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Aspergillus species Updated September, 2011
Nina Singh, M.D., David L. Paterson, M.D.
MICROBIOLOGY Guided Medline Search Aspergillus species are ubiquitous molds which can grow in decaying vegetation, soil and water. In culture, Aspergillus species have septate, hyaline, branched hyphae which give rise to upright conidiophores that terminate in a swollen cell (vesicle). Aspergillus fumigatus is the most common species to cause serious infections in humans, especially pulmonary infection. Aspergillus flavus is a less common cause of pulmonary infection. However it is responsible for relatively more infections of the sinuses and skin than A. fumigatus. A. niger is rarely responsible for life-threatening infections, but may produce otitis externa. Species rarely associated with human disease include A. terreus, A. ustus, A. sydowi, A. nidulans and others. Baron EJ. Mold Baron EJ. Common Aspergillus Lee J. The Curse of the Mummy's Tomb and Its Link to Aspergillosis. Lee J. Discovery of Aspergillus as a Human Pathogen. EPIDEMIOLOGY Guided Medline Search Hospital renovation and construction activities producing bursts of airborne conidia have resulted in numerous clusters of hospital-acquired infections in immunosuppressed patients (10). However, there has been an important recent challenge to the traditional viewpoint that Aspergillus infections are primarily airborne. Anaissie and colleagues have found high concentrations of Aspergillus in hospital water systems, and have shown that water isolates may be genotypically identical to isolates from patients with invasive infections (7, 8). Outside of hospital, direct inoculation from environmental sources occasionally occurs. For example, keratitis after trauma to the cornea is well described. Several types of immunosuppression predispose to invasive aspergillosis. Numerically the most important are patients with prolonged neutropenia and transplant recipients, including both solid organ and stem cell/bone marrow transplant recipients (18,196). In addition to neutropenia, corticosteroid use is a clear risk factor for invasive aspergillosis. Advanced human immunodeficiency virus (HIV) infection, even in the absence of neutropenia or corticosteroid use, may also predispose to serious Aspergillus infections (35). Children with chronic granulomatous disease are also at significant risk for Aspergillus infections (1). Although Aspergillus may be responsible for trivial infections (such as otitis externa) or may merely colonize damaged lungs, invasive aspergillosis carries a high mortality. In many immunosuppressed populations mortality from invasive aspergillosis has approached or even exceeded 90%. Although removal of immunosuppression is many times the key to successful resolution of Aspergillus infections, choice of antifungal agent is also of importance. This chapter discusses traditional antifungal therapy as well as new agents for the treatment of invasive aspergillosis. Review Article: Singh N, Perfect J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. The Lancet Infectious Diseases 2007;7:395-401. Review Article: Singh N. Novel immune regulatory pathways and their role in immune reconstitution syndrome in organ transplant recipients with invasive mycoses. Eur J Clin Microbiol Infect Dis 2008;27(6):403-408. Guidelines: Walsh TJ, et al. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46(3):327-360.
CLINICAL MANIFESTATIONS Guided Medline Search The most numerous manifestations of Aspergillus infections are those related to the lungs. However, numerous extrapulmonary sites of infection have been described.
Pulmonary
Disease: The finding of Aspergillus species in respiratory tract
secretions can represent (1) a laboratory contaminant, (2) colonization without
invasive disease, (3) a loosely-defined entity called chronic necrotizing
aspergillosis or (4) invasive pulmonary aspergillosis
Chronic necrotizing Aspergillosis is a loosely defined disease entity consisting of a group of non-angioinvasive, indolent Aspergillus pulmonary infections. Other names used to describe members of this disease complex include semi-invasive aspergillosis, subacute aspergillosis, chronic cavitary aspergillosis, and chronic fibrosing aspergillosis (75a, 116a). As these names all imply, the clinical hallmark of chronic necrotizing aspergillosis is a subacute to chronic progression of constitutional symptoms, including fevers, malaise, weight loss, productive cough and/or hemoptysis, although some patients may also present asymptomatically (116a, 207). Symptoms are produced that can be either minimally or highly locally invasive, but never angioinvasive, and can contain various amounts of necrosis, inflammation, and hyphal elements. Risk factors for chronic necrotizing aspergillosis include chronic granulomatous disease, corticosteroid treatment, non-neutropenic hematopoetic stem cell transplants, solid organ transplants, HIV/AIDS, chronic lung disease (including COPD, previous pulmonary TB, interstitial lung disease, and cystic fibrosis, and other mild immunocompromised states (e.g: diabetes, alcohol, malnutrition, chronic liver disease) (75a, 116a, 207). Because of the differing magnitudes of inflammation and necrosis produced by variants of this disease complex, there are a constellation of radiographic findings that can be seen, including ground-glass opacifications, subsegmental or segmental consolidations, nodular infiltrates, pleural thickening, and/or cavitary lung lesions. These radiographic abnormalities usually occur in the upper lobes of the lung and are characterized by slow evolution over periods of weeks to months, consistent with the tempo of clinical symptomatology (75a). Local pulmonary parenchymal invasion can result in bronchopleural fistulas. Further, inflammation frequently leads to pulmonary necrosis, resulting in cavities that may contain aspergillomas in up to 50% of patients with chronic necrotizing aspergillosis. The clinical manifestations of acute invasive pulmonary aspergillosis in immunocompromised patients are varied. Unfortunately some patients have no recognizable symptoms or signs of the infection. In neutropenic patients, fever unresponsive to antibiotic therapy may be the only sign. Typically though, fever is accompanied by a nonproductive cough. Progression to pneumonia, with resulting hypoxemia and dyspnea, may occur extremely rapidly (1-2 days). Pleuritic chest pain and slight hemoptysis, suggestive of pulmonary infarction, may be an alternative presentation. A pleural rub is sometimes heard. Massive, life-threatening hemoptysis may occur in the neutropenic patient. Typically, corticosteroid-treated patients do not have fever, but present with cough and low-grade, non-pleuritic chest pain. The rare immunocompetent patient with invasive pulmonary aspergillosis usually have an extremely indolent presentation, and it may take weeks for symptoms to be of sufficient severity to warrant medical attention. Diabetic patients also share this subacute mode of presentation. Although, a number of characteristic radiographic signs of invasive pulmonary aspergillosis have been described, it must be emphasized that appearances of the infection can be extremely heterogeneous. Indeed, in neutropenic patients plain chest radiographs may appear normal early in the course of infection. Similarly, solid-organ transplant recipients in the early post-operative period may have no radiographic changes distinguishable from other common causes of pulmonary infiltrate. Early radiographic findings include small, pleural-based, wedge-shaped lesions or small parenchymal nodules. Nodules are more likely multiple than solitary. The halo sign is a characteristically described feature which is visualized as an area of low attenuation around a nodule or pleural-based lesion. The halo sign is not specific for aspergillosis, nor is it commonly seen in solid organ transplant recipients with aspergillosis, but its presence in neutropenic patients whose fevers have not responded to antibiotics strongly suggests invasive pulmonary aspergillosis. Cavitation of nodules characteristically occurs in invasive pulmonary aspergillosis, although in neutropenic patients this is usually not evident until the neutrophil count starts to recover. Cavitation results in a classical crescent of air adjacent to a nodule ("air crescent sign"). Occasionally, especially in patients with profound neutropenia, spontaneous pneumothorax is evident radiologically (and clinically). Pleural effusions accompanying invasive pulmonary aspergillosis are rare. Greene RE, Schlamm HT, et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical signficance of the halo sign. Clin Infect Dis. 2007;44:373-9. High-resolution thoracic computed tomographic scans allow a much more specific radiologic examination for invasive pulmonary aspergillosis. High-resolution CT scanning performed in neutropenic patients whose fever persists for more than two days despite empiric antibiotic treatment can show findings highly suggestive of invasive pulmonary aspergillosis five days earlier than use of plain chest radiography. In settings other than transplantation or neutropenia, patients with invasive pulmonary aspergillosis may present with symptoms progressing over several weeks to months. This chronic form of invasive pulmonary aspergillosis is considerably less common than the acute invasive form. Patients may lack immunocompromise or have received corticosteroids for chronic pulmonary diseases such as sarcoidosis, be alcoholic or have diabetes mellitus, chronic granulomatous disease or HIV infection. The usual symptoms are chronic productive cough, low-grade fever, occasional hemoptysis, malaise and weight loss. Radiologically, cavitation of an area of consolidated lung is usual. The finding of Aspergillus in sputum is suggestive, but as noted above, smokers particularly may have colonization in the absence of invasive disease. Diagnosis, therefore, usually requires biopsy evidence of invasive Aspergillus hyphae in lung tissue. Often hyphae are scant, however. Granulomata are typical; sometimes the process is described histologically as an angioinvasive necrotizing granulomatous pneumonia. One histologic appearance of chronic pulmonary aspergillosis is bronchocentric granulomatosis. About 50% of patients have asthma. Hence, bronchocentric granulomatosis is regarded by some as more akin to a localized ABPA than to a true invasive process. Patients usually have chronic symptoms such as cough, low-grade fever, malaise, dull chest pain and hemoptysis. Radiologically, a focal upper lobe lesion is usually seen. Aspergillus tracheobronchitis is characteristically seen in lung transplant recipients, although has also been observed rather commonly in HIV-infected and immunocompetent patients. Rare cases have been reported in other groups, such as bone marrow transplant recipients. In lung transplant recipients the disease usually occurs in the first month post-transplant. Tracheobronchitis is observed on routine bronchoscopy, centered around the suture line. Patients are generally asymptomatic or have symptoms attributable to the transplant, with chest radiographs unchanged from baseline. However, as the disease progresses, symptoms become more pronounced with a monophonic wheeze becoming particularly prominent. Bronchoscopically, the appearance is of severe tracheobronchitis progressing to multiple ulcers at the site of anastomosis. Sequelae include acute invasive pulmonary aspergillosis, severe bronchial stenosis, anastomotic dehiscence and bronchial necrosis with bronchoarterial fistula formation. Some patients develop extensive pseudomembranes, which can completely occlude the lumen of large airways. Such patients are extremely difficult to ventilate, and may die of respiratory insufficiency. Bronchial stump aspergillosis is a rare and unusal sequel of lung resection, first described in Japan. Typically, 6-12 months after lung resection (during which silk sutures were used), the patient develops productive cough and hemoptysis. The sputum may be foul smelling and contain fungal material or silk suture material. The cause is secondary colonization of the suture material which is protruding into the bronchial lumen. Local inflammation and then necrosis of the bronchial mucosa results. Chest radiography is usually unchanged compared to baseline. Allergic bronchopulmonary aspergillosis (ABPA) is an important syndrome associated with Aspergillus. The usual clinical presentation of ABPA is that of an atopic asthmatic who intermittently expectorates tenacious, rubbery mucus plugs. The mucus plugs may take on the appearance of a bronchial cast. Almost all patients with ABPA have episodic airway obstruction. There may be a history of recurrent pulmonary infiltrates or segmental or lobar collapse. During acute episodes, fever, chest pain, hemoptysis, cough and wheeze may be present. Currently accepted diagnostic criteria for ABPA include (1) episodic asthma, (2) peripheral blood eosinophilia (usually above 1000/μL), (3) transient or migratory pulmonary infiltrates, (4) elevated serum concentrations of total IgE (usually >1000 ng/ml), (5) Type 1 (immediate) cutaneous wheal and flare reactivity to Aspergillus antigens, (6) serum precipitins against Aspergillus antigens, (7) specific anti-Aspergillus IgE and IgG antibodies and (8) central saccular bronchiectasis. It should be noted that patients with disease of more recent onset are likely to have fewer diagnostic criteria positive than patients with long-standing disease. Cutaneous reactivity, elevated IgE and serum precipitins can all be found in asthma without ABPA. However, a negative skin test virtually excludes the diagnosis of ABPA. The changes of bronchiectasis occur late in the disease course.
Pulmonary aspergillomas result from fungal growth within a pre-existing
pulmonary cavity. Recognized etiologies of cavities include neoplasms,
tuberculosis, cystic fibrosis, healed pyogenic abscess cavities, bullous
emphysema and congenital cysts. Pathologically, an aspergilloma represents a
mass of living and dead fungal elements, mucus, blood, inflammatory cells and
debris occupying a cavity communicating with the bronchial tree
Chest radiography characteristically shows a solid round mass within a cavity in the upper lobes, although early in the process the only signs may be thickening of a cavity wall or increased pleural thickening. If erect and decubitus films are compared, movement of the fungus ball can be appreciated. A classic radiologic sign of aspergilloma is a crescent-shaped patch of air around the solid mass (Monod’s sign). Computed tomographic scans are particularly useful at demonstrating the characteristic features described above. Burgos A, et al. Pediatric Invasive Aspergillosis: A Multicenter Retrospective Analysis of 139 Contemporary Cases. Pediatrics 2008;121:e1286-e1294 Zaoutis T. et al. A Prospective, Multicenter Study of Caspofungin for the Treatment of Documented Candida or Aspergillus Infections in Pediatric Patients. Pediatrics. 2009;123:877-84. Extrapulmonary Manifestations: Invasive Aspergillus sinusitis may accompany pulmonary infection or be an isolated condition. The infection occurs particularly in neutropenic patients, including bone marrow transplant recipients. For unknown reasons, it is under-reported in solid organ transplant recipients. Presenting symptoms include fever, orbital swelling, facial pain and nasal congestion. Aspergillus sinusitis is frequently aggressive and destructive, extending beyond the sinuses to the orbit or brain. CT scans are more sensitive than plain radiographs for revealing the changes of Aspergillus sinusitis. Opacification of the sinuses, sometimes with bony destruction or invasion into adjacent tissues are usually well characterized. Chronic Aspergillus infection in the ethmoid sinus may result in bony erosion towards the orbit or the cavernous sinuses, particularly in patients on systemic corticosteroids, with HIV infection or with diabetes mellitus. The features of chronic sinusitis are often seen, and may be accompanied by headaches, loss of the sense of smell and diplopia. The condition has a poor prognosis, with relapse common in those patients with initial response to therapy. In contrast, allergic sinusitis due to Aspergillus may manifest as chronic, intractable sinusitis and nasal polyposis. Computed tomographic scans show no evidence of invasive disease. A. flavus sometimes produces regional tissue invasion and noncaseating granulomata in immunocompetent persons, primarily from Sudan, India and Pakistan, but also from the United States. This produces the curious syndrome known as primary paranasal granuloma. Extension into the orbit, dura and brain may result. Aspergillus infection of the central nervous system is manifest usually as cerebral space occupying lesions in the context of disseminated disease in immunocompromised patients. Aspergillus is the most common cause of brain abscess in solid organ transplant recipients. Less commonly, cerebral abscesses may be an isolated finding in immunocompromised patients, follow neurosurgical procedures or be a result of direct extension from neglected sinus disease. Meningitis and spinal cord involvement are rare. Most commonly, hypodense CNS lesions are observed on CT scan in severely immunocompromised patients with known pulmonary infection. The patient is frequently ventilated and unable to show signs of neurologic disturbance apart from seizures or poor responsiveness to noxious stimuli. Occasional patients present with sudden onset of CNS hemorrhage.
Aspergillus has been documented as a frequent cause of post-traumatic
keratitis. Less commonly
endophthalmitis may result as part of disseminated
infection (for example, in solid organ transplant recipients) or may occur de
novo in intravenous drug abusers or post ophthalmic surgery.
Orbital infection
can occur as a result of invasion from infected sinuses
Aspergillus bone infection can be part of disseminated or local disease in immunocompromised patients (including transplant recipients, neutropenic patients and children with chronic granulomatous disease), can be related to intravenous drug use, trauma or surgery, or may occur by direct extension from the sinuses or ear. Aspergillus may involve the skin and soft tissues in the following ways: cutaneous manifestations of systemic disseminated infection; primary cutaneous aspergillosis in the immunocompromised patient; postsurgical or posttraumatic wound infections; burn wound infections; otitis externa (noninvasive); invasive external otitis; primary cutaneous aspergillosis associated with central venous lines. A. flavus is more common than A. fumigatus in many of these manifestations. A. niger may be associated with otitis externa. Occasionally, rare species such as A. ustus may be involved in primary cutaneous infections associated with immunosuppression. Aspergillus has been reported to cause endocarditis, myocarditis, pericarditis, mediastinitis, septic thrombophlebitis and infections of aortic grafts. Infection is associated with high mortality despite treatment. In addition, some cases are unsuspected during life and are only discovered at autopsy. Most cases occur in solid organ transplant recipients, although the infection has been reported even in immunocompetent patients. Septic thrombophlebitis characteristically occurs in neutropenic patients with long-standing central venous access devices. Aspergillus endocarditis may occur as part of disseminated disease, as a complication of cardiac surgery or rarely may occur de novo. Both pericarditis and myocarditis are almost always complications of widely disseminated disease. Septic thrombophlebitis due to Aspergillus has been reported in association with infection of longstanding central venous catheters. In such patients histologic examination may show fungal invasion of the vein wall. Virtually any organ can be infected by A. fumigatus as part of disseminated infection. For example, at autopsy of a transplant recipient with known pulmonary and brain infection, sites such as thyroid, kidney and liver will be found to be infected. LABORATORY DIAGNOSIS Guided Medline Search
Aspergillus infections may be diagnosed by the clinical microbiology or
anatomical pathology laboratories. From a microbiologic perspective, both
macroscopic and microscopic characteristics are required for the differentiation
of Aspergillus species. Macroscopically, colony growth rates, obverse and
reverse colors, texture and topography are important
Aspergillus infections are diagnosed by pathologic examination of lung
tissue. The appearance of Aspergillus hyphae may vary with the type
of pathology. For example, in invasive aspergillosis hyphae proliferate
extensively throughout the lung tissue, often in parallel or radial arrays. The
hyphae in invasive aspergillosis characteristically branch dichotomously at
acute (45°) angles, are closely septate (with no constriction at the septa) and
have smooth parallel walls
Chronic necrotizing Aspergillosis is a difficult diagnosis to make. The gold standard is the histologic and microbiologic demonstration of a lung infection due to Aspergillus spp. Affected tissue reveals pyogranulomatous inflammation with or without necrosis, and hyphal elements showing varying amounts of tissue invasion (207). In making a tissue diagnosis, however, transbronchial and percutaneous biopsies are hampered by low yields, and thorascopic or open lung biopsies are highly impractical. More commonly, clinical symptoms are combined with radiographic and laboratory data to help make a probable diagnosis of chronic necrotizing aspergillosis. Laboratory measures used for this purpose include elevated inflammatory markers, isolation of Aspergillus spp from pulmonary tissue or respiratory cultures, positive serum Aspergillus precipitins, positive skin reactivity against Aspergillus antigens, and exclusion of other pulmonary pathogens or malignancies that can mimic the indolent clinical presentation of chronic necrotizing aspergillosis (207). No single test is diagnostic, and because the diagnosis is difficult to make, patients often are diagnosed late into the disease, contributing to the morbidity and mortality associated with this disease complex. An enzyme immunoassay which detects galactomannan, a component of the Aspergillus cell wall is available for testing of sera in patients with hematological malignancy,, neutropenia and recipients of bone marrow transplants. This test has also been used for bronchoalveolar lavage (BAL) fluid in immunosuppressed patients being evaluated for pneumonia. The role of these tests is not as a single-use test for definitive diagnosis of invasive aspergillosis. Rather they serve as a means of surveillance monitoring for early aspergillosis in patients at high risk for the infection. This can allow pre-emptive treatment (that is, treatment before symptoms have developed). The usual protocol is to perform the test twice each week during the post-transplant period or period of neutropenia. ELISA results can be available within four hours of collecting the sample. If a positive result is recorded the test can be repeated on a sample taken the next day. In general, because of uncertainty regarding the positive predictive value of an isolated positive result, treatment is only commenced after two positive results are recorded. Review Article: Wheat JL, Walsh TJ. Diagnosis of Invasive Aspergillosis by Galactomannan Antigenemia Detection Using an Enzyme Immunoassay. 2007. In some patients, results are positive as much as 28 days before symptoms or clinical and radiographic signs of invasive aspergillosis become apparent. Caveats to use of antigen detection tests include the lack of data in solid organ transplant recipients and the expense involved in performing the test and treating false positive cases. A competitive polymerase chain reaction (PCR) assay involving the use of bronchoalveolar lavage samples has been developed. Such a test is attractive given the poor sensitivity of culture from respiratory tract samples. Unfortunately in early studies of the PCR technique a very high rate of false positive results was observed. This was presumably due to contamination of reaction buffers or biological samples with Aspergillus conidia.
PATHOGENESIS Guided Medline Search The spores of A. fumigatus are very small (3-5 μm), thereby allowing penetration deep into the lung. In the immunocompetent host, pulmonary defense mechanisms almost always deal adequately with the fungal challenge provided by potentially pathogenic species. Exceptions do occur, but usually follow damage to the lungs, such as following influenza (19). Spores are ingested and killed by macrophages resident in the lungs. Hyphae are primarily killed by neutrophils. Since Aspergillus hyphae are too large to be ingested by neutrophils, killing occurs extracellularly. Immunocompromise heightens the risk of infection with the pathogenic species of Aspergillus by impairing the ability of macrophages or neutrophils to kill spores and hyphae. Most obviously, patients with hematological malignancy have heightened risk of invasive aspergillosis because of a decrease in neutrophil numbers. Patients with AIDS or chronic granulomatous disease have dysfunctional neutrophils. Patients receiving corticosteroids or other immunosuppressive therapy have impaired macrophage and neutrophil function, diminishing their ability to kill Aspergillus spores and hyphae, respectively. The pathology induced by Aspergillus infection depends on both the type of disease and type of underlying immunocompromise. Florid granulomata with few organisms may be observed (classically, in bone infection in patients with chronic granulomatous disease). In contrast, granulomata are usually absent in patients with neutropenia as a result of treatment for hematologic malignancies. Such patients have extensive necrosis invaded by extensive networks of Aspergillus hyphae. Unfortunately, A. fumigatus has a predilection for invasion of blood vessels. This contributes to the clinical findings of life-threatening hemoptysis (rupture of blood vessel walls into airways) or a presentation akin to pulmonary embolism (due to pulmonary infarction). Review Article: Singh N, Perfect J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. Lancet Infect Di 2007;7:395-401. SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo Single Drug In Vitro Studies Resistance of Aspergillus isolates to amphotericin, itraconazole and voriconazole has either been observed in isolates from patients or been created in the laboratory (38, 42, 51,116). It has been suggested that in vitro susceptibility testing of Aspergillus spp. is a predictor of clinical outcome in invasive aspergillosis (100). In this study, all nine patients with A. terreus infection and treated with amphotericin died; all A. terreus isolates were resistant to amphotericin. However, clinical failure in invasive aspergillosis may have many causes other than drug resistance; furthermore in patients who have died from invasive aspergillosis despite amphotericin treatment, emergence of resistance to amphotericin during treatment has not been detected (127). In mouse models of A. fumigatus, A. flavus and A. terreus infections, there was no correlation between susceptibility in vitro and outcome in vivo (82, 129). Itraconazole resistance in A. fumigatus has been correlated with clinical failure in both humans and experimental animal models of infection (38). However, susceptibility testing of A. flavus to itraconazole has been extremely difficult because of inoculum dependence. Despite the tantalizing data showing some links between in vitro susceptibility and clinical outcome, the interpretation of in vitro susceptibility data for Aspergillus species has long been difficult because much data have been based upon nonstandardized testing methods. The method for testing susceptibility, morphologic variations in the fungus, differences in growth rates and optimal growth conditions may all influence determination of the susceptibility of the fungi to antifungal drugs. In view of this, the National Committee for Clinical Laboratory Standards (NCCLS) has proposed a reference method for broth dilution antifungal susceptibility testing of conidium-forming fungi in their document M38-P. A number of test strains have been evaluated (51). An Etest method has also been studied, with reproducible results in preliminary studies (50). It should be noted that Aspergillus spp. are relatively insensitive to the echincandins in standard broth dilution susceptibility assays (14). With these caveats in mind, data are presented for recently published studies exploring the susceptibility of Aspergillus species to a variety of antifungal agents (Tables 1-3). As can be seen, the newer azole antifungal agents have greater in vitro activity than amphotericin B against most Aspergillus isolates. Fluconazole is essentially ineffective against Aspergillus spp. A. terreus is relatively insensitive to amphotericin. Resistance to itraconazole is occasionally seen, and cross-resistance to other azoles occasionally occurs. From structural considerations and some in vitro data (128), the susceptibility patterns of itraconazole and posaconazole are similar, as are those of voriconazole and ravuconazole. However, for individual isolates cross-resistance is somewhat unpredictable. At least two mechanisms of resistance are likely responsible for azole resistance (42). Itraconazole interferes with ergosterol biosynthesis by inhibiting sterol 14μ-demethylation. However, itraconazole resistant isolates may have either increased expression of the sterol 14μ-demethylase or altered affinity of the enzyme for itraconazole. In addition, a reduced intracellular concentration of itraconazole was observed in one of the resistant isolates suggesting that altered uptake or efflux mechanisms may be occurring. In Vivo (Animal) Studies Using Amphotericin B Preparations Amphotericin B Deoxycholate: Amphotericin B deoxycholate ("conventional" amphotericin B, Fungizone, Apothecon, Princeton, NJ) has been widely used in animal models of invasive aspergillosis. The effectiveness of amphotericin B in animal models has varied with its dose and duration, the timing of amphotericin B administration relative to time of infection, the mode of administration (intravenous, intraperitoneal or aerosolized), the type of animal model used and the Aspergillus inoculum dose and site of infection. Effectiveness of amphotericin B against A. fumigatus in animal models appeared to be dose-related (192). For example, amphotericin B at 1.5 mg/kg, but not at 0.5 mg/kg, was able to sterilize tissues infected with A. fumigatus (55). Recent studies assessing systemic invasive aspergillosis in immunocompromised animals have shown that amphotericin B use results in delayed and/or reduced mortality compared to control animals in which no antifungal agents was used (54, 55, 65, 136, 144, 145). Treatment with amphotericin B has also been associated with decreased tissue burden of Aspergillus in immunocompromised animal models (54,144). In contrast, two studies of invasive pulmonary aspergillosis were unable to show that use of amphotericin B was associated with a statistically significant decrease in mortality compared to controls, although mortality was slightly lower in the amphotericin B treated animals (36, 52, 53). In both of these studies (mirroring what occurs in real-life clinical scenarios) amphotericin B administration was delayed as compared to time of infection. Animal studies of pulmonary aspergillosis in which amphotericin B use was associated with 100% survival were notable for administration of the drug immediately after infection. Aerosolized Amphotericin B: Inhalation of airborne Aspergillus with deposition in the lungs is commonly believed to be the initial step leading to invasive pulmonary aspergillosis. However as noted in both the animal models above and in human studies, intravenous amphotericin B use is associated with poor outcome from invasive pulmonary aspergillosis. It is hypothesized that inhalation of amphotericin B aerosols could maximize local effectiveness of the drug while limiting its systemic toxicity. Hence the aerosolized drug may have particular use as prophylaxis against pulmonary aspergillosis in those at high risk of the disease. A number of studies have examined the use of aersolized amphotericin B in animal models (30, 99, 175). In each case the model used was that of Sprague-Dawley rats immunocompromised by use of cortisone acetate. The animals were infected via the trachea with an inoculum of 106 conidia of A. fumigatus. This model produces a progressive bronchopulmonary aspergillosis. Death occurs in untreated animals from 48 hours after inoculation (139). In each study, use of a single dose of aerosolized amphotericin B prior to infection resulted in statistically significant improvements in survival compared to control animals not given prophylaxis or treatment (30, 99). Survival for at least 10 days in animals given 1.6 mg/kg aerosolized over 15 minutes, 48 hours before infection, was 50-88.9% compared to 0-30% in control animals (30, 175). In a study in which 0.8 mg/kg aerosolized amphotericin B was administered 2 hours prior to infection, survival at 7 days was 100% in animals given prophylaxis and 20% in controls (99). While a single dose of aerosolized amphotericin B as prophylaxis was highly effective in decreasing mortality, it did not completely eradicate proliferation of the fungus. When survivors were sacrificed and examined, Aspergillus could still be cultured from the lungs of animals given prophylaxis (135). Furthermore, when immunosuppression was recommenced in other survivors, rapid proliferation of Aspergillus could be noted within 2-3 weeks (135). It would seem likely from these results that additional doses of aerosolized amphotericin B may be necessary in order to prevent reactivation of infection or reinfection from environmental sources. Aerosolized amphotericin B lipid complex (ABLC in doses from 0.4 to 1.6 mg/kg) given to rats two days before pulmonary infection significantly delayed mortality compared to the motality of rats given placebo (p<0.001) (30). Furthermore, aerosolized ABLC was more effective than an equivalent dose of aerosolized amphotericin B in prolonging survival, with 100% survival at 14 days postinfection in the ABLC group compared to 62.5% survival in the amphotericin B group. Mean concentrations of Amphotericin B in the lungs were 3.7 times higher at day 1 and almost six times higher at day 7 after treatment with aerosolized ABLC (30). Delivery Systems for Amphotericin B Involving Lipids: A large number of novel delivery systems for amphotericin B utilizing lipids or liposomes have been developed and tested in animal models. The premise behind such methods is that incorporation of amphotericin B into lipid structures can reduce the toxicity of amphotericin B while maintaining its efficacy. This is important since treatment of aspergillosis requires high dose therapy for a prolonged duration, often in patients with concomitant renal dysfunction. The various compounds reported have used different lipids, including the presence or absence of sterols (for example, cholesterol) and particles of different sizes. Some studies have used liposomes (broadly defined as concentric bilayers of lipid material with aqueous phase material between), whereas others have used unusual lipid structures or aggregates of lipid and amphotericin B, which are not liposomes. The interest in lipid delivery systems for amphotericin B relates to the finding that such formulations are less toxic than amphotericin B deoxycholate for mammalian cells, but retain the activity of amphotericin B deoxycholate against fungi (13, 106). For example, marked renal toxicity developed in rabbits treated with amphotericin B deoxycholate at 1 mg/kg/day for 10 days, whereas the serum creatinine remained normal in rabbits treated with 1 mg/kg/day or 5 mg/kg/day of liposomal amphotericin B (52). Three to five fold increases in mean serum urea and creatinine levels occurred, however, in rabbits treated with liposomal amphotericin B at a dose of 10 mg/kg/day (52). The reduction in toxicity is thought to be the result of differential affinities of the lipids in the lipid carrier to the ergosterol in the fungus membrane (highest affinity) versus the cholesterol in the human cell membrane (lowest affinity). Interaction of the human cell membrane with amphotericin B may be minimized because of selective transfer of amphotericin B from the lipid carrier to the fungus (107). An alternative suggestion has been that the reduced nephrotoxicity of lipid preparations results from lower serum and renal levels. For example, levels of amphotericin B in the kidney in animals administered amphotericin B colloidal dispersion (ABCD) were lower than in animals receiving standard amphotericin B (80). In view of the expense of commercial lipid-based delivery systems of amphotericin B, some groups have mixed amphotericin B with a parenteral fat emulsion (Intralipid) used in administration of total parenteral nutrition. One small study (performed by the manufacturers of amphotericin B lipid complex) showed that amphotericin B-intralipid emulsion, unlike ABLC, was associated with toxicity in animals almost identical to that of use of amphotericin B deoxycholate (185). However the results of this study have been disputed; other experiments show that amphotericin B-intralipid emulsion (LD50 for mice 4.5 mg/kg) is less toxic than amphotericin B deoxycholate (LD50 for mice 2.5 mg/kg) (29). Lipid preparations of amphotericin B differ markedly in their organ distribution compared to amphotericin B deoxycholate. Plasma concentrations of amphotericin B lipid complex (ABLC) are actually lower, for example, than the same dose (1mg/kg) administered as amphotericin B deoxycholate (31). In contrast, concentrations in the liver and spleen are two to five times higher in ABLC treated mice compared to the same dose given as amphotericin B deoxycholate (31). When a higher, but still tolerable dose of ABLC was given, liver and spleen concentrations were nine to seventy times those achieved by using conventional doses of amphotericin B deoxycholate (31). Lung concentrations of amphotericin B after administration of ABLC were considerably lower than liver or spleen concentrations but were still higher than those achieved by the same dose of amphotericin B deoxycholate (31). Use of high-dose ABLC (10 mg/kg) achieved lung concentrations 5-15 times higher than use of standard dose amphotericin B deoxycholate (1 mg/kg). Renal and brain concentrations of amphotericin B were only higher after ABLC administration compared to amphotericin B deoxycholate when high doses of ABLC (10 mg/kg) were given (31). A number of studies which have compared the efficacy of lipid formulations of amphotericin B with amphotericin B deoxycholate have been performed in animal models. Some of these have shown that if the lipid formulations are used at the same dose as amphotericin B deoxycholate, efficacy is actually inferior to that seen with amphotericin B deoxycholate (101,198). However, survival of animals with invasive aspergillosis given lipid formulations at doses of 5-12.5 mg/kg was superior to amphotericin B deoxycholate at 0.8 - 1 mg/kg (31, 52, 101). Organism burdens in infected tissues were significantly reduced by the lipid formulations at doses of 6-15 mg/kg, but were not reduced by conventional amphotericin B deoxycholate (101,198). It has been hypothesized that the efficacy of liposomal amphotericin may not be optimal because of delays in the release of free amphotericin (because the drug is liposome encapsulated) (15). Becker and colleagues have shown a significantly reduced efficacy when delays in availability of free amphotericin occur (15). The addition of a single dose of conventional amphotericin (1mg/kg) at the start of a course of liposomal amphotericin significantly enhanced rat survival. In Vivo (Animal) Studies Using Azoles Miconazole: Miconazole had little useful activity in the treatment of aspergillosis in the one animal model in which it has been studied (173). Ketoconazole: In studies of murine disseminated aspergillosis, ketoconzaole use has had little or no survival advantage compared to no treatment (158,172). Fluconazole: The efficacy of flucoanzole is dose-related, being no different compared to untreated controls at 5 and 20 mg/kg (23) but being significantly better than untreated controls at 60 and 120 mg/kg (54). However, fluconazole is clearly inferior to amphotericin B, amphotericin B lipid complex and itraconazole in the therapy of experimental invasive aspergillosis (31, 67, 68). Itraconazole: Use of itraconazole administered orally in animal models of invasive aspergillosis has resulted in superior survival compared to no treatment or compared to treatment with fluconazole in most (11, 67, 68, 132), but not all (31, 59) studies. Erratic absorption with subsequent low serum levels has been an ongoing problem in studies of orally administered itraconazole, particularly in rodents. However, when given intraperitoneally in treatment of rabbits with experimental A. fumigatus endocarditis, itraconazole has actually been shown to be superior to amphotericin B (105). Intravenous administration of itraconazole (10 or 20 mg/kg/day) resulted in 100% survival when given to rats, immunosuppressed with cortisone acetate and infected intratracheally with A. fumigatus (124). Similar survival was seen in rats given amphotericin B intravenously (1mg/kg/day), whereas all untreated rats died. All rats given a higher dose of intravenous itraconazole (30 mg/kg and 40 mg/kg) also died, although the mode of toxicity was not investigated (124). Absorption in animal models has been found to be improved when itraconazole is solubilized in compounds known as the cyclodextrins (76). The beta-cyclodextrins are naturally occurring cyclic oligosaccharides of seven glucose units produced as a result of the enzymatic degradation of starch by Bacillus macerans (76). Highly lipophilic drugs such as itraconazole can be carried by the cyclodextrins, since the cyclodextrins contain a hydrophobic interior and hydrophilic exterior. Solubilization of itraconazole in cyclodextrin allows delivery of high concentrations of itraconazole via an oral route. Peak serum concentrations of itraconazole in mice (measured 2 hours after administration of a 25 mg/kg dose in cyclodextrin) have been as high as 14.5 mg/L (36). Itraconazole solubilized in cyclodextrin has been found to be equivalent in efficacy to amphotericin B in rabbit models of infection (144). Voriconazole: Voriconazole is a monotriazole antifungal agent which has solubility characteristics permitting both intravenous and oral administration. In animal studies its efficacy has been compared to both itraconazole and amphotericin B. Survival rates in animals with experimental invasive aspergillosis treated with voriconazole have been impressive. Studies of experimental Aspergillus endocarditis in guinea pigs have shown 100% survival when voriconazole was given orally at doses of 5, 7.5 and 10 mg/kg, compared to 0% survival in those treated with itraconazole given orally at 10 mg/kg (120). Although all animals survived in the different voriconazole dose groups, only animals treated with 10 mg/kg had no Aspergillus recoverable from the heart after treatment (120). In a study of experimental pulmonary aspergillosis in Sprague-Dawley rats, survival was 100% in rats treated with voriconazole (30mg/kg once daily by gavage) compared to 75% for rats treated with itraconazole (30mg/kg once daily by gavage) (132). This difference was not statistically significant. It should be noted that be noted that in neither of the two studies mentioned above was the itraconazole used solubilized in cyclodextrin (120, 132). Voriconazole has been at least as effective as amphotericin when evaluated in animal models. Kirkpatrick et al (87), in an immunosuppressed guinea pig model of invasive aspergillosis, showed that voriconazole was more effective than either amphotericin or itraconazole cyclodextrin solution. Others have shown survival rates of 100% in animals treated with voriconazole at a dose of 30 mg/kg/day and animals treated with at least 1.5mg/kg/day of amphotericin (120, 132). Posaconazole: Posaconazole is a new triazole agent with a broad spectrum of in vitro activity (136,147). It is structurally similar to itraconazole. Animal studies have shown that its in vivo activity is as good as, if not better than, that of amphotericin B (86, 136, 147). Oakley (136) showed that use of posaconazole at 10 mg/kg or 25 mg/kg once daily in a neutropenic murine model of disseminated aspergillosis was statistically significantly better than amphotericin B (5mg/kg once daily by intraperitoneal injection) at reducing mortality. Furthermore, posaconazole at 25 mg/kg once daily was significantly better than amphotericin B at reducing fungal burdens in the lung or kidney (136). Posaconazole was equivalent or superior to itraconazole in reducing mortality in two studies (86, 136). Finally, posaconazole was effective at treating experimental infection with an itraconazole-resistant isolate of Aspergillus fumigatus (136). Walsh TJ, Raad I, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 2007;44:2-12. Ravuconazole: Ravuconazole is another new triazole compound. Kirkpatrick et al (89) evaluated ravuconazole in a guinea pig model of disseminated aspergillosis. Ravuconazole, at doses of 5, 10 or 25 mg/kg/day, improved survival compared to untreated controls. Results were at least as good as observed with itraconazole cyclodextrin solution or amphotericin (89). Petraitis (152) evaluated ravuconazole in the treatment of invasive pulmonary aspergillosis in persistently neutropenic rabbits. Survival was achieved in 90% (36/40) rabbits treated with ravuconazole compared with 50% (3/6) treated with amphotericin and 0% (0/10) untreated controls. In Vivo (Animal) Studies Using Echinocandins Caspofungin: Caspofungin is an echinocandin, a promising class of antifungal compounds which are potent inhibitors of fungal (1, 4)-β-D-glucan synthase, a cell wall polymer vital to the structural integrity of Aspergillus (3, 4). In models of disseminated aspergillosis, caspofungin was at least as effective as conventional amphotericin (34, 20). Petraitiene, Walsh and co-workers have investigated the efficacy of caspofungin in experimental pulmonary aspergillosis in persistently neutropenic rabbits (148). Rabbits treated with caspofungin had improved survival, but had a paradoxical trend towards increased fungal lung burden and increased serum galactomannan antigen index. However, histological examination revealed significant hyphal damage. Somewhat similar results have been found in a guinea pig model of invasive aspergillosis (88). Mortality occurred in 12 of 12 untreated controls, 0 of 12 animals treated with voriconazole, 3 of 12 animals treated with amphotericin, 4 of 12 animals treated with caspofungin 1 mg/kg/day and 6 of 12 animals treated with caspofungin 2.5 mg/kg/day. Treatment with voriconazole or amphotericin produced greater reductions in colony counts of amphotericin in tissues than caspofungin. These investigators also examined the combination of caspofungin with voriconazole -- these results are discussed below in the section on combination therapy. Micafungin: Micafungin (FK463) is another new echinocandin. Like caspofungin, in animal models micafungin prolongs survival and reduces the level of pulmonary infarction in experimental invasive aspergillosis, but does not eliminate Aspergillus organisms from tissues (78, 122, 150). Histologically, the hyphae are fragmented; the reduction in pulmonary infarction suggests that damaged hyphal elements have reduced angioinvasive properties (150). Anidulafungin: Anidulafungin (LY-303366), as noted above, has excellent in vitro activity against A. fumigatus. Like the other echinocandins, it has been shown to reduce mortality in animal models of invasive aspergillosis (149, 162, 195). Elimination of Aspergillus from tissues did not occur (162); additionally, in one model of mice pretreated with glucocorticoids, unexpectedly high mortality was observed (32). In Vivo (Animal) Studies Involving Other Antifungal Agents Liposomal Nystatin: Nystatin is a polyene antibiotic derived from Streptomyces noursei. Its previous use intravenously in humans has been associated with systemic toxicity. In the late 1980s, Lopez-Berestein and coworkers demonstrated in mice that encapsulation of nystatin in liposomes reduced toxicity while preserving efficacy (123). A number of studies have assessed the efficacy of liposomal nystatin againsts disseminated or invasive Aspergillus fumigatus infection. Wallace (197), in a study of neutropenic mice given intravenous A. fumigatus, showed that liposomal nystatin treatment at doses of 2 to 8 mg/kg/day resulted in survival of 59 to 70% of mice, compared to only 19 to 33% of mice in untreated control groups (p<0.0001). However survival in liposomal nystatin treated animals was statistically significantly inferior to the 93% survival seen after treatment with amphotericin B at a dose of 1 mg/kg/day (p<0.006). No renal or hepatic toxicity was observed in animals treated with liposomal nystatin. Flucytosine: Flucytosine as monotherapy for experimental disseminated aspergillosis in immunosuppressed rabbits has been shown to have a mortality rate comparable to no treatment, even in animals not given a lethal challenge (54). Terbinafine: Compared with the in vitro activities of itraconazole and amphotericin, the in vitro activity of terbinafine is inferior against A. fumigatus, and superior against A. flavus, A. terreus and A. niger (126). However, a study in a rat model showed little efficacy of the drug against experimental pulmonary aspergillosis (174). A possible explanation for the disparity between in vitro and in vivo results is the rapid first-pass hepatic metabolism of terbinafine in rodents, reducing serum levels of the drug. Combinations of Antifungal Agents In Vitro Studies Utilizing Combinations of Antifungal Agents Potentially, one of the most exciting developments in therapy of fungal infections is the opportunity for combination therapy. However, for many years, there have been concerns over the potential risk of antagonism, especially when an azole is administered first with sequential administration of amphotericin. Combinations of amphotericin and azoles have had conflicting results when tested in vitro, but do not appear to reliably add significantly to each other's activity against A. fumigatus. Amphotericin and itraconazole have been synergistic in 14-40% of strains tested, additive in 20-26% but antagonistic in 26% of 15 strains in one series (114) and none of five strains in another series (37). In one isolate from a patient in whom the combination of amphotericin and itraconazole failed, antagonism between amphotericin and itraconazole was demonstrated (171). Amphotericin and ketoconazole or fluconazole are rarely synergistic and may be antagonistic combinations in upwards of 20% of strains tested against A. fumigatus (77, 114). In a study using E tests as the testing method for assessment of drug combinations, amphotericin and itraconazole were antagonistic, especially when the amphotericin strip was applied after the itraconazole strip (94). This negative interaction is presumed secondary to subtle alterations of the sterol composition of the fungal membrane following exposure of the fungus to the azole (94). Voriconazole and amphotericin appear to be an indifferent combination (115). Indifference or antagonism occurs when two azoles are used together (77, 114). Combinations of amphotericin and flucytosine, although additive or synergistic in some studies, are more likely to be an indifferent combination in vitro (37, 137). Antagonism has been reported in 23% (6/26) strains in one study (37, 137). Combinations of amphotericin and rifampin or rifabutin are frequently synergistic (37, 77,137). Addition of rifampin consistently lowers the MICS of amphotericin B by two to ten fold (77). In 92% (36/39) Aspergillus strains from one study, amphotericin and rifampin were synergistic (37). Terbinafine and itraconazole were synergistic in all four strains tested in one small study (166). The combination of terbinafine and amphotericin B was synergistic in one of four and indifferent in three of four strains tested (166). Significant interest has been generated by the potential usefulness of echinocandins in combination with other antifungal classes in the therapy of invasive aspergillosis. Rex and colleagues (9) have investigated the in vitro interaction between caspofungin and amphotericin using the checkerboard method. The combination was synergistic or synergistic to additive for at least half of the isolates. Antagonism was not observed for any of the isolates tested (9). Micafungin and liposomal amphotericin have been investigated in combination (181). In seven of ten isolates tested, there was a trend towards synergy, and no antagonism was seen. In another study, combinations of either caspofungin or micafungin with amphotericin were synergistic, whilst caspofungin or micafungin with voriconazole was additive (115). Amphotericin B lipid complex and caspofungin demonstrated synergistic activity in vitro for the majority of isolates tested (115). Caspofungin plus amphotericin B was additive against 66% of the isolates (34). Combination of caspofungin with flucytosine was synergistic against Aspergillus spp. for 92% of the strains tested (34). Voriconazole plus flucytosine on the other hand was either indifferent (42%) or antagonistic (58%). Combination of caspofungin with voriconazole when tested for 48 clinical Aspergillus isolates was synergistic and in 87.5%, additive in 4.2%, and indifferent in 8.3%. Antagonism was not observered (146). Micafungin when combined with voriconazole was synergistic for 79% of Aspergillus fumigatus isolates (75). In Vivo (Animal) Studies Utilizing Combinations of Antifungal Agents Following on from the promising studies of combination therapy in vitro, a number of animal studies have addressed combination therapy. Most groups have shown enhanced killing when an echinocandin has been combined with either amphotericin or voriconazole. Kohno et al (91) showed that the survival of mice with invasive pulmonary aspergillosis was significantly improved when micafungin was combined with amphotericin than when either micafungin or amphotericin were administered alone. On pathologic examination, hyphal growth can still be observed at day 6 when monotherapy was used, whereas no hyphal growth was observed when combination therapy was used (134). Petraitis, Walsh and colleagues (151), in a study of experimental pulmonary aspergillosis in rabbits, showed that survival was achieved in 55% (5/9) rabbits treated with a combination of micafungin and conventional amphotericin, 44% (4/9) treated with a combination of micafungin and liposomal amphotericin, 33% (3/9) treated with conventional amphotericin alone, 22% (2/9) treated with liposomal amphotericin alone and 0% (0/20) untreated controls. No statistically significant differences in outcome could therefore be confirmed between combination therapy and monotherapy, but the number of mice tested was small. Caspofungin has been combined with voriconazole in a guinea pig model of invasive aspergillosis (88). No mortality occurred among 12 animals treated with both caspofungin and voriconazole, whereas 4/12 and 6/12 animals treated with caspofungin at 1 and 2.5 mg/kg/day, respectively, died. No animal treated with voriconazole alone died. There has long been concern about combining amphotericin B with an azole in the treatment of fungal infections. Some of this concern stems from experimental studies in which ketoconazole has been shown to be antagonistic to amphotericin B in animal models of disseminated apsergillosis (134, 157, 158, 172). Neither antagonism nor synergy has been observed however when amphotericin B has been combined with fluconazole (54) or posaconazole (22). The combination of amphotericin B and itraconazole has been synergistic (192), indifferent (59, 157) or antagonistic (157), depending on the study method and strains used. No conclusive result can be drawn from studies of the combination of amphotericin B and flucytosine in experimental aspergillosis. The combination has been reported to be synergistic (12, 105, 158) or indifferent (54,158). Similarly, results of studies on combinations of itraconazole and flucytosine have shown either synergy or indifference (157). Synergy was observed only when the organism was susceptible to flucytosine in vitro and the enhancement of activity was relatively minor (157). A single model has examined the combination of amphotericin B and rifampin (12). Rifampin is not active as monotherapy against aspergillosis, but synergy was observed in the instance reported.
ANTIMICROBIAL THERAPY Guided Medline Search Smart search General - Invasive Pulmonary Aspergillosis The optimal approach to treatment of invasive aspergillosis has yet to be determined, but the availability of new azoles and echinocandins may well revolutionize therapy within the next five years. The possibility of combination therapy has opened the way for particularly attractive investigations. Early initiation of treatment by way of early diagnosis must always play an important role, as do reduction of immunosuppression and recovery from neutropenia. Local lesions should be resected if possible. The discussion below concentrates on treatment recommendations for invasive pulmonary aspergillosis but apply, with some modifications, to treatment of other invasive forms of the infection (182). Although amphotericin preparations have been the drugs of choice for invasive aspergillosis for many years, a recent randomized trial (73) comparing amphotericin with voriconazole appears to have placed voriconazole as treatment of choice for invasive aspergillosis. However, it must be recognized that the clinical appearance of invasive aspergillosis may be mimicked by mucormycosis and some other fungal infections. Voriconazole lacks activity against the zygomycetes, so amphotericin should retain the mantle of drug of choice if microbiologic confirmation of Aspergillus infection is lacking.
The design of the study comparing voriconazole with amphotericin was as follows.
The study was an open, randomized comparison of voriconazole and conventional amphotericin (73). Patients received conventional amphotericin (1mg/kg/day) or
voriconazole (6 mg/kg intravenously for 2 doses, and then 4 mg/kg every 12 hours
intravenously, which could be followed by 200mg every twelve hours orally).
Patients could be switched to other licensed antifungal therapy (for example,
lipid preparations of or Unanswered questions include whether voriconazole versus lipid preparations of amphotericin from the outset of therapy would have provided the same results. Three lipid preparations of amphotercin are now marketed for clinical use; amphotericin liposome for injection (AmBisome, Fujisawa, Deerfield, IL), amphotericin colloidal dispersion (Amphotec, Sequus, Menlo Park, CA) and amphotericin B lipid complex (Abelcet, The Lipsome Company, Princeton, NJ). Guidelines: Walsh TJ, et al. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46(3):327-360. Cornely MA, Maertens J, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis 2007;44:1289-1297. There is conflicting data as to which lipid preparation should be preferred in treatment of invasive aspergillosis. However, a dose of 5 mg/kg/day is currently accepted as appropriate for all of these drugs in the treatment of invasive aspergillosis. Caspofungin when used as salvage therapy in patients with invasive aspergillosis was associated with a favorable response in 45% (111). Given lack of data regarding its use as primary therapy and a potentially fungistatic action against Aspergillus, caspofungin monotherapy is not suitable as primary therapy for invasive aspergillosis.
A number of studies have addressed salvage therapy in patients who have
previously failed, or become intolerant to, conventional amphotericin. Reviews
of several hundred patients treated for aspergillosis (predominantly pulmonary)
with lipid preparations of amphotericin in open-label emergency-use protocols,
show clinical responses in 40-60% of patients (104,
199, 202). Most patients
received 5 mg/kg/day. This figure of approximately 40% clinical response in
"rescue" therapy has been remarkably consistent when a number of drugs,
including the azoles, have been evaluated (39,
182). Of recent note are the
following studies. Denning et al (39) have studied
v Caspofungin has received Food and Drug Administration approval for the indication of refractory aspergillosis in 2004. Caspofungin has been evaluated in a multicenter, noncomparative study of 83 patients who failed or were intolerant to conventional amphotericin, lipid preparations of amphotericin or azoles (113). The majority of patients had hematologic malignancies, as their predominant underlying disease and 86% were refractory to previous therapy. A favorable response was observed in 45% of the patients with pulmonary aspergillosis and 23% of patients with disseminated infection. In another report, where caspofungin was employed as salvage therapy for invasive Aspergillosis, a compassionate-use study, 44% of the patients had favorable response (84). Limited experience exists with the use of caspofungin as primary therapy with invasive Aspergillosis. Of 32 patients who received caspofungin as first-line therapy, 56% had a complete or partial response (25). However, only 7 of 32 patients had invasive aspergillosis (25). It should be noted that a potential difficulty with use of caspofungin in the empiric treatment of patients with suspected invasive aspergillosis is the possibility of unsuspected infection with an organism resistant to the drug. Caspofungin is not active against Trichosporon species or Cryptococcus neoformans. Goodman et al (57) have described an allogeneic peripheral blood stem cell recipient who developed tenosynovitis due to T. beigelii, while receiving caspofungin for a presumed fungal pneumonia.
Micafungin has potent in vitro activity against Aspergillus
species at concentrations lower than Another study involving stem cell transplant recipients evaluated the safety and efficacy of micafungin in combination with other antifungal drugs for the treatment of refractory aspergillosis in 85 patients of whom 50 had proven invasive aspergillosis (160). Complete or partial treatment success was observed in 28% and 39% of patients, respectively. An open-label micafungin study from Japan reported success rates of 60% (6 of 10 patients) for invasive pulmonary aspergillosis-67% (6 of 9) for chronic necrotizing pulmonary Aspergillosis, and 55% (12 of 22) for pulmonary aspergilloma (93). Overall, 57% of Aspergillus-infected patients had a satisfactory response (138, 140, 178, 205). In an umbilical cord stem cell transplant recipient with invasive pulmonary aspergillosis due to Aspergillus terreus. Clinical improvement was documented with micafungin and oral itraconazole after progression on amphotericin B (189). Examination of the in vitro susceptibility of A. terreus isolate to reveal a good minimum inhibitor concentration and good time-kill assay results compared to amphotericin B. Thus, micafungin might be useful for invasive pulmonary aspergillosis caused by A. terreus. Anidulafungin has demonstrated potent in vitro activity against Aspergillus species with MIC90 of < 0.03 µg/ml compared to 0.25 µg/ml for caspofungin and 1.0 µg/ml for amphotericin B (153, 177). Additionally, its coadministration with liposomal amphotericin B or voriconazole resulted in no pharmacokinetic interaction and was well tolerated (48, 49). Clinical trials are underway to assess the efficacy of anidulafungin for invasive Aspergillosis. Raad II, Hanna HA, et al. Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin. Leukemia 2007 Dec. 20 [Epub ahead of print]. Combination Therapy: The efficacy of combination therapy for invasive aspergillosis remains unproven and has largely only been assessed in case series using historic controls or as case reports. In a sequential cohort of recipients of hematopoietic stem cell transplant or cytotoxic chemotherapy who received either voriconazole (n=31) or voriconazole plus caspofungin (n=16) as salvage therapy for pulmonary aspergillosis, 3 month survival was significantly better with combination therapy (HR 0.42, 95% CI 0.17-1.1, p = .048) (117). Salvage therapy with voriconazole and caspofungin was associated with lower mortality in multivariate models, independent of other prognostic variables, e.g. receipt of transplant and type of conditioning regimen (117). In another report, the combination of caspofungin and liposomal amphotericin was utilized as salvage therapy in patients who had an inadequate response to liposomal amphotericin monotherapy or as primary therapy (95). The combination was more successful as a primary therapy than as salvage therapy, although the response rates were not statistically significant (53 versus 35%; p = 0-.36). The combination of liposomal AmB and caspofungin was utilized in 30 leukemic patients who had inadequate responses to amphotericin alone (2). In 60% of these patients a favorable antifungal response was seen when combination therapy was utilized. It should be noted, however, that 20 of 30 patients in this study had possible invasive aspergillosis (5). In solid organ transplant recipients with invasive aspergillosis, voriconazole plus caspofungin when used as primary therapy was associated with 90 d survival rate of 67.5% compared to 51% with lipid formulation of amphotericin B (Hazard ratio 0.58, 95% CI 0.30-1.14, p=0.117) (179). However, in transplant recipients with renal failure (adjusted HR 0.32, 95% CI: 0.12-0.85, P=0.022), and in those with A. fumigatus infection (adjusted HR 0.37, 95% CI: 0.16-0.84, P=0.0019), combination therapy was independently associated with an improved 90-day survival in multivariate analysis. Interestingly, no correlation was found between in vitro antifungal interactions of the Aspergillus isolates to the combination of voriconazole and caspofungin and clinical outcome in this study. Other case reports have assessed the combination of caspofungin and voriconazole (33) or triple combination using an amphotericin, azole, and an echinocandin (187). Caspofungin and itraconazole were used successfully in combination in the treatment of invasive pulmonary aspergillosis in one case of amphotericin-resistant A. terreus infection and in another case of A. fumigatus infection in a patient who developed renal impairment with amphotericin B lipid complex (165). Special Situations Infections of the Respiratory Tract
Tracheobronchitis: Aspergillus tracheobronchitis is most common in
lung transplant recipients, but has also been described in other immunocompromised groups (AIDS, hematologic malignancies) and rarely in immunocompetent patients. In lung transplant recipients, a spectrum of disease
occurs, with the most dangerous end of the spectrum being ulcerative
tracheobronchial aspergillosis at the anastomosis site. The disease may also be
a precursor to invasive pulmonary aspergillosis. Descriptions of treatment
regimens have been in retrospective, non-randomized series which evaluated only
a small number of patients. A common, although unproven, practice is to combine
systemic antifungal therapy (with intravenous amphotericin or
v
Kramer (98) in the initial description of this entity treated six patients with
Treatment recommendations in patient groups other than lung transplant recipients are based solely on small case series and case reports. Extrapolation from these must be preceded by recognition of reporting bias and the heterogeneity of the clinical illnesses and immunosuppression in the reported patients. Successful treatment of a critically ill immunocompetent female with tracheobronchial aspergillosis with liposomal amphotericin, aerosolized amphotericin and adjuvant interferon-gamma and GM-CSF has been recently reported (19). Allergic Bronchopulmonary Aspergillosis (ABPA): For many years the only treatment available for allergic bronchopulmonary aspergillosis has been steroids. However, a randomized double blind study of itraconazole (200mg twice a day for 16 weeks, then 200mg once a day for 16 weeks) or placebo for steroid dependent ABPA showed a significantly greater chance of response occurring in patients given itraconazole (183). 46% of patients treated with itraconazole were able to achieve at least a 50% reduction in steroid dose, 25% greater exercise tolerance and 25% reduction in serum IgE levels. Itraconazole and corticosteroids should now be regarded as the standard of care for most patients with ABPA. Voriconazole has not yet been studied in the context of ABPA. Aspergilloma: Pulmonary aspergillomas result from fungal growth within a pre-existing pulmonary cavity. Unfortunately, although the infection is usually localized, erosion of a bronchial artery can lead to life-threatening hemoptysis. Systemic administration of antifungal agents is nearly always ineffective (85). Rare successes with oral itraconazole have been described, although these studies were retrospective, unblinded and did not contain a control group (182) Early surgical resection (lobectomy) is the treatment of choice in those patients with adequate lung function. However, because the surgery may be technically difficult and associated with significant morbidity and sometimes mortality, and because the underlying lung disease which predisposed to cavity formation is often severe, lobectomy is not a realistic option for some patients. In patients in whom lobectomy is precluded, a surgical alternative is cavernostomy performed under local or regional anesthesia. Intracavitary instillation of antifungal agents, in combination with cavernostomy or as an alternative to surgery, has been well described although only occasionally cures aspergillomas. Symptomatic relief may be marked however (203). Intracavitary instillation of amphotericin has been by percutaneous or bronchoscopic routes. Both a solution of amphotericin diluted in dextrose water (79) or a paste made by dissolving amphotercin in molten gelatin (56, 131) have been successfully used. An advantage of the paste (which is injected warm, percutaneously under radiologic control) is that it solidifies at body temperature keeping the drug within the cavity and therefore precludes the necessity for multiple drug instillations (131). The optimal dose and number of instillations of the amphotericin/dextrose water solution is unknown. Chest radiographs are an insensitive method of monitoring treatment. In practice, treatment is continued until symptoms have fully resolved and then continued for a further arbitrary period. It is not certain whether the intracavitary administration of antifungal agents is successful because of local irritiation and sclesosis or cidal activity against the Aspergillus. Chronic Necrotizing Aspergillosis: Antimicrobial therapy recommendations for chronic necrotizing aspergillosis are based on limited case series. Based on available data, voriconazole remains the preferred treatment for chronic necrotizing aspergillosis. In one prospective study of 39 patients with chronic necrotizing aspergillosis, 200 mg of voriconazole given twice daily for 4-24 weeks led to complete or partial response in 43% of patients, and improvement or stability of disease in 80% of patients (168a). This is in comparison to mortality rates quoted as high as 39% in other studies of this disease (207). Amphotericin B dosed at 0.5-1 mg/kg/day and liposomal amphotericin dosed at 4-5 mg/kg/day are useful alternative antifungal agents, but are associated with significant toxicities (207). Echinocandins, used alone or in combination with azoles, show promise for the treatment of chronic necrotizing aspergillosis in small case series studies (78a, 140a). Response to all of these antimicrobial regimens is assessed using clinical symptoms in combination with radiographic and laboratory data. Surgical resection is not a mainstay of therapy, but is reserved for young, otherwise healthy patients with good pulmonary reserve who do not tolerate or respond to antifungal therapy (207). Infections of the Sinuses Sinus infection by Aspergillus takes a variety of forms ranging in severity from fulminant acute invasive sinusitis to allergic sinusitis. Allergic sinusitis due to Aspergillus may manifest as chronic, intractable sinusitis and nasal polyposis. There is no evidence at present that antifungal agents are useful in the managemnet of this condition. Usual management involves endoscopic removal of polyps and inflammatory material followed by long-term intranasal corticosteroids and short-term systemic corticosteroids (44). In contrast, fulminant invasive Aspergillus infection of the sinuses, particularly in neutropenic patients (including bone marrow transplant recipients) and persons infected with HIV has a high mortality. Survival in this condition is often determined by early diagnosis, recovery from neutropenia and possibly ability to aggressively debride devitalized tissue (44). Although a review in 1990 (40) showed that mortality was higher in those treated with a combination of medical and surgical therapy than in those treated with medical therapy alone, it is possible that the apparent increase in mortality following surgery reflected more severe disease in this group. Chronic Aspergillus infection in the ethmoid sinus may result in bony erosion towards the orbit or the cavernous sinuses, particularly in patients on systemic corticosteroids or with diabetes mellitus. The condition has a poor prognosis and should be treated in a similar manner to acute invasive sinusitis. A. flavus sometimes produces regional tissue invasion and noncaseating granulomata in immunocompetent persons, primarily from Sudan, India and Pakistan, but also from the United States. This produces the curious syndrome known as primary paranasal granuloma. Extension into the orbit, dura and brain may result. Extensive surgery is indicated, although relapse postoperatively is common. Itraconazole may reduce the postoperative relapse rate (61). Infections of the Central Nervous System Aspergillus infection of the central nervous system is manifest usually as cerebral space occupying lesions in the context of disseminated disease in immunocompromised patients. Less commonly, cerebral abscesses may be an isolated finding in immunocompromised patients, follow neurosurgical procedures or be a result of direct extension from neglected sinus disease. Meningitis and spinal cord involvement are rare. It is difficult to make conclusions as to optimal management of cerebral aspergillosis other than to reiterate the role of reduction of immunosuppression and surgical drainage of lesions if possible. Clinical response to voriconazole has been extremely good (39, 108, 176, 194), and this drug may replace amphotericin as treatment of choice. Studies in guinea pigs have shown that voriconazole has excellent penetration into the CSF and the brain (81). At steady-state, CNS levels were double that found in plasma. If amphotericin is used, although unproven in clinical trials, the addition of flucytosine appears sensible based on its good penetration into brain tissue and limited human data. It is unclear whether adding rifampin adds any benefit to the above regimen. Lipid preparations of amphotericin in high dose may be useful, because the high doses of amphotericin used are likely to cause nephrotoxicity when conventional amphotericin is given. Long-term intracavitary administration of amphotericin B via an Ommaya reservoir has been utilized as an adjunct to radical debridement and use of systemic antifungal therapy (24). Gubler C, Wildi SM, et al. Disseminated Invasive Aspergillosis with Cerebral Involvement Successfully Treated with Caspofungin and Voriconazole. Infection. 2007;35:364-6. Infections of the Eye Aspergillus has been documented as a frequent cause of post-traumatic keratitis. Less commonly endophthalmitis may result as part of disseminated infection or may occur de novo in intravenous drug abusers or post ophthalmic surgery. Orbital infection can occur as a result of invasion from infected sinuses.
Time between injury and recognition of fungal keratitis is a major determinant
of success in treatment of Aspergillus keratitis. The condition is
usually treated empirically with 5% natamycin suspension administered every hour
while awake (164). Many clinicians also use a systemic antifungal agent (such as
Aspergillus endophthalmitis has a very poor prognosis as a result of delays in diagnosis and its frequent coexistence with disseminated disease. Therapeutic vitrectomy is usually essential. Although intravitreal injection of amphotericin B is said to be hazardous, as much as 5-10mg has been safely injected into the center of the vitreous cavity (60). Most authors have used much smaller doses intravitreally (0.005 to 0.01 mg). Daily administration of subconjunctival amphotericin B (1-2 mg) can follow (163). The question of concomitant systemic antifungal therapy is vexed. Penetration of amphotericin into the eye is poor. After intravenous administration, levels of amphotericin B in the human aqueous humor remain less than 0.5 µg per mL. There is little data on penetration of lipid formulations of amphotericin B or voriconazole into the eye at this stage. In contrast, flucytosine penetrates reasonably well into the eye (161). Yu reported a patient with aggressive eye disease who was treated successfully with a combination of amphotericin, rifampin and flucytosine (206).
Review Article: Javey G, Zuravleff J. Retinitis and Endophthalmitis. 2007. Review Article: Javey G, Zuravleff J. Keratitis. 2007. Review Article: Javey G, Zuravleff J. Sino-Orbital. 2007. Infections of Skin and Soft Tissue Guided Medline Search Aspergillus may involve the skin and soft tissues in the following ways: cutaneous manifestations of systemic disseminated infection; primary cutaneous aspergillosis in the immunocompromised patient; postsurgical or posttraumatic wound infections; burn wound infections; otitis externa (noninvasive); invasive external otitis; primary cutaneous aspergillosis associated with central venous lines. A. flavus is more common than A. fumigatus in many of these manifestations. A. niger may be associated with otitis externa. Occasionally, rare species such as A. ustus may be involved in primary cutaneous infections associated with immunosuppression.
Patients with cutaneous manifestations of documented systemic infections have a
poor prognosis despite active therapy. An exception may be in patients with
hematologic disorders in which neutropenia may be reversed. Successful treatment
of primary cutaneous aspergillosis associated with neutropenia has been
associated with reversal of neutropenia by use of granulocyte colony stimulating
factor (G-CSF) (72). Amphotericin preparations or Numerous reports have demonstrated that postsurgical or posttraumatic wound infection requires aggressive surgical intervention in addition to antifungal drugs for successful resolution (26, 72). The surgery may be as aggressive as limb amputation or extensive debridement of the kind seen in cases of necrotizing fasciitis. Inadequate debridement can result in deep invasion into subcutaneous tissue, muscle and sometimes deep viscera. Systemic antifungal therapy should accompany surgery.
Although Aspergillus may colonize burn wounds, true infection is
associated with mortality of approximately 50% (102). Extensive radical surgery
is needed with the addition of systemic antifungal therapy. Burn units with
higher than expected cases of burn wound aspergillosis have routinely irrigated
uninfected wounds with mafenide acetate plus
Although the isolation of Aspergillus from an ear canal usually
represents saprophytic colonization rather than infection, otitis externa can
indeed occur. Thorough cleaning and debridement is the mainstay of management.
Boric acid powder, Cutaneous infection associated with long-standing central venous access devices (especially Hickman catheters) has been reported in neutropenic patients and patients with human immunodeficiency virus infection, and is sometimes associated with development of underlying pulmonary aspergillosis. Once Aspergillus infection is suspected, the catheter should be removed (6). In the largest series reported, nine patients were treated with intravenous amphotericin (0.75 to 1.25 mg/kg/day) plus 5-flucytosine (3 to 8 g per day) and seven of the nine survived (6). The two patients who died did not recover from their neutropenia. These authors chose to defer wide debridement of the eschar until neutropenia had resolved (6). An alternative approach is immediate extensive chest wall debridement even while the patient was neutropenic. Osteomyelitis Aspergillus bone infection can be part of disseminated or local disease in immunocompromised patients (including transplant recipients, neutropenic patients and children with chronic granulomatous disease), can be related to intravenous drug use, trauma or surgery, or may occur by direct extension from the sinuses or ear. There appears to be an advantage of surgical therapy in the treatment of bony aspergillosis. Surgery may be important because amphotericin B achieves only low concentrations in bone and joint fluid. Furthermore the pathology of aspergillosis involves infarction and necrosis, which results in poor drug delivery to tissues.
Although not well studied, it would not appear that lipid preparations of amphotericin enhance penetration of amphotericin into bone. However, an
advantage of lipid preparations may be that their comparative lack of nephrotoxicity allow longer courses to be given such as may be required for
treatment of osteomyelitis. Both
flucytosine and
rifampin penetrate well into
bone. Tissue concentrations of
Adjuncts to surgery and antifungal agents have included hyperbaric oxygen (97) and interferon-gamma. Interferon-gamma was only used in children with chronic granulomatous disease (1). Infections of the Heart and Vascular System Aspergillus has been reported to cause endocarditis, myocarditis, pericarditis, mediastinitis, septic thrombophlebitis and infections of aortic grafts. Infection is associated with high mortality despite treatment. In addition, some cases are unsuspected during life and are only discovered at autopsy (142).
Aspergillus endocarditis may occur as part of disseminated disease, as a
complication of cardiac surgery or rarely may occur de novo (62,154). Early
surgical intervention with valve replacement is the cornerstone of successful
management. Only a small number of patients have been reported who received
medical therapy alone and survived (109,159). Amphotericin penetrates poorly
into cardiac vegetations, but nevertheless should probably be used as adjunctive
therapy. High doses (for example, 10 mg/kg/day) of lipid preparations of
amphotericin B have been used (159). There is very little or no clinical data on
use of Drug Interactions
Drug interactions may be particularly problematic with a number of antifungal
agents used to treat Aspergillus infections. The use of the
immunosuppressive agent sirolimus is contraindicated in patients receiving
Coadministration of posaconazole increased cyclosporine exposure and necessitated dosage reductions of 14-29% for cyclosporine (169). Posaconazole increased the maximum blood concentration and the area under the concentration-time curve for tacrolimus by 121% and 357% respectively (169). The pharmacokinetics of caspofungin is unaltered by coadministration of tacrolimus, but caspofungin may reduce tacrolimus concentrations by up to 20% and may increase cyclosporine A plasma concentrations by 35% (27, 167). Five of twelve healthy volunteers given cyclosporine and caspofungin experienced transient elevations of serum transaminase levels. Therefore patients receiving cyclosporine were excluded from the initial phase II/III clinical studies of caspofungin (167). In clinical setting, however, coadministration of caspofungin with cyclosporine A has been well tolerated (117, 170). Nevertheless, it is prudent to monitor hepatic enzyme in cyclosporine recipients treated with caspofungin. There is no interaction between caspofungin and mycophenolate mofetil. No interactions would be expected between caspofungin and antiretroviral medications and none were documented with nelfinavir (184). Rifampin both inhibits and induces caspofungin disposition (184). Consideration should be given to increasing caspofungin dose to 70 mg daily when coadministered with rifampin (184). Anidulafungin is unique among echinocandins in that it undergoes chemical degradation without being metabolized with >90% of the degraded products eliminated in the feces (46). Less than 1% of Anidulafungin and its degradation products are excreted in urine. No dosage adjustment therefore is necessary for hepatic or renal dysfunction (45). Anidulafungin clearance is not affected by drugs that are substrates, inducers, or inhibitor of cytochrome P450 hepatic isoenzymes, including rifampin (193). Further, since the drug is negligibly excreted in the urine, drug-drug interactions due to competitive renal elimination are unlikely (193, 49). Coadministration with tacrolimus documented no pharmacokinetic interaction between the two agents (45). When administered with cyclosporine A, a small (22%) increase in anidulafungin concentration was observed after 4 days of dosing with cyclosporine A and was not considered to be clinically relevant (49). A loading dose, 200 g intravenously, twice the maintenance dose (100 mg) achieves steady state after a single dose (46). Micafungin is a weak substrate and a mild inhibitor of the CYP3A enzyme, but not of P-glycoproteins (83). In healthy volunteers, micafungin was shown to be a mild inhibitor of cyclosporine levels (70). No significant pharmacokinetic interactions have been documented when tacrolimus and micafungin were coadministered (70). Patients receiving sirolimus and nifedipine, serum concentrations of these drugs were increased by 21% and 18%, respectively (28, 83). No drug interactions have been noted between micafungin and rifampicin, fluconazole, prednisolone and amphotericin B (83,103,191). Dosage adjustment in micafungin dosage is not necessary for patients with renal or moderate hepatic dysfunction (70). (Printable Version of Antimicrobial Therapy for Aspergillus) Review Article: Singh, N., Perfect, J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. The LANCET Infectious Diseases 2007; Vol.7, Issue 6, 395-401.
ADJUNCTIVE THERAPY Guided Medline Search The most established indication for immunotherapy is in chronic granulomatous disease (CGD) (1). In a randomized controlled trial, patients with chronic granulomatous disease were either given placebo or interferon-gamma 50 µg/m2 body surface area three times a week, as prophylaxis against infection. 4/65 placebo treated patients developed Aspergillus pneumonia compared to 1/63 given placebo. Adverse effects from the interferon-gamma included fever, chills, headache and erythema at the injection site. No serious or life-threatening toxic events occurred however (1). Recent experimental studies suggest that higher doses of interferon-gamma than those used in the randomized controlled trial may further enhance protection against A. fumigatus (5). A small number of clinical reports have described use of interferon-gamma as an adjunct to antigfungal therapy in children with Aspergillus osteomyelitis who were not previously given interferon-gamma as prophylaxis (71, 90, 140). Although some experimental and limited clinical evidence suggests that administration of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or interferon-gamma may be useful as immunotherapy against Aspergillus infections in situations outside of chronic granulomatous disease, there is no definitive evidence on this point as yet. A number of groups have strongly advocated surgery as an important part of management of invasive pulmonary aspergillosis (16, 58, 63, 121, 168). In a recent series, Gossot and colleagues (58) have performed surgery on 19 patients with invasive pulmonary aspergillosis. Nine of the patients were thrombocytopenic (platelet count less than 60,000) on the day of surgery. Wedge resections were performed on 7 patients and lobectomies for 12. All but one patient had surgery via a thoracoscopic approach. There was no intraoperative mortality and no patient died in the first 30 postoperative days.
ENDPOINTS FOR MONITORING THERAPY Guided Medline Search In years past, the endpoint of therapy for invasive aspergillosis was the premature death of the patient. However, with improved survival from the infection, "knowing when to stop" has become an important issue. At a bare minimum therapy should be continued until clinical and radiological abnormalities have resolved. The issue then becomes the duration of treatment necessary to treat foci of infection not visible to radiologic examination ("microfoci"). The decision to stop therapy also depends on likelihood of resolution of immunodeficiency. Recovery from neutropenia is a prerequisite to discontinuing therapy. Most patients will require approximately 6 weeks of therapy, but in the absence of complete clinical and radiological resolution therapy will need to be prolonged past this point. The availability of orally administered voriconazole or itraconazole makes prolonged therapy feasible. It is hoped that the serum galactomannan assay will be useful for monitoring the success of therapy, but at the present time, data is limited on this point. Since there are no definitive studies or incontrovertible data for concrete recommendations on the optimum duration of therapy, the prudent approach is to use the most effective therapy first and to continue treatment for 10-12 weeks or for at least 4-6 weeks beyond resolution of all clinical and radiographic abnormalities, whichever is longer. Recovery from neutropenia is one of the most important determinants of outcome in patients with haematological malignant disorders and invasive aspergillosis. Extent and type of pulmonary involvement has also been related to response. Focal, peripheral disease without cavitation is predictive of a favorable response, whereas diffuse and centrally located lesions have been associated with poorer outcome. After transplantation or haemopoeitic stem cells, active acute grade-2 (or higher) or extensive chronic graft-versus-host disease indicates a poorer outcome. In orgran-transplant recipients, dissemination beyond the lungs, requirement for dialysis, and previous cytomegalovirus infection predicted poorer survival in patients with invasive aspergillosis. In these patients at risk of poor outcome, the response to therapy may be slower and therefore, the duration of therapy may have to be longer (180). Review Article: Singh, N., Treatment of opportunistic mycoses: how long is long enough? Lancet Infect Dis 2003;3:703-08. VACCINES Guided Medline Search No vaccines are commercially available at the present time.
PREVENTION Guided Medline Search Smart search Preemptive Strategy In patients with hematologic malignancy and neutropenia twice weekly surveillance monitoring using Aspergillus galactomannan antigen combined with computed tomography (CT) imaging of the chest to initiate antifungal therapy was superior to the standard approach of employing antifungal therapy based on the onset of fever (110). The preemptive therapy approach led to the initiation of antifungal therapy in fewer patients and identified cases of invasive Aspergillus that would otherwise have remained undetectable due to absence of fever. Other studies have shown similar results in neutropenic patients undergoing cancer chemotherapy or stem cell transplant recipients (21). Given a lower sensitivity of the galactomannan antigen for immunosuppressed patients other than neutropenic hosts (especially organ transplant recipients), this approach cannot be used for all immunosuppressed patients at risk for developing invasive Aspergillosis. Review Article: Wheat JL, Walsh TJ. Diagnosis of Invasive Aspergillosis by Galactomannan Antigenemia Detection Using an Enzyme Immunoassay. 2007.
Infection Control Measures Hospital construction (including indoor renovation) is a well acknowledged risk factor for invasive aspergillosis. Vigorous attempts should be made to prevent airborne transmission of Aspergillus from the sites of construction to the location of immunosuppressed patients, by use of physical barriers. Additionally, air filtration systems through high-efficiency particulate air filtration (HEPA) filters for units such as bone marrow transplantation have been shown to reduce the occurrence of invasive aspergillosis (139). As noted earlier, there is emerging evidence that hospital water supplies may also be a potential source of Aspergillus spp. (7, 8). Precise recommendations on how to monitor hospital water systems have not yet been forthcoming.
TABLES Table 1: In Vitro Susceptibility of Aspergillus Fumigatus to Antifungal Agents Table 2: In Vitro Susceptibility of Aspergillus Flavus to Antifungal Agents Table 3: In Vitro Susceptibility of Aspergillus Terreus to Antifungal Agents
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