Article

Amphotericin B-resistant Aspergillus flavus infection successfully treated with caspofungin, a novel antifungal agent

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Abstract

Invasive aspergillosis is uncommon in immunocompetent hosts but is the second most common opportunistic fungal infection in immunocompromised patients. There has been a dramatic increase in the incidence of life-threatening aspergillosis during the past 2 decades, and the morbidity and mortality of these infections despite antifungal therapy remain unacceptably high. We describe a patient with amphotericin B-resistant Aspergillus flavus successfully treated with caspofungin, an agent belonging to a new class of antifungal drugs. Caspofungin shows great promise in the treatment of invasive aspergillosis.

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... Caspofungin has been used successfully in the clinical arena for the treatment of candidiases as well as candidemia (2,7,12,13). Caspofungin has also been shown to be efficacious in the treatment of Aspergillus infections (11,15,17) and invasive aspergillosis in patients refractory or intolerant to amphotericin B (J. Maertens, I. Raad, C. A. Sable, A. Ngai, R. Berman, T. F. Patterson, D. Denning, and T. Walsh, Abstr. 40th Intersci. ...
... After dosing, the catheter was flushed with 1 ml of saline. Blood samples were collected from a central auricular artery or a marginal ear vein via venipuncture into tubes containing heparin before the dose, at 0.083, 0.25, 0.50, 1, 2, 4, 8, and 24 h after the dose, and at days 2, 3,4,5,6,7,9,11,13,15,17,19,21,23,25,27, and 28 after dose administration. ...
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The metabolism, excretion, and pharmacokinetics of caspofungin (Cancidas; Merck & Co., Inc.) were investigated after administration of a single intravenous dose to mice, rats, rabbits, and monkeys. Caspofungin had a low plasma clearance (0.29 to 1.05 ml/min/kg) and a long terminal elimination half-life (11.7 h to 59.7 h) in all preclinical species. The elimination kinetics of caspofungin were multiphasic and displayed an initial distribution phase followed by a dominant beta-elimination phase. The presence of low levels of prolonged radioactivity in plasma was observed and was partially attributable to the chemical degradation product M0. Excretion studies with [(3)H]caspofungin indicated that the hepatic and renal routes play an important role in the elimination of caspofungin, as a large percentage of the radiolabeled dose was recovered in urine and feces. Excretion of radioactivity in all species studied was slow, and low levels of radioactivity were detected in daily urine and fecal samples throughout a prolonged collection period. Although urinary profiles indicated the presence of several metabolites (M0, M1, M2, M3, M4, M5, and M6), the majority of the total radioactivity was associated with the polar metabolites M1 [4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine] and M2 [N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine]. Caspofungin was thus primarily eliminated by metabolic transformation; however, the rate of metabolism was slow. These results suggest that distribution plays a prominent role in determining the plasma pharmacokinetics and disposition of caspofungin, as very little excretion or biotransformation occurred during the early days after dose administration, a period during which concentrations in plasma fell substantially. The disposition of caspofungin in preclinical species was similar to that reported previously in humans.
... Breakthrough infections have been reported for C. rugosa (26), C. lusitaniae, (27), C. tropicalis (28) and frequently for C. auris (29). Among the Aspergillus spp., primary resistance to amphotericin B has been reported for strains of A. terreus (30), A. flavus (31), and A. ustus (32). ...
Chapter
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This chapter focuses on the epidemiologic, biological, and molecular nature of antifungal drug resistance. Antifungal drug action and the host immune system often must work synergistically to control and clear an infection. “Microbiological resistance” refers to decreased susceptibility of a fungal strain to an antifungal agent, which is reflected in standardized antifungal in vitro susceptibility testing relative to susceptible standard reference strains, as defined by the Clinical Laboratory Standards Institute and the European Committee on Antimicrobial Susceptibility Testing. The azole antifungal agents are the most prominent example of drug selection for less susceptible species. The polyene drug amphotericin is fungicidal, and resistance rarely occurs. Fungi encode numerous putative drug efflux transporters that have the potential to influence susceptibility to azole antifungal agents by reducing the effective cellular concentration of drugs below their inhibitory threshold. Biofilms are among the most prevalent forms of microbial growth in nature.
... The ongoing spread of antifungal resistance can threaten the successful treatment of invasive aspergillosis. Although AmB has been generally used as an option for the chemotherapy of azole-resistant invasive Aspergillus infection, an increase was observed in the treatment failure rate for AmB [93,94,95]. Another concern that raises questions about currently employed treatments is the association between the large particle sizes of various AmB formulations and high nephrotoxicity [96,97,98,99]. ...
Article
The challenges of the invasive infections caused by the resistant Aspergillus species include the limited access to antifungals for treatment and high mortality. This study aimed to provide a global perspective of the prevalence of amphotericin B resistance (AmBR), geographic distribution, and the trend of AmBR from 2010 to 2020. To analyze the prevalence of in vitro AmBR in clinical Aspergillus species, we reviewed the literature and identified a total of 72 articles. AmBR was observed in 1128 out of 3061 Aspergillus terreus (36.8%), 538 out of 3663 Aspergillus flavus (14.9%), 141 out of 2691 Aspergillus niger (5.2%), and 353 out of 17494 Aspergillus fumigatus isolates (2.01%). An increasing trend in AmB-resistant isolates of A. fumigatus and a decreasing trend in AmB-resistant A. terreus and A. flavus isolates were observed between 2016 and 2020. AmB-resistant A. terreus and A. niger isolates, accounting for 40.4% and 20.9%, respectively, were the common AmB-resistant Aspergillus species in Asian studies. However, common AmB-resistant Aspergillus species reported by European and American studies were A. terreus and A. flavus isolates, accounting for 40.1% and 14.3% in 31 studies from Europe and 25.1% and 11.7% in 14 studies from America, respectively. The prevalence of AmB-resistant A. niger in Asian isolates was higher than in American and European. We found a low prevalence of A. terreus in American isolates (25.1%) compared to Asian (40.4%) and European (40.1%). Future studies should focus on analyzing the trend of AmBR on a regional basis and using the same methodologies.
... Furthermore, intrinsically resistant isolates have been suggested for several other Aspergillus spp. such as A. flavus [145,148] and Aspergillus lentulus [145,149]. It should be noted that some studies [150] report a low incidence of AmB resistance in Aspergillus spp. ...
Article
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Although polyenes were the first broad spectrum antifungal drugs on the market, after 70 years they are still the gold standard to treat a variety of fungal infections. Polyenes such as amphotericin B have a controversial image. They are the antifungal drug class with the broadest spectrum, resistance development is still relatively rare and fungicidal properties are extensive. Yet, they come with a significant host toxicity that limits their use. Relatively recently, the mode of action of polyenes has been revised, new mechanisms of drug resistance were discovered and emergent polyene resistant species such as Candida auris entered the picture. This review provides a short description of the history and clinical use of polyenes, and focusses on the ongoing debate concerning their mode of action, the diversity of resistance mechanisms discovered to date and the most recent trends in polyene resistance development.
... Penicillium species produce toxins that can harm mammals, including humans, if inhaled or ingested (Behbahani et al., 2016). Aspergillus is responsible for causing aspergillosis, which can be dangerous if contracted by immune-compromised patients (Koss et al., 2002). ...
Chapter
This study deals with the assessment of mangrove floral diversity at three major districts of Odisha: Kendrapara, Jagatsinghpur, and Bhadrak, which constitute major parts of state mangrove vegetation. In these three districts, the study sites included Mahanadi mangrove wetland (MMW) of Kendrapara, the river mouth regions of the river Devi (DRM) and Baitarani (BRM) in Jagatsinghpur and Bhadrak district, respectively, and the Baitarani river bank (BRB) region of Bhadrak district. The total area of study included 1 ha in MMW, 0.5 ha in DRM, and 0.1 ha each in BRM and BRB. A total of 63 species of plant were found to be distributed within the study sites that included 27 trees, 13 herbs, 17 shrubs, 5 climbers, and 1 creeper. Among trees, Avicennia marina came out as the dominant species for BRM (important value index-IVI=70.33) and MMW (IVI=117.308), while Avicennia alba was dominant in DRM (IVI=108.33), and Sonneratia caseolaris was dominant in BRB (IVI=137.40). The highest diversity was found at MMW (Shannon diversity index=0.79±0.38 and Simpson’s index=0.42±0.22), and the least diversity was found at BRB (Shannon diversity index=0.76±0.08 and Simpson’s index=1.19±0.15), but the evenness was highest in BRB (0.63±0.06) followed by MMW (0.48±0.15) and lowest in DRM (0.38±0.13). The soil parameters of the study sites showed variations with a mean pH ranging from 5.1 in BRM to 7.12 BRB, electrical conductivity from 0.01 to 0.05 S/m and organic carbon from 0.51% in BRB to 1.97% in DRM. This study will act as supplement information for mangrove vegetation of Odisha, which may be implemented further for the conservation and management of mangroves on the east coast of India.
... AMB resistance may be explained by multiple mechanisms, among them modifications in the cell wall architecture (Seo et al., 1999;Mesa-Arango et al., 2016). Aspergillus flavus isolates with AMB resistance have been related to invasive fungal infections with poor prognosis in neutropenic patients (Koss et al., 2002;Hadrich et al., 2012). Seo, Akiyoshi, and Ohnishi demonstrated that in vitro AMB-resistant mutant strains of A. flavus have similar sterol content in the cell membrane when compared to susceptible strains (Seo et al., 1999). ...
Article
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The cell wall is an essential component in fungal homeostasis. The lack of a covering wall in human cells makes this component an attractive target for antifungal development. The host environment and antifungal stress can lead to cell wall modifications related to drug resistance. Antifungals targeting the cell wall including the new β-D-glucan synthase inhibitor ibrexafungerp and glycosyl-phosphatidyl Inositol (GPI) anchor pathway inhibitor fosmanogepix are promising weapons against antifungal resistance. The fosmanogepix shows strong in vitro activity against the multidrug-resistant species Candida auris, Fusarium solani, and Lomentospora prolificans. The alternative carbon sources in the infection site change the cell wall β-D-glucan and chitin composition, leading to echinocandin and amphotericin resistance. Candida populations that survive echinocandin exposure develop tolerance and show high chitin content in the cell wall, while fungal species such as Aspergillus flavus with a higher β-D-glucan content may show amphotericin resistance. Therefore understanding fungal cell dynamics has become important not only for host-fungal interactions, but also treatment of fungal infections. This review summarizes recent findings regarding antifungal therapy and development of resistance related to the fungal cell wall of the most relevant human pathogenic species.
... As the different species of Aspergillus may vary in their clinical presentation, response to antifungal drugs and virulence factors, it is critical to identify clinical isolates of Aspergilli at the species level. For example, different reports have indicated the importance of precise speciation during treatment with amphotericin B, because species such as A. flavus or A. terreus present to a certain extent resistance to polyenes (Blum et al., 2008;Koss et al., 2002). ...
... Primary resistance to amphotericin B is well recognized in A. terreus, and in some A. flavus and A. ustus isolates [21][22][23][24]. Different species of Aspergillus genus belonging to the same section may present distinct antifungal susceptibility profiles. ...
Article
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Azole resistance in Aspergillus has emerged as an escalating problem in health care, and it has been detected in patients exposed, or not, to these drugs. It is known that azole antifungals are widely applied not only in clinical treatments for fungal infections, but also as agricultural fungicides, resulting in a significant threat for human health. Although the number of cases of azole-resistant aspergillosis is still limited, various resistance mechanisms are described from clinical and environmental isolates. These mechanisms consist mainly of alterations in the target of azole action (CYP51A gene)—specifically on TR34/L98H and TR46/Y121F/T289A, which are responsible for over 90% of resistance cases. This review summarizes the epidemiology, management, and extension of azole resistance in A. fumigatus worldwide and its potential impact in Latin American countries, emphasizing its relevance to clinical practice.
... As the different species of Aspergillus may vary in their clinical presentation, response to antifungal drugs and virulence factors, it is critical to identify clinical isolates of Aspergilli at the species level. For example, different reports have indicated the importance of precise speciation during treatment with amphotericin B, because species such as A. flavus or A. terreus present to a certain extent resistance to polyenes (Blum et al., 2008;Koss et al., 2002). ...
... Other treatment options for aspergillosis include itraconazole, caspofungin, or voriconazole in combination with terbinafine (54,55). Topical voriconazole solution combined with a systemic antifungal has also been reported as effective for secondary cutaneous aspergillosis (56,57). ...
Article
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Abstract. The opportunistic mould Aspergillus is a ubiquitous fungus. Diseases caused by Aspergillus species are most commonly caused by Aspergillus fumigatus. The spectrum of disease caused by Aspergillus is dependent on the health of the immune system. The ranges of illnesses individuals acquire are aspergilloma, allergic bronchopulmonary aspergillosis, invasive aspergillosis, sinusitis, otomycosis, ocular infections, CNS nfection, osteomyelitis, cutaneous aspergillosis, endocarditis, urinary tract infection. Aspergilloma is the most common clinical presentations of lung infections due to Aspergillus species. Allergic Bronchopulmonary Aspergillosis is a result of an immune reaction to colonization of Aspergillus fumigatus within the airways of patients. Invasive aspergillosis is generally seen in severely immunocompromised individuals. Aspergillus sinonasal infections may or may not be invasive and can follow a fulminant or an indolent course. Otomycosis has typically been described as fungal infection of the external auditory canal. Aspergillus endophthalmitis may occur by several mechanisms, including direct inoculation by trauma after surgical procedures or by hematogenous spread. Central nervous system (CNS) aspergillosis is a rare and uniformly fatal complication of disseminated disease, involving the cerebral hemispheres and cerebellum. The mechanism for Aspergillus bone infections is by direct extension, traumatic injury, inoculation by a surgical intervention, hematogenous spread and injection drug abusers. Primary cutaneous disease is a rare disease caused by Aspergillus fumigatus. Aspergillus species have been reported as a cause of both native and prosthetic valve endocarditis. Aspergillosis of urinary tract may occur by three ways namely, by ascending infection from the lower tract, from haematogenous dissemination or due to Aspergillus cast in renal pelvis.
... Resistance to polyenes was also found in 14% of the A. flavus isolates found. Resistance to these drugs in A. flavus has being described in several papers (47,48). In agreement with previous studies (49), all of the isolates of A. alliaceus were also classified as resistant. ...
Article
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A population-based survey was conducted to investigate the epidemiology of and antifungal resistance in Spanish clinical strains of filamentous fungi isolated from deep tissue samples, blood cultures, and respiratory samples. The study was conducted in two different periods (October 2010 and May 2011) to analyze seasonal variations. A total of 325 strains were isolated in 29 different hospitals. The average prevalence was 0.0016/1,000 inhabitants. Strains were identified by sequencing of DNA targets and susceptibility testing by the European Committee for Antimicrobial Susceptibility Testing reference procedure. The most frequently isolated genus was Aspergillus, accounting for 86.3% of the isolates, followed by Scedosporium at 4.7%; the order Mucorales at 2.5%; Penicillium at 2.2%, and Fusarium at 1.2%. The most frequent species was Aspergillus fumigatus (48.5%), followed by A. flavus (8.4%), A. terreus (8.1%), A. tubingensis (6.8%), and A. niger (6.5%). Cryptic/sibling Aspergillus species accounted for 12% of the cases. Resistance to amphotericin B was found in 10.8% of the isolates tested, while extended-spectrum triazole resistance ranged from 10 to 12.7%, depending on the azole tested. Antifungal resistance was more common among emerging species such as those of Scedosporium and Mucorales and also among cryptic species of Aspergillus, with 40% of these isolates showing resistance to all of the antifungal compounds tested. Cryptic Aspergillus species seem to be underestimated, and their correct classification could be clinically relevant. The performance of antifungal susceptibility testing of the strains implicated in deep infections and multicentric studies is recommended to evaluate the incidence of these cryptic species in other geographic areas.
... Zur Therapie primärer kutaner Aspergillosen werden aktuell Amphotericin B−Zubereitungen sowie das neue Triazol Voricona− zol empfohlen. Koss et al. [16] behandelten einen Patienten mit kutaner A. flavus−Infektion nach Versagen von Amphotericin B−Lipid−Komplexen erfolgreich mit dem erst kürzlich zugelasse− nen Caspofungin. ...
Article
Infektionen der Haut und Nägel durch Schimmelpilze sind selten. Insbesondere bei immunsupprimierten Patienten müssen kutane Schimmelpilzinfektionen jedoch zunehmend in die Differenzialdiagnose einbezogen werden. Neben Aspergillus spp. werden mehr und mehr weitere Schimmelpilzarten als ätiologisches Agens isoliert. Das sind neben Fusarium spp. vor allem Schwärzepilze, an erster Stelle Pseudallescheria boydii (Anamorph von Scedosporium apiospermum), aber auch Zygomyzeten, u. a. Mucor oder Rhizopus. Auch bei Onychomykosen kann im Einzelfall ein Schimmelpilz als Ursache der Nagelveränderung isoliert werden, meist Scopulariopsis brevicaulis, aber auch verschiedene Aspergillus-Arten. Darüber hinaus spielen Schimmelpilze auch bei Otomykosen eine Rolle. Bei Immigranten aus tropischen Ländern sind Eumyzetome in die Differenzialdiagnose von knotigen Veränderungen an den unteren Extremitäten einzubeziehen.
... has only been sporadically investigated and reported. However, since some of these species (e.g. A. terreus, A. flavus and A. nidulans) exhibit reduced susceptibility to amphotericin B4950515253545556, the importance of azole susceptibility surveillance of such species should not be underestimated. We recently demonstrated elevated azole MICs for two A. terreus iso- lates [57, 58@BULLET], one of which had a cyp51a M217I mutation (equivalent to M220I in A. fumigatus) [58@BULLET]. ...
Article
Full-text available
Azole resistance in Aspergillus fumigatus has been increasingly reported particularly over the last decade. Two routes of acquisition are described: selection of resis-tance during long term azole therapy in the clinical setting, and primary acquisition of resistant isolates from the envi-ronment due to the considerable use of azole fungicides in agriculture and for material preservation. Three specific resistance genotypes have been found in azole naïve patients. Two of these have also been found in the environ-ment and are characterized by a tandem repeat in the pro-moter region of the target gene coupled with point mutation (s) in CYP51A (TR 34 /L98H and TR 46 /Y121F/T289A). In the third a single target enzyme alteration (G432S) is found. These resistant "environmental" strains have been detected in many West-European countries as well as in the Asia-Pacifics. Noticeably, these two continents account for the highest fungicide use in the global perspective (37 % and 24 %, respectively). Among the 25 azole fungicides, five have been associated with the potential to select for the TR 34 /L98H genotype; three of these are among those most frequently used. Although the number of antifungal fungi-cide compounds and classes available is impressive com-pared to the armamentarium in human medicine, azoles will remain the most important group in agriculture due to supe-rior field performance and significant resistance in fungal pathogens to other compounds. Hence, further spread of environmental resistant Aspergillus genotypes may occur and will depend on the fitness of each resistant phenotype and the pattern of azole fungicide use.
... Several studies have reported in vitro susceptibility of A. flavus strains with elevated MICs for AMB (2 mg/l) [49]. The MICs of A. flavus clinical isolates to AMB are consistently twofold dilution steps higher than those of A. fumigatus [47,50]. ...
Article
Full-text available
Although the arsenal of agents with anti-Aspergillus activity has expanded over the last decade, mortality due to invasive aspergillosis remains unacceptably high. Resistance of the Aspergillus spp. species to antifungal drugs increased in the last 20 years with the increase in antifungal drugs use and might partially account for treatment failures. Recent advances in our understanding of mechanisms of antifungal drug action in Aspergillus, along with the standardization of in vitro susceptibility testing methods, have brought resistance testing to the forefront of clinical mycology. Recent modifications in taxonomy and understanding of the acquired resistance mechanisms of Aspergilli to drugs should support a better management of Aspergillus infections. In this paper, we review the current knowledge on epidemiology and underlying mechanisms involved in antifungal resistance in Aspergillus.
... However, infections with filamentous fungi (molds, such as Aspergillus species) are becoming more common. 1,2 Aspergilli are opportunistic molds that are ubiquitous in nature; they can be found in soil, water, and organic debris. 3 They have also been found in buildings under construction. ...
... Echinocandins are a new class of synthetic antifungals that act by noncompetitive inhibition of the synthesis of 1,3-␤-Dglucan synthase (16). They have demonstrated clinical efficacy in candidemia, in esophageal candidiasis, and as salvage therapy in invasive aspergillosis (2,9,12,14). The concern with echinocandins, as with any new antimicrobial agent, is the potential for the emergence of drug-resistant organisms. ...
Article
Full-text available
Echinocandins are approved for the treatment of candidal infections. In vitro they have been shown to be less potent against strains of Candida parapsilosis than against other Candida spp. This is the first case report describing the development of a secondary multidrug (echinocandin-azole)-resistant Candida strain during therapy.
... Caspofungin has demonstrated potent antifungal activity in vitro against Candida and Aspergillus isolates (Bartizal et al., 1997) and in vivo efficacy in mouse models of disseminated aspergillosis and candidiasis . Caspofungin has been successfully used in the clinical arena for the treatment of esophageal candidiases, candidemia, and invasive aspergillosis (Arathoon et al., 2002;Koss et al., 2002;Mora-Duarte et al., 2002). More recently, caspofungin has also been used as an empirical antifungal therapy for patients with persistent fever and neutropenia (Walsh et al., 2004). ...
Article
Caspofungin (CANCIDAS, a registered trademark of Merck & Co., Inc.) is a novel echinocandin antifungal agent used in the treatment of esophageal and invasive candidiases, invasive aspergillosis, and neutropenia. Available data suggest that the liver is a key organ responsible for caspofungin elimination in rodents and humans. Caspofungin is primarily eliminated by metabolic transformation; however, the rate of metabolism is slow. Accordingly, it was hypothesized that drug uptake transporters expressed on the basolateral domain of hepatocytes could significantly influence the extent of caspofungin uptake and subsequent elimination. In this study, experiments ranging from perfused rat livers to heterologous expression of individual hepatic uptake transporters were utilized to identify the transporter(s) responsible for the observed liver-specific uptake of this compound. Data from perfused rat liver studies were consistent with the presence of carrier-mediated caspofungin hepatic uptake, although this process appeared to be slow. To identify a relevant hepatic uptake transporter, we developed novel Tet-on HeLa cells expressing OATP1B1 (OATP-C, SLC21A6) and OATP1B3 (OATP8, SLC21A8), whose target gene can be overexpressed by the addition of doxycycline. A modest but statistically significant uptake of caspofungin was observed in cells overexpressing OATP1B1, but not OATP1B3. Taken together, these findings suggest that OATP1B1-mediated hepatic uptake may contribute to the overall elimination of this drug from the body.
... Caspofungin, using MEC as the in vitro susceptibility testing endpoint (1,15), also had excellent in vitro activity against all species of Aspergillus tested, inhibiting 90% of isolates at an MEC of 0.06 g/ml and Ͼ98% at an MEC of Յ1 g/ml. Caspofungin has been approved by the U.S. Food and Drug Administration for use in refractory cases of invasive asper- gillosis and may hold promise for treatment of amphotericin B-resistant aspergillosis or as part of combination regimens with triazoles or amphotericin (2,13,14,26). Importantly, direct comparisons of MIC and MEC values should not be made, since they represent different inhibition endpoints for different antifungal classes. In particular, the MEC endpoint for echinocandins recognizes that they do not produce complete macroscopic growth inhibition of Aspergillus spp. ...
Article
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We examined the in vitro activity of caspofungin, posaconazole, voriconazole, ravuconazole, itraconazole, and amphotericin B against 448 recent clinical mold isolates. The endpoint for reading caspofungin was the minimum effective concentration (MEC). Among the triazoles, posaconazole was most active, inhibiting 95% of isolates at ≤1 μg/ml, followed by ravuconazole (91%), voriconazole (90%), and itraconazole (79%). Caspofungin and amphotericin B inhibited 93% and 89% of isolates at ≤1 μg/ml, respectively, with caspofungin demonstrating an MEC 90 of 0.12 μg/ml. All three new triazoles and caspofungin inhibited >95% of Aspergillus spp. at ≤1 μg/ml compared to 83% for itraconazole and 91% for amphotericin B. Amphotericin B inhibited only 38% of Aspergillus terreus isolates at ≤1 μg/ml, whereas the three new triazoles and caspofungin inhibited all A. terreus at ≤0.5 μg/ml. The new triazoles and caspofungin have excellent in vitro activity against a very large collection of recent clinical isolates of Aspergillus spp., and some in vitro activity against selected other filamentous fungi.
Chapter
This chapter focuses on the epidemiologic, biological, and molecular nature of antifungal drug resistance. Antifungal drug action and the host immune system often must work synergistically to control and clear an infection. “Microbiological resistance” refers to decreased susceptibility of a fungal strain to an antifungal agent, which is reflected in standardized antifungal in vitro susceptibility testing relative to susceptible standard reference strains, as defined by the Clinical Laboratory Standards Institute and the European Committee on Antimicrobial Susceptibility Testing. The azole antifungal agents are the most prominent example of drug selection for less susceptible species. The polyene drug amphotericin is fungicidal, and resistance rarely occurs. Fungi encode numerous putative drug efflux transporters that have the potential to influence susceptibility to azole antifungal agents by reducing the effective cellular concentration of drugs below their inhibitory threshold. Biofilms are among the most prevalent forms of microbial growth in nature.
Article
Aim. Melanized fungi were rarely studied for their antifungal resistance (AFR) or clinical outcome, despite rising incidence of melanized fungal ocular infections and AFR in general. We report the antifungal resistance patterns, clinical outcome and clinico-microbiological correlation in two commonly isolated melanized fungi from ocular infections, Curvularia lunata and Lasiodiplodia theobromae , at a tertiary eyecare centre in South India. Gap statement . Despite melanized fungi accounting for a significant proportion of ocular fungal infections in the Indian subcontinent, and despite there being a limited selection of effective antifungal agents available for these infections, the existing data and studies on these issues remain sparse. Therefore, this study aimed to investigate the prevalence of antifungal resistance in two of the most common melanized fungal pathogens in ocular infections, Curvularia lunata and Lasiodiplodia theobromae and correlate it with the treatment given and the clinical outcome in patients. Methodology. Electronic medical records provided the clinical data. Standard broth microdilution was performed for antifungal susceptibility testing (AFST) in 30 isolates (17 C . lunata and 13 L . theobromae ) for amphotericin B and natamycin (polyenes): voriconazole, ketoconazole, posaconazole, itraconazole and fluconazole (azoles) and caspofungin (echinocandin). Multidrug resistance (MDR) was defined as resistance to more than or equal to two classes of antifungals. DNA sequencing was performed for the isolates for species confirmation. The multivariate analysis was done for determining poor prognostic factors. Results. AFST showed highest susceptibility of study isolates for voriconazole (83.3% isolates), followed by natamycin (80%), fluconazole (80%), itraconazole (76.7%), ketoconazole (70%), posaconazole (66.7%), caspofungin (66.7%) and lastly amphotericin B (63.3%). All patients empirically received topical natamycin; additional oral ketoconazole/intraocular voriconazole was administered in select few. MDR was strongly associated with poor clinical outcome (multivariate analysis: P = 0.03, odds ratio = 7.8). All patients had microbial keratitis, one progressed to endophthalmitis. Additionally, therapeutic penetrating keratoplasty was required in 40% of cases. Globe salvage was possible in 80% patients, though good visual outcome was seen in only half of them. Both, anatomical and visual outcomes, were poor in 20% of patients. DNA sequencing showed C. lunata as the highest study species. Conclusion. C. lunata and L. theobromae showed varying in vitro antifungal susceptibility and clinical outcome in ocular infections. Voriconazole had significantly higher activity, while amphotericin B had lower activity in vitro for these melanized fungi. MDR isolates showed poorer clinical outcome.
Chapter
There has been a progressive increase in the incidence of invasive fungal infections over the last two decades (1). Most occur in severely immunocompromised patients, such as those with hematological malignancy or undergoing stem cell transplantation. While candidal infections predominate, mortality rates from this infection have progressively decreased. Conversely, infections caused by molds are associated with high mortality and have continued to increase disproportionately. Many centers report that the largest increase is seen with emerging fungi, including Aspergillus terreus, Aspergillus flavus, Fusarium spp, and Scedosporium spp (2).
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The significant increase in the use of antifungal agents, both for the treatment of candidiasis and invasive aspergillosis and as azole fungicides in agricultural crop protection has resulted in the emergence of resistant clinical isolates, particularly to triazoles and echinocandins. Notably, among isolates that were primarily sensitive to fluconazole such as Candida parapsilosis and Candida tropicalis have witnessed an emerging resistance development. Also for echinocandins, the occurrence of Candida isolates with lower susceptibility to these drugs has been reported, which is possibly due to its broad clinical use. Triazole resistance among Aspergillus fumigatus and other Aspergillus species is commonly found in European and Asian countries. Specific mutations are associated with azole resistance in A. fumigatus and these mutations are now reported globally from six continents. Therefore, we highlight the need to conduct antifungal resistance surveillance studies using clinical isolates of Candida and Aspergillus in different geographical regions and monitoring of the infection rates in distinct population groups for early detection of resistance to these drugs and implementation of efficient policies for infection control and treatment.
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Objective: To investigate the isolating rate, species distribution and drug resistance of fungal isolates from blood culture in our hospital during the past three years. Methods: Blood samples were collected in our hospital between August 2004 and July 2007, cultured with BacT/ALERT 3D, separated with Sobaurand's agar culture medium, identified with CHROMager medium and VITEK-60 YBC, tested the drug sensitivity with Rosco disk diffusion method. Results: Of the specimens in 8707 cases, there were 93 fungal isolates, and the isolating rate was 1.07%. Among the 97 isolates, 41 (44.09%) were Candida. albicans, 16 (17.20%) were C. tropicalis, 13 (13.98%) were C. glabrata. And their drug resistance rates to fluconazole were 2.4%, 6.3% and 23.1%, respectively. All isolates were sensitive to amphotericin B and nystatin. Conclusions: The majority of tested strains from blood were C. albicans, followed by C. tropicalis and C. glabrata, C. albicans and C. tropicalis were sensitive to azoles class antifungal agent. C. glabrata was resistant to azoles. Antifungi activity of amphotericin B and nystatin were higher than others.
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Infections of the skin and nails due to moulds are rare. Cutaneous infections by moulds should be considered increasingly for differential diagnosis in immunocompromised patients. Besides in particular Aspergillus spp. a lot of other mould species might be isolated as causing agent. Among them are Fusanum spp. and black moulds (dematiaceous fungi) - first of all Pseudallescheria boydii (anamorph of Scedosporium apiospermum), and zygomycetes, e. g. Mucor or Rhizopus. In addition, in single cases a mould may be isolated as causing agents in onychomycoses, too, most of all Scopulariopsis brevicaulis, and several Aspergillus species. Also moulds may play a role in patients suffering from otomycoses. In immigrants from tropical countries with nodular lesions of the lower limbs a mycetoma should be considered for differential diagnosis.
Article
After the discovery of the first antifungal therapy five decades ago, these therapeutic agents have gone through a constant development. Since these agents are associated with increase in resistance, toxicity, adverse drug interactions as well as limited spectrum of activity, it is that new antifungal agents have been created: second generation triazoles (voriconazole, posaconazole, ravuconazole, albaconazole), echinocandin (caspofungin, anidulafungin, micafungin) among others. Voriconazole is an FDA approved medication for the treatment for invasive and resistant aspergillus infection. The echinocandins have a high selectivity against Candida spp., Aspergillus spp., and Pneumocistis carinii. In dermatology, voriconazole has been used successfully for treatment of dermatophytes, deep mycoses caused by Fonseca pedrosoi, Paecilomyces lilacinus and Scedosporium apiospemum. Ravuconazole has been used as well with good results for onychomycoses by dermatophytes and caspofungin for treatment of Aspergillus resistant to Anfotericin B.
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Voriconazole is the recommended agent for invasive aspergillosis, with lipid amphotericin B or caspofungin as second line treatment choices. Being the only agents available in oral formulation, azoles are used in chronic infections and often over longer time periods. In addition to being used in clinical medicine, azoles are employed extensively in agriculture. Azole-resistant Aspergillus has been isolated in azole naïve patients, in azole exposed patients and in the environment. The primary underlying mechanism of resistance is as a result of alterations in the cyp51A target gene, with a variety of mutations found in clinical isolates but just one identified in a environmental strain (a point mutation at codon 98 accompanied by a tandem repeat in the promoter region). Much less is currently known about echinocandin resistance in Aspergillus, in part because susceptibility testing is not routinely performed and because the methods suffer from technical difficulties and suboptimal reproducibility. Clinical breakthrough cases have been reported however, and resistance has been confirmed in vivo. In this paper we review the current knowledge on epidemiology, susceptibility testing and underlying mechanisms involved in azole and echinocandin resistance in Aspergillus.
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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.
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Invasive aspergillosis is rare in immunocompetent people but contributes to significant morbidity and mortality in immunosuppressed patients. The majority (approximately 80%) of invasive Aspergillus infections is caused by Aspergillus fumigatus. The second most frequent (approximately 15-20%) pathogenic species is Aspergillus flavus and to a lesser extent, Aspergillus niger and Aspergillus terreus. Aspergillus flavus has emerged as a predominant pathogen in patients with fungal sinusitis and fungal keratitis in several institutions worldwide. To date, there has not been any publication exclusively reviewing the topic of A. flavus in the literature. This article reviews the microbiology, toxigenicity and epidemiology of A. flavus as well as describes the clinical characteristics, diagnosis and management of infections caused by this organism.
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Fungi are ubiquitous in the environment. Opportunistic fungal pneumonias in the immunocompromised host continue to increase most commonly due to Aspergillus sp. Affected patients are usually hematopoietic stem cell and lung transplant recipients. Clinical presentation is protean, and the diagnosis is challenging. Culture of respiratory specimens has limited utility. The detection of circulating fungal antigens and DNA seems promising, but more studies are needed. Value of prophylactic strategies or preemptive therapy remains contentious. New antifungal drugs for managing invasive pulmonary aspergillosis continue to emerge, with better safety, efficacy, and pharmacologic profiles.
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Caspofungin (Cancidas, Merck & Co. Inc.) is the first echinocandin antifungal agent to gain FDA-approval for use in the US. It has excellent clinical activity against Candida spp. and Aspergillus spp. but lacks significant activity against Cryptococcus neoformans. Caspofungin may have some activity against dimorphic fungi such as Histoplasma capsulatum and Coccidioides immitis, but no clinical data is available for treatment of these infections. Caspofungin has demonstrated poor activity against most filamentous fungi in vitro. Several clinical trials have demonstrated its efficacy in the treatment of oropharyngeal, oesophageal and invasive candidiasis, as well as invasive aspergillosis. As a result of caspofungin's unique mechanism of action, and the high morbidity and mortality of invasive fungal infections, there is considerable interest in using this new antifungal agent as part of a combination antifungal therapy. In vitro studies and small case series indicate that caspofungin does not appear to be antagonistic when combined with other antifungals, such as itraconazole, voriconazole or amphotericin B against Aspergillus spp. Caspofungin exerts concentration-dependent killing effects in many different in vitro and animal models of disseminated fungal infection. The usual daily dose is 50 mg/day i.v. following a 70 mg i.v. loading dose. However, higher caspofungin doses have been safely administered and up to 70 mg/day can be administered for patients who fail to respond to lower doses. Caspofungin has an excellent safety profile with reduced toxicities, compared to other licensed antifungal agents. Fever, thrombophlebitis, headache and liver enzyme elevations were the most common drug-related side effects reported in clinical trials so far. Additional data are needed to document its safety in long-term use, and with higher doses in patients with invasive fungal infections. Caspofungin is a promising agent as first-line therapy for invasive candidiasis, and as salvage therapy for invasive aspergillosis. However, more clinical data are needed to define its role as primary therapy for invasive aspergillosis, and its role in combination antifungal therapy.
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Aspergillus infections are occurring with an increasing frequency in transplant recipients. Notable changes in the epidemiologic characteristics of this infection have occurred; these include a change in risk factors and later onset of infection. Management of invasive aspergillosis continues to be challenging, and the mortality rate, despite the use of newer antifungal agents, remains unacceptably high. Performing molecular studies to discern new targets for antifungal activity, identifying signaling pathways that may be amenable to immunologic interventions, assessing combination regimens of antifungal agents or combining antifungal agents with modulation of the host defense mechanisms, and devising diagnostic assays that can rapidly and reliably diagnose infections represent areas for future investigations that may lead to further improvement in outcomes.
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Aspergillus infection is a known complication of lung transplantation and remains associated with high mortality rates. The manifestation of the infection varies from simple colonization of the lung to disseminated complicated infections. Early Aspergillus infection has been rarely observed in a small number of lung transplant recipients; most cases occur during the late post-operative period. The pulmonary involvement has often been described as the first clinical localization of the disease. Although other various forms of Aspergillus infection are not uncommonly encountered after lung transplantation, Aspergillus mitral valve endocarditis is rare. We present a case of disseminated Aspergillus fumigatus infection with consecutive mitral valve endocarditis having developed 78 days after double-lung transplantation for cystic fibrosis.
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Invasive aspergillosis occurs in a wide range of immunocompromised patients and is typically associated with an extremely poor prognosis. Caspofungin represents an additional therapeutic alternative to standard antifungal therapies in patients with suspected or confirmed invasive aspergillosis, as evidenced by a growing body of experience confirming its utility in treating this patient population. Caspofungin has demonstrated clinical efficacy when administered as salvage therapy in patients refractory to or intolerant of standard antifungal therapies, as first-line empirical therapy in patients with persistent febrile neutropenia and as combination therapy in difficult-to-treat patients refractory to or intolerant of standard therapies. Further studies are warranted to establish the effectiveness of caspofungin either alone or in combination as primary therapy for invasive aspergillosis.
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The control of Leishmania infections relies primarily on chemotherapy. The arsenal of drugs available against Leishmania infections is limited and includes pentavalent antimonials, pentamidine, amphotericin B, miltefosine, paromomycin, allopurinol, and few other drugs at various stages of their development process. Knowledge about action and resistance mechanisms involved may allow the development of new drugs that minimise or circumvent drug resistance or may identify new targets for drug development. The aim of this review is to propose some chemical topics to design new modulators from the mechanisms of action of drugs and resistance mechanisms to drugs used in the clinic against Leishmania infections. Thus, different classes of ABC transporters extrude antimonials in Leishmania resulting in drug-resistant phenotypes. Compounds interfering with thiol and polyamine metabolism could be designed to inhibit the antimonial detoxication and therefore, such compounds could be used in combination with antimonials. New diamidines could be synthesized in regard to their ability to inhibit topoisomerase II. The challenge for amphotericin B is to be absorbed by oral route requiring labile physico-chemical modifications. New sesquiterpens and flavonoids have to be developed as reversant of antimonial resistance. Although some studies have focused on developing inhibitors against these resistant phenotypes, new efficient modulators that are able to inhibit drug efflux are needed.
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Resistance of parasitic protozoa such as Leishmania to therapeutic drugs continues to escalate in developing countries. Treatment programs for human leishmaniasis are still based on pentavalent antimonials but resistance to these compounds has been a persistent problem. In many instances, resistance of the parasite is due to over-expressed ABC efflux pumps. In Leishmania different classes of ABC transporters extrude antimonials, azoles and folates resulting in drug-resistant phenotypes. Although some studies have focused on developing inhibitors against these resistant phenotypes, new efficient modulators that are able to inhibit drug efflux are needed.
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The pneumocandins are natural lipopeptide products of the echinocandin class which inhibit the synthesis of 1,3-beta-D-glucan in susceptible fungi. The lack of a corresponding pathway in mammalian hosts makes this mode of action an attractive one for treating systemic infections. Substitution by an aminoethyl ether at the hemiaminal and dehydration and reduction of the glutamine of pneumocandin B0 produced a semisynthetic compound (L-733,560) with intrinsic water solubility, significantly increased potency, and a broader antifungal spectrum. To evaluate the mechanism for the improved antifungal efficacy, we determined that L-733,560 was a more potent inhibitor of glucan synthase activity in vitro, did not affect the other membrane-bound enzymes tested, conferred susceptibility to lysis in the absence of osmotic support, and did not disrupt currents in liposomal bilayers or 86Rb+ fluxes from liposomes. In Aspergillus species L-733,560 also produced the same morphological alterations as pneumocandin B0. A stereoisomer of L-733,560 with poor antifungal activity was a weak inhibitor of glucan synthase. All of these results support the notion that the enhanced antifungal activity of L-733,560 is achieved by superior inhibition of glucan synthesis and not by nonspecific membrane effects or a second mode of action.
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Aspergillosis comprises a variety of manifestations of infection. These guidelines are directed to 3 principal entities: invasive aspergillosis, involving several organ systems (particularly pulmonary disease); pulmonary aspergilloma; and allergic bronchopulmonary aspergillosis. The recommendations are distilled in this summary, but the reader is encouraged to review the more extensive discussions in subsequent sections, which show the strength of the recommendations and the quality of the evidence, and the original publications cited in detail. Invasive aspergillosis. Because it is highly lethal in the immunocompromised host, even in the face of therapy, work-up must be prompt and aggressive, and therapy may need to be initiated upon suspicion of the diagnosis, without definitive proof (BIII). Intravenous therapy should be used initially in rapidly progressing disease (BIII). The largest therapeutic experience is with amphotericin B deoxycholate, which should be given at maximum tolerated doses (e.g., 1-1.5 mg/kg/d) and should be continued, despite modest increases in serum creatinine levels (BIII). Lipid formulations of amphotericin are indicated for the patient who has impaired renal function or who develops nephrotoxicity while receiving deoxycholate amphotericin (AII). Oral itraconazole is an alternative for patients who can take oral medication, are likely to be adherent, can be demonstrated (by serum level monitoring) to absorb the drug, and lack the potential for interaction with other drugs (BII). Oral itraconazole is attractive for continuing therapy in the patient who responds to initial iv therapy (CIII). Therapy should be prolonged beyond resolution of disease and reversible underlying predispositions (BIII). Adjunctive therapy (particularly surgery and combination chemotherapy, also immunotherapy), may be useful in certain situations (CIII). Aspergilloma. The optimal treatment strategy for aspergilloma is unknown. Therapy is predominantly directed at preventing life-threatening hemoptysis. Surgical removal of aspergilloma is definitive treatment, but because of significant morbidity and mortality it should be reserved for high-risk patients such as those with episodes of life-threatening hemoptysis, and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). Surgical candidates would need to have adequate pulmonary function to undergo the operation. Bronchial artery embolization rarely produces a permanent success, but may be useful as a temporizing procedure in patients with life-threatening hemoptysis. Endobronchial and intracavitary instillation of antifungals or oral itraconazole may be useful for this condition. Since the majority of aspergillomas do not cause life-threatening hemoptysis, the morbidity and cost of treatment must be weighed against the clinical benefit. Allergic bronchopulmonary aspergillosis (APBA). Although no well-designed studies have been carried out, the available data support the use of corticosteroids for acute exacerbations of ABPA (AII). Neither the optimal corticosteroid dose nor the duration of therapy has been standardized, but limited data suggest the starting dose should be approximately 0.5 mg/kg/d of prednisone. The decision to taper corticosteroids should be made on an individual basis, depending on the clinical course (BIII). The available data suggest that clinical symptoms alone are inadequate to make such decisions, since significant lung damage may occur in asymptomatic patients. Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids should be used (BII). Multiple asthmatic exacerbations in a patient with ABPA suggest that chronic corticosteroid therapy should be used (BIII). Itraconazole appears useful as a corticosteroid sparing agent (BII). (ABSTRACT TRUNCATED)
Article
Solid-organ transplantation is a therapeutic option for many human diseases. Infections are a major complication of solid-organ transplantation. All candidates should undergo a thorough infectious-disease screening prior to transplantation. There are three time frames, influenced by surgical factors, the level of immunosuppression, and environmental exposures, during which infections of specific types most frequently occur posttransplantation. Most infections during the first month are related to surgical complications. Opportunistic infections typically occur from the second to the sixth month. During the late posttransplant period (beyond 6 months), transplantation recipients suffer from the same infections seen in the general community. Opportunistic bacterial infections seen in transplant recipients include those caused by Legionella spp., Nocardia spp., Salmonella spp., and Listeria monocytogenes. Cytomegalovirus is the most common cause of viral infections. Herpes simplex virus, varicella-zoster virus, Epstein-Barr virus and others are also significant pathogens. Fungal infections, caused by both yeasts and mycelial fungi, are associated with the highest mortality rates. Mycobacterial, pneumocystis, and parasitic diseases may also occur.
Article
Fungal infections in immunocompromised hosts cause major morbidity and mortality. The Candida and Aspergillus species are the most common causes, but many rarer organisms, once considered "contaminants," are being reported. The number of patients who receive immunosuppressive agents for the treatment of malignancy or for organ transplantation is increasing as well as the potential for local or disseminated fungal infections. The diagnosis of these infections is often difficult and the existing methods for treatment are often ineffective. A high degree of suspicion to identify fungal infections and to prompt initiation of treatment must be maintained if the survival rate of these patients is expected to improve.
Article
The lipopeptide antifungal agents, echinocandins, papulacandins, and pneumocandins, kill Candida albicans by inhibiting glucan synthesis. For this fungus, there is a good correlation of in vitro enzyme inhibition with in vitro assays of MICs. Semisynthetic lipopeptides such as cilofungin, LY303366, L-693,989, and L-733,560 have activity in vivo against Aspergillus infections but appear to be inactive in broth dilution in vitro tests (MICs, > 128 micrograms/ml). To understand how compounds which lack activity in vitro can have good in vivo activity, we monitored the effect of pneumocandins on the morphology of Aspergillus fumigatus and A, flavus strains by light microscopy and electron microscopy and related the changes in growth to inhibition of glucan synthesis. Pneumocandin B0 caused profound changes in hyphal growth; light micrographs showed abnormally swollen germ tubes, highly branched hyphal tips, and many cells with distended balloon shapes. Aspergillus electron micrographs confirmed that lipopeptides produce changes in cell walls; drug-treated germlings showed very stubby growth with thick walls and a conspicuous dark outer layer which was much thicker in the subapical regions. The rest of the hyphal tip ultrastructure was unaffected by the drug, indicating considerable specificity for the primary target. The drug-induced growth alteration produced very compact clumps in broth dilution wells, making it possible to score the morphological effect macroscopically. The morphological changes could be assayed quantitatively by using conventional broth microdilution susceptibility assay conditions. We defined the endpoint as the lowest concentration required to produce the morphological effect and called it the minimum effective concentration to distinguish it from the no-growth endpoints used in MIC determinations. The minimum effective concentration assay was related to inhibition of glucan synthase activity in vitro and may provide a starting point for development of susceptibility testing methods for lipopeptides.
Article
Oncologic patients constitute a population whose susceptibility to infections is conditioned by a broad variety of factors. Advances in antineoplastic treatments have resulted in significant prevalence of severe immunosuppression among such patients. Although impairment of more than one distinct effector limb of host defenses occurs in each patient, infections can usually be attributed to a particular deficiency. Major risk factors for infections include granulocytopenia and defects of cell-mediated immunity or of humoral immunity. In the extreme situation of allogeneic bone marrow transplantation, the multitude and the timing of infections can be explained by significant dysfunction of all types of specific immune deficiencies. Treatment of bacterial infections has become more effective with the advent of broad-spectrum antibiotics; however, the dreadful emergence of polyresistant strains may be a serious problem in the near future. Prevention strategies have reduced the risk posed by important pathogens such as CMV or PCP, whereas we still lack reliable treatment against invasive mycoses. The advent of growth factors is a useful adjunct in our armamentarium; in addition to shortening the neutropenic periods after chemotherapy, they may restore qualitative defects of phagocytes. Their exact usefulness and role in managing infections remains to be defined.
Article
Aspergillosis comprises a spectrum of diseases caused by species of a ubiquitous saprophytic mold, Aspergillus, that usually live on decaying vegetation. Aspergillus organisms rarely behave as pathogens in an immunocompetent host. In the presence of immunosuppression, however, aspergillus may be invasive and take a fulminant course. Aspergillosis is the second most frequent opportunistic fungal infection surpassed only by candidiasis; therefore, early detection and treatment are essential to minimize morbidity and mortality. This article reviews the historical aspects, etiology, epidemiology, clinical manifestations, pathology, and treatment of this disease and focuses on the cutaneous aspects of species of Aspergillus known to infect humans.
Article
Solid-organ transplantation is a therapeutic option for many human diseases. Infections are a major complication of solid-organ transplantation. All candidates should undergo a thorough infectious-disease screening prior to transplantation. There are three time frames, influenced by surgical factors, the level of immunosuppression, and environmental exposures, during which infections of specific types most frequently occur posttransplantation. Most infections during the first month are related to surgical complications. Opportunistic infections typically occur from the second to the sixth month. During the late posttransplant period (beyond 6 months), transplantation recipients suffer from the same infections seen in the general community. Opportunistic bacterial infections seen in transplant recipients include those caused by Legionella spp., Nocardia spp., Salmonella spp., and Listeria monocytogenes. Cytomegalovirus is the most common cause of viral infections. Herpes simplex virus, varicella-zoster virus, Epstein-Barr virus and others are also significant pathogens. Fungal infections, caused by both yeasts and mycelial fungi, are associated with the highest mortality rates. Mycobacterial, pneumocystis, and parasitic diseases may also occur.
Article
Invasive aspergillosis has increasingly been recognised to cause significant morbidity and mortality in immunocompromised patients. Fever unresponsive to broad-spectrum antibiotics is the earliest and most common sign of an invasive fungal infection. As invasive Aspergillus infections are usually acquired by inhalation of Aspergillus conidia, symptoms of a pulmonary infection such as cough, rales and marked pleuritic chest pain can be noted early in the course, whereas hemoptysis typically comes late after neutrophil recovery. Aspergillus infections of the upper respiratory tract may also involve the nasal cavity or sinuses resulting in nasal obstruction, epistaxis, facial pain, periorbital swelling and even palate destruction. Primary cutaneous infections present as non-purulent ulcerations and may be seen in association with implantable intravenous devices. Other sites of infections, such as the central nervous system, originate from dissemination of molds and may be suspected when focal neurological findings or meningism develop. The recognition of symptoms associated with invasive aspergillosis in patients at risk should prompt further diagnostic procedures, as an early diagnosis and immediate institution of antifungal therapy might improve the treatment outcome in this life-threatening condition.
Romagnoli is on the Speakers Bureau of Merck Labora-tories, Inc. Reprint requests: Marc E. Grossman, MD, 12 Greenridge Ave #403, White Plains, NY 10605
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  • Dr
  • Marlo
Medical Center. Dr Marlo F. Romagnoli is on the Speakers Bureau of Merck Labora-tories, Inc. Reprint requests: Marc E. Grossman, MD, 12 Greenridge Ave #403, White Plains, NY 10605. Published online December 5, 2001. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 ϩ 0 16/91/120627 doi:10.1067/mjd.2001.120627 REFERENCES
Synthesis and antifungal activity of novel cationic pneumocandin B 0 derivatives
  • Zambias Ra Bouffard Fa
  • Dropinski Jf
  • Jm Balkovec
  • Hammond Lm
  • Abruzzo
  • Gk
Bouffard FA, Zambias RA, Dropinski JF, Balkovec JM, Hammond LM, Abruzzo GK, et al. Synthesis and antifungal activity of novel cationic pneumocandin B 0 derivatives. J Med Chem 1994;37: 222-5.