Efficacy Of Antifungal Drugs Research Articles

Curcumin potentiates the fungicidal effect of dodecanol by inhibiting drug efflux in wild-type budding yeast.

Drug resistance commonly occurs when treating immunocompromised patients who have fungal infections. Curcumin, is a compound isolated from Curcuma longa, has been reported to inhibit drug efflux in several human cell lines and nonpathogenic budding yeast Saccharomyces cerevisiae cells that overexpresses the ATP-binding cassette (ABC) transporters S. cerevisiae Pdr5p and pathogenic Candida albicans Cdr1p and Cdr2p. The aim of this study was to examine the effects of curcumin on multidrug resistance in a wild-type strain of the budding yeast with an intrinsic expression system of multidrug efflux-related genes. The antifungal activity of dodecanol alone was temporary against S. cerevisiae; however, restoration of cell viability was completely inhibited when the cells were co-treated with dodecanol and curcumin. Furthermore, restriction of rhodamine 6G (R6G) efflux from the cells and intracellular accumulation of R6G were observed with curcumin treatment. Reverse transcription-polymerase chain reaction analysis revealed that curcumin reduced the dodecanol-induced overexpression of the ABC transporter-related genes PDR1, PDR3 and PDR5 to their control levels in untreated cells. Curcumin can directly restrict the glucose-induced drug efflux and inhibits the expression of the ABC transporter gene PDR5, and can thereby inhibit the efflux of dodecanol from S. cerevisiae cells. Curcumin is effective in potentiating the efficacy of antifungal drugs via its effects on ABC transporters. SIGNIFICANCE AND IMPACT OF THE STUDY: Drug resistance is common in immunocompromised patients with fungal infections. Curcumin, isolated from Curcuma longa, inhibits drug efflux in nonpathogenic budding yeast Saccharomyces cerevisiae cells overexpressing ABC transporters S. cerevisiae Pdr5p and pathogenic Candida albicans Cdr1p and Cdr2p. We examined the effects of curcumin on multidrug resistance in a wild-type strain of the budding yeast with an intrinsic expression system of multidrug efflux-related genes. Curcumin directly inhibited drug efflux and also suppressed the PDR5 expression, thereby enhancing the antifungal effects. Thus, curcumin potentially promotes the efficacy of antifungals via its effects on ABC transporters in wild-type fungal strains.

Efficacy of antifungal drugs in the treatment of vulvovaginal candidiasis: a Bayesian network meta-analysis.

PurposeAntifungal drugs are used frequently in the treatment of vulvovaginal candidiasis (VVC), but have shown controversial results. In this study, we aimed to evaluate the effectiveness of different antifungal drugs in the treatment of VVC and to provide an evidence-based reference for clinical use.MethodsThe published studies on the effectiveness of antifungal drugs in the treatment of VVC (up to April 2018) were retrieved from PubMed, Embase, the Cochrane Library, and Clini-calTrials.gov. We sifted through the literature according to Patients, Interventions, Comparisons and Outcomes principle, extracted data on the basic characteristics of the study, and evaluated the quality of included studies. We used R software for statistical analysis.ResultsIn total, 41 randomized controlled trials were included in this meta-analysis. The relative risk of VVC associated with ten drugs, including placebo, fluconazole, clotrimazole, miconazole, itraconazole, ketoconazole, econazole, butoconazole, terbinafine, and terconazole, was analyzed. The following drugs appeared to show more efficacy than placebo in the treated patients: fluconazole (OR =6.45, 95% CrI 4.42–9.41), clotrimazole (OR =2.99, 95% CrI 1.61–5.55), miconazole (OR =5.96, 95% CrI 3.17–11.2), itraconazole (OR =2.29, 95% CrI 1.21–4.33), ketoconazole (OR =2.40, 95% CrI 1.55–3.71), butoconazole (OR =1.18, 95% CrI 1.06–1.31), and terconazole (OR =5.60, 95% CrI 2.78–11.3). The value of surface under the cumulative ranking curve of each drug was as follows: placebo (0.5%), fluconazole (91.5%), clotrimazole (61.8%), miconazole (33.8%), itraconazole (50.5%), ketoconazole (42.8%), econazole (46.8%), butoconazole (82.2%), terbinafine (20.9%), and terconazole (65.0%).ConclusionAntifungal drugs are effective in the treatment of VVC. Fluconazole appeared to be the best drug for the treatment of VVC according to our analysis.

The Use of Galleria mellonella Larvae to Identify Novel Antimicrobial Agents against Fungal Species of Medical Interest.

The immune system of insects and the innate immune response of mammals share many similarities and, as a result, insects may be used to assess the virulence of fungal pathogens and give results similar to those from mammals. Larvae of the greater wax moth Galleria mellonella are widely used in this capacity and also for assessing the toxicity and in vivo efficacy of antifungal drugs. G. mellonella larvae are easy to use, inexpensive to purchase and house, and have none of the legal/ethical restrictions that are associated with use of mammals. Larvae may be inoculated by intra-hemocoel injection or by force-feeding. Larvae can be used to assess the in vivo toxicity of antifungal drugs using a variety of cellular, proteomic, and molecular techniques. Larvae have also been used to identify the optimum combinations of antifungal drugs for use in the treatment of recalcitrant fungal infections in mammals. The introduction of foreign material into the hemocoel of larvae can induce an immune priming effect which may operate independently with the activity of the antifungal drug. Procedures to identify this effect and limit its action are required.

Effect of combination therapy with ceftizoxime and clotrimazole in the treatment of otomycosis


 
 
 
 
 Background and Purpose: There are controversial findings regarding the efficacy of antifungal drugs in the treatment of a ruptured eardrum following fungal infections. Regarding this, the aim of the present study was to evaluate the therapeutic effect of the co-administration of antifungal and antibacterial agents in the treatment of otomycosis with tympanic membrane perforation.
 Materials and Methods: This analytical, clinical trial was conducted on 87 patients with otomycosis showing no bacterial elements in the direct observation and culture. The study population was assigned into two groups of intervention (n=45) and control (n=42). The demographic and clinical data, as well as the data related to the direct observation and culture of the ear samples were recorded in a checklist. All statistical analysis was performed in SPSS (version 24).
 Results: The most prevalent symptoms in both groups were hearing loss and itching, and the most common finding was secretion. Aspergillus and Candida were the most frequent fungi isolated from the samples. After the implementation of combination therapy, the intervention group demonstrated a significant decrease in symptoms and signs, compared to the control group (P=0.005).
 Conclusion: The findings of the present study indicated that the use combination therapy with ceftizoxime powder and clotrimazole ointment was effective the in treatment of the patients with tympanic membrane rupture showing no bacterial effects in direct examination and culture.
 
 
 

Effect of combination therapy with ceftizoxime and clotrimazole in the treatment of otomycosis.

Background and Purpose:There are controversial findings regarding the efficacy of antifungal drugs in the treatment of a ruptured eardrum following fungal infections. Regarding this, the aim of the present study was to evaluate the therapeutic effect of the co-administration of antifungal and antibacterial agents in the treatment of otomycosis with tympanic membrane perforation.Materials and Methods: This analytical, clinical trial was conducted on 87 patients with otomycosis showing no bacterial elements in the direct observation and culture. The study population was assigned into two groups of intervention (n=45) and control (n=42). The demographic and clinical data, as well as the data related to the direct observation and culture of the ear samples were recorded in a checklist. All statistical analysis was performed in SPSS (version 24).Results:The most prevalent symptoms in both groups were hearing loss and itching, and the most common finding was secretion. Aspergillus and Candida were the most frequent fungi isolated from the samples. After the implementation of combination therapy, the intervention group demonstrated a significant decrease in symptoms and signs, compared to the control group (P=0.005).Conclusion:The findings of the present study indicated that the use combination therapy with ceftizoxime powder and clotrimazole ointment was effective the in treatment of the patients with tympanic membrane rupture showing no bacterial effects in direct examination and culture.

Amphotericin B-conjugated polypeptide hydrogels as a novel innovative strategy for fungal infections.

The present work is focused on the design and development of novel amphotericin B (AmB)-conjugated biocompatible and biodegradable polypeptide hydrogels to improve the antifungal activity. Using three kinds of promoting self-assembly groups (2-naphthalene acetic acid (Nap), naproxen (Npx) and dexamethasone (Dex)) and polypeptide sequence (Phe-Phe-Asp-Lys-Tyr, FFDKY), we successfully synthesized the Nap-FFDK(AmB)Y gels, Npx-FFDK(AmB)Y gels and Dex-FFDK(AmB)Y gels. The AmB-conjugated hydrogelators are highly soluble in different aqueous solutions. The cryo-transmission electron microscopy and scanning electron microscopy micrographs of hydrogels afford nanofibres with a width of 20–50 nm. Powder X-ray diffraction analyses demonstrate that the crystalline structures of the AmB and Dex are changed into amorphous structures after the formation of hydrogels. Circular dichroism spectra of the solution of blank carriers and the corresponding drug deliveries further help elucidate the molecular arrangement in gel phase, indicating the existence of turn features. The in vitro drug releases suggest that the AmB-conjugated hydrogels are suitable as drug-controlled release vehicles for hydrophobic drugs. The antifungal effect of AmB-conjugated hydrogels significantly exhibits the antifungal activity against Candida albicans. The results of the present study indicated that the AmB-conjugated hydrogels are suitable carriers for poorly water soluble drugs and for enhancement of therapeutic efficacy of antifungal drugs.

Identification of yeast deletions strains that alter the efficacy of antifungal drugs

In recent years, a significant increase in mortality of patients with fungal infections has been observed. This is primarily due to a higher incidence of individuals who are immunocompromised including HIV‐infected patients, patients undergoing cancer therapy, organ transplant recipients, and patients with advanced stages of diabetes. A complication in treating patients with fungal infections is the development of drug resistant fungi. With the limited number of effective antifungal drugs and the increase of drug resistance, fungal infections and pathogenesis is a major threat to human health. The proposed studies help to solve this issue by identifying genes that alter antifungal drug sensitivity. Our central hypothesis is that a subset of transcriptional regulators are needed for pathways critical for altering antifungal drug resistance. This project used growth assays to determine the effects of the antifungal drugs, ketoconazole and amphotericin B, on yeast deletions strains. Overall, the proposed work will have an impact on human health related to fungal pathogenesis and drug resistance.Support or Funding InformationNational Science Foundation

Extensive functional redundancy in the regulation of Candida albicans drug resistance and morphogenesis by lysine deacetylases Hos2, Hda1, Rpd3 and Rpd31.

Current treatment efforts for fungal infections are hampered by the limited availability of antifungal drugs and by the emergence of drug resistance. A powerful strategy to enhance the efficacy of antifungal drugs is to inhibit the molecular chaperone Hsp90. Hsp90 governs drug resistance, morphogenesis and virulence in a leading fungal pathogen of humans, Candida albicans. Our previous work with Saccharomyces cerevisiae established acetylation as a novel mechanism of posttranslational control of Hsp90 function in fungi. We implicated lysine deacetylases (KDACs) as key regulators of resistance to the most widely deployed class of antifungals, the azoles, in both S. cerevisiae and C. albicans. Here, we demonstrate high levels of functional redundancy among the KDACs that are important for regulating Hsp90 function. We identify Hos2, Hda1, Rpd3 and Rpd31 as the KDACs mediating azole resistance and morphogenesis in C. albicans. Furthermore, we identify lysine 30 and 271 as critical acetylation sites onC. albicans Hsp90, and substitutions at these residues compromise Hsp90 function. Finally, we show that pharmacological inhibition of KDACs phenocopies pharmacological inhibition of Hsp90 and abrogates Hsp90-dependent azole resistance in numerous Candida species. This work illuminates new facets to the impact of KDACs on fungal drug resistance and morphogenesis, provides important insights into the divergence of the C. albicans Hsp90 regulatory network and reveals new targets for development of antifungal drugs.

Melanins Protect Sporothrix brasiliensis and Sporothrix schenckii from the Antifungal Effects of Terbinafine.

Terbinafine is a recommended therapeutic alternative for patients with sporotrichosis who cannot use itraconazole due to drug interactions or side effects. Melanins are involved in resistance to antifungal drugs and Sporothrix species produce three different types of melanin. Therefore, in this study we evaluated whether Sporothrix melanins impact the efficacy of antifungal drugs. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) of two Sporothrix brasiliensis and four Sporothrix schenckii strains grown in the presence of the melanin precursors L-DOPA and L-tyrosine were similar to the MIC determined by the CLSI standard protocol for S. schenckii susceptibility to amphotericin B, ketoconazole, itraconazole or terbinafine. When MICs were determined in the presence of inhibitors to three pathways of melanin synthesis, we observed, in four strains, an increase in terbinafine susceptibility in the presence of tricyclazole, a DHN-melanin inhibitor. In addition, one S. schenckii strain grown in the presence of L-DOPA had a higher MFC value when compared to the control. Growth curves in presence of 2×MIC concentrations of terbinafine showed that pyomelanin and, to a lesser extent, eumelanin were able to protect the fungi against the fungicidal effect of this antifungal drug. Our results suggest that melanin protects the major pathogenic species of the Sporothrix complex from the effects of terbinafine and that the development of new antifungal drugs targeting melanin synthesis may improve sporotrichosis therapies.

Role of Antifungal Susceptibility Testing in Non-Aspergillus Invasive Mold Infections.

No clinical breakpoints are available to delineate antifungal drug efficacy in non-Aspergillus invasive mold infections (NAIMIs). In this analysis of 39 NAIMI episodes, the MIC of the first-line antifungal drug was the most important predictor of therapeutic response. For amphotericin B, an MIC of ≤0.5 μg/ml was significantly associated with better 6-week outcomes.

The iron-responsive microsomal proteome of Aspergillus fumigatus

Aspergillus fumigatus is an opportunistic fungal pathogen. Siderophore biosynthesis and iron acquisition are essential for virulence. Yet, limited data exist with respect to the adaptive nature of the fungal microsomal proteome under iron-limiting growth conditions, as encountered during host infection. Here, we demonstrate that under siderophore biosynthetic conditions — significantly elevated fusarinine C (FSC) and triacetylfusarinine C (TAFC) production (p<0.0001), extensive microsomal proteome remodelling occurs. Specifically, a four-fold enrichment of transmembrane-containing proteins was observed with respect to whole cell lysates following ultracentrifugation-based microsomal extraction. Comparative label-free proteomic analysis of microsomal extracts, isolated following iron-replete and -deplete growth, identified 710 unique proteins. Scatterplot analysis (MaxQuant) demonstrated high correlation amongst biological replicates from each growth condition (Pearson correlation >0.96 within groups; biological replicates (n=4)). Quantitative and qualitative comparison revealed 231 proteins with a significant change in abundance between the iron-replete and iron-deplete conditions (p<0.05, fold change ≥2), with 96 proteins showing increased abundance and 135 with decreased abundance following iron limitation, including predicted siderophore transporters. Fluorescently labelled FSC was only sequestered following A. fumigatus growth under iron-limiting conditions. Interestingly, human sera exhibited significantly increased reactivity (p<0.0001) against microsomal protein extracts obtained following iron-deplete growth. Biological significanceThe opportunistic fungal pathogen Aspergillus fumigatus must acquire iron to facilitate growth and pathogenicity. Iron-chelating non-ribosomal peptides, termed siderophores, mediate iron uptake via membrane-localised transporter proteins. Here we demonstrate for the first time that growth of A. fumigatus under iron-deplete conditions, concomitant with siderophore biosynthesis, leads to an extensive remodelling of the microsomal proteome which includes significantly altered levels of 231 constituent proteins (96 increased and 135 decreased in abundance), many of which have not previously been localised to the microsome. We also demonstrate the first synthesis of a fluorescent version of fusarinine C, an extracellular A. fumigatus siderophore, and its uptake and localization under iron-restricted conditions. This infers the use of an A. fumigatus siderophore as a ‘Trojan horse’ to potentiate the efficacy of anti-fungal drugs. Finally, in addition to revealing the Aspergillus-specific IgG reactivity in normal human sera against microsomal proteins, there appears to be a significantly increased reactivity against microsomal proteins obtained following iron-restricted growth. We hypothesise that iron-limiting environment in humans, which has evolved to nutritionally limit pathogen growth in vivo, may also alter the fungal microsomal proteome.

Topical Amphotericin B solid lipid nanoparticles: Design and development

The present work is focused on design and development of topical Amphotericin B solid lipid nanoparticles (SLNs) to improve the therapeutic antifungal activity. Amphotericin B loaded SLNs were prepared by novel solvent diffusion method and were characterized for particle size, zeta potential, drug entrapment, surface morphology, in vitro antifungal activity, ex vivo permeation, retention and skin-irritation. Optimized SLNs were spherical with average size of 111.1±2.2nm, zeta potential of −23.98±1.36mV and 93.8±1.8% of drug entrapment. Characterization of Amphotericin B SLNs by differential scanning calorimetry, Fourier transform infrared spectroscopy and Powder X-ray diffraction studies revealed absence of interaction between Amphotericin B and lipid. Amphotericin B is well dispersed in the lipid matrix without any crystallization. The SLNs were lyophilized with and without cryoprotectants to evaluate the stability and it was observed that the particle size of the SLNs significantly increased in SLN formulations lyophilized without cryoprotectant. The optimized SLN 5 formulation exhibited 2 fold higher drug permeation as compared to plain drug dispersion and higher zone of inhibition in Trichophyton rubrum fungal species. Formulation was found to be stable at 2–8°C and 25±2°C for the period of three months. Results of present study indicate that SLNs are suitable carriers for entrapment of poorly water soluble drugs and for enhancement of therapeutic efficacy of antifungal drug.

Galleria mellonella: An invertebrate model to study pathogenicity in correctly defined fungal species

The high mortality rates and economic burden associated with fungal infections, plus the emergence of fungal strains resistant to antifungal drugs, make it necessary to get a deeper understanding of fungal pathogenesis, as well as to identify new target structures for antifungal drug development. Still, murine models are considered as the gold standard for studying pathogenesis, quantifying virulence, and analysing the efficacy of antifungal drugs. However, invertebrates, such as the larvae of the greater wax moth Galleria mellonella, are promising alternative hosts to address some of these questions, especially when a large number of fungal strains need to be evaluated. The purpose of this review is to summarize the benefits and drawbacks, explain the utilization of the invertebrate model host G. mellonella, and compare the virulence potential of the most important human fungal pathogens, with the focus on different virulence potential of closely related species.

Aspergillus Spondylodiscitis in Immunocompetent Patients: A Report of Two Cases

Introduction The term spondylodiscitis refers to infection of the disc space and adjacent vertebrae. It is commonly caused by Mycobacterium tuberculosis and bacterial pathogens; whereas fungal spondylodiscitis is extremely rare in immunocompetent individuals.1 The reported incidence of fungal spondylodiscitis in studies is 0.5 to 1.6%.2 Aspergillus species (normal inhabitants of the respiratory tract) are commonly responsible for fungal spondylodiscitis. They invade the spine in immunocompromised hosts, such as postorgan transplant, chronic steroid treatment, or chemotherapy.3,4 Only a few case reports are published on aspergillus spondylodiscitis in immunocompetent persons.5,6 Tubercular and pyogenic spondylodiscitis being more common, fungal causes are often ignored.1,2 The absence of specific clinical and radiological features often makes the diagnosis challenging and this delay causes more spinal destruction with devastating consequences. We are reporting two cases of aspergillus spondylodiscitis in immunocompetent patients, the diagnostic dilemma, and its management. Materials and Methods: Case 1: A 33-year-old female patient presented with severe back pain with visual analog score (VAS) as 8. She had recent history of cesarean section under spinal anesthesia. MRI was suggestive of infective spondylodiscitis L2–L3. The patient underwent surgical disco-vertebral debridement, posterior stabilization, and interbody fusion. Aspergillus fumigatus was isolated from the surgical specimen. No evidence of an immunosuppressive status was found. Postoperatively, she was treated with intravenous voriconazole 4 mg/kg body weight twice daily for 1 week followed by oral voriconazole 200 mg twice daily for 3 months. Case 2: A 40-year-old male patient presented with progressive low back pain, 4 weeks after microlumbar discectomy. Examination revealed tenderness in lower lumbar region with associated paraspinal muscle spasm without any neurological deficits. MRI was suggestive of infective spondylodiscitis L4–L5. The patient underwent surgical disco-vertebral debridement, posterior stabilization, and fusion. Aspergillus flavus was isolated from the surgical specimen. There was no evidence of immunosuppressive status. Postoperatively, he was treated with intravenous voriconazole 4 mg/kg body weight twice daily for 3 weeks followed by oral voriconazole 200 mg twice daily for 3 months. Results: The patients were evaluated after 1 week and followed-up at the 1st, 3rd, and 6th month. In case 1, ESR, C-reactive protein (CRP), and total leukocyte count (TLC) normalized in 1 week. In case 2, ESR was normal throughout and TLC normalized after 3 weeks. Pain reduced dramatically after surgery and both patients had total relief from pain by 1 month. Gradual signs of radiological union at interbody site were noticed during follow-ups and total fusion was noticed by the end of 3 months in both the patients. The course of treatment was uneventful. Conclusion: Aspergillus spondylodiscitis is a diagnostic and therapeutic challenge. Fungal spondylodiscitis affecting immunocompetent patient being rare, a differential diagnosis of the same should always be kept in mind. We recommend that tissue sample should always be sent for fungal culture and sensitivity in addition to routine bacterial and tubercular culture. Surgical debridement helps in decreasing fungal load, which in turn increases the efficacy of antifungal drugs, and thus prevents rapid progression of invasive aspergillosis and subsequent neurological damage.

Progress and prospects for targeting Hsp90 to treat fungal infections

Fungal pathogens pose a major threat to human health worldwide. They infect billions of people each year, leading to at least 1·5 million deaths. Treatment of fungal infections is difficult due to the limited number of clinically useful antifungal drugs, and the emergence of drug resistance. A promising new strategy to enhance the efficacy of antifungal drugs and block the evolution of drug resistance is to target the molecular chaperone Hsp90. Pharmacological inhibitors of Hsp90 function that are in development as anticancer agents have potential to be repurposed as agents for combination antifungal therapy for some applications, such as biofilm infections. For systemic infections, however, effective combination therapy regimens may require Hsp90 inhibitors that can selectively target Hsp90 in the pathogen, or alternate strategies to compromise function of the Hsp90 chaperone machine. Selectively impairing Hsp90 function in the pathogen could in principle be achieved by targeting Hsp90 co-chaperones or regulators of Hsp90 function that are more divergent between pathogen and host than Hsp90. Antifungal combination therapies could also exploit downstream effectors of Hsp90 that are critical for fungal drug resistance and virulence. Here, we discuss the progress and prospects for establishing Hsp90 as an important therapeutic target for life-threatening fungal infections.

The non-mammalian hostGalleria mellonellacan be used to study the virulence of the fungal pathogenCandida tropicalisand the efficacy of antifungal drugs during infection by this pathogenic yeast

Although Candida tropicalis is a frequent cause of invasive fungal diseases, its interaction with the host remains poorly studied. Galleria mellonella is a Lepidoptera model which offers a useful tool to study virulence of different microorganisms and drug efficacy. In this work we investigated the virulence of C. tropicalis in G. mellonella at different temperatures and the efficacy of antifungal drugs in this infection model. When larvae were infected with yeast inocula suspensions of different concentrations (4 × 10(6), 2 × 10(6), 10(6) and 5 × 10(5) cells/larva), we observed a dose-dependent effect on the killing of the insect (50% survival ranging from 1.4 ± 0.8 to 8.8 ± 1.2 days with the higher and lower inocula, respectively). Candida tropicalis killed G. mellonella larvae at both 30°C and 37°C, although at 37°C the virulence was more evident. Haemocytes phagocytosed C. tropicalis cells after 2 hours of infection, although the phagocytosis rate was lower when compared with other fungal pathogens, such as Cryptococcus neoformans. Moreover, the haemocyte density in the haemolymph decreased during infection and the yeast formed pseudohyphae in G. mellonella. The efficacy of amphotericin B, caspofungin, fluconazole and voriconazole was tested at different concentrations, and a protective effect was observed with all the drugs at concentrations equivalent to therapeutic dose. Fungal burden increased in infected larvae during time of infection and amphotericin B and fluconazole reduced the number of colony-forming units in the worms. Moreover, antifungal treatment was associated with the presence of cell aggregates around infected areas. We conclude that G. mellonella offers a simple and feasible model to study C. tropicalis virulence and drug efficacy.

Pleiotropic drug resistance ABC transporters in fungi

Overexpression of pleiotropic drug resistance (PDR) efflux pumps of the ATP-binding cassette (ABC) transporter superfamily is the major cause of fungal multi-drug resistance and decreased efficacy of antifungal drugs. This review focused on recent progresses in understanding of the PDR efflux pumps of ABC transporter superfamily in Saccharomyces cerevisiae and the fungal pathogens Candida albicans, Cryptococcus neoformans, and Aspergillus fumigates. The mechanisms underlying efflux pump-mediated drug resistance and the regulatory networks involved were discussed. Investigation of the PDR efflux pumps of ABC transporter superfamily and their impact on drug resistance may lead to strategies to overcome fungal multi-drug resistance and improve drug efficacy.

Topical delivery of antifungal agents

Importance of the field: Superficial fungal infections of skin, hair, nails and the eye are among the most widespread diseases known to man. Topical therapy is the most favored form of treatment for these infections because it lends itself to self-administration, patient compliance, and absence of systemic adverse effects.Areas covered in this review: The clinical efficacy of antifungal drugs depends on the concentration achieved in cutaneous/ocular tissue, which in turn depends on the molecular mass, route of administration, duration of contact and ability of the compound to penetrate the tissue. Several of these agents have a high molecular mass > 500 Da (such as amphotericin B, natamycin, or ketoconazole), resulting in their poor penetration (even if they are lipophilic in nature). The latter causes relapse infections and requires frequent administration. Packaging these agents into suitable delivery systems can improve the effectiveness of these agents. The usefulness of liposomes/niosomes, lipid emulsions, nanoparticles including solid lipid nanoparticles and microemulsions for development of these agents is discussed.What the reader will gain: This article aims to discuss limitations to the topical therapy of antifungal agents, and delivery approaches used to enhance their effectiveness.Take home message: A physicochemical and pharmacokinetic guided approach can help to tailor-make therapeutically effective systems for existing antifungal agents, thus doing away with the need for newer agents, which will save on time, money and manpower.

Aspergillusspecies intrinsically resistant to antifungal agents

Polyphasic taxonomy has had a major impact on the species concept of the genus Aspergillus. New sibling species have been described that exhibit in vitro susceptibility profiles that differ significantly from that of Aspergillus fumigatus. While acquired resistance is an emerging problem in A. fumigatus, non-A. fumigatus Aspergillus species may be intrinsically resistant to specific classes of antifungal agents. Minimum inhibitory concentrations of amphotericin B and azoles for some of the non-A. fumigatus Aspergillus species are elevated compared to A. fumigatus. Furthermore, the clinical presentation and evolution of invasive infections caused by these species may differ from that commonly observed for A. fumigatus. As the role of the newly identified Aspergillus species in causing invasive aspergillosis remains unclear, surveillance networks that incorporate sequence-based identification of clinical isolates are needed to determine the species distribution, the clinical disease and outcome of patients with invasive aspergillosis. Preclinical and clinical studies are needed to further improve the methods for in vitro susceptibility testing and to investigate the impact of elevated MICs on antifungal drug efficacy.

Antifungal Dose Adjustment in Renal and Hepatic Dysfunction: Pharmacokinetic and Pharmacodynamic Considerations

Adjusting the dose of antifungal agents for renal and hepatic impairment can be challenging given that clinicians must rely on limited pharmacokinetic data to derive specific regimens. These pharmacokinetic studies are typically performed in a small number of patients without invasive fungal infection, and results are not often reported in concert with accepted pharmacodynamic indices. This article aims to review pertinent pharmacokinetic studies of antifungal drugs in patients with renal or hepatic dysfunction. The impact of novel continuous renal replacement therapy techniques on the pharmacokinetic disposition of antifungal agents will also be described where data are available. Subsequently, this review provides recommendations for antifungal drug dosing in patients with kidney or liver dysfunction after accounting for established or emerging pharmacokinetic-pharmacodynamic relationships as they relate to antifungal drug efficacy in vivo.