with itraconazole, but ketoconazole and voriconazole should be avoided if possible or be underwent therapeutic drug monitoring of apatinib. A further clinical study should be conducted to investigate the inhibitory effect of azole antifungal drugs on the apatinib plasma concentration.

Ketoconazole plus Lenalidomide in patients with Castration-Resistant Prostate Cancer (CRPC): results of an open-label phase II study.

Introduction Ketoconazole is CYP-17 inhibitor with demonstrated activity in men with castration-resistant prostate cancer (CRPC). Lenalidomide is an antiangiogenic and immunomodulatory agent with broad antitumor activity. We hypothesized that the modulation of the cellular immune response to apoptosis caused by ketoconazole may be increased with the addition of lenalidomide. Methods This is an open-label, non-randomized, single-arm phase II study evaluating the efficacy and safety of the combination of ketoconazole and lenalidomide in patients with CRPC. Treatment schema included standard ketoconazole 400 mg orally three times daily plus hydrocortisone orally (20 mg in the morning and 10 mg at night) in combination with lenalidomide 25 mg orally daily for 21 days in a 28-day cycle and aspirin 75 mg daily. The primary endpoint of this study was response (either by ≥ 50% PSA decline or objective disease assessed by RECIST v1.0). Exploratory endpoints included changes in T cell, dendritic cell (DC) marker counts, and their correlation with PSA response to treatment. Results A total of 34 CRPC patients, median age 69 years, 76% ECOG 0 and 76% with metastases participated in the study. Patients received a median of 2 cycles (range 1-35); nine patients (26%) received >10 cycles of treatment. PSA responses were observed in 17 patients (50%) with 11 patients (32%) achieving a PSA decline of >90%. Among the 9 patients with measurable disease, 2 patients (22%) had PR and 2 other (22%) had SD as best response. Median time to failure (TTF) was 2.7 months (range 0.2-32.8); and 8 patients were treated for ≥ 15 months. Most common adverse events included fatigue (76%), skin reactions (62%), lymphopenia (44%) and anemia (44%). One possible treatment-related death was noted. For 16 patients with available serial correlative data, there was a significant increase in the dendritic cells subsets BDCA-1 (+146.7, -20.1 to +501.1%, p = 0.018) and BDCA-3 (39.8%, -100 to 282.6%, p = 0.001) after 8 weeks of treatment. No association between immune cell counts and PSA response at 8 weeks was observed. Conclusion The combination of ketoconazole and lenalidomide was well tolerated but did not meet the primary endpoint of response, despite durable responses were observed in a selected group of patients. Although ketoconazole has now been replaced with more active novel agents, the combination of novel CYP-17 inhibitors with agents capable of modulating the immune system warrants further prospective investigation. NCT00460031.

Pityrosporum folliculitis: A retrospective review of 110 cases.

BACKGROUND: Pityrosporum folliculitis is an under-recognized eruption of the face and upper portion of the trunk that may be confused with, or occur simultaneously with, acne vulgaris. OBJECTIVE: We sought to characterize risk factors for Pityrosporum folliculitis, its clinical presentation, and its response to treatment. METHODS: A retrospective chart review was performed on all patients age 0 to 21 years seen at our facility from 2010 to 2015 with Pityrosporum folliculitis confirmed by a potassium hydroxide preparation. RESULTS: Of 110 qualifying patients, more than 75% had acne that had recently been treated with antibiotics, and when recorded, 65% reported pruritus. Clinical examination demonstrated numerous 1- to 2-mm monomorphic papules and pustules that were typically on the forehead extending into the hairline and on the upper portion of the back. The most common treatment was ketoconazole shampoo, which led to improvement or resolution in most cases. Some patients required oral azole antifungals. LIMITATIONS: This study was retrospective and relied on providers describing and interpreting the clinical findings and potassium hydroxide preparations. No standard grading system was used. CONCLUSION: Unlike classic acne vulgaris, Pityrosporum folliculitis was more common after antibiotic use. It presented as fine monomorphic, pruritic papules and pustules along the hairline and on the upper portion of the back, and it improved with topical or oral azole antifungal therapy.

Tinea capitis in children: a systematic review of management.

BACKGROUND: Tinea capitis is the most common cutaneous fungal infection in children. OBJECTIVES: This review aims to evaluate the differences that exist between medications for the treatment of tinea capitis, to determine whether there are any significant adverse effects associated and to define the usefulness of sample collection methods. METHODS: We conducted a systematic literature search of available papers using the databases PubMed, OVID, Cochrane Libraries and ClinicalTrials.gov. Twenty-one RCTs and 17 CTs were found. RESULTS: Among the different antifungal therapies (oral and combination thereof), continuous itraconazole and terbinafine had the highest mycological cure rates (79% and 81%, respectively), griseofulvin and terbinafine had the highest clinical cure rates (46% and 58%, respectively) and griseofulvin and terbinafine had the highest complete cure rate (72% and 92%, respectively). Griseofulvin more effectively treated Microsporum infections; terbinafine and itraconazole more effectively cured Trichophyton infections. Only 1.0% of children had to discontinue medication based on adverse events. T. tonsurans was the most common organism found in North America, and hairbrush collection method is the most efficient method of sample collection. Additionally, using a hairbrush, toothbrush or cotton swab to identify the infecting organism(s) is the least invasive and most efficient method of tinea capitis sample collection in children. CONCLUSIONS: Current dosing regimens of reported drugs are effective and safe for use in tinea capitis in children.

Oxythiamine improves antifungal activity of ketoconazole evaluated in canine Malassezia pachydermatis strains.

BACKGROUND: Malassezia pachydermatis is an opportunistic yeast involved in skin and ear canal infections of dogs and cats. Reports suggest that strains of M. pachydermatis resistant to commonly used antifungal agents may be emerging. Therefore, new therapeutic strategies should be explored. OBJECTIVES: The synergistic effect of oxythiamine (OT) and ketoconazole (KTC) was analysed using a reference strain and field isolates (n = 66) of M. pachydermatis. Hydrogel formulations containing these components also were evaluated. METHODS AND MATERIALS: The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of OT, KTC and their mixtures were determined by a broth macrodilution method. The antifungal effects of hydrogel formulations were determined by a plate diffusion method. RESULTS: The MIC and MFC values of OT were in the range 0.08 × 103 to 10 × 103  mg/L. All M. pachydermatis strains showed higher susceptibility to KTC (MICs and MFCs in the range 0.04-0.32 mg/L). Formulations that combined OT and KTC showed a synergistic effect for all tested isolates (n = 66). Hydrogels that contained OT at a concentration of 10 × 103 or 20 × 103  mg/L and KTC at the concentration of 0.1 × 103  mg/L showed a stronger effect than a commercially available product with KTC alone (20 × 103  mg/L). CONCLUSIONS AND CLINICAL IMPORTANCE: Synergy of these drugs may allow for successful topical treatment which utilizes lower doses of KTC without changing its therapeutic effectiveness. Hydrogel formulations proved to be attractive drug carriers for potential topical use.