RESUMEN
Staphylococcus aureus is a leading cause of hospital- and community-acquired infections. Despite current advances in antimicrobial chemotherapy, the infections caused by S. aureus remain challenging due to their ability to readily develop resistance. Indeed, antibiotic resistance, exemplified by methicillin-resistant S. aureus (MRSA) is a top threat to global health security. Furthermore, the current rate of antibiotic discovery is much slower than the rate of antibiotic-resistance development. It seems evident that the conventional in vitro bacterial growth-based screening strategies can no longer effectively supply new antibiotics at the rate needed to combat bacterial antibiotic-resistance. To overcome this antibiotic resistance crisis, screening assays based on host-pathogen interactions have been developed. In particular, the free-living nematode Caenorhabditis elegans has been used for drug screening against MRSA. In this review, we will discuss the general principles of the C. elegans-based screening platform and will highlight its unique strengths by comparing it with conventional antibiotic screening platforms. We will outline major hits from high-throughput screens of more than 100,000 small molecules using the C. elegans-MRSA infection assay and will review the mode-of-action of the identified hit compounds. Lastly, we will discuss the potential of a C. elegans-based screening strategy as a paradigm shift screening platform.
Asunto(s)
Antibacterianos/farmacología , Caenorhabditis elegans/microbiología , Evaluación Preclínica de Medicamentos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Animales , Ensayos Analíticos de Alto Rendimiento , Humanos , Resistencia a la Meticilina , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant 'persister' subpopulations that exhibit high levels of tolerance to antibiotics and have a role in chronic or recurrent infections. As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans-MRSA infection screen to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.
Asunto(s)
Antibacterianos/clasificación , Antibacterianos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Retinoides/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Animales , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Benzoatos/química , Benzoatos/farmacología , Benzoatos/uso terapéutico , Benzoatos/toxicidad , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/microbiología , Muerte Celular/efectos de los fármacos , Línea Celular , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Gentamicinas/farmacología , Gentamicinas/uso terapéutico , Humanos , Membrana Dobles de Lípidos/química , Staphylococcus aureus Resistente a Meticilina/citología , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Ratones , Pruebas de Sensibilidad Microbiana , Simulación de Dinámica Molecular , Mutación , Naftoles/química , Naftoles/farmacología , Naftoles/uso terapéutico , Naftoles/toxicidad , Retinoides/química , Retinoides/uso terapéutico , Retinoides/toxicidadRESUMEN
Francisella tularensis is a highly infectious Gram-negative intracellular pathogen that causes tularemia. Because of its potential as a bioterrorism agent, there is a need for new therapeutic agents. We therefore developed a whole-animal Caenorhabditis elegans-F. tularensis pathosystem for high-throughput screening to identify and characterize potential therapeutic compounds. We found that the C. elegans p38 mitogen-activate protein (MAP) kinase cascade is involved in the immune response to F. tularensis, and we developed a robust F. tularensis-mediated C. elegans killing assay with a Z' factor consistently of >0.5, which was then utilized to screen a library of FDA-approved compounds that included 1,760 small molecules. In addition to clinically used antibiotics, five FDA-approved drugs were also identified as potential hits, including the anti-inflammatory drug diflunisal that showed anti-F. tularensis activity in vitro Moreover, the nonsteroidal anti-inflammatory drug (NSAID) diflunisal, at 4× MIC, blocked the replication of an F. tularensis live vaccine strain (LVS) in primary human macrophages and nonphagocytic cells. Diflunisal was nontoxic to human erythrocytes and HepG2 human liver cells at concentrations of ≥32 µg/ml. Finally, diflunisal exhibited synergetic activity with the antibiotic ciprofloxacin in both a checkerboard assay and a macrophage infection assay. In conclusion, the liquid C. elegans-F. tularensis LVS assay described here allows screening for anti-F. tularensis compounds and suggests that diflunisal could potentially be repurposed for the management of tularemia.
Asunto(s)
Antibacterianos/farmacología , Antiinflamatorios/farmacología , Caenorhabditis elegans/efectos de los fármacos , Francisella tularensis/efectos de los fármacos , Animales , Vacunas Bacterianas/inmunología , Caenorhabditis elegans/inmunología , Línea Celular Tumoral , Ciprofloxacina/farmacología , Eritrocitos/microbiología , Francisella tularensis/inmunología , Células Hep G2 , Humanos , Hígado/microbiología , Macrófagos/microbiología , Vacunas Atenuadas/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
INTRODUCTION: The emergence of antibiotic-resistant and -tolerant bacteria is a major threat to human health. Although efforts for drug discovery are ongoing, conventional bacteria-centered screening strategies have thus far failed to yield new classes of effective antibiotics. Therefore, new paradigms for discovering novel antibiotics are of critical importance. Caenorhabditis elegans, a model organism used for in vivo, offers a promising solution for identification of anti-infective compounds. Areas covered: This review examines the advantages of C. elegans-based high-throughput screening over conventional, bacteria-centered in vitro screens. It discusses major anti-infective compounds identified from large-scale C. elegans-based screens and presents the first clinically-approved drugs, then known bioactive compounds, and finally novel small molecules. Expert opinion: There are clear advantages of using a C. elegans-infection based screening method. A C. elegans-based screen produces an enriched pool of non-toxic, efficacious, potential anti-infectives, covering: conventional antimicrobial agents, immunomodulators, and anti-virulence agents. Although C. elegans-based screens do not denote the mode of action of hit compounds, this can be elucidated in secondary studies by comparing the results to target-based screens, or conducting subsequent target-based screens, including the genetic knock-down of host or bacterial genes.
Asunto(s)
Antibacterianos/farmacología , Caenorhabditis elegans , Descubrimiento de Drogas/métodos , Animales , Antibacterianos/toxicidad , Bacterias/efectos de los fármacos , Bacterias/genética , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Farmacorresistencia Bacteriana , Técnicas de Silenciamiento del Gen , Ensayos Analíticos de Alto Rendimiento/métodos , HumanosRESUMEN
Persisters are a subpopulation of normal bacterial cells that show tolerance to conventional antibiotics. Persister cells are responsible for recalcitrant chronic infections and new antibiotics effective against persisters would be a major development in the treatment of these infections. Using the reporter dye SYTOX Green that only stains cells with permeabilized membranes, we developed a fluorescence-based screening assay in a 384-well format for identifying compounds that can kill methicillin-resistant Staphylococcus aureus (MRSA) persisters. The assay proved robust and suitable for high throughput screening (Z`-factor: >0.7). In screening a library of hits from a previous screen, which identified compounds that had the ability to block killing of the nematode Caenorhabditis by MRSA, we discovered that the low molecular weight compound NH125, a bacterial histidine kinase inhibitor, kills MRSA persisters by causing cell membrane permeabilization, and that 5 µg/mL of the compound can kill all cells to the limit of detection in a 108 CFU/mL culture of MRSA persisters within 3h. Furthermore, NH125 disrupts 50% of established MRSA biofilms at 20 µg/mL and completely eradicates biofilms at 160 µg/mL. Our results suggest that the SYTOX Green screening assay is suitable for large-scale projects to identify small molecules effective against MRSA persisters and should be easily adaptable to a broad range of pathogens that form persisters. Since NH125 has strong bactericidal properties against MRSA persisters and high selectivity to bacteria, we believe NH125 is a good anti-MRSA candidate drug that should be further evaluated.
Asunto(s)
Antibacterianos/farmacocinética , Biopelículas/efectos de los fármacos , Caenorhabditis elegans/microbiología , Fluorescencia , Staphylococcus aureus Resistente a Meticilina/fisiología , Infecciones Estafilocócicas/tratamiento farmacológico , Animales , Antibacterianos/química , Evaluación Preclínica de Medicamentos , Compuestos Orgánicos/químicaRESUMEN
Chromoblastomycosis, a chronic fungal infection of skin and subcutaneous tissue caused by dematiaceous fungi, is associated with low cure and high relapse rates. Among all factors affecting clinical outcome, etiological agents have an important position. In southern China, Fonsecaea pedrosoi and Fonsecaea monophora are main causative agents causing Chromoblastomycosis. We treated one case of chromoblastomycosis by photodynamic therapy (PDT) of 5-aminolevulinic acid (ALA) irradiation combined with terbinafine 250 mg a day. The lesions were improved after two sessions of ALA-PDT treatment, each including nine times, at an interval of 1 week, combined with terbinafine 250 mg/day oral, and clinical improvement could be observed. In the following study, based on the clinical treatment, the effect of PDT and antifungal drugs on this isolate was detected in vitro. It showed sensitivity to terbinafine, itraconazole or voriconazole, and PDT inhibited the growth. Both the clinic and experiments in vitro confirm the good outcome of ALA-PDT applied in the inhibition of F. monophora. It demonstrated that combination of antifungal drugs with ALA-PDT arises as a promising alternative method for the treatment of these refractory cases of chromoblastomycosis.
Asunto(s)
Antifúngicos/uso terapéutico , Ascomicetos/efectos de los fármacos , Cromoblastomicosis/tratamiento farmacológico , Naftalenos/uso terapéutico , Fotoquimioterapia , Ácido Aminolevulínico/uso terapéutico , Ascomicetos/genética , Ascomicetos/aislamiento & purificación , Quimioterapia Combinada , Humanos , Itraconazol/uso terapéutico , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Piel/microbiología , Terbinafina , Resultado del Tratamiento , Voriconazol/uso terapéuticoRESUMEN
OBJECTIVE: Biologic agents are increasingly used to treat patients with rheumatoid arthritis (RA). We aimed to review their association with opportunistic infections (OIs), including fungal, viral (with a focus on herpesvirus-related infections), tuberculosis and other mycobacterial infections. METHODS: We searched PubMed and EMBASE through June 24, 2013, and complemented the search with the reference lists of eligible articles. The analysis included randomized trials on RA that compared any approved biologic agent with controls and reported the risk of OIs. RESULTS: A total of 70 trials that included 32 504 patients (21 916 patients receiving biologic agents and 10 588 receiving placebo) were deemed eligible. Biologic agents increased the risk of OIs (pooled Peto odds ratio [OR], 1.79; 95% confidence interval [CI], 1.17-2.74; I(2) = 3%), resulting in 1.7 excess infections per 1000 patients treated (number needed to harm, 582). A significant risk was noted for mycobacterial (OR, 3.73; 95% CI, 1.72-8.13; I(2) = 0), and viral (OR, 1.91; 95% CI, 1.02-3.58; I(2) = 0) infections. Interestingly, no significant differences were found for invasive and superficial fungal infections (1.31; 95% CI, .46-3.72), invasive fungal infections (2.85; .68-11.91), P. jirovecii pneumonia (1.77; .42-7.47), varicella-zoster virus (1.51; .71-3.22), as well as overall mortality attributed to OIs (1.91; .29-12.64). CONCLUSIONS: Among patients with RA, biologic agents are associated with a small but significant risk of specific OIs. This increase is associated with mycobacterial diseases and does not seem to affect overall mortality. Because OIs are a relatively rare complication of biologic agents, large registries are needed to identify the exact effect in different OIs and to compare the different biologic agents.
Asunto(s)
Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Terapia Biológica/efectos adversos , Infecciones por Mycobacterium/epidemiología , Micosis/epidemiología , Infecciones Oportunistas/epidemiología , Virosis/epidemiología , Anticuerpos Monoclonales/efectos adversos , Humanos , Infecciones Oportunistas/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de RiesgoRESUMEN
Staphylococcus aureus, the leading cause of hospital-acquired infections in the United States, is also pathogenic to the model nematode Caenorhabditis elegans. The C. elegans-S. aureus infection model was previously carried out on solid agar plates where the bacteriovorous C. elegans feeds on a lawn of S. aureus. However, agar-based assays are not amenable to large scale screens for antibacterial compounds. We have developed a high throughput liquid screening assay that uses robotic instrumentation to dispense a precise amount of methicillin resistant S. aureus (MRSA) and worms in 384-well assay plates, followed by automated microscopy and image analysis. In validation of the liquid assay, an MRSA cell wall defective mutant, MW2ΔtarO, which is attenuated for killing in the agar-based assay, was found to be less virulent in the liquid assay. This robust assay with a Z'-factor consistently greater than 0.5 was utilized to screen the Biomol 4 compound library consisting of 640 small molecules with well characterized bioactivities. As proof of principle, 27 of the 30 clinically used antibiotics present in the library conferred increased C. elegans survival and were identified as hits in the screen. Surprisingly, the antihelminthic drug closantel was also identified as a hit in the screen. In further studies, we confirmed the anti-staphylococcal activity of closantel against vancomycin-resistant S. aureus isolates and other Gram-positive bacteria. The liquid C. elegans-S. aureus assay described here allows screening for anti-staphylococcal compounds that are not toxic to the host.
Asunto(s)
Antibacterianos/farmacología , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/microbiología , Evaluación Preclínica de Medicamentos/métodos , Staphylococcus aureus Resistente a Meticilina/genética , Animales , Ensayos Analíticos de Alto Rendimiento/métodos , Salicilanilidas , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Pterostilbene (PTE) is a stilbene-derived phytoalexin that originates from several natural plant sources. In this study, we evaluated the activity of PTE against Candida albicans biofilms and explored the underlying mechanisms. In 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assays, biofilm biomass measurement, confocal laser scanning microscopy, and scanning electron microscopy, we found that ≤16 µg/ml PTE had a significant effect against C. albicans biofilms in vitro, while it had no fungicidal effect on planktonic C. albicans cells, which suggested a unique antibiofilm effect of PTE. Then we found that PTE could inhibit biofilm formation and destroy the maintenance of mature biofilms. At 4 µg/ml, PTE decreased cellular surface hydrophobicity (CSH) and suppressed hyphal formation. Gene expression microarrays and real-time reverse transcription-PCR showed that exposure of C. albicans to 16 µg/ml PTE altered the expression of genes that function in morphological transition, ergosterol biosynthesis, oxidoreductase activity, and cell surface and protein unfolding processes (heat shock proteins). Filamentation-related genes, especially those regulated by the Ras/cyclic AMP (cAMP) pathway, including ECE1, ALS3, HWP1, HGC1, and RAS1 itself, were downregulated upon PTE treatment, indicating that the antibiofilm effect of PTE was related to the Ras/cAMP pathway. Then, we found that the addition of exogenous cAMP reverted the PTE-induced filamentous growth defect. Finally, with a rat central venous catheter infection model, we confirmed the in vivo activity of PTE against C. albicans biofilms. Collectively, PTE had strong activities against C. albicans biofilms both in vitro and in vivo, and these activities were associated with the Ras/cAMP pathway.
Asunto(s)
Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Biopelículas/efectos de los fármacos , Candida albicans/efectos de los fármacos , Candida albicans/fisiología , Estilbenos/farmacología , Estilbenos/uso terapéutico , Animales , Candida albicans/metabolismo , Femenino , Proteínas Fúngicas/metabolismo , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica de Rastreo , Ratas , Ratas Sprague-DawleyRESUMEN
Bacteriophages were discovered almost a century ago. With the advent of antibiotics, the use of bacteriophages for treatment of infections fell out of favor in Western medicine. In light of the rise of antibiotic resistance, phages and their products (lysins) are rediscovered as antibacterial bioagents. This overview summarizes principles of phage biology and their translation for therapeutic and preventive applications. Examples are presented to highlight their therapeutic promise for prophylaxis and treatment of bacterial infections including multidrug-resistant organisms in humans and animals, and their use as decontaminants of food supplies and environments. Besides research on the in vivo behavior of phages and lysins, dialogues between researchers and regulatory agencies are necessary to publish guidelines for bacteriophage manufacturing and formulation for human use. Only well-designed, double-blind randomized controlled trials will determine if phages and lysins are safe and effective adjuncts or alternatives to antibiotic therapy for infections with multidrug-resistant organisms.
Asunto(s)
Bacterias/virología , Infecciones Bacterianas/terapia , Infecciones Bacterianas/veterinaria , Bacteriófagos/crecimiento & desarrollo , Terapia Biológica/métodos , Endopeptidasas/uso terapéutico , Animales , Infecciones Bacterianas/prevención & control , Terapia Biológica/efectos adversos , Ensayos Clínicos como Asunto , Endopeptidasas/efectos adversos , HumanosRESUMEN
Candida albicans is an opportunistic fungal pathogen capable of life-threatening disseminated infections particularly in immunocompromised patients. Resistance to many clinically used antifungal agents has created a need to identify and develop a new generation of compounds for therapeutic use. A compound screen to identify potential antifungal natural products was undertaken, identifying 12 saponins, some of which have not been previously described. In the Caenorhabditis elegans model, some saponins conferred nematode survival comparable to that of amphotericin B. Of the 12 antifungal saponins identified, two were selected for further analysis. C. albicans isolates were inhibited by these compounds at relatively low concentrations (16 and 32 microg mL(-1)) including isolates resistant to clinically used antifungal agents. C. albicans hyphae and biofilm formation were also disrupted in the presence of these natural products, and studies demonstrate that fungal cells in the presence of saponins are more susceptible to salt-induced osmotic stress. Although saponins are known for their hemolytic activity, no hemolysis of erythrocytes was observed at three times the minimal inhibitory concentration for C. albicans, suggesting the saponins may have a preference for binding to fungal ergosterol when compared to cholesterol. Importantly, when used in combination with photosensitizer compounds, the fungus displayed increased susceptibility to photodynamic inactivation due to the ability of the saponins to increase cell permeability, thereby facilitating penetration of the photosensitizers. The large proportion of compounds identified as antifungal agents containing saponin structural features suggests it may be a suitable chemical scaffold for a new generation of antifungal compounds.
Asunto(s)
Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Extractos Vegetales/farmacología , Saponinas/farmacología , Animales , Antifúngicos/química , Interacciones Farmacológicas , Eritrocitos/efectos de los fármacos , Fluconazol/farmacología , Hemólisis/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Presión Osmótica/efectos de los fármacos , Fotoquímica , Extractos Vegetales/química , Saponinas/química , OvinosRESUMEN
Candida albicans, the most common human pathogenic fungus, can establish a persistent lethal infection in the intestine of the microscopic nematode Caenorhabditis elegans. The C. elegans-C. albicans infection model was previously adapted to screen for antifungal compounds. Modifications to this screen have been made to facilitate a high-throughput assay including co-inoculation of nematodes with C. albicans and instrumentation allowing precise dispensing of worms into assay wells, eliminating two labor-intensive steps. This high-throughput method was utilized to screen a library of 3,228 compounds represented by 1,948 bioactive compounds and 1,280 small molecules derived via diversity-oriented synthesis. Nineteen compounds were identified that conferred an increase in C. elegans survival, including most known antifungal compounds within the chemical library. In addition to seven clinically used antifungal compounds, twelve compounds were identified which are not primarily used as antifungal agents, including three immunosuppressive drugs. This assay also allowed the assessment of the relative minimal inhibitory concentration, the effective concentration in vivo, and the toxicity of the compound in a single assay.
Asunto(s)
Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Técnicas Químicas Combinatorias , Pruebas de Sensibilidad Microbiana , Animales , Caenorhabditis elegans , Química Farmacéutica/métodos , Diseño de Fármacos , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Inmunosupresores/uso terapéutico , MutaciónRESUMEN
Invasive fungal infections are a leading cause of mortality among immunocompromised individuals. Treatment is notoriously difficult with the limited armamentarium of antifungal drugs, whose efficacy is compromised by host toxicity, a limited activity spectrum, or the emergence of drug resistance. We previously established that the molecular chaperone Hsp90 enables the emergence and maintenance of fungal drug resistance. For the most prevalent fungal pathogen of humans, Candida albicans, Hsp90 mediates resistance to azoles, which inhibit ergosterol biosynthesis and are the most widely deployed antifungals in the clinic. For the emerging opportunistic pathogen Aspergillus terreus, Hsp90 is required for basal resistance to echinocandins, which inhibit beta(1, 3)-glucan synthesis and are the only new class of antifungals to reach the clinic in decades. Here, we explore the therapeutic potential of Hsp90 inhibitors in fungal disease using a tractable host-model system, larvae of the greater wax moth Galleria mellonella, and a murine model of disseminated disease. Combination therapy with Hsp90 inhibitors that are well tolerated in humans and an azole rescued larvae from lethal C. albicans infections. Combination therapy with an Hsp90 inhibitor and an echinocandin rescued larvae from infections with the most lethal mold, Aspergillus fumigatus. In a murine model of disseminated candidiasis, genetic compromise of C. albicans HSP90 expression enhanced the therapeutic efficacy of an azole. Thus, harnessing Hsp90 provides a much-needed strategy for improving the treatment of fungal disease because it enhances the efficacy of existing antifungals, blocks the emergence of drug resistance, and exerts broad-spectrum activity against diverse fungal pathogens.
Asunto(s)
Proteínas HSP90 de Choque Térmico/fisiología , Micosis/terapia , Animales , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Fluconazol/farmacología , Fluconazol/uso terapéutico , Hongos/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/genética , Humanos , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Micosis/tratamiento farmacológico , Micosis/microbiología , Micosis/fisiopatologíaRESUMEN
The rising incidence of invasive fungal infections and the emergence of broader fungal resistance have led to the need for novel antifungal agents. Posaconazole is a new member of the triazole class of antifungals. It is available as an oral suspension and has a favorable toxicity profile, has demonstrated clinical efficacy in the treatment of oropharyngeal candidiasis and has shown promise as salvage therapy for invasive aspergillosis, zygomycosis, cryptococcal meningitis and a variety of other fungal infections. In addition, data from randomized controlled studies support its efficacy for use in prophylaxis of invasive fungal infections in patients who are severely immunocompromised. The wide spectrum activity of posaconazole in in vitro studies, animal models and preliminary clinical studies suggest that posaconazole represents an important addition to the antifungal armamentarium.
Asunto(s)
Antifúngicos/uso terapéutico , Micosis/tratamiento farmacológico , Triazoles/uso terapéutico , Animales , Antifúngicos/efectos adversos , Antifúngicos/farmacocinética , Antifúngicos/farmacología , Modelos Animales de Enfermedad , Farmacorresistencia Fúngica , Hongos/efectos de los fármacos , Humanos , Huésped Inmunocomprometido , Pruebas de Sensibilidad Microbiana , Terapia Recuperativa , Triazoles/efectos adversos , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
The incidence of oesophageal candidiasis, candidaemia and disseminated candidiasis has increased dramatically. In addition to the amphotericin B formulations and fluconazole, the echinocandins anidulafungin, caspofungin and micafungin and the newer triazoles posaconazole and voriconazole are in the last stages of development and are becoming available for the management of candidiasis. This review presents these new agents and addresses their role in the treatment of candidiasis. All new antifungal agents exhibit potent activity against Candida spp. and echinocandins are fungicidal against most Candida spp. but appear to be less potent against certain species, such as Candida parapsilosis and C. guilliermondii. Systemic antifungal therapy can now be individualised based on the severity of the infection, comorbid conditions and the Candida spp. causing the infection. Studies are needed to investigate the possible development of resistance and the efficacy of these antifungal agents against the more resistant Candida spp.
Asunto(s)
Antifúngicos/uso terapéutico , Candidiasis/tratamiento farmacológico , Drogas en Investigación/uso terapéutico , Animales , Candida/efectos de los fármacos , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
New triazole antifungals (voriconazole, posaconazole, ravuconazole and albaconazole) have been developed to meet the increasing need for new antifungals, and address the rising incidence of invasive fungal infections and the emergence of fungal resistance. This report describes the spectrum of activity of the newer-generation triazoles based on data from in vitro, animal and clinical studies. The authors discuss the use of these agents in combination with other antifungals, the extent of cross-resistance, their toxicity profile and pharmacokinetic properties. A total of two agents are currently available: voriconazole (which is becoming a primary treatment for the management of invasive aspergillosis) and posaconazole (which demonstrates a broad antifungal spectrum). A further two agents, albaconazole and ravuconazole, are undergoing early clinical evaluation and their future is uncertain. For all newer triazoles, concerns about emerging drug-resistant fungi and the incidence and management of breakthrough infections will dictate their role in antifungal prophylaxis and treatment.