Leaf-cutting ants such as Acromyrmex octospinosus live in obligate symbiosis with fungi of the genus Leucoagaricus, which they grow with harvested leaf material. The symbiotic fungi, in turn, serve ...as a major food source for the ants. This mutualistic relation is disturbed by the specialized pathogenic fungus Escovopsis sp., which can overcome Leucoagaricus sp. and thus destroy the ant colony. Microbial symbionts of leaf-cutting ants have been suggested to protect the fungus garden against Escovopsis by producing antifungal compounds Currie CR, Scott JA, Summerbell RC, Malloch D (1999) Fungus-growing ants use antibiotic-producing bacteria to control garden parasites. Nature 398:701-704.. To date, however, the chemical nature of these compounds has remained elusive. We characterized 19 leaf-cutting ant-associated microorganisms (5 Pseudonocardia, 1 Dermacoccus, and 13 Streptomyces) from 3 Acromyrmex species, A. octospinosus, A. echinatior, and A. volcanus, using 16S-rDNA analysis. Because the strain Streptomyces sp. Ao10 proved highly active against the pathogen Escovopsis, we identified the molecular basis of its antifungal activity. Using bioassay-guided fractionation, high-resolution electrospray mass spectrometry (HR-ESI-MS), and UV spectroscopy, and comparing the results with an authentic standard, we were able identify candicidin macrolides. Candicidin macrolides are highly active against Escovopsis but do not significantly affect the growth of the symbiotic fungus. At least one of the microbial isolates from each of the 3 leaf-cutting ant species analyzed produced candicidin macrolides. This suggests that candicidins play an important role in protecting the fungus gardens of leaf-cutting ants against pathogenic fungi.
Purpose
This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the ...intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients.
Methods
Literature review and analysis were performed by Panel Members nominated by the endorsing organisations, European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/Pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and International Society of Antimicrobial Chemotherapy (ISAC). Panel members made recommendations for whether TDM should be applied clinically for different antimicrobials/classes.
Results
TDM-guided dosing has been shown to be clinically beneficial for aminoglycosides, voriconazole and ribavirin. For most common antibiotics and antifungals in the ICU, a clear therapeutic range has been established, and for these agents, routine TDM in critically ill patients appears meritorious. For the antivirals, research is needed to identify therapeutic targets and determine whether antiviral TDM is indeed meritorious in this patient population. The Panel Members recommend routine TDM to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients.
Conclusion
Although TDM should be the standard of care for most antimicrobials in every ICU, important barriers need to be addressed before routine TDM can be widely employed worldwide.
is an aggressive phytopathogen that affects various plant species, resulting in extensive local and global economic losses. Therefore, the search for competent alternatives is a constant pursuit. ...Quinolizidine alkaloids (QA) are naturally occurring compounds with diverse biological activities. The structural diversity of quinolizidines is mainly contributed by species of the family Fabaceae, particularly the genus
. This quinolizidine-based chemo diversity can be explored to find antifungals and even mixtures to address concomitant effects on
Thus, the antifungal activity of quinolizidine-rich extracts (QREs) from the leaves of eight greenhouse-propagated
species was evaluated to outline promising QA mixtures against
Thirteen main compounds were identified and quantified using an external standard. Quantitative analysis revealed different contents per quinolizidine depending on the
plant, ranging from 0.003 to 32.8 mg/g fresh leaves. Bioautography showed that all extracts were active at the maximum concentration (5 µg/µL). They also exhibited >50% mycelium growth inhibition. All QREs were fungistatic except for the fungicidal QRE of
Lindl. Angustifoline, matrine, 13α-hydroxylupanine, and 17-oxolupanine were ranked to act jointly against the phytopathogen. Our findings constitute reference information to better understand the antifungal activity of naturally afforded QA mixtures from these globally important plants.
Background. Candidemia is common and associated with high morbidity and mortality; changes in population-based incidence rates have not been reported. Methods, We conducted active, population-based ...surveillance in metropolitan Atlanta, Georgia, and Baltimore City/County, Maryland (combined population 5.2 million), during 2008–2011. We calculated candidemia incidence and antifungal drug resistance compared with prior surveillance (Atlanta, 1992–1993; Baltimore, 1998–2000). Results. We identified 2675 cases of candidemia with 2329 isolates during 3 years of surveillance. Mean annual crude incidence per 100 000 person-years was 13.3 in Atlanta and 26.2 in Baltimore. Rates were highest among adults aged ≥65 years (Atlanta, 59.1; Baltimore, 72.4) and infants (aged <1 year; Atlanta, 34.3; Baltimore, 46.2). In both locations compared with prior surveillance, adjusted incidence significantly declined for infants of both black and white race (Atlanta: black risk ratio RR, 0.26 95% confidence interval {CI}, .17–.38; white RR: 0.19 95% CI, .12–.29; Baltimore: black RR, 0.38 95% CI, .22–.64; white RR: 0.51 95% CI: .29–.90). Prevalence of fluconazole resistance (7%) was unchanged compared with prior surveillance; 32 (1%) isolates were echinocandin-resistant, and 9 (8 Candida glabrata) were multidrug resistant to both fluconazole and an echinocandin. Conclusions. We describe marked shifts in candidemia epidemiology over the past 2 decades. Adults aged ≥65 years replaced infants as the highest incidence group; adjusted incidence has declined significantly in infants. Use of antifungal prophylaxis, improvements in infection control, or changes in catheter insertion practices may be contributing to these declines. Further surveillance for antifungal resistance and efforts to determine effective prevention strategies are needed.
Background. Invasive aspergillosis (IA) is an important cause of morbidity and mortality among immunocompromised patients. Echinocandins are novel antifungal molecules with in vitro and in vivo ...activity against Aspergillus species. Methods. We investigated the efficacy and safety of caspofungin in the treatment of IA. Ninety patients with IA who were refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B, or triazoles were enrolled to receive caspofungin. Results. Efficacy was assessed for 83 patients who had infection consistent with definitions of IA and who received ⩾1 dose of study drug. Common underlying conditions included hematologic malignancy (48% of patients), allogeneic blood and marrow transplantation (25% of patients), and solid-organ transplantation (11% of patients). Seventy-one patients (86%) were refractory to and 12 patients (14%) were intolerant of previous therapy. A favorable response to caspofungin therapy was observed in 37 (45%) of 83 patients, including 32 (50%) of 64 with pulmonary aspergillosis and 3 (23%) of 13 with disseminated aspergillosis. Two patients discontinued caspofungin therapy because of drug-related adverse events. Drug-related nephrotoxicity and hepatotoxicity occurred infrequently. Conclusion. Caspofungin demonstrated usefulness in the salvage treatment of IA.
Host-defense cationic antimicrobial peptides (≈12-50 aa long) play an essential protective role in the innate immune system of all organisms. Lipopeptides, however, are produced only in bacteria and ...fungi during cultivation, and they are composed of specific lipophilic moieties attached to anionic peptides (six to seven amino acids). Here we report the following. (i) The attachment of an aliphatic chain to otherwise inert, cationic D,L tetrapeptides endows them with potent activity against various microorganisms including antibiotic resistance strains. (ii) Cell specificity is determined by the sequence of the short peptidic chain and the length of the aliphatic moiety. (iii) Despite the fact that the peptidic chains are very short, their mode of action involves permeation and disintegration of membranes, similar to that of many long antimicrobial peptides. Besides adding important information on the parameters necessary for host-defense lipopeptides to kill microorganisms, the simple composition of these lipopeptides and their diverse specificities should make them economically available, innate immunity-mimicking antimicrobial and antifungal compounds for various applications.
Fungal infections are a global concern and the evolution of intrinsic resistance to current antifungals presents an alarming problem. For Cryptococcus neoformans, a human fungal pathogen of primarily ...immunocompromised individuals, resistance toward treatment strategies demands alternative approaches. Given the prevalence of virulence factor production during cryptococcal infection, an emerging and important field of research encompasses the development of novel antivirulence therapies proposed to improve host immune responses and promote fungal clearance. To accomplish this task, information regarding the presence and role of virulence factors, the mechanisms of action within the host, and the ability to influence fungal susceptibility to antifungals is pertinent. Research into mechanisms of antifungal resistance for C. neoformans is limited but extrapolation from successful studies in other fungal species can improve our understanding of mechanisms employed by C. neoformans and suggest targeted strategies to enhance our ability to combat the pathogen. In this Review, we highlight antifungal therapy options against Cryptococcus, explore current knowledge of underlying mechanisms promoting resistance, and present new opportunities for novel and effective strategies to overcome fungal infections and reduce, or possibly even reverse, the effects of resistance evolution.
Combatting the evolution of antifungal resistance in Cryptococcus neoformans. Three antifungals, including amphotericin B, flucytosine, and fluconazole are commonly used to treat cryptococcal infections; however, development of resistance has been reported for each treatment strategy. Such resistance is attributed to alterations of drug targets, upregulation of multi‐drug transporters, and/or the overexpression of drug target or chromosomal aneuploidy. In this Review, we discuss opportunities to overcome antifungal resistance and reduce selective pressures towards resistance through the use of surveillance data collection, anti‐virulence strategies, and drug‐repurposing approaches.
Frequent fungal infections in immunocompromised patients and mortality due to invasive mycosis are important clinical problems. Opportunistic pathogenic
species remain one of the leading causes of ...systemic mycosis worldwide. The repertoire of antifungal chemotherapeutic agents is very limited. Although new antifungal drugs such as lanosterol 14α-demethylase and β-glucan synthase inhibitors have been introduced into clinical practice, the development of multidrug resistance has become increasingly significant. The urgency to expand the range of therapeutic options for the treatment of fungal infections has led researchers in recent decades to seek alternative antifungal targets to the conventional ones currently used. Among them, many compounds containing an acridine scaffold have been synthesized and tested. In this review, the applicability of acridines and their functional analogues acridones as antifungal agents is described. Acridine derivatives usage in photoantifungal chemotherapy, interactions with fungal transporters resulting in modulation of efflux/influx pumps and the effect of acridine derivatives on fungal topoisomerases are discussed. This article explores new perspectives on the mechanisms of antifungal acridine-peptide conjugates and acridine-based hybrid molecules to effectively combat fungal infections.
Antifungal resistance in mucorales Dannaoui, E.
International journal of antimicrobial agents,
November 2017, 2017-Nov, 2017-11-00, 20171101, 2017-11, Letnik:
50, Številka:
5
Journal Article
Recenzirano
•There is a great diversity among the order Mucorales.•Mucorales are characterised by their antifungal resistance to most commonly available antifungal drugs.•Amphotericin B, posaconazole and ...isavuconazole are the three drugs currently used for the treatment of mucormycosis.•Animal models are important to assess antifungal efficacy for this rare disease.
The order Mucorales, which includes the agents of mucormycosis, comprises a large number of species. These fungi are characterised by high-level resistance to most currently available antifungal drugs. Standardised antifungal susceptibility testing methods are now available, allowing a better understanding of the in vitro activity of antifungal drugs against members of Mucorales. Such tests have made apparent that antifungal susceptibility within this group may be species-specific. Experimental animal models of mucormycosis have also been developed and are of great importance in bridging the gap between in vitro results and clinical trials. Amphotericin B, posaconazole and isavuconazole are currently the most active agents against Mucorales; however, their activity remains suboptimal and new therapeutic strategies are needed. Combination therapy could be a promising approach to overcome resistance, but further studies are required to confirm its benefits and safety for patients.
Trichoderma is a saprophytic fungus that is used worldwide as a biocontrol and biofertilizer agent. Although considered nonpathogenic until recently, reports of human infections produced by members ...of the Trichoderma genus are increasing. Numerous sources of infection were proposed based upon patient data and phylogenetic analysis, including air, agriculture, and healthcare facilities, but the deficit of knowledge concerning Trichoderma infections makes patient treatment difficult. These issues are compounded by isolates that present profiles which exhibit high minimum inhibitory concentration values to available antifungal drugs. The aim of this review is to present the global distribution and sources of infections that affect both immunocompetent and immunocompromised hosts, clinical features, therapeutic strategies that are used to treat patients, as well as highlighting treatments with the best responses. In addition, the antifungal susceptibility profiles of Trichoderma isolates that have emerged in recent decades were examined and which antifungal drugs need to be further evaluated as potential candidates to treat Trichoderma infections are also indicated.
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