Recent advances in the epidemiology, prevention, diagnosis, and treatment of fungal pneumonia Melanie W. Pounda,c, Richard H. Drewb and John R. Perfectc Although pneumonia caused by fungi is not a common occurrence in the general population, disease in an enlarging immunocompromized population is encountered with increasing frequency. Fungal pneumonias are most frequently caused by Aspergillus spp., dimorphic fungi and Cryptococcus neoformans. Recent studies have identified risk factors of thrombocytopenia, environmental events (such as construction or renovation) and immunosuppressive drug therapies as being specific risk factors for invasive fungal disease in select patient populations. Diagnostic strategies to detect circulating antigens and polymerase chain reaction based detection systems have been explored to improve identification prior to the progressive advanced disease. Advances in prophylactic strategies include increased use of aerosolized formulations of amphotericin B, usually in conjunction with new and old systemic antifungal agents. Despite recent published guidelines for treatment of fungal pneumonia based on etiology, mortality remains high in some infections with advanced disease. Caspofungin, a new echinocandin antifungal, has recently been approved by the US Food and Drug Administration for the treatment of invasive Aspergillus infections in patients unresponsive to or unable to receive amphotericin B. A triazole antifungal, voriconazole, has shown promise in phase III clinical trials in patients with refractory fungal infections and is expected to be available in early 2002. Other echinocandin and triazole antifungals are under development in attempts to provide improved effective therapy for fungal pneumonia. Curr Opin Infect Dis 15:183±194. # 2002 Lippincott Williams & Wilkins. a Internal Medicine/Infectious Diseases/Academia, bCampbell University School of Pharmacy, Buies Creek and cDivision of Infectious Diseases, Duke University Medical Center, Durham, North Carolina, USA Correspondence to Melanie W. Pound PharmD, P.O. Box 3089, Duke University Medical Center, Durham, NC 27710, USA Tel: +1 919 684 6364; fax: +1 919 681 2741; e-mail: [email protected] Current Opinion in Infectious Diseases 2002, 15:183±194 Abbreviations ELISA FDA IPA enzyme-linked immunosorbent assay US Food and Drug Administration invasive pulmonary aspergillosis # 2002 Lippincott Williams & Wilkins 0951-7375 Introduction Fungi rarely cause lower respiratory tract infections in the general population. Only one of three recent studies reported fungi as an etiology in this clinical setting [1±3]. In contrast, directed epidemiological studies have described the growing incidence of fungal pneumonia in high-risk patient populations (such as those with AIDS or those who have undergone hematopoietic stem cell replacement or solid organ transplantation) ranging from 3±56% (Table 1) [4±20]. Speci®c risk factors in these patients include poor allograft function and fulminant hepatic failure before transplantation (in liver transplant recipients), increased immunosuppression, cytomegalovirus infection, airway colonization with Aspergillus (in lung transplant recipients), history of coccidioidal pulmonary infections, thrombocytopenia, dialysis dependency and use of OKT3 monoclonal antibodies . Lower respiratory tract infections can either be the primary presentation of the disease, such as in the case of invasive aspergillosis or coccidioidomycosis, or be a manifestation of a disseminated fungal infection such as cryptococcosis. A recent study of infectious complications in heart transplant recipients reported invasive fungal infections in 10.2% of patients . Of these infections, 37.6% were limited to pulmonary infections whereas 27% were disseminated disease. The most common pathogens causing pulmonary fungal infections in a retrospective study of 140 patients from 1988 to 1997 were Aspergillus (57%), Cryptococcus (21%) and Candida (14%) [22 . .]. Comprehensive reviews have been previously published summarizing diagnostic and treatment strategies for fungal pneumonia [20,23 . .,24 . .,25]. The purpose of this review is to provide a summary of recent (year 2000 to present) advances in information regarding the epidemiology, risk factors, prevention, diagnosis and treatment of fungal pneumonia. In addition, data regarding potential new treatments undergoing evaluations will be summarized. Epidemiology and risk factors While fungal pneumonia is rare in the general population, it is increasing in incidence in immunocompromised populations. Certain fungal species can be especially problematic for these individuals; these are discussed below. 183 184 Respiratory infections Table 1. Incidence of fungal pneumonia in special patient populations Population Incidence of fungal pneumonia Fungal pathogens HIV-infected patients Unavailable (30±45% Cryptococcus) [4,5] Bone marrow transplant patients Allogeneic Cryptococcus neoformans, Aspergillus spp., Coccidioides immitus, Histoplasma capsulatum, Blastomyces dermatitidis 12±56% Aspergillus spp, Scedosporium spp., Fusarium spp., Candida spp. [6±8] Autologous Solid organ transplant patients Liver Kidney Rare 37% Unavailable Lung Unavailable Heart 3±10.2% Aspergillosis Aspergillus spp. were found to be the primary cause of fungal pneumonia in a recent review examining pulmonary infections in cancer patients [24 . .]. Up to 90% of invasive aspergillosis cases start in or are con®ned to the lungs . In one series, the incidence of invasive aspergillosis in patients undergoing hematopoietic stem cell transplantation increased from 7.3% in 1992 to 16.9% in 1998 . While allogeneic recipients continued to show the greatest risk of infection, increases were also observed in those receiving autologous transplantation. Differences in the onset of invasive fungal infections relative to transplantation type have been reported. While the highest period of risk for invasive fungal infections in liver transplant recipients (including the risk of aspergillosis) is within 4 weeks of transplantation, invasive fungal infections in lung transplant recipients may present several months after transplantation . The median time of presentation of invasive aspergillosis in lung transplantation was 120 days, with 49% of infections occurring within 3 months, 68% within 6 months, and 79% within 9 months of transplantation . The highest risk of Aspergillus infections in patients undergoing bone marrow transplantation is thought to be during the period of neutropenia. However, recent reports have cited Aspergillus infections occurring after engraftment and are associated with graft-versus-host disease and administration of high doses of steroids. The risk for bone marrow transplant patients may extend over the entire year after transplantation . Aspergillus infections in heart transplant recipients may also have a variable time course, including late infection. The ®ndings of a recent study by Montoya et al.  describe the median onset of Aspergillus infection as 52 days after transplantation. Although A. fumigatus is the predominant species causing invasive disease, an increase in the incidence of nonfumigatus aspergillosis has been noted in several studies Aspergillus spp., Cryptococcus neoformans Cryptococcus neoformans, Aspergillus spp., Mucor spp. Aspergillus spp., Cryptococcus neoformans, Candida spp. Aspergillus spp., Candida spp. Reference [9,10] [11±13] [14,15] [16,17] [18,19] [28 .,29,30 .,31 .]. Of 12 allogeneic bone marrow transplant patients with Aspergillus infection, seven infections were caused by A. fumigatus and the rest by A. terreus (n = 3), A. versicolor (n = 1) and A. ustus (n = 1) [30 .]. Other studies have reported the rate of non-fumigatus aspergillosis to be as high as 25% [31 .]. This has a signi®cant impact on treatment, since infections due to A. terreus are usually poorly responsive to amphotericin B therapy [32,33]. Pulmonary aspergillosis has been associated with the use of other immunosuppressive therapies besides corticosteroids, such as in¯iximab therapy, desferrioxamine, cyclosporin A and even high-dose inhaled ¯uticasone use, although these ®ndings are rare and have only been noted in case reports [34±36,37 .]. Among other risk factors for aspergillosis are coinfection with or treatment for cytomegalovirus infection. For example, bone marrow recipients receiving more than 4 weeks of ganciclovir preemptive therapy for cytomegalovirus infections had an increased risk of invasive aspergillosis . Each week of ganciclovir treatment beyond 4 weeks increased the risk of invasive fungal infection by 1.4. The association of cytomegalovirus with aspergillosis was also observed in other recent studies [18,39 .]. Recent associations have been made with thrombocytopenia and the risk of Aspergillus infections in patients undergoing liver transplantation. One report describes preinfection thrombocytopenia (platelet counts below 306103/cmm) in all 21 liver transplant patients with fungal infections . A recent study found those at high-risk for invasive aspergillosis after culture isolation of Aspergillus from a nonsterile body site to include groups such as allogeneic bone marrow transplant patients, hematologic cancer patients, and those with signs such as neutropenia and malnutrition [31 .]. The ability to interpret a positive Aspergillus culture from a sterile body site is directly related to underlying disease. While above-high-risk Fungal pneumonia Pound et al. 185 patients are likely to have infection, others like patients with cystic ®brosis and connective tissue diseases are more likely to be colonized. There is an intermediate risk group, which includes AIDS patients, solid organ transplant patients, and those receiving corticosteroids, in whom there needs to be more clinical information to help in prediction of disease [31 .]. Environmental risk factors, such as Aspergillus spores secondary to hospital construction or renovation and water supplies, have previously been identi®ed . A recent retrospective study found 72 cases of invasive aspergillosis compared with 433 patients colonized with Aspergillus . Of these cases, 25% were nosocomially acquired, 62.5% were acquired in the community, and only 12.5% were from unknown sites or geography . Other investigators have reported the role of environmental control (in combination with the use of itraconazole prophylaxis) in reducing the rate of Aspergillus infection from 42% to 22.5% in lung transplant patients, while the absolute reduction in nosocomial Aspergillus infection was 5.8% . A signi®cant contribution to describing the epidemiology of Aspergillus infections and its treatment outcomes is the establishment of standard de®nitions of disease, as well as responses to therapy, based on patient risk factors, and histopathologic and culture evidence [31 .]. The diagnosis of invasive aspergillosis is considered de®nite if there are both positive tissue sample and culture from that site or if there is a positive sample from a sterile site regardless of the tissue results. Probable invasive aspergillosis is de®ned as having an immunocompromised host with positive sputum cultures or another organ system meeting de®nite invasive aspergillosis criteria. The diagnosis of possible invasive aspergillosis is based on a variety of criteria including symptoms, chest radiograph and inability to make a de®nitive diagnosis [31 .]. These de®nition criteria are necessary due to a high incidence of Aspergillus colonization in lung transplant recipients (23%) and tracheobronchitis (4%) when compared with invasive disease (6%) . Criteria for disease and uniform criteria for treatment outcome have helped make comparisons between treatment modalities more robust. Despite potent antifungal agents, the prognosis of patients with invasive aspergillosis remains grim [41,42 .]. In one series, the overall mortality of patients with invasive aspergillosis was 58%, and was highest for bone marrow transplant recipients (86.7%) and for patients with central nervous system or disseminated aspergillosis (88.1%) [42 .]. Other investigators describe 3-month survival to be as low as 38% [31 .]. Despite treatment with amphotericin B deoxycholate and lipid formulations of amphotericin B, one-half to two-thirds of patients died as a result of infection. Other forms of Aspergillus pulmonary disease besides invasive aspergillosis can be confusing in their management and outcome. According to a recent study, chronic necrotizing aspergillosis, aspergilloma and allergic bronchopulmonary aspergillosis were reported at 2%, 4% and 3% respectively from patients with positive Aspergillus cultures (n = 1209) [31 .]. Of the chronic necrotizing aspergillosis patients, 16% died within 3 months of positive culture and this group received a variety of treatments or no treatment. Only one patient died in a 3 month follow-up among the aspergilloma patients. Treatment for these patients included amphotericin B, itraconazole and ¯uconazole, but only one case of surgical resection which probably re¯ects poor pulmonary functions in this group. As for the allergic bronchopulmonary aspergillosis patients, only 17% received itraconazole therapy, but a recent study suggested bene®t from this azole . There were no deaths in this group [31 .]. Candidiasis While most fungal infections are due to Candida spp., pneumonia due to Candida spp. is quite rare and is usually associated with severely ill, immunocompromised individuals or those with septic pulmonary emboli [44 . .]. In contrast to infection, Candida colonization is common, and is found in the respiratory tract of up to 12% of mechanically ventilated patients without evidence of disease . A recent prospective study examined Candida infections among predominately cancer patients and found C. albicans to account for 67.3% (n = 349) . Only 5% of C. albicans were resistant to the azoles. However, 114 patients were infected with other Candida species, including C. glabrata (45.6%), C. tropicalis (18.4%), C. parapsilosis (16.6%) and C. krusei (9.6%). The presence of non-albicans Candida in up to one-half of patients with invasive candidiasis raises concerns over the empiric use of ¯uconazole therapy for these patients, since nonalbicans Candida are less predictably susceptible to ¯uconazole, and C. krusei is considered resistant. The overall Candida species resistance rate to ¯uconazole was 9.4%. Prior use of an azole antifungal led to a signi®cant association with C. albicans resistance to ¯uconazole . However, in fungal pneumonias, Candida is a minor cause. Cryptococcus Infections due to Cryptococcus neoformans are usually manifested as meningitis; in fact, prior to highly active antiretroviral therapy, as many as 5±15% of HIV patients were diagnosed with this fungal meningitis . Even in 186 Respiratory infections non-HIV infected patients, the overall mortality rate for disseminated infection may be as high as 30% [48 . .]. This infection is usually contracted through inhalation of small yeasts or basidiospores directly into the pulmonary tract. Pulmonary symptoms, if they occur, are often similar to other bacterial pneumonia although infection can progress to acute respiratory failure, even in nonHIV patients . However, this respiratory failure is most often described in those patients with disseminated disease . On the other hand, Pappas et al. reported that as many as 25% of patients with cryptococcal pulmonary involvement lack respiratory symptoms [48 . .]. While most patients in the study received antifungal therapy for isolation of Cryptococcus neoformans from the lung or airways and ¯uconazole appears to be the drug of choice for uncomplicated pulmonary infection, only 10% were considered treatment failures [48 . .]. Coccidioidomycosis Pulmonary manifestations of coccidioidomycosis are caused by infection with Coccidioides immitis arthrospores and account for approximately 100 000 fungal infections per year [50 . .]. Areas endemic for Coccidioides infections (the southwestern portion of the US, particularly areas of Arizona, New Mexico, Texas and California, and parts of Central and South America) often have an increased infection rate during dust storms, construction and high winds. Infections have become more frequent as increased populations move into these areas [50 . .,51]. However, a recent case series reported coccidioidomycosis occurring in non-endemic areas . Therefore, this disease should be considered in the differential diagnosis regardless of the geographic area, especially with immunosuppressed patients and those with a history of recent travel to endemic areas . Manifestations include primary pulmonary coccidioidomycosis, chronic progressive pulmonary coccidioidomycosis and pulmonary manifestations of disseminated coccidioidomycosis. A recent study examined the risk factors associated with development of coccidioidomycosis and found a statistically signi®cant association for this fungal infection with diabetic patients, cigarette smokers, and those having undergone previous antifungal therapy . Blastomycosis The dimorphic fungus, Blastomyces dermatitidis, causes pulmonary manifestations of blastomycosis. Like Coccidioides, it is also found in certain geographic regions such as the southeast and central US (in particular the Mississippi and Ohio River valleys). While this type of fungal pneumonia is usually infrequent in these endemic areas, there have been several outbreaks of disease reported . Acute infection is usually mild and very seldom is it diagnosed, or therapy given, in the immunocompetent individual. However, as with any patient, there is always the potential for dissemination to occur and patients can develop severe infection (acute respiratory distress syndrome) or chronic pulmonary lesions. Histoplasmosis Histoplasmosis is caused by Histoplasma capsulatum and is a frequent respiratory pathogen in endemic areas. This fungus is found worldwide, including North and Latin America, and parts of Europe and Asia. In the US, it is commonly found in the Ohio and Mississippi River valleys. Like other dimorphic pulmonary fungal infections, histoplasmosis also presents clinically in several different ways, including acute pulmonary pneumonitis, mediastinal granulomatous in¯ammation and ®brosis, chronic pulmonary, cavitary and disseminated disease. Other fungal pathogens Paracoccidioidomycosis, penicillinosis and zygomycosis can also cause pneumonia. Paracoccidioidomycosis is problematic in Central and South America within subtropical areas. Penicillinosis is found solely in Southeast Asia and has the potential to disseminate from the respiratory tract to other organs like the skin in HIVinfected patients. Zygomycosis includes fungi from the Absidia, Mucor and Rhizomucor classes. While these fungal pneumonias are rare, they can be fatal if untreated. A recent report summarized the experience of four patients with Cunninghamella bertholletiae pulmonary infection . Of these patients, all four were treated with amphotericin B or liposomal amphotericin B and three patients died . Zygomycosis among solid organ transplant patients is also associated with a high mortality rate (up to 60%), emphasizing the critical importance of treatment . We generally recommend medical treatment with lipid products of amphotericin B and surgical debulking or removal of infarcted lung tissue. Diagnostic advances Because the symptoms of fungal pneumonia are often nonspeci®c, a de®nitive clinical diagnosis based on presentation is usually impossible and diagnosis is only helped by risk factors of patients. While histopathologic and culture methods have become the standard diagnostic tools, these often require invasive procedures to obtain suf®cient pathologic evidence of invasive disease, and the airway cultures are from nonsterile sites with frequent fungal colonization. In addition, cultures from bone marrow, cerebrospinal ¯uid and blood infrequently yield Aspergillus growth, and Aspergillus hyphae can be indistinguishable from certain other hyalohyphomycetes such as Fusarium or Scedosporium species [57 . .]. Since respiratory tract cultures may simply be the result of fungal colonization, the culture isolates from these sites, Fungal pneumonia Pound et al. 187 which are not sterile, do not necessarily correspond to disease [31 .,57 . .]. However, risk-strati®cation may help predict disease. For example, in one study the risk of invasive aspergillosis was 50±70% in high-risk patients such as bone marrow transplant patients with a positive culture for Aspergillus, but in cystic ®brosis patients a positive sputum culture was rarely associated with invasive aspergillosis [31 .]. Because of the high mortality rate associated with these pulmonary fungal infections, especially invasive pulmonary aspergillosis (IPA), early diagnosis is likely essential to survival. In addition to the radiologic diagnosis of IPA by characteristic ®ndings seen on chest computed tomography (halo sign and cavitary lesions), detection of circulating fungal antigens would be useful in the establishment of a diagnosis in immunocompromised hosts. Enzyme-linked immunosorbent assay (ELISA) and latex agglutination tests can detect circulating galactomannan in cases of aspergillosis. In addition, detection of plasma (1?3)-b-D-glucan may also be useful in screening for invasive mycoses. While the ELISA and b-glucan tests are highly speci®c (97% and 84%, respectively in one study of invasive aspergillosis [58 .]), they may detect disease only in the advanced stages in some patients. One study reported a mean of 25.8 days and 25.6 days for positive results in latex agglutination and b-glucan evaluations, respectively , and both of these assays were preceded by a computed tomography diagnosis of infection by an average of 10.3± 11.3 days. Furthermore, given the species-speci®city of the galactomannan assay, some emerging non-Aspergillus mycoses will not be detected . In addition, falsepositive reactions occurred at a rate of 14% in one study . It is likely that these tests will perform best with serial screening of high-risk patients and must be accompanied by other diagnostic strategies (such as cultures, histopathology, and appropriate radiographic imaging techniques). Molecular diagnostic techniques are being evaluated to quickly and accurately identify certain fungal species. A recent study revealed polymerase chain reaction technology to be a useful tool in identifying Aspergillus species. While maintaining high speci®city for IPA (92%), polymerase chain reaction techniques improved sensitivity to 79% (compared with 58% and 68% seen with ELISA and b-glucan, respectively) [58 .]. This same assay was also shown to be useful for other fungal species, including Candida and Cryptococcus . The role of antifungal susceptibility testing has recently been reviewed  The US National Committee for Clinical Laboratory Standards has approved a reference in-vitro method for testing selected antifungal agents (¯uconazole, itraconazole and ¯ucytosine) against Candi- da spp. and Cryptococcus neoformans. The majority of the data on outcomes of patients with candidiasis represented patients with oropharyngeal disease and not invasive infections. Therefore, it is more likely that such susceptibility testing will identify patients who will fail with a certain therapy, rather than predict those that will respond. Methods for testing moulds (including Aspergillus spp., Fusarium spp., Rhizopus spp., Pseudallescheria boydii and Sporothrix schenckii) have also been published . However, these techniques are often time-consuming and require consistent standards. Also, further validation of their clinical applications is needed. Prophylactic strategies A recent metaanalysis describes the use of oral ¯uconazole as prophylaxis in neutropenic patients (predominantly cancer patients) and failed to demonstrate a reduction in mortality or systemic fungal infections . In contrast to this general population, guidelines have recently been published which discuss appropriate prophylaxis against opportunistic infections in high-risk stem cell transplant recipients [64 . .]. As a primary fungal infection in this population is candidiasis, and ¯uconazole has been shown to reduce infections and mortality in this group, the drug is recommended for allogeneic stem cell transplant patients. Because the rate of fungal infections is low in autologous bone marrow transplant patients, antifungal prophylaxis is not generally required [64 . .]. However, the increasing population of stem cell transplants with aspergillosis makes the evaluation of measures to prevent aspergillosis critical. Prophylactic strategies against invasive fungal infections in patients undergoing solid organ transplantation has also been recently reviewed . While ¯uconazole has proven to be an effective option in prevention of Candida infections in liver transplant patients, in certain high-risk patients, this option is inadequate to provide effective prophylaxis against Aspergillus infections . Since lung transplant patients are at very high risk for developing invasive aspergillosis, directed antifungal prophylaxis is supported . Although not a new strategy, the application of aerosolized amphotericin B as a prophylactic strategy (with or without additional systemic prophylaxis) has received recent attention. The data regarding aerosolized amphotericin B as a prophylactic strategy have been previously reviewed . Because of its lack of signi®cant systemic toxicity, ease of administration, low expense, lack of drug interactions, and ease of monitoring, aerosolized amphotericin B may be an attractive prophylactic strategy in the prevention of fungal infections. It has been administered to a variety of immunocompromised patient populations with variable results [18,67]. A statistically signi®cant decrease 188 Respiratory infections (P50.005) in the incidence of fungal infections was observed in patients with lung, heart-lung and heart transplants following prophylactic administration of aerosolized amphotericin B . A more recent randomized study examined aerosolized amphotericin B to prevent invasive aspergillosis in patients with prolonged neutropenia . These patients were predominantly leukemia and autologous bone marrow transplant patients. The results of this study revealed a lower, but not statistically signi®cant incidence of invasive aspergillosis, although the overall incidence of aspergillosis was low . While experience with the use of intravenous lipidbased formulations of amphotericin B (such as amphotericin B lipid complex and liposomal amphotericin B) for treatment of known or suspected invasive infection is growing, there is limited published experience with these preparations administered prophylactically as an aerosol [39 .,69]. Experience in the use of the aerosolized lipid complex in 51 patients undergoing lung transplantation has been recently published . Administration of 100 mg (ventilated patients) or 50 mg (nonventilated patients) was well tolerated in the majority of patients studied (98%). Only two patients had either proven or probable pulmonary fungal infections due to Candida during the study. However, extrapulmonary fungal infection was reported in 8% of the participants, indicating the potential need for adjunctive systemic antifungal prophylaxis. Thus, amphotericin B lipid complex in the aerosol form may be a safe alternative to traditional aerosolized amphotericin B therapy . Controversies surrounding environmental control for prevention of aspergillosis have been recently addressed. Hajjeh and Warnock  suggested that invasive aspergillosis cases are often sporadic in nature and seem to occur from both the hospital setting as well as the community. While control measures can be taken to prevent nosocomial infections, protecting patients once they leave the hospital is more dif®cult . However, the introduction of high-ef®ciency particulate air ®lters at one center dramatically reduced the incidence of IPA in leukemia patients in the hospital setting with a statistically signi®cant difference in the rates of IPA before and after installation of the ®lters (P50.0003) [70 .]. There has also been concern about the water supply as a vehicle for transmission of moulds in the hospital setting, and this potential environmental contamination needs to be checked in each high-risk area for patient management . Advances in treatment options The current therapy for treating fungal pneumonia may be effective for some cases, but limitations of treatment still exist. Newer agents, however, have been researched and offer promise in the treatment of fungal infections. Such new agents are discussed below. Caspofungin Echinocandins are a new class of antifungals which inhibit fungal cell wall synthesis by interfering with glucan synthesis. Caspofungin is the ®rst echinocandin to be approved by the US Food and Drug Administration (FDA) for treatment [72,73 . .]. It demonstrates activity in vitro against a broad spectrum of fungal pathogens, including A. fumigatus, A. ¯avus, A. terreus and A. niger and Candida species, including azoleresistant isolates . In contrast, caspofungin lacks reliable activity against Cryptococcus, other moulds, and endemic dimorphic fungi . In-vitro and animal studies regarding caspofungin were recently summarized [73 . .]. An equal or increased survival rate associated with caspofungin-treated mice was demonstrated when compared with either placebo or amphotericin B-treated mice models for disseminated and pulmonary aspergillosis. In a clinical trial for IPA (de®nite or probable) refractory or intolerant to conventional therapy, approximately 40% of patients showed a complete or partial response to caspofungin when treated for up to 162 days (mean 31.1 days) . Caspofungin is currently FDA-approved as therapy for IPA refractory to other ®rst-line agents. An intravenous loading dose of 70 mg on day one is followed by 50 mg per day on subsequent days, infused over 1 h. While no adjustment is necessary for patients with renal dysfunction, reductions are recommended for patients with moderate hepatic insuf®ciency. Caspofungin is not metabolized by, nor does it induce or inhibit, cytochrome P450 enzymes frequently responsible for drug interactions. However, increases in alanine aminotransferase concentrations have occurred in normal subjects during coadministration with cyclosporin A. Therefore, the concomitant use of these medications must be justi®ed by clinical bene®t. Decreases have been observed in the tacrolimus area under the time±concentration curve by 20%, thereby necessitating close monitoring of tacrolimus concentrations if coadministered with caspofungin. The most commonly associated side-effects include fever, nausea, vomiting and infusion-related venous effects . Several questions remain regarding the application of caspofungin in clinical practice. While it demonstrates activity in vitro against Candida spp., published human experience for Candida infections is limited to esophageal candidiasis [77 .]. Data are lacking in humans regarding its ef®cacy in invasive candidiasis but should be available soon, and it is likely that this class of agents will become part of the routine management of candidiasis [78±80]. It is also not clear as to the use of Fungal pneumonia Pound et al. 189 caspofungin in combination with other antifungal agents, but its mechanism of action would suggest that bene®t would be increased if the drug was administered early in infection. Dif®culties in establishing reliable in-vitro susceptibility testing methodologies for caspofungin against Aspergillus and Candida may limit use of the predictive role of this test in patients undergoing caspofungin therapy. Amphotericin B aerosol The role of aerosolized amphotericin B deoxycholate as an adjunct to systemic therapy for the treatment of refractory invasive pulmonary fungal infections is not well de®ned. Previously published case reports have described its use in combination with systemic therapy for infections such as tracheobronchial aspergillosis . However, data are lacking from randomized, controlled trials to adequately describe its role in therapy. Intravenous itraconazole Erratic absorption of oral itraconazole capsules has limited its use in the treatment of severe, invasive fungal infections . While the oral cyclodextrin solution has improved bioavailability, it is still recommended to monitor serum concentrations of itraconazole following oral administration in patients with invasive fungal infections [83 . .]. The introduction of the intravenous formulation of itraconazole was intended to produce a faster and more consistent serum concentration. Caillot et al.  evaluated 14 days of intravenous itraconazole followed by 12 weeks of oral itraconazole therapy in 31 patients with IPA. The results showed a 48% complete or partial response without severe sideeffects. Intravenous itraconazole has been FDAapproved for the treatment of blastomycosis (pulmonary and extrapulmonary), histoplasmosis (including chronic cavitary pulmonary disease and disseminated disease), nonmeningeal histoplasmosis, and aspergillosis (pulmonary and extrapulmonary) in patients who are intolerant of or who are refractory to amphotericin B therapy [82,85]. The current dosing recommendations for intravenous itraconazole include 200 mg (infused over 1 h) twice a day for a total of four doses, followed by 200 mg per day for a maximum of 14 days. At this point the patient should be placed on oral itraconazole. Patients with renal dysfunction (creatinine clearance 530 ml/min) should not be placed on intravenous itraconazole because of the reduced clearance of hydroxypropyl-b-cyclodextrin, a side-chain moiety. Drug interactions can be problematic (as with the oral formulation) and certain drugs are contraindicated with intravenous itraconazole (e.g. cisapride, pimozide, quinidine and dofetilide). It also interacts with 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors metabolized by cytochrome P3A4 . Commonly occurring adverse events include diarrhea, abdominal pain and nausea and vomiting. Liver function tests should also be monitored especially in those patients with liver disease . Lipid-based formulations of amphotericin B Amphotericin B lipid complex (Abelcet; Elan Pharmaceuticals, San Francisco, California, USA), liposomal amphotericin B (Ambisome; Fujisawa, Deer®eld, Illinois, USA) and amphotericin B colloidal dispersion (Amphotec; Intermune Pharmaceuticals, Brisbane, California, USA) are lipid-based formulations of amphotericin B that have demonstrated reductions in the incidence of nephrotoxicity when compared with amphotericin B deoxycholate. In addition, liposomal amphotericin B has demonstrated a reduction in infusion-related reactions when compared with the deoxycholate, but the acquisition cost of these agents is several-fold higher. In addition, data are lacking to demonstrate their superiority in the treatment of invasive pulmonary fungal infections despite the high concentrations of amphotericin B delivered to the lungs of those receiving the lipid complex formulation. According to the Infectious Diseases Society of America guidelines, these agents are rarely used as ®rst-line agents and primarily play a role when the patient experiences worsening renal function with the traditional treatments [44 . .,50 . .,57 . .,83 . .,86 . .,87]. However, practically they become attractive agents to use when nephrotoxicity is an issue and high doses of drug need to be delivered rapidly. This translates into frequent use of these agents in transplant patients and those with renal dysfunction. Voriconazole Newer triazole antifungal agents have recently been investigated in attempts to improve upon the activity of existing agents such as ¯uconazole against Aspergillus spp. and non-albicans Candida. Voriconazole exhibits fungistatic activity in vitro against the Candida spp., and fungicidal activity against the Aspergillus species [88±93]. Voriconazole has been studied in solid organ and bone marrow transplant patients with histoplasmosis and invasive pulmonary disease (C. glabrata) . Early data suggest that voriconazole may be useful in the treatment of these diseases when patients are unable to take ®rstline therapy. Data from a recent randomized study were presented which compared initial therapy with amphotericin B to voriconazole in 392 patients with invasive aspergillosis . Pulmonary invasive aspergillosis was seen in 84% and 83% of patients, respectively. Patients in this study were randomized to initial therapy with either amphotericin B deoxycholate 1 mg/kg (n = 133) or voriconazole 6 mg/kg62, then 4 mg/kg every 12 h followed by 200 mg twice daily (n = 144). Therapy could then continue with alternate agents. The mean length of therapy for the initial randomized treatment was 11 days 190 Respiratory infections for amphotericin B deoxycholate and 77 days for voriconazole. A complete or partial response at week 12 was seen in 31.6% and 52.8% of amphotericin B deoxycholate- and voriconazole-treated patients, respectively (95% con®dence interval for difference 10.4± 32.9%). Survival was 57.9% and 70.8%, respectively (hazard ratio 0.59, 95% con®dence interval 0.40±0.88). This study is the ®rst to indicate a signi®cant advance in the treatment of invasive aspergillosis over standard amphotericin B deoxycholate. Voriconazole was recently reviewed by the Advisory Committee of the FDA . The most common sideeffects observed in the investigational trials included hepatotoxicity and visual adverse events. Hepatotoxicity was demonstrated through liver function tests abnormalities, while the visual effects were predominantly enhanced or altered visual perception with an incidence as high as 46% . Animal studies suggest that voriconazole may also prolong QT intervals. Drug interactions may also be problematic, because it is metabolized via cytochrome P450. Coadministration of rifampin and sirolimus with voriconazole is contraindicated. Other drugs that may need to be adjusted or carefully monitored when coadministered with voriconazole include (but are not limited to) phenytoin, warfarin, tacrolimus and cyclosporin. While an exact dosing regimen is unknown at this time, it appears that it may need to be given twice daily . Cytokine therapy Available data suggest that cytokines or chemokines may play a role in assisting in the eradication of fungi [97 . .,98,99 .]. Interferon-g and granulocyte±macrophage colony-stimulating factor have been demonstrated to augment hyphal destruction when used independently against Aspergillus and Fusarium spp. . Recent publications have reviewed the potential role of leukocyte transfusions, colony-stimulating factors, and interleukin therapy in the treatment of invasive fungal infections [97 . .,99 .]. However, more data are needed in this area before these modalities could be considered for routine clinical practice. In fact, there is concern that occasionally cytokines such as granulocyte±macrophage colony-stimulating factor or granulocyte colony-stimulating factor may bring back a cellular reaction so intense that it can cause acute respiratory distress syndrome as neutrophils migrate and degranulate in the site of a fungal pulmonary infection. It makes a clinician consider some down regulation of this cytokine cascade with corticosteroids. However, precise management of the patient is not clear and needs to be individualized. Future therapies In addition to voriconazole, newer triazoles are being investigated with increased activity in vitro against Aspergillus and non-albicans Candida. Ravuconazole (formerly known as BMS-207147) demonstrates in-vitro activity against A. fumigatus and Cryptococcus neoformans [100,101]. Animal models suggest favorable penetration of drug into lung tissue . However, clinical studies are needed to assess ravuconazole's ef®cacy in pulmonary infections. Posaconazole (formerly known as SCH56592) exhibits in-vitro and in-vivo activity against Cryptococcus neoformans, Candida spp., Aspergillus spp., Fusarium solani, Blastomyces dermatitidis, Coccidioides immitis and Zygomycetes [103±110]. It has demonstrated ef®cacy in animal models of invasive aspergillosis , and has shown effectiveness against zygomycosis (Mucor spp.) , and coccidioidomycosis . In addition, activity was demonstrated against disseminated histoplasmosis in CD4, CD8 depleted mice, with ef®cacy equivalent to amphotericin B and superior to itraconazole . Posaconazole has also been studied in combination therapy . Posaconazole in combination with ¯ucytosine, was signi®cantly more effective (P50.01) than when ¯ucytosine was used alone in the treatment of cryptococcal meningitis in mice . However, the combination was not more effective than posaconazole alone. The most common side-effects associated with posaconazole administration include diarrhea, ¯atulence, muscle weakness and ocular discomfort . Further evaluations are needed in the pulmonary setting to fully assess its utility in fungal pneumonia, but our preliminary experience suggests that it should effectively treat fungal pneumonias. In addition to caspofungin, other echinocandins are being investigated for their potential role in the treatment of invasive fungal infections. Micafungin (formerly FK 463) is an echinocandin-like antifungal agent demonstrating in-vitro activity against Candida, Aspergillus and Penicillium [115,116]. A recent study showed that clearance of C. albicans in disseminated disease was dose-dependent . However this was not the case in IPA with A. fumigatus . In addition, combination therapy with amphotericin B has demonstrated synergism in treating pulmonary aspergillosis in mice [118,119]. Another echinocandin, anidulafungin (formerly LY303366) has also shown in-vitro activity against Candida spp. and in-vitro and in-vivo activity (animal models) against invasive aspergillosis [100,120±122]. Clinical trials are currently evaluating anidulafungin's ef®cacy. Conclusion Because of the signi®cant morbidity and mortality associated with fungal pneumonia, improvements in prevention, diagnosis and treatment are essential to the survival of these patients. Prophylactic strategies in highrisk patient populations (such as those undergoing bone Fungal pneumonia Pound et al. 191 Table 2. Summary of Infectious Diseases Society of America guidelines on the management of primary pulmonary fungal disease Pathogen Diagnosis Treatment Aspergillus Invasive pulmonary aspergillosis Aspergilloma Allergic bronchopulmonary aspergillosis Mild±moderate pulmonary symptoms or culture-positive from respiratory tract Severe symptoms and immunocompromised hosts Pneumonia Primary respiratory uncomplicated diffuse pneumonia Pulmonary nodule, asymptomatic Pulmonary cavity asymptomatic symptomatic ruptured Chronic fibrocavitary pneumonia Life-threatening Mild to moderate Acute pulmonary Chronic pulmonary AmB (initially), Itra Surgical resection Itra, corticosteroids FLU, Itra, AmB Cryptococcus Candida Coccidioidomyces Blastomyces Histoplasma AmB+5-FC, FLU, Itraa AmB or FLU AmB or FLUb AmB, then oral azole Surgical resection No antifungal therapy recommended Oral azoles if complicationsc Surgery and AmB Oral azoles, AmB or surgery if needed AmB Itra AmB + corticosteroids, then Itra AmB, then Itra Reference [57 . .] [86 . .] [44 . .] [50 . .]  [83 . .] a Treatment choice based on phase of therapy: induction, consolidation or maintenance. bTreatment recommended if symptomatic. cComplications include local discomfort, fungal or bacterial superinfection, hemoptysis. AmB, amphotericin B; Itra, itraconazole; FLU, fluconazole; 5-FC, 5-flucytosine. marrow transplantation, solid organ transplantation or certain immunosuppressive cancer chemotherapy) often require systemic antifungal agents. This may be augmented with aerosolized amphotericin B to protect the lung entry of invasive fungi. Advances in diagnostic laboratory tests may aid in the early detection of disease if properly studied. Recently published treatment guidelines aid in the selection of treatment for fungal pneumonias (Table 2), while recent advances in drug discovery will allow for additional treatment options for pulmonary disease. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: . of special interest .. of outstanding interest 1 Bochud PY, Moser F, Erard P, et al. Community-acquired pneumonia. A prospective outpatient study. 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