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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... 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.
... 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). ...
... 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.
... 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.
... 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. ...
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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.
... 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. ...
Article
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.
... 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. ...
... 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
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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.
... 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.
... 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.
... 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). ...
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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.
... 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
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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.
... 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. ...
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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.
... 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
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... 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). ...
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... 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). ...
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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.
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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.
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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.
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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.
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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.
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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.
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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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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
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