Guidelines for Management of Cryptococcosis ��� CID 2010:50 (1 February) ��� 291 I D S A G U I D E L I N E S Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America John R. Perfect,1 William E. Dismukes,2 Francoise Dromer,11 David L. Goldman,3 John R. Graybill,4 Richard J. Hamill,5 Thomas S. Harrison,14 Robert A. Larsen,6,7 Olivier Lortholary,11,12 Minh-Hong Nguyen,8 Peter G. Pappas,2 William G. Powderly,13 Nina Singh,10 Jack D. Sobel,10 and Tania C. Sorrell15 1Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina 2Division of Infectious Diseases, University of Alabama at Birmingham 3 Department of Pediatric Infectious Diseases, Albert Einstein College of Medicine, Bronx, New York 4 Division of Infectious Diseases, University of Texas San Antonio, Audie L. Murphy Veterans Affairs Hospital, San Antonio, and 5Division of Infectious Diseases, Veteran���s Affairs (VA) Medical Center, Houston, Texas Departments of 6Medicine and 7Infectious Diseases, University of Southern California School of Medicine, Los Angeles 8Division of Infectious Diseases, University of Pittsburgh College of Medicine, and 9 Infectious Diseases Section, VA Medical Center, Pittsburgh, Pennsylvania 10 Wayne State University, Harper Hospital, Detroit, Michigan 11Institut Pasteur, Centre National de Re ��fe ��rence Mycologie et Antifongiques, Unite �� de Mycologie Moleculaire, and 12Universite �� Paris- Descartes, Service des Maladies Infectieuses et Tropicales, Ho ��pital Necker-Enfants Malades, Centre d���Infectiologie Necker-Pasteur, Paris, France 13University College, Dublin, Ireland 14 Department of Infectious Diseases, St. George���s Hospital Medical School, London, United Kingdom 15 Centre for Infectious Diseases and Microbiology, University of Sydney at Westmead, Sydney, Australia Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)���infected individuals, (2) organ transplant recipients, and (3) non���HIV- infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary crypto- coccosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and crypto- coccomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients. EXECUTIVE SUMMARY In 2000, the Infectious Diseases Society of America (IDSA) first published ���Practice Guidelines for the Management of Cryptococcal Disease��� [1]. In this up- dated version of the guidelines, a group of medical Received 12 October 2009 accepted 15 October 2009 electronically published 4 January 2010. Reprints or correspondence: Dr John R. Perfect, Div Infectious Diseases, Duke University Medical Center, Hanes House, Rm 163, Trent Dr, Box 102359, Durham, NC 27710 (perfe001@mc.duke.edu). Clinical Infectious Diseases 2010 50:291���322 2010 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2010/5003-0001$15.00 DOI: 10.1086/649858 mycology experts have approached cryptococcal man- agement using the framework of key clinical questions. The goal is to merge recent and established evidence- based clinical data along with shared expert clinical opinions and insights to assist clinicians in the man- agement of infection with this worldwide, highly rec- ognizable invasive fungal pathogen. The foundation for the successful management of cryptococcal disease was It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient���s individual circumstances.

292 ��� CID 2010:50 (1 February) ��� Perfect et al carefully detailed in the previous IDSA guidelines published in 2000. In fact, by following specific parts of these guidelines for management of cryptococcal meningoencephalitis, an improve- ment in outcome has been validated in retrospective studies [2, 3]. However, over the past decade a series of new clinical issues and host risk groups have arisen, and it is timely that these guidelines be revised to assist practicing clinicians in man- agement of cryptococcosis. Cryptococcus neoformans and Cryptococcus gattii have now been divided into separate species, although most clinical lab- oratories will not routinely identify cryptococcus to the species level [4]. C. gattii has recently been responsible for an ongoing outbreak of cryptococcosis in apparently immunocompetent humans and animals on Vancouver Island and surrounding areas within Canada and the northwest United States, and the management of C. gattii infection in immunocompetent hosts needs to be specifically addressed [5]. Similarly, the human immunodeficiency virus (HIV) pandemic continues, and cryp- tococcosis is a major opportunistic pathogen worldwide, but its management strongly depends on the medical resources available to clinicians in specific regions. In the era of highly active antiretroviral therapy (HAART), the management of cryptococcosis has become a blend of established antifungal regimens together with aggressive treatment of the underlying disease. Although the widespread use of HAART has lowered the incidence of cryptococcosis in medically developed countries [6���9], the incidence and mortality of this infection are still extremely high in areas where uncontrolled HIV disease persists and limited access to HAART and/or health care occurs [10]. It is estimated that the global burden of HIV-associated cryp- tococcosis approximates 1 million cases annually worldwide [11]. In medically developed countries, the modest burden of patients with cryptococcal disease persists, largely consisting of patients with newly diagnosed HIV infection a growing and heterogeneous group of patients receiving high-dose cortico- steroids, monoclonal antibodies such as alemtuzumab and in- fliximab, and/or other immunosuppressive agents [12, 13] and otherwise ���normal��� patients. It is sobering that, despite access to advanced medical care and the availability of HAART, the 3-month mortality rate during management of acute crypto- coccal meningoencephalitis approximates 20% [14, 15]. Fur- thermore, without specific antifungal treatment for cryptococ- cal meningoencephalitis in certain HIV-infected populations, mortality rates of 100% have been reported within 2 weeks after clinical presentation to health care facilities [16]. It is apparent that insightful management of cryptococcal disease is critical to a successful outcome for those with disease caused by this organism. Antifungal drug regimens for management of cryptococcosis are some of the best-characterized for invasive fungal diseases [17]. However, there remain poorly studied issues and con- founders, many of which revolve around the host. For example, correcting and controlling host immunodeficiency and immune reconstitution, respectively, can become a complex clinical sce- nario during management of cryptococcal meningoencepha- litis. Furthermore, specific complications, such as immune re- constitution inflammatory syndrome (IRIS), increased intra- cranial pressure, and cryptococcomas, may require special strat- egies for their successful management in cryptococcosis. Since the last IDSA guidelines in 2000, only the extended-spectrum azoles (posaconazole and voriconazole) and the echinocandins (anidulafungin, caspofungin, and micafungin) have become available as new antifungal drugs. The former have been studied clinically in salvage situations [18, 19], and the latter have no in vivo activity versus Cryptococcus species. Also, additional experience with lipid polyene formulations and drug combi- nation studies have added to our direct anticryptococcal drug treatment insights [20, 21]. Pathobiologically, although recent studies from the cryptococcosis outbreak in Vancouver support the observation that a recombinant strain in nature became more virulent than its parent [22], there are few other clinical data to suggest that cryptococcal strains have become more virulent or drug resistant over the past decade. In fact, control of host immunity, the site of infection, antifungal drug toxicity, and underlying disease are still the most critical factors for successful management of cryptococcosis, and these will be emphasized in these new management guidelines. TREATMENT STRATEGIES FOR PATIENTS WITH CRYPTOCOCCAL MENINGOENCEPHALITIS The strength of the recommendations and the quality of evi- dence are described in Table 1. HIV-Infected Individuals Primary therapy: induction and consolidation 1. Amphotericin B (AmB) deoxycholate (AmBd 0.7���1.0 mg/kg per day intravenously [IV]) plus flucytosine (100 mg/ kg per day orally in 4 divided doses IV formulations may be used in severe cases and in those without oral intake where the preparation is available) for at least 2 weeks, followed by flucon- azole (400 mg [6 mg/kg] per day orally) for a minimum of 8 weeks (A-I). Lipid formulations of AmB (LFAmB), including liposomal AmB (3���4 mg/kg per day IV) and AmB lipid complex (ABLC 5 mg/kg per day IV) for at least 2 weeks, could be substituted for AmBd among patients with or predisposed to renal dysfunction (B-II). Primary therapy: alternative regimens for induction and con- solidation (listed in order of highest recommendation top to bottom) 2. AmBd (0.7���1.0 mg/kg per day IV), liposomal AmB (3���4

Guidelines for Management of Cryptococcosis ��� CID 2010:50 (1 February) ��� 293 Table 1. Strength of Recommendation and Quality of Evidence Assessment Type of evidence Strength of recommendation Grade A Good evidence to support a recommendation for or against use Grade B Moderate evidence to support a recommendation for or against use Grade C Poor evidence to support a recommendation Quality of evidence Level I Evidence from at least 1 properly designed randomized, controlled trial Level II Evidence from at least 1 well-designed clinical trial, without ran- domization from cohort or case-controlled analytic studies (pref- erably from 11 center) from multiple time series or from dra- matic results of uncontrolled experiments Level III Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees NOTE. Adapted from the Canadian Task Force on the Periodic Health Examination Health Canada [23].Reproduced with the permission of the Minister of Public Health Works and Government Services Canada, 2009. mg/kg per day IV), or ABLC (5 mg/kg per day IV) for 4���6 weeks (A-II). Liposomal AmB has been given safely at 6 mg/ kg per day IV in cryptococcal meningoencephalitis and could be considered in the event of treatment failure or high���fungal burden disease. 3. AmBd (0.7 mg/kg per day IV) plus fluconazole (800 mg per day orally) for 2 weeks, followed by fluconazole (800 mg per day orally) for a minimum of 8 weeks (B-I). 4. Fluconazole ( 800 mg per day orally 1200 mg per day is favored) plus flucytosine (100 mg/kg per day orally) for 6 weeks (B-II). 5. Fluconazole (800���2000 mg per day orally) for 10���12 weeks a dosage of 1200 mg per day is encouraged if flucona- zole alone is used (B-II). 6. Itraconazole (200 mg twice per day orally) for 10���12 weeks (C-II), although use of this agent is discouraged. Maintenance (suppressive) and prophylactic therapy 7. Fluconazole (200 mg per day orally) (A-I). 8. Itraconazole (200 mg twice per day orally drug-level monitoring strongly advised) (C-I). 9. AmBd (1 mg/kg per week IV) this is less effective than azoles and is associated with IV catheter���related infections use for azole-intolerant individuals (C-I). 10. Initiate HAART 2���10 weeks after commencement of ini- tial antifungal treatment (B-III). 11. Consider discontinuing suppressive therapy during HAART in patients with a CD4 cell count 1100 cells/mL and an undetectable or very low HIV RNA level sustained for 3 months (minimum of 12 months of antifungal therapy) (B- II) consider reinstitution of maintenance therapy if the CD4 cell count decreases to !100 cells/mL (B-III). 12. For asymptomatic antigenemia, perform lumbar punc- ture and blood culture if results are positive, treat as symp- tomatic meningoencephalitis and/or disseminated disease. Without evidence of meningoencephalitis, treat with flucona- zole (400 mg per day orally) until immune reconstitution (see above for maintenance therapy) (B-III). 13. Primary antifungal prophylaxis for cryptococcosis is not routinely recommended in HIV-infected patients in the United States and Europe, but areas with limited HAART availability, high levels of antiretroviral drug resistance, and a high burden of disease might consider it or a preemptive strategy with serum cryptococcal antigen testing for asymptomatic antigenemia (see above) (B-I). Organ Transplant Recipients 14. For central nervous system (CNS) disease, liposomal AmB (3���4 mg/kg per day IV) or ABLC (5 mg/kg per day IV) plus flucytosine (100 mg/kg per day in 4 divided doses) for at least 2 weeks for the induction regimen, followed by fluconazole (400���800 mg [6���12 mg/kg] per day orally) for 8 weeks and by fluconazole (200���400 mg per day orally) for 6���12 months (B- II). If induction therapy does not include flucytosine, consider LFAmB for at least 4���6 weeks of induction therapy, and li- posomal AmB (6 mg/kg per day) might be considered in high��� fungal burden disease or relapse (B-III). 15. For mild-to-moderate non-CNS disease, fluconazole (400 mg [6 mg/kg] per day) for 6���12 months (B-III). 16. For moderately severe���to-severe non-CNS or dissemi- nated disease (ie, 11 noncontiguous site) without CNS involve- ment, treat the same as CNS disease (B-III). 17. In the absence of any clinical evidence of extrapulmonary or disseminated cryptococcosis, severe pulmonary disease is treated the same as CNS disease (B-III). For mild-to-moderate

294 ��� CID 2010:50 (1 February) ��� Perfect et al symptoms without diffuse pulmonary infiltrates, use flucona- zole (400 mg [6 mg/kg] per day) for 6���12 months (B-III). 18. Fluconazole maintenance therapy should be continued for at least 6���12 months (B-III). 19. Immunosuppressive management should include se- quential or step-wise reduction of immunosuppressants, with consideration of lowering the corticosteroid dose first (B-III). 20. Because of the risk of nephrotoxicity, AmBd should be used with caution in transplant recipients and is not recom- mended as first-line therapy in this patient population (C-III). If used, the tolerated dosage is uncertain, but 0.7 mg/kg per day is suggested with frequent renal function monitoring. In fact, this population will frequently have reduced renal func- tion, and all antifungal dosages will need to be carefully mon- itored. Non���HIV-Infected, Nontransplant Hosts 21. AmBd (0.7���1.0 mg/kg per day IV) plus flucytosine (100 mg/kg per day orally in 4 divided doses) for at least 4 weeks for induction therapy. The 4-week induction therapy is reserved for persons with meningoencephalitis without neurological complications and cerebrospinal fluid (CSF) yeast culture re- sults that are negative after 2 weeks of treatment. For AmBd toxicity issues, LFAmB may be substituted in the second 2 weeks. In patients with neurological complications, consider extending induction therapy for a total of 6 weeks, and LFAmB may be given for the last 4 weeks of the prolonged induction period. Then, start consolidation with fluconazole (400 mg per day) for 8 weeks (B-II). 22. If patient is AmBd intolerant, substitute liposomal AmB (3���4 mg/kg per day IV) or ABLC (5 mg/kg per day IV) (B- III). 23. If flucytosine is not given or treatment is interrupted, consider lengthening AmBd or LFAmB induction therapy for at least 2 weeks (B-III). 24. In patients at low risk for therapeutic failure (ie, they have an early diagnosis by history, no uncontrolled underlying disease or immunocompromised state, and excellent clinical response to initial 2-week antifungal combination course), con- sider induction therapy with combination of AmBd plus flu- cytosine for only 2 weeks, followed by consolidation with flu- conazole (800 mg [12 mg/kg] per day orally) for 8 weeks (B-III). 25. After induction and consolidation therapy, use main- tenance therapy with fluconazole (200 mg [3 mg/kg] per day orally) for 6���12 months (B-III). Management of Complications in Patients with Cryptococcosis Persistence 26. Check that adequate measures have been taken to im- prove immune status (eg, decrease immunosuppressants and introduce HAART) and optimize management of increased in- tracranial pressure (B-III). 27. Reinstitute induction phase of primary therapy for longer course (4���10 weeks) (B-III). 28. Consider increasing the dose if the initial dosage of in- duction therapy was 0.7 mg/kg IV of AmBd per day or 3 mg/kg of LFAmB per day (B-III), up to 1 mg/kg IV of AmBd per day or 6 mg/kg of liposomal AmB per day (B-III) in general, combination therapy is recommended (B-III). 29. If the patient is polyene intolerant, consider fluconazole ( 800 mg per day orally) plus flucytosine (100 mg/kg per day orally in 4 divided doses) (B-III). 30. If patient is flucytosine intolerant, consider AmBd (0.7 mg/kg per day IV) plus fluconazole (800 mg [12 mg/kg] per day orally) (B-III). 31. Use of intrathecal or intraventricular AmBd is generally discouraged and is rarely necessary (C-III). 32. Ideally, persistent and relapse isolates should be checked for changes in the minimum inhibitory concentration (MIC) from the original isolate a 3-dilution difference suggests de- velopment of direct drug resistance. Otherwise, an MIC of the persistent or relapse isolate 16 mg/mL for fluconazole or 32 mg/mL for flucytosine may be considered resistant, and alter- native agents should be considered (B-III). 33. In azole-exposed patients, increasing the dose of the az- ole alone is unlikely to be successful and is not recommended (C-III). 34. Adjunctive immunological therapy with recombinant in- terferon (IFN)-g at a dosage of 100 mg/m2 for adults who weigh 50 kg (for those who weigh !50 kg, consider 50 mg/m2) 3 times per week for 10 weeks can be considered for refractory infection, with the concomitant use of a specific antifungal drug (B-III). Relapse 35. Restart induction phase therapy (see ���Persistence,��� above) (B-III). 36. Determine susceptibility of the relapse isolate (see ���Per- sistence,��� above) (B-III). 37. After induction therapy and in vitro susceptibility test- ing, consider salvage consolidation therapy with either flucona- zole (800���1200 mg per day orally), voriconazole (200���400 mg twice per day orally), or posaconazole (200 mg orally 4 times per day or 400 mg twice per day orally) for 10���12 weeks (B- III) if there are compliance issues and a susceptible isolate, prior suppressive doses of fluconazole may be reinstituted (B- III). Elevated CSF pressure 38. Identify CSF pressure at baseline. A prompt baseline

Guidelines for Management of Cryptococcosis ��� CID 2010:50 (1 February) ��� 295 lumbar puncture is strongly encouraged, but in the presence of focal neurologic signs or impaired mentation, it should be delayed pending the results of a computed tomography (CT) or magnetic resonance imaging (MRI) scan (B-II). 39. If the CSF pressure is 25 cm of CSF and there are symptoms of increased intracranial pressure during induction therapy, relieve by CSF drainage (by lumbar puncture, reduce the opening pressure by 50% if it is extremely high or to a normal pressure of 20 cm of CSF) (B-II). 40. If there is persistent pressure elevation 25 cm of CSF and symptoms, repeat lumbar puncture daily until the CSF pressure and symptoms have been stabilized for 12 days and consider temporary percutaneous lumbar drains or ventricu- lostomy for persons who require repeated daily lumbar punc- tures (B-III). 41. Permanent ventriculoperitoneal (VP) shunts should be placed only if the patient is receiving or has received appropriate antifungal therapy and if more conservative measures to control increased intracranial pressure have failed. If the patient is re- ceiving an appropriate antifungal regimen, VP shunts can be placed during active infection and without complete steriliza- tion of CNS, if clinically necessary (B-III). Other medications for intracranial pressure 42. Mannitol has no proven benefit and is not routinely recommended (A-III). 43. Acetazolamide and corticosteroids (unless part of IRIS treatment) should be avoided to control increased intracranial pressure (A-II). Recurrence of signs and symptoms 44. For recurrence of signs and symptoms, reinstitute drain- age procedures (B-II). 45. For patients with recurrence, measurement of opening pressure with lumbar puncture after a 2-week course of treat- ment may be useful in evaluation of persistent or new CNS symptoms (B-III). Long-term elevated intracranial pressure 46. If the CSF pressure remains elevated and if symptoms persist for an extended period of time in spite of frequent lumbar drainage, consider insertion of a VP shunt (A-II). IRIS 47. No need to alter direct antifungal therapy (B-III). 48. No definitive specific treatment recommendation for mi- nor IRIS manifestations is necessary, because they will resolve spontaneously in days to weeks (B-III). 49. For major complications, such as CNS inflammation with increased intracranial pressure, consider corticosteroids (0.5���1.0 mg/kg per day of prednisone equivalent) and possibly dexamethasone at higher doses for severe CNS signs and symp- toms. Length and dose of the corticosteroid taper are empir- ically chosen and require careful following of the patient, but a 2���6-week course is a reasonable starting point. The course should be given with a concomitant antifungal regimen (B-III). 50. Nonsteroidal anti-inflammatory drugs and thalidomide have been used but with too little experience to make a rec- ommendation (C-III). Cerebral cyptococcomas 51. Induction therapy with AmBd (0.7���1 mg/kg per day IV), liposomal AmB (3���4 mg/kg per day IV), or ABLC (5 mg/kg per day IV) plus flucytosine (100 mg/kg per day orally in 4 divided doses) for at least 6 weeks (B-III). 52. Consolidation and maintenance therapy with flucona- zole (400���800 mg per day orally) for 6���18 months (B-III). 53. Adjunctive therapies include the following: A. Corticosteroids for mass effect and surrounding edema (B-III). B. Surgery: for large ( 3-cm lesion), accessible lesions with mass effect, consider open or stereotactic-guided debulkment and/or removal also, enlarging lesions not explained by IRIS should be submitted for further tissue diagnosis (B-II). Treatment Strategies for Patients with Nonmeningeal Cryptococcosis Pulmonary (immunosuppressed) 54. In immunosuppressed patients with pulmonary cryp- tococcosis, meningitis should be ruled out by lumbar puncture the presence of CNS disease alters the dose and duration of induction therapy and the need for intracranial pressure mon- itoring (B-II). 55. Pneumonia associated with CNS or documented dissem- ination and/or severe pneumonia (acute respiratory distress syndrome [ARDS]) is treated like CNS disease (B-III). 56. Corticosteroid treatment may be considered if ARDS is present in the context of IRIS (B-III). 57. For mild-to-moderate symptoms, absence of diffuse pul- monary infiltrates, absence of severe immunosuppression, and negative results of a diagnostic evaluation for dissemination, use fluconazole (400 mg [6 mg/kg] per day orally) for 6���12 months (B-III). 58. In HIV-infected patients who are receiving HAART with a CD4 cell count 1100 cells/mL and a cryptococcal antigen titer that is 1:512 and/or not increasing, consider stopping main- tenance fluconazole after 1 year of treatment (B-II). 59. Surgery should be considered for either diagnosis or persistent radiographic abnormalities and symptoms not re- sponding to antifungal therapy (B-III).