隐球菌病治疗指南

Clinical Practice Guidelines for the Managementof Cryptococcal Disease:2010Update by the Infectious Diseases Society of AmericaJohn R.Perfect,1William E.Dismukes,2Francoise Dromer,11David L.Goldman,3John R.Graybill,4Richard J.Hamill,5Thomas S.Harrison,14Robert rsen,6,7Olivier Lortholary,11,12Minh-Hong Nguyen,8Peter G.Pappas,2William G.Powderly,13Nina Singh,10Jack D.Sobel,10and Tania C.Sorrell151Division of Infectious Diseases,Duke University Medical Center,Durham,North Carolina;2Division of Infectious Diseases,University of Alabama at Birmingham; 3Department of Pediatric Infectious Diseases,Albert Einstein College of Medicine,Bronx,New York;4Division of Infectious Diseases,University of Texas San Antonio,Audie L.Murphy Veterans Affairs Hospital,San Antonio,and5Division of Infectious Diseases,Veteran’s Affairs(VA)Medical Center,Houston,Texas; Departments of6Medicine and7Infectious Diseases,University of Southern California School of Medicine,Los Angeles;8Division of Infectious Diseases, University of Pittsburgh College of Medicine,and9Infectious Diseases Section,VA Medical Center,Pittsburgh,Pennsylvania;10Wayne State University,Harper Hospital,Detroit,Michigan;11Institut Pasteur,Centre National de Re´fe´rence Mycologie et Antifongiques,Unite´de Mycologie Moleculaire,and12Universite´Paris-Descartes,Service des Maladies Infectieuses et Tropicales,Hoˆpital Necker-Enfants Malades,Centre d’Infectiologie Necker-Pasteur,Paris,France;13University College,Dublin,Ireland;14Department of Infectious Diseases,St.George’s Hospital Medical School,London,United Kingdom;15Centre for Infectious Diseases and Microbiology,University of Sydney at Westmead,Sydney,AustraliaCryptococcosis 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 from2000and include new sections.There is a discussion of the management of cryptococcal meningoencephalitis in3risk 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 andflucytosine,followed by suppressive regimens usingfluconazole;(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 SUMMARYIn2000,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 medicalReceived12October2009;accepted15October2009;electronically published 4January2010.Reprints or correspondence:Dr John R.Perfect,Div Infectious Diseases,Duke University Medical Center,Hanes House,Rm163,Trent Dr,Box102359,Durham, NC27710(perfe001@).Clinical Infectious Diseases2010;50:291–322ᮊ2010by the Infectious Diseases Society of America.All rights reserved. 1058-4838/2010/5003-0001$15.00DOI:10.1086/649858mycology 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 clinicalopinions and insights to assist clinicians in the man-agement of infection with this worldwide,highly rec-ognizable invasive fungal pathogen.The foundation forthe successful management of cryptococcal disease wasIt is important to realize that guidelines cannot always account for individualvariation among patients.They are not intended to supplant physician judgmentwith respect to particular patients or special clinical situations.The InfectiousDiseases Society of America considers adherence to these guidelines to bevoluntary,with the ultimate determination regarding their application to be madeby the physician in the light of each patient’s individual circumstances.Guidelines for Management of Cryptococcosis•CID2010:50(1February)•291carefully 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 approximates1million 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 approximates20%[14,15].Fur-thermore,without specific antifungal treatment for cryptococ-cal meningoencephalitis in certain HIV-infected populations, mortality rates of100%have been reported within2weeks 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 in2000,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.TREA TMENT STRATEGIES FOR PATIENTS WITH CRYPTOCOCCAL MENINGOENCEPHALITISThe strength of the recommendations and the quality of evi-dence are described in Table1.HIV-Infected IndividualsPrimary therapy:induction and consolidation1.Amphotericin B(AmB)deoxycholate(AmBd;0.7–1.0 mg/kg per day intravenously[IV])plusflucytosine(100mg/ kg per day orally in4divided doses;IV formulations may be used in severe cases and in those without oral intake where the preparation is available)for at least2weeks,followed byflucon-azole(400mg[6mg/kg]per day orally)for a minimum of8 weeks(A-I).Lipid formulations of AmB(LFAmB),including liposomal AmB(3–4mg/kg per day IV)and AmB lipid complex (ABLC;5mg/kg per day IV)for at least2weeks,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(0.7–1.0mg/kg per day IV),liposomal AmB(3–4292•CID2010:50(1February)•Perfect et alTable1.Strength of Recommendation and Quality of EvidenceAssessment Type of evidenceStrength of recommendationGrade 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 recommendationQuality of evidenceLevel I Evidence from at least1properly designed randomized,controlledtrialLevel II Evidence from at least1well-designed clinical trial,without ran-domization;from cohort or case-controlled analytic studies(pref-erably from11center);from multiple time series;or from dra-matic results of uncontrolled experimentsLevel III Evidence from opinions of respected authorities,based on clinicalexperience,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(5mg/kg per day IV)for4–6 weeks(A-II).Liposomal AmB has been given safely at6mg/ kg per day IV in cryptococcal meningoencephalitis and could be considered in the event of treatment failure or high–fungal burden disease.3.AmBd(0.7mg/kg per day IV)plusfluconazole(800mg per day orally)for2weeks,followed byfluconazole(800mg per day orally)for a minimum of8weeks(B-I).4.Fluconazole(у800mg per day orally;1200mg per day is favored)plusflucytosine(100mg/kg per day orally)for6 weeks(B-II).5.Fluconazole(800–2000mg per day orally)for10–12 weeks;a dosage ofу1200mg per day is encouraged ifflucona-zole alone is used(B-II).6.Itraconazole(200mg twice per day orally)for10–12 weeks(C-II),although use of this agent is discouraged. Maintenance(suppressive)and prophylactic therapy7.Fluconazole(200mg per day orally)(A-I).8.Itraconazole(200mg twice per day orally;drug-level monitoring strongly advised)(C-I).9.AmBd(1mg/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 HAART2–10weeks after commencement of ini-tial antifungal treatment(B-III).11.Consider discontinuing suppressive therapy during HAART in patients with a CD4cell count1100cells/m L and an undetectable or very low HIV RNA level sustained forу3 months(minimum of12months of antifungal therapy)(B-II);consider reinstitution of maintenance therapy if the CD4 cell count decreases to!100cells/m L(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 withflucona-zole(400mg 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 Recipients14.For central nervous system(CNS)disease,liposomal AmB(3–4mg/kg per day IV)or ABLC(5mg/kg per day IV) plusflucytosine(100mg/kg per day in4divided doses)for at least2weeks for the induction regimen,followed byfluconazole (400–800mg[6–12mg/kg]per day orally)for8weeks and by fluconazole(200–400mg per day orally)for6–12months(B-II).If induction therapy does not includeflucytosine,consider LFAmB for at least4–6weeks of induction therapy,and li-posomal AmB(6mg/kg per day)might be considered in high–fungal burden disease or relapse(B-III).15.For mild-to-moderate non-CNS disease,fluconazole (400mg[6mg/kg]per day)for6–12months(B-III).16.For moderately severe–to-severe non-CNS or dissemi-nated disease(ie,11noncontiguous 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-moderateGuidelines for Management of Cryptococcosis•CID2010:50(1February)•293symptoms without diffuse pulmonary infiltrates,useflucona-zole(400mg[6mg/kg]per day)for6–12months(B-III). 18.Fluconazole maintenance therapy should be continued for at least6–12months(B-III).19.Immunosuppressive management should include se-quential or step-wise reduction of immunosuppressants,with consideration of lowering the corticosteroid dosefirst(B-III).20.Because of the risk of nephrotoxicity,AmBd should be used with caution in transplant recipients and is not recom-mended asfirst-line therapy in this patient population(C-III). If used,the tolerated dosage is uncertain,but0.7mg/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 Hosts21.AmBd(0.7–1.0mg/kg per day IV)plusflucytosine(100 mg/kg per day orally in4divided doses)for at least4weeks for induction therapy.The4-week induction therapy is reserved for persons with meningoencephalitis without neurological complications and cerebrospinalfluid(CSF)yeast culture re-sults that are negative after2weeks of treatment.For AmBd toxicity issues,LFAmB may be substituted in the second2 weeks.In patients with neurological complications,consider extending induction therapy for a total of6weeks,and LFAmB may be given for the last4weeks of the prolonged induction period.Then,start consolidation withfluconazole(400mg per day)for8weeks(B-II).22.If patient is AmBd intolerant,substitute liposomal AmB (3–4mg/kg per day IV)or ABLC(5mg/kg per day IV)(B-III).23.Ifflucytosine is not given or treatment is interrupted, consider lengthening AmBd or LFAmB induction therapy for at least2weeks(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 initial2-week antifungal combination course),con-sider induction therapy with combination of AmBd plusflu-cytosine for only2weeks,followed by consolidation withflu-conazole(800mg[12mg/kg]per day orally)for8weeks(B-III).25.After induction and consolidation therapy,use main-tenance therapy withfluconazole(200mg[3mg/kg]per day orally)for6–12months(B-III).Management of Complications in Patients with Cryptococcosis Persistence26.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(4–10weeks)(B-III).28.Consider increasing the dose if the initial dosage of in-duction therapy wasр0.7mg/kg IV of AmBd per day orр3 mg/kg of LFAmB per day(B-III),up to1mg/kg IV of AmBd per day or6mg/kg of liposomal AmB per day(B-III);in general,combination therapy is recommended(B-III).29.If the patient is polyene intolerant,considerfluconazole (у800mg per day orally)plusflucytosine(100mg/kg per day orally in4divided doses)(B-III).30.If patient isflucytosine intolerant,consider AmBd(0.7 mg/kg per day IV)plusfluconazole(800mg[12mg/kg]per day orally)(B-III).e 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;aу3-dilution difference suggests de-velopment of direct drug resistance.Otherwise,an MIC of the persistent or relapse isolateу16m g/mL forfluconazole orу32 m g/mL forflucytosine 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 of100m g/m2for adults who weigh у50kg(for those who weigh!50kg,consider50m g/m2)3 times per week for10weeks can be considered for refractory infection,with the concomitant use of a specific antifungal drug (B-III).Relapse35.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 eitherflucona-zole(800–1200mg per day orally),voriconazole(200–400mg twice per day orally),or posaconazole(200mg orally4times per day or400mg twice per day orally)for10–12weeks(B-III);if there are compliance issues and a susceptible isolate, prior suppressive doses offluconazole may be reinstituted(B-III).Elevated CSF pressure38.Identify CSF pressure at baseline.A prompt baseline294•CID2010:50(1February)•Perfect et allumbar 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 isу25cm of CSF and there are symptoms of increased intracranial pressure during induction therapy,relieve by CSF drainage(by lumbar puncture,reduce the opening pressure by50%if it is extremely high or to a normal pressure ofр20cm of CSF)(B-II).40.If there is persistent pressure elevationу25cm of CSF and symptoms,repeat lumbar puncture daily until the CSF pressure and symptoms have been stabilized for12days 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 pressure42.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 symptoms44.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 a2-week course of treat-ment may be useful in evaluation of persistent or new CNS symptoms(B-III).Long-term elevated intracranial pressure46.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). IRIS47.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 (0.5–1.0mg/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 a2–6-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 cyptococcomas51.Induction therapy with AmBd(0.7–1mg/kg per day IV), liposomal AmB(3–4mg/kg per day IV),or ABLC(5mg/kg per day IV)plusflucytosine(100mg/kg per day orally in4 divided doses)for at least6weeks(B-III).52.Consolidation and maintenance therapy withflucona-zole(400–800mg per day orally)for6–18months(B-III).53.Adjunctive therapies include the following:A.Corticosteroids for mass effect and surrounding edema (B-III).B.Surgery:for large(у3-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 CryptococcosisPulmonary(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, usefluconazole(400mg[6mg/kg]per day orally)for6–12 months(B-III).58.In HIV-infected patients who are receiving HAART witha CD4cell count1100cells/m L and a cryptococcal antigen titer that isр1:512and/or not increasing,consider stopping main-tenancefluconazole after1year 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).Guidelines for Management of Cryptococcosis•CID2010:50(1February)•295Pulmonary(nonimmunosuppressed)60.For mild-to-moderate symptoms,administerflucona-zole(400mg per day orally)for6–12months;persistently positive serum cryptococcal antigen titers are not criteria for continuance of therapy(B-II).61.For severe disease,treat similarly to CNS disease(B-III).62.Itraconazole(200mg twice per day orally),voriconazole (200mg twice per day orally),and posaconazole(400mg twice per day orally)are acceptable alternatives iffluconazole is un-available or contraindicated(B-II).63.Surgery should be considered for either diagnosis or persistent radiographic abnormalities and symptoms not re-sponding to antifungal therapy(B-III).64.In nonimmunocompromised patients with pulmonary cryptococcosis,consider a lumbar puncture to rule out asymp-tomatic CNS involvement.However,for normal hosts with asymptomatic pulmonary nodule or infiltrate,no CNS symp-toms,and negative or very low serum cryptococcal antigen,a lumbar puncture can be avoided(B-II).65.ARDS in the context of an inflammatory syndrome re-sponse may require corticosteroid treatment(B-III). Nonmeningeal,nonpulmonary cryptococcosis66.For cryptococcemia or dissemination(involvement of at least2noncontiguous sites or evidence of high fungal burden based on cryptococcal antigen titerу1:512),treat as CNS dis-ease(B-III).67.If CNS disease is ruled out,fungemia is not present, infection occurs at single site,and there are no immunosup-pressive risk factors,considerfluconazole(400mg[6mg/kg] per day orally)for6–12months(B-III).Treatment in Special Clinical Situations(Pregnant Women, Children,Persons in a Resource-Limited Environment,and C. gattii–Infected Persons)Pregnant women with cryptococcosis68.For disseminated and CNS disease,use AmBd or LFAmB,with or withoutflucytosine(B-II).Flucytosine is a category C drug for pregnancy,and therefore,its use must be considered in relationship to benefit versus risk.69.Startfluconazole(pregnancy category C)after delivery; avoidfluconazole exposure during thefirst trimester;and dur-ing the last2trimesters,judge the use offluconazole with the need for continuous antifungal drug exposure during preg-nancy(B-III).70.For limited and stable pulmonary cryptococcosis,per-form close follow-up and administerfluconazole after delivery (B-III).71.Watch for IRIS in the postpartum period(B-III).Children with cryptococcosis72.Induction and consolidation therapy for CNS and dis-seminated disease is AmBd(1mg/kg per day IV)plusflucy-tosine(100mg/kg per day orally in4divided doses)for2weeks (for the non–HIV-infected,non-transplant population,follow the treatment length schedule for adults),followed byflucona-zole(10–12mg/kg per day orally)for8weeks;for AmB-in-tolerant patients,either liposomal AmB(5mg/kg per day)or ABLC(5mg/kg per day)(A-II).73.Maintenance therapy isfluconazole(6mg/kg per day orally)(A-II).74.Discontinuation of maintenance therapy in children re-ceiving HAART is poorly studied and must be individualized (C-III).75.For cryptococcal pneumonia,usefluconazole(6–12mg/ kg per day orally)for6–12months(B-II). Cryptococcosis in a resource-limited health care environment 76.For CNS and/or disseminated disease whereflucytosine is not available,induction therapy is AmBd(1mg/kg per day IV)for2weeks or AmBd(0.7mg/kg per day IV)plusflucona-zole(800mg per day orally)for2weeks,followed by consol-idation therapy withfluconazole(800mg per day orally)for 8weeks(A-I).77.Maintenance therapy isfluconazole(200–400mg per day orally)until immune reconstitution(A-I).78.With CNS and/or disseminated disease where polyene is not available,induction therapy isfluconazole(у800mg per day orally;1200mg per day is favored)for at least10weeks or until CSF culture results are negative,followed by mainte-nance therapy withfluconazole(200–400mg per day orally) (B-II).79.With CNS and/or disseminated disease when polyene is not available butflucytosine is available,induction therapy is fluconazole(у800mg per day orally;1200mg per day is fa-vored)plusflucytosine(100mg/kg per day orally)for2–10 weeks,followed by maintenance therapy withfluconazole(200–400mg per day orally)(B-II).80.With use of primaryfluconazole therapy for induction, both primary or secondary drug resistance of the isolate may be an issue,and MIC testing is advised(B-III).81.For azole-resistant strains,administer AmBd(1mg/kg per day IV)until CSF,blood,and/or other sites are sterile(B-III).C.gattii infection82.For CNS and disseminated disease due to C.gattii,in-duction,consolidation,and suppressive treatment are the same as for C.neoformans(A-II).83.More diagnostic focus by radiology and follow-up ex-aminations are needed for cryptococcomas/hydrocephalus due296•CID2010:50(1February)•Perfect et al。

隐球菌病的药物治疗
一、隐球菌脑膜炎(非AIDS患者)：
首选抗真菌药：两性霉素B静脉注射，一次0.5～0.8mg/kg,一日1次，加氟胞嘧啶口服，一次25～37.5mg/kg，每6小时一次，至患者退热及病原菌阴性(约6周)，后改用氟康唑口服，一次200mg，一日1次。

对轻症可用口服氟康唑一次400mg，一日1次，连续8～10周。

说明：脑积水可用导管行脑室腹膜腔分流或脑室心房分流术
二、肺隐球菌病或隐球菌性血流感染(非AIDS，非脑膜炎)：
首选抗真菌药：病情较严重者：两性霉素B静脉注射，一日0.5～0.8mg/kg，至病情好转后改用氟康唑口服，一次400mg，一日1次，连续8～10周。

病情较轻者可用氟康唑，静脉注射或口服，一日400mg，连续8周至6个月。

备选抗菌药：伊曲康唑，口服一次200～400mg，一日1次，连续6～12个月。

或两性霉素B静脉注射，一日0.3mg/kg，加氟胞嘧啶口服，一次37.5mg/kg，一日3次，连续6周。

说明：单用氟康唑治疗脑膜炎和非脑膜型隐球菌病90%有效。

氟康唑治疗和两性霉素B的效果相同。

对治疗失败的病例，用干扰素加脂质体两性霉素B。

1。

隐球菌感染的主要类型与治疗隐球菌病(cryptococcosis，torulosis)是亚急性或慢性传染病，由新型隐球菌(cryptococcusneoformans)所致，以侵犯中枢神经系统为主，近年来真菌性脑膜炎、脑脓肿和肉芽肿已不少见，易与其他颅内疾病混淆而延误治疗，故病死率高，应予以警惕。

本病亦可累及肺、皮肤、皮下组织、骨骺、关节和其他内脏、组织等，可发生于任何年龄，但10岁以下小儿发病率较低。

男性多于女性(3∶1)。

我国自1946年正式报道此病以来，儿科各地均有发现。

正常人常暴露于新生隐球菌的环境中，但发病者极少，人体对隐球菌的免疫包括细胞免疫与体液免疫。

巨噬细胞、中性粒细胞、淋巴细胞、自然杀伤细胞起着重要作用。

体液免疫包括：抗荚膜多糖抗体以及补体参与调理吞噬作用，协助吞噬细胞吞噬隐球菌。

只有当机体抵抗力降低时，病原菌才易于侵入人体而致病。

一般起病缓慢，开始症状多为轻度阵发性头痛，以后则逐渐加重，但仍可自然缓解，经常反复;多伴有恶心、呕吐、晕眩及不同程度的发热，数周或数月后可出现颅内压增高症状，如颈项强直，脑膜刺激征阳性及各种眼部征象(有视力模糊、眩晕、复视、畏光、眼球麻痹、震颤、弱视等)。

常伴有眼底水肿及视网膜渗出性改变3.皮肤粘膜隐球菌病皮肤粘膜隐球菌病很少单独发生，常为全身性隐球菌病的局部表现，可能由脑膜、肺部和其他病灶播散所致，主要表现为面部座疮样皮疹、硬结或随病变扩大而中心坏死，形成溃疡。

间或也有发生于硬腭、软腭、舌、齿龈、咽部、鼻腔等粘膜上。

自觉症状并不严重，病程漫长。

一、隐球菌感染的主要类型1. 中枢神经系统隐球菌病：新型隐球菌易侵袭中枢神经系统，原因不清，可能与脑脊液中存在天门冬素及肌酐有助于菌生长有关。

也易引起亚急性或慢性脑膜炎及脑膜脑炎。

1978年Forar统计220例隐球菌感染病例中，仅有19例无中枢神经受累，因此隐球菌脑膜炎是真菌所致胸膜炎中最常见的类型。

其临床表现颇似结核性脑膜炎，但有时隐球菌性肉芽肿局限于脑和脊髓的某个部位，则与脑瘤或脑脓肿等相似。

中国感染与化疗杂志２０１０年５月２０日第１０卷第３期ＣｈｉｎＪＩｎｆｅｃｔＣｈｅｍｏｔｈｅｒ，Ｍａｙ．２０１０，Ｖ０１．１０，Ｎｏ．３１６５处，不常规推荐（Ａ一Ⅲ）。

乙酰唑胺和皮质类固醇（除非ＩＲＩＳ）应避免用于控制颅内压力（Ａ一Ⅱ）。

（２Ｅ）症状和体征再发症状和体征再发，重新开始引流（ＢⅡ）。

再发的患者，治疗２周后进行腰椎穿刺测定脑脊液压力，以评价病情（昏ｍ）。

（六）长期脑脊液压力升高如果频繁腰椎穿刺引流，脑脊液压力仍持续升高，或症状持续存在，考虑ＶＰ分流术（Ａ一Ⅱ）。

（七）ＩＲＩＳ没有必要改变抗真菌治疗（Ｂ－１１１）轻度的ＩＲＩＳ可以在数天或数周内自愈，无需特殊处理（Ｂ－１１Ｉ）。

治疗主要并发症，如中枢炎症反应致脑脊液压力升高，可考虑使用皮质类固醇（相当于泼尼松０．５～１．０ｍｇ·ｋｇ叫·ｄ叫），对于中枢神经系统症状和体征严重的患者，可以使用更高剂量的地塞米松。

根据经验决定激素的疗程并逐渐减量，一般为２～６周，但需要个体化。

同时给予抗真菌治疗（１３－ｍ）。

非皮质类固醇抗炎药物和沙利度胺也有使用，但经验太少无法做出推荐（Ｃ－Ⅲ）。

（八）大脑隐球菌球ＡｍＢｄ（０．７～１ｍｇ·ｋｇ。

１·ｄ～，静脉滴注），ＡｍＢ脂质体（３～４ｍｇ·ｋｇ。

１·ｄ～，静脉滴注），或ＡＢＬＣ（５ｍｇ·ｋｇ叫·ｄ～，静脉滴注）联合氟胞嘧啶（１００ｍｇ·ｋｇ叫·ｄ～，分４次口服）治疗至少６周（Ｂ－Ⅲ）。

氟康唑巩固和维持治疗（４００～８００ｍｇ／ｄ，口服）治疗６～１８个月（Ｂ－１１１）。

辅助治疗包括：①皮质类固醇治疗占位效应及水肿（Ｂ－Ⅲ）。

②外科治疗：大的病灶（≥３ｃｍ），可能存在占位效应，需开颅或立体定向治疗减负或（和）完全去除病灶；ＩＲＩＳ不能解释病灶变大，应进一步组织活检，明确诊断（ＢⅡ）。

三、非中枢神经系统隐球菌病的治疗推荐（表５）（一）肺部感染（免疫抑制患者）免疫抑制患者肺部隐球菌病，需作腰椎穿刺以除外脑膜炎。

隐球菌病怎样治疗？*导读：本文向您详细介绍隐球菌病的治疗方法，治疗隐球菌病常用的西医疗法和中医疗法。

隐球菌病应该吃什么药。

*隐球菌病怎么治疗？*一、西医*1、治疗1.抗真菌药物治疗根据病变部位和患者的免疫状态的不同，隐球菌病的抗病原治疗有差异。

无明显免疫缺陷的肺隐球菌病患者通常无需抗真菌治疗而很快自愈。

其他部位的隐球菌病，尤其是中枢神经系统隐球菌病和有免疫缺陷的肺隐球病患者，如艾滋病等，或同时有肺外隐球菌病，以及肺隐球菌病进行性加重时，均应进行抗真菌治疗。

(1)两性霉素B：仍是治疗中枢神经系统隐球菌病的首选药物，静脉滴注须从小剂量开始，以后每日递增。

对于危重病人还可采用鞘内注射治疗，以提高脑脊液内的药物浓度。

常见两性霉素B毒副作用：①即刻反应：如发热、寒战、头痛、恶心、呕吐及食欲不振。

②重要脏器损害：如肾功能损害，可见于半数患者。

尿中出现蛋白，红、白细胞及管型。

若血尿素氮超过正常1倍、血清肌酐高于265.2 mol/L时，应减量或停药;肝功能及心肌损害亦较常见，曾有出现心室纤颤而死亡的报道。

部分患者出现贫血，偶有血小板及白细胞减少。

③电解质紊乱：其中低钾血症最多。

④静脉炎：见于多次注射后的静脉。

孕妇禁用本药。

(2)两性霉素B脂质体：减少了与人体细胞膜上胆固醇的结合，却增加了对真菌外膜上麦角固醇的结合，且脂质体中的两性霉素B缓慢释放进人体内，故降低了两性霉素B的毒副作用，特别是降低了对肾的毒性作用。

适应证：各种严重的系统性真菌病;用传统两性霉素B或其他抗真菌药治疗无效的病人;对传统两性霉素B不能耐受或有禁忌的真菌感染，如肾功能不全、明显的贫血患者等;用于器官移植、骨髓移植等真菌感染的治疗和预防。

(3)氟胞嘧啶：对隐球菌的最低抑菌浓度为0.097～78 g/ml，口服吸收良好，易透过血脑屏障，脑脊液的浓度可达血浓度的64%～68%。

可口服或静脉用药。

主要不良反应：食欲不振，恶心、呕吐等消化道症状;肝功能损害，造血系统抑制，对肾功能亦有影响。

隐球菌病治疗指南.隐球菌病治疗指南全国变态反应性和___（NIAID）真菌病研究组由8人组成，评估了现有的有关隐球菌病治疗的资料，并总结了隐球菌病最佳治疗的方法。

每种推荐方法的相对推荐强度是根据相应的临床证据的类型和级别作出分级的，与___（IDSA）此前公布的指南相一致。

专门小组通过2次电话会议和撰写原稿评论加以确定。

对于新生隐球菌病的治疗方法的选择，需要考虑侵犯部位及感染宿主的免疫状态。

对于免疫正常宿主的局限性肺隐球菌病，必须保证严密的观察。

在有症状的病例，建议使用氟康唑，剂量为200～400mg/d，共3～6个月。

对于那些血清隐球菌抗原滴度>1:8而无CNS侵犯的隐球菌血症，或泌尿道、皮肤感染的病例，推荐使用唑类（氟康唑）3～6个月。

在所有病例中，均需严密观测以排除潜在的CNS感染可能。

对于不能耐受氟康唑的病人，伊曲康唑（200～400mg/d，共6～12个月）是一种可接受的选择方案。

对于严重的感染病例，需采用两性霉素B（0.5～1mg/kg/d）治疗6～10周。

对于健康宿主的CNS感染病例，标准的治疗方案是采用两性毒素B（0.7～1mg/kg/d），与氟胞嘧啶（100mg/kg/d）联合使用2周，然后使用氟康唑（400mg/d）至少10周。

根据病人的临床状况，氟康唑“巩固”治疗需持续6～12个月。

对HIV阴性的免疫抑制病例，不管其感染部位，均需按CNS感染来治疗。

目前还没有临床对照试验来研究AIDS相关的隐球菌性肺炎治疗的疗效（表2）。

实际上，对于HIV感染病人的肺部或非CNS隐球菌感染治疗的疗效极少有人研究。

因此，特异性的可选择治疗方案还未完全阐明。

但由于所有HIV感染病人存在播散感染的危险，治疗是必要的。

对于持续或顽固的肺部或骨损害，外科治疗是需要考虑的。

对于血清隐球菌抗原滴度（1:8）阳性而无临床表现的HIV感染病人，虽然还没有进行特异的研究，但他们也必须进行治疗。

治疗的预期结果是消除症状，如咳嗽、气急、咳痰、胸痛、发热，以及改善胸片异常表现（侵润、结节、肿块等）。