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美国感染性疾病协会隐球菌治疗指南(2010)[1].jsp

I D S A G U I D E L I N E S

Clinical Practice Guidelines for the Management

of Cryptococcal Disease:2010Update by the Infectious Diseases Society of America

John R.Perfect,1William E.Dismukes,2Francoise Dromer,11David L.Goldman,3John R.Graybill,4

Richard J.Hamill,5Thomas S.Harrison,14Robert https://www.doczj.com/doc/0e11525180.html,rsen,6,7Olivier Lortholary,11,12Minh-Hong Nguyen,8

Peter G.Pappas,2William G.Powderly,13Nina Singh,10Jack D.Sobel,10and Tania C.Sorrell15

1Division 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,Ho?pital 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,Australia

Cryptococcosis is a global invasive mycosis associated with signi?cant 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 immunode?ciency virus(HIV)–infected individuals,(2)organ transplant recipients,and(3)non–HIV-

infected and nontransplant hosts.There are speci?c 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 in?ammatory syndrome(IRIS),drug resistance,and crypto-coccomas.Three key management principles have been articulated:(1)induction therapy for meningoencephalitis

using fungicidal regimens,such as a polyene and?ucytosine,followed by suppressive regimens using?uconazole;(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 de?nitive studies.However,if the diagnosis is made

early,if clinicians adhere to the basic principles of these guidelines,and if the underlying disease is controlled,then cryptococcosis can be managed successfully in the vast majority of patients.

EXECUTIVE SUMMARY

In2000,the Infectious Diseases Society of America (IDSA)?rst published“Practice Guidelines for the Management of Cryptococcal Disease”[1].In this up-dated version of the guidelines,a group of medical

Received12October2009;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@https://www.doczj.com/doc/0e11525180.html,).

Clinical Infectious Diseases2010;50:000–000

DOI:10.1086/649858

mycology experts have approached cryptococcal man-

agement using the framework of key clinical questions.

The goal is to merge recent and established evidence-

based clinical data along with shared expert clinical

opinions and insights to assist clinicians in the man-

agement of infection with this worldwide,highly rec-

ognizable invasive fungal pathogen.The foundation for

the successful management of cryptococcal disease was

It is important to realize that guidelines cannot always account for individual

variation among patients.They are not intended to supplant physician judgment

with respect to particular patients or special clinical situations.The Infectious

Diseases Society of America considers adherence to these guidelines to be

voluntary,with the ultimate determination regarding their application to be made

by the physician in the light of each patient’s individual circumstances.

Guidelines for Management of Cryptococcosis?CID2010:50(1February)?000

carefully detailed in the previous IDSA guidelines published in 2000.In fact,by following speci?c 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 speci?cally addressed[5].Similarly,the human immunode?ciency 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 speci?c 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-?iximab,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 speci?c 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 immunode?ciency and immune reconstitution,respectively,can become a complex clinical sce-nario during management of cryptococcal meningoencepha-litis.Furthermore,speci?c complications,such as immune re-constitution in?ammatory 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 MENINGOENCEPHALITIS

The strength of the recommendations and the quality of evi-dence are described in Table1.

HIV-Infected Individuals

Primary therapy:induction and consolidation

1.Amphotericin B(AmB)deoxycholate(AmBd;0.7–1.0 mg/kg per day intravenously[IV])plus?ucytosine(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 by?ucon-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(3–4

000?CID2010:50(1February)?Perfect et al

Table1.Strength of Recommendation and Quality of Evidence

Assessment Type of evidence

Strength of recommendation

Grade A Good evidence to support a recommendation for or against use Grade B Moderate evidence to support a recommendation for or against use Grade C Poor evidence to support a recommendation

Quality of evidence

Level I Evidence from at least1properly designed randomized,controlled

trial

Level 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 experiments

Level III Evidence from opinions of respected authorities,based on clinical

experience,descriptive studies,or reports of expert committees NOTE.Adapted from the Canadian Task Force on the Periodic Health Examination Health Canada[23].Reproduced with the permission of the Minister of Public Health Works and Government Services Canada,2009.

mg/kg per day IV),or ABLC(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)plus?uconazole(800mg per day orally)for2weeks,followed by?uconazole(800mg per day orally)for a minimum of8weeks(B-I).

4.Fluconazole(у800mg per day orally;1200mg per day is favored)plus?ucytosine(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 if?ucona-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 therapy

7.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 with?ucona-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 Recipients

14.For central nervous system(CNS)disease,liposomal AmB(3–4mg/kg per day IV)or ABLC(5mg/kg per day IV) plus?ucytosine(100mg/kg per day in4divided doses)for at least2weeks for the induction regimen,followed by?uconazole (400–800mg[6–12mg/kg]per day orally)for8weeks and by ?uconazole(200–400mg per day orally)for6–12months(B-II).If induction therapy does not include?ucytosine,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,?uconazole (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-moderate

Guidelines for Management of Cryptococcosis?CID2010:50(1February)?000

symptoms without diffuse pulmonary in?ltrates,use?ucona-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 dose?rst(B-III).

20.Because of the risk of nephrotoxicity,AmBd should be used with caution in transplant recipients and is not recom-mended as?rst-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 Hosts

21.AmBd(0.7–1.0mg/kg per day IV)plus?ucytosine(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 cerebrospinal?uid(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 with?uconazole(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.If?ucytosine 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 plus?u-cytosine for only2weeks,followed by consolidation with?u-conazole(800mg[12mg/kg]per day orally)for8weeks(B-III).

25.After induction and consolidation therapy,use main-tenance therapy with?uconazole(200mg[3mg/kg]per day orally)for6–12months(B-III).

Management of Complications in Patients with Cryptococcosis Persistence

26.Check that adequate measures have been taken to im-prove immune status(eg,decrease immunosuppressants and introduce HAART)and optimize management of increased in-tracranial pressure(B-III).

27.Reinstitute induction phase of primary therapy for longer course(4–10weeks)(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,consider?uconazole (у800mg per day orally)plus?ucytosine(100mg/kg per day orally in4divided doses)(B-III).

30.If patient is?ucytosine intolerant,consider AmBd(0.7 mg/kg per day IV)plus?uconazole(800mg[12mg/kg]per day orally)(B-III).

https://www.doczj.com/doc/0e11525180.html,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 for?uconazole orу32 m g/mL for?ucytosine 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 speci?c antifungal drug (B-III).

Relapse

35.Restart induction phase therapy(see“Persistence,”above)(B-III).

36.Determine susceptibility of the relapse isolate(see“Per-sistence,”above)(B-III).

Elevated CSF pressure

38.Identify CSF pressure at baseline.A prompt baseline

000?CID2010:50(1February)?Perfect et al

lumbar puncture is strongly encouraged,but in the presence of focal neurologic signs or impaired mentation,it should be delayed pending the results of a computed tomography(CT) or magnetic resonance imaging(MRI)scan(B-II).

39.If the CSF pressure 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 pressure

42.Mannitol has no proven bene?t and is not routinely recommended(A-III).

43.Acetazolamide and corticosteroids(unless part of IRIS treatment)should be avoided to control increased intracranial pressure(A-II).

Recurrence of signs and symptoms

44.For recurrence of signs and symptoms,reinstitute drain-age procedures(B-II).

45.For patients with recurrence,measurement of opening pressure with lumbar puncture after a2-week course of treat-ment may be useful in evaluation of persistent or new CNS symptoms(B-III).

Long-term elevated intracranial pressure

46.If the CSF pressure remains elevated and if symptoms persist for an extended period of time in spite of frequent lumbar drainage,consider insertion of a VP shunt(A-II). IRIS

47.No need to alter direct antifungal therapy(B-III).

48.No de?nitive speci?c 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 in?ammation 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-in?ammatory drugs and thalidomide have been used but with too little experience to make a rec-ommendation(C-III).

Cerebral cyptococcomas

51.Induction therapy with AmBd(0.7–1mg/kg per day IV), liposomal AmB(3–4mg/kg per day IV),or ABLC(5mg/kg per day IV)plus?ucytosine(100mg/kg per day orally in4 divided doses)for at least6weeks(B-III).

52.Consolidation and maintenance therapy with?ucona-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).

Treatment Strategies for Patients with Nonmeningeal Cryptococcosis

Pulmonary(immunosuppressed)

54.In immunosuppressed patients with pulmonary cryp-tococcosis,meningitis should be ruled out by lumbar puncture; the presence of CNS disease alters the dose and duration of induction therapy and the need for intracranial pressure mon-itoring(B-II).

55.Pneumonia associated with CNS or documented dissem-ination and/or severe pneumonia(acute respiratory distress syndrome[ARDS])is treated like CNS disease(B-III).

56.Corticosteroid treatment may be considered if ARDS is present in the context of IRIS(B-III).

57.For mild-to-moderate symptoms,absence of diffuse pul-monary in?ltrates,absence of severe immunosuppression,and negative results of a diagnostic evaluation for dissemination, use?uconazole(400mg[6mg/kg]per day orally)for6–12 months(B-III).

58.In HIV-infected patients who are receiving HAART with

a CD4cell count1100cells/m L and a cryptococcal antigen titer that isр1:512and/or not increasing,consider stopping main-tenance?uconazole 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)?000

Pulmonary(nonimmunosuppressed)

60.For mild-to-moderate symptoms,administer?ucona-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 if?uconazole 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 in?ltrate,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 in?ammatory syndrome re-sponse may require corticosteroid treatment(B-III). Nonmeningeal,nonpulmonary cryptococcosis

66.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,consider?uconazole(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 cryptococcosis

68.For disseminated and CNS disease,use AmBd or LFAmB,with or without?ucytosine(B-II).Flucytosine is a category C drug for pregnancy,and therefore,its use must be considered in relationship to bene?t versus risk.

69.Start?uconazole(pregnancy category C)after delivery; avoid?uconazole exposure during the?rst trimester;and dur-ing the last2trimesters,judge the use of?uconazole 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 administer?uconazole after delivery (B-III).

71.Watch for IRIS in the postpartum period(B-III).Children with cryptococcosis

72.Induction and consolidation therapy for CNS and dis-seminated disease is AmBd(1mg/kg per day IV)plus?ucy-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 by?ucona-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 is?uconazole(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,use?uconazole(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 where?ucytosine is not available,induction therapy is AmBd(1mg/kg per day IV)for2weeks or AmBd(0.7mg/kg per day IV)plus?ucona-zole(800mg per day orally)for2weeks,followed by consol-idation therapy with?uconazole(800mg per day orally)for 8weeks(A-I).

77.Maintenance therapy is?uconazole(200–400mg per day orally)until immune reconstitution(A-I).

78.With CNS and/or disseminated disease where polyene is not available,induction therapy is?uconazole(у800mg per day orally;1200mg per day is favored)for at least10weeks or until CSF culture results are negative,followed by mainte-nance therapy with?uconazole(200–400mg per day orally) (B-II).

79.With CNS and/or disseminated disease when polyene is not available but?ucytosine is available,induction therapy is ?uconazole(у800mg per day orally;1200mg per day is fa-vored)plus?ucytosine(100mg/kg per day orally)for2–10 weeks,followed by maintenance therapy with?uconazole(200–400mg per day orally)(B-II).

80.With use of primary?uconazole 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 infection

82.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 due

000?CID2010:50(1February)?Perfect et al

to C.gattii than that due to C.neoformans,but the management principles are the same(B-II).

84.Pulmonary cryptococcosis(same as C.neoformans):sin-gle,small cryptococcoma suggests?uconazole(400mg per day orally);for very large and multiple cryptococcomas,consider a combination of AmBd and?ucytosine therapy for4–6weeks, followed by?uconazole for6–18months,depending on whether surgery was performed(B-III).

85.Consider surgery if there is compression of vital struc-tures,failure to reduce size of cryptococcoma after4weeks of therapy,or failure to thrive(B-III).

86.Recombinant IFN-g use remains uncertain(C-III).

INTRODUCTION

These recommendations represent an excellent starting point for the development of a management strategy for cryptococcal disease and are organized under4major headings:“Treatment of Meningoencephalitis,”“Complications during Treatment,”“Treatment of Nonmeningeal Cryptococcosis,”and“Crypto-coccosis in Special Clinical Situations.”In“Treatment of Cryp-tococcal Meningoencephalitis,”the recommendations are di-vided into3speci?c risk groups:(1)HIV-infected individuals, (2)transplant recipients,and(3)non–HIV-infected and non-transplant hosts.For the section on complications and their management in cryptococcosis,4areas were examined:(1)per-sistence and relapse,(2)elevated intracranial pressure,(3)IRIS, and(4)mass lesions(cryptococcomas).For further recom-mendations regarding non-CNS infections,sites were separated into pulmonary(immunosuppressed vs nonimmunosuppres-sed host)and extrapulmonary sites.Finally,for management of cryptococcosis in4special clinical situations,recommen-dations were made for(1)pregnant women,(2)children,(3) resource-limited environments,and(4)C.gattii infections. PRACTICE GUIDELINES

“Practice guidelines are systematically developed statements to assist practitioners and patients in making decisions about ap-propriate health care for speci?c clinical circumstances”[24]. Attributes of good guidelines include validity,reliability,re-producibility,clinical applicability,clinical?exibility,clarity, multidisciplinary process,review of evidence,and documen-tation[24].

UPDATE METHODOLOGY

Panel composition.The IDSA Standards and Practice Guide-lines Committee(SPGC)convened experts in the management of patients with cryptococcal disease.

Literature review and analysis.For the2010update,the Expert Panel completed the review and analysis of data pub-lished https://www.doczj.com/doc/0e11525180.html,puterized literature searches of the PubMed database were performed.The searches of the English-language literature from1999through2009used the terms,“cryptococcal,”“cryptococcosis,”“Cryptococcus,”“meningeal,”“pulmonary,”“pregnancy,”“children,”“cerebrospinal?uid,”“intracranial,”“cerebral,”“immunosuppressed,”“HIV,”“trans-plant,”and“Immune Reconstitution In?ammatory Syndrome”and focused on human studies.Data published up to December 2009were considered during?nal preparation of the manu-script.Relevant studies included randomized clinical trials, open-label clinical trials,retrospective case series,cohort stud-ies,case reports,reports of in vitro studies,and animal model experiments.Abstracts from international meetings were also included.Because of the limited nature of the data in many areas,the Expert Panel made a decision to also retain high-quality reviews or background papers.Expert Panel members were assigned sections of the guideline and reviewed the rel-evant literature.

Limitations in the literature.Review of the literature re-vealed a paucity of clinical trials evaluating the newer agents for treatment of cryptococcal disease.Most data came from cohort studies;case series;small,nonrandomized clinical trials; or case reports.

Process overview.In evaluating the evidence regarding the management of cryptococcal disease,the Expert Panel followed a process used in the development of other IDSA guidelines. This included a systematic weighting of the quality of the evi-dence and the grade of recommendation(Table1)[23]. Consensus development based on evidence.The Expert Panel met on3occasions via teleconference and once in person to complete the work of the guideline.The purpose of the teleconferences was to discuss the questions to be addressed, make writing assignments,and discuss recommendations.All members of the Expert Panel participated in the preparation and review of the draft guideline.Feedback from external peer reviews was obtained.The guidelines were reviewed and ap-proved by the SPGC and the Board of Directors prior to dis-semination.

Guidelines and con?icts of interest.All members of the Expert Panel complied with the IDSA policy on con?icts of interest,which requires disclosure of any?nancial or other interest that might be construed as constituting an actual,po-tential,or apparent con?ict.Members of the Expert Panel were provided the IDSA’s con?ict of interest disclosure statement and were asked to identify ties to companies developing prod-ucts that might be affected by promulgation of the guideline. Information was requested regarding employment,consultan-cies,stock ownership,honoraria,research funding,expert tes-timony,and membership on company advisory committees. The Expert Panel made decisions on a case-by-case basis as to whether an individual’s role should be limited as a result of a

Guidelines for Management of Cryptococcosis?CID2010:50(1February)?000

000?CID 2010:50(1February)?Perfect et al

Table 2.Antifungal Treatment Recommendations for Cryptococcal Meningoencephalitis in Human Immunode?ciency Virus–Infected Individuals

Regimen

Duration Evidence Induction therapy

AmBd (0.7–1.0mg/kg per day)plus ?ucytosine (100mg/kg per day)a

2weeks A-I Liposomal AmB (3–4mg/kg per day)or ABLC (5mg/kg per day,with renal function concerns)plus ?ucytosine (100mg/kg per day)a 2weeks B-II AmBd (0.7–1.0mg/kg per day)or liposomal AmB (3–4mg/kg per day)or ABLC (5mg/kg per day,for ?ucytosine-intolerant patients)4–6weeks

B-II Alternatives for induction therapy b

AmBd plus ?uconazole

…B-I Fluconazole plus ?ucytosine …B-II Fluconazole …B-II Itraconazole

…C-II Consolidation therapy:?uconazole (400mg per day)8weeks A-I Maintenance therapy:?uconazole (200mg per day)a

у1year

A-I Alternatives for maintenance therapy b Itraconazole (400mg per day)d

у1year c

C-I AmBd (1mg/kg per week)d

у1year c

C-I

NOTE.ABLC,amphotericin B lipid complex;AmB,amphotericin B;AmBd,amphotericin B deoxycholate;HAART ,highly active antiretroviral therapy.

Begin HAART 2–10weeks after the start of initial antifungal treatment.

b In unique clinical situations in which primary recommendations are not available,consideration of alternative regimens may be made—but not encouraged—as substitutes.See text for dosages.c

With successful introduction of HAART ,a CD4cell count у100cells/m L,and low or nondetectable viral load for у3months with minimum of 1year of antifungal therapy.d

Inferior to the primary recommendation.

con?ict.Potential con?icts are listed in the Acknowledgements section.

Revision dates.At annual intervals,the Expert Panel Chair,the SPGC liaison advisor,and the Chair of the SPGC will de-termine the need for revisions to the guideline on the basis of an examination of current literature.If necessary,the entire Expert Panel will be reconvened to discuss potential changes,and when appropriate,the Expert Panel will recommend re-vision of the guideline to the SPGC and the IDSA Board for review and approval.

GUIDELINE RECOMMENDATIONS FOR THE MANAGEMENT OF CRYPTOCOCCAL DISEASE The guideline recommendations for cryptococcal meningo-encephalitis management are summarized in Tables 2–5.I.WHA T ARE THE MOST APPROPRIATE TREA TMENT STRATEGIES IN THE PATIENT WITH CRYPTOCOCCAL MENINGOENCEPHALITIS?

HIV-Infected Individuals

The treatment of cryptococcal meningoencephalitis in patients with HIV coinfection has received substantial attention over the past 2decades.Its principles are based on a high burden

of yeasts at the site of infection and a severely depressed im-mune system (ie,profound CD4lymphocytopenia).With the recent advances of HAART,immune enhancement during treat-ment of cryptococcosis can occur.These therapeutic advances may be followed by both positive consequences (goal of com-plete yeast elimination from host and limited therapy)and negative consequences (IRIS).Furthermore,the treatment of meningoencephalitis in HIV-infected individuals formalized the concept of induction,consolidation (clearance),and mainte-nance (suppression)phases in management of invasive mycoses in a severely immunosuppressed host.

Primary therapy:induction and consolidation

1.AmBd (0.7–1.0mg/kg per day IV)plus ?ucytosine (100mg/kg per day orally in 4divided doses;IV formulations may be used in severe cases and in those without oral intake where the preparation is available)for at least 2weeks,followed by ?uconazole (400mg [6mg/kg]per day orally)for a minimum of 8weeks (A-I).LFAmB,including liposomal AmB (3–4mg/kg per day IV)and ABLC (5mg/kg per day IV)for at least 2weeks,could be substituted for AmBd among patients with or predisposed to renal dysfunction (B-II).

Table3.Antifungal Treatment Recommendations for Cryptococcal Meningoencephalitis in Transplant Recipients

Regimen Duration Evidence Induction therapy:a liposomal AmB(3–4mg/kg per day)or

ABLC(5mg/kg per day)plus?ucytosine(100mg/kg per day)2weeks B-III Alternatives for induction therapy

Liposomal AmB(6mg/kg per day)or ABLC(5mg/kg per day)4–6weeks B-III AmBd(0.7mg/kg per day)b4–6weeks B-III Consolidation therapy:?uconazole(400–800mg per day)8weeks B-III Maintenance therapy:?uconazole(200–400mg per day)6months to1year B-III

NOTE.ABLC,amphotericin B lipid complex;AmB,amphotericin B;AmBd,amphotericin B deoxycholate.

a Immunosuppressive management may require sequential or step-wise reductions.

b Many transplant recipients have been successfully treated with AmBd;however,issues of renal dysfunction with calcineurin inhibitors are important and the effective dose is imprecise.

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(3–4 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)plus?uconazole(800mg per day orally)for2weeks,followed by?uconazole(800mg per day orally)for a minimum of8weeks(B-I).

4.Fluconazole(у800mg per day orally;1200mg per day is favored)plus?ucytosine(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 if?ucona-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. Evidence summary.Cryptococcal disease in HIV-infected pa-tients always warrants therapy.Current recommendations for drug(s)of choice are essentially the same as in the previous IDSA Guidelines.Ideally,antifungal therapy should rapidly and consistently sterilize the CNS and other infected sites,and the principle of rapid fungicidal activity should be the primary focus of any induction strategy[25].A CSF culture at2weeks that is sterile after the start of therapy should provide an ap-preciation of a successful fungicidal induction regimen and has been linked to favorable outcome[27].For example,a large clinical trial compared AmBd(0.4–0.5mg/kg per day)with ?uconazole(200mg per day)for the treatment of AIDS-as-sociated cryptococcal meningoencephalitis[26],demonstrated disappointing clinical outcomes(success rates of40%of63 AmBd recipients and34%of131?uconazole recipients),and emphasized the need for a more effective primary therapy for AIDS-associated cryptococcal meningoencephalitis.This study also demonstrated higher early mortality and reduced ability to rapidly convert CSF culture results to negative with?ucona-zole alone.

In a subsequent trial for the treatment of AIDS-associated cryptococcal meningoencephalitis,a higher dosage of AmBd (0.7mg/kg per day)was used,along with a lower dosage of ?ucytosine(100mg/kg per day)[27]than earlier antifungal combination studies involving HIV-uninfected patients[28, 29].After2weeks of therapy,CSF culture results were negative 9%more often in patients receiving AmBd plus?ucytosine than in patients treated with AmBd alone().The im-

P p.06

pact of the combination on mycological outcome was further demonstrated in the multivariate analysis.Three hundred six patients were then eligible for the consolidation phase of this study:151patients received?uconazole,and155received itra-conazole.After8weeks of consolidation therapy,CSF culture results were negative in72%of the patients receiving?ucona-zole and in60%of the patients receiving itraconazole.This treatment trial de?ned our preferred regimen of AmBd and ?ucytosine followed by?uconazole,as noted in the previous IDSA guidelines,and likely re?ects differences in the phar-macokinetics,bioavailability,and drug interactions between the 2azoles.

Additional supportive evidence for the ef?cacy of AmBd plus ?ucytosine for induction therapy is provided by a uniquely designed randomized trial that evaluated4different antifungal therapies.Sixty-four patients with AIDS in Thailand with a?rst episode of cryptococcal meningoencephalitis were randomized to receive primary therapy with AmBd(0.7mg/kg per day), AmBd(0.7mg/kg per day)plus?ucytosine(100mg/kg per day),AmBd(0.7mg/kg per day)plus?uconazole(400mg per day),or a triple-drug regimen consisting of AmBd,?ucytosine, and?uconazole at the dosages above[21].The primary end

Guidelines for Management of Cryptococcosis?CID2010:50(1February)?000

Table4.Antifungal Treatment Recommendations for Cryptococcal Meningoencephalitis in Non–Human Immunode?ciency Virus–Infected and Nontransplant Patients

Regimen Duration Evidence Induction therapy

AmBd(0.7–1.0mg/kg per day)plus?ucytosine(100mg/kg per day)у4weeks a,b B-II AmBd(0.7–1.0mg/kg per day)cу6weeks a,b B-II Liposomal AmB(3–4mg/kg per day)or ABLC(5mg/kg per day)combined with?ucytosine,if possible dу4weeks a,b B-III AmBd(0.7mg/kg per day)plus?ucytosine(100mg/kg per day)e2weeks B-II Consolidation therapy:?uconazole(400–800mg per day)f8weeks B-III Maintenance therapy:?uconazole(200mg per day)b6–12months B-III

NOTE.ABLC,amphotericin B lipid complex;AmB,amphotericin B;AmBd,amphotericin B deoxycholate.

a Four weeks are reserved for patients with meningitis who have no neurological complications,who have no signi?cant underlying diseases or immu-nosuppression,and for whom the cerebrospinal?uid culture performed at the end of2weeks of treatment does not yield viable yeasts;during the second 2weeks,lipid formulations of AmB may be substituted for AmBd.

b Fluconazole is given at200mg per day to prevent relapse after induction therapy,and consolidation therapy is recommended.

c For?ucytosine-intolerant patients.

d For AmBd-intolerant patients.

e For patients who have a low risk o

f therapeutic failure.Low risk is de?ned as an early diagnosis by history,no uncontrolled underlyin

g condition or severe immunocompromised state,and an excellent clinical response to initial2-week antifungal combination course.

f A higher dosage of?uconazole(800m

g per day)is recommended if the2-week induction regimen was used and if there is normal renal function.

point of this study was the rate of reduction in CSF cryptococcal colony-forming units(CFUs)from serial quantitative CSF cul-tures obtained on days3,7,and14of treatment.AmBd plus ?ucytosine was the most rapidly fungicidal regimen.Clearance of cryptococci from the CSF was exponential and signi?cantly faster with AmBd and?ucytosine than with AmBd alone,AmBd plus?uconazole,and triple-drug therapy.Logistic regression modeling in this study showed that both cerebral dysfunction and high counts of C.neoformans per milliliter of CSF at base-line were independently associated with early death.Finally, results from a recent cohort study with208HIV-positive and HIV-negative patients with meningoencephalitis clearly em-phasized the success of therapy with AmBd plus?ucytosine for 14days over any other induction regimen in persons with high–fungal burden disease and abnormal neurological features, showing a26%failure rate in the combination group versus a 56%failure rate for other treatments().Less than14

P!.001

days of?ucytosine treatment was also independently associated with treatment failure at3months in168cases of cryptococ-cosis[3].The use of different dosages of AmBd(0.7vs1.0mg/ kg per day)plus?ucytosine has recently been compared,and the higher dosage was more fungicidal and had manageable toxicity,although no difference in2-and10-week mortality was observed[30].

This primary induction/consolidation therapeutic regimen for cryptococcal meningoencephalitis may need to be adjusted for individual patients.For example,continuation of combi-nation induction therapy beyond2weeks may be considered if(1)a patient remains comatose;(2)the patient is clinically deteriorating;(3)the patient has not improved,with persisting elevated,symptomatic intracranial pressure;and/or(4)the re-sults of CSF culture obtained after2weeks of induction therapy is anticipated to remain positive.These patients may require additional weeks(eg,1–6weeks)of the induction phase of treatment.If the CSF culture after2weeks of treatment is reported to be positive after discontinuation of the induction regimen,reinstitution of at least another2-week combination induction course might be considered,depending on the clin-ical assessment of the patient.In cases in which?uconazole cannot be given as consolidation therapy because of patient intolerance or drug toxicity,itraconazole is an acceptable,albeit less effective,azole alternative and requires careful serum drug level monitoring.LFAmB may be substituted for AmBd,es-pecially if there is concern regarding nephrotoxicity[31–34]. There are still scant reports of LFAmB in combination with ?ucytosine for treatment of cryptococcal meningoencephalitis, but clinical experience strongly suggests that combination ther-apy with LFAmB is effective.The optimal dosage of LFAmB remains uncertain.In a comparative study of100patients treated with liposomal AmB versus AmBd,the2-week myco-logical success of liposomal AmB dosages between3mg/kg per day(64%)and6mg/kg per day(54%)was similar.The clinical response was75%(3mg/kg per day)and66%(6mg/kg per day)and showed no difference;at10weeks,there was no signi?cant difference in outcome with the2dosages[34].In smaller studies,liposomal AmB at4mg/kg per day was more fungicidal than AmBd at0.7mg/kg per day[7,20].

Other primary treatment regimens for AIDS-associated cryp-tococcal meningoencephalitis have been used but are consid-ered to be suboptimal alternatives to the induction/consoli-dation regimen described https://www.doczj.com/doc/0e11525180.html,bination therapy with ?uconazole and?ucytosine has been shown to be moderately effective as primary therapy[35,36],and use of?ucytosine improves induction therapy with?uconazole at dosages of800–

000?CID2010:50(1February)?Perfect et al

Table5.Antifungal Treatment Recommendations for Nonmeningeal Cryptococcosis

Patient group Initial antifungal regimen Duration Evidence Immunosuppressed patients and immunocompetent

patients with mild-to-moderate pulmonary

cryptococcosis Fluconazole(400mg per day)6–12months B-III Immunosuppressed patients a and immunocompetent pa-

tients with severe pulmonary cryptococcosis Same as CNS disease12months B-III Patients with nonmeningeal,nonpulmonary cryptococcosis

Patients with cryptococcemia Same as CNS disease12months B-III Patients for whom CNS disease has been ruled out

with no fungemia,with a single site of infection,and

with no immunosuppressive risk factors Fluconazole400mg per day6–12months B-III https://www.doczj.com/doc/0e11525180.html,S,central nervous system.

a Should directly rule out CNS disease with lumbar puncture.

2000mg per day[37].In a very recent study of143randomized patients,the combination use of AmBd(0.7mg/kg per day) plus?uconazole(800mg per day)demonstrated satisfactory outcomes,compared with AmBd alone,and may be a reason-able approach to therapy in settings where?ucytosine is not available or contraindicated[38].In this phase II study,the14-day end point of success in the AmBd alone,AmBd plus?ucon-azole(400mg[6mg/kg]per day),and AmBd plus?uconazole (800mg[12mg/kg]per day)treatment arms was41%,27%, and54%,respectively.If this combination is used,the higher ?uconazole dosage is recommended.Primary therapy with ei-ther?uconazole or itraconazole alone administered for10–12 weeks has also been evaluated in several trials,with variable responses[26,39–43].Results of large-scale experiences with ?uconazole in Africa have been very disappointing,and?ucon-azole monotherapy is not recommended as primary therapy if polyene therapy is available,not contraindicated,and can be monitored.If?uconazole is used alone,then higher daily doses should be administered.Notably,low success rates at800mg per day have been substantially improved with dosages of1200–2000mg per day[37].When using higher daily doses of?ucon-azole,divided doses are recommended to minimize gastroin-testinal toxicity,and it should be emphasized that the possible ?uconazole toxicity with these very high doses will need to be carefully monitored.Experiences with itraconazole,a triazole, which produces minimal concentrations of active drug in the CSF,as primary therapy for AIDS-associated cryptococcal me-ningoencephalitis have been very limited and demonstrated only moderate success[42,43].Generally,the panel recom-mends itraconazole only if other regimens have failed or are not available.If used,the suspension preparation should be preferred over the capsule formulation because of absorption issues,and drug levels must be monitored to ensure bioavail-ability.

Routine in vitro susceptibility testing of C.neoformans iso-lates during initiation of therapy is not recommended for2 principal reasons:(1)primary resistance to?rst-line antifungal drugs is not currently a signi?cant clinical problem,and(2)in vitro susceptibility testing(including methods and breakpoints) for Cryptococcus species against azoles and AmB is not well validated.For example,primary in vitro resistance to?ucy-tosine is low for C.neoformans[44],and?ucytosine resistance does not abrogate synergy or produce antagonism of the com-bination with speci?c in vivo methods[45,46].Furthermore, in vitro susceptibility testing has not yet been shown to predict early treatment outcome[47].However,there are reports of reduced ef?cacy when?uconazole MICs areу16m g/mL[48, 49].Secondary resistance to?uconazole is an emerging problem in some areas of the world—especially Africa,where prophy-lactic?uconazole is prescribed widely and where the drug is often used alone as primary therapy for cryptococcosis.In a small,unvalidated retrospective analysis of27patients with HIV-associated cryptococcal meningoencephalitis who received ?uconazole as initial therapy,32episodes of relapse were doc-umented[50].Seventy-six percent of the culture-positive re-lapse episodes were associated with isolates that had reduced susceptibility to?uconazole(MIC,у64m g/mL),raising con-cerns about the ef?cacy of?uconazole alone as initial therapy for this disease,particularly in those with prior azole exposure. Generally,in vitro susceptibility testing should be reserved for patients for whom primary therapy has failed,for those who experience relapse after apparently successful primary therapy, and for those who develop cryptococcosis and had recent ex-posure to an antifungal drug(eg,a patient receiving long-term prophylactic?uconazole therapy for oral/esophageal candidi-asis).Ideally,original C.neoformans and C.gattii isolates should be stored so that relapse isolates can be compared with previous isolate(s)for in vitro drug susceptibility.When possible,relapse isolate(s)from an area where resistance has been documented should undergo in vitro susceptibility testing.

Flucytosine treatment recipients should be carefully moni-tored for serious toxicities,such as cytopenia,with frequent complete blood cell counts.Serum?ucytosine levels should be measured after3–5days of therapy,with a target2-h postdose

Guidelines for Management of Cryptococcosis?CID2010:50(1February)?000

level of30–80m g/mL;?ucytosine levels1100m g/mL should be avoided.In areas where?ucytosine serum level measurements are unavailable or untimely,careful attention to hematologic parameters(white blood cell and platelet counts)and dose adjustments of?ucytosine according to creatinine clearance are critical(eg,50%of standard dose for creatinine clearance of 20–40mL/min,25%of standard dose for creatinine clearance of10–20mL/min);see speci?c adjustment schedules for severe renal dysfunction and dialysis[51].

Maintenance(suppressive)and prophylactic therapy. Maintenance therapy should be initiated after completion of primary therapy with an induction and consolidation regimen. Ideally,this is begun when CSF yeast culture results are negative and continued until there is evidence of persistent immune reconstitution with successful HAART.

Maintenance(suppressive)and prophylactic therapy

7.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).

Evidence summary.Early in the history of the AIDS pan-demic,primary therapy for cryptococcal meningoencephalitis was associated with high relapse rates in patients who did not receive long-term maintenance therapy.In1991,in a placebo-controlled double-blind trial,Bozzette et al[52]demonstrated the effectiveness of?uconazole(no relapses)compared with placebo(15%relapses)as maintenance therapy for patients with cryptococcal meningoencephalitis who had received suc-cessful primary therapy with AmBd,with or without?ucyto-sine.

Recommendations for initial maintenance therapy have not changed since they were initially published.Three options exist for antifungal maintenance therapy of AIDS-associated cryp-tococcal meningoencephalitis:(1)oral?uconazole(200mg per day),(2)oral itraconazole(200mg twice per day orally),or (3)AmBd(1mg/kg per week IV).Two large,prospective,ran-domized,comparative trials showed that?uconazole is the most effective maintenance therapy[53].The?rst trial demonstrated the superiority of?uconazole(200mg per day)over AmBd (1.0mg/kg per week)[53].Relapses of symptomatic crypto-coccal disease were observed in18%and2%of AmBd and ?uconazole recipients,respectively().In addition,pa-

P!.001

tients receiving AmBd had more frequent adverse events and associated bacterial infections,including bacteremia.A second trial compared?uconazole(200mg per day)with itraconazole (200mg per day)for12months as maintenance therapy for cryptococcal disease.This trial,which proved?uconazole to be superior,was terminated prematurely after interim analysis re-vealed that23%of itraconazole-treated patients had a relapse, compared with only4%of the?uconazole-treated patients.In addition,this trial demonstrated that the risk of relapse was increased if the patient had not received?ucytosine during the initial2weeks of primary therapy for cryptococcal meningo-encephalitis[54].Results of these2trials established?ucona-zole as the drug of choice for maintenance therapy of AIDS-associated cryptococcal disease.These studies provide clinical experience with AmBd and itraconazole as alternative,albeit less effective,choices for maintenance therapy.Their toxicities and effectiveness must be balanced against the potential rapid immune reconstitution of HAART impact on relapse rates with-out maintenance therapies and close monitoring.Intermittent AmBd should be reserved for patients who have had multiple relapses following azole therapy or who are intolerant of azoles. Oral itraconazole may be used if the patient is intolerant of ?uconazole[42].Limited experience suggests that a higher dos-age of itraconazole(eg,200mg twice per day orally)may be more effective than200mg per day as maintenance therapy, and drug interactions must be considered.

The precision of when to start HAART in the treatment of coinfection with cryptococci and HIV to avoid IRIS remains uncertain.In our recommendations,there is a wide range of 2–10weeks to accommodate this uncertainty.Recent studies suggest earlier initiation of HAART within2weeks may be possible without triggering an unacceptable increase in the fre-quency or severity of IRIS,but there was still a limited number of cryptococcosis cases,making it dif?cult to assess the impact of timing on outcome in cryptococcal infection[55,56].How-ever,in some clinical settings,long delays in HAART can place

000?CID2010:50(1February)?Perfect et al

patients at risk of dying of other complications of HIV infec-tion.It is also important to anticipate complications of drug interactions with HAART and antifungal drugs.

Until recently,life-long maintenance therapy to prevent dis-ease relapse was recommended for all patients with AIDS after successful completion of primary induction therapy for cryp-tococcal meningoencephalitis.Speci?cally,risk factors for cryp-tococcal relapse in HIV-infected patients during the HAART era were found to be a CD4cell count!100cells/m L,receipt of antifungal therapy for!3months during the previous6 months,and serum cryptococcal antigen titerу1:512[15]. However,several recent studies indicate that the risk of relapse is low provided patients have successfully completed primary therapy,are free of symptoms and signs of active cryptococcosis, and have been receiving HAART with a sustained CD4cell count1100cells/m L and an undetectable viral load.Several recent studies have examined the stopping of maintenance ther-apy and support our recommendations[57–61].Results of the 2largest studies are summarized.A prospective,multicenter trial conducted among42patients with AIDS in Thailand ran-domized subjects to continue or discontinue maintenance?u-conazole therapy when the CD4cell count had increased to 1100cells/m L and an undetectable HIV RNA level had been sustained for3months[58].There were no episodes of relapse of cryptococcal meningitis in either group at a median of48 weeks of observation after randomization.A second retro-spective multicenter study was conducted among100patients with AIDS living in6different countries[57].Inclusion criteria were a proven diagnosis of cryptococcal meningoencephalitis, a CD4cell count of1100cells/m L while receiving HAART,and the subsequent discontinuation of maintenance antifungal ther-apy.Primary end points or events were a con?rmed diagnosis of relapse(recurrent cryptococcal meningoencephalitis),any other evidence of active cryptococcal disease,or death.No events occurred during a median period of26.1months when patients were receiving both HAART and maintenance therapy for cryptococcal meningitis(0%incidence per100person-years).After discontinuation of maintenance therapy,4relapses occurred(incidence,1.53cases per100person-years)during a median period of observation of28.4months.All relapses were among patients whose antifungal maintenance therapy was dis-continued after they had a CD4cell count of1100cells/m L for у6months,and1patient had a relapse with a positive culture result,which is consistent with our de?nition for relapse.It does illustrate that careful follow-up of these patients after ter-mination of maintenance therapy is necessary.Collectively,re-sults of these and other studies indicate that maintenance ther-apy for cryptococcal meningitis may be safely discontinued in most patients responding to HAART with a CD4cell count 1100cells/m L,an undetectable or low HIV RNA level sustained forу3months,and at least1year of antifungal drug exposure,with close patient follow-up and serial cryptococcal serum an-tigen tests.Reinstitution of?uconazole maintenance therapy should be considered if the CD4cell count decreases to!100 cells/m L and/or the serum cryptococcal antigen titer increases [55].

Asymptomatic antigenemia is a well-documented clinical condition in advanced HIV disease;it has been noted to appear in4%–12%of HIV-infected patients per year in certain pop-ulations[62–66].Antigenemia preceded symptoms of menin-gitis by a median of22days in1study in Uganda[16],and if not detected,it makes appearance of disease unlikely over the next year.Cryptococcal antigenemia has been shown to be associated with increased mortality among those initiating HAART,and persons with asymptomatic antigenemia are at theoretical risk of the“unmasking”form of cryptococcal IRIS [67].The precision of asymptomatic antigenemia management remains uncertain,but an aggressive diagnostic and preemptive therapeutic stance is warranted in high-incidence locales.De-spite the possibility that a false-positive antigen test result has occurred with a negative diagnostic work-up,this high-risk group probably bene?ts from preemptive therapy. Although?uconazole and itraconazole have been shown to reduce frequency of primary cryptococcal disease among those who have CD4cell counts!50cells/m L[68,69],primary pro-phylaxis for crytococcosis is not routinely recommended in this group with advanced medical care.This recommendation is based on the relative infrequency of cryptococcal disease,lack of survival bene?ts,possibility of drug-drug interactions,cre-ation of direct antifungal drug resistance,medication compli-ance,and costs.However,in areas in which the availability of HAART is limited,HIV-drug resistance is high,and the inci-dence of cryptococcal disease is very high,prophylaxis or pre-emptive strategies with the use of serum cryptococcal antigen might be considered[70].

Organ Transplant Recipients

Cryptococcosis has been documented in an average of2.8%of solid-organ transplant recipients[71,72].The median time to disease onset is21months after transplantation;68.5%of the cases occur11year after transplantation.Approximately25%–54%of organ transplant recipients with cryptococcosis have pulmonary infection,and in6%–33%,the disease is limited to the lungs only[73,74].CNS involvement and disseminated infections(involvement ofу2sites)have been documented in 52%–61%of patients[71,74].Approximately25%of the trans-plant recipients with C.neoformans disease have fungemia[71, 73].

Recommendations

14.For CNS disease,liposomal AmB(3–4mg/kg per day IV)or ABLC(5mg/kg per day IV)plus?ucytosine(100mg/ kg per day in4divided doses)for at least2weeks for the

Guidelines for Management of Cryptococcosis?CID2010:50(1February)?000

induction regimen,followed by?uconazole(400–800mg[6–12mg/kg]per day orally)for8weeks and by?uconazole(200–400mg per day orally)for6–12months(B-II).If induction therapy does not include?ucytosine,consider LFAmB for at least4–6weeks of induction therapy,and liposomal AmB(6 mg/kg per day)might be considered in high–fungal burden disease or relapse(B-III).

15.For mild-to-moderate non-CNS disease,?uconazole (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-moderate symptoms without diffuse pulmonary in?ltrates,use?ucona-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 dose?rst(B-III).

Evidence summary.Given the risk of nephrotoxicity as-sociated with concurrent use of AmBd and calcineurin inhib-itors and the fact that～25%of the transplant recipients with cryptococcosis have renal dysfunction(creatinine level,12.0 mg/dL)at the time of diagnosis,LFAmB is preferable as in-duction therapy for CNS and severe non-CNS disease.Induc-tion therapy should include?ucytosine(100mg/kg per day in 4divided doses,adjusted for renal function).In patients with a positive CSF culture result at baseline,an additional lumbar puncture is recommended at2weeks,but lumbar puncture may be repeated earlier for increased intracranial pressure man-agement or concern about potential microbiological failure.In a small prospective study of CNS cryptococcosis in transplant recipients,the median time to CSF sterilization was10days (mean,16days)[75].A positive CSF culture result after2weeks of induction treatment identi?ed a poor outcome in transplant recipients and supports a prolonged induction period with LFAmB in these patients[76].CSF cryptococcal antigen titer in transplant recipients correlated neither with CSF sterilization at2weeks nor with outcome at180days[75].Although initial CSF antigen titers did correlate with sterilization of CSF in HIV-infected individuals[27],serial evaluations of CSF or se-rum cryptococcal antigen titers were not precisely helpful in the acute management of either transplant recipients or HIV-infected patients[77].

Suggested therapy for the consolidation phase of treatment is?uconazole(400–800mg[6–12mg/kg]per day)for8weeks, adjusted for renal function,followed by?uconazole(200–400 mg[3–6mg/kg]per day)for6–12months as maintenance therapy.A very low relapse rate has been documented with such an approach.A prospective study of79solid-organ trans-plant recipients who survived at least3weeks and in whom maintenance therapy was employed for a median of183days had a risk of relapse of1.3%[75].In contrast,the same group reported high rates of relapse in transplant recipients who did not receive maintenance therapy.Relapse was documented a median of3.5months after initial diagnosis and in all cases within1year after cessation of antifungal therapy[75].This study also evaluated the risk of relapse in all previously reported cases of solid-organ transplant recipients with cryptococcosis ()in whom maintenance therapy was noted and who n p59

had been observed for a median of12months[75].The an-tifungal agent used as primary therapy in11patients who ex-perienced relapse included AmB preparations in7patients,?uconazole in3patients(with?ucytosine in1),and?ucytosine alone in1patient[75].The median duration of primary therapy was8weeks(range,3–10weeks).On the basis of these data, it can be concluded that most relapses occur within6months in patients who do not receive maintenance therapy,and con-tinuation of maintenance antifungal therapy in solid-organ transplant recipients for at least6and up to12months is rational.

Although C.neoformans may be isolated from sputum sam-ples of asymptomatic individuals[78],its identi?cation in res-piratory tract specimens in a transplant recipient should be considered as representing a pathogen and warrants an inves-tigation for invasive pulmonary disease.A positive serum cryp-tococcal antigen titer has been documented in33%–90%of transplant recipients with pulmonary cryptococcosis[78].In a prospective study comprising60solid-organ transplant recip-ients with pulmonary cryptococcosis,84%of those with any pulmonary involvement and73%of those in whom the disease was limited only to the lungs had a positive serum cryptococcal antigen result[79].However,a negative cryptococcal antigen result does not exclude the diagnosis of disseminated crypto-coccosis.By comparison,patients with CNS disease(97%)or disseminated cryptococcosis(95%)were more likely to have a positive serum cryptococcal antigen result[73],and therefore, a positive serum cryptococcal antigen test in a transplant re-cipient warrants investigation for disseminated disease such as meningoencephalitis.

Stable patients,presenting with cavitary or nodular lung le-

000?CID2010:50(1February)?Perfect et al

sions and in whom the infection is limited to the lungs may be treated with?uconazole at a dose of400mg orally per day for the duration of induction and consolidation phases.For example,in a small prospective observational study,mortality in solid-organ transplant recipients with extraneural crypto-coccosis who received an AmB-containing regimen(2[11%] of18)did not differ from those who received?uconazole(2 [10%]of21).In a retrospective review of19solid-organ trans-plant recipients with cryptococcosis,14received?uconazole as primary therapy for a median of60days,and no therapeutic failures were documented in those with extraneural disease[9]. Successful outcome was also documented in4of4solid-organ transplant recipients who received?uconazole for treatment of pulmonary cryptococcosis and had no evidence of extrapul-monary disease.Patients with skin,soft-tissue,and osteoarti-cular infection without evidence of dissemination have also been treated successfully with?uconazole[75,80].Pulmonary cryptococcosis in transplant recipients occasionally presents with acute respiratory failure[81].Patients who have extensive involvement on imaging studies and require mechanical ven-tilation have mortality rates exceeding50%[81].These patients and those with severe or progressive pulmonary infection should be treated in the same fashion as those with CNS cryp-tococcosis.

In the current era of organ transplantation,immunosup-pressive regimens in a vast majority of the transplant recipients with cryptococcosis include a calcineurin inhibitor(eg,tac-rolimus,cyclosporine,or sirolimus),and drug-drug interac-tions must be considered.Additionally,80%–90%of these pa-tients are receiving corticosteroids at the time of onset of cryptococcal disease[71].Although a reduction in immuno-suppressive therapy should be considered in transplant recip-ients with cryptococcosis,it has been proposed that abrupt withdrawal or reversal of immunosuppression could potentially lead to a shift towards a Th1proin?ammatory state.Although helpful in killing the yeast in tissue,it may pose a risk of IRIS [82]or organ rejection.

Transplant recipients who develop IRIS are more likely to have received a potent immunosuppressive regimen than those who do not develop IRIS.Renal transplant recipients with cryp-tococcosis may experience allograft loss temporally related to the onset of IRIS through TH1up-regulation[82].The overall probability of allograft survival after C.neoformans infection is signi?cantly lower in patients who develop IRIS than in those who do not.In therapy-naive HIV-infected patients with op-portunistic infection,deferring the start of antiretroviral ther-apy for2–10weeks until the infection seems to be microbio-logically controlled has been proposed for several opportunists including cryptococcus(see recommendation10).A similar rationale can also be applied to the management of immu-nosuppression in transplant recipients with these infections.Thus,careful adjustment of the reduction in posttransplanta-tion immunosuppression by spacing the reduction of immu-nosuppressants over time and/or providing a step-wise elimi-nation of immunosuppressants following initiation of anti-fungal therapy is a prudent approach to the management of transplant recipients with cryptococcosis[83].In the careful reduction in immunosuppressives during management of se-vere cryptococcosis,it may be helpful to reduce the cortico-steroids before the calcineurin inhibitors,because these inhib-itors have direct anticryptococcal activity[70,81].

Despite existing evidence suggesting that most cryptococcal disease in transplant recipients likely results from reactivation of a subclinical infection[84],because of the lack of precision in de?ning subclinical infection and in predicting subsequent disease,routine primary prophylaxis for cryptococcosis in transplant recipients is not recommended at present.

Non–HIV Infected,Nontransplant Hosts

In general,non-transplant patients with disseminated crypto-coccosis have been screened with an HIV test and CD4cell count determination.Recommendations for“presumably im-munocompetent hosts”are limited,because the majority of patients in the2landmark studies of cryptococcal meningo-encephalitis prior to the HIV epidemic were signi?cantly im-munosuppressed(eg,they had received steroids or had con-nective tissue diseases or cancer)[28,29].However,it is clear that those with apparently much less severe or variable host immune defects,compared with HIV infection or transplan-tation,can still present serious therapeutic challenges[85],and yet patients with idiopathic CD4lymphocytopenia can fre-quently be managed successfully[86]. Recommendations

21.AmBd(0.7–1.0mg/kg per day IV)plus?ucytosine(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 CSF yeast culture results that are negative after2weeks of treatment.For AmBd toxicity issues,LFAmB may be substituted in the second2weeks.In patients with neurological complications,consider extending induction ther-apy for a total of6weeks,and LFAmB may be given for the last4weeks of the prolonged induction period.Then,start consolidation with?uconazole(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.If?ucytosine 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

Guidelines for Management of Cryptococcosis?CID2010:50(1February)?000

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 plus?u-cytosine for only2weeks,followed by consolidation with?u-conazole(800mg[12mg/kg]per day orally)for8weeks(B-III).

25.After induction and consolidation therapy,use main-tenance therapy with?uconazole(200mg[3mg/kg]per day orally)for6–12months(B-III).

Evidence summary.A comparative study convincingly showed that a combination of AmBd and?ucytosine using low doses of the polyene and high doses of?ucytosine is better than low doses of AmBd alone for non–HIV-infected patients with cryptococcal meningoencephalitis[28],and that6weeks of low-dose polyene and?ucytosine are better than4weeks of therapy[29],but even in these combination studies mortality rate was～24%.These studies were performed in the era pre-ceding the availability of azole agents and LFAmB and predate the use of higher doses of AmBd with the concept of induction, consolidation,and maintenance therapy.To date,the infor-mation about these newer strategies for cryptococcal meningo-encephalitis in non–HIV-infected and non-transplant patients remain limited,retrospective,and extrapolative.It is important to note that this is a very heterogeneous population ranging from hosts who are apparently normal to those with hema-tological malignancies and severe liver disease.Therefore,it is impossible to tailor a regimen that?ts all patients.In fact, among the opinion leaders writing this document there remains no consensus regarding the length of induction therapy in this group,with some favoring the2-week induction regimen,as for HIV-infected patients and transplant recipients(recom-mendation24),and others supporting a4–6-week induction therapy(recommendation21).

Clinical experience with AmBd therapy is much more ex-tensive than at the time of the Bennett and Dismukes trials [28,29].AmBd dosages of0.7mg/kg per day with adjunctive saline infusions are generally well tolerated for2weeks[21,27, 87],and toxicity issues with prolonged use can be averted in some cases by substituting LFAmB for AmBd in the second2–4weeks of induction therapy.Furthermore,?ucytosine dosages of100mg/kg per day are better tolerated than dosages of150 mg/kg per day,thus leading to these modi?ed recommenda-tions[27,35].

Alternative therapy to AmBd is liposomal AmB(3–4mg/kg per day)in patients with initial or developing renal dysfunction or who are receiving other nephrotoxic agents.There are few reports of LFAmB treatment in non–HIV-infected and non-transplant patients,but in HIV-infected patients with primary cryptococcal meningoencephalitis,liposomal AmB(4mg/kg per day)resulted in a signi?cantly earlier CSF sterilization than did AmBd at0.7mg/kg per day.It was less toxic and had equivalent clinical ef?cacy[7,20].ABLC at5mg/kg per day has been successfully used for cryptococcal meningoencepha-litis in salvage regimens and can also be considered in patients with AmBd nephrotoxicity[32].This experience in severely immunosuppressed patients gives con?dence for its success in this patient population.

Although there have been anecdotal reports or case series of ?uconazole as primary therapy for cryptococcal meningoen-cephalitis in non–HIV-infected patients,these studies are non-randomized and noncontrolled[88,89].Given the continuing high morbidity and mortality of cryptococcal meningoenceph-alitis in non–HIV-infected patients associated with suboptimal treatment regimens and the poor results of?uconazole alone for cryptococcal meningoencephalitis in HIV-infected patients, there is insuf?cient evidence to recommend?uconazole alone or combined with?ucytosine as primary induction therapy for non–HIV-infected,nontransplant patients.A polyene should be part of an induction regimen for cryptococcal meningo-encephalitis in this patient population.

The rate of relapse of cryptococcal meningoencephalitis in the non–HIV-infected patient ranged from15%to25%[29] prior to the AIDS epidemic and use of?uconazole.Relapses occurred primarily in the?rst year after initial treatment. Therefore,?uconazole is now recommended by the majority of experts as maintenance therapy in non–HIV-infected pa-tients with cryptococcal meningoencephalitis during the?rst6 months to1year after initial diagnosis and administration of primary induction therapy.

II.HOW ARE COMPLICA TIONS MANAGED

IN PATIENTS WITH CRYPTOCOCCOSIS?

De?nition of Persistent or Relapsed Infection

The de?nition of persistent infection is somewhat arbitrary,but on a practical basis,persistently positive results of cultures of CSF after4weeks of proven antifungal therapy at an established effective dose is a reasonable starting point.Relapse of infection has2important features.First,the recovery of viable crypto-cocci from a previously checked sterile body site is essential; and second,recrudescence of signs and symptoms at the pre-vious site of disease supports presence of disease.In a relapsed infection,both of these features have normalized and then re-curred.

It is important to de?ne persistence and relapse,because changing antigen titers,presence of positive India ink exami-nation results,and abnormal cellular reactions or chemistries are insuf?cient to diagnose a microbiological relapse with an implied need to alter direct antifungal treatment strategies. Most cases of relapse are attributable to inadequate primary therapy(dose and/or duration)or failure of compliance with consolidation or maintenance of?uconazole dose.

000?CID2010:50(1February)?Perfect et al

Persistence

Recommendations

26.Check that adequate measures have been taken to im-prove immune status(eg,decrease immunosuppressants and introduce HAART)and optimize management of increased in-tracranial pressure(B-III).

27.Reinstitute induction phase of primary therapy for longer course(4–10weeks)(B-III).

29.If the patient is polyene intolerant,consider?uconazole (у800mg per day orally)plus?ucytosine(100mg/kg per day orally in4divided doses)(B-III).

30.If patient is?ucytosine intolerant,consider AmBd(0.7 mg/kg per day IV)plus?uconazole(800mg[12mg/kg]per day orally)(B-III).

https://www.doczj.com/doc/0e11525180.html,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 MIC from the original isolate;aу3-dilution difference suggests development of direct drug resistance.Oth-erwise,an MIC of the persistent or relapse isolateу16m g/mL for?uconazole orу32m g/mL for?ucytosine may be consid-ered resistant,and alternative 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 IFN-g at a dosage of100m g/m2for adults who weighу50kg (for those who weigh!50kg,consider50m g/m2)3times per week for10weeks can be considered for refractory infection, with the concomitant use of a speci?c antifungal drug(B-III). Relapse

Recommendations

35.Restart induction phase therapy(see“Persistence,”above)(B-III).

36.Determine susceptibility of the relapse isolate(see“Per-sistence,”above)(B-III).

37.After induction therapy and in vitro susceptibility test-ing,consider salvage consolidation therapy with either?ucona-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 of?uconazole may be reinstituted(B-III).Evidence summary.Because no signi?cant comparative trials/ studies have been conducted to evaluate“salvage therapy”for patients for whom primary therapy fails or who experience relapse after successful primary therapy,our recommendations are based solely on clinical experience/personal preference and several small,open trial studies with refractory disease.For example,the use of IFN-g treatment was tested during primary therapy and not salvage therapy,and even in this clinical setting, its positive impact on outcome was not de?nitive[42,90]. There are no data regarding the newer azoles(voriconazole and posaconazole)as primary treatment of cryptococcal menin-goencephalitis in HIV-infected or non–HIV-infected individ-uals.However,these azoles have been used as salvage therapy for HIV-infected individuals in open trials.For instance,small, open-label salvage trials suggest that voriconazole(200mg twice per day orally)and posaconazole(400mg twice per day orally) have therapeutic ef?cacy.Among patients with refractory cryp-tococcosis,voriconazole demonstrated success in7(39%)of 18patients overall and led to stable disease in10(89%)of11 patients.Among patients treated with posaconazole,14(48%) of29experienced success,and6(40%)of15had stable disease [18,19].In any relapse case,it is essential to determine whether compliance or drug interactions are an issue.If so,these will need to be addressed in the therapeutic strategy after reinduc-tion therapy.

It is important to emphasize that CSF culture should rep-resent at least3–5mL of?uid,and positive CSF India ink or Gram stain by itself is not suf?cient for determining relapse. CSF and serum pronase-treated cryptococcal antigen titers are not precise indicators for relapse or for making therapeutic decisions except possibly for late relapses in HIV-infected pa-tients taken off suppressive therapy.Finally,the2-week lumbar puncture culture result is a test for determining fungicidal suc-cess of induction therapy.Generally,laboratories will keep fun-gal cultures for3–4weeks for detection of yeast growth,and most persistently positive cryptococcal cultures on therapy will grow within2weeks.In all non–HIV-infected and in most HIV-infected patients receiving combination antifungal therapy with AmBd plus?ucytosine,negative cultures at2weeks of therapy should be a goal.Patients who do not reach this goal will need follow-up lumbar punctures until the CSF is sterile and will need more attention given to prolonging their induc-tion therapy.

Elevated CSF Pressure

One of the most critical determinants of outcome for cryp-tococcal meningoencephalitis is control of CSF pressure.Ap-proximately one-half of HIV-infected patients with cryptococ-cal meningoencephalitis have elevated baseline intracranial pressures(ie,125cm of CSF).This elevated CSF pressure level is generally linked to a high burden of yeast in the CSF[91].

Guidelines for Management of Cryptococcosis?CID2010:50(1February)?000

This increased CSF pressure can be associated with increased morbidity and mortality,especially early in the treatment course,but its level in an individual patient is less precise.Also, development of classic hydrocephalus later during treatment and follow-up can occur.

If cryptococcal meningoencephalitis is suspected,opening pressure during the initial lumbar puncture should be mea-sured.The presence of impaired mentation or focal neurologic signs may prompt radiographic imaging before the lumbar puncture,but most of these study?ndings are normal or show no focal lesions in cryptococcal disease,and the lumbar punc-ture can be safely performed.Acute elevated symptomatic CSF pressure with initial antifungal therapy should be managed ag-gressively by decompression,either via repeated lumbar punc-tures,temporary lumbar drainage catheter,or ventriculostomy in selected patients.There are much less data on treatment of HIV-negative patients with acute elevated intracranial pressure with regard to recommendations of pressure control,compared with HIV-positive patients.

Recommendations

38.Identify CSF pressure at baseline.A prompt baseline lumbar puncture is strongly encouraged,but in the presence of focal neurologic signs or impaired mentation,it should be delayed pending the results of a CT or 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).

41.Permanent VP shunts should be placed only if the pa-tient is receiving or has received appropriate antifungal therapy and if more conservative measures to control increased intra-cranial pressure have failed.If the patient is receiving an ap-propriate antifungal regimen,VP shunts can be placed during active infection and without complete sterilization of CNS,if clinically necessary(B-III).

Evidence summary.The recommendations above are sim-ilar to those made in the2000IDSA guidelines[1].Since then, the strength of these guidelines has been supported by reports of adverse consequences when they are not followed[2,92]. Role of imaging.The most immediate determinant of out-come of cryptococcal meningoencephalitis is control of symp-tomatic increased intracranial pressure.This complication of increased intracranial pressure must be reduced without caus-ing cerebral herniation.Patients without HIV disease may be at increased risk of cryptococcal cerebral mass lesions and more robust in?ammatory responses in meninges,with the conse-quences of cerebral vasculitis and potential cerebral herniation. Cranial neuropathy,other focal neurologic signs,papilledema, and impaired mentation re?ect this risk and should prompt CT or MRI to determine the risk of complications associated with lumbar puncture.MRI is more effective than CT in iden-tifying CNS cryptococcal lesions in HIV-infected patients and can re?ect the burden of yeasts at the start of therapy[93].If there is evidence of obstruction that needs decompression, drainage may be done safely via ventriculostomy or VP shunt [94].Patients with HIV disease generally do not have classic hydrocephalus or cryptococcal mass lesions on presentation, and radiographic images commonly show no abnormality or cerebral atrophy without obstruction or other pathology[95]. Reduction of CSF pressure.The National Institute of Allergy and Infectious Disease Mycoses Study Group published a large series of HIV-infected patients managed under speci?c treat-ment protocols for cryptococcal meningoencephalitis[95].Of 221patients receiving baseline CSF pressure recordings,one-half had recordings125cm of CSF and one-fourth had re-cordings135cm of CSF.This upper quartile had increased evidence of papilledema(29%)and impaired mentation(18%). Furthermore,patients who died(11of12)in the?rst2weeks of therapy had baseline intracranial pressures measured atу25 cm of CSF.Of161patients treated by CSF lumbar drainage to reduce the pressure,there were fewer cases of clinical failure in those with controlled CSF pressure,compared with those who have persistently elevated pressure.CSF drainage was often immediately followed by relief of severe headaches and im-proved sense of well being.Recurrence of elevated intracranial pressure was often associated with worsening symptoms.In cases of very high pressure(135cm of CSF),some have sug-gested CSF pressure drainage to35cm of water initially with lumbar puncture,followed by lower levels later,but this is not uniformly accepted[96].

Consequence of failure to reduce elevated CSF pressure.In a retrospective series of26patients(19of whom had AIDS),14 had major deviations from IDSA2000guidelines,of whom13 had failure to measure baseline CSF pressure and9did not undergo drainage for elevated CSF pressure[2].Of these14 patients,7developed new neurologic abnormalities during treatment,compared with1of12who were managed with no more than minor deviations from the2000IDSA Guidelines and developed new signs or symptoms.

Other medications for intracranial pressure.Medications other than antifungal drugs are not useful in the management of increased intracranial pressure in cryptococcal meningoen-cephalitis.

A randomized trial in Thailand found severe metabolic ac-

000?CID2010:50(1February)?Perfect et al

idosis and other complications associated with acetazolamide therapy and was stopped prematurely[97].Despite not being included in the protocol,high-dose corticosteroids were used in41of110HIV-infected patients during initial therapy[95]. Ten of13patients with pressures135cm of CSF were treated with corticosteroids speci?cally for intracranial pressure ele-vation.Of all patients given high-dose corticosteroids,there was no bene?t observed,and indeed,mortality and clinical deterioration were observed more commonly in recipients of corticosteroids.

Recurrence of signs and symptoms.In the case of the re-currence of symptoms and signs of increased intracranial pres-sure after initial improvement or elimination of signs and symptoms during initial management of cryptococcal menin-goencephalitis,guidelines are less certain.

There is no general agreement on the timing of above,and there are no systematically collected data assessing effect of delay of re-initiating repeated lumbar punctures and other drainage procedures.With recurrence of symptoms,it will be necessary to restage the patient with brain imaging and lumbar puncture for CSF pressure measurements,culture,and other general CSF parameters and to reassess other potentially in-fected sites outside CSF to also rule out relapse and/or IRIS. Long-term elevated intracranial pressure.When intracranial pressure remains elevated for an extended period of time,what is the most ef?cient therapeutic strategy?

Similar to VP shunts,data on the use of lumbar drains are limited to collections of case series.These vary in speci?c rec-ommendations for type of drain and duration that they can safely be left in place[98].In one report,a lumbar drain was used successfully for13days[99].However,with these external lumbar drains,exogenous infections are possible,but bacterial superinfection occurred in!5%of cases in one case series[100]. Furthermore,some have recommended placing intracranial pressure monitors in patients with severe bacterial meningitis and using the pressure(115cm of CSF is considered elevated for ventricular pressures)to monitor the need for interventions [101].This could also be applicable to patients with severe intracranial pressure issues with cryptococcal meningoenceph-alitis,but it has not been extensively evaluated.Ventricular shunts may also be used if pressure is uncontrolled by lesser measures[92,94,98].In one series of27patients with ob-structive hydrocephalus and cryptococcal meningoencephalitis, 63%had good outcomes following permanent shunt place-ment.Outcome was worse in those who had developed a Glas-gow coma score!9;thus,early placement in dif?cult cases may be bene?cial[94].

It should be noted that after management of cryptococcal meningoencephalitis,signs and symptoms of classical hydro-cephalus can develop and placement of a VP shunt will be required.VP shunts can be placed during active infection as long as effective antifungal therapy has been introduced prior to shunt placement[98].

IRIS

IRIS caused by various microorganisms has emerged as a major complication in patients with AIDS since the introduction of HAART,and in persons with cryptococcal meningoencephalitis, it has potential for producing treatment failure[67,102–105]. In cryptococcosis,IRIS can occur in2forms:(1)“unmasking”IRIS,in which cryptococcal symptoms?rst appear after the start of HAART;or(2)“paradoxical”IRIS during the treatment of cryptococcosis and administration of HAART.Cases of cryp-tococcosis-associated IRIS have also been reported as a com-plication in solid-organ transplant recipients[82]and in ap-parently healthy hosts[85].During organ transplantation,it has occurred more frequently in patients receiving tacrolimus, mycophenolate mofetil,and prednisone than in patients re-ceiving less-immunosuppressive regimens.Previous alemtu-zumab therapy has also been recently recognized as a potential risk factor for IRIS.

IRIS can present in body sites that were not initially identi?ed as infected.It consists of clinical manifestations compatible with exuberant tissue in?ammation in patients experiencing rapid improvement in cellular immunity,and generally,results of cultures for the site of infection are negative.For example,this may occur following introduction of HAART in the setting of AIDS with the restoration of pathogen-speci?c CD4cells or decreasing immunosuppressive therapy in transplant recipients with the reversal of a predominantly Th2to a Th1proin?am-matory response or in those ceasing monoclonal antibody ther-apy with anti–tumor necrosis factor agents.IRIS has to be differentiated from microbiological progression of the disease (although both phenomena can appear simultaneously)or from other opportunistic infections,tumors,drug-related compli-cations that may occur in these heavily immunocompromised patients[67,83].More-severe cryptococcal disease,including fungemia,an extremely low CD4cell count,cryptococcosis revealing initial HIV infection,lack of previous antiretroviral therapy,lack of CSF sterilization at week2,introduction of HAART during early part of induction therapy,and rapid initial decrease in HIV load in response to HAART have all been recognized as risk factors for IRIS[104].Presence of cerebral lesions during the initial treatment phase of the disease is not predictive of the subsequent occurrence of symptomatic ce-rebral IRIS[93].

IRIS may either occur early(ie,within a few days)or late after the introduction of HAART,sometimes up to several months thereafter.Time of occurrence appears shorter in cases of cerebral IRIS.In solid-organ transplant recipients,IRIS has been described a mean of6weeks after the initiation of anti-fungal therapy.Manifestations of IRIS consist frequently of

Guidelines for Management of Cryptococcosis?CID2010:50(1February)?000

fever with peripheral or mediastinal/abdominal lymphadenitis or CNS signs and/or symptoms of disease(meningitis or ce-rebral abscesses and their clinical consequences with or without an increase of CSF opening pressure),and these new symptoms can be construed as signs of treatment failure.Furthermore,in kidney transplant recipients,graft loss has appeared as a con-sequence of IRIS.Severe manifestations of IRIS can be lethal if not taken into consideration[102]. Recommendations

47.No need to alter direct antifungal therapy(B-III).

48.No de?nitive speci?c treatment recommendation for mi-nor IRIS manifestations is necessary,because they will resolve spontaneously in days to weeks(B-III).

50.Nonsteroidal anti-in?ammatory drugs and thalidomide have been used but with too little experience to make a rec-ommendation(C-III).

Evidence summary.In the clinical milieu associated with management of cryptococcosis,the appearance of IRIS is prob-ably more common than clinicians appreciate.Many times, IRIS is considered to be treatment failure,and new antifungal regimens are considered when in fact,the essential immune reconstitution has simply overshot in its recovery;thus,IRIS causes persistent disease or recurrent symptoms,particularly in the CNS.Because there is no speci?c laboratory test for de-tection,IRIS becomes a clinical diagnosis.Speci?c recommen-dations for IRIS management are not robust and have not faced the scrutiny of clinical trials.The most important issues are clinical identi?cation and prevention,and?nally,when it is causing severe disease,IRIS management requires the use of an anti-in?ammatory strategy to prevent further host damage and not a change in direct antifungal drug(s).It has been dem-onstrated,even in HIV-infected individuals,that corticosteroids can be safely administered for limited durations as long as viral load is controlled[106,107].

Cerebral Cryptococcomas

Cerebral cryptococcomas can cause signi?cant short-and long-term neurological morbidity,are dif?cult-to-treat,and require prolonged antifungal therapy[108,109].Antifungal drugs and relief of increased intracranial pressure are the mainstays of management.In severely immunosuppressed patients with nonresponding parenchymal brain mass,it is essential to con-sider that the mass may represent a second pathogen or tumor, and a brain biopsy or aspirate will be necessary for identi?-cation.

Recommendations

52.Consolidation and maintenance therapy with?ucona-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). Evidence summary.Lesions detected by CT are more com-mon in apparently healthy hosts(114%)than those compro-mised by AIDS(4%–5%)or for other reasons(10%)[110]and are usually associated with meningitis.Although probably more common in

C.gattii infection[93,107,108],they are also caused by C.neoformans[85,110].For instance,in a recent study involving62patients coinfected with HIV and C.neo-formans,MRI identi?ed masses in21%and dilated perivascular spaces in46%[88].In apparently healthy hosts,CT most com-monly reveals small,ring-enhancing lesions.Nonenhancing “pseudocysts”are more common in immunosuppressed hosts [109,111].Presentations with single large lesions(у3cm) indistinguishable from acute pyogenic abscesses or with symp-tomatic hydrocephalus are less common but necessitate early consideration of surgery for partial removal,histopathology and culture for con?rmation of diagnosis,and/or CSF VP shunt insertion[108,112].

There are no prospective studies of therapy for cerebral cryp-tococcomas.Recommendations are derived from case reports [113,114],retrospective analyses of HIV-negative patients with neurocryptococcosis[14,108,109,115,116],prospective ob-servational studies of cryptococcosis[14,89],randomized clin-ical trials in non–HIV-associated and HIV-associated menin-goencephalitis[20,27–29,117],and expert opinion[1].Some of these studies predated the introduction of azoles and HAART.The suggested treatment of choice is induction therapy with AmBd combined with?ucytosine followed by consoli-dation therapy with?uconazole.Induction phase may be longer for cryptococcomas than for meningitis alone.The duration of induction and consolidation therapy depends on the clinical, imaging,and mycological responses.Reliance on imaging alone can be misleading,because some brain lesions persist for long periods of time[111]and/or develop surrounding edema dur-ing effective antifungal therapy,presumably because of an im-

000?CID2010:50(1February)?Perfect et al

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2006年全国数学建模A题题目和优秀论文赏析

2006高教社杯全国大学生数学建模竞赛题目（请先阅读“对论文格式的统一要求”） A题:出版社的资源配置出版社的资源主要包括人力资源、生产资源、资金和管理资源等，它们都捆绑在书号上，经过各个部门的运作，形成成本（策划成本、编辑成本、生产成本、库存成本、销售成本、财务与管理成本等）和利润。某个以教材类出版物为主的出版社，总社领导每年需要针对分社提交的生产计划申请书、人力资源情况以及市场信息分析，将总量一定的书号数合理地分配给各个分社，使出版的教材产生最好的经济效益。事实上，由于各个分社提交的需求书号总量远大于总社的书号总量，因此总社一般以增加强势产品支持力度的原则优化资源配置。资源配置完成后，各个分社（分社以学科划分）根据分配到的书号数量，再重新对学科所属每个课程作出出版计划，付诸实施。资源配置是总社每年进行的重要决策，直接关系到出版社的当年经济效益和长远发展战略。由于市场信息（主要是需求与竞争力）通常是不完全的，企业自身的数据收集和积累也不足，这种情况下的决策问题在我国企业中是普遍存在的。本题附录中给出了该出版社所掌握的一些数据资料，请你们根据这些数据资料，利用数学建模的方法，在信息不足的条件下，提出以量化分析为基础的资源（书号）配置方法，给出一个明确的分配方案，向出版社提供有益的建议。 [附录] 附件1：问卷调查表；附件2：问卷调查数据（五年）；附件3：各课程计划及实际销售数据表（5年）；附件4：各课程计划申请或实际获得的书号数列表（6年）；附件5：9个分社人力资源细目。

出版社的资源优化配置摘要本文针对出版社资源分配问题，在满足利润最大化的追求目标的前提下，以量化分析为基础，对出版社的资源进行优化合理的分配。首先，对题目给出的海量数据进行分析，提取有用的信息，以学科为基本单位，从市场满意度，市场占有率和经济效益三项指标来综合考虑总的效益。根据盈利和销售额的同一性，预测出06年的实际销售额。利用层次分析法，确定了三项指标的权重，将所得数据归一化得到最后的分社的综合排名。其次，根据出版社人力资源的限制，考虑到每年有限的工作能力问题，求的各分社的工作能力的最小值。而对于各分社计划销量过多与实际销量，为了资源的有效利用，降低申请书号的浪费，又对申请书号进行了校正，得到校正后的有效书号。最后应用贪心算法对06年实际分配到的书号做出了分配。

2例新型隐球菌脑膜炎病人的护理

2例新型隐球菌脑膜炎病人的护理发表时间：2010-05-01T01:10:01.797Z 来源：《中外健康文摘》2009年18期供稿作者：马红英[导读] 结合新型隐球菌性脑膜炎的发病特点探讨适合的护理方法以减少并发症，提高护理质量。马红英 (南宁市第一人民医院神经内科广西南宁 530022) 【摘要】目的结合新型隐球菌性脑膜炎的发病特点探讨适合的护理方法以减少并发症，提高护理质量。方法对确诊为新型隐球菌性脑膜炎的2例患者给予针对性护理。结果 2例病人均无护理并发症。结论本病病情重，变化快，治疗时间长且效果缓慢，费用高，通过加强针对性护理及与病人、家属的沟通，可以减少并发症，减轻病人痛苦。【关键词】新型隐球菌性脑膜炎护理新型隐球菌性脑膜炎是中枢神经系统最常见的真菌感染，发病率低，但感染后病情重，病死率高。我科于2008年收治2例该病病人，护理体会总结如下： 1 一般资料收集2008年1月至12月在我院神经内科住院的患者2例，男性，职业农民。2例均经脑脊液离心沉淀后墨汁染色检出隐球菌而确诊。例1，45岁。因反复呕吐10余天伴头晕头痛以“慢性浅表性胃炎、电解质紊乱”收住消化内科。治疗5天后头痛加剧,请本科会诊后转入。追问病史，有发热近2月，以夜间明显。腰椎穿刺检查，脑脊液压力360mmH2O，颈强直、克氏征（+）、布氏征（+），渐出现双耳听力下降，视物模糊、重影。入本科后第5天反复出现双瞳孔不等大，昏迷，经脱水、给氧等一系列抢救后转ICU治疗2天，因呼吸衰竭死亡。例2，60岁。首发症状为突发头痛，呈持续、搏动性痛，以后枕部明显，次日出现呕吐胃内容物。入院后经2次腰椎穿刺术，脑脊液压力分别为300mmH2O，80 mmH2O，颈强直、克氏化征（+）、布氏怔（+）于入院后第3天出现，头痛为其主要主诉。后因经济原因，确诊后要求自动出院，电话回访于出院后一个月内死亡。 2 护理 2.1一般护理将病人置于安静病室，卧床休息，床头抬高150-300，减少探视。保持室内光线柔和。各项操作轻柔、缓慢，避免噪杂，防止对病人造成不良刺激。并指导家属陪护时减少与病人谈话时间，使其充分休息。例1病人因反复出现昏迷，严格按昏迷病人护理，取头偏一侧卧位，床边备吸引器，保持呼吸道通畅。上床档，每2小时翻身拍背，及时处理二便，保持床单元及皮肤整洁、干燥，遵医嘱保证液体入量。 2.2头痛的护理 2例病人均有剧烈头痛阵发性加剧。严格遵医嘱及时使用脱水剂。充分给氧，改善脑缺氧状况，降低血流量。例2病人头痛剧烈伴全身不适、疼痛，经口服曲马多缓释胶囊0.1g，每12小时1次及间隔6小时交替使用20%甘露醇125ml，甘油果糖250 ml后止痛效果仍不明显。夜间常诉疼痛难忍，严重影响睡眠。主要原因是由于弥漫性脑膜炎症影响脑脊液循环和脑实质充血使颅内压增高引起的[1]。因此，除应及时给予脱水剂外，还应认真倾听病人主诉，观察用药疗效，必要时遵医嘱临时给用止痛剂和镇静剂。同时，需密切观察神志、瞳孔变化。例2病人在入院第5天下午即出现突发意识不清，呼之不应，双瞳孔不等大，由于报告医师及时，快速滴入20%甘露醇后125ml很快恢复清醒，但在此后约2个小时内，又反复出现意识不清、昏迷、瞳孔忽大忽小3次，均因发现及时，处理正确，使病人转危为安。但也提示了我们在该病的急性期，由于颅内压增高所致的脑危象变化多端且迅速，应严格巡视，每15分钟-30分钟一次。另发热可使头痛加剧，应积极降温，可戴冰帽，降低脑代谢。 2.3呕吐的护理剧烈头痛时常伴发呕吐，2例病人呕吐均非喷射状，例2与进食有关，表现为进食后即吐。注意观察呕吐次数、量及诱发原因、伴发症状等。呕吐时指导病人侧卧，头偏一侧，防止呕吐物呛入气管。协助清理污物，保持衣被整洁。呕吐后予温开水漱口。安慰病人，告知并使其了解呕吐为本病常见症状以减轻病人恐惧、烦躁心理。备好卷纸等用品。频繁呕吐、脱水等可致电解质紊乱，应定期进行血生化检查，并配合用药。例2病人入院时血钠即为120mmol/L，多次遵医嘱予10%氯化钠10ml加入0.9%氯钠500ml中静滴，在其自动出院前3天复查血纳仍为123mmol/L，告知其回家后注意摄入钠盐。 2.4心理的护理由于该病病情重，症状反复且逐渐加重，治疗费用高，治疗时间长，疗效缓慢，病人及家属均承受较大精神压力。病人易产生急躁、焦虑或悲观失望心理以及挑剔、不愿配合等反应。家属则表现出对医护工作不满、要求增多。因此，须及时进行有效沟通，取得理解和配合，认真倾听病人主诉。了解其心理要求,通过细致周到的护理使病人建立信心,消除不良情绪。 2.5饮食的护理因频繁呕吐、长期发热、头痛及药物毒副作用的影响，病人食欲低下、逐渐消瘦。因此应加强营养，增强其抗病能力，及时给予饮食指导。告知病人应进食高热量、高蛋白、高维生素等富含营养的低渣或流质饮食，于头痛缓解期进食较为合适。同时静脉补充营养，可输入氨基酸等改善机体营养状况。例1病人因进食后即吐，体重下降明显。又因来自农村，疾病知识缺乏，其家人在其频繁呕吐时仍准备了米饭和油腻肉类，认为这样可以补充营养。发现后予以指出，并帮助其在医院订制了瘦肉面条、肉稀饭等并告知可补充牛奶、新鲜蔬菜、水果等食物。 3 讨论新型隐球菌脑膜炎发病率虽低，但临床表现不突出，常被误诊。本组例2病人曾被误诊为病毒性脑炎，至第2次腰椎穿刺脑脊液检出隐球菌而确诊。所以，对需反复做腰椎穿刺的病人，应做好解释。术前、术后予正确指导，避免病人因不理解而不配合检查或引起低颅压头痛等不良反应的发生。隐球菌多在潮湿土壤、腐烂水果、鸽粪和其他鸟粪的粪便中存活。本组2例病人均为农民，可能因机体抵抗力下降及与病原体接触机会较多而发病。故应提高对农民对此病的防护能力并做好他们患病入院后的心理、饮食及症状护理。例1病人转至ICU后开始使用两性霉素B，未能进行用药后的观察。后因呼吸衰竭死亡。例2病人也因经济原因中断治疗，出院后一个月内死亡。提醒我们在护理此类病人时及早发现病情变化，尽快采取正确的治疗护理措施，防治并发症，减轻病人痛苦同样具有重要意义。参考文献 [1] 赵宏文,郭毅.6例隐球菌性脑膜炎的临床观察和护理.齐齐哈尔医学院学报,2003,24(9):1061.

隐球菌性脑膜炎诊治专家共识

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图 1 靶标上圆的像有人设计靶标如下，取1个边长为100mm的正方形，分别以四个顶点（对应为A、C、D、E）为圆心，12mm为半径作圆。以AC 边上距离A点30mm处的B为圆心，12mm为半径作圆，如图2所示。

图3 靶标的像请你们：（1）建立数学模型和算法以确定靶标上圆的圆心在该相机像平面的像坐标, 这里坐标系原点取在该相机的焦点，x-y平面平行于像平面；（2）对由图2、图3分别给出的靶标及其像，计算靶标上圆的圆心在像平面上的像坐标, 该相机的像距（即焦点到像平面的距离）是1577个像素单位(1毫米约为3.78个像素单位)，相机分辨率为1024×786；（3）设计一种方法检验你们的模型，并对方法的精度和稳定性进行讨论；

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第一部分病原学以及实验室检查隐球菌性脑膜炎的病原菌为隐球菌，隐球菌属至少有30多个种，其中具有致病性的绝大多数为新型隐球菌和格特隐球菌（过去分别称之为新型隐球菌新生变种和新型隐球菌格特变种），其他种类隐球菌如罗伦隐球菌、浅白隐球菌等偶可引起人类感染。一、隐球菌的微生物学鉴定 1. 脑脊液墨汁染色涂片： 2. 脑脊液的隐球菌培养： 3. 新型隐球菌的菌落形态： 4. 隐球菌的生理生化实验：二、隐球菌病的免疫学诊断（血清学试验） 1. 乳胶凝集试验(LA)： 2. 侧流免疫层析法(LFA)：

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主坐焦鎏煎苤查！！！！至！旦筮！！鲞筮！塑堡堕！』！璺鱼堕望！！垒Ｐ！！！！！！！！∑！！：！ｉ！塑！：！重视隐球菌脑膜炎的治疗翁心华朱利平近年来，隐球菌脑膜炎的患病率呈上升趋势，已引起国内外同行的高度关注。本期刊登的几篇文章对隐球菌脑膜炎的临床特点进行了充分阐述，需要说明的是在治疗方面国内同行基本上已达成共识。目前治疗的主要参考标准是２０００年美国真菌治疗协作组制定的隐球菌病诊治指南，其中隐球菌脑膜炎治疗共分为三个阶段，①急性期（诱导期）：首选两性霉素ＢＯ．７～１．０ｍｇ?ｋｇ－１?ｄ＿１联合氟胞嘧啶１００ｍｇ?ｋｇ＿１?ｄ＿１治疗２周； ②巩固期：改用氟康唑４００ｍｇ／ｄ巩固治疗１０周以上；③慢性期（维持治疗期）：氟康唑２００～４００ｍｇ／ｄ，长期维持治疗。急性期、巩固期的次选方案包括：两性霉素ＢＯ．７～１．Ｏｍｇ?ｋｇ－１?ｄ叫联合氟胞嘧啶１００ｍｇ?ｋｇ－１?ｄ叫治疗６～１０周，或单用两性霉素Ｂ０．７～１。Ｏｍｇ?ｋｇ＿１?ｄ１治疗６～１０周，或两性霉素Ｂ脂质体３～６ｍｇ?ｋｇ叫?ｄ＿１治疗６～１０周。ＡＩＤＳ患者也可单用氟康唑４００～８００ｍｇ／ｄ治疗１０～１２周，或伊曲康唑４００ｍｇ／ｄ治疗１０～１２周，或氟康唑４００～８００ｍｇ／ｄ联合氟胞嘧啶１００～１５０ｍｇ?ｋｇ－１?ｄ－１治疗６周。慢性期维持治疗主要针对ＡＩＤＳ或器官移植等严重免疫低下患者，因其免疫缺陷而需长期（６～１２个月）用药，甚至终生治疗。在维持治疗期间患者若不能耐受氟康唑，可换用伊曲康唑４００ｍｇ／ｄ，或两性霉素Ｂ静脉滴注，每周１～３次，每次１ｍｇ／ｋｇ。但在指南中也指出，ＡＩＤＳ患者在有效抗病毒治疗后，是否还需维持治疗尚不明确。．由于国内仍以非ＡＩＤＳ相关性隐球菌脑膜炎为主，所以在治疗上也略有不同之处。氟胞嘧啶应用剂量为１００ｍｇ?ｋｇ＿１?ｄ－１左右，与国外基本一致，两性霉素Ｂ常用剂量则为Ｏ．５～Ｏ．７ｍｇ－ｋｇ－１?ｄ～。具体用法：初始３ｄ的剂量分别作者单位：２０００４０上海，复旦大学附属华山医院感染科 ?述评? 为１、３和５ｍｇ，加入５％葡萄糖液５００ｍＬ内缓慢静脉滴注６～８ｈ，若无严重不良反应，第４天起剂量可每日增加５ｍｇ，直至每日剂量达２５～３５ｍｇ，以后维持该剂量静脉滴注。疗程长短主要根据疗效判断，一般需２～３个月，总剂量２～３ｇ。对少数患者根据临床症状及脑脊液变化，总剂量可超过４ｇ，以达到治愈目的。对于一些难治性隐球菌脑膜炎患者，采用两性霉素Ｂ静脉滴注联合鞘内注射治疗较单用疗效好。鞘内注射具体用法：两性霉素Ｂ开始时剂量为ｏ．０５～ｏ．１０ｍｇ，加地塞米松２ｍｇ。注入时用脑脊液反复稀释，以免因药物刺激而导致下肢瘫痪等严重后果。以后渐增加剂量至单次１ｍｇ为高限，鞘内给药一般可隔日或每周２次，累计总量以２０ｍｇ为宜。由于近年来ＡＩＤＳ相关性隐球菌脑膜炎在我国有增多趋势，因而在治疗过程中，需要和ＡＩＤＳ抗病毒治疗后发生的隐球菌脑膜炎相关性免疫重建炎症综合征（ｉｍｍｕｎｅｒｅｃｏｎｓｔｉｔｕｔｉｏｎｉｎｆｌａｍｍａ—ｔｏｒｙｓｙｎｄｒｏｍｅ，ＩＲＩＳ）相鉴别，ＩＲＩＳ是指ＡＩＤＳ患者在开始高效抗逆转录病毒疗法（ＨＡＡＲＴ）治疗后８周内，迟者甚或半年内，发生类似隐球菌脑膜炎复发或加重的临床表现，如再次出现发热、头痛、颈抵抗等，此时脑脊液压力增高、细胞数也明显增多，但隐球菌培养阴性。这是由于ＨＡＡＲＴ治疗后患者免疫缺陷逐渐得到恢复重建，即ＣＤ４淋巴细胞计数逐步回升、ＨＩＶ病毒载量不断下降，特异性免疫应答开始恢复，由此诱导的炎症反应得到强化而导致ＩＲＩＳ发生，易与隐球菌脑膜炎复发或加重混淆。因此，一方面需要加以鉴别，更主要的是加以预防，国外学者对此总结出ＡＩＤＳ相关性隐球菌脑膜炎患者应在治疗６～８周后再进行ＨＡＡＲＴ治疗，以避免ＩＲＩＳ的发生。此外，一些新型抗真菌药物用于治疗隐球菌脑膜炎，如两性霉素Ｂ脂质制剂，早在１９９７年就进行首个两性霉素万方数据