Aspergillus fumigatus and aspergillosis: From basics to clinics.

The airborne fungus Aspergillus fumigatus poses a serious health threat to humans by causing numerous invasive infections and a notable mortality in humans, especially in immunocompromised patients. Mould-active azoles are the frontline therapeutics employed to treat aspergillosis. The global emergence of azole-resistant A. fumigatus isolates in clinic and environment, however, notoriously limits the therapeutic options of mould-active antifungals and potentially can be attributed to a mortality rate reaching up to 100 %. Although specific mutations in CYP 51A are the main cause of azole resistance, there is a new wave of azole-resistant isolates with wild-type CYP 51A genotype challenging the efficacy of the current diagnostic tools. Therefore, applications of whole-genome sequencing are increasingly gaining popularity to overcome such challenges. Prominent echinocandin tolerance, as well as liver and kidney toxicity posed by amphotericin B, necessitate a continuous quest for novel antifungal drugs to combat emerging azole-resistant A. fumigatus isolates. Animal models and the tools used for genetic engineering require further refinement to facilitate a better understanding about the resistance mechanisms, virulence, and immune reactions orchestrated against A. fumigatus. This review paper comprehensively discusses the current clinical challenges caused by A. fumigatus and provides insights on how to address them.

Potent in vitro activity of curcumin and quercetin co-encapsulated in nanovesicles without hyaluronan against Aspergillus and Candida isolates.

The rapid emergence of resistance to classical antifungals has increased the interest in novel antifungal compounds. Curcumin and quercetin are two natural plant-derived bioactive molecules shown to promote wound healing in injured tissues. In this study, we investigated the in vitro susceptibility of several Aspergillus and Candida isolates to curcumin and quercetin encapsulated in nanovesicles with and without hyaluronan and elucidated the efficacy of these nanovesicles as topical drug delivery systems. Antifungal susceptibility testing performed according to the CLSI guidelines indicated that curcumin-quercetin co-encapsulated in nanovesicles without hyaluronan (CUR-QUE-NV-WH) had stronger activity against Candida isolates than fluconazole. Furthermore, CUR-QUE-NV-WH showed efficacy against fluconazole-resistant Candida isolates as evidenced by MICs at least two times lower than those of fluconazole. Examination of skin permeation profiles using an in vitro Franz diffusion cell system revealed that curcumin and quercetin delivered by nanovesicles were released and accumulated in the skin; however, only quercetin could penetrate through the skin layers. Collectively, our results demonstrate that CUR-QUE-NV-WH has potent antifungal activity against Candida isolates and might be a topical treatment, which warrants its further investigation as a novel antifungal agent.

Combination of Amphotericin B and Flucytosine against Neurotropic Species of Melanized Fungi Causing Primary Cerebral Phaeohyphomycosis.

Primary central nervous system phaeohyphomycosis is a fatal fungal infection due mainly to the neurotropic melanized fungiCladophialophora bantiana,Rhinocladiella mackenziei, andExophiala dermatitidis.Despite the combination of surgery with antifungal treatment, the prognosis continues to be poor, with mortality rates ranging from 50 to 70%. Therefore, a search for a more-appropriate therapeutic approach is urgently needed. Ourin vitrostudies showed that with the combination of amphotericin B and flucytosine against these species, the median fractional inhibitory concentration (FIC) indices for strains ranged from 0.25 to 0.38, indicating synergy. By use of Bliss independence analysis, a significant degree of synergy was confirmed for all strains, with the sum ΔE ranging from 90.2 to 698.61%. No antagonism was observed. These results indicate that amphotericin B, in combination with flucytosine, may have a role in the treatment of primary cerebral infections caused by melanized fungi belonging to the orderChaetothyriales Furtherin vivostudies and clinical investigations to elucidate and confirm these observations are warranted.

Clinical features, diagnosis, and outcomes of rhino-orbito-cerebral mucormycosis- A retrospective analysis.

BACKGROUND AND PURPOSE: Rhino-orbito-cerebral mucormycosis (ROCM) is a rare disease with acute and fulminant manifestation. This infection is associated with high morbidity and mortality rates. Herein, we reviewed the manifestations, underlying conditions, medical treatments, and surgical interventions in ROCM patients admitted to a tertiary referral center in northern Iran over a seven-year period. MATERIALS AND METHODS: In a retrospective analysis, 15 cases of ROCM were identified from 2007 to 2013 in Bu Ali Sina Hospital, Sari, Iran. All the ROCM cases were clinically diagnosed and confirmed by histopathological and/or mycological examination. The relevant demographic data, clinical, ophthalmic, and neurologic manifestations, underlying conditions, medical treatments, and surgical interventions were recorded and analyzed. RESULTS: The mean age of the patients was 54±11 years (age range: 28-70 years); 26.7% of the patients were male and 73.3% female (male: female ratio of 1: 2.7). Uncontrolled diabetes was noted in at least 86.7% (13/15) of the cases. The maxillary sinuses were the most frequently involved sites (66.7% of the cases) followed by the ethmoid sinus. Amphotericin B in combination with surgical debridement was used in the treatment of 80% of the cases. Furthermore, 73.3% of the patients who were diagnosed early and underwent medical and extensive surgical debridement of the infected tissues survived. CONCLUSION: Uncontrolled diabetes mellitus is considered to be the main predisposing factor for ROCM. To prevent and reduce mortality rate of this acute disease, early diagnosis based on clinical findings and biopsy is recommended.

Aspergillus species in indoor environments and their possible occupational and public health hazards.

The genus Aspergillus, which consists of a few hundred opportunistic mold species found in various climatic conditions, causes diseases including localized infections, fatal diseases, allergic responses, and inhaled conidia in humans. Herein, we present an overview of the most common diseases and allergic infections caused by Aspergillus species and their associated health hazards in various indoor environments worldwide.

In vitro antifungal susceptibility of Trichophyton violaceum isolated from tinea capitis patients.

OBJECTIVES: Trichophyton violaceum is an anthropophilic dermatophyte that is endemic to parts of Africa and Asia and is sporadic in Europe. T. violaceum mainly causes tinea capitis in both children and adolescents. Although the infections caused by T. violaceum are of considerable medical importance, its antifungal susceptibility profile remains poorly examined. METHODS: In this study, we tested the in vitro antifungal susceptibility of a set of clinical T. violaceum isolates obtained from tinea capitis patients, using the CLSI broth microdilution method. We tested eight antifungals and used isolates collected from Western China (21), Eastern China (12), the Middle East (1), Europe (20), South Africa (7) and Canada (1). RESULTS: The geometric means of the MICs of the antifungals for all isolates were as follows (in increasing order): posaconazole, 0.021 mg/L; terbinafine, 0.023 mg/L; voriconazole, 0.062 mg/L; amphotericin B, 0.20 mg/L; itraconazole, 0.34 mg/L; caspofungin, 0.56 mg/L; fluconazole, 4.23 mg/L; and flucytosine, 8.46 mg/L. No statistically significant differences in the susceptibility profiles of T. violaceum were detected within the geographical regions tested. CONCLUSIONS: Posaconazole, terbinafine and voriconazole were shown to be the most potent antifungal agents against T. violaceum isolates obtained from tinea capitis patients worldwide. These results might help clinicians in developing appropriate therapies that have a high probability of successfully treating tinea capitis due to T. violaceum.

Candida vaginitis during contraceptive use: the influence of methods, antifungal susceptibility and virulence patterns.

No consensus exists about whether contraceptives cause an increased risk of vaginitis, including vulvovaginal candidosis (VVC). We investigated 495 women (252 who used contraceptives; 243 who did not) for the presence of VVC. Antifungal susceptibility testing was performed for five antifungal agents and for boric acid, and three virulence factors were also examined. We recovered 129 (26.1%) monofungal populations from vaginal samples of women with acute VVC (AVVC, n = 18), symptomatic recurrent VVC (RVVC, n = 22) and asymptomatic RVVC (n = 28), as well as of other contraceptive users who carried Candida in their vaginas (n = 61). It is important to note that the women who had VVC used the same contraceptive methods (p > 0.05). Candida albicans was the most common species isolated (45%), followed by C. glabrata (40.3%). Most of the vaginal yeast isolates exhibited low minimum inhibitory concentration levels for the five antifungals tested. However, this was not the case for boric acid. In addition, the yeast fungi that was derived from the AVVC and RVVC patients showed higher amounts of haemolytic activity than the yeast fungi found among the controls (p < 0.05). The use of contraception does not predispose women to VVC (p > 0.05). Also, both host- and organism-related factors were required to achieve optimal clinical treatment for VVC.

Candida vaginitis in non-pregnant patients: a study of antifungal susceptibility testing and virulence factors.

Vulvovaginal candidosis (VVC) is a major problem for the female population worldwide, and considerably little is known about the difference between acute VVC (AVVC) and recurrent VVC (RVVC). We investigated the susceptibility to six antifungal agents and boric acid of Candida spp. isolated from vaginal cultures, as described in the CLSI document M27-A3, from 228 non-pregnant sexually active women (aged 18-49 years), and the virulence factors of these isolates. The isolates were derived from patients with AVVC (n = 64), those with RVVC (n = 125) and those without signs or symptoms (n = 39). In total, C. albicans was the most commonly isolated species (50%), followed by C. glabrata (35.5%) and other Candida spp. (14.5%). We observed slightly different minimum inhibitory concentration (MICs) for various antifungals among the species and study groups that could have potential therapeutic benefits for the treatment. Analysis of the virulence factors revealed that haemolytic activity is not involved in VVC pathogenesis but that germ-tube formation, adhesion to VECs, and proteinase and phospholipase production may be important in the pathogenesis of VVC.

Comparison of hairbrush, toothbrush and cotton swab methods for diagnosing asymptomatic dermatophyte scalp carriage.

BACKGROUND: Tinea capitis may also present as a minimal infection, termed carrier state. Anthropophilic dermatophytes (i.e. Trichophyton tonsurans and Trichophyton violaceum) have been generally associated with high rates of asymptomatic carriage. OBJECTIVES: The aim of this study was to compare the efficacy of the hairbrush, toothbrush and cotton swab methods for diagnosing scalp carriage as well as to determine the prevalence and related dermatophyte species for both asymptomatic and symptomatic tinea capitis in Adana Province, Turkey. PATIENTS AND METHODS: A screening study was carried out between February 2006 and May 2006, covering three schools and a total of 1560 children with 857 (54.9%) boys and 703 (45.1%) girls, aged between 7 and 17 years (10.6 +/- 2.3 years). The diagnosis was made by using three of the methods mentioned above with inoculation onto Sabouraud glucose agar. RESULTS: Symptomatic tinea capitis was not detected in the study; however, 21 (1.3%) asymptomatic carriers, with 9 (42.9%) boys and 12 (57.1%) girls, aged 7 to 13 years (9.7 +/- 1.9 years) were detected. The diagnosis was made via hairbrush in 13, via cotton swab in 4 and via toothbrush in 4. The mean age (P = 0.075) and gender differences were found to be statistically insignificant (P = 0.26). The most common isolated species was Trichophyton mentagrophytes var. mentagrophytes (90.4%) followed by Trichophyton audouinii (4.8%) and Microsporum gypseum (4.8%). Nine children had Arab origin (P = 0.005), and 12 had immigrated from the south-eastern region of Anatolia, Turkey. The screening of 32 households of 21 children with asymptomatic carriage enabled the researchers to detect the carrier state in three mothers and one sister, resulting in a total of four households (12.5%), with T. mentagrophytes var. mentagrophytes isolated, by hairbrush method in three cases and cotton swab in one case. If the methods were to be used alone, the prevalence of asymptomatic carriage would be found as 1.0% (16 of 1592) in the hairbrush, 0.3% (4 of 1592) in the toothbrush and 0.3% (5 of 1592) in the cotton swab methods; whereas the combined use of these three methods could reveal a total prevalence of 1.6% (25 of 1592). The hairbrush method was significantly found to be more effective in detecting dermatophyte fungi than the toothbrush (P < 0.01) and the cotton swab methods (P < 0.05). There was also a statistically significant difference between the use of a single method and the combination of all other three methods (P < 0.005). CONCLUSIONS: In summary, it was found that the prevalence of asymptomatic carriage did not cover symptomatic tinea capitis prevalence (1.6% vs. 0%), and the dominant species was zoophilic T. mentagrophytes (92%, 23 of 25). Asymptomatic carriage was not found to be related to age, gender and the coexistence of other dermatophytoses; however, race (Arab origin) was found to be the only risk factor. For laboratory diagnosis, no method was found to be nominated as a gold standard; hence, a combined use of diagnosing methods was suggested.

Clinical and mycological efficacy of single-day oral treatment with itraconazole (400 mg) in acute vulvovaginal candidosis.

This study aimed to investigate the effectiveness of single-day oral treatment with itraconazole in acute vulvovaginal candidosis (VVC). Vaginitis was demonstrated by both detection of yeast cells and pseudohyphae formation on microscopic examination of vaginal discharge and mycological culture as well as by the clinical signs and symptoms. Clinical and mycological examinations of the 52 patients were performed before, 1 week (short-term) and 4 weeks (long-term) after single-day oral treatment with itraconazole 200 mg b.i.d. The causative yeast fungi were: Candida albicans (76.9%), C. glabrata (9.6%), C. kefyr (9.6%) and C. krusei (3.9%), respectively. In short- and long-term examinations, clinical cure rates were found to be 61.5% and 90.4%, and mycological cure rates were 63.5% and 90.4%, respectively. Itraconazole was found to be 95.0% effective with C. albicans and 75.0% with other Candida species. It is concluded that treatment of acute VVC with itraconazole is safe and effective in the long-term.

Detection of Cryptococcus neoformans var. grubii in honeybee (Apis mellifera) colonies.

The plant flora has an important role in the ecology of Cryptococcus neoformans. It is estimated that the environmental spreading and contamination of human beings with this yeast occurs via contaminated particles of plants. Cultivation of canopy parts of plants in selective media is the most widely used isolation method of this yeast. Cryptococcus neoformans var. grubii was isolated from honeybee colonies in Eucalyptus forests but was not isolated from the places where this flora did not exist. Our results indicate that the occurrence of C. neoformans in honeybee colonies during the flowering season of Eucalyptus spp. trees can be an important bioindicator for environmental yeast presence. The screening of honeybee colonies is a practical and a rapid method for the monitoring of the C. neoformans presence in flowering plants.

Prevalence and causative agents of superficial mycoses in a textile factory in Adana, Turkey.

This study was carried out in a textile factory settled in the city center of Adana, Turkey. The workers were evaluated for the presence of superficial mycoses and the interaction of their working environment or working condition. A total of 431 textile workers were included in the study, with a male to female ratio of 378 (87.7%) to 53 (12.3%) and an age range of 19-52 (mean: 33.7 +/- 6.8). Direct examination and/or culture revealed superficial mycoses in 73 (16.9%) workers, among them 56 (76.7%) were classified as dermatophytoses, 8 (11.0%) as Pityriasis versicolor while in nine (12.3%) of the cases, no causative agent could be determined. Trichophyton rubrum (57.1%) and T. mentagrophytes (42.9%) were the two species isolated on culture. This study emphasized that textile workers should be admitted as a risk group for superficial mycoses, especially tinea pedis.