隐球菌病治疗实用指南
隐球菌病诊治指南2010(1)
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。
隐球菌新指南
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;50:000–000ᮊ2010by the Infectious Diseases Society of America.All rights reserved. 1058-4838/2010/5003-00XX$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)•000carefully 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(3–4000•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)•000symptoms 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 baseline000•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)•000Pulmonary(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 due000•CID2010:50(1February)•Perfect et al。
播散性隐球菌病的治疗及护理
播散性隐球菌病的治疗及护理
01.
播散性隐球菌病的概述
02.
03.
目录
播散性隐球菌病的治疗
播散性隐球菌病的护理
1
播散性隐球菌病的概述
疾病定义
播散性隐球菌病是一种由隐球菌引起的真菌感染性疾病
隐球菌是一种广泛存在于自然界的真菌，主要存在于土壤、鸟类粪便和腐烂的植物中
02
播散性隐球菌病主要通过呼吸道吸入孢子而感染，也可通过皮肤伤口或消化道传播
营养支持：为患者提供营养丰富的饮食，增强免疫力
2
物理治疗：如按摩、针灸等，缓解患者疼痛和不适
3
康复治疗：帮助患者恢复身体机能，提高生活质量
4
3
播散性隐球菌病的护理
生活护理
保持良好的生活习惯，如按时作息、饮食规律等
保持良好的个人卫生，如勤洗手、洗澡等
避免接触感染源，如避免接触宠物、土壤等
保持良好的心理状态，如保持乐观、积极等
播散性隐球菌病可引起多种临床症状，包括肺部感染、脑膜炎、皮肤感染等
04
发病原因
01
免疫力低下：如艾滋病、恶性肿瘤、长期使用免疫抑制剂等
03
接触感染：如接触隐球菌污染的物品或环境
02
环境因素：如土壤、空气、水源等污染
04
遗传因素：部分患者可能存在遗传易感性
临床表现
发热：体温升高，持续时间较长
01
头痛：持续性头痛，可能伴有恶心、呕吐
康复护理
STEP4
STEP3
STEP2
STEP1
保持良好的生活习惯：注意个人卫生，保持室内通风，避免过度劳累
饮食调理：增加营养摄入，多吃新鲜水果和蔬菜，避免辛辣、油腻食物
2022 WHO指南：成人、青少年、儿童HIV感染者隐球菌病的诊断、预防和管理
2022 WHO指南：成人、青少年、儿童HIV感染者隐球菌病的诊断、预防和管理隐球菌病是晚期艾滋病（HIV）患者中最常见的机会性感染之一，也是导致疾病、残疾和死亡的主要原因。
目前为止，隐球菌病最常见的表现是隐球菌性脑膜炎。
2014年，HIV感染者中约有223100例隐球菌性脑膜炎患者，其中181100例患者死亡，占全球死于HIV相关死亡总人数的15%。
为进一步对相关疾病作出指导，2022年6月，世界卫生组织（WHO）更新并发布了成人、青少年、儿童HIV感染者隐球菌病管理指南。
本文汇总了诊断、预防和管理等相关问题的推荐建议。
隐球菌性脑膜炎诊断相关建议1.对于疑似首次发作隐球菌性脑膜炎的成人、青少年和儿童HIV感染者，推荐首选的诊断方法为及时行腰椎穿刺术并测量脑脊液（CSF）开放压力以及行快速隐球菌抗原检测试验。
（强推荐；成人和青少年-中等质量证据，儿童-低质量证据）2.对于可随时进行腰椎穿刺且没有腰穿禁忌证的患者：（1）如果可以进行隐球菌抗原检测（侧流免疫层析法或乳胶凝集试验）并快速获取结果（小于24小时），腰椎穿刺联合CSF快速检测隐球菌抗原是首选的诊断方法。
（强推荐；成人和青少年-中等质量证据，儿童-低质量证据）。
注：对于首次发作疾病的患者，有条件的话，推荐在隐球菌抗原检测的同时进行CSF隐球菌培养。
（2）如果无法进行隐球菌抗原检测和/或无法快速获取结果，则首选腰椎穿刺和CSF印度墨汁染色试验进行诊断。
（强推荐；成人和青少年-中等质量证据，儿童-低质量证据）3.对于无法立即进行腰椎穿刺或当腰椎穿刺是临床禁忌证的患者b：（1）如果可以进行隐球菌抗原检测并快速获取结果（小于24小时），则快速血清、血浆或全血隐球菌抗原检测是首选的诊断方法。
（强推荐；成人和青少年-中等质量证据，儿童-低质量证据）（2）如果无法进行隐球菌抗原检测和/或不能确保快速获得结果，则应立即转诊进行进一步检查和治疗。
（强推荐；成人和青少年-中等质量证据，儿童-低质量证据）。
隐球菌感染的主要类型与治疗
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。
隐球菌性脑炎的治疗及护理
✓ 建立良好的护患关系：与患者保 持良好的沟通，了解患者的心理 需求，给予关心和支持
✓ 提供心理支持：鼓励患者积极 面对疾病，增强战胜疾病的信 心
✓ 减轻心理压力：帮助患者减轻 心理压力，避免焦虑、抑郁等 负面情绪
12 34
✓ 提供心理辅导：对于心理问题较 为严重的患者，可以提供专业的 心理辅导服务，帮助患者调整心 态，积极面对治疗和康复过程
04
康复评估：定期评估康复效果，调整康复计划
护理措施
生活护理
01
保持良好的生活习惯，如 按时作息、饮食规律等
03
保持个人卫生，勤洗手、 洗澡、刷牙等
05
定期进行健康检查，及时 发现并治疗隐球菌感染
02
保持室内空气流通，避免 长时间待在密闭空间
04
避免接触宠物、鸟类等可 能携带隐球菌的动物
心理护理
隐球菌性脑炎的治疗及护理
x
目录
01. 隐球菌性脑炎概述 02. 治疗方法 03. 护理措施
隐球菌性脑炎概述
病因
隐球菌感染： 隐球菌是一 种真菌，可
引起脑炎
免疫功能低 下：患者免 疫功能低下， 易感染隐球
菌
环境因素： 潮湿、阴暗 的环境有利 于隐球菌生
长
接触史：与 隐球菌感染 者或携带者 接触，可能
Hale Waihona Puke 饮食护理饮食原则：清淡、易消化、营 养丰富
食物选择：蔬菜、水果、瘦肉、 蛋类、豆类等
避免刺激性食物：辛辣、油腻、 生冷等
饮食规律：定时定量，避免暴 饮暴食
水分补充：保证充足的水分摄 入，预防脱水
营养补充：适当补充维生素、 矿物质等营养素，增强免疫力
谢谢
05
诊断标准：结合临床症状、影像 学检查、实验室检查和病原学检 查结果进行综合诊断
隐球菌的诊治进展
隐球菌病的并发症 IRIS（免疫重建炎症综合征）
学者观察到,部分HIV/AIDS患者在开始HAART后,
当患者免疫功能得到部分恢复时,其机会性感染
症状反而加重,甚至死亡。把这种现象称为免疫
重建炎症综合征immune reconstitution inflammatory syndrome,IRIS。
隐球菌病诊治进展
指南指出了治疗的三个关键原则：
1、脑膜脑炎采用杀菌剂诱导治疗，如多烯
类联合氟胞嘧啶，随后氟康唑维持治疗；
2、颅内压升高和（或）IRIS（免疫重建炎
症综合征）的早期治疗至关重要；
3、肾功能损害的患者可以使用两性霉素B含
脂制剂。
HIV感染患者隐球菌脑膜脑炎的抗真菌治疗
器官移植受者隐球菌脑膜脑炎治疗方案
隐球菌肺疾病的治疗
氟康唑400mg/d至少6-12月
替代：伊曲康唑400mg/d 免疫受损患者
诱导：两性霉素B0.5-0.7mg/d/kg或 脂质体±氟胞嘧啶2-4周 巩固：氟康唑400mg/d，8-10周，氟 康唑200mg/d至少6-12月
免疫正常患者
无症状或轻症：氟康唑400mg/d612月
NIAID指南（变态反应性和感染性疾病பைடு நூலகம்会）
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，200-400mg/d，共3-6个月 泌尿系、皮肤感染者200-400mg/d，共3-6个月。 不能耐受氟康唑，伊曲康唑 200-400mg/d，共6-12个月是一种可接 受的选择方案。 对于健康宿主的CNS感染，标准的方案是采用两性霉素B和5-FC联合 治疗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6-12个月。 对于HIV阴性的免疫抑制患者，不管其感染部位，均需按CNS感染治 疗。 HIV感染的隐球菌病例均需治疗。需终生维持抗真菌治疗。非CNS感 染的严重病例，可选择氟康唑400mg/d和5-FC（100-150mg/kg/d)的 联合治疗10周，然后氟康唑维持治疗。
隐球菌病处理临床实践指南 2010年美国感染病学会更新
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。
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隐球菌病治疗实用指南
为了帮助医师在治疗隐球菌病时正确选用抗真菌药，制定合理的给药方案。
美国国立变态反应和感染病研究院真菌病研究组(NIAID MSG)组织有关专家根据循证医学的原则制订了隐球菌病的处理指南。
该指南提出的建议适用于绝大多数隐球菌病患者。
虽然该指南系2000年制订，且所依据的临床证据均为国外资料，但由于该指南是在大量临床证据基础上制订对我们当前的临床实践仍具有重要的指导意义。
现将其主要内容编译供临床参考。
该指南的全文见Clinical InfectiousDisease 2000，30：710—718，并将于2008年更新。
本指南推荐强度和证据力度分级系统同其他美国感染病学会(IDSA)指南(附件)。
在过去的20余年，随着各类抗真菌药物的不断问世，新型隐球菌病的治疗发生了很大变化。
新型隐球菌病治疗方案的选择，主要取决于罹患部位和患者的免疫功能状况。
一、非HIV感染者隐球菌病的治疗指南
(一)肺部及非中枢神经系统隐球菌病治疗目的为治愈感染并预防感染播散至中枢神经系统。
所有免疫缺陷者均应接受治疗，因易发生播散性感染。
有症状的患者均需治疗。
虽然所有培养阳性的无症状患者应接受治疗，但许多免疫功能正常的痰培养阳性患者即使不治疗亦预后良好。
肺外及中枢神经系统以外的感染(如骨骼或皮肤)需要特殊的抗真菌治疗。
持续性或难治性肺部或骨骼感染需要手术治疗。
所有患者需作腰穿以除外中枢神经系统感染。
肺部隐球菌病的治疗见表1。
早期适当治疗可降低病死率，防止中枢感染发生。
对于实体器官移植患者，可以防止感染导致的移植失败。
治疗主要的不良反应为药物相关的毒性反应，以及药物相互作用。
(二)中枢神经系统隐球菌病治疗目的为治愈感染并预防中枢神经系统后遗症，如脑神经瘫痪、听力丧失和失明。
中枢神经系统隐球菌病的治疗见表1。
治疗2周后需随访脑脊液(CSF)检查，如果培养阳性，需要延长诱导期疗程。
氟康唑联合氟胞嘧啶作为初始治疗疗效不佳，即使是低危患者。
免疫抑制患者，如实体器官移植患者，需要延长疗程。
有严重肾脏疾病的患者，诱导治疗时可用两性霉素B含脂制剂替代两性霉素B(C Ⅲ)，无法耐受氟康唑的患者，可选伊曲康唑(200 mg，每日2次)替代(CⅢ)。
大部分病变抗真菌治疗有效，>3 cm的中枢神经系统病变需要手术。
所有的患者都应密切监测颅内压。
治疗决策不应常规或仅仅依据血清或CSF隐球菌抗原滴度
(A工)。
鞘内或脑室内注射两性霉素B仅用于全身抗真菌治疗无效的患者，由于毒性大，给药困难，仅用于补救治疗(CⅡ)。
早期适当治疗可降低病死率。
治疗不良反应主要为药物相关的反应。
二、HIV感染者隐球菌病的治疗
(一)AIDS相关隐球菌肺炎对患肺炎的HIV患者(CD4+T淋巴细胞计数<200／mL)，应进行痰真菌培养、血真菌培养、血清隐球菌抗原检测。
如果结果阳性，需进行CSF检查，以除外隐球菌脑膜炎。
治疗目的为治愈感染并预防感染播散至中枢神经系统。
所有的HIV感染者均需治疗。
如为肺部或骨骼持续性或难治性隐球菌感染，需手术治疗。
如患者为隐球菌血症、或隐球菌抗原滴度阳性(>1：8)，即使无临床症状，亦应予以治疗。
HIV感染者肺部隐球菌病的治疗见表2。
早期适当治疗可降低病死率，防止中枢神经系统感染发生。
(二)AIDS相关隐球菌脑膜炎
1．诱导治疗：治疗目的为清除感染和控制颅内高压。
然而，HIV 感染者常不能清除感染，治疗目标则为长期控制感染和改善症状和体征。
AIDS相关隐球菌脑膜炎的治疗方案见表2。
对于全身治疗失败的难治性感染，可鞘内或脑室内注射两性霉素B。
由于毒性大给药困难，故仅用于补救治疗(CⅡ)。
对部分病例，可测定新型隐球菌的药敏试验并
对前后结果进行比较，用于指导治疗，尤其是复发或难治性患者。
但并不常规推荐(CⅢ)。
早期适当治疗可降低与该病相关的病死率。
2．维持治疗：AIDS患者隐球菌脑膜炎治疗有效后，如果不维持治疗，极易复发。
维持治疗之根本目的为预防复发。
预防隐球菌脑膜炎复发的两个基本要点为：①HAART治疗有效控制HIV病毒复制；② 长期抗真菌治疗预防复发。
维持治疗的方案见表2。
预防复发可以降低该病相关病死率，延缓AIDS病发展进程。
氟康唑耐受良好。
约半数以上患者存在颅内高压。
控制颅内压力，可降低病死率。
控制颅内高压的方法有间歇性腰穿引流CSF、CSF持续外引流或脑室腹腔分流术，见表3 。
药物治疗包括皮质类固醇、乙酰唑胺或甘露醇，但疗效不肯定。