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Treatment of Fungal Infections in Adult Pulmonary and Critical Care Patients

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Treatment of Fungal Infections in Adult Pulmonary and Critical Care Patients American Thoracic Society Documents An Official American Thoracic Society Statement: Treatment of Fungal Infections in Adult Pulmonary and Critical Care Patients Andrew H. Limper, Kenneth S. Knox, George A. Sarosi, Neil M. Ampel, John E. Bennett, Antonino Catanzaro, Scott F. Davies, William E. Dismukes, Chadi A. Hage, Kieren A. Marr, Christopher H. Mody, John R. Perfect, and David A. Stevens, on behalf of the American Thoracic Society Fungal Working Group THIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY (ATS) WAS APPROVED BY THE ATS BOARD OF DIRECTORS, MAY 2010 CONTENTS immune-compromised and critically ill patients, including crypto- coccosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; Introduction and rare and emerging fungal infections. Methods Antifungal Agents: General Considerations Keywords: fungal pneumonia; amphotericin; triazole antifungal; Polyenes echinocandin Triazoles Echinocandins The incidence, diagnosis, and clinical severity of pulmonary Treatment of Fungal Infections fungal infections have dramatically increased in recent years in Histoplasmosis response to a number of factors. Growing numbers of immune- Sporotrichosis compromised patients with malignancy, hematologic disease, Blastomycosis and HIV, as well as those receiving immunosupressive drug Coccidioidomycosis regimens for the management of organ transplantation or Paracoccidioidomycosis autoimmune inflammatory conditions, have significantly con- Cryptococcosis tributed to an increase in the incidence of these infections. Aspergillosis Definitive diagnosis of pulmonary fungal infections has also Candidiasis increased as a result of advances in diagnostic methods and Pneumocystis Pneumonia techniques, including the use of computed tomography (CT) Treatment of Other Fungi and positron emission tomography (PET) scans, bronchoscopy, Glossary of Terms mediastinoscopy, and video-assisted thorascopic biopsy. At the same time, the introduction of new treatment modalities has With increasing numbers of immune-compromised patients with significantly broadened options available to physicians who malignancy, hematologic disease, and HIV, as well as those receiving treat these conditions. Once largely limited to the use of immunosupressive drug regimens for the management of organ amphotericin B, flucytosine, and a handful of clinically available transplantation or autoimmune inflammatory conditions, the in- azole agents, today’s pharmacologic treatment options include cidence of fungal infections has dramatically increased over recent potent new azole compounds with extended antifungal activity, years. Definitive diagnosis of pulmonary fungal infections has also novel lipid forms of amphotericin B, and a new class of antifungal been substantially assisted by the development of newer diagnostic methods and techniques, including the use of antigen detection, drugs known as echinocandins. In light of all these developments polymerase chain reaction, serologies, computed tomography and in the incidence, diagnosis, and treatment of pulmonary fungal positron emission tomography scans, bronchoscopy, mediastino- infections, the American Thoracic Society convened a working scopy, and video-assisted thorascopic biopsy. At the same time, the group on fungi to develop a concise clinical summary of the introduction of new treatment modalities has significantly broad- current therapeutic approaches for those fungal infections of ened options available to physicians who treat these conditions. particular relevance to pulmonary and critical care practice. This While traditionally antifungal therapy was limited to the use of document focuses on three primary areas of concern: the amphotericin B, flucytosine, and a handful of clinically available endemic mycoses, including histoplasmosis, sporotrichosis, blas- azole agents, current pharmacologic treatment options include tomycosis, and coccidioidomycosis; fungal infections of special potent new azole compounds with extended antifungal activity, concern for immune-compromised and critically ill patients, lipid forms of amphotericin B, and newer antifungal drugs, including including cryptococcosis, aspergillosis, candidiasis, and Pneumo- the echinocandins. In view of the changing treatment of pulmonary cystis pneumonia; and rare and emerging fungal infections. fungalinfections,theAmericanThoracicSociety conveneda working group of experts in fungal infections to develop a concise clinical statement of current therapeutic options for those fungal infections METHODS of particular relevance to pulmonary and critical care practice. This document focuses on three primary areas of concern: the endemic For each fungal infection evaluated, the available literature has mycoses, including histoplasmosis, sporotrichosis, blastomycosis, been thoroughly reviewed and interpreted by the experts in- and coccidioidomycosis; fungal infections of special concern for volved in this statement. In the search for published evidence, workgroup members reviewed journal articles and previously published guidelines, and conducted an evaluation of electronic Am J Respir Crit Care Med Vol 183. pp 96–128, 2011 DOI: 10.1164/rccm.2008-740ST databases, including PubMed and MEDLINE. In general, only Internet address: www.atsjournals.org articles written in English were used in the final recommenda- American Thoracic Society Documents 97 TABLE 1. CATEGORIES INDICATING THE STRENGTH OF EACH TABLE 2. GRADES OF EVIDENCE QUALITY ON WHICH RECOMMENDATION FOR OR AGAINST ITS USE IN THE RECOMMENDATIONS ARE BASED TREATMENT OF FUNGAL INFECTIONS Grade Definition Category Definition I Evidence from at least 1 properly randomized, controlled trial A Good evidence to support a recommendation for use Evidence from at least 1 well-designed clinical trial without B Moderate evidence to support a recommendation for use randomization, from cohort or case-controlled analytic studies C Poor evidence to support a recommendation for or against use (preferably from . 1 center), from multiple patient series studies, D Moderate evidence to support a recommendation against use II or from dramatic results of uncontrolled experiments E Good evidence to support a recommendation against use Evidence from opinions of respected authorities, that is based on clinical III experience, descriptive studies, or reports of expert committees. tions. The most relevant literature references are included in this publication. Discussion and consensus among workgroup mem- mend that patients with any degree of renal insufficiency be more bers formed the basis for the recommendations made in this closely monitored. Many experienced clinicians pre-medicate statement. The authors reviewed the evidence base for each patients with antipyretics, antihistamines, anti-emetics, or me- major recommendation of this consensus statement and graded peridine to decrease the common febrile reaction and shak- according to an approach developed by the U.S. Preventive ing chills associated with infusion (BIII). Meperidine is Services Task Force (Tables 1 and 2). Although the American most effective for ameliorating the severe rigors. Rapid in- Thoracic Society (ATS) and Infectious Disease Society of travenous administration of amphotericin B has been observed America (IDSA) have recently adopted the GRADE approach to precipitate life-threatening hyperkalemia and arrhythmias to grading the quality of evidence and strength of recommenda- (5); therefore, the daily dose of amphotericin B deoxycholate tions for clinical guidelines, the current project was initiated and should be infused over 2 to 6 hours. Hypotension and shock much of the work was completed prior to the official adoption of have also occasionally been observed during amphotericin B GRADE. The recommendations included were, therefore, infusion. Amphotericin B should not be administered simulta- graded according to the system used in prior guidelines (1–3). neously with leukocytes, as this may possibly precipitate pul- Each section also includes expert interpretations regarding the monary toxicity (6). There appears to be an additive, and best approach for challenging clinical situations that have not possibly synergistic, nephrotoxicity with other nephrotoxic been well studied in the literature, but that are the basis for agents such as aminoglycoside antibiotics (7). Adequate intra- frequent consultation of the members of the ATS working group venous fluid hydration has been shown to reduce the risk of on fungal infections. For convenience, a glossary of definitions of nephrotoxicity (8). In complicated patients, consultation with an uncommon terms is also included at the end of the document. experienced clinical pharmacist or use of tools such as software Each member of the writing committee has declared any programs that delineate drug interactions, particularly those conflict of interest, and every effort was made by the Chair as with suspected synergistic nephrotoxicity or those requiring adjudicator to ensure that recommendations were free of any real renal clearance, is recommended. Additional side effects are com- or perceived conflict of interest; however, it should be noted that mon, and may include hypokalemia, phlebitis/thrombophlebitis, the process predates the official development and adoption of the anorexia and weight loss, fever and chills, headache and malaise, revised ATS Conflict of Interest guidelines in 2008 (4). and cardiac dysrhythmias. Liver toxicity may also occur, but its incidence is rare compared with renal toxicity. Nephrotoxicity ANTI-FUNGAL
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