[ Recent Advances in Chest Medicine ] Clinical Approach and Management for Selected Fungal Infections in Pulmonary and Critical Care Patients Andrew H. Limper, MD, FCCP Fungal lung infections are widely encountered and present both diagnostic and therapeutic challenges. The increasing prevalence of fungal infections is correlated with increasing numbers of immunocompromised patients, enhanced awareness of these infections, and improved methodologies for diagnosis. Fortunately, additional antifungal agents are available to combat these important infections. This review covers the clinical approach to fungal lung infections encountered in pulmonary and critical care practice. CHEST 2014; 146(6):1658-1666 Fungal lung infections are widely diagnosed and managed by pulmonary and critical care physicians.1 The increasing prevalence of fungal infections is associated with growing numbers of immunocompromised patients, clinical awareness of these infections, and improved approaches for diagnosis.2 Fortunately, newer antifungal agents have been developed to combat these important infections. This review will discuss the clinical approach to fungal lung infections. Traditional and Newer Classes of Antifungal Agents While the past decade has seen an increase in the number of antifungal agents (Table 1), these agents must be considered in balance with traditional agents and the appropriate agent selected depending on the clinical scenario. In general, individualized Manuscript received February 6, 2014; revision accepted July 28, 2014. AFFILIATIONS: From the Thoracic Diseases Research Unit and the Division of Pulmonary and Critical Medicine, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN. CORRESPONDENCE TO: Andrew H. Limper, MD, FCCP, Mayo Clinic College of Medicine, Gonda Bldg 18-S, Rochester, MN 55905; e-mail: limper.andrew@mayo.edu 1658 Recent Advances in Chest Medicine therapies for fungal infections must be based upon defining the causative fungus, considering the severity of infection, and placing treatment options in perspective with selected features of individual patients. Polyenes Amphotericin B: The archetypal polyene antifungal is amphotericin B deoxycholate. Despite concerns about host toxicities, this agent continues to be used as a therapeutic option for severe fungal infections. This is particularly true for life-threatening infection, including invasive aspergillosis, in some cases of systemic candidiasis and cryptococcosis, and for severe histoplasmosis, blastomycosis, coccidioidomycosis, and mucormycosis. Polyene antifungals bind to sterols present in the fungal membrane, inducing a defect in the membrane that leads to cell leakage and death.3 © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0305 [ 146#6 CHEST DECEMBER 2014 ] TABLE 1 ] Current Antifungal Agents and Mechanisms of Action Class Relevant Medications Mechanisms of Action Polyenes Amphotericin B deoxycholate, lipid formulations of amphotericin B Binds to ergosterol, leading to pore formation in the fungal cell membrane Triazoles Fluconazole Inhibits fungal membrane ergosterol synthesis by inhibiting C-14-a-demethylase Itraconazole Voriconazole Posaconazole Echinocandins Caspofungin Inhibits fungal cell wall b-1,3-D-glucan synthesis Anidulafungin Micafungin Amphotericin B deoxycholate must be administered intravenously. Careful monitoring during therapy is essential and includes measuring creatinine, BUN, potassium, and magnesium levels; monitoring CBC counts; and assessing liver function. In general, monitoring should be performed frequently (every day or two) during the administration of amphotericin. Renal toxicity can develop precipitously. Many practitioners premedicate patients with antipyretics, antihistamines, antiemetics, or meperidine to decrease febrile reaction and chills. IV infusion should be over 2 to 6 h, since rapid administration may precipitate life-threatening hyperkalemia and arrhythmias.4 There is additive renal toxicity with other nephrotoxic agents, such as aminoglycosides. Adequate hydration reduces the risk of nephrotoxicity. Nephrotoxicity of amphotericin B is predominantly dose dependent. In severely immunocompromised patients, in patients with renal impairment, in patients receiving other nephrotoxic drugs, or in situations requiring doses of amphotericin B ⱖ 1.0 mg/kg/d, strong consideration should be given for lipid preparations of amphotericin to avoid the high incidence of renal toxicity. Liver toxicity can occur, but it is rare. Lipid Formulations of Amphotericin: Several lipidassociated formulations have been developed, including liposomal amphotericin B, amphotericin B lipid complex, and amphotericin B-cholesterol sulfate complex. These agents are significantly less nephrotoxic than amphotericin B deoxycholate.5 Lipid formulations have largely supplanted the use of amphotericin B deoxycholate in the United States and most of Europe and Canada, particularly in immunocompromised patients. However, in developing portions of the world, amphotericin B deoxycholate continues to be used more frequently. Information supporting improved efficacy of lipid formulations over amphotericin B deoxycholate is limited. Monitoring journal.publications.chestnet.org for side effects should be performed in a fashion parallel to that described for amphotericin B deoxycholate. Studies in animal models indicate that liposomal formulations of amphotericin exhibit higher effective CNS concentrations than either amphotericin B deoxycholate or amphotericin B lipid complex.6 Conclusive data in humans to further support this finding are not yet available.7 Triazole Antifungals The azole antifungals are orally active and include itraconazole, fluconazole, voriconazole, and posaconazole. Triazoles inhibit fungal C-14-a-demethylase mediating conversion of lanosterol to ergosterol. Interactions of azole drugs with human P450 cytochromes are well described.8 Hence, azole-related drug interactions can be challenging in immunocompromised hosts, particularly patients receiving multiple other agents, such as those who have undergone transplant and those with HIV. Interactions occur with cyclosporine, benzodiazepines, statins, and certain anti-HIV drugs as a result of altered rates of metabolism and induction of the relative cytochrome P450 activity. In addition, all of the azole agents have the ability to prolong QTc and should be used with caution, particularly in the presence of other agents that may also exert this effect. Earlier agents such as ketoconazole, which is an imidazole, have significant adverse effects on steroid hormone levels and adrenal function and have been supplanted by the newer triazole agents. In view of adrenal and potentially severe liver toxicity of oral ketoconazole, and with available less toxic and more effective triazoles, ketoconazole should no longer be used as frontline therapy.9,10 In addition, azoles are class C drugs and contraindicated during pregnancy. In contrast, amphotericin is rated class B for pregnancy and is preferred during severe infection. 1659 Itraconazole: Itraconazole contains a lipophilic tail enhancing activity against molds such as Aspergillus species.11 Itraconazole is effective for some Aspergillus species infections, mucosal candidal infections, histoplasmosis, blastomycosis, and coccidioidomycosis. Unfortunately, due to high protein binding and poor penetration, it is not effective for CNS infections. Itraconazole is manufactured as either oral capsules or oral solution. The oral form requires gastric acid for absorption, and should be administered with food or acidic beverages. Concurrent use of antacids and proton-pump inhibitors should be avoided. To overcome problems with variable absorption, itraconazole is also available in a cyclodextrin solution. The oral solution should be provided on an empty stomach. When using itraconazole, it is important to routinely assure that adequate levels of itraconazole are present in serum. Dose adjustments of orally administered itraconazole are not required in patients with renal impairment. Itraconazole is metabolized in the liver and caution should be used in patients with significant hepatic impairment. Side effects of itraconazole are uncommon, but may include peripheral edema, rash, diarrhea, and nausea. Serious, though uncommon, side effects include worsening of congestive heart failure, Stevens-Johnson syndrome, and hepatotoxicity. As with other azole compounds, interactions occur with many such drugs related to its metabolism by the cytochrome P450 and related systems. Voriconazole: Voriconazole is an additional extendedspectrum azole available in both IV and oral forms. Voriconazole is widely used for invasive aspergillosis and other fungal infections.12 As with most azoles, the drug should be used cautiously in patients receiving other drugs that are metabolized via the cytochrome P450 pathways and related pathways, including CYP34A, CYP2C9, CYP2C19, and CYP3A4. Voriconazole should also be used with caution in patients with hepatic cirrhosis. Due to the cyclodextrin component, IV voriconazole should also be used with restraint in patients with renal insufficiency, as the cyclodextrin component may accumulate. In such instances, the oral form, which lacks cyclodextrin, may be used instead. Dose modifications are not required for voriconazole in patients with mild to moderate renal impairment. If IV voriconazole is absolutely necessary in patients with moderate to severe renal insufficiency, serum creatinine levels should be monitored. Voriconazole should generally not be used in patients with severe hepatic insufficiency unless other options are limited and potential benefits outweigh the risks. Patients should avoid direct sunlight, since photo- 1660 Recent Advances in Chest Medicine sensitivity occurs.13 With widening use of voriconazole in prophylaxis of severely immunosuppressed patients, chronic dermatologic photosensitivity reactions have been reported. Furthermore, there appear to be increased reports of nonmelanomatous skin cancer in such patients.13 However, such immunosuppressed individuals have multiple risk factors for skin cancer, and recent studies suggest that the risk of malignancies directly attributable to voriconazole alone may not be significant.14 Nonetheless, clinicians caring for such patients need to be vigilant of skin toxicity and malignancies (including melanoma).15 Side effects also include nausea, vomiting, rash, and liver abnormalities. Severe liver dysfunction has rarely been reported. Peripheral edema does occur with voriconazole, though much less frequently than observed with itraconazole. Approximately one-third of patients experience visual disturbances, including photopsia, while receiving voriconazole. This complication generally lasts only for several hours and then dissipates. Over days to weeks, the visual disturbance becomes less obvious to the patient.1 Metabolism of the drug can be variable and monitoring of serum levels can be helpful. Posaconazole: Posaconazole is useful for use as prophylaxis against invasive fungal infections including aspergillosis and disseminated candidiasis in immunocompromised patients and for the treatment of oropharyngeal candidiasis in patients with HIV or severe oropharyngeal candidiasis refractory to fluconazole and itraconazole.16 This agent has proven effective when used as second-line therapy in severely immunocompromised patients with refractory Aspergillus species infection, and also has been used to treat coccidioidomycosis.17 The agent also has activity against Mucorales fungi. Typical adverse effects of posaconazole include abdominal discomfort and diarrhea. Serious toxicities also include occasional hepatic dysfunction. Posaconazole has saturable absorption and requires adequate dietary fat for optimal uptake. Dose adjustments for posaconazole are not necessary in patients with mild to severe hepatic impairment or renal insufficiency. Clinical monitoring for potential drug toxicity should include evaluating liver function tests. There are now oral extendedrelease tablets of posaconazole available that are replacing the older oral suspensions, which were more poorly absorbed. In addition, an IV formulation of posaconazole has been released, which will expand its use in serious fungal infections. Fluconazole: Fluconazole exhibits reduced lipophilicity, allowing for easier administration, and has good activity [ 146#6 CHEST DECEMBER 2014 ] against Candida albicans.1 It is used for prevention and treatment of both mucosal and invasive candidal diseases, but also exhibits significant activity against coccidioidomycosis and cryptococcosis. Modifications of fluconazole dosing are necessary in renal insufficiency. Doses are reduced by 50% when the creatinine clearance is , 50 mL/min. Patients on hemodialysis require replacement of the entire dosage following dialysis. Compared with other azole antifungal agents, such as itraconazole, voriconazole, and posaconazole, drug-drug interactions are relatively less frequent with fluconazole, as fluconazole is a less active inhibitor of P450 and related pathways. Side effects are relatively uncommon, but can include rash, pruritus, headache, nausea and vomiting, and increased transaminase levels. Other Emerging Azoles: Additional studies are underway with ravuconazole, isavuconazole, and albaconazole in a variety of fungal infections.18 The relative efficacies and indications of these agents have not yet been well defined. Echinocandins This class of agents acts to disrupt fungal cell walls by inhibiting of b-1,3-d-glucan synthase enzymes located in the plasma membrane. Caspofungin: Caspofungin exerts fungicidal activity against candida organisms and fungistatic activity against Aspergillus species. The principal initial usage for caspofungin was chiefly for candidiasis. However, this agent has also been used in the treatment of febrile neutropenia and as a component of salvage therapy for invasive Aspergillus pneumonia. Indications for use not approved by the US Food and Drug Administration also include empirical use in patients with suspected invasive fungal infection and as prophylaxis in severely immunocompromised patients. Basic investigations indicate potential activity against Pneumocystis species. However, definitive clinical data to support use of echinocandins in patients with Pneumocystis jirovecii pneumonia are lacking, and echinocandins should not be used as firstline or stand-alone therapies.19,20 Cryptococcosis is resistant to caspofungin, in part due to melanization of the cell wall.21 Caspofungin is available as an IV infusion. Since it is metabolized in the liver, dosage adjustment is required during hepatic impairment. Caution should be used in patients with impaired liver function, during pregnancy, or in patients receiving cyclosporine. Of interest, caspofungin and the other echinocandins do not interfere with the cytochrome enzymes. However, drug-drug interactions may still occur with cyclosporine journal.publications.chestnet.org and tacrolimus, rifampin, and certain anti-HIV drugs. Other side effects include elevations of liver enzymes, facial swelling, headache, pruritus, and nausea. Rarely, hypersensitivity reactions and, very rarely, anaphylaxis has occurred with all of the echinocandin agents. Anidulafungin: Anidulafungin is used in candidemia, invasive candidiasis, and candidal esophagitis.22 Anidulofungin also has activity against Aspergillus species. It is used off label as empirical therapy for suspected candidemia in non-neutropenic patients. Anidulofungin is well tolerated. Common side effects include hypokalemia and diarrhea. More clinically significant side effects include DVT and, on rare occasions, liver toxicity. Micafungin: Micafungin has activity against Candida species and Aspergillus species, and has been approved for treatment of invasive candidiasis and for prophylaxis against invasive candidal infection in patients who have received hematopoietic cell transplant and against candidal esophagitis.23 Adverse events include rash; abdominal discomfort with nausea, vomiting, or diarrhea; and hyperbilirubinemia. Phlebitis may occur in the injection site. All three of the currently licensed echinocandins should be regarded as equally effective for candidemia. Clinical Features of Fungal Lung Infections Fungal infections can occur in either immunocompetent or immunosuppressed individuals. The clinician should be aware of clinical signs that may suggest the presence of fungal infections, such as persistent lung infiltrates, with or without mediastinal lymphadenopathy (Table 224). Disseminated calcified granulomas in lung and spleen may also be observed and are typical of endemic fungal infections, particularly infection with histoplasmosis. Such infiltrates do not respond to usual antibacterial antibiotics. Most fungal infections in immunocompromised hosts are due to either candidal bloodstream infections or to invasive Aspergillus species tissue infections, including invasive Aspergillus pneumonia. However, other infections, including the endemic mycoses (coccidioidomycosis, histoplasmosis, and blastomycosis, depending on regional geography) and P jirovecii pneumonia remain a threat to immunocompromised patients, as well. It is also important to be aware that the incidence of candidal infections by species other than C albicans, as well as the incidence of more resistant mycelial mold infections, including mucormycosis and Scedosporium species infections, are also increasing. 1661 TABLE 2 ] Factors Suggesting Possible Fungal Lung Infections Factors Nonresolving pulmonary infiltration with fever that fails to resolve with standard antibiotic therapies directed at bacteria Patients with significant neutropenia (absolute neutrophil counts , 500/mL for . 21 d), hematologic malignancy or hematopoietic cell transplant or solid organ transplantation, patients with malignancies receiving chemotherapy Patient with emerging immunocompromising conditions (chronic corticosteroid use, novel immune suppression, renal insufficiency, COPD, diabetes mellitus, cirrhosis) Exposure or recent travel to endemic geographic regions Hilar and/or mediastinal adenopathy (may or may not be present) Associated skin lesions (erythema nodosum, morbilliform or toxic rash), arthritis, bone lesions, CNS dissemination Adapted from Limper.24 Therapeutic Approaches to the Endemic Mycoses The endemic mycoses include histoplasmosis, blastomycosis, and coccidioidomycosis. These fungi can infect both immunocompetent and immunocompromised individuals. Cryptococcal pneumonia and meningitis are also considerations in such patients. Effective diagnosis of the endemic mycoses relies on accurate recognition of geographic predilections, clinical features, and effective use of relevant serologic and polymerase chain reaction assays, bronchoscopy, and lumbar puncture, when indicated. The clinical diagnoses of these infections are reviewed in detail elsewhere.25-27 Therapeutic decisions for the endemic mycoses are based on whether the host exhibits immunocompetence. In general, infections of lesser severity are managed with extended-spectrum azoles, while more severe infections may require initial therapy with liposomal amphotericin to induce remission prior to longer-term therapy with extended-spectrum azoles. Detailed guidelines outlining therapies for each of the endemic mycoses and cryptococcosis should be consulted to guide individual clinical decisions.1 Histoplasmosis and Related Sequelae Histoplasma capsulatum can cause infections including solitary pulmonary nodules with or without adenopathy, broncholithiasis, and mediastinal granuloma and fibrosis; symptomatic or progressive disseminated pulmonary histoplasmosis, including histoplasmosis- 1662 Recent Advances in Chest Medicine associated ARDS; and chronic pulmonary histoplasmosis. In immunocompetent patients with pulmonary nodules or isolated broncholithiasis and minimal symptoms, azole therapy is usually not required. In patients with symptomatic or active histoplasmosis nodular infiltration with or without significant adenopathy, therapy with itraconazole at a dosage of 200 mg bid for 3 months is often prescribed to resolve the infection and to possibly reduce sequelae such as fibrosing mediastinitis. However, there are no data available that definitely demonstrate that antifungal therapy reduces the incidence of fibrosing mediastinitis. In the setting of mediastinal granuloma with associated bulky adenopathy, with positive serologies or urine antigen testing documenting recent or active infection, a trial of itraconazole, 200 mg bid, may also be instituted for 12 weeks.25 In patients with clinical improvement, treatment up to 12 months may be then prescribed. Unfortunately, in most cases of well-established fibrosing mediastinitis, azole therapy has not proven effective. Antifibrotic agents and systemic corticosteroids are also generally not useful in fibrosing mediastinitis. Fibrosing mediastinitis may also result in severe vascular or airway compromise requiring intravascular stents, placement of ronchial stents, or both and potentially bronchoplasty or other surgical interventions. Broncholithiasis can result from calcification of a lymph node previously infected with histoplasmosis that may erode into an airway. When broncholithiasis is complicated by hemoptysis or atelectasis, bronchoscopic evaluation and either bronchoscopic or surgical removal is indicated, with the caution that broncholiths may cause significant bleeding when removed endoscopically. In symptomatic patients with mild or moderate symptomatic pulmonary histoplasmosis-related pneumonia, therapy is usually initiated with itraconazole for 12 weeks. However, in patients with severe pulmonary histoplasmosis, such as those with life-threatening disseminated pulmonary infections with severe gas-exchange abnormality (Fig 1), therapy should be initiated with liposomal amphotericin B until clinical improvement is established. This is followed by maintenance therapy with itraconazole, 200 mg bid, for at least 3 months. In patients with chronic pulmonary histoplasmosis, often with cavitary disease, itraconazole, 200 mg bid, for 12 to 24 months may be used.28 Immunocompromised patients with histoplasmosis are usually managed in a parallel fashion with modifications. [ 146#6 CHEST DECEMBER 2014 ] nodules, and chronic fibrocavitary disease. Dissemination does occur with spread to the skin being most common. Dissemination to bone, and rarely to the CNS, can also occur. For mild to moderately ill immunocompetent patients, oral itraconazole, 200 bid for 6 months, will generally suffice.26 However, in patients with bone involvement, prolonging the treatment course with itraconazole to a total of 12 months is needed. In severe pulmonary blastomycosis, such as with diffuse lung injury or severe systemic disease, initial therapy should be based on daily IV liposomal amphotericin B until clinical improvement is established.1 Subsequently, oral itraconazole, 200 mg bid for an additional 6 months, should be administered. Voriconazole, 200 mg bid, may be used as an alternative, based on in vitro and limited clinical data.31 Adjunctive corticosteroids, such as for histoplasmosis, can be beneficial in selected cases of severe blastomycosisrelated ARDS. Figure 1 – CT image of progressive disseminated histoplasmosis. This image was obtained from a 72-y-old woman with rheumatoid arthritis who was undergoing immunosuppression treatment with adalimumab and methotrexate. She developed progressive gas-exchange abnormalities. CT scanning documented widely disseminated miliary micronodular infiltrates. Histoplasmosis was confirmed by bronchoscopy with BAL and with Histoplasma species urinary antigen. For instance, immunocompromised patients with mild to moderate symptomatic histoplasmosis are often treated with itraconazole, 200 mg tid, for the first 3 days followed by 200 mg bid for 12 months.1 Severely immunocompromised patients, such as patients with AIDS, having progressive disseminated histoplasmosis should initially be treated with IV liposomal amphotericin B until clinical response and stabilization has been achieved.29 At that point, stable and improving patients may be switched to oral itraconazole, 200 mg bid, until effective immune reconstitution has been established, with the CD41 counts rising above 200/mL. Patients who remain immunosuppressed may require lifelong maintenance therapy.25 For some immunocompromised patients with severe pulmonary histoplasmosis and diffuse lung injury, the addition of adjunctive glucocorticosteroid therapy at a suggested dosage of prednisone of 40 to 60 mg/d for 1 to 2 weeks may be beneficial.1 For immunocompromised patients with mild to moderate pulmonary blastomycosis without evidence of CNS involvement, oral itraconazole, 200 mg bid for at least 12 months, can be used.1 However, in cases of severe pulmonary blastomycosis without CNS involvement, again liposomal amphotericin B is required until clinical improvement is definitively established, followed by oral itraconazole therapy for at least 12 months. Patients with AIDS require ongoing oral itraconazole, 200 mg/d, indefinitely or until immunity is well reconstituted. In patients with pulmonary blastomycosis and concurrent CNS involvement, initial therapy with lipid formulations of amphotericin B (5 mg/kg/d) should also be administered daily from the beginning of therapy until clinical improvement is well established. Subsequently, fluconazole is used for at least 12 months total after discontinuation of initial IV amphotericin B. Voriconazole, 200 mg bid, may be considered as an alternative to fluconazole.1 Patients with AIDS having CNS disease should continue to receive oral fluconazole, 400 mg/d, indefinitely or until immunity is fully restored. Coccidioidomycosis Blastomycosis Infections Blastomyces dermatidis, a dimorphic fungus endemic in the central and southeast United States, causes acute, subacute, and chronic lung infections. A limited number of cases present with blastomycosis-associated ARDS and fulminant diffuse pneumonia.30 More commonly, the manifestations are less severe, such as lobar pneumonia, mass-like consolidative lesions, pulmonary journal.publications.chestnet.org Coccidioidomycosis is caused by inhalation of soildwelling Coccidioides immitis or C posadasii and has its highest incidence in the San Joaquin Valley of California, in south-central Arizona, and in northwestern Mexico.27 Many coccidioidal infections are minimally symptomatic. However, some infections induce pulmonary symptoms resembling community-acquired pneumonia. Acute pulmonary coccidioidomycosis may be distinguished 1663 from bacterial community-acquired pneumonia by its failure to respond to usual antibacterial therapy and by associated hilar adenopathy, peripheral blood eosinophilia, fatigue, night sweats, and skin lesions that include erythema multiforme or erythema nodosum, in some cases. Acute primary pulmonary coccidioidomycosis is frequently self-limited, and most immunocompetent patients with primary pulmonary coccidioidomycosis and no risk factors for systemic dissemination do not require treatment. However, risk factors for dissemination must be carefully assessed in each patient.27 These risk factors are discussed in Table 3. In addition, certain medical conditions place patients at higher risk for severe pulmonary infections, including COPD and other structural lung disease, renal failure, and congestive heart failure. coccidioidomycosis-related lung nodules in patients with additional risk factors for disseminated disease, or in cavitary disease with or without hemoptysis, treatment with either fluconazole or itraconazole is indicated. Azole therapy for chronic nodular or cavitary pulmonary coccidioidomycosis with symptoms lasting for . 3 months is generally prolonged for 12 to 18 months or longer until the cavities and symptoms stabilize.27 In cases of diffuse pulmonary coccidioidomycosis with diffuse lung injury and gas-exchange impairment, initial amphotericin B is necessary to establish clinical improvement.1 This is followed by fluconazole (400 mg/d) or itraconazole (400 mg/d) for at least one additional year. Patients have ongoing immunosuppression require ongoing azole therapy until immune reconstitution occurs. For immunocompetent patients with pulmonary coccidioidomycosis and moderate to severe symptoms, treatment is usually initiated with either fluconazole (400 mg/d) or itraconazole (400 mg/d) for at least 6 months, or even longer if symptoms and radiographic abnormalities persist.1 Posaconazole also has activity against coccidioidomycosis and is sometimes used in resistant cases.32 For patients with coccidioidomycosis-related pulmonary nodules alone, observation for at least 1 year without antifungal treatment can be undertaken. However, either fluconazole or itraconazole may be administered during periods of significant immunosuppression (ie, chemotherapy, systemic corticosteroid therapy, or CD4 counts , 200/mL). Disseminated coccidioidomycosis with spread from the lungs to bone, joints, skin, CNS, or elsewhere, whether in immunocompetent or immunocompromised patients, requires therapy. For nonmeningeal disseminated disease, fluconazole (400 mg/d) or itraconazole (400 mg/d) is administered for at least 1 year and until clinical stabilization.27 Itraconazole is preferred in the case of bone or joint disease. In severe cases, IV liposomal amphotericin B should be initiated until clinical improvement, followed by fluconazole (400 mg/d) or itraconazole (400 mg/d) for at least another year. In patients presenting with neurologic symptoms with primary coccidioidomycosis, lumbar puncture is required to evaluate for the possibility of Coccidioides species-induced meningitis. In patients with disseminated coccidioidomycosis and meningitis, initial liposomal amphotericin therapy is followed by azole therapy such as fluconazole (800-1,000 mg/d), which may be necessary for life, as these cases frequently relapse if therapy is discontinued.1 Therapy for primary pulmonary coccidioidomycosis should be considered for all patients with risk factors for dissemination and for immunocompromised patients (Table 3). Either fluconazole (400 mg/d) or itraconazole (400 mg/d) would be appropriate in these cases. For TABLE 3 ] Risk Factors for Dissemination of Coccidioidomycosis Factors Immunosuppressed patients HIV/AIDS Hematologic malignancies, including lymphoma Chronic corticosteroid therapy Treatment with immunosuppressing agents such as tumor necrosis factor-a antagonists Diabetes mellitus Third trimester of pregnancy Male sex Patients of black or Filipino descent 1664 Recent Advances in Chest Medicine Therapeutic Options for Aspergillosis Treatment approaches for Aspergillus species lung disease depend upon the setting, immunocompetence, and tempo of disease. For instance, aspergillomas represent a mycetomatous colonization of preexisting cavitary spaces in the lung, with such lesions having a significant tendency for bleeding. In the setting of significant bleeding, interventional radiology with embolization can be life saving. Surgical management of fungus balls does have relatively high associated morbidity and mortality. However, there are still selective cases where surgical resection becomes a necessity. On occasion, aspergillomas can proceed into chronic necrotizing aspergillosis if patients are immunosuppressed. [ 146#6 CHEST DECEMBER 2014 ] Significant invasive Aspergillus species pneumonia only occurs in immunosuppressed hosts, generally in those with neutropenia, significant corticosteroid exposure, or cytotoxic chemotherapy. Current firstline therapy for invasive Aspergillus pneumonia is based on IV voriconazole therapy (6 mg/kg q12h) for the first day, followed by 4 mg/kg IV q12h until improvement.33 After stabilization, therapy can be switched to oral voriconazole, 200 mg q12h, until the lesion resolves. Alternatively, IV liposomal amphotericin B can be used (3-5 mg/kg/d) until the patient improves, followed by oral voriconazole, 200 mg q12h.1 Whenever possible, reversal of immunosuppression will often be necessary for therapy to be effective. In patients with invasive pulmonary aspergillosis who fail initial therapy, an echinocandin such as IV caspofungin (70 mg on day 1 and 50 mg/d thereafter) may be used as salvage therapy. There are not definitive data documenting additive benefit from echinocandins administered concurrently with voriconazole.34 In addition, oral posaconazole may also be attempted as a salvage strategy.35 In selected patients with refractory, focal, invasive pulmonary aspergillosis failing aggressive therapy, surgical excision may also be considered. Management of chronic necrotizing aspergillosis (“minimally invasive” disease) requires individualization based upon disease severity and the relative immunocompetency of the host. In patients with mild to moderate infection, oral voriconazole or itraconazole may be attempted until clinical stabilization occurs. In patients with more severe disease, initial therapy with either IV voriconazole or liposomal amphotericin B may be considered.1 Once again, surgical resection may be needed in selected cases, based upon severity, extent of infection (focal vs diffuse), and initial responses to antifungal therapy. Conclusions Studies indicate increasing populations of patients susceptible to fungal lung infections.24,36 A high index of suspicion is necessary to detect invasive fungal infection in immunocompromised patients. Appropriate application of available diagnostic testing and rapid implementation of therapy are necessary to secure optimal clinical response. Acknowledgments Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. journal.publications.chestnet.org References 1. Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011;183(1):96-128. 2. Singh N. Trends in the epidemiology of opportunistic fungal infections: predisposing factors and the impact of antimicrobial use practices. Clin Infect Dis. 2001;33(10):1692-1696. 3. Mukherjee PK, Sheehan DJ, Hitchcock CA, Ghannoum MA. Combination treatment of invasive fungal infections. Clin Microbiol Rev. 2005;18(1):163-194. 4. Craven PC, Gremillion DH. Risk factors of ventricular fibrillation during rapid amphotericin B infusion. Antimicrob Agents Chemother. 1985;27(5):868-871. 5. Cagnoni PJ. Liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients. J Antimicrob Chemother. 2002;49(suppl 1):81-86. 6. Groll AH, Giri N, Petraitis V, et al. 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